A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin as Monotherapy in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Lexicon Pharmaceuticals

Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel-
group, Multicenter Study to Evaluate the Efficacy and Safety 
of Sotagliflozin as Monotherapy in Patients with Type 2 
Diabetes Mellitus Who Have Inadequate Glycemic Control 
  
NCT Number: NCT02926937 
  
Document Date: Protocol Amendment 2: 19-December-2017  
 

 
 
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 
 
 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 02 
COMPOUND: sotagliflozin/SAR439954 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study 
to Evaluate the Efficacy and Safety of Sotagliflozin as Monotherapy in Patients 
with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control 
STUDY NUMBER: EFC14833  
STUDY NAME: SOTA-MONO (SOTAgliflozin MONOtherapy) 
VERSION DATE / STATUS: 19-Dec-2017 / Approved 
Protocol Amendment 02 
Version number: 1 (electronic 1.0) 
Date : 19-Dec-2017 
Amended Clinical Trial Protocol 01 
Version number: 1 (electronic 1.0) 
Date : 11-Apr-2017 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 11-Apr-2017 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 27-Jul-2016 
EudraCT  
2016-001799-31 
IND Number(s) 
 
Version Number: 
1  
WHO universal trial number: 
U1111-1180-6169 
Date: 
19-Dec-2017 
Total number of pages: 
119 
 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Type here
Type here
Type here
Type here

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 3 
CLINICAL TRIAL SUMMARY 
 
COMPOUND: sotagliflozin/SAR439954 
STUDY No.:  EFC14833  
TITLE 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin 
as Monotherapy in Patients with Type 2 Diabetes Who Have 
Inadequate Glycemic Control 
INVESTIGATOR/TRIAL LOCATION 
Multinational 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVES  
 
Primary objective:  
The primary objective of this study is to demonstrate the superiority of 
sotagliflozin 400 mg versus placebo on hemoglobin A1c (HbA1c) 
reduction at Week 26 in patients with type 2 diabetes (T2D) who have 
inadequate glycemic control on diet and exercise. 
Secondary objectives: 
• 
To compare sotagliflozin 400 mg versus placebo for:  
- 
Change from Baseline in 2-hour postprandial glucose 
(PPG) following a mixed meal at Week 26  
- 
Change from Baseline in fasting plasma glucose (FPG) 
at Week 26 
- 
Change from Baseline in body weight at Week 26 
- 
Change from Baseline in systolic blood pressure (SBP) 
at Week 12 for patients with Baseline SBP 
≥130 mmHg  
- 
Change from Baseline in SBP at Week 12 for all 
patients 
- 
Proportion of patients with HbA1c <6.5%, <7.0% at 
Week 26 
• 
To compare sotagliflozin 200 mg versus placebo for:  
- 
Change from Baseline in HbA1c at Week 26 
- 
Change from Baseline in 2-hour PPG following a 
mixed meal at Week 26  
- 
Change from Baseline in body weight at Week 26 
- 
Change from Baseline in SBP at Week 12 for all 
patients 
• 
To evaluate the safety of sotagliflozin 400 mg and 200 mg 
doses versus placebo 
Other: 
• 
To compare sotagliflozin 400 mg and 200 mg doses versus 
placebo with respect to change from Baseline for the 
following endpoints: 
- 
Urine albumin-creatinine ratio (ACR) 
- 
Urinary glucose excretion (UGE) and urine 
glucose-creatinine ratio (GCR)  
- 
Estimated glomerular filtration rate (eGFR) 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 4 
- 
Reduction in body weight by ≥2%, ≥5%, and ≥10%  
• 
To compare sotagliflozin 200 mg versus placebo for: 
- 
Change from Baseline in FPG at Week 26 
- 
Change from Baseline in SBP at Week 12 for patients 
with baseline SBP ≥130 mmHg  
- 
Proportion of patients with HbA1c <6.5%, <7.0% at 
Week 26 
• 
To compare sotagliflozin 400 mg and 200 mg doses with 
placebo for change from Baseline in SBP at Week 26 for all 
patients and for patients with Baseline SBP ≥130 mmHg 
• 
To compare sotagliflozin 400 mg and 200 mg doses with 
placebo for the use of rescue medications for 
hyperglycemia 
• 
To assess plasma concentrations of sotagliflozin and its 
3-O-glucuronide metabolite in each sotagliflozin treatment 
group 
STUDY DESIGN 
This is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study that is anticipated to enroll a 
total of approximately 400 patients. This number includes patients 
randomized under the initial protocol, and patients to be randomized 
under the amended, current, version of this protocol (see below).  
Patients who previously managed their T2D with a single oral 
antidiabetic drug (OAD) may be eligible for screening if they have 
discontinued the OAD and been maintained on diet and exercise for 
at least 12 weeks before the Screening Visit. 
All patients will have a Screening Period comprised of an up to 
2 week Screening Phase and a 2-week, single-blind placebo Run-in 
Phase prior to randomization. In order to qualify for randomization, 
patients must demonstrate compliance during the single-blind placebo 
Run-in Phase based upon tablet count (≥80%).  
Randomization will be stratified by: 
• 
HbA1c at screening (≤8%, >8%) and 
• 
SBP at screening visit (<130 mmHg, ≥130 mmHg).  
Following randomization, patients will have a 26-week, double-blind 
Treatment Period, and an on-site 4-week post-treatment Follow-up 
visit. 
All patients will have PPG assessed following a mixed meal tolerance 
text (MMTT) at Weeks 0 and 26. 
In the original version of this protocol, it was planned for a total of 
240 patients ≥18 years of age to be randomly assigned 1:1 to the 
following 2 treatment groups: 
• 
Sotagliflozin 400 mg as two (2) 200-mg tablets, once daily 
• 
Placebo as two (2) placebo tablets (identical to sotagliflozin 
in appearance), once daily 
At the time of amendment to the current version of the protocol, 
approximately 100 patients had been randomized under this study 
design.  
In the amended, current, version of this protocol, approximately 
300 further patients ≥18 years of age will be randomly assigned 1:1:1 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 5 
to the following 3 treatment groups: 
• 
Sotagliflozin 200 mg as one (1) 200 mg tablet and 
one (1) placebo tablet (identical to sotagliflozin in 
appearance), once daily 
• 
Sotagliflozin 400 mg as two (2) 200 mg tablets, once daily 
• 
Placebo as two (2) placebo tablets (identical to sotagliflozin 
in appearance), once daily 
The enrollment will be completed when each of the 3 treatment 
groups (placebo, sotagliflozin 200 mg, sotagliflozin 400 mg) reaches 
approximately 100 randomized patients. 
Hemoglobin A1c, FPG, and PPG (from MMTT assessment) will be 
masked to study sites and patients after randomization and until study 
end. To prevent partial unblinding, UGE and urine GCR results will be 
masked to study sites and patients. Additionally, urinalysis by dipstick 
will not include the measurement of urine glucose. Urine glucose, 
albumin, calcium and creatinine will be measured separately at all on-
site visits by the central laboratory. 
Early termination 
If a patient discontinues treatment with investigational medicinal 
product (IMP) early during the 26-week Treatment Period, the patient 
will have a Premature End-of-Treatment (EOT) Visit, and a Follow-up 
Visit 4 weeks after the last dose of IMP. In addition, every effort will 
be made to have all patients return to the site at the time 
corresponding to their scheduled visits, particularly the Week 26 Visit. 
If the patient does not agree to site visits, they will be contacted by 
telephone to inquire about their safety status, particularly at the time 
of the scheduled Week 26 Visit.  
The study design is presented graphically at the end of the synopsis. 
STUDY POPULATION  
 
Main selection criteria: 
Inclusion criteria: 
• 
Patients (male and female) with T2D, who are treated with 
diet and exercise only during the 12 weeks prior to 
screening  
• 
Signed written informed consent  
Major exclusion criteria: 
• 
Age <18 years at the Screening Visit or < legal age of 
majority, whichever is greater 
• 
Type 1 diabetes mellitus 
• 
Body Mass Index (BMI) ≤20 or >45 kg/m2 at Screening 
• 
HbA1c <7% or HbA1c >10% via central laboratory test at 
Screening 
• 
Fasting plasma glucose >15 mmol/L (270 mg/dL) measured 
by the central laboratory at screening (Visit 1) and 
confirmed by a repeat test (>15 mmol/L [270 mg/dL]) before 
randomization 
• 
Women of childbearing potential not willing to use highly 
effective method(s) of birth control during the study 
treatment period and the follow-up period, or who are 
unwilling or unable to be tested for pregnancy (see 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 6 
Appendix A), during the study 
• 
Treated with an antidiabetic pharmacological agent within 
the 12 weeks prior to the Screening Visit 
• 
Previous use of any types of insulin for >1 month (at any 
time, except for treatment of gestational diabetes)  
• 
History of gastric surgical procedure including gastric 
banding within 3 years before the Screening Visit  
• 
History of diabetic ketoacidosis or nonketotic hyperosmolar 
coma within 12 weeks prior to the Screening Visit 
• 
Mean of 3 separate blood pressure measurements 
>180 mmHg (SBP) or >100 mmHg (diastolic blood pressure 
[DBP]) 
• 
History of hypertensive emergency within 12 weeks prior to 
Screening (1) 
• 
Patients with severe anemia, severe cardiovascular 
(including congestive heart failure New York Heart 
Association [NYHA] IV), respiratory, hepatic, neurological, 
psychiatric, or active malignant tumor or other major 
systemic disease or patients with short life expectancy that, 
according to the Investigator, will preclude their safe 
participation in this study, or will make implementation of the 
protocol or interpretation of the study results difficult 
• 
Aspartate aminotransferase and/or alanine 
aminotransferase: >3 times the upper limit of the normal 
laboratory range 
• 
Total bilirubin: >1.5 times the upper limit of the normal 
laboratory range (except in case of Gilbert’s syndrome) 
• 
Use of systemic glucocorticoids (excluding topical or 
ophthalmic application or inhaled forms) for more than 
10 consecutive days within 90 days prior to the Screening 
Visit 
• 
Patient who has taken other investigational drugs or 
prohibited therapy for this study within 12 weeks or 
5 half-lives from screening or randomization, whichever is 
longer. Current enrollment in any other clinical study 
involving an investigational study treatment or any other 
type of medical research. 
• 
Pregnant (confirmed by serum pregnancy test at Screening) 
or breastfeeding women 
• 
Severe renal disease as defined by eGFR of 
<30 mL/min/1.73m² at screening by the 4 variable 
Modification of Diet in Renal Disease (MDRD) equation. 
• 
Patient is unwilling or unable to perform self-monitoring of 
blood glucose (SMBG), complete the patient diary, or 
comply with study visits and other study procedures as 
required per protocol 
Total expected number of patients: 
 
Approximately 400. Including: 
• 
Approximately 100 patients randomized under the original 
protocol design (2-arm design sotagliflozin 400 mg and 
placebo) 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 7 
• 
Approximately 300 patients to be randomized under the 
amended, current protocol design 
 
STUDY TREATMENT(s) 
 
Investigational medicinal product  
 
 
 
• 
Sotagliflozin 200 mg administered as one (1) 200 mg tablet 
and one (1) placebo tablet (identical to sotagliflozin 200 mg 
tablets in appearance), once daily, before the first meal of 
the day  
• 
Sotagliflozin 400 mg administered as two (2) 200 mg 
tablets, once daily, before the first meal of the day 
• 
Placebo administered as two (2) placebo tablets (identical 
to sotagliflozin 200 mg tablets in appearance), once daily, 
before the first meal of the day 
Noninvestigational medicinal Product 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rescue therapy 
The threshold values are defined as follows, depending on study 
period: 
• 
FPG >270 mg/dL (15.0 mmol/L) from Randomization up 
through the scheduled Week 8 visit 
• 
FPG >240 mg/dL (13.3 mmol/L) after the Week 8 visit up 
through the scheduled Week 12 visit 
• 
FPG >200 mg/dL (11.1 mmol/L) after the Week 12 visit 
through the end of the 26-week Treatment Period  
Routine fasting SMBG and central laboratory alerts on FPG are set 
up to ensure that glycemic parameter results remain under predefined 
thresholds. 
• 
If one fasting SMBG value exceeds the specific glycemic 
limit on one day, the patient checks it again during the two 
following days. If all the values in three consecutive days 
exceed the specific limit, the patient should contact the 
Investigator and a central laboratory FPG measurement be 
performed as soon as possible, preferably within 7 days, to 
confirm the hyperglycemia.  
• 
Upon receipt of a central laboratory rescue alert, a central 
laboratory re-test must be completed and confirmed as 
exceeding the threshold for rescue before rescue therapy is 
initiated. The re-test confirmation should be performed as 
soon as possible, but within 7 days of receipt, by 
unscheduled visit.  
In the event that a confirmatory FPG exceeds the threshold, the 
Investigator should ensure that no reasonable explanation exists for 
insufficient glucose control and in particular that: 
• 
The increased FPG has been tested at a fasting status (ie, 
no food intake for ≥8 hours) 
• 
Investigational medicinal product is given at the planned 
dose 
• 
There is no intercurrent disease, which may jeopardize 
glycemic control (eg, infectious disease) 
• 
Compliance to treatment is appropriate 
• 
Compliance to diet and lifestyle is appropriate 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 8 
 
 
 
 
 
If any of the above can reasonably explain the insufficient glycemic 
control, the Investigator should consider not initiating rescue 
medication and should undertake appropriate action, ie: 
• 
Assess plasma glucose in fasting condition (ie, after at least 
8 hours fast) 
• 
Initiate an evaluation and treatment of intercurrent disease 
(to be reported in AE/concomitant medication parts of the 
e-CRF and the medical record) 
• 
Stress the absolute need to be compliant with treatment 
• 
Organize a specific interview with the patient and a 
Registered Dietician or other qualified nutrition professional 
to reinforce the absolute need to be compliant with diet and 
lifestyle recommendations, and schedule a FPG 
assessment at the next visit. 
If none of the above mentioned reasons can be found, or if 
appropriate action fails to decrease FPG under the threshold values, 
rescue medication may be introduced. 
Open label rescue medication(s) to treat hyperglycemia will be at the 
discretion of the investigator and in accordance with local standard of 
care and prescribing practice. Except for sodium-glucose 
cotransporter type 2 (SGLT2) inhibitors, any approved medication(s) 
including oral antidiabetic drugs or insulin can be prescribed to treat 
the hyperglycemia. For patients with renal impairment, 
contraindications to antihyperglycemic drugs should be taken into 
consideration. If a patient requires glycemic rescue, the IMP received 
during the randomized, double-blind Treatment Period should 
continue and must remain blinded until the end of the study. 
ENDPOINTS  
 
Primary efficacy endpoint: 
Comparison of sotagliflozin 400 mg versus placebo in change from 
Baseline to Week 26 in HbA1c  
Secondary efficacy endpoints: 
Comparison of sotagliflozin 400 mg versus placebo for:  
• 
Change from Baseline to Week 26 in 2-hour PPG following 
a mixed meal (MM) 
• 
Change from Baseline to Week 26 in FPG  
• 
Change from Baseline to Week 26 in body weight 
• 
Change from Baseline to Week 12 in SBP for patients with 
baseline SBP ≥130 mmHg  
• 
Change from Baseline to Week 12 in SBP for all patients 
• 
Proportion of patients with HbA1c <6.5%, <7.0% at 
Week 26 
Comparison of sotagliflozin 200 mg versus placebo for:  
• 
Change from Baseline to Week 26 in HbA1c 
• 
Change from Baseline to Week 26 in 2-hour PPG following 
an MM 
• 
Change from Baseline to Week 26 in body weight 
• 
Change from Baseline to Week 12 in SBP for all patients 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 9 
Other efficacy endpoints: 
Comparison of sotagliflozin 400 mg and 200 mg doses versus 
placebo for:  
• 
Change from Baseline to Week 12 in SBP for patients with 
baseline SBP <130 mmHg 
• 
Changes from Baseline to Week 12 in diastolic blood 
pressure (DBP) 
• 
Proportion of patients achieving SBP <130 mmHg for those 
with Baseline SBP ≥130 mmHg  
• 
Proportion of patients achieving DBP <80 mmHg for those 
with Baseline DBP ≥80 mmHg 
• 
Change from Baseline in: 
- 
Urine albumin-creatinine ratio (ACR), urinary glucose 
excretion (UGE), and urine glucose-creatinine ratio 
(GCR)   
- 
Serum creatinine 
- 
eGFR 
• 
Proportion of patients with reduction in body weight by 
≥2%, ≥5%, and ≥10% from Baseline  
• 
Change from Baseline to Week 26 in SBP for all patients 
and for patients with Baseline SBP ≥130 mmHg 
• 
Proportion of patients requiring rescue for hyperglycemia 
Comparison of sotagliflozin 200 mg versus placebo for: 
• 
Change from baseline in FPG at Week 26 
• 
Change from baseline in SBP at Week 12 for patients with 
Baseline SBP ≥130 mmHg 
• 
Proportion of patients with HbA1c <6.5%, <7.0% at 
Week 26 
Safety endpoints: 
• 
Adverse events (AEs), hypoglycemia (all, severe, and/or 
documented symptomatic hypoglycemia), events of special 
interest (EOSIs), adverse events of special interest (AESIs), 
AEs leading to discontinuation from the IMP, SAEs, and 
deaths 
• 
Clinical laboratory results including fasting lipids, vital signs, 
and electrocardiogram (ECG) results 
• 
Markers of bone and calcium metabolism 
• 
Markers of intestinal transit and absorption 
Pharmacokinetic endpoints 
• 
Plasma concentrations of sotagliflozin and its metabolite 
predose at Weeks 4, 18 and 26 (End-of-treatment) and 
2 hours 30 minutes post-dose at Week 26 (End-of-
treatment) 
ASSESSMENT SCHEDULE 
See Study Flow Chart 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
In the original version of this protocol, the sample size/power 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 10 
calculations were based on the primary variable, change from 
baseline to Week 26 in HbA1c. Assuming a common standard 
deviation (SD) of 1.2% and using a 2-sided test at a 0.05 α-level, 120 
patients per arm would have 95% power to detect a treatment 
difference of 0.6% in mean HbA1c change from Baseline to Week 26 
between sotagliflozin 400 mg and placebo. 
In the amended, current, version of this protocol, the sample 
size/power has been recalculated to account for the addition of the 
sotagliflozin 200 mg treatment group after enrollment had 
commenced. Assuming a common SD of 1.2% and using a 2-sided 
test at a 0.05 α-level, 100 patients per arm will have: 
• 
94% power to detect a treatment difference of 0.6% in 
mean HbA1c change from Baseline to Week 26 between 
sotagliflozin 400 mg and placebo, and  
• 
84% power to detect a treatment difference of 0.5% in 
mean HbA1c change from Baseline to Week 26 between 
sotagliflozin 200 mg and placebo. 
As a result, the total number of patients will include:  
• 
Approximately 100 patients from the initial randomization 
(1:1) according to the original protocol, balanced between 
placebo and sotagliflozin 400 mg, and 
• 
Approximately 300 patients from the subsequent 
randomization (1:1:1) according to the amended, current, 
protocol, balanced between placebo and the sotagliflozin 
200 mg and 400 mg doses.   
Analysis population: 
Efficacy analyses will be based on the intention to treat (ITT) 
population, defined as all randomized patients irrespective of 
compliance with the study protocol and procedures. Patients will be 
analyzed for efficacy analyses according to the treatment group to 
which they are randomized, that is, sotagliflozin 400 mg versus 
placebo (those randomized to placebo), and sotagliflozin 200 mg 
versus placebo (those randomized to placebo in the amended 
randomization only). 
Primary analysis: 
Analysis of the primary efficacy endpoint (change from Baseline to 
Week 26 in HbA1c) will be performed on the ITT population, using 
HbA1c measurements obtained during the study, including those 
obtained after IMP discontinuation or introduction of rescue therapy. 
The primary efficacy endpoint of change in HbA1c from baseline to 
Week 26 will be analyzed with missing values imputed by 
control-based multiple imputation method under the missing not at 
random frame work.  
• 
For placebo patients, missing data will be imputed based on 
the placebo group data, 
• 
For patients in the sotagliflozin 400 mg group, missing data 
will be imputed as if the patients were on placebo 
throughout the study, where all patients’ measurements 
including the on-treatment measurements will be 
considered as if the measurements were from the placebo 
group in the imputation model. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 11 
Each of the complete datasets will be analyzed by the Analysis of 
Covariance (ANCOVA) model with treatment groups (sotagliflozin 
400 mg, placebo), randomization stratum of HbA1c (≤8.0%, >8.0%), 
randomization stratum of SBP (<130, ≥130 mmHg), and country as 
fixed effects, and baseline HbA1c value as a covariate. Results from 
each complete dataset will be combined to provide the adjusted mean 
change in HbA1c from Baseline to Week 26 for each treatment group, 
as well as the between-group difference (comparing sotagliflozin 
400 mg vs placebo) and the 95% confidence intervals (CI) for the 
difference.  
 
Summary statistics (for screening value, baseline value, observed 
values, and observed changes from Baseline) at scheduled visits will 
be provided for each treatment group. The summary will include the 
number of observations, mean, SD, standard error (SE), minimum, 
median, and maximum. Graphical presentations will also be used to 
examine trends over time using mean values (±SE) and mean 
changes from baseline (±SE) at each of the scheduled visits (using 
observed cases [OC]).  
Analysis of secondary efficacy endpoints: 
The secondary endpoints will be analyzed using a similar approach to 
the primary efficacy endpoint, with missing values imputed by 
control-based multiple imputation method under the missing not at 
random frame work.  
For each of the continuous secondary endpoints, each of the 
complete datasets will be analyzed by the ANCOVA model. To 
compare sotagliflozin 400 mg versus placebo, the model will include 
treatment groups (400 mg sotagliflozin, placebo), randomization 
stratum of HbA1c (≤8.0%, >8.0%), randomization stratum of SBP 
(<130, ≥130 mmHg), and country as fixed effects, and baseline 
secondary endpoint value as a covariate. To compare sotagliflozin 
200 mg versus placebo, the model will include treatment groups 
(sotagliflozin 200 mg, placebo), randomization stratum of HbA1c 
(≤8.0%, >8.0%), randomization stratum of SBP (<130, ≥130 mmHg), 
and country as fixed effects, and baseline secondary endpoint value 
as a covariate. Results from each complete dataset will be combined 
to provide the adjusted mean change from Baseline to Week 26 for 
each treatment group, as well as the between-group difference 
(comparing each sotagliflozin group vs its corresponding placebo 
group) and the 95% CI for the difference. 
The categorical secondary efficacy variables of HbA1c <6.5%, <7% at 
Week 26 will be analyzed using a Cochran-Mantel-Haenszel method 
stratified by randomization stratum of HbA1c (≤8.0%, >8.0%), and 
randomization stratum of SBP (<130, ≥130 mmHg). 
Analysis of other efficacy endpoints 
The analysis of other endpoints will be descriptive with no formal 
testing. Summary statistics at scheduled visits using OC will be 
provided by each treatment group. Graphical presentations will also 
be used to illustrate trends over time. 
Analyses of safety data 
All safety summaries will be descriptive; no statistical significance 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 12 
tests will be performed on safety data. These analyses will be based 
on the Safety Population, which is defined as all randomized patients 
who receive at least 1 dose of double-blind treatment, regardless of 
the amount of treatment administered. Patients will be analyzed for 
safety analyses according to the treatment actually received. 
DURATION OF STUDY PERIOD (per 
patient) 
Up to 34 weeks, including a Screening Period consisting of a 
Screening Phase of up to 2 weeks and a 2-week single-blind placebo 
Run-in Phase, a 26-week double-blind Treatment Period, and a 
4-week post-treatment Follow-up visit to collect safety information. 
STUDY COMMITTEES 
Steering committee:  
 Yes    
 No 
Data monitoring committee: 
 Yes    
 No 
Clinical endpoint committee(s):  
 Yes  
 No 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 13 
1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
Abbreviations: HbA1c: hemoglobin A1c; R: randomization; T2D: type 2 diabetes mellitus. 
(electronic 
 
 
2.0)
(electronic 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 14 
1.2 
STUDY FLOW CHART 
 
Screening Period 
 
Screening 
Run-in 
                        Double Blind Treatment Perioda 
Follow-
upb 
VISIT 
1 
2 
3 
(Randomization) 
4 
5 
6 
7 
8 
9 
10 
Week 
Up to -4 
-2 
0  
Baseline 
1 
4 
8 
12 
18 
26 
30 
Day (window [days]) 
 
(-7/+3) 
1 
7 (±3) 
28 (±3) 
56 (±3) 
84 (±3) 
126 (±3) 
182 (±3) 
210 (±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
Body weight, heightc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam: 
 
 
 
 
 
 
 
 
 
 
    complete 
X 
 
 
 
  
 
 
 
X 
 
    abbreviated 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Diet & exercise instruction 
 
X 
X 
 
 
 
 
 
X 
 
Instruction on basic genitourinary 
hygiene & hydration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Interactive response technology 
(IRT) contact 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Dispense glucose meter  
 
X 
 
 
 
 
 
 
 
 
Dispense diary  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect/review diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Instruction on diabetic 
ketoacidosis symptoms and 
glucose testing 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Dispense IMP  
 
X 
X 
 
X 
X 
X 
X 
 
 
IMP accounting & compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(electronic 
 
 
2.0)
(electronic 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 15 
Screening Period 
 
Screening 
Run-in 
                        Double Blind Treatment Perioda 
Follow-
upb 
VISIT 
1 
2 
3 
(Randomization) 
4 
5 
6 
7 
8 
9 
10 
Week 
Up to -4 
-2 
0  
Baseline 
1 
4 
8 
12 
18 
26 
30 
Day (window [days]) 
 
(-7/+3) 
1 
7 (±3) 
28 (±3) 
56 (±3) 
84 (±3) 
126 (±3) 
182 (±3) 
210 (±3) 
Self-monitored blood glucosee 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
 
X 
 
 
 
 
 
X 
 
Standard mixed meal tolerance 
testg 
 
 
X 
 
 
 
 
 
X 
 
Laboratory testingh 
 
 
 
 
 
 
 
 
 
 
FPG 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
HbA1c 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Chemistry (including amylase 
and lipase) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
 
 
 
X 
 
X 
 
Fasting lipids 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Pregnancy test (WOCBP)i 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Serum follicle stimulating 
hormone and estradiol 
(menopausal women only)i 
X 
 
 
 
 
 
 
 
 
 
Plasma concentrationj 
 
 
 
 
X 
 
 
X 
X 
 
Markers of intestinal transit & 
absorptionk 
 
 
X 
 
 
 
 
 
X 
X 
Markers of bone & calcium 
metabolisml 
 
 
X 
 
 
 
 
 
X 
 
Urinalysis (dipstick and 
microscopy)m 
X 
 
X 
 
 
 
 
 
X 
 
Urine albumin, calcium, 
glucose & creatinine 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Evaluate for glycemic rescue 
 
 
 
To be assessed and reported throughout the treatment period 
 
Hypoglycemia 
To be assessed and reported throughout the study 
AEs/SAEs/AESIs/EOSIs 
To be assessed and reported throughout the studyp 
(electronic 
 
 
2.0)
(electronic 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 16 
a If a patient discontinues treatment with IMP early during the Treatment Period, the patient will have a Premature EOT Visit, and a Follow-up Visit 4 weeks after the last dose of IMP. However, every effort will be 
made to have all patients return to the site for all scheduled visits, in particular the Week 26 Visit. If the patient does not agree to a site visit, they will be contacted by telephone to inquire about safety status. If a 
patient discontinues (or completes) treatment and study at the same time, a single visit will be performed using the procedure normally planned for the EOT visit. 
b Four weeks after the last dose of IMP. 
c Height to be measured only at screening 
d Vital sign measurements (sitting BP and heart rate): 3 separate seated BP and heart rate measurements should be taken with at least 1 minute between readings, following a 5-minute rest period and prior to 
phlebotomy (see Section 9.2.1.4 and detailed instructions in Appendix D).  
e See Section 9.2.1.6 for details of SMBG measurements. Glucose meters used for SMBG display results as plasma glucose concentration. Patients should measure their fasting plasma glucose at least 3 times per 
week (including on day of each on-site study visit). 
f 
The 12-lead ECG recordings should be obtained prior to IMP administration. The ECG will be evaluated as “normal” or “abnormal”. 
g Postprandial plasma glucose will be assessed by central laboratory at Baseline and 2 hours after consuming a standard mixed liquid breakfast meal and via a mixed meal tolerance test (MMTT) on Day 1 and 
Week 26. If a patient withdraws from IMP early, please see Section 10.3.4. 
h All laboratory assessments occur prior to first dose of double-blind IMP. The first dose of double-blind IMP occurs after samples for the mixed liquid meal have been collected. All visit dates will be scheduled based 
on the date of randomization with a ±3 days visit window allowed during the treatment period. Serum chemistry parameters (clinical chemistry [including amylase and lipase], hematology, and other blood 
parameters) are listed in Table 2. 
i 
Serum pregnancy testing only at screening; urine pregnancy testing subsequently. Serum pregnancy test results must be reviewed prior to beginning the Run-in Phase for all women of childbearing potential 
(WOCBP). Any positive urine test results must be confirmed based on serum pregnancy test. The Investigator may perform additional tests at their discretion or as required by local regulations. For women of 
nonreproductive potential (Appendix A), follicle stimulating hormone (FSH) and/or estradiol levels should be tested if the definition of postmenopausal or premenopausal cannot be satisfied, eg, no medical 
document of hysterectomy or cessation of menses <12 months without an alternative medical cause. 
j 
Plasma concentration samples (ie, for sotagliflozin and sotagliflozin-3-O-glucuronide) on Weeks 4 and Week 18 should be drawn with the other laboratory assessments. For Week 26, plasma concentration 
samples should be drawn at predose and 2 hours 30 minutes, immediately after the respective glucose assessments during the MMTT. PK samples (except the 2 hours 30 minute sample during the MMTT) MUST 
be collected before administration of IMP. The date and time of the last intake of IMP prior to visits where PK samples are taken should be recorded by the patient in the patient diary. Patients should be reminded 
of this at visits preceding PK time points to ensure these details are captured. In the case of Premature IMP discontinuation, PK samples should not be drawn at the Premature EOT visit, nor at any subsequent 
visits. 
k The markers of intestinal transit and absorption include vitamins B6, B12, K, E, and A, serum folate, and ferritin. 
l 
Markers of bone and calcium metabolism include:  serum and urinary calcium, serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum and urinary phosphorus, serum parathyroid hormone, markers of 
bone resorption (serum NTX, serum β-CTX-1), and bone formation (serum P1NP). 
m Urinalysis includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte esterase. Microscopy includes detection 
of formed cellular elements, casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. In the event of abnormal urinalysis findings suspicious of urinary tract infection, urine culture should be 
performed. Positive urine culture determination will be based upon the criteria of the reporting laboratory. 
 
p All serious adverse events (SAEs), adverse events (AEs), AEs of special interest (AESIs), and Events of Special Interest (EOSIs) will be collected starting with signing informed consent and continue until the end 
of the study. All AEs that occur during treatment should be followed until study completion (or until patients leave the study) or until the event has resolved, the condition has stabilized, or the patient is lost to 
follow-up. All patients will have a follow-up contact 4 weeks after the last dose of IMP to collect safety information. 
(electronic 
 
 
2.0)
(electronic 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 17 
2 
TABLE OF CONTENTS 
 
1 
FLOW CHARTS.............................................................................................................................13 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................13 
1.2 
STUDY FLOW CHART ..................................................................................................................14 
2 
TABLE OF CONTENTS ................................................................................................................17 
2.1 
LIST OF TABLES...........................................................................................................................23 
2.2 
LIST OF FIGURES.........................................................................................................................23 
3 
LIST OF ABBREVIATIONS ..........................................................................................................24 
4 
INTRODUCTION AND RATIONALE.............................................................................................26 
4.1 
BACKGROUND:  SOTAGLIFLOZIN AND DISEASE ....................................................................26 
4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS ................................................................27 
4.3 
RATIONALE FOR CURRENT STUDY ..........................................................................................28 
4.3.1 
Rationale for selection of doses.....................................................................................................28 
4.3.2 
Rationale for study design and control groups ..............................................................................28 
4.4 
BENEFIT/RISK OF SOTAGLIFLOZIN...........................................................................................29 
5 
STUDY OBJECTIVES ...................................................................................................................31 
5.1 
PRIMARY.......................................................................................................................................31 
5.2 
SECONDARY ................................................................................................................................31 
5.3 
OTHER...........................................................................................................................................31 
6 
STUDY DESIGN ............................................................................................................................33 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................33 
6.1.1 
Screening period............................................................................................................................33 
6.1.1.1 
Screening Phase (Visit 1) ..............................................................................................................33 
6.1.1.2 
Run-in Phase (Visit 2) ....................................................................................................................33 
6.1.2 
Double-blind treatment period (Week 0 to Week 26).....................................................................34 
 
.........................................................................................................34 
6.1.4 
Follow-up period.............................................................................................................................35 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 18 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................35 
6.2.1 
Duration of study participation for each patient .............................................................................35 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................35 
6.3 
INTERIM ANALYSIS......................................................................................................................35 
6.4 
STUDY COMMITTEES..................................................................................................................35 
6.4.1 
Data monitoring committee ............................................................................................................35 
6.4.2 
Clinical endpoint committee(s).......................................................................................................35 
6.4.3 
Safety adjudication of events requiring ongoing monitoring ..........................................................36 
6.4.4 
Steering Committee .......................................................................................................................36 
7 
SELECTION OF PATIENTS..........................................................................................................37 
7.1 
INCLUSION CRITERIA..................................................................................................................37 
7.2 
EXCLUSION CRITERIA ................................................................................................................37 
7.2.1 
Exclusion criteria related to study methodology ............................................................................37 
7.2.2 
Exclusion criteria related to diabetes history and treatment..........................................................38 
7.2.3 
Exclusion criteria related to the current knowledge of sotagliflozin ...............................................39 
7.2.4 
Additional exclusion criteria during or at the end of the Run-in phase before Randomization......39 
8 
STUDY TREATMENTS .................................................................................................................41 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................41 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................41 
8.2.1 
Rescue therapy..............................................................................................................................42 
8.3 
BLINDING PROCEDURES............................................................................................................44 
8.3.1 
Methods of blinding........................................................................................................................44 
8.3.2 
Randomization code breaking during the study.............................................................................44 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................45 
8.5 
PACKAGING AND LABELING ......................................................................................................45 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................46 
8.7 
RESPONSIBILITIES ......................................................................................................................46 
8.7.1 
Treatment accountability and compliance......................................................................................46 
8.7.2 
Return and/or destruction of treatments ........................................................................................47 
8.8 
CONCOMITANT MEDICATION.....................................................................................................47 
8.8.1 
Prohibited prior and concomitant medications...............................................................................47 
8.8.2 
Concomitant diabetes therapy .......................................................................................................48 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 19 
8.9 
POSTSTUDY TREATMENT..........................................................................................................48 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................49 
9.1 
EFFICACY ENDPOINTS ...............................................................................................................49 
9.1.1 
Primary efficacy endpoint...............................................................................................................49 
9.1.2 
Secondary efficacy endpoints........................................................................................................49 
9.1.3 
Other efficacy endpoints ................................................................................................................49 
9.1.4 
Assessment methods of efficacy endpoints...................................................................................50 
9.1.4.1 
HbA1c ............................................................................................................................................50 
9.1.4.2 
Postprandial glucose and mixed meal tolerance test ....................................................................50 
9.1.4.3 
Fasting plasma glucose measurement ..........................................................................................51 
9.1.4.4 
Body weight measurement ............................................................................................................51 
9.1.4.5 
Blood pressure measurements ......................................................................................................52 
9.1.4.6 
Kidney function parameter measurement......................................................................................52 
9.1.4.7 
Proportion of patients requiring rescue for hyperglycemia ............................................................52 
9.2 
SAFETY ENDPOINTS ...................................................................................................................52 
9.2.1 
Assessment methods of safety endpoints .....................................................................................53 
9.2.1.1 
Adverse events ..............................................................................................................................53 
9.2.1.2 
Hypoglycemia.................................................................................................................................53 
9.2.1.3 
Laboratory safety variables............................................................................................................54 
9.2.1.4 
Vital signs and physical exam........................................................................................................56 
9.2.1.5 
Electrocardiogram variables ..........................................................................................................56 
9.2.1.6 
Self-monitoring of blood glucose....................................................................................................56 
9.2.1.7 
Diabetic ketoacidosis .....................................................................................................................57 
9.3 
OTHER ENDPOINTS.....................................................................................................................57 
9.3.1 
Pharmacokinetics...........................................................................................................................57 
9.3.1.1 
Sampling time ................................................................................................................................57 
9.3.1.2 
Pharmacokinetics handling procedure...........................................................................................58 
9.3.1.3 
Bioanalytical method......................................................................................................................58 
 
.........................................................................................58 
 
..............................................................................59 
9.6 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................59 
10 
STUDY PROCEDURES ................................................................................................................61 
10.1 
VISIT SCHEDULE..........................................................................................................................61 
10.1.1 
Screening Period............................................................................................................................61 
10.1.1.1 Screening Phase............................................................................................................................61 
10.1.1.2 Run-in Phase (Visit 2, Week -2).....................................................................................................63 
10.1.2 
Double-blind randomized treatment period....................................................................................64 
10.1.2.1 Treatment Period (Day 1 to Week 26) ...........................................................................................64 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 20 
10.1.3 
Post-treatment Follow-up period....................................................................................................68 
10.1.3.1 On-site follow-up Visit 10 (Week 30) – End of Study.....................................................................68 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................69 
10.2.1 
Source data to be found in patient’s file.........................................................................................69 
10.2.2 
Source data verification requirements for screen failures .............................................................70 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................70 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................70 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................70 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................71 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................71 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................72 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................73 
10.4.1 
Definitions of adverse events.........................................................................................................73 
10.4.1.1 Adverse event ................................................................................................................................73 
10.4.1.2 Serious adverse event ...................................................................................................................73 
10.4.1.3 Adverse event of special interest...................................................................................................74 
10.4.1.4 Events of Special Interest ..............................................................................................................75 
10.4.2 
General guidelines for reporting adverse events ...........................................................................75 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................76 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................77 
10.4.5 
Guidelines for reporting events of special interest.........................................................................77 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................77 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................77 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................78 
10.6.1 
Hypoglycemia.................................................................................................................................78 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................80 
11 
STATISTICAL CONSIDERATIONS..............................................................................................81 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................81 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................81 
11.3 
ANALYSIS POPULATIONS...........................................................................................................82 
11.3.1 
Efficacy populations .......................................................................................................................82 
11.3.1.1 Intent-to-treat population................................................................................................................82 
11.3.2 
Safety population ...........................................................................................................................83 
11.4 
STATISTICAL METHODS .............................................................................................................83 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 21 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................84 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................84 
11.4.1.2 Compliance ....................................................................................................................................84 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................84 
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................84 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................86 
11.4.2.3 Analyses of other efficacy endpoints .............................................................................................87 
11.4.2.4 Multiplicity considerations ..............................................................................................................87 
11.4.3 
Analyses of safety data..................................................................................................................88 
11.4.3.1 Analysis of adverse events ............................................................................................................88 
11.4.3.2 Analyses of hypoglycemia .............................................................................................................89 
11.4.3.3 Analyses of adverse events of special interest..............................................................................90 
11.4.3.4 Analyses of events of special interest............................................................................................90 
11.4.3.5 Analyses of laboratory variables....................................................................................................90 
11.4.3.6 Analyses of vital sign variables ......................................................................................................90 
11.4.3.7 Analyses of 12 lead ECG status ....................................................................................................91 
11.4.4 
Analyses of pharmacokinetic variables..........................................................................................91 
11.5 
INTERIM ANALYSIS......................................................................................................................91 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................92 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................92 
12.2 
INFORMED CONSENT .................................................................................................................92 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................92 
13 
STUDY MONITORING...................................................................................................................94 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR............................................................................94 
13.2 
RESPONSIBILITIES OF THE SPONSOR OR SERVICE PROVIDER .........................................94 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................94 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................95 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................95 
14 
ADDITIONAL REQUIREMENTS...................................................................................................96 
14.1 
CURRICULUM VITAE....................................................................................................................96 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................96 
14.3 
CONFIDENTIALITY .......................................................................................................................96 
14.4 
PROPERTY RIGHTS.....................................................................................................................97 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 22 
14.5 
DATA PROTECTION.....................................................................................................................97 
14.6 
INSURANCE COMPENSATION....................................................................................................98 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................98 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................98 
14.8.1 
By the Sponsor...............................................................................................................................98 
14.8.2 
By the Investigator .........................................................................................................................99 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................99 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................99 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................101 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................102 
17 
APPENDICES..............................................................................................................................104 
APPENDIX A GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION....................................................................................................105 
APPENDIX B TWO-HOUR STANDARDIZED MIXED MEAL ..................................................................108 
APPENDIX C RECOMMENDATIONS ON BASIC GENITOURINARY HYGIENE, MAINTAINING 
HYDRATION, AND RECOGNIZING DIABETIC KETOACIDOSIS..............................................110 
APPENDIX D MEASUREMENT OF BLOOD PRESSURE AND PULSE RATE......................................113 
APPENDIX E GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................114 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 23 
2.1 
LIST OF TABLES 
Table 1 – Summary of investigational medicinal products............................................................................41 
Table 2 – Serum chemistry parameters ........................................................................................................54 
Table 3 – Samples identification ...................................................................................................................57 
 
2.2 
LIST OF FIGURES 
Figure 1 - Hypoglycemia classification in Study EFC14833..........................................................................79 
 
 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 24 
3 
LIST OF ABBREVIATIONS 
 
ACR: 
albumin-creatinine ratio 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
Analysis of Covariance 
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
BP: 
blood pressure 
CEC: 
Clinical Endpoint Committee 
CI: 
confidence interval 
CRO: 
contract research organization 
CSR: 
clinical study report 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DILI: 
drug-induced liver injury 
DKA: 
diabetic ketoacidosis 
DMC: 
Data Monitoring Committee 
DRF: 
Discrepancy Resolution Form 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOSI: 
Events of Special Interest 
EOT: 
End-of-Treatment 
FPG: 
fasting plasma glucose 
FSH: 
follicle-stimulating hormone 
GCR: 
glucose-creatinine ratio 
GI: 
gastrointestinal 
GLP-1: 
glucagon-like peptide-1 
GU: 
genitourinary 
HbA1c: 
hemoglobin A1c 
HLGT: 
high-level group term 
HLT: 
high level term 
HRT: 
hormone replacement therapy 
IB: 
Investigator's Brochure 
ICF: 
informed consent form 
IEC: 
independent ethics committee 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
IRT: 
Interactive Response Technology 
ITT: 
intent-to-treat 
MACE: 
major adverse cardiovascular events 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 25 
MI: 
myocardial infarction 
MM: 
mixed meal 
MMTT: 
mixed meal tolerance test 
NIMP: 
noninvestigational medicinal product 
OC: 
observed cases 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
P-gp: 
P-glycoprotein 
PI: 
Principal Investigator 
PK: 
pharmacokinetic 
PPG: 
postprandial glucose 
PT: 
preferred term 
PYY: 
peptide YY 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SC: 
Steering Committee 
SD: 
standard deviation 
SE: 
standard error 
SGLT: 
sodium-glucose cotransporter 
SGLT1: 
sodium-glucose cotransporter type 1 
SGLT2: 
sodium-glucose cotransporter type 2  
SMBG: 
self-monitoring of blood glucose 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
T1D: 
type 1 diabetes mellitus 
T2D: 
type 2 diabetes mellitus 
TEAE: 
treatment-emergent adverse events 
TG: 
triglycerides 
UGE: 
urinary glucose excretion 
ULN: 
upper limit of normal 
WOCBP: 
woman of child-bearing potential 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 26 
4 
INTRODUCTION AND RATIONALE 
4.1 
BACKGROUND:  SOTAGLIFLOZIN AND DISEASE 
Sotagliflozin is a dual inhibitor of the sodium-glucose cotransporters type 1 and 2 (SGLT1 and 2) 
being developed for use in type 2 diabetes mellitus (T2D), a metabolic disorder characterized by 
hyperglycemia that results from a combination of increased insulin resistance and beta cell 
dysfunction. The microvascular complications of diabetes are well known and can result in 
impaired renal function, retinopathy and neuropathy. Other comorbidities that are frequently 
associated with diabetes are hypertension, obesity, and cardiovascular (CV) disease. Recently, the 
Centers for Disease Control and Prevention released a report stating that if current trends 
continue, 1 in 3 Americans will have diabetes by the year 2050. According to the most recent 
International Diabetes Federation Diabetes Atlas, the estimates in 2015 were that 1 in 11 adults 
have diabetes, which means 415 million people, estimated to rise to 642 million by 2040 (2). 
In 2010, 33 million people in the European Union had diabetes, 9% of the adult population. This 
number is projected to increase to 38 million by 2030 (3). While these numbers include both 
people with T2D and type 1 diabetes (T1D), over 90% of adults with diabetes have T2D. Diabetes 
is among the leading causes of death by disease and is a leading cause of heart disease, stroke, 
blindness, kidney disease, and amputation (2,3). Despite the fact that the population of people 
with diabetes is growing, none of the current therapies is curative and the results of treatment are 
variable. 
Although lifestyle changes, including diet, exercise, and education, are valuable components of 
diabetes treatment, the vast majority of people with T2D require pharmacological therapy to 
control the disease. In the United States and Europe, metformin is the standard first-line therapy in 
the absence of any contraindications or tolerability issues as per guidance from the American 
Association of Diabetes (4).  
Despite the numerous treatment options available, monotherapy fails in many patients as beta-cell 
function continues to deteriorate leading to progressively increasing hyperglycemia. Aggressive 
glycemic control with the currently available agents often leads to side effects, most notably 
weight gain and an increased frequency of hypoglycemia. These concerns emphasize the need to 
develop new agents that effectively and safely lower glucose in diabetic patients. 
In patients with diabetes, it is desirable to maintain blood glucose in the normal range without 
exhausting the ability of the pancreatic beta-cells to produce insulin. Glucose is transported across 
the cell membrane by 2 different types of glucose transporters:  glucose-facilitated transporters 
and sodium-glucose cotransporter (SGLT) proteins (5). In the kidney, after blood is filtered by the 
glomerulus, glucose passes into the urine, but 99% is reabsorbed, primarily via SGLT2, which is 
responsible for 90% of glucose reabsorption, while 10% is reabsorbed by SGLT1. When 
functional SGLT2 is lacking in humans, a significant amount of glucose remains in the urine and 
is removed from the body (6). This way of reducing blood glucose is not an insulin-dependent 
mechanism; therefore hyperglycemia may be reduced while the pancreas is spared from an 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 27 
increased demand for insulin production that is caused by hyperglycemia. Since obesity is a 
significant comorbidity in T2D, and insulin resistance is increased in obesity, the caloric loss from 
glucose in the urine may represent an additional benefit resulting in decreased weight, which 
should result in decreased insulin resistance (6).  
The sodium-glucose cotransporter type 1 (SGLT1) is expressed predominantly in the 
gastrointestinal (GI) tract; SGLT1 is responsible for the majority of glucose absorption by the 
small intestine (7). Inhibition of SGLT1 in the GI tract prevents glucose from being absorbed. 
Additionally, there is accumulating evidence that SGLT1 inhibition stimulates secretion of 
glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), gut hormones involved in pancreatic 
beta-cell function and appetite control, respectively. Reduced glucose absorption in the proximal 
intestine leads to more glucose being delivered distally, which allows L cells in both the ileum 
and the colon to sense glucose and its byproducts, and as a result, they secrete GLP-1 and PYY. 
Although a complete lack of functional SGLT1 may be associated with symptoms of glucose and 
galactose malabsorption, (8) pharmacologic inhibition of SGLT1 by sotagliflozin has not 
produced these effects in preclinical models or patients with T2D. Selective inhibitors of the 
SGLT1 transporter are in early stages of development. 
Extensive clinical studies conducted for selective SGLT2 inhibitors have established this class as 
effective agents for the treatment of T2D (9,10,11) and have led to approvals by the US Food and 
Drug Administration (FDA) and the European Medicines Agency (EMA). Studies with 
sotagliflozin, a potent dual inhibitor of SGLT2 and SGLT1, have shown that this agent produces 
significant glucosuria in preclinical animal models, healthy human volunteers, and patients with 
T2D. Single- and multiple-dose administration of sotagliflozin to healthy human patients has 
resulted in dose-dependent increases in glucosuria. Multiple-dose (28-day) administration in 
diabetic patients produced improvements in several metabolic parameters, including urinary 
glucose excretion (UGE), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), GLP-1, and 
PYY. These data suggest that sotagliflozin should be of therapeutic benefit to patients with T2D.  
4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS 
Approximately 780 subjects (639 assigned to sotagliflozin and 141 assigned to placebo) have 
participated in completed clinical studies of sotagliflozin. No significant safety concerns have 
been identified in the sotagliflozin drug program, and sotagliflozin has been well-tolerated in all 
studies to date. Serious adverse events (SAEs) and discontinuations due to adverse events (AEs) 
have been infrequent and have been balanced between treatment and comparator groups. Reports 
of treatment-emergent adverse events (TEAE) across all sotagliflozin studies for which data are 
available were generally balanced between treatment and comparator groups. The most frequently 
reported TEAEs (≥2.0%) were headache, nausea, diarrhea, constipation, and dizziness, all of 
which were reported at a frequency greater than placebo. However, most were described as mild 
to moderate, and most resolved spontaneously.  
In completed and ongoing clinical trials, no safety issues in addition to those already described in 
the current Investigator Brochure were observed. In general, no significant imbalances of 
SAE/AEs between sotagliflozin and comparators were observed in completed studies. 
Cumulatively, during the clinical trial program 8 SAEs were reported by 6 patients (4 T2D and 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 28 
2 T1D), all of which were assessed as unrelated to study drug; those reported by 4 T2D patients 
who received sotagliflozin included pulmonary embolism, deep vein thrombosis, bile duct stone, 
cholangitis and lower limb fracture, while a myocardial infarction (MI) was experienced by a 
patient receiving placebo. Two SAEs of diabetic ketoacidosis (DKA) were reported by 2 T1D 
patients receiving 400 mg once daily sotagliflozin in the Phase 2 T1D study LX4211.1 
203-TIDM; both SAEs were assessed as due to failure of insulin delivery via insulin pump. 
A drug interaction study with digoxin, a sensitive P-glycoprotein (P-gp) substrate, indicated that 
sotagliflozin acts as a weak P-gp inhibitor. 
More information on the safety of sotagliflozin and on the clinical program can be found in the 
Investigator Brochure (IB). 
4.3 
RATIONALE FOR CURRENT STUDY 
4.3.1 Rationale for selection of doses 
The selection of 400 mg and 200 mg once-daily doses is based on the results of the Phase 2b 
study LX4211.1-202-DM. In this study, doses of 75 mg once daily, 200 mg once daily, 200 mg 
twice daily, and 400 mg once daily sotagliflozin were tested over a 12-week, double-blind period. 
The 400 mg and 200 mg once daily doses were chosen for further evaluation based on their 
HbA1c-lowering effects and the overall safety and tolerability observed at these doses. At 
12 weeks, the 400 mg dose lowered HbA1c by a mean of 0.93% and the 200 mg dose by a mean 
of 0.48%, while placebo lowered HbA1c by a mean of 0.14%. Other doses did not have any 
advantages in efficacy, safety, or tolerability. The overall incidence of AEs in patients receiving 
400 mg or 200 mg once daily was similar to that seen with placebo. 
In healthy subjects sotagliflozin was well-tolerated following single doses up to 2000 mg, and in 
multiple doses up to 800 mg over 10 days. Furthermore, in a thorough QT study, single doses of 
sotagliflozin (800 mg and 2000 mg) were well tolerated and did not prolong the QT interval. 
Additionally, evaluation of metabolites in urine and plasma of healthy subjects resulted in no 
safety concerns following single doses of 400 mg sotagliflozin. Single doses of 400 mg in 
combination with sitagliptin, and multiple doses up to 400 mg in combination with metformin 
over 12 weeks were also well tolerated in patients with T2D.  
4.3.2 Rationale for study design and control groups 
This study is designed to demonstrate the efficacy and safety of sotagliflozin when used as 
monotherapy in patients with T2D who have inadequate glycemic control with diet and exercise. 
Sotagliflozin 200 mg and 400 mg will be compared to placebo, consistent with regulatory 
guidance. Based on the study design, the protocol stipulates that patients be provided antidiabetic 
agent rescue therapy according to a predefined algorithm. Safety, tolerability, pharmacokinetic 
(PK) and pharmacodynamic (PD) effects of sotagliflozin are supported by Phase 1 and Phase 2 
studies and toxicology data in rats up to 26 weeks and dogs up to 39 weeks as well as 2-year 
carcinogenicity data in rats.  
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 29 
To achieve balanced randomization for assessment of the primary endpoint, randomization will be 
stratified based on preexisting metabolic control (Screening HbA1c ≤8.0% versus >8.0%). 
Another stratification factor (systolic blood pressure [SBP] 130 < versus ≥130 mmHg) has been 
added to ensure balance in randomization for a secondary endpoint (change from baseline to 
12 weeks in SBP for patients with baseline SBP ≥130 mmHg). 
A placebo control will be used to allow for an unbiased assessment of treatment effects and safety 
data. Bias will be minimized by randomizing the patients to treatment groups, blinding the 
patients, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating the 
endpoints in a blinded fashion. 
A parallel-group, randomized placebo-controlled design was selected because trial participants are 
exposed to a single treatment and assignment to that treatment is based solely on chance. This 
design is free of the limitations of competing designs such as crossover in which there may be a 
carryover of effect from one treatment to the second treatment. Although this carryover effect can 
be minimized with a washout period, it is possible that some longer term effects may persist. 
While the sample size of the parallel group design is larger to account for more variability when 
participants cannot serve as their own control, the above-mentioned limitations of the crossover 
design have led the randomized controlled trial design to be the standard for therapeutic 
confirmatory trials for regulatory approval such as this trial. 
4.4 
BENEFIT/RISK OF SOTAGLIFLOZIN 
Sotagliflozin is currently being investigated as an adjunct to diet and exercise to improve 
glycemic control in adults with T2D. The study program will also provide efficacy and safety data 
for sotagliflozin in combination with other antidiabetic medications. In addition the study program 
will evaluate clinical outcomes in patients with high CV risk and in patients with renal 
impairment. The use of sotagliflozin in the treatment of T1D is also being studied in a separate 
development program. 
Sotagliflozin may benefit a wide variety of diabetic patients based on multiple potential beneficial 
effects of dual SGLT2/SGLT1 inhibition, and its insulin-independent mechanism of action. 
Improvements in HbA1c, FPG, and postprandial glucose (PPG) were observed with sotagliflozin 
in multiple studies. As anticipated from the mechanism of action, treatment with sotagliflozin 
resulted in increased UGE (from inhibition of SGLT2) as well as increased incretin levels (from 
inhibition of SGLT1). In addition, the improvements in body weight, blood pressure (BP), and 
triglycerides (TG) observed with sotagliflozin treatment have the potential to benefit patients with 
diabetes through their effects on common diabetic comorbidities.  
Overall, sotagliflozin has been well tolerated in all studies to date, with the majority of events 
assessed as mild to moderate; most of which resolved spontaneously. Serious adverse events and 
discontinuations due to AEs have been limited and balanced between treatment and comparator 
groups. Severe hypoglycemia, genital mycotic infections, urinary tract infections, DKA, volume 
depletion with serious consequence (orthostasis, falls, fractures), severe diarrhea, pancreatitis, 
bone fractures, venous thrombotic events, drug-induced liver injuries (DILI), severe renal events 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 30 
and malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, prostate, 
and thyroid carcinoma) are monitored closely as identified and potential risks. 
The improvement in glycemic control, the reductions in weight and BP, and the tolerability and 
safety profile of sotagliflozin to date, demonstrate a favorable benefit-risk assessment for 
sotagliflozin.  
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 31 
5 
STUDY OBJECTIVES 
5.1 
PRIMARY  
The primary objective of this study is to demonstrate the superiority of sotagliflozin 400 mg 
versus placebo on HbA1c reduction at Week 26 in patients with T2D who have inadequate 
glycemic control on diet and exercise. 
5.2 
SECONDARY  
• To compare sotagliflozin 400 mg versus placebo for:  
- 
Change from Baseline in 2-hour PPG following a mixed meal (MM) at Week 26 
- 
Change from Baseline in FPG at Week 26 
- 
Change from Baseline in body weight at Week 26 
- 
Change from Baseline in SBP at Week 12 for patients with baseline SBP ≥130 mmHg  
- 
Change from Baseline in SBP at Week 12 for all patients 
- 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
• To compare sotagliflozin 200 mg versus placebo for:  
- 
Change from Baseline in HbA1c at Week 26 
- 
Change from Baseline in 2-hour PPG following a mixed meal at Week 26  
- 
Change from Baseline in body weight at Week 26 
- 
Change from Baseline in SBP at Week 12 for all patients 
• To evaluate the safety of sotagliflozin 400 mg and 200 mg doses versus placebo 
5.3 
OTHER 
- 
Urine albumin-creatinine ratio (ACR) 
- 
Urinary glucose excretion (UGE) and urine glucose-creatinine ratio (GCR)  
- 
Estimated glomerular filtration rate (eGFR)  
- 
Reduction in body weight by ≥2%, ≥5%, and ≥10% 
- 
Change from Baseline in FPG at Week 26  
- 
Change from Baseline in SBP at Week 12 for patients with baseline SBP ≥130 mmHg 
- 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 32 
• To compare sotagliflozin 400 mg and 200 mg doses with placebo for change from 
Baseline in SBP at Week 26 for all patients and for patients with Baseline SBP 
≥130 mmHg 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 33 
6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This study is a Phase 3, multicenter and multinational, 1:1:1 randomized, double-blind, placebo 
controlled, parallel group study that is anticipated to enroll approximately 400 patients. This 
number includes approximately 100 patients enrolled under the original protocol study design, 
and approximately 300 patients to be enrolled under the amended, current, study design.  
The study will comprise a Screening period consisting of a Screening Phase and a single-blind 
placebo Run-in Period, a double-blind Treatment Period, and a Follow-up period.  
The study design is presented graphically at the end of the synopsis. 
6.1.1 Screening period 
6.1.1.1 Screening Phase (Visit 1) 
The Screening Phase will last up to 2 weeks. The period must be long enough to collect the data 
required to establish whether the patient satisfies the inclusion/exclusion criteria. 
Patients with T2D currently managed with diet and exercise alone are eligible for enrollment in 
this study. Patients who previously managed their T2D with a single oral antidiabetic drug (OAD) 
may be eligible for Screening if they have discontinued the OAD and been maintained on diet and 
exercise for at least 12 weeks before the screening visit.  
At the Screening Visit after signing of the informed consent form (ICF), eligibility criteria will be 
assessed and Screening assessment will be performed. Women of childbearing potential 
(WOCBP) not willing to use highly effective method(s) of birth control during the study treatment 
period and the follow-up period, or who are unwilling or unable to be tested for pregnancy will be 
excluded from the study; guidance on highly effective contraceptive methods and collection of 
pregnancy information is provided in Appendix A. If another contraceptive method is used (such 
as a barrier method), it should be used in combination with one of the highly effective methods in 
Appendix A (such as an oral contraceptive). 
The Interactive Response Technology (IRT; either Interactive Voice Response System or 
Interactive Web Response System) will be contacted at Visit 1 for notification of screening and 
for patient number allocation. 
6.1.1.2 Run-in Phase (Visit 2) 
The Run-in Phase will last 2 weeks. Patients will be treated in a single-blind manner with placebo 
(2 tablets) once daily during the Run-in Period, starting from Visit 2. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 35 
6.1.4 Follow-up period 
Following the last dose of IMP (either as scheduled or prematurely), a post treatment follow-up 
should be scheduled for all patients 4 weeks (±3 days) after permanent IMP discontinuation. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The duration of the study for each patient will include a Screening Phase of up to 2 weeks, a 
2-week Run-in Phase, and a 26-week double-blind treatment period. 
After completion of study treatment, each patient will enter a 4-week Follow-up Period. The total 
study duration for each patient will be up to 34 weeks. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is defined as being the “last patient last visit” planned with the protocol, 
including the follow-up visit. 
The Sponsor can terminate the trial prematurely based on the advice of the Independent Data 
Monitoring Committee (DMC) or other unforeseen developments. 
6.3 
INTERIM ANALYSIS 
No interim analysis is planned. 
6.4 
STUDY COMMITTEES 
6.4.1 Data monitoring committee 
A DMC with members who are independent from the Sponsor and the Investigators will meet on 
a regular basis, and will be responsible for: 
Safety data to be reviewed will be unblinded and include events and outcomes described below 
for adjudication, as well as any additional safety data considered relevant. Details describing the 
DMC processes and procedures are outlined in a separate DMC Charter. To maintain continuous 
blinding and study integrity, the analysis will be conducted by an independent statistician, and 
measures will be taken to ensure the validity of the data. 
6.4.2 Clinical endpoint committee(s) 
The Clinical Endpoint Committee(s) (CEC) is/are comprised of experts in cardiology and 
nephrology (and other appropriate medical specialties such as neurology and endocrinology, as 
needed) who are independent of the Sponsor and the contract research organization (CRO). The 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 36 
CECs will review and adjudicate all deaths, major adverse cardiovascular events 
(MACE)/selected CV events (MI, stroke, unstable angina leading to hospitalization, and heart 
failure leading to hospitalization), selected renal events, bone fracture, and DKA. 
The details regarding the CEC processes and procedures will be outlined in the CEC Charter(s). 
6.4.3 Safety adjudication of events requiring ongoing monitoring  
Two independent committees will review safety events that require ongoing monitoring to ensure 
timing protocol amendments in case a safety signal is identified. These events are: 1) potential 
cases of DILI, and 2) cases of amputations. 
The two committees will review the cases in a treatment-blinded manner and will present their 
assessment to the DMC. 
The members, roles and responsibilities of the two committees will be described in separate 
Charters. 
6.4.4 Steering Committee 
The Steering Committee (SC) is composed of experts in diabetes and scientists with clinical and 
methodological expertise. 
This Committee, led by a Chair, in collaboration with the Sponsor, is responsible for producing 
and conducting a scientifically sound study and for ensuring accurate reporting of the study. In 
that capacity, the SC must address and resolve scientific issues encountered during the study. The 
members will remain blinded until completion of the study. 
Among its responsibilities, the SC will receive blinded study status reports from Sponsor, and will 
review the recommendations from the DMC throughout the study. The SC members will 
participate in face-to-face meetings at regular intervals throughout the study and in regularly 
scheduled teleconferences. 
Detailed activities and responsibilities of the SC are provided in the SC charter. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 37 
7 
SELECTION OF PATIENTS 
Note: A patient should not be randomized more than once. In cases where original screen failure 
was due to reasons expected to change at rescreening and based upon the Investigator’s clinical 
judgment, the patient can be rescreened once prior to entering Run-in for this study.   
7.1 
INCLUSION CRITERIA 
Patients meeting all of the following inclusion criteria will be screened: 
I 01. Patients (male and female) with T2D currently treated with diet and exercise only during 
the 12 weeks prior to the screening  
I 02. Signed written informed consent 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 4 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Age <18 years at the time of Screening or < legal age of majority, whichever is greater 
E 02. Type 1 diabetes  
E 03. Body mass index (BMI) ≤20 or >45 kg/m² at Screening 
E 04. Previous use of any antidiabetic drug unless the drug has been discontinued for a period of 
at least 12 weeks before the Screening Visit 
E 05. Use of systemic glucocorticoids (excluding topical or ophthalmic application, nasal spray 
or inhaled forms) for more than 10 consecutive days within 90 days prior to the Screening 
Visit  
E 06. Use of weight loss medications within 12 weeks or weight change of 5 kg or more during 
the 12 weeks before screening 
E 07. Likelihood of requiring treatment during the study period with drugs not permitted by the 
study protocol (eg, long-term systemic glucocorticoids) and refusing or unable to take 
alternative treatment 
E 08. Patients who have previously participated in any clinical trial of sotagliflozin/LX4211 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 38 
E 09. Patients with severe anemia, severe CV (including congestive heart failure New York 
Heart Association IV), respiratory, hepatic, neurological, psychiatric, or active malignant 
tumor or other major systemic disease or patients with short life expectancy that, according 
to the Investigator, will preclude their safe participation in this study, or will make 
implementation of the protocol or interpretation of the study results difficult 
E 10. Current diagnosis of chronic hepatitis and/or other clinically active liver disease requiring 
treatment 
E 11. Known presence of factors that interfere with the Central Lab HbA1c measurement (eg, 
genetic Hb variants) compromising the reliability of HbA1c assessment, or medical 
conditions that affect interpretation of HbA1c results (eg, blood transfusion or severe blood 
loss in the last 3 months prior to randomization, any condition that shortens erythrocyte 
survival) 
E 12. History of drug or alcohol abuse within 6 months prior to screening 
E 13. Patient is an employee of the Sponsor, or is the Investigator or any Sub-investigator, 
research assistant, pharmacist, study coordinator, other staff or relative thereof directly 
involved in conducting the study 
E 14. Patient who has taken other investigational drugs or prohibited therapy for this study 
within 12 weeks or 5 half-lives, whichever is longer, prior to the screening. Current 
enrollment in any other clinical study involving an investigational study treatment or any 
other type of medical research. 
E 15. Patients unwilling or unable to perform self-monitoring of blood glucose (SMBG), 
complete the patient diary, or comply with study visits and other study procedures as 
required per protocol 
7.2.2 Exclusion criteria related to diabetes history and treatment 
E 16. HbA1c <7% or >10% measured by the central laboratory at screening 
E 17. Fasting plasma glucose >15 mmol/L (270 mg/dL) measured by the central laboratory at 
screening (Visit 1) and confirmed by a repeat test (>15 mmol/L [270 mg/dL]) before 
randomization 
E 18. Previous use of any types of insulin for >1 month (at any time, except for treatment of 
gestational diabetes) 
E 19. Previous use of any antidiabetic medication(s) for >4 months at any time 
E 20. History of DKA or nonketotic hyperosmolar coma within 12 weeks prior to the Screening 
Visit 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 39 
7.2.3 Exclusion criteria related to the current knowledge of sotagliflozin  
E 21. Pregnant (confirmed by serum pregnancy test at the screening) or breast-feeding women 
E 22. Women of childbearing potential (WOCBP) not willing to use highly effective method(s) 
of birth control during the study treatment period and the follow-up period, or who are 
unwilling or unable to be tested for pregnancy (see contraceptive guidance in Appendix 
A), during the study  
E 23. Mean of 3 separate blood pressure measurements >180 mmHg (SBP) or >100 mmHg 
(diastolic blood pressure [DBP]) 
E 24. History of hypertensive emergency within 12 weeks prior to Screening (1) 
E 25. History of gastric surgery, including gastric banding, within 3 years or inflammatory bowel 
disease 
E 26. Difficulty swallowing such that the patient cannot take the IMP 
E 27. Known allergies, hypersensitivity, or intolerance to SGLT2 inhibitor or any inactive 
component of sotagliflozin or placebo (ie, microcrystalline cellulose, croscarmellose 
sodium [disintegrant], talc, silicone dioxide, and magnesium stearate [nonbovine]), unless 
the reaction is deemed irrelevant to the study by the Investigator 
E 28. Laboratory findings with the central lab tests at Visit 1 
- 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x the upper 
limit of the normal laboratory range (ULN) 
- 
Total bilirubin >1.5 x ULN (except in case of Gilbert’s syndrome) 
- 
Neutrophils <1500/mm3 (or according to ethnic group; see Appendix E for details) 
and/or platelets <100 000/mm3 
- 
Amylase and/or lipase >3 x ULN 
E 29. Severe renal disease as defined by eGFR of <30 mL/min/1.73m² at screening by the 
4 variable Modification of Diet in Renal Disease (MDRD) equation  
E 30. Any country-related specific regulation that would prevent the patient from entering the 
study (eg, individuals committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities). 
7.2.4 Additional exclusion criteria during or at the end of the Run-in phase before 
Randomization 
E 31. Informed consent withdrawal before randomization (patient who is not willing to continue) 
or patient fails to return. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 40 
E 32. Any clinically significant abnormality identified on physical examination, laboratory tests, 
ECG or vital signs at the time of Screening or any AE during Screening period which, in 
the judgment of the Investigator or any Sub-investigator, would preclude safe completion 
of the study or constrains efficacy assessment. 
E 33. Patients insufficiently compliant during Run-in phase. Noncompliance will be based on 
tablet count (<80%) or based on the opinion of the Investigator. 
E 34. Lower extremity complications (such as skin ulcers, infection, osteomyelitis, and 
gangrene) identified during the Screening period, and still requiring treatment at 
Randomization. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 41 
8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The IMPs are sotagliflozin 400 mg, sotagliflozin 200 mg, and matching placebo. Patients will be 
provided with: 
- 
Placebo kits: 76 placebo tablets 
- 
Sotagliflozin 200 mg kits: 38 placebo tablets and 38 sotagliflozin 200 mg tablets 
- 
Sotagliflozin 400 mg kits: 76 sotagliflozin 200 mg tablets 
Table 1 provides a summary of each IMP.  
Table 1 – Summary of investigational medicinal products 
IMP: 
Sotagliflozin 200 mg 
Sotagliflozin 400 mg 
Placebo 
Name of the IMPs 
Sotagliflozin (SAR439954) 
Sotagliflozin (SAR439954) 
Placebo 
Pharmaceutical 
form 
Sotagliflozin (SAR439954) 
will be supplied as 200 mg 
tablets 
Placebo will be supplied as 
tablets (identical to 
sotagliflozin in appearance) 
Sotagliflozin (SAR439954) 
will be supplied as 200 mg 
tablets 
Placebo will be supplied as 
tablets (identical to 
sotagliflozin in appearance)  
Dose, timing and 
route of 
administration 
One sotagliflozin 200 mg 
tablet, and one placebo 
tablet, taken orally once daily, 
before first meal of the daya 
Two sotagliflozin 200 mg 
tablets, taken orally once 
daily, before first meal of the 
daya 
Two placebo tablets, taken 
orally once daily, before first 
meal of the daya 
Duration of 
treatment 
26 weeks following 
randomization. 
26 weeks following 
randomization. 
26 weeks following 
randomization. 
Storage conditions  
Store between +15°C and 
+30°C (59°F and 86°F) 
Store between +15°C and 
+30°C (59°F and 86°F) 
Store between +15°C and 
+30°C (59°F and 86°F) 
a On study visit days occurring on Day 1 (Visit 3) and Week 26 (Visit 9), IMP should be administered according to the 
schedule outlined in Appendix B. 
IMP: Investigational medicinal product 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
Non-IMP treatment is defined as the rescue medication(s) that will be used to treat hyperglycemia 
when a patient’s hyperglycemia reaches the rescue threshold (see Section 8.2.1 for details).  
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 42 
8.2.1 Rescue therapy 
The threshold values are defined as follows, depending on study period: 
Routine fasting SMBG (see Section 9.2.1.6) and central laboratory alerts on FPG are set up to 
ensure that glycemic parameter results remain under predefined thresholds.  
• To compare sotagliflozin 400 mg and 200 mg doses versus placebo with respect to change 
from Baseline for the following endpoints: 
• To compare sotagliflozin 200 mg versus placebo for:  
• To compare sotagliflozin 400 mg and 200 mg doses with placebo in the use of rescue 
medications for hyperglycemia  
• To assess plasma concentrations of sotagliflozin and its 3-O-glucuronide metabolite in 
each sotagliflozin treatment group 
• HbA1c at Screening (≤8%, >8%) 
• SBP at Screening (<130 mmHg, ≥130 mmHg)  
• Sotagliflozin 400 mg as two 200 mg tablets, once daily  
• Placebo as two placebo tablets (identical to sotagliflozin in appearance), once daily 
• Review of accumulating clinical study safety data by treatment 
• Making a recommendation to the Sponsor regarding the study following each meeting 
• Run in kit containing 1 wallet of 34 placebo tablets for the Run-in phase 
• Treatment kit containing 2 wallets of 38 tablets each will be dispensed as needed for the 
duration of the treatment period: 
• FPG >270 mg/dL (15.0 mmol/L) from Randomization up through the scheduled Week 8 
visit 
• FPG >240 mg/dL (13.3 mmol/L) after the Week 8 visit up through the scheduled Week 12 
visit 
• FPG >200 mg/dL (11.1 mmol/L) after the Week 12 visit through the end of the 26-week 
Treatment Period  
• If one fasting SMBG value exceeds the specific glycemic limit on one day, the patient 
checks it again during the two following days. If all the values in three consecutive days 
exceed the specific limit, the patient should contact the Investigator and a central 
laboratory FPG measurement be performed as soon as possible, preferably within 7 days, 
to confirm the hyperglycemia.  
• Upon receipt of a central laboratory rescue alert, a central laboratory re-test must be 
completed and confirmed as exceeding the threshold for rescue before rescue therapy is 
initiated. The re-test confirmation should be performed as soon as possible, but within 
7 days of receipt, by unscheduled visit.  
• The increased FPG has been tested at a fasting status (ie, no food intake for ≥8 hours) 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 43 
• Investigational medicinal product is given at the planned dose 
• There is no intercurrent disease, which may jeopardize glycemic control (eg, infectious 
disease) 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
• Assess plasma glucose in fasting condition (ie, after at least 8 hours fast) 
• Initiate an evaluation and treatment of intercurrent disease (to be reported in 
AE/concomitant medication parts of the e-CRF and the medical record) 
• Stress the absolute need to be compliant with treatment 
• Organize a specific interview with the patient and a Registered Dietician or other qualified 
nutrition professional to reinforce the absolute need to be compliant with diet and lifestyle 
recommendations, and schedule a FPG assessment at the next visit. 
In the event that a confirmatory FPG exceeds the threshold, the Investigator should ensure that no 
reasonable explanation exists for insufficient glucose control and in particular that: 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider not initiating rescue medication and should undertake appropriate action, ie: 
If none of the above mentioned reasons can be found, or if appropriate action fails to decrease 
FPG under the threshold values, rescue medication may be introduced. 
Initiation of open-label rescue medication(s) to treat hyperglycemia will be at the discretion of the 
Investigator and in accordance with local standard of care and prescribing practice; except for 
SGLT2 inhibitors, any approved medication(s) including oral antidiabetic drugs or insulin can be 
prescribed to treat the hyperglycemia. The patient continues the study treatment (blinded) and 
stays in the study in order to collect efficacy and safety information. The planned visits and 
assessments should occur until the last scheduled visit. For patients with renal impairment, 
contraindications to antihyperglycemic drugs should be taken into consideration. If a patient 
requires glycemic rescue, the IMP received during the randomized, double-blind Treatment 
Period should continue and must remain blinded until the end of the study. 
Rescue therapy is considered a noninvestigational medicinal product (NIMP). Rescue therapy is 
to be reported in the e-CRF. This information should include specific drug name, dose, route of 
administration, and frequency. 
If not covered by health insurance, the cost of the rescue therapy will be reimbursed by the 
Sponsor where permitted by local regulations. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 44 
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
To maintain blinding sotagliflozin and placebo tablets and packaging will be blinded and 
indistinguishable. 
During the double-blind Treatment Period each treatment package will be labeled with a number, 
which is generated by a computer program from Sanofi. Investigators will not have access to the 
randomization (treatment) code except under circumstances described in Section 8.3.2. 
The randomization and the treatment allocation will be performed centrally by an IRT. The study 
biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the patient 
randomization list from which it allocates treatment arms to the patients. 
Fasting glucose (plasma or serum), HbA1c, and PPG will be masked to study sites and patients 
after randomization and until study end. To prevent partial unblinding, UGE and GCR results will 
be masked to study sites and patients, and the central laboratory urine dipstick will not include the 
measurement of urine glucose. 
The CEC members will perform adjudication in a blinded manner. 
8.3.2 Randomization code breaking during the study 
In case of an AE, the randomization code should only be broken in circumstances when 
knowledge of the IMP is required for treating the patient.  
Code breaking can be performed at any time by using the proper module of the IRT and/or by 
calling any other phone number provided by the Sponsor for that purpose. Code breaking can be 
performed by a local study Investigator, sponsor physician or healthcare professional with direct 
responsibility for patient care. If the blind is broken, the Investigator should document the date, 
time of day, and reason for code breaking. The identity of the unblinded personnel, how the code 
was broken, and the treatment kit number should also be recorded. The Sponsor should also be 
informed. If the code is broken by the Investigator (or other medical doctor in an emergency 
situation), the patient must be withdrawn from IMP administration.  
Randomization code breaking will also be performed during the analysis of the Pharmacokinetic 
plasma concentration samples. Only the Project manager and lead scientist at the Bioanalytical 
laboratory will have access to the randomization code to allow for the sorting of the sotagliflozin 
plasma samples. The Bioanalytical lab and responsible personnel will follow the standard 
procedures to ensure the protection of the blind within the Sponsor’s clinical team. The 
randomization code or the individual analytical results will not be disclosed to any clinical team 
personnel prior to the database lock. 
Refer to Section 10.5 for suspected unexpected serious adverse drug reaction unblinding by the 
Sponsor. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 46 
Treatment labels will indicate the treatment number (used for treatment allocation and reported in 
the e-CRF). 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures. 
Control of IMP storage conditions, especially control of temperature and instructions for handling 
the Sanofi compound should be managed according to the rules provided by the Sponsor. 
The expiry date and storage conditions are written on the IMP labels. The IMP should be stored 
between 15°C and 30°C (59°F and 86°F) 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMPs will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor or Delegate. 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 or Delegate, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for 
direct-to-patient shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in any 
other manner. 
8.7.1 Treatment accountability and compliance 
Accounting and compliance for IMPs will be performed at Visit 3 and all subsequent visits.  
The Investigator will check the compliance to the study treatments based on the patient diary and 
will then complete the appropriate Site treatment and patient treatment log forms. Returned IMP 
should be counted by site staff. In addition the dosing information will be recorded on the 
appropriate pages of the e-CRF. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 47 
If compliance is inadequate as determined by the Principal Investigator (PI), patients will be 
trained again and mentored. If suboptimal compliance continues after training and mentoring, 
patients may be discontinued at the discretion of the PI after discussion with the Sponsor’s 
medical monitor.  
8.7.2 Return and/or destruction of treatments 
Patients are to return all IMP (unused, in-use or used wallet[s]) at each on-site visit (see 
Section 1.2).  
At Visit 4 (Week 1), because no IMP re-supply is planned during this visit, patients will be sent 
home after this visit with the in-use wallet(s) dispensed at randomization. 
Patients are to return all the used, in-use and unused IMP at Visit 9 (or final assessment 
on-treatment visit in case of permanent premature discontinuation).  
All used, partially-used or unused IMPs will be retrieved by the Sponsor or Delegate. A detailed 
site and patient treatment log of the returned IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
The IMP includes placebo, sotagliflozin 400 mg and sotagliflozin 200 mg. 
All concomitant medications should be documented on the Medications page of the e-CRF. This 
includes all non–IMP treatments that are taken by the patients at any time during the clinical 
study, beginning at Visit 1. 
Additionally, all medications taken in the 3 months prior to Visit 1 and prior use of SGLT2 
inhibitors should be reported.  
8.8.1 Prohibited prior and concomitant medications 
During the study treatment period, the following medications are prohibited: 
• Initiation of any antidiabetic agents, including oral or injectable antihyperglycemic agents 
other than the IMP is not allowed before the rescue therapy 
• Systemic use of glucocorticoids is not allowed for more than 10 consecutive days (topical, 
ophthalmic, nasal spray or inhaled applications are allowed) 
• Initiation of any weight loss drugs (eg, phentermine, orlistat)  
• Investigational medicinal products in any other clinical study 
• SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin) are not allowed for 
rescue 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 48 
Note: short term use (< 10 consecutive days) of the prohibited medication, eg, short-acting insulin 
for treatment of acute illness or surgery is allowed. 
Reduction of digoxin dose should be considered because sotagliflozin acts as a weak P-gp 
inhibitor and increases systemic exposure to digoxin. Patients taking sotagliflozin with 
concomitant digoxin should have digoxin concentrations monitored and doses reduced as needed. 
In addition, other P-gp substrates may be affected and the labels of P-gp substrate drugs should be 
consulted with regards to monitoring and dose adjustments. 
Other medications which are unlikely to interfere with the PK or PD of the IMP or confound 
interpretation of the study endpoints are allowed as needed and following discussion between the 
Investigator and the Sponsor. However, doses of chronically administered medicines should be 
kept fixed during the trial if at all possible. 
After premature permanent discontinuation of the IMPs, any treatments (other than SGLT2 
inhibitors) are permitted, as deemed necessary by the Investigator. 
The dose of all antihypertensive agents should be kept constant during the 12 weeks following 
randomization and no antihypertensive agents should be added or withdrawn for the 12 weeks 
following randomization unless it is considered necessary for safety reasons. 
8.8.2 Concomitant diabetes therapy 
Non-IMP treatment is defined as the rescue medication(s) that will be used to treat hyperglycemia 
when a patient’s hyperglycemia reaches the rescue threshold. Except for SGLT2 inhibitors, any 
approved medication(s) including oral antidiabetic drugs or insulin can be prescribed at the 
Investigator’s discretion to treat the hyperglycemia. The regimen of the rescue medications will be 
in accordance with local standard of care and prescribing practice. 
8.9 
POSTSTUDY TREATMENT 
Because sotagliflozin may reduce BP, adjustment of antihypertensive medication may be needed 
during the study in patients with hypertension. Conversely, monitoring for an increase in BP 
should be performed after withdrawal of study medication. If the BP is elevated after withdrawal 
of study treatment, the Investigator should consider adding or adjusting antihypertensive 
medication. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 49 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
EFFICACY ENDPOINTS 
The methods of assessment of efficacy endpoints are detailed in Section 9.1.4. 
9.1.1 Primary efficacy endpoint 
• Comparison of sotagliflozin 400 mg versus placebo in change from Baseline to Week 26 
in HbA1c (%).  
9.1.2 Secondary efficacy endpoints 
The continuous secondary efficacy endpoints are: 
• Comparison of sotagliflozin 400 mg versus placebo for:  
- 
Change from Baseline to Week 26 in 2-hour PPG following a MM 
- 
Change from Baseline to Week 26 in FPG 
- 
Change from Baseline to Week 26 in body weight 
- 
Change from Baseline to Week 12 in SBP for patients with baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all patients 
- 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
• Comparison of sotagliflozin 200 mg versus placebo for:  
- 
Change from Baseline to Week 26 in HbA1c 
- 
Change from Baseline to Week 26 in 2-hour PPG following an MM 
- 
Change from Baseline to Week 26 in body weight 
- 
Change from Baseline to Week 12 in SBP for all patients 
9.1.3 Other efficacy endpoints 
Comparison of sotagliflozin 400 mg and 200 mg doses versus placebo for: 
• Change from Baseline to Week 12 in SBP for patients with baseline SBP <130 mmHg 
• Changes from Baseline to Week 12 in DBP 
• Proportion of patients achieving SBP <130 mmHg for those with Baseline 
SBP ≥130 mmHg 
• Proportion of patients achieving DBP <80 mmHg for those with Baseline DBP ≥80 mmHg 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 50 
• Change from Baseline in: 
- 
Urine ACR, UGE, and urine GCR 
- 
Serum creatinine 
- 
eGFR 
• Proportion of patients with reduction in body weight by ≥2%, ≥5%, and ≥10% from 
Baseline  
• Change from Baseline to Week 26 in SBP for all patients and for patients with Baseline 
SBP ≥130 mmHg 
• Proportion of patients requiring rescue for hyperglycemia 
Comparison of sotagliflozin 200 mg versus placebo for: 
• Change from baseline in FPG at Week 26 
• Change from baseline in SBP at Week 12 for patients with Baseline SBP ≥130 mmHg 
• Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
9.1.4 Assessment methods of efficacy endpoints 
9.1.4.1 HbA1c 
Hemoglobin A1c will be assessed at Screening (Visit 1), Baseline (Visit 3), and all on-site visits 
during the double-blind treatment period with the exception of Week 1 (Visit 4). 
For the eligibility and efficacy assessments of the study, HbA1c is measured by a certified level I 
“National Glycohemoglobin Standardization Program” central laboratory to allow estimation of 
the change from Baseline to Week 26 in HbA1c and the proportion of patients with HbA1c 
<6.5%, <7.0% at Week 26. 
If a patient needs to receive rescue antidiabetic medication, assessment of HbA1c should be 
performed before the introduction of the rescue medication. 
9.1.4.2 Postprandial glucose and mixed meal tolerance test 
Patients will undergo assessment of PPG at Visit 3 (Baseline) and Visit 9 (Week 26) via a mixed 
meal tolerance test (MMTT) to allow estimation of change from Baseline to Week 26 in 2-hour 
PPG following a MM. Full details of the MMTT procedure at Baseline and Week 26 are 
presented in Appendix B. 
At Visit 3 (Baseline) and Visit 9 (Week 26), PPG values will be assessed by MMTT at baseline 
(fasting) and 2 hours after consuming a standard mixed liquid breakfast meal. 
The first dose of double-blind IMP on Day 1 (Baseline; Visit 3) will be given after completion of 
the 2-hour PPG collection. For the Week 26 standardized MM, the patient should take the dose of 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 51 
double-blind IMP immediately after the fasting blood samples are obtained, and approximately 
30 minutes before ingestion of the standardized MM begins. 
Plasma concentration samples at Week 26 should be taken at the same times as the fasting blood 
sample and the 2-hour central laboratory plasma PPG collection (see Section 9.3.1.1). 
The composition and the quantity of the standard mixed liquid breakfast meal must be identical 
throughout the study; see Appendix B for further details.  
All patients should undergo the standardized MMTT at Visit 9 (Week 26), including those 
rescued before Visit 9. 
In case of permanent discontinuation of the treatment with IMP before Visit 9 (Week 26), every 
effort will be made to have the patient return to the site at the time of their Visit 9 (Week 26); 
however the MMTT should not be performed at this or any other visit following a Premature EOT 
visit. 
On the days of the MMTT, patients will come to the investigational site in the morning, in fasting 
conditions for at least 8 hours and must not eat any food or drink, except water, before the 
scheduled standardized meal test.  
The exact times of the IMP administration, standard mixed liquid breakfast meal intake, and the 
blood draws are to be documented. 
9.1.4.3 Fasting plasma glucose measurement 
Plasma glucose is measured in the fasting state at Screening (Visit 1) and all on-site visits during 
the treatment period. For the eligibility and efficacy assessments of the study, FPG is measured at 
a central laboratory to allow estimation of change from Baseline to Week 26 in FPG. 
9.1.4.4 Body weight measurement 
Body weight is measured at all on-site visits to allow the estimation of change from Baseline to 
Week 26 in body weight and reduction in body weight by ≥2%, ≥5%, and ≥10% from Baseline. 
Body weight should be obtained with the patient wearing undergarments or very light clothing 
and no shoes, and with an empty bladder. The same scale should be used throughout the study, 
and calibrated on a regular basis as recommended by the manufacturer. 
The same scale should be used throughout the study, and calibrated on a regular basis as 
recommended by the manufacturer. Calibration should be documented in source documents. The 
use of balance scales is recommended. The floor surface on which the scale rests must be hard and 
should not be carpeted or covered with other soft material. The scale should be balanced with both 
weights at zero and the balance bar aligned. The patient should stand in the center of the platform 
as standing off-center may affect measurement. The weights are moved until the beam balances 
(the arrows are aligned). The weight is read and recorded in the e-CRF and Source Data. Self-
reported weights are not acceptable; patients must not read the scales themselves. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 52 
9.1.4.5 Blood pressure measurements 
Systolic BP and DBP will be assessed at all on-site visits. Blood pressure measurements must be 
taken as described in Section 9.2.1.4 with details provided in Appendix D. 
9.1.4.6 Kidney function parameter measurement 
Urine albumin, creatinine and glucose, and serum creatinine are assessed at Baseline (Visit 3) and 
all subsequent on-site visits. A central laboratory will analyze samples and estimate change from 
Baseline in urine ACR, UGE, urine GCR, serum creatinine and eGFR (by the 4 variable MDRD 
equation). To prevent partial unblinding, UGE and GCR results will be masked to investigational 
sites. 
9.1.4.7 Proportion of patients requiring rescue for hyperglycemia 
The use of rescue medications for hyperglycemia will be assessed and reported throughout the 
treatment period. Routine alerts on FPG will be sent to the Investigator from the central laboratory 
to ensure that glycemic parameter results remain within predefined thresholds. For details and 
further actions should FPG values fall above thresholds, refer to Section 8.2.1. 
9.2 
SAFETY ENDPOINTS 
Assessments for safety include AEs, SMBG, clinical laboratory assessments, physical 
examination, electrocardiogram (ECG), weight, and vital signs. An independent DMC will meet 
on a regular basis to review accumulating clinical trial safety data. 
Adjudication of all deaths, MACE/other selected CV events (MI, stroke, unstable angina leading 
to hospitalization, and heart failure leading to hospitalization), selected renal events, bone 
fracture, and DKA will be performed in a blinded manner by a CEC(s) comprised of experts. 
Details will be provided in the charter of the CEC(s). Further details are available in Section 6.4.2. 
Two expert committees will review all potential cases of DILIs and cases of amputation in a 
treatment-blinded manner to evaluate causality. 
The following safety endpoints will be assessed: 
• Adverse events, AEs leading to discontinuation from the IMP, adverse events of special 
interest (AESIs), Events of Special Interest (EOSIs), SAEs and deaths 
• Hypoglycemia (all, severe, and/or documented symptomatic hypoglycemia) 
• Clinical laboratory results (including fasting lipids; see Section 9.2.1.3), vital signs and 
ECG results 
• Markers of bone and calcium metabolism  
• Markers of intestinal transit and absorption 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 53 
Observation period of safety endpoints 
The observation period of safety data will be divided into 3 segments: 
• The pre-treatment period is defined as the time between the date of the informed consent 
and the first dose of double-blind IMP.  
• The on-treatment period (TEAE period) is defined as the time from the first dose of 
double-blind IMP up to 10 days (1 day for hypoglycemia) after the last dose of 
double-blind IMP, regardless of the introduction of rescue therapy. The 10-day interval is 
chosen based on the half-life of the IMP (approximately 5 times the half-life of 
sotagliflozin) in patients with moderate renal dysfunction.  
• The post-treatment period is defined as the time starting 11 days after the last dose of 
double-blind IMP (after the on-treatment period).  
The baseline value for safety endpoints in the safety population is the last available value (or the 
average of all values for creatinine or eGFR) prior to the first administration of the double-blind 
IMP. 
9.2.1 Assessment methods of safety endpoints 
9.2.1.1 Adverse events 
Adverse events including SAE, AESI and EOSI will be assessed. Refer to Section 10.4 to 
Section 10.6 for details. 
9.2.1.1.1 Adverse Events of Special Interest 
Adverse Events of Special Interest are listed in Section 10.4.1.3, reporting requirements for AESI 
are presented in Section 10.4.4. 
9.2.1.1.2 Events of Special Interest 
Events of Special Interest are separate from AESIs. For a list of events defined as EOSIs and their 
reporting requirements see Section 10.4.1.4 and Section 10.4.5, respectively. 
9.2.1.2 Hypoglycemia 
Hypoglycemia will be assessed from Visit 2 onwards and continue until 4 weeks after the last 
dose of IMP (note: for patients who discontinue treatment before Week 26, safety data will be 
collected until scheduled study end). Patients will also complete the hypoglycemia log (as part of 
the patient diary) from Visit 2 onwards, which will be regularly reviewed by Investigators. See 
Section 10.6.1 for further details. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 54 
9.2.1.3 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry, 
amylase, lipase, lipid profile) and urinalysis, according to the schedule presented in Section 1.2. 
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. Table 2 lists the hematology, clinical 
chemistry and other blood safety parameters to be assessed by the central laboratory. 
Alerts to the Investigator are set up for specific laboratory abnormalities. Investigators should 
review these alerts and follow-up if needed as per his/her medical judgement. Re-tests at central 
laboratory are acceptable if needed.  
In addition, for WOCBP a serum pregnancy test is performed at Screening and urine pregnancy 
tests are taken at all on-site visits during the double-blind Treatment Period excluding Visit 4 
(Week 1). Any positive urine test results must be confirmed by a serum pregnancy test. The 
Investigator may perform additional tests at their discretion or as required by local regulations. 
For women of nonreproductive potential (Appendix A), follicle-stimulating hormone (FSH) 
and/or estradiol levels should be tested if the definition of postmenopausal or premenopausal 
cannot be satisfied, eg, no medical document of hysterectomy or cessation of menses <12 months 
without an alternative medical cause. 
Table 2 – Serum chemistry parameters 
Clinical chemistry 
Hematology 
Other blood parameters 
Sodium 
Complete blood count (CBC) 
Lipid profile 
Potassium 
Differential 
Total cholesterol (TC) 
Chloride 
Platelet count 
High-density lipoprotein cholesterol (HDL-C) 
Carbon dioxide (bicarbonate) 
Hemoglobin 
Low-density lipoprotein cholesterol (LDL-C) will 
be calculated by Friedwald equation 
Blood urea nitrogen (BUN) 
Hematocrit 
Non-HDLC will be calculated as the difference 
between TC and HDLC 
Creatinine (eGFR will be calculated) 
 
Triglycerides (TG) 
Glucose (serum) 
 
Blood Markers of Intestinal Transit and 
Absorptiona 
Alanine aminotransferase (ALT) 
 
Vitamins: B6, B12, K, E, A 
Aspartate aminotransferase (AST) 
 
Serum folate 
Total bilirubin (TB) 
 
Ferritin 
Alkaline phosphatase (ALP) 
 
Markers of bone and calcium metabolismb 
Uric acid 
 
Calcium 
Calcium 
 
25-hydroxyvitamin D 
Phosphorus 
 
1,25-dihydroxyvitamin D 
Total protein 
 
Phosphorus 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 55 
Clinical chemistry 
Hematology 
Other blood parameters 
Albumin 
 
Parathyroid hormone (PTH) 
Magnesium 
 
Markers of bone resorption: N-terminal telopeptide 
(NTX), beta-C-terminal telopeptide (β-CTX-1) 
Creatine phosphokinase (CPK) 
 
Marker of bone formation: type 1 procollagen 
N-terminal (P1NP) 
Lactic acid dehydrogenase (LDH)  
 
 
Amylase 
 
 
Lipase 
 
 
All assessments to be performed by central laboratory. 
All assessment measured in serum. 
a To be collected at Baseline (Visit 3), Week 26 (Visit 9), and Follow-up Visit (Visit 10). 
b To be collected at Baseline (Visit 3) and Week 26 (Visit 9). Urine markers of bone and calcium metabolism are listed in Section 9.2.1.3.1. 
9.2.1.3.1 Urinalysis 
Urinalysis (urine dipstick with microscopy) by central laboratory will be performed at Screening 
(Visit 1), Baseline (Visit 3) and Week 26 (Visit 9). To prevent partial unblinding, UGE results 
will be blinded to investigational sites and patients, and the central laboratory urine dipstick will 
not include the measurement of urine glucose. Central urinalysis includes: 
• Urine dipstick includes: specific gravity, pH, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, and leukocyte esterase 
• Urine microscopy includes, but is not limited to: detection of formed cellular elements, 
casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment 
In the event of abnormal urinalysis findings suspicious of urinary tract infection, urine culture 
should be performed. Positive urine culture determination will be based upon the criteria of the 
reporting laboratory. 
If the urine dipstick is positive for blood, the central laboratory will perform reflexive testing to 
include microscopy. Additional testing will be performed according to the judgment of the 
Investigator. Referral to urology/urologic evaluation is recommended for new or unexplained 
cases of confirmed hematuria (urology/urologic evaluation is not required where hematuria is 
considered to be related to diabetic nephropathy). 
In addition, urine albumin, calcium, glucose and creatinine will be assessed at Baseline (Visit 3) 
and all subsequent on-site visits. 
Urine markers of bone and calcium metabolism will be assessed at Baseline (Visit 3), and 
Week 26 (Visit 9), and include: calcium and phosphorus. Serum markers of bone and calcium 
metabolism are listed in Table 2. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 56 
9.2.1.4 Vital signs and physical exam 
A complete physical exam (including sitting blood pressure and heart rate, temperature and 
respiratory rate) will be performed at Visit 1 (Screening) and Visit 9 (Week 26); abbreviated 
physical exams (including sitting blood pressure and heart rate) will be performed at all other 
on-site visits. The abbreviated physical exam should focus on cardiac and respiratory systems, as 
well as any areas important for assessment of AEs if necessary. Three separate seated BP and 
heart rate measurements should be taken with at least 1 minute between measurements following 
a 5-minute rest period, and prior to phlebotomy. Full details and directions for the measurement of 
blood pressure are presented in Appendix D.  
9.2.1.5 Electrocardiogram variables 
The ECG assessment of “normal” or “abnormal” will be analyzed. 
A 12-lead ECG record is performed locally at Screening (Visit 1), Baseline (Visit 3) and Week 26 
(Visit 9). 
The 12-lead ECG should be performed after at least 10 minutes in supine position and prior to the 
morning IMP administration. The Investigator should review the ECG and document the 
interpretation, sign and date it on the ECG print out and report it in the e-CRF. Each ECG trace is 
analyzed in comparison with the screening recorded trace. All original traces are kept as source 
data. 
Note: Any new ECG abnormality should be rechecked for confirmation and reported as 
appropriate for that finding. 
9.2.1.6 Self-monitoring of blood glucose 
A meter for self-assessment of blood glucose will be dispensed at the Run-in visit (Visit 2). In 
addition to home measurements of self-monitored blood glucose, self-monitoring of blood glucose 
will be performed at Run-in (Visit 2) and all subsequent on-site visits. Glucose meters used for 
SMBG display results as plasma glucose concentration. 
Patients will also receive a patient diary at all on-site visits from Visit 1 to Visit 9. The diary will 
be reviewed at all on-site visits from Visit 2 to Visit 10. Self-assessed blood glucose levels will be 
entered in the patient diary. 
Patients will be asked to self-assess blood glucose levels at least 3 times a week from the run-in 
Visit (Visit 2) to Week 26. 
Patients will be requested to self-assess blood glucose levels in the fasted state and whenever they 
experience any illnesses (eg, cold, flu), or symptoms of hyperglycemia or hypoglycemia. 
Symptoms of hypoglycemia may include shakiness, dizziness, sweating, hunger, headache, pale 
skin color, sudden moodiness or behavior changes (such as crying for no apparent reason), clumsy 
or jerky movements, seizure, difficulty paying attention or confusion, or tingling sensations 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 57 
around the mouth. Patients will be instructed to record the presence of absence of hypoglycemic 
episodes or hypoglycemic symptoms in the patient diary provided. 
Patients will also be instructed to record SMBG values that are ≤70 mg/dL (≤3.9 mmol/L) in the 
patient diary. Patients should be instructed to contact the site if fasting SMBG values over 
3 consecutive days are:  
• >270 mg/dL (15.0 mmol/L) from Randomization up through the scheduled Week 8 visit 
• >240 mg/dL (13.3 mmol/L) after the Week 8 visit up through the scheduled Week 12 visit  
• >200 mg/dL (11.1 mmol/L) after the Week 12 visit and through the end of the 26-week 
double-blind Treatment Period 
9.2.1.7 Diabetic ketoacidosis 
Patients will be provided with instructions on how to recognize the symptoms of DKA and 
instructed to contact the site (or seek emergency medical services if after business hours) if these 
symptoms develop. Patients should have a full clinical evaluation with laboratory testing for 
possible DKA by the Investigator or emergency medical services physician. If such evaluation 
and laboratory testing confirm the presence of metabolic acidosis, then appropriate treatment 
should be implemented and the “Possible DKA” e-CRF should be completed. See Appendix C for 
further details. 
9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacokinetics 
The PK endpoint is: 
• Plasma concentrations of sotagliflozin and its metabolite pre-dose at Weeks 4, 18 and 
26 and 2 hours 30 minutes post-dose at Week 26 
9.3.1.1 Sampling time 
At Weeks 4 and 18 (Visits 5 and 8, respectively), blood samples for PK assessment are to be 
drawn with the other laboratory assessments. At Week 26, PK samples should be drawn at 
pre-dose and at 2 hours 30 minutes postdose, immediately after the respective glucose 
assessments during the MMTT. Pharmacokinetic samples (with the exception of the 2 hours 
30 minute sample during the Week 26 MMTT) must be collected before administration of IMP. 
See Table 3 for the identification of samples.  
Table 3 – Samples identification  
Visit 
Week 
Relative to dosing 
PK 
Visit 5 
Week 4 
Pre-dose 
P00 
Visit 8 
Week 18 
Pre-dose 
P01 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 60 
Improvements in FPG and PPG have been observed with sotagliflozin in multiple studies. 
Therefore assessment of both fasting and post-prandial glucose (after a MM) is relevant in this 
study. These 2 parameters are also considered by regulatory agencies to be supportive of efficacy 
of an antidiabetic agent. 
Phase 2 data indicated that sotagliflozin may reduce SBP by 10 to 15 mmHg in patients with 
SBP ≥130 mmHg at baseline, while having no significant effect in patients with SBP 
<130 mmHg, and did not induce hypotension. Since this could be of benefit to patients with T2D, 
this finding is being followed up as a secondary objective in this trial, as well as the potential in 
patients with DBP >80 mmHg. Although effects on BP in Phase 2 data were observed with the 
400 mg dose at 12 weeks, the effects will be examined at Weeks 12 and 26. 
Endpoints for evaluating renal function include eGFR, based on serum creatinine, and urine 
albumin to creatinine ratio as well as routine monitoring of urine via dipstick and microscopy. 
UGE and urine GCR are other valid markers of renal function, and will be assessed at appropriate 
time points in this study. 
Due to potential effects on bone and calcium metabolism, specific biomarkers for bone and 
calcium metabolism will be assessed at regular time points. In view of the SGLT1 inhibitory 
effects in the GI tract, specific markers of intestinal transit and absorption will also be measured. 
The other efficacy and safety assessments in this study are standard, well-established 
measurements for a Phase 3 study evaluating the treatment of T2D in adult participants.  
The length of the study is considered appropriate for detection of the primary endpoint given the 
power estimates (see Section 11). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 61 
10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The visit schedule and procedures/assessments are listed in the “Study Flow Chart” (Section 1.2). 
The aim of this section is to provide details on how some of the procedures/assessments should be 
performed. 
This is an out-patient study and consists of 10 on-site visits, although optional on-site and/or 
telephone visits can be scheduled at any time for any reason during the study whenever 
considered necessary by the Investigator. 
The patients need to be fasting for on-site visits V1 through V9 (Week -4 through Week 26), 
unless instructed otherwise by the Investigator. Throughout the study, “fasting” is defined as 
8 hours without food. Note: If the patient is not fasting at the visits specified above, the blood 
sample will not be collected and a new appointment should be given to the patient for the 
following day if possible, with instruction to be fasted.   
The Run-in visit can be performed as soon as the results of all screening tests are available and the 
patient is confirmed to be eligible for participation in the study. The visit window for visits V4 
through V10 should occur within ±3 days. If one visit date is changed, the next visit should occur 
according to the original schedule, ie calculated from the date of Baseline visit (Visit 3, Week 0). 
For a complete list of procedures scheduled for each study visit please refer to the Study Flow 
Chart (Section 1.2), which details the procedures to be performed.  
All data obtained during the trial visits will be reviewed by the Investigator and sub-investigators 
who are qualified in treatment of T2D and are trained on the study. 
10.1.1 Screening Period 
The Screening period is up to 4 weeks and includes the Screening Phase and the Run-in Phase. 
10.1.1.1 Screening Phase 
The duration of the Screening Phase is up to 2 weeks and includes only the Screening Visit 1 
(Week -4). The period must be long enough to collect the data to establish whether the patient 
satisfies the inclusion/exclusion criteria. 
Patients will undergo screening assessments at Visit 1 (Week -4) following signing of the ICF. 
Patients who meet the inclusion criteria as noted in Section 7.1 and have no exclusion criteria as 
noted in Section 7.2 will be randomized at Visit 3 (Day 1). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 63 
• The following laboratory testing (by the central laboratory) 
- 
Fasting plasma glucose 
- 
HbA1c 
- 
Serum pregnancy testing for WOCBP 
- 
Serum FSH and estradiol (for women of nonreproductive potential if definition of 
postmenopausal or premenopausal cannot be satisfied; see Appendix A). 
- 
Hematology 
- 
Clinical chemistry to include amylase and lipase 
- 
Fasting lipids 
- 
Urinalysis (dipstick and microscopy) 
• Patients are instructed to return to the site for Visit 2 (Week -2) in a fasted state.  
10.1.1.2 Run-in Phase (Visit 2, Week -2) 
The Run-in Phase is 2 weeks and includes Visit 2 (Week -2). 
10.1.1.2.1 On-site Visit 2 (Run-in, Week -2) 
The following procedures/assessments will be performed at Visit 2 (Week -2): 
• Measurement of body weight 
• Abbreviated physical examination including vital signs performed after the patient has 
been seated for at least 5 minutes (SBP and DBP, and heart rate). Systolic and diastolic BP 
and heart rate will be assessed 3 times with at least 1 minute between each measurement 
(see Appendix D for details)  
• Diet and exercise instruction 
• Instruction on basic GU hygiene and hydration (See Appendix C) 
• IRT to be notified 
• Patient diary is collected/reviewed. A new diary, including hypoglycemia log (as part of 
the diary), is dispensed and instructions/training are provided 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported, including those occurring 
since Visit 1 
• Run-in kit/placebo is dispensed 
• Blood glucose meter is dispensed and instructions/training is provided  
• Concomitant medication 
• Fasting SMBG is assessed 
• Patients are instructed to return to the site in the fasting state for Visit 3 (Randomization) 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 64 
10.1.2 Double-blind randomized treatment period 
10.1.2.1 Treatment Period (Day 1 to Week 26) 
Upon successful completion of the Run-in Phase, patients will be randomly allocated to either 
sotagliflozin 400 mg, sotagliflozin 200 mg, or placebo for the double-blind treatment period 
lasting 26 weeks. All randomized patients will be followed at regular on-site visits for the duration 
of the treatment period. 
In addition to routine laboratory testing, the following will be performed at specified time points: 
plasma concentrations; markers of intestinal transit and absorption; markers of bone and calcium 
metabolism; urine albumin, calcium, glucose and creatinine.  
The date and time of the last intake of IMP prior to visits where PK samples are taken should be 
recorded by the patient in the patient diary. Patients should be reminded of this at visits preceding 
PK time points to ensure these details are captured. 
In the event of abnormal urinalysis findings suspicious of urinary tract infection, urine culture 
should be performed. Positive urine culture determination will be based upon the criteria of the 
reporting laboratory. 
In addition, PPG will be assessed at Baseline and 2 hours after consuming a standard mixed liquid 
breakfast meal vial a MMTT on Day 1 and at Week 26. On Day 1 the first dose of double-blind 
IMP will be given AFTER completion of the 2-hour PPG collection. For the Week 26 
standardized MM, the patient should take the dose of double-blind IMP immediately after the 
fasting blood samples are obtained, and approximately 30 minutes before ingestion of the 
standardized MM begins. 
10.1.2.1.1 Randomization Visit on Day 1 (Baseline; Week 0; Visit 3) 
The following procedures will be performed at this visit: 
• Exclusion criteria are to be reviewed, including assessment of compliance during Run-in 
Phase 
• Concomitant medications are assessed 
• Measurement of body weight 
• Abbreviated physical examination including vital signs performed after the patient has 
been seated for at least 5 minutes. Systolic and diastolic BP and heart rate will be assessed 
3 times with at least 1 minute between each measurement (see Appendix D for details). 
• IMP accounting and compliance for single-blind placebo Run-in phase 
• IRT is notified and randomization will occur 
• AEs/SAEs/AESIs/EOSIs and hypoglycemia (if any) are reported, including those 
occurring since Visit 2 
• Diet and exercise instruction 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 65 
• Patient diary, including hypoglycemia log, is collected/reviewed and dispensed and 
instructions/training are provided as needed 
• Instruction on DKA symptoms (see Appendix C) is provided 
• Instruction on basic GU hygiene and hydration is provided (see Appendix C) 
• 12-lead ECG, prior to IMP administration 
• Fasting SMBG is assessed 
• Standard MMTT (2-hour PPG measurements) 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose 
- 
HbA1c 
- 
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test) 
- 
Hematology 
- 
Clinical chemistry to include amylase and lipase 
- 
Fasting lipids 
- 
Urinalysis (dipstick and microscopy) 
- 
Urine analysis for albumin, calcium, glucose, and creatinine 
• Additional laboratory testing at this visit: 
- 
Markers of intestinal transit and absorption (vitamins B6, B12, K, E, and A, serum 
folate, and ferritin) 
- 
Markers of bone and calcium metabolism (serum and urinary calcium, serum 
25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum and urinary 
phosphorus, serum PTH, markers of bone resorption [serum NTX, serum β-CTX-1], 
and bone formation [serum P1NP]) 
- 
 
- 
 
• IMP is dispensed 
• Patients are instructed to return to the site in the fasting state for V4 (Week 1). 
• For accountability and compliance purposes, patients are instructed to return to the site 
with their in-use wallet(s) dispensed during Visit 3. 
10.1.2.1.1.1 
On-site visits at Weeks 1, 4, 8, 12, and 18 (Visits 4 to 8) 
The following will be performed at these visits: 
• IRT is notified (all visits except Visit 4) 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 66 
• IMP accounting and compliance 
• Patient diary, including hypoglycemia log, is collected/reviewed and dispensed and 
instructions/training are provided as needed 
• Concomitant medications are assessed 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• Patients are evaluated for glycemic rescue (see Section 9.1.4.7) 
• Measurement of body weight 
• Abbreviated physical examination including vital signs performed after the patient has 
been seated for at least 5 minutes. Systolic and diastolic BP and heart rate will be assessed 
3 times with at least 1 minute between each measurement (see Appendix D for details) 
• Instruction on DKA symptoms (see Appendix C) is provided 
• Instruction on basic GU hygiene and hydration (see Appendix C) 
• Fasting SMBG is assessed 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose (for all visits) 
- 
HbA1c (all visits except Visit 4) 
- 
Urine pregnancy testing for WOCBP (all visits except Visit 4; any positive urine test 
results must be confirmed by a serum pregnancy test) 
- 
Hematology (Visit 7 only) 
- 
Clinical chemistry to include amylase and lipase (all visits except Visit 4) 
- 
Fasting lipids (all visits except Visit 4) 
- 
Urine analysis for albumin, calcium, glucose, and creatinine (for all visits) 
• Pre-dose plasma concentration samples are collected and sent to the appropriate laboratory 
(Visits 5 and 8 only) 
• Patients should be reminded to record the time of IMP intake on the day before their next 
visit (reminders at Visits 4, 7 and 8 only) 
• IMP is dispensed (all visits except Visit 4) 
• Patients are instructed to return to the site in the fasting state for their next visit. 
• For accountability and compliance purposes, patients are instructed to return to the site 
with their wallet(s) at the next visit. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 67 
10.1.2.1.2 On-site Visit 9 at Week 26 – End-of-treatment 
The following will be performed at this visit: 
• IRT to be notified for EOT (if EOT visit is also last visit, IRT should be notified for end of 
study) 
• IMP accounting and compliance  
• Patient diary, including hypoglycemia log, is collected/reviewed and dispensed and 
instructions/training are provided as needed 
• Concomitant medications are assessed 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• Patients are evaluated for glycemic rescue (see Section 9.1.4.7) 
• Measurement of body weight 
• Complete physical examination including vital signs (SBP and DBP, temperature, heart 
rate, and respiratory rate). Three separate seated BP and heart rate measurements should be 
taken with at least 1 minute between measurements following a 5-minute rest period, and 
prior to phlebotomy (see Appendix D for details of BP procedure) 
• Diet and exercise instruction is provided 
• Instruction on DKA symptoms is provided 
• Instruction on basic GU hygiene and hydration is provided (see Appendix C) 
• 12-lead ECG, prior to the IMP administration 
• Fasting SMBG is assessed 
• Standard MMTT (2-hour PPG measurements) (not to be performed if patient has 
discontinued prior to Premature EOT visit; see Section 10.3.4) 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose 
- 
HbA1c 
- 
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test) 
- 
Hematology 
- 
Clinical chemistry to include amylase and lipase 
- 
Fasting lipids 
- 
Urinalysis (dipstick and microscopy) 
- 
Urine analysis for albumin, calcium, glucose, and creatinine 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 69 
• Additional laboratory testing at this visit: 
- 
Markers of intestinal transit and absorption (vitamins B6, B12, K, E, and A, serum 
folate, and ferritin) 
• The patient is instructed to schedule future follow-up with their own personal physician. 
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 ICF with the study identification 
• Study identification (name) 
• Patient number, confirmation of randomization, treatment batch number, dates and doses 
of study medication administration 
• Medical, surgical, diabetes history, including information on: 
- 
Demography, inclusion and exclusion criteria 
- 
Last participation in a clinical trial 
- 
Contraception method for WOCBP 
- 
Previous and concomitant medication 
• Dates and times of visits and assessments including examination results 
• Vital signs, height, body weight, Laboratory reports, Investigation results (eg, ECG traces, 
imaging 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 treatment discontinuation (if any) and reason 
• Date of premature study discontinuation (if any) and reason 
• Nursing notes 
• Dietician’s notes 
• Physician’s notes 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 70 
10.2.2 Source data verification requirements for screen failures 
For screen failure patients, the following source data must be verified: patient's identification 
details, the informed consent signed by the patient, the study identification (name), dates of study 
visits and the main reasons for screen failure. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the e-CRF. In any case, the 
patient should remain in the study and followed for the remainder of the study duration to collect 
vital safety status and endpoint data. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Lower extremity complications (such as skin ulcers, infection, osteomyelitis, and gangrene) 
requiring treatment should lead to temporary discontinuation of IMP. Reinitiating treatment with 
the IMP will be done under close and appropriate clinical and/or laboratory monitoring once the 
Investigator will have considered according to his/her best medical judgment that the occurrence 
of the concerned event was unlikely to be related to the IMP. 
It is in the interest of the patient to monitor blood glucose during the temporary discontinuation 
period, therefore regular determination of SMBG is to be performed and documented. 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the e-CRF when considered as confirmed. 
Temporary treatment discontinuation decided by the Investigator corresponds to more than 1 dose 
not administered to the patient. 
Use of any different anti-hyperglycemic medication during the time of temporary treatment 
discontinuation (ie, insulin during a hospitalization) is recorded as concomitant medication with 
the name and doses recorded in the e-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. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 71 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP at any time for any reason or this may be 
the Investigator’s decision. Patients should discuss stopping study medication with the site before 
doing so in order that questions can be addressed, glycemic therapy adjusted, and a follow-up 
assessment arranged. All efforts should be made to document 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 (ie, withdrawal of consent for treatment) 
• 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 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 (in female patients) 
• Specific request of the Sponsor 
Any abnormal laboratory value will be rechecked immediately for confirmation before making a 
decision of permanent discontinuation of the IMP for the concerned patient. 
For patients who prematurely discontinue the IMP, the assessments planned at EOT visit 
(Section 10.1.2.1.2) will be performed at the Premature EOT Visit, scheduled preferably prior to 
treatment discontinuation or as soon as possible after time of discontinuation the latest at the next 
on-site visit). Reason for IMP discontinuation will be clearly specified. This Premature EOT 
assessment may occur at a regularly scheduled visit or at an unscheduled visit. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Every effort should be made to maintain patients in the study. Patients should be followed up 
according to the study procedures as specified in this protocol up to the scheduled date of study 
completion, or up to recovery or stabilization of any AE to be followed-up as specified in this 
protocol, whichever comes last. 
If a patient prematurely discontinues study treatment, a Premature EOT visit (see 
Section 10.1.2.1.2) should be scheduled prior to treatment discontinuation, if possible. If not 
possible, the Premature EOT should be scheduled as soon as possible after treatment 
discontinuation. In the case of early discontinuation, no sample for measuring plasma 
concentration should be taken at the Premature EOT visit, nor at any subsequent visits. For 
patients who discontinue treatment but remain in the study, the remaining visits should occur as 
scheduled where possible. The IRT should be notified of EOT. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 73 
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 a medically important event. The list is not 
intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN 
- 
Suicide attempt or any event suggestive of suicidality 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 74 
- 
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 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study  
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
The AESIs for this study: 
• Pregnancy of a female patient entered in a study as well as pregnancy occurring in a 
female partner of a male patient entered in a study with IMP/NIMP.  
- 
Pregnancy occurring in a female patient included 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 patient, IMP should be discontinued,  
- 
Follow-up of the pregnancy in a female patient or in a female partner of a male patient 
is mandatory until the outcome has been determined (see Appendix A). 
• Symptomatic overdose (serious or nonserious) 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 accompanied by administration of more than twice the 
intended daily dose within a 24-hour period. 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. 
(Please note that an Asymptomatic overdose with the IMP/NIMP, accidental or 
intentional, defined as administration of more than twice the intended daily dose 
within a 24-hour period, without clinical symptoms and/or signs, either suspected by 
the Investigator or spontaneously notified by the patient, not based on accountability 
assessment. It will be recorded as an AE “Asymptomatic OVERDOSE, accidental or 
intentional.”) 
• ALT increase >3X ULN (refer to related flow chart in Appendix E) 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 75 
10.4.1.4 Events of Special Interest 
An EOSI is a serious or non-serious AE of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring may be appropriate. Such events 
may require further investigation in order to characterize and understand them. These events 
should be reported on the specific e-CRF page (where applicable) and will only qualify for 
expedited reporting when serious (fulfilling SAE criteria). 
The EOSIs for this study are: 
• Major adverse cardiovascular events (MACE [cardiovascular death, myocardial infarction, 
or stroke]) and other specific CV events (eg, heart failure leading to hospitalization) 
• Severe hypoglycemia (see Section 10.6.1) 
• Genital mycotic infections (to include vulvovaginal candidiasis in females and candidal 
balanitis in males) 
• Urinary tract infections 
• Clinically relevant volume depletion and events related/possibly related to volume 
depletion 
• Diarrhea 
• Pancreatitis 
• Bone fractures 
• Venous thrombotic events, to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism) 
• Diabetic ketoacidosis 
• Renal events, to include 50% decline in eGFR, end stage kidney disease, renal death 
• Malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, 
prostate, and thyroid cancer) 
• Adverse event leading to an amputation 
10.4.2 General guidelines for reporting adverse events 
• All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the ICF until the end of the study as defined by the protocol for that patient, 
are to be recorded on the corresponding page(s) or screen(s) of the e-CRF. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s).  
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 76 
• In this study, the use of concomitant medications including antidiabetic medications may 
make it difficult to assess the causal relationship, particularly for hypoglycemia. Global 
Safety Officer with input from other appropriate study team members will determine the 
causal relationship when it is not clearly provided by the Investigator. 
• 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 if they are 
medically relevant based on the investigator’s medical judgment, eg,:  
- 
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 or EOSI 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send the notification to the Monitoring team and 
Pharmacovigilance after approval of the Investigator within the e-CRF. 
• 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. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 77 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. 
10.4.5 Guidelines for reporting events of special interest 
If an EOSI fulfills the criteria of an SAE, reporting should be performed according to the 
instructions for reporting of SAEs (see Section 10.4.3). Otherwise, reporting should follow the 
instructions for an AE (see Section 10.4.2).  
10.4.6 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix E.   
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
• Neutropenia 
• Thrombocytopenia 
• Increase in ALT 
• Acute renal insufficiency 
• Suspicion of rhabdomyolysis 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction [SUSAR]),), to the regulatory authorities, independent 
ethics committees (IECs)/institutional review boards (IRBs) as appropriate and to the 
Investigators.   
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
• The following AESIs to those regulatory authorities who require such reporting: 
- 
Pregnancy 
- 
Symptomatic overdose 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 78 
- 
ALT increase > 3 X ULN 
Adverse events that are considered expected will be specified by the reference safety information 
provided in the current Investigator’s Brochure.  
If required, unblinding of SUSARs will be the responsibility of the Sponsor. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Hypoglycemia 
During the study, patients are instructed to document any hypoglycemic episodes in their study 
diary. The hypoglycemia will be reported in the specific e-CRF page with onset date and time, 
symptoms and/or signs, the SMBG value if available, and the treatment. If the event fulfills SAE 
criteria, hypoglycemia will also be reported as an SAE.  
Hypoglycemia is categorized according to the ADA workgroup on hypoglycemia classification 
(12,13) and summarized in Figure 1. 
In addition to the threshold of ≤3.9 mmol/L (≤70 mg/dL), hypoglycemia episodes with a plasma 
glucose of <3.0 mmol/L (<54 mg/dL) will be analyzed separately. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 79 
Figure 1 - Hypoglycemia classification in Study EFC14833 
 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, intravenous glucose or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. 
Self-monitored plasma glucose values may not be available, 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. 
Note: “requiring assistance of another person” means that the patient could not help himself or 
herself to treat the hypoglycemia. Assisting a patient out of kindness, when assistance is not 
required, should not be considered a “requires assistance” incident. 
Any hypoglycemic event which leads to unconsciousness, coma, or seizure should also be 
reported as an SAE. 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L 
(≤70 mg/dL).  
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. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 80 
Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL).   
Note: low plasma glucose values without symptoms or signs should not be reported more than 
once within 30 minutes. Repeated low glucose values within a short period could be due to 
malfunction of the device, error testing or following up a low glucose reading. The Investigator 
should try not to document false low SMBG values or redundant low glucose values as 
asymptomatic hypoglycemic event. Further clarification with the patients is needed.     
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms of hypoglycemia are not 
accompanied by a plasma glucose determination, (but that was presumably caused by a plasma 
glucose concentration ≤3.9 mmol/L [≤70 mg/dL]), ie, symptoms treated with oral carbohydrate 
without a test of plasma glucose.  
Relative hypoglycemia 
Relative hypoglycemia, recently termed “pseudo-hypoglycemia” (14) is an event during which the 
patient reports typical symptoms of hypoglycemia, and interprets the symptoms as indicative of 
hypoglycemia, but with a measured plasma glucose concentration >3.9 mmol/L (>70 mg/dL). 
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. 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 81 
11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
In the original version of this protocol, the sample size/power calculations were performed based 
on the primary variable, change in HbA1c from baseline to Week 26. Assuming a common 
standard deviation (SD) of 1.2% and using a 2-sided test at a 0.05 α-level, 120 patients per arm 
would have 95% power to detect a treatment difference of 0.6% in mean HbA1c change from 
Baseline to Week 26 between sotagliflozin 400 mg and placebo. 
In the amended, current, version of this protocol, the sample size/power has been recalculated to 
account for the addition of the sotagliflozin 200 mg treatment group after enrollment had 
commenced. Assuming a common SD of 1.2% and using a 2-sided test at a 0.05 α-level, 
100 patients per arm will have: 
• 94% power to detect a treatment difference of 0.6% in mean HbA1c change from Baseline 
to Week 26 between sotagliflozin 400 mg and placebo, and  
• 84% power to detect a treatment difference of 0.5% in mean HbA1c change from Baseline 
to Week 26 between sotagliflozin 200 mg and placebo. 
As a result, the total number of patients will include:  
• Approximately 100 patients from the initial randomization (1:1) according to the original 
protocol, balanced between placebo and sotagliflozin 400 mg, and 
• Approximately 300 patients from the subsequent randomization (1:1:1) according to the 
amended protocol, balanced between placebo, sotagliflozin 200 mg and sotagliflozin 
400 mg. 
11.2 
DISPOSITION OF PATIENTS 
 
The total number of patients for each of the following categories will be presented in the CSR: 
 
• Screened patients: patients who have signed the ICF 
• Run-in patients 
• Randomized patients: patients with a treatment kit number allocated and recorded in IRT 
database, and regardless of whether the treatment kit was used or not 
• The safety population (ie, randomized and treated patients) 
• The intent-to-treat (ITT) population (as defined in Section 11.3.1.1 and analyzed as 
randomized) 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 82 
• The randomization strata [HbA1c at Screening (≤8.0%, >8.0%) and SBP (<130, 
≥130 mmHg)]. The discrepancy between the strata assigned by IRT and the information 
reported on the e-CRF will be listed for all randomized patients 
• Patients who have completed the treatment period 
• Patients who discontinued the IMP during the 26-week treatment period, and the reasons 
for treatment discontinuation 
• Patients who have completed the study 
• Patients who discontinued the study, and the reasons for study discontinuation 
For all categories of patients except screened, percentages will be calculated using the number of 
randomized patients as denominator for each treatment group. 
A list of patients prematurely discontinued from the treatment, along with reasons for 
discontinuation, will be provided. Similarly, a list of patients prematurely discontinued from the 
study, along with reasons for discontinuation, will be provided. 
Patients treated but not randomized, patients randomized but not treated and patients randomized 
but not treated as randomized will be identified and described in separate listings. The safety 
experience of patients treated and not randomized will be reported separately, and these patients 
will not be in the safety population. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
Efficacy analyses will be based on the treatment group allocated by the IRT according to the 
randomization schedule at randomization visit (as randomized), irrespective of the treatment 
actually received. 
11.3.1.1 Intent-to-treat population 
Efficacy analyses will be based on the ITT population, defined as all randomized patients, 
irrespective of compliance with the study protocol and procedures. Patients will be analyzed for 
efficacy analyses according to the treatment group to which they are randomized, that is, 
sotagliflozin 400 mg versus placebo (those randomized to placebo), and sotagliflozin 200 mg 
versus placebo (those randomized to placebo in the amended randomization only). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 83 
11.3.2 Safety population 
Safety analyses will be based on the safety population, defined as all randomized patients who 
receive at least one dose of double-blind IMP (regardless of the amount of treatment 
administered). 
Patients will be analyzed for safety analyses according to the treatment actually received, that is, 
sotagliflozin 400 mg versus placebo, and sotagliflozin 200 mg versus placebo (those randomized 
in the amended randomization and exposed to placebo only). 
In addition: 
• Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately 
• Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized 
• When a patient is exposed to both sotagliflozin and placebo, the patient will be analyzed in 
the appropriate sotagliflozin group (depending on the treatment kits taken [400 mg or 
200 mg]) 
• When a patient is exposed to both sotagliflozin 400 mg (treatment kits) and 200 mg 
(treatment kits), the patient will be analyzed in the sotagliflozin 200 mg group 
• Randomized patients will be excluded from the safety population only if there is 
documented evidence (ie, all study dates recorded as no medication taken) that patients 
have not taken the study medication 
11.4 
STATISTICAL METHODS 
Continuous data will be summarized by treatment group using the number of observations 
available, mean, SD, minimum, median, and maximum. 
Categorical data will be summarized by treatment group using count and percentage. 
In general, descriptive statistics of quantitative efficacy and safety parameters (result and change 
from Baseline) by scheduled visits will be provided on observed cases (OC), ie, inclusion of only 
patients having non-missing assessments at a specific visit. 
The baseline value is defined generally as the last available value before the first dose of 
double-blind IMP or the last available value prior to randomization for patients who were 
randomized but never exposed to IMP. 
For serum creatinine and eGFR, the Baseline value is defined as the average of all values before 
the first dose of double-blind IMP for those randomized and exposed or before randomization for 
those who were randomized but never exposed to IMP. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 84 
Analysis of demographics and baseline characteristics, prior and concomitant medications will be 
provided in detail in the statistical analysis plan (SAP).  
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 in the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
The extent of study treatment exposure will be assessed by the duration of treatment exposure 
during the study.  
The duration of treatment exposure will be the total number of days of administration of the 
double-blind IMP, regardless of unplanned intermittent discontinuations. The duration of IMP 
exposure will be calculated as: 
(Date of the last double-blind IMP taken – Date of the first double-blind IMP taken) + 1. 
The number (%) of patients randomized and exposed to double-blind IMP will be presented by 
specific time periods for each treatment group. The time periods of interest will be defined in the 
SAP. 
Descriptive statistics of duration of treatment exposure (number, mean, SD, minimum, median, 
and maximum) and cumulative exposure in patient year will also be presented by treatment group 
in the safety population. 
11.4.1.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, mean, SD, median, min, and max). The percentage of patients with compliance 
<80% will be summarized. In addition, the number and percentage of patients with at least 1 
above-planned dosing administration will be given, as well as the number and percentage of 
patients with 0, >0 to 20%, and >20% under-planned dosing administrations. 
11.4.2 Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population. 
11.4.2.1 Analysis of primary efficacy endpoint 
The statistical test will be two-sided tests at a nominal 5% significance level. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 85 
Analysis of the primary efficacy endpoint (change from Baseline to Week 26 in HbA1c; see 
Section 9.1.1) will be performed on the ITT population, using HbA1c measurements obtained 
during the study, including those obtained after IMP discontinuation or introduction of rescue 
therapy. 
The primary efficacy endpoint of change in HbA1c from baseline to Week 26 will be analyzed 
with missing values imputed by control-based multiple imputation method under the missing not 
at random frame work.  
• For placebo patients, missing data will be imputed based on the placebo group data, 
• For patients in the sotagliflozin 400 mg group, missing data will be imputed as if the 
patients were on placebo throughout the study, where all patients’ measurements including 
the on-treatment measurements will be considered as if the measurements were from the 
placebo group in the imputation model. 
Each of the complete datasets will be analyzed by the Analysis of Covariance (ANCOVA) model 
with treatment groups (sotagliflozin 400 mg, placebo), randomization stratum of HbA1c (≤8.0%, 
>8.0%), randomization stratum of SBP (<130, ≥130 mmHg), and country as fixed effects, and 
baseline HbA1c value as a covariate. Results from each complete dataset will be combined to 
provide the adjusted mean change in HbA1c from Baseline to Week 26 for each treatment group, 
as well as the between-group difference (comparing sotagliflozin 400 mg vs placebo) and the 95% 
confidence interval (CI) for the difference.  
Summary statistics (for Screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided for each treatment group. The summary will 
include the number of observations, mean, SD, standard error (SE), minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from baseline (±SE) at each of the scheduled visits (using OC). 
Assessment of treatment effect by subgroup 
Descriptive analyses will be performed on the primary endpoint to summarize the treatment 
effects across subgroups defined by the following Baseline or Screening factors: 
• Race 
• Ethnicity (Hispanic, Not Hispanic) 
• Age group (<50, ≥50 to <65, ≥65 years) 
• Gender 
• Baseline BMI level (<30, ≥30 kg/m²) 
• Baseline HbA1c (≤8.0%, >8.0%) 
• Baseline HbA1c (≤8.5%, >8.5%)  
• Baseline SBP (<130 mmHg, ≥130 mmHg)  
• Country 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 86 
The treatment effects across the subgroups defined for each of these factors will be estimated for 
the change from Baseline to Week 26 in HbA1c in the ITT population, and using a similar 
approach to the analysis for the primary efficacy endpoint. The adjusted estimates of treatment 
mean differences (sotagliflozin 400 mg versus placebo) with SE and 95% CIs will be provided as 
appropriate across the subgroups. 
In the case that the subgroup factor is identical or similar to a randomization strata factor 
(eg, baseline HbA1c category), only the subgroup factor will be included in the model in order to 
avoid the issue of collinearity in the analysis. 
11.4.2.2 Analyses of secondary efficacy endpoints 
The secondary endpoints (see Section 9.1.2) will be analyzed using a similar approach to the 
primary efficacy endpoint with missing values imputed by control-based multiple imputation 
method under the missing not at random frame work.  
To compare sotagliflozin 400 mg versus placebo (those randomized to placebo): 
• For placebo patients, missing data will be imputed based on the placebo group data, 
• For patients in the sotagliflozin 400 mg group, missing data will be imputed as if the 
patients were in the placebo group throughout the study, where all patients’ measurements 
including the on-treatment measurements will be considered as if the measurements were 
from the placebo group in the imputation model. 
To compare sotagliflozin 200 mg versus placebo (those randomized to placebo in the amended 
randomization only): 
• For placebo patients, missing data will be imputed based on the placebo group data, 
• For patients in the sotagliflozin 200 mg group, missing data will be imputed as if the 
patients were in the placebo group throughout the study, where all patients’ measurements 
including the on-treatment measurements will be considered as if the measurements were 
from the placebo group in the imputation model. 
For each of the continuous secondary endpoints, each of the complete datasets will be analyzed by 
an ANCOVA model. To compare sotagliflozin 400 mg versus placebo, the model will include 
treatment groups (sotagliflozin 400 mg, placebo), randomization stratum of HbA1c (≤8.0%, 
>8.0%), randomization stratum of SBP (<130, ≥130 mmHg), and country as fixed effects, and 
baseline secondary endpoint value as a covariate. To compare sotagliflozin 200 mg versus 
placebo, the model will include treatment groups (sotagliflozin 200 mg, placebo), randomization 
stratum of HbA1c (≤8.0%, >8.0%), randomization stratum of SBP (<130, ≥130 mmHg), and 
country as fixed effects, and baseline secondary endpoint value as a covariate. Results from each 
complete dataset will be combined to provide the adjusted mean change from Baseline to 
Week 26 (or Week 12 for SBP) for each treatment group, as well as the between-group difference 
(comparing each sotagliflozin group vs its corresponding placebo group) and the 95% CI for the 
difference. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 87 
The categorical secondary efficacy variables of HbA1c <6.5%, <7% at Week 26 will be analyzed 
using a Cochran-Mantel-Haenszel method stratified by randomization stratum of HbA1c (≤8.0%, 
>8.0%), and randomization stratum of SBP (<130, ≥130 mmHg). The proportion in each 
treatment group will be provided, as well as the difference of proportions between each 
sotagliflozin group and its corresponding placebo group with associated 2-sided 95% CI. For 
HbA1c responders at Week 26 (<6.5%, <7% respectively), all values at Week 26 will be used to 
determine whether a patient is a responder or not, even if they are measured after IMP 
discontinuation or rescue medication use. Patients who have no HbA1c measurement at Week 26 
will be treated as non-responders. 
For all secondary endpoints, summary statistics at scheduled visits will be provided for each 
treatment group. The summary will include the number of observations, mean, SD, SE, minimum, 
median, and maximum. Graphical presentations will also be used to examine trends over time 
using mean values (±SE) and mean changes from baseline (±SE) at each of the scheduled visits 
(using OC). 
11.4.2.3 Analyses of other efficacy endpoints 
The analysis of other endpoints (see Section 9.1.3) will be descriptive with no formal testing. 
Summary statistics at scheduled visits using OC will be provided by each treatment group. 
Graphical presentations will also be used to illustrate trends over time. 
11.4.2.4 Multiplicity considerations 
To control the family-wise type I error, a fixed-sequence testing procedure will be applied.   
Once the primary variable (change from Baseline to Week 26 in HbA1c) is statistically significant 
at α = 0.05 (2-sided), a hierarchical testing procedure will be performed to test the following 
secondary efficacy variables in the following prioritized order. The testing will stop as soon as an 
endpoint is found not to be statistically significant at α=0.05 (2-sided). 
• Comparing sotagliflozin 400 mg versus placebo: 
- 
Change from Baseline to Week 26 in 2-hour PPG following a MM 
- 
Change from Baseline to Week 26 in FPG 
- 
Change from Baseline to Week 26 in body weight 
- 
Change from Baseline to Week 12 in SBP for patients with baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all patients  
- 
Proportion of patients with HbA1c <7.0% at Week 26 
• Comparing sotagliflozin 200 mg versus placebo:  
- 
Change from Baseline to Week 26 in HbA1c 
- 
Change from Baseline to Week 26 in 2-hour PPG following a MM 
- 
Change from Baseline to Week 26 in body weight 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 88 
- 
Change from Baseline to Week 12 in SBP for all patients 
No multiplicity adjustment will be made on other secondary efficacy variables than mentioned 
above.   
11.4.3 Analyses of safety data 
Safety endpoints are presented in Section 9.2. The summary of safety results will be presented by 
treatment group. All safety analyses will be performed on the Safety population as defined in 
Section 11.3.2 using the following common rules: 
The following definitions will be applied to laboratory parameters and vital signs: 
• The potentially clinically significant abnormality (PCSA) values for clinical laboratory 
tests and vital signs are defined as abnormal values considered medically important by the 
Sponsor’s Global Pharmacovigilance and Epidemiology department and in effect at the 
time of the final SAP approval. PCSA criteria for parameters not cited in the protocol as 
safety parameters will not be analyzed 
• PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage 
The “observation periods” defined in Section 9.2.1 are applicable for classification of AEs, 
determination of on-treatment PCSA values and the last on-treatment value for the laboratory, 
vital sign and ECG parameters. 
11.4.3.1 Analysis of adverse events 
Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
Treatment-emergent AEs (TEAEs) are AEs that developed or worsened (according to the 
Investigator’s opinion) 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. 
The primary focus of AE reporting in the CSR will be on TEAEs. Pre- and post-treatment AEs 
will be described separately. 
All adverse events 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (n) and percentage 
(%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 89 
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.  
Summaries of all TEAEs in each treatment group will include: 
• The overview of AEs, summarizing number (%) of patients with any 
- 
TEAE, 
- 
Serious TEAE, 
- 
TEAE leading to death, 
- 
TEAE leading to permanent treatment discontinuation. 
• The number (n) and percentage (%) of patients with at least one TEAE by primary SOC, 
HLGT, HLT and PT, 
• Summary of TEAEs by maximal severity (severe, moderate, mild), presented by primary 
SOC and PT, 
• Summary of TEAEs possibly related to IMP, presented by primary SOC, HLGT, HLT and 
PT. 
A detailed listing of TEAE summaries will be provided in the SAP. 
Death and serious adverse events 
Death and treatment-emergent SAEs will be summarized and presented as number and percent of 
patients in each treatment group. 
The following deaths summaries will be generated: 
• Number (%) of patients who died by study period (on-study, on-treatment, post-study) 
summarized on the safety population by treatment received 
• Death in nonrandomized patients or randomized and not treated patients 
• TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT 
Adverse events leading to permanent treatment discontinuation 
TEAEs leading to permanent treatment discontinuation will be summarized and presented as 
number and percent of patients in each treatment group. 
11.4.3.2 Analyses of hypoglycemia 
The number (%) of patients and rate in patient years (2 types: the number of patients with events 
or the total number of events per 100 patient-year) of all Investigator reported hypoglycemia, 
severe hypoglycemia, and documented symptomatic hypoglycemia will be summarized by 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 90 
treatment group respectively. Their pattern of occurrence over time will also be assessed, as 
appropriate. 
11.4.3.3 Analyses of adverse events of special interest 
Pregnancy and overdose will be included in overall AE summaries if any are reported. ALT 
increase > 3 x ULN is included in laboratory PCSA summary if any. 
11.4.3.4 Analyses of events of special interest 
The number (%) of patients with each EOSI event will be summarized by treatment group. All 
events reported by the Investigators on the AE forms for special interests will be listed along with 
the adjudication outcome (if applicable). 
11.4.3.5 Analyses of laboratory variables 
The number and percentage of patients with PCSA or by the pre-defined categories (if no PCSA 
criterion is defined) at any evaluation during the on-treatment period will be summarized for each 
clinical laboratory test within each treatment group. The summaries will include patients in the 
safety population who have at least one laboratory test performed during the on-treatment period 
and, when required by the definition of the abnormality, with an available baseline value and 
available laboratory normal ranges. 
Descriptive statistics will be used to summarize the laboratory results and the changes from 
baseline by visit and for the last on-treatment value within each treatment group. Shift tables and 
other tabular and graphical methods may be used to present the results for laboratory tests of 
interest. Listings will be provided with flags indicating the out of laboratory range values as well 
as the PCSA values. 
The liver function tests, namely ALT, AST, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
postbaseline visit by baseline status will be displayed by treatment group for each parameter. 
11.4.3.6 Analyses of vital sign variables 
The number and percentage of patients with PCSA at any evaluation during the on-treatment 
period will be summarized for each vital sign parameter within each treatment group. The 
summaries will include patients in the safety population who have at least one parameter to be 
analyzed during the on-treatment period. Descriptive statistics will be used to summarize the 
results and the changes from baseline by visit and for the last on-treatment value within each 
treatment group. Tabular and graphical methods may be used to present the results for parameters 
of interest. Listings will be provided with flags indicating the PCSA values. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 91 
11.4.3.7 Analyses of 12 lead ECG status 
A shift table will be provided to present the ECG on-treatment status according to the baseline 
status within each treatment group. 
11.4.4 Analyses of pharmacokinetic variables 
The PK endpoint is presented in Section 9.3.1. Individual plasma concentrations of sotagliflozin 
and of its 3-O-glucuronide at nominal sampling times will be listed.  
Concentration data will be summarized by visit and, if appropriate, within visit by nominal 
sampling times (predose, 2 hours 30 minutes postdose), using descriptive statistics by N, 
geometric mean, coefficient of variation, median, minimum and maximum at each visit/nominal 
sampling time point for sotagliflozin-treated patients. 
11.5 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned for this study. The study will not be terminated 
early for excellent efficacy. 
An independent DMC will monitor and assess the safety of patients from this trial through 
periodic review of the accumulated safety data provided by an independent statistical group. 
Related details are provided in separate documents (DMC charter and DMC statistical analysis 
plan). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 93 
documents (summary of product characteristics, package insert), Investigator’s curriculum vitae 
[CV], etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC, before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the Investigator’s Brochure or 
labeling information, will be sent to the IRB/IEC and to health authorities (competent regulatory 
authority), as required by local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 94 
13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR OR SERVICE PROVIDER 
The Sponsor and/or service provider 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 and EOSI documentation, IMP allocation, 
patient compliance with the IMP regimen, IMP accountability, concomitant therapy use and 
quality of data.  
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 95 
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/service provider 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/service provider 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/service provider and Investigator study files. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 96 
14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor/service 
provider prior to the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 98 
the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). They may be further 
processed if they have been anonymized. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, good clinical practice, and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he/she 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 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 99 
• Patient enrollment is unsatisfactory 
• The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon 
• Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP 
• The total number of patients are included earlier than expected 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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.  
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 100 
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 101 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be re-collected if necessary. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 102 
16 
BIBLIOGRAPHIC REFERENCES 
1. Cremer A, Amraoui F, Lip GY, Morales E, Rubin S, Segura J, et al. From malignant 
hypertension to hypertension-MOD: a modern definition for an old but still dangerous 
emergency. J Hum Hypertens. 2016;30(8):463-6. 
2. International Diabetes Federation Diabetes Atlas 7th Edition.  
http://www.diabetesatlas.org/resources/2015-atlas.html. Accessed 15 July 2016 
3. American Diabetes Association. American Diabetes Association Applauds Two-Year Re 
Authorization of Special Diabetes Program. American Diabetes Association. Available from: 
http://www.diabetes.org/newsroom/press-releases/2010/re-authorization-special-diabetes-
program.html. Accessed July 12, 2016. 
4. American Diabetes Association. Standards of Medical Care in Diabetes – 2013. Diabetes Care 
2013 Jan;36(Suppl 1):S11-S66. 
5. Castaneda-Sceppa C, Castaneda F. Sodium-dependent glucose transporter protein as a 
potential therapeutic target for improving glycemic control in diabetes. Nutr Rev. 2011 Dec; 
69(12):720-9. 
6. Mudalier S. Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal 
Glucose Transport; From Bench to Bedside. Diabetes Care 2015; 38: 2344–53. 
7. Hediger HA. Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. 
Nature 1987; 330:379-81. 
8. Wright EM. I. Glucose galactose malabsorption. Am J Physiol. 1998;275:G879-G882. 
9. Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M. Dapagliflozin, a novel, 
selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 
diabetes mellitus. Clinical Pharmacology & Therapeutics. 2009 May;85(5):513-9. 
10. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with 
dapagliflozin in type 2 diabetes. Diabetes care. 2009 Apr 1;32(4):650-7. 
11. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
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 Jun;35(6):1364-79. 
12. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on 
Hypoglycemia. Diabetes Care. 2005 May;28(5):1245-9. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 103 
13. FDA Guidance for Industry:  Diabetes Mellitus - Developing Drugs and Therapeutic Biologics 
for Treatment and Prevention. Lines 1144 – 1215. Available from: 
http://www.fda.gov/downloads/ 
Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071624.pdf. Accessed 
July 12, 2016 
14. Seaquist ER, Anderson J, Childs B, Cryer P, Dagoga-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 
 
 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 104 
17 
APPENDICES 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 105 
Appendix A 
Guidance on contraceptive methods and collection of pregnancy 
information 
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy. 
1. Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.  
- 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Women of reproductive potential (WOCBP) must use a highly effective method of contraception 
during the treatment period and the post-treatment follow up period (28 ±3 days). If another 
contraceptive method is used (such as a barrier method), it should be used in combination with 
one of the highly effective methods (such as an oral contraceptive). 
Female patients: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 
− oral 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 106 
− intravaginal 
− transdermal 
• Progestogen-only hormone contraception associated with inhibition of ovulation 
− oral 
− injectable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulation  
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method(s) of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.) 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the patient.) 
NOTE: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for patients 
participating in clinical studies. 
 
 
 
COLLECTION OF PREGNANCY INFORMATION 
Male patients with partners of reproductive potential who become pregnant  
• The Investigator will attempt to collect pregnancy information on any female partner of a 
male study patient who becomes pregnant while participating in this study. This applies 
only to patients who receive study treatment. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 107 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy  
• Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor.  
• Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure  
Female patients who become pregnant  
• The Investigator will collect pregnancy information on any female patient, who becomes 
pregnant while participating in this study  
• Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a patient’s pregnancy.  
• Patient will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on patient and neonate, which will be forwarded to the 
Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.  
• Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.  
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the study treatment by the Investigator, will be reported to the Sponsor as described in 
Section 10.4.1.2. While the Investigator is not obligated to actively seek this information in 
former study patients, he or she may learn of an SAE through spontaneous reporting.  
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 108 
Appendix B 
Two-hour standardized mixed meal 
A 2-hour PPG will be obtained after a standardized MM in all patients at Baseline (Day 1, Visit 3) 
and at Week 26 (Visit 9), or earlier if the patient terminates study participation before Week 26. 
Any patient who requires the addition of rescue medication should undergo the second 
standardized MMTT at Visit 9 (Week 26).  
The standardized MM must not be done while patients are temporarily off IMP; the Medical 
Monitor will address any episodes on a case-by-case basis and the standardized MM will be 
rescheduled when the patient can resume IMP, if applicable. 
The first dose of double-blind IMP on Day 1 (Visit 3) will be given AFTER completion of the 
2-hour PPG collection. For the Week 26 standardized MM, the patient should take the dose of 
double-blind IMP immediately after the fasting blood samples are obtained, and approximately 
30 minutes before ingestion of the standardized MM begins. 
Standard Meal for the Standardized Mixed Meal: 
The standard (breakfast) meal will be provided by the Sponsor as a liquid nutrition drink (Boost®, 
Ensure®, or similar), with ~40 g carbohydrate and ~240 calories per bottle (~8 ounces). The 
caloric composition of the meal is ~ 65% carbohydrate, ~15% protein, and ~20% fat. The amount 
given is 6 mL/kg body weight up to a maximum of 360 mL. Therefore for patients ≥60 kg, the 
standard meal consists of ~60 g carbohydrate and 360 calories.  
Patients are instructed to completely consume the meal within 15 minutes, and every effort should 
be made to complete the meal within 20 minutes after it is started. Water or noncaffeinated, 
zero-calorie beverages may be consumed ad libitum. No other food may be consumed until the 
2-hour postprandial plasma glucose sample has been collected. If the patient is unable to consume 
at least 50% of the standard meal during the MMTT at Baseline (Day 1, Visit 3), the patient 
should not be randomized. If a MMTT after randomization is not tolerated, effort should be made 
to repeat the testing at the discretion of the Investigator. If the patient cannot tolerate MMTT upon 
repeat testing, this should be documented in the e-CRF with the reason and the patient should 
continue in the study. If the patient is able to consume >50% of the standardized MM, the 
approximate amount should be recorded, and an equivalent amount should be consumed at the 
subsequent standardized MM. 
Baseline Visit (Day 1, Visit 3) Standardized MM: 
1. Record the amount and brand name of the standard meal liquid nutrition drink the patient 
is instructed to consume in the source documents 
2. Fasting blood samples are obtained, including Time 0 fasting FPG 
3. Record the time of blood sample collection in the source documents 
4. Immediately after the fasting blood samples are collected, the patient starts consuming the 
standard meal 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 109 
5. Record the time the meal ingestion starts in the source documents 
6. The 2-hour countdown for the 2-hour plasma PPG starts immediately after the patient 
begins ingestion of the standard meal 
7. The patient is instructed to ingest the prescribed amount within 15 to 20 minutes. 
8. Record the time ingestion is completed, measure the portion of the meal not ingested (if 
any), and record the assessed percent of prescribed amount ingested in the source 
documents 
9. No blood samples for PK are collected at this visit 
10. Two hours after the meal ingestion starts, the 2-hour plasma PPG is collected 
11. Record the time the 2-hour plasma PPG is collected in source documents 
12. Double-blind IMP is administered after the blood sample is drawn at 120 minutes 
13. Record the time the double-blind IMP is administered in the source documents 
Week 26 Visit (Visit 9) Standardized MM: 
1. Record the amount and brand name of the standard meal liquid nutrition drink the patient 
is instructed to consume in the source documents 
2. Fasting blood samples are obtained, including Time 0 FPG and predose PK samples 
3. Record the time of blood sample collection in the source documents 
4. Double-blind IMP is administered after the fasting blood samples are obtained 
5. Record the time the double-blind IMP is administered in the source documents 
6. Thirty-minutes after the double-blind IMP is administered, the patient starts consuming the 
standard meal 
7. Record the time the meal ingestion starts in the source documents 
8. The 2-hour countdown for the 2-hour PPG starts immediately after the patient begins 
ingestion of the standard meal 
9. The patient is instructed to ingest the prescribed amount within 15 to 20 minutes 
10. Record the time ingestion is completed, measure the portion of the meal not ingested 
(if any), and record the assessed percent of prescribed amount ingested in the source 
documents 
11. Two hours after the meal ingestion starts, the 2-hour PPG and 2-hour 30 minute PK 
samples are collected 
12. Record the time the 2-hour postprandial blood samples are collected in the source 
documents 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 110 
Appendix C 
Recommendations on basic genitourinary hygiene, maintaining 
hydration, and recognizing diabetic ketoacidosis 
Patients with T2D are at risk for developing GU infections. The following guidelines should be 
communicated to females and uncircumcised males regarding GU infections. Patient 
communication cards will be printed with the following: 
For females: 
“The following advice may be useful in helping you to keep your bladder and urethra free from 
infection: 
• Go to the toilet as soon as you feel the need to urinate, rather than holding it in.  
• Wipe from front to back after going to the toilet.  
• Practice good hygiene by washing your genitals every day, and before having sex.  
• Empty your bladder after having sex.”  
For uncircumcised males: 
“The following advice may be useful in helping you to keep the foreskin free from infection: 
• Wash the end of your penis and foreskin with soap and water (do not let soap get in the 
opening).  
• After your shower or bath, dry the end of your penis and foreskin properly and replace the 
foreskin.  
• Also, when you urinate, slide the foreskin back enough so that urine does not get on the 
foreskin-this helps to keep it clean.” 
Maintaining Hydration: 
Sodium-glucose cotransporter type 2 inhibitors are associated with osmotic diuresis and volume 
depletion, which may lead to dizziness or hypotension, especially in the elderly. Before initiating 
study drug (at Screening, Run-in and Randomization) and during all on-site study visits thereafter, 
assess volume status in patients with renal impairment, the elderly, in patients with low SBP, or if 
receiving diuretics, angiotensin-converting-enzyme inhibitors, or angiotensin receptor blockers. 
All patients will be advised to maintain proper fluid intake and to consider increasing it if they 
sense greater thirst, more urine production, or if they feel dizzy or faint. 
Patient communication cards will be printed with the following for patients with T2D: 
“The following advice may be useful in helping you to maintain proper hydration and prevent 
dehydration: 
• Dehydration is when your body loses too much fluid, frequently due to diarrhea or 
increased urination 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 111 
• Consider increasing the amount of fluids you drink if: 
- 
You sense greater thirst than usual 
- 
You have a dry mouth or cracked lips 
- 
You have a fever 
- 
You have diarrhea or vomiting  
- 
You urinate more frequently or in larger amounts than usual 
- 
You get up in the middle of the night to urinate (more than usual) 
- 
You feel dizzy or light-headed 
- 
You exercise, or when it is hot outside” 
Recognizing DKA 
Potential GI adverse events occurring with sotagliflozin may mask presenting symptoms of DKA. 
Patient communication cards will be printed with the following: 
“If you have any of these symptoms on the list, then contact your study site immediately for 
assistance with managing your diabetes: 
• Inability to maintain oral intake  
• Generalized weakness  
• Abdominal (belly) pain  
• Increased weight loss 
• Fever  
• Frequent urination, including at night 
• Fruity-scented breath 
• Confusion 
• Acute illness  
• Consistently elevated blood glucose  
• Feeling very thirsty or drinking a lot 
• Nausea or vomiting 
• Having trouble thinking clearly or feeling tired 
It is possible to have DKA even if your blood glucose is not elevated. Regardless of your blood 
glucose level, if you have any of these symptoms on the list, then contact your study site 
regarding the need to be evaluated for possible DKA, which will include specific blood testing. If 
your study site is closed and your study doctor is not available, go to the nearest emergency room 
for evaluation. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 112 
If you are scheduled for a procedure or surgery that requires you to not take any food or liquids, 
please contact your study doctor for instructions on continuing study drug. In such cases your 
study doctor may advise you NOT to take your study drug from the day prior to the procedure or 
surgery until after the procedure or surgery is complete, and you are taking food and liquids as 
you normally do.” 
Whenever AE data is collected or the patient reports DKA or intercurrent illness (including 
infections), generalized weakness, increased weight loss, gastrointestinal symptoms including 
nausea, vomiting, or abdominal pain or other symptoms or signs that the Investigator believes 
may be consistent with DKA, then the site will determine if an assessment for DKA is 
appropriate. If laboratory testing confirms presence of metabolic acidosis, then the “Possible 
DKA” e-CRF will be completed. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 113 
Appendix D 
Measurement of Blood Pressure and Pulse Rate 
The BP measurement device should be calibrated according to manufacturer instructions.  
Equipment 
1. Blood pressure measurements will be taken by an automated blood pressure monitor or a 
manual sphygmomanometer 
2. Bladder Length – Should nearly or completely encircle the patient’s arm. For many adults, 
the standard “adult” size bladder is not long enough and the “large” size bladder is 
recommended 
3. Bladder Width – Should be at least 40% of the bladder length 
Patient Factors 
Extraneous variables associated with the measurement of BP should be minimized. These include: 
1. Food intake, caffeine-containing beverages, cigarette smoking, or strenuous exercise 
within 2 hours prior to measurement 
2. Full urinary bladder 
3. The patient should not be allowed to talk while BP is being measured 
4. The patient should be placed in the examination room and the cuff should be placed on the 
patient’s nondominant arm. The proper sized cuff should fit snugly with the lower edge 2 
to 3 cm above the antecubital fossa. 
5. The patient should be allowed to sit quietly in a comfortably warm place (temperature 
around 25°C or 77°F) for 5 minutes with the arm supported at heart level, preferably with 
the cuff in place and with no restrictive clothing on the arm. The patient should be 
encouraged not to tense his or her muscles. 
Nondominant Arm 
The patient’s nondominant arm should be the arm declared by the patient as being nondominant. 
The nondominant arm should then be used for all seated BP measurements throughout the study. 
Measurement Technique 
Following the 5-minute rest period, 3 separate seated BPs should be measured with at least 
1 minute between BP measurements and with the cuff fully deflated between measurements. 
All 3 BPs will be recorded in the patient’s e-CRF. The mean of the 3 seated BPs will constitute 
the BP value for that visit. 
Three seated pulse rate measurements will be obtained. The mean of the 3 seated pulse rate 
measurements will constitute the pulse rate value for that visit. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 02  
19-Dec-2017 
EFC14833 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 115 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.4.2 is met. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)