A 26-week Randomized, Double-blind, Controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin Compared to Empagliflozin, and Placebo in Participants With Type 2 Diabetes Who Have Inadequate Glycemic Control on Dipeptidyl Peptidase 4 Inhibitor (DPP4(i)) With or Without Metformin
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Lexicon Pharmaceuticals

Official Title: A 26-week Randomized, Double-blind, Controlled, Parallel-group, 
Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin 
compared to Empagliflozin, and Placebo in Patients with Type 2 
Diabetes Who Have Inadequate Glycemic Control on Dipeptidyl 
Peptidase 4 Inhibitor (DPP4(i)) With or Without Metformin 
NCT Number: NCT03351478 
Document Date: Protocol Version 2: 12-April -2018 

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 26-week Randomized, Double-blind, Controlled, Parallel-group, Multicenter 
Study to Evaluate the Efficacy and Safety of Sotagliflozin compared to 
Empagliflozin, and Placebo in Patients with Type 2 Diabetes Who Have Inadequate 
Glycemic Control on Dipeptidyl Peptidase 4 Inhibitor (DPP4(i)) With or Without 
Metformin
STUDY NUMBER: EFC14867
STUDY NAME: SOTA-EMPA
VERSION DATE / STATUS: Approval date (11-Apr-2018) / Approved
Protocol Amendment 02
Version number: 1 (electronic 1.0)
Date : 11-Apr-2018
Amended Clinical Trial Protocol 01 
Version number: 1 (electronic 1.0)
Date : 29-Sep-2017
Protocol Amendment 01
Version number: 1 (electronic 1.0)
Date : 29-Sep-2017
Clinical Trial Protocol
Version number: 1 (electronic 1.0)
Date : 27-Jun-2017
Version Number:
1
EudraCT:
2016-001803-22
IND Number(s):
WHO universal trial:
U1111-1190-7607
Date:
11-Apr-2018
Total number of pages:
122
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 2 of 298

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Page 3 of 298
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Amended Clinical Trial Protocol No. 02
11-Apr-2018
EFC14867 - sotagliflozin
Version number: 1
Property of the Sanofi Group - strictly confidential
Page 3
CLINICAL TRIAL SUMMARY
COMPOUND: sotagliflozin/SAR439954
STUDY No.: EFC14867
STUDY NAME: SOTA-EMPA
TITLE
A 26-week Randomized, Double-blind, Controlled, Parallel-group, 
Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin 
compared to Empagliflozin, and Placebo in Patients with Type 2 Diabetes 
Who Have Inadequate Glycemic Control on Dipeptidyl Peptidase 
4 Inhibitor (DPP4(i)) With or Without Metformin
INVESTIGATOR/TRIAL LOCATION
Multinational
PHASE OF DEVELOPMENT
3
STUDY OBJECTIVE(S)
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 a DPP4(i) with or without metformin.
Secondary objective:
The secondary objectives of this study are to demonstrate:

Noninferiority of sotagliflozin 400 mg versus empagliflozin on 
HbA1c reduction from Baseline at Week 26

Superiority of sotagliflozin 400 mg versus placebo with respect 
to:
-
Change from Baseline in 2-hour postprandial glucose 
(PPG) reduction following a mixed meal tolerance test 
(MMTT) at Week 26
-
Change from Baseline in Fasting plasma glucose (FPG) 
reduction at Week 26
-
Change from Baseline in Body weight reduction at Week 26
-
Proportion of patients with HbA1c <6.5% and <7.0% at 
Week 26
-
Change from baseline in sitting systolic blood pressure 
(SBP) reduction at Week 12 in Patients with SBP
≥130 mmHg at Baseline
-
Change from baseline in sitting SBP reduction at Week 12 
in all patients

Superiority of sotagliflozin 400 mg versus empagliflozin with 
respect to change from baseline in 
-
HbA1c reduction at Week 26
-
Sitting SBP reduction at Week 12 in patients with SBP
≥130 mmHg at Baseline
-
Sitting SBP reduction at Week 12 in all patients

To evaluate the safety of sotagliflozin 400 mg versus 
empagliflozin 25 mg, and placebo, throughout the 26-week trial.
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Other objectives:
Other objectives of this study are:

To compare sotagliflozin versus empagliflozin and placebo with 
respect to change from Baseline in:
-
Estimated glomerular filtration rate (eGFR)
-
Serum creatinine
-
Urinary glucose excretion (UGE) and urine glucose to 
creatinine ratio (UGCR)
-
Urine albumin to creatinine (UACR) for all patients and
patients with UACR >30 mg/g at Baseline
-
Sitting SBP for patients with Baseline SBP <130 mmHg at 
Weeks 12 and 26
-
Sitting SBP for patients with Baseline SBP ≥130 mmHg at 
Week 26
-
Sitting SBP for all patients at Week 26
-
Sitting diastolic blood pressure (DBP) for patients with 
Baseline SBP ≥130 mmHg at Weeks 12 and 26
-
Reduction in body weight by ≥2%, ≥5%, and ≥10%.

To compare sotagliflozin versus empagliflozin with respect to 
change from Baseline in:
-
2-hour PPG reduction following an MMTT at Week 26
-
FPG reduction at Week 26
-
Body weight reduction at Week 26.

To compare the use of rescue medications for hyperglycemia in 
the sotagliflozin and empagliflozin treatment groups

To assess plasma levels of sotagliflozin and sotagliflozin-3-O-
glucuronide in the sotagliflozin treatment arm

To compare hemodynamic markers (including plasma renin 
activity [PRA], aldosterone, angiotensinogen 1, angiotensinogen 
2 and glucagon) in the sotagliflozin and empagliflozin treatment 
groups.
Ambulatory Blood Pressure Monitoring substudy
A substudy will be undertaken to monitor ambulatory blood pressure (BP) 
over 24 hours (in addition to all other study assessments) in a subset of 
the study population (approximately 180 patients).
The objective of the ambulatory blood pressure monitoring (ABPM)
substudy is to compare the effect of sotagliflozin, empagliflozin, and
placebo in a subset of patients based on:

24-hour average SBP and DBP

Average adjusted awake time BP as measured by SBP and DBP 
with adjustment based on actigraphy

Average adjusted sleeping time BP as measured by SBP and 
DBP with adjustment based on actigraphy.
STUDY DESIGN
This study is a Phase 3, multicenter and multinational, 2:2:1 randomized, 
double-blind (single-blind Run-in Phase), placebo- and active-controlled, 
double-dummy, parallel-group study that is anticipated to enroll 
approximately 700 subjects. Patients with T2D who have inadequate 
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glycemic control on DPP4(i) with or without metformin for at least 
12 weeks prior to Screening will be eligible for enrollment in this study. To 
ensure an approximately equal number of patients have Screening SBP 
<130 mmHg or SBP ≥130 mmHg, the number of patients enrolled in each 
category will be limited to 60% of all patients (≤420 patients).
All patients will have an up to 4-week Screening Period (consisting of a 
Screening Phase up to 2-weeks and a 2-week, single-blind Run-in phase 
prior to randomization, followed by a 26-week Double-blind Treatment 
Phase and a 4-week post-treatment Follow-up visit. To qualify for 
randomization, patients must demonstrate compliance based upon tablet 
and capsule count (≥80%) during the Run-in Phase.
Randomization will be stratified by:

HbA1c at Screening (≤8.5%, >8.5%)

SBP at Screening (<130 mmHg, ≥130 mmHg)

Metformin use at Screening (Yes, No)
Patients will be randomly assigned 2:2:1 to the following 3 treatment 
groups on top of DPP4(i) with or without metformin:

Sotagliflozin 400 mg

Empagliflozin 25 mg

Placebo
The patient’s HbA1c, FPG, PPG, UGE, and UGCR will be masked to study 
centers and patients after randomization and until the end of the study. 
Additionally, urinalysis by dipstick will not include the measurement of 
urine glucose. Urine glucose, albumin, calcium, and creatinine will be 
measured separately at Visits 3, 6, and 8 by the central laboratory.
To further evaluate the diurnal effect of sotagliflozin on SBP compared 
with the comparator arms (placebo and empagliflozin) and to avoid the 
white-coat effect, SBP will be evaluated by 24-hour ABPM in a subset of 
180 patients.
Early termination
If a patient discontinues treatment with investigational medicinal product 
(IMP) early during the double-blind Treatment Period, the patient will have 
a Premature End of Treatment (EOT) Visit, and Follow-up Visit 4 weeks
after the last dose of IMP. In addition, every effort will be made to have the 
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 safety status 
and collect adverse event (AE) data.
STUDY POPULATION
Main selection criteria
Inclusion criteria:

Patients with Type 2 Diabetes on DPP4(i) with or without 
metformin at a stable dose for at least 12 weeks prior to 
Screening Visit will be included. Metformin dose will be 
≥1500 mg per day (or maximum tolerated dose [documented]). 
DPP4(i) dose must be the appropriate dose as per local label.

Signed written informed consent.
Exclusion criteria:

At the time of Screening age <18 years or less than legal age of 
majority, whichever is greater

Type 1 diabetes mellitus
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
Body mass index (BMI) ≤20 kg/m² or >45 kg/m² at Screening

Use of any antidiabetic drug other than DPP4(i) and metformin 
within 12 weeks preceding the Screening Visit

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

Use of weight loss medications or weight change of 5 kg or more 
during the 12 weeks before Screening

Likelihood of requiring treatment during the study period with 
drugs not permitted by the study protocol (eg, long-term 
systemic glucocorticoids) and refusing to or unable to take 
alternative treatment

Patients who have previously participated in any clinical trial of 
sotagliflozin/LX4211

Use of a selective sodium-glucose cotransport type 2 (SGLT2) 
inhibitor (eg, canagliflozin, dapagliflozin, or empagliflozin) within 
3 months prior to Screening Visit.

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 Investigator, will preclude their 
safe participation in this study, or will make implementation of 
the protocol or interpretation of the study results difficult

Current diagnosis of chronic hepatitis, and/or other clinically 
active liver disease requiring treatment

Known presence of factors that interfere with the central 
laboratory 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 Visit, any condition that shortens erythrocyte 
survival)

Patient who has taken other investigational drugs or prohibited 
therapy for this study within 12 weeks or 5 half-lives from prior to 
Screening, whichever is longer

Patients with contraindication to empagliflozin as per local 
labeling

Patients with contraindication to metformin as per local labeling

Hemoglobin A1c <7.0% or >11.0% at Screening (central 
laboratory)

FPG >270 mg/dL (>15.0 mmol/L) measured by the central 
laboratory at Screening (Visit 1), and confirmed by a repeat test 
(>270 mg/dL [>15.0 mmol/L]) before Randomization

Previous use of any types of insulin for >1 month (except for 
treatment of gestational diabetes)

Pregnant (confirmed by serum pregnancy test at Screening) or 
breast-feeding women
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
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 Appendix A), during the study

Mean of 3 separate BP measurements >180 mmHg (SBP) or 
>100 mmHg (DBP)

History of hypertensive crisis resulting in emergency medical 
care within 12 weeks prior to Screening

Known allergies, hypersensitivity, or intolerance to SGLT2 
inhibitor or any inactive component or placebo 
(ie, microcrystalline cellulose, croscarmellose sodium 
[disintegrant], talc, silicone dioxide, and magnesium stearate 
[nonbovine]), or intolerance of empagliflozin unless the reaction 
is deemed irrelevant to the study by the Investigator

Laboratory findings with the central laboratory tests at Visit 1:
-
Alanine aminotransferase or aspartate aminotransferase >3 
times the upper limit of the normal laboratory range (x ULN)
-
Total bilirubin >1.5 times the ULN (except in case of 
Gilbert’s syndrome)
-
Neutrophils <1 500/mm3 (or according to ethnic group) 
and/or platelets <100 000/mm3
-
Amylase and/or lipase >3 times the ULN
-
Patients with renal impairment as defined by the eGFR 
criterion that precludes initiation of empagliflozin as per the 
approved local label (eg, <45 mL/min/1.73 m2 in the United 
States; <60 mL/min/1.73 m2 in EU)

At the sites with participating ABPM patients, patient works a 
night (third) shift (defined as 11:00 PM [2300] to 7:00 AM [0700])

Patient has an upper arm circumference <24 cm or >42 cm

Secondary hypertension of any etiology (eg, renovascular 
disease, pheochromocytoma, Cushing's syndrome)

If the patient is on hypertensive medications, the 
antihypertensive has been changed in the 8 weeks prior to 
Screening (new drug or new dose)
Total expected number of patients
Approximately 700 patients
STUDY TREATMENTS
Single-blind placebo Run-in Phase: All patients will receive two (2) 
placebo tablets (identical to sotagliflozin in appearance) and one placebo 
capsule (identical to empagliflozin capsule in appearance).
26-week Randomized Double-blind Treatment Period: Patients will 
receive sotagliflozin, empagliflozin, or placebo treatment.
Investigational medicinal products
Sotagliflozin arm: sotagliflozin 400 mg, given as two (2) 200 mg tablets 
and one (1) placebo capsule (identical to empagliflozin capsule), once 
daily before the first meal of the day.
Empagliflozin arm: placebo, given as two (2) placebo tablets (identical to 
sotagliflozin in appearance) and one capsule of empagliflozin 25 mg, once 
daily before the first meal of the day.
Placebo: given as two (2) placebo tablets (identical to sotagliflozin) and 
one placebo capsule (identical to empagliflozin) once daily before the first 
meal of the day.
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Formulation:
Tablet or capsule
Route(s) of administration:
Oral
Dose regimen:
Once daily before the first meal of the day
Noninvestigational medicinal products
Patients will continue on their existing DPP4(i) with or without metformin, if 
applicable. The doses should remain unchanged during the study period 
unless as needed for safety reason.
Rescue therapy (Glycemic Parameters)
The threshold values for rescue are defined as follows, depending on the 
study period:

From Baseline Visit (V3, Day 1) to Visit 5 (Week 8) (including 
value at Visit 5): FPG >270 mg/dL (>15.0 mmol/L)

From Visit 5 (Week 8) to Visit 6 (Week 12) (including value at 
Visit 6): FPG >240 mg/dL (>13.3 mmol/L)

From Visit 6 (Week 12) up to the end of the treatment period 
Visit 8 (Week 26): FPG >200 mg/dL (>11.1 mmol/L) or HbA1c 
≥8.5% (the 8.5% criteria does not apply if the HbA1c decrease 
from Baseline was ≥1.0%)
Routine fasting self-monitored blood glucose (SMBG) and central 
laboratory alerts on FPG (and HbA1c after Week 12 and onwards) are set 
up to ensure that glycemic parameter results remain within predefined 
thresholds.
If a central laboratory FPG and/or HbA1c is above the threshold, the 
Investigator will receive an alert from the central laboratory. Upon receipt 
of a central laboratory rescue alert, a central laboratory retest must be 
completed and confirmed.
Likewise, patients are instructed to contact the sites for a confirmatory 
FPG test via central laboratory in case of high fasting SMBG readings for 
3 consecutive days. Hyperglycemia must be confirmed as exceeding the 
criterion for rescue before rescue therapy is initiated. The central 
laboratory FPG confirmation should be performed as soon as possible 
preferably within 7 days by unscheduled visit.
If rescue thresholds are reached, it is recommended to use sulfonylurea 
(glimepiride, if available) first (unless there is a contraindication to 
sulfonylurea treatment per label). In case of contraindication to 
sulfonylurea, another antidiabetic medication, eg, insulin or oral 
antidiabetic drugs (except SGLT2 inhibitors) will be added according to the 
Investigator’s clinical judgment and in accordance with the treatment 
guidelines.
If a patient requires rescue, the IMP received at Randomization should 
continue and must remain blinded until the end of the study.
ENDPOINT(S)
Primary efficacy endpoint:

Change from Baseline to Week 26 in HbA1c.
Secondary efficacy endpoints:

Change from Baseline to Week 26 in 2-hour PPG following an
MMTT

Change from Baseline to Week 26 in FPG
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
Change from Baseline to Week 26 in body weight

Proportion of patients with HbA1c <6.5%, <7.0% at Week 26
(HbA1c responders)

Change from Baseline to Week 12 in sitting SBP in patients with 
SBP ≥130 mmHg at Baseline

Change from Baseline to Week 12 in sitting SBP in all patients.
Other efficacy endpoints:

Change from Baseline in:
-
eGFR
-
Serum creatinine
-
UGE and UGCR
-
UACR for all patients and patients with UACR >30 mg/g
-
Sitting SBP for patients with Baseline SBP <130 mmHg at 
Weeks 12 and 26
-
Sitting SBP for patients with Baseline SBP ≥130 mmHg at
Week 26
-
Sitting SBP for all patients at Week 26
-
Sitting DBP for patients with Baseline SBP ≥130 mmHg at 
Weeks 12 and 26
-
Reduction in body weight by ≥2%, ≥5%, and ≥10%

Use of rescue medications for hyperglycemia in the sotagliflozin 
and empagliflozin treatment groups.

Plasma concentration of sotagliflozin and 
sotagliflozin-3-O-glucuronide for patients receiving sotagliflozin

Hemodynamic markers (including plasma renin activity [PRA], 
aldosterone, angiotensinogen 1, angiotensinogen 2 and 
glucagon).
Safety endpoints:
To be collected throughout trial:

Adverse events (AEs), hypoglycemia (all, severe, and/or
documented symptomatic hypoglycemia), events of special 
interest (EOSI), adverse events of special interest (AESI), AEs 
leading to discontinuation from the IMP, serious adverse events 
(SAEs), and deaths

Acute renal failure

Clinical laboratory and vital signs results.
Other endpoints:

Plasma levels of sotagliflozin and sotagliflozin-3-O-glucuronide 
in the sotagliflozin treatment arm

Hemodynamic markers (including PRA, aldosterone, 
angiotensinogen 1, angiotensinogen 2 and glucagon)
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ABPM substudy endpoints:
The ABPM endpoints are changes from Baseline to Week 12 and 
Week 26 for all patients participating in the substudy, patients with 
baseline 24-hour average SBP ≥130 mmHg and patients with baseline 
24-hour average SBP <130 mmHg in:

24-hour average SBP and DBP

Average adjusted awake time BP as measured by SBP and DBP 
with adjustment based on actigraphy

Average adjusted sleeping time BP as measured by SBP and 
DBP with adjustment based on actigraphy.
ASSESSMENT SCHEDULE
See Study Flow Chart (Section 1.2)
STATISTICAL CONSIDERATIONS
Sample size determination:
A sample size of 280 patients in the sotagliflozin group and 140 patients in 
the placebo group will provide more than 90% power to detect a difference 
of 0.6% for change from Baseline to Week 26 in HbA1c between 
sotagliflozin and placebo (standard deviation [SD]=1.1%; 5% significance 
level 2-sided).
A sample size of 280 patients in the sotagliflozin group and 280 patients in 
the empagliflozin group will ensure that the upper bound of the 2-sided 
95% confidence interval (CI) of the adjusted mean difference would not 
exceed 0.3% with more than 80% power to show noninferiority for 
intent-to-treat (ITT) analysis and for completer analysis considering 
15% dropout. This calculation assumes a common SD of 1.1%, and the 
true difference between sotagliflozin and empagliflozin is zero for change 
from Baseline to Week 26 in HbA1c.
The total sample size will be 700 patients to be randomized (sotagliflozin 
group: 280; empagliflozin group: 280; placebo group: 140).
Analysis population:
Efficacy analyses will be based on the ITT population, defined as all 
randomized patients, irrespective of compliance with the study protocol 
and procedures.
Analysis of the primary efficacy endpoint:
Analysis of the primary efficacy endpoints will be performed using the ITT 
population, using measurements obtained during the study, including 
those obtained after IMP discontinuation or introduction of rescue therapy.
The statistical test will be two-sided tests at a nominal 5% significance 
level.
The primary efficacy endpoint of change from Baseline to Week 26 in 
HbA1c will be analyzed with missing post-baseline values imputed by 
placebo control-based copy reference multiple imputation method under 
the missing not at random framework.

For placebo patients, missing data will be imputed based on the 
placebo group data

For patients in the active arms (sotagliflozin and empagliflozin),
missing data will be imputed as if the patients were on 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.
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Each of the complete datasets will be analyzed by the analysis of 
covariance (ANCOVA) model with treatment groups (sotagliflozin, 
empagliflozin, placebo), randomization strata of Screening HbA1c (≤8.5%, 
>8.5%), randomization strata of Screening SBP (<130 mmHg, 
≥130 mmHg) and metformin use at Screening (Yes, No), 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 
from Baseline to Week 26 in HbA1c for each treatment group, as well as 
the between-group difference (comparing sotagliflozin 400 mg versus 
placebo) and the 95% CI for the between-group 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:
For each of the continuous secondary endpoints, a similar approach to the 
primary efficacy endpoint will be used, with missing values imputed by 
placebo control-based copy reference multiple imputation method under 
the missing not at random framework:

For placebo patients, missing data will be imputed based on the 
placebo group data

For patients in the active arms (sotagliflozin and empagliflozin) 
missing data will be imputed as if the patients were on 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.
Each of the complete datasets will be analyzed by the ANCOVA model 
with treatment groups (sotagliflozin, empagliflozin, placebo), randomization 
strata of Screening HbA1c (≤8.5%, >8.5%), randomization strata of 
Screening SBP (<130 mmHg, ≥130 mmHg) and metformin use at 
Screening (Yes, No) and country as fixed effects, and Baseline value as a 
covariate. Results from each complete dataset will be combined to provide 
the adjusted mean change from Baseline to Week 12/Week 26 for each 
treatment group, as well as the between-group differences and the 95% 
CIs for the differences.
Categorical secondary endpoints such as HbA1c responders (<6.5%, 
<7.0%) at Week 26 will be analyzed using a Cochran-Mantel-Haenszel 
method stratified by randomization strata of Screening HbA1c (≤8.5%, 
>8.5%), Screening SBP (<130 mmHg, ≥130 mmHg), and metformin use at 
Screening (Yes, No). The proportion in each treatment group will be 
provided, as well as the difference of proportions between sotagliflozin and 
placebo with associated 2-sided 95% CI. For HbA1c responders at 
Week 26, 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 nonresponders.
A sensitivity analysis to noninferiority test will be conducted with the 
26-week treatment completers (ie, all patients who complete the 26-week 
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Treatment Period and do not start rescue therapy) using the Week 26 
values and the same ANCOVA model described above.
Multiplicity considerations:
To control for the family-wise Type I error, a fixed-sequence testing 
procedure will be applied.
Once the primary hypothesis (superiority of the change from Baseline to 
Week 26 in HbA1c comparing sotagliflozin 400 mg versus placebo) is 
established statistically significant for the primary efficacy endpoint, the 
following secondary hypotheses will be tested in the following prioritized 
order:
1.
The noninferiority of sotagliflozin versus empagliflozin on HbA1c 
reduction at Week 26
2.
The superiority of sotagliflozin versus placebo on 2-hour PPG 
reduction at Week 26
3.
The superiority of sotagliflozin versus placebo on FPG reduction 
at Week 26
4.
The superiority of sotagliflozin versus placebo on body weight 
reduction at Week 26
5.
The superiority of sotagliflozin versus placebo on HbA1c 
responder analysis (HbA1c<7.0% at Week 26)
6.
The superiority of sotagliflozin versus placebo on sitting SBP 
reduction at Week 12 in patients with Baseline SBP ≥130 mmHg
7.
The superiority of sotagliflozin versus placebo on sitting SBP 
reduction at Week 12
8.
The superiority of sotagliflozin versus empagliflozin on HbA1c 
reduction at Week 26
9.
The superiority of sotagliflozin versus empagliflozin on sitting 
SBP reduction at Week 12 in patients with Baseline SBP 
≥130 mmHg
10. The superiority of sotagliflozin versus empagliflozin on sitting 
SBP reduction at Week 12.
If any hypothesis is found to be not statistically significant, the testing 
procedure will be stopped and the following hypotheses will not be tested. 
The noninferiority hypothesis will be declared statistically significant if the 
upper bound of the 2-sided 95% CI for the adjusted mean difference is 
<0.3. The superiority hypothesis will be declared statistically significant at 
α = 0.05 (2-sided).
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.
Analysis of safety data:
All safety summaries will be descriptive; no statistical significance 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.
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Analysis of ABPM endpoints:
The analysis of ABPM endpoints will be descriptive with no formal testing. 
Summary statistics at scheduled visits using OC of sufficient quality will be 
provided by each treatment group.
DURATION OF STUDY PERIOD (per 
patient) 
Up to 34 weeks, including a Screening Phase of up to 2 weeks, a 2-week 
Run-In Phase, a 26-week double-blind Treatment Period and a 4-week 
post-treatment Follow-up Period to collect safety information. 
STUDY COMMITTEES
Steering Committee:
Yes
No
Data monitoring committee: 
Yes
No
Clinical Endpoint Committees:
Yes
No
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1
FLOW CHARTS
1.1
GRAPHICAL STUDY DESIGN
Abbreviations: ABPM = ambulatory blood pressure monitoring; BP = blood pressure; DPP4(i) = dipeptidyl peptidase 4 inhibitor; HbA1c = hemoglobin A1c; R = randomization; T2D = Type 2 Diabetes; V = visit; 
W = week.
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1.2
STUDY FLOW CHART
Screening Period
Double-blind Treatment Perioda
Follow-
upb
Screening
Run-in
Visit
1
2
3A
ABPM
3 
Rando-
mization
4
5
6A
ABPM
6
7
8A
ABPM
8
9
Week
Up to -4
-2
-1
0 
Baseline
4
8
12
12
18
26
26
30
Day (window [days])
-14 
(±3)
-7
1
28 
(±3)
56 
(±3)
83 
(±3) 
84 
(±3)
126 
(±5)
181 
(±5)
182 
(±5)
210 
(±5)
Informed consent
X
Interactive Response 
Technology (IRT) contact
X
X
X
X
X
X
X
X
X
Inclusion criteria
X
Exclusion criteria
X
X
Demographics
X
Medical and surgical history
X
Medication history
X
Concomitant medication
X
X
X
X
X
X
X
X
X
Body weight, heightc
X
X
X
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
X
X
Physical examination:
Complete
X
X
Abbreviatede
X
X
X
X
X
X
X
Diet and exercise instruction
X
X
X
Instruction on basic 
genitourinary (GU) hygiene and 
hydration
X
X
X
X
X
X
X
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Screening Period
Double-blind Treatment Perioda
Follow-
upb
Screening
Run-in
Visit
1
2
3A
ABPM
3 
Rando-
mization
4
5
6A
ABPM
6
7
8A
ABPM
8
9
Week
Up to -4
-2
-1
0 
Baseline
4
8
12
12
18
26
26
30
Day (window [days])
-14 
(±3)
-7
1
28 
(±3)
56 
(±3)
83 
(±3) 
84 
(±3)
126 
(±5)
181 
(±5)
182 
(±5)
210 
(±5)
Randomization
X
Dispense glucose meter
X
Collect glucose meter
X
Dispense diary
X
X
X
X
X
X
X
Collect/review diary
X
X
X
X
X
X
X
Instruction on diabetic 
ketoacidosis symptoms and 
glucose testing
X
X
X
X
X
X
X
Dispense investigational 
medicinal product (IMP)
X
X
X
X
X
X
IMP accounting and compliance
X
X
X
X
X
X
SMBGf
X
X
X
X
X
X
X
12-lead electrocardiogramg
X
X
MMTT/Postprandial glucoseh
X
X
Ambulatory blood pressure 
monitoring (ABPM)i
X
X
X
Central Laboratory testingj
Fasting plasma glucose 
(FPG)k
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
Chemistry
X
X
X
X
X
X
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Screening Period
Double-blind Treatment Perioda
Follow-
upb
Screening
Run-in
Visit
1
2
3A
ABPM
3 
Rando-
mization
4
5
6A
ABPM
6
7
8A
ABPM
8
9
Week
Up to -4
-2
-1
0 
Baseline
4
8
12
12
18
26
26
30
Day (window [days])
-14 
(±3)
-7
1
28 
(±3)
56 
(±3)
83 
(±3) 
84 
(±3)
126 
(±5)
181 
(±5)
182 
(±5)
210 
(±5)
Hematology
X
X
X
X
X
Fasting lipids
X
X
Pregnancy test (WOCBP)l
X
X
X
X
X
X
X
FSH and/or estradiol as 
neededl
X
Sotagliflozin plasma 
concentrationm
X
X
X
Hemodynamic markersn
X
X
X
Urinalysis with microscopyo
X
X
X
Collection of home overnight 
urine for albumin, total protein, 
creatinine, calcium, phosphorus, 
magnesium, and glucosepp
X
X
X
Evaluate for glycemic rescue
To be assessed and reported throughout the treatment period
Hypoglycemia
To be assessed and reported throughout the studys
AEs/SAEs/AESI/EOSIs
To be assessed and reported throughout the studys
a
If a patient discontinues treatment with IMP early during the Double-blind Treatment Period, the patient will have a Premature EOT Visit (similar to Visit 8) and a Follow-up Visit 4 weeks ± 5 days after the last dose 
of IMP. In addition, every effort will be made to have the patient return to the site at the time corresponding to their scheduled visits, particularly 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.
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b
The Follow-up Visit will take place 4 weeks ± 5 days after the last dose of IMP. All attempts will be made to contact the patient to inquire about safety status.
c
Height will be measured only at Screening Visit.
d
Vital sign measurements (sitting blood pressure [BP] and heart rate): At the Screening Visit, BP will be measured on both arms to identify and select the appropriate arm for future measurements. Three 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. Assessment for volume contraction and correct volume 
status, if indicated, will be done before randomization.
e
The abbreviated physical examination should focus on cardiac and respiratory systems, as well as any areas important for assessment of adverse events if necessary.
f
The SMBG is to be performed fasting (before first meal of the day) for at least 3 days in the week prior to each study visit. The SMBG should be performed in case of hypoglycemia symptoms; any SMBG values 
≤70 mg/dL (≤3.9 mmol/L) should be documented in the diary and collected in the hypoglycemia event case report form (CRF). The SMBG will be presented as equivalent SMPG.
g
The 12-lead ECG should be performed after the patient has spent at least 10 minutes in supine position and prior to IMP administration. The ECG results will be evaluated as “normal” or “abnormal”.
h
Plasma postprandial glucose will be assessed at Baseline Week 0 and Week 26, 2 hours after consuming a standard mixed liquid breakfast meal via an MMTT.
i
Visit for ABPM for a subset of patients (180 patients) will occur 1 week before the Randomization Visit; patients will return the ABPM device by mail after 24-hour monitoring is complete. Patients will also have 
additional in-person visits for placement of the ABPM device on the day before Week 12 and 26 visits. At least 70% recording of the expected BP recording is needed in each 24-hour period. The measurement will 
be done on the nondominant upper arm. Patients who discontinue the IMP before the visit for ABPM will not continue in the ABPM substudy post-IMP discontinuation. Patients who receive rescue therapy but 
remain on IMP will continue on the ABPM substudy as planned.
j
With the exception of PPG, all laboratory assessments will occur prior to IMP administration on the day of the visit. All visit dates will be scheduled based on the date of randomization with a ±3-day visit window 
allowed during the core treatment period, except for Visits 7, 8A, 8, and 9, when a ±5 days visit window will apply. Laboratory tests are outlined in Table 2.
k
The FPG collection will be performed on the morning of visit.
l
Serum pregnancy testing will be performed only at Screening and urine pregnancy testing is performed at subsequent visits. Serum pregnancy test results must be reviewed prior to beginning the Run-in Phase for 
all women of childbearing potential (WOCBP, Appendix A). 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.
m Plasma concentration samples (ie, of sotagliflozin and sotagliflozin-3-O-glucuronide) should be drawn with the other laboratory assessments. However, timing should be carefully recorded; previous dose should be 
captured in the eCRF. Samples will be collected at predose and for Week 26 an additional sample will be collected 3 hours postdose.
n
Hemodynamic markers including PRA, aldosterone, angiotensinogen 1, angiotensinogen 2, and glucagon will be checked to provide better characterization of hemodynamic markers in relation to sotagliflozin 
treatment.
o
Urinalysis will include urine dipstick and microscopy. Dipstick will include assessment of specific gravity, pH, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte esterase. Microscopy will include, 
but not be 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 (UTI), urine culture should be performed. Positive urine culture determination will be based upon the criteria of the reporting laboratory. Additionally, urine culture should be performed if at any point the 
Investigator suspects the presence of a UTI.
p
Patients will collect overnight urine on Week 0, 12, and 26 (Visits 3, 6 and 8). In the night prior to the visits, the urine before sleep will be discarded and the urine during sleep and the first morning urine 
(after getting up) will be collected. The visits should be rescheduled to allow for urine collection in case a patient missed it. Urinary albumin, total protein, creatinine, calcium (adjusted for creatinine), phosphorus 
(adjusted for serum phosphorus and creatinine), magnesium (adjusted for serum magnesium and urinary creatinine), and glucose will be assessed.
s
All SAEs, AEs, AESI, and EOSI will be collected starting from 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 visit 4 weeks ±5 days after the last dose of IMP to collect 
safety information.
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2
TABLE OF CONTENTS
1
FLOW CHARTS.............................................................................................................................14
1.1
GRAPHICAL STUDY DESIGN ......................................................................................................14
1.2
STUDY FLOW CHART ..................................................................................................................15
2
TABLE OF CONTENTS ................................................................................................................19
2.1
LIST OF TABLES...........................................................................................................................25
2.2
LIST OF FIGURES.........................................................................................................................25
3
LIST OF ABBREVIATIONS ..........................................................................................................26
4
INTRODUCTION AND RATIONALE.............................................................................................28
4.1
BACKGROUND: SOTAGLIFLOZIN AND DISEASE .....................................................................28
4.2
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS ................................................................29
4.3
RATIONALE FOR SELECTION OF DOSE ...................................................................................30
4.4
RATIONALE FOR STUDY DESIGN AND CONTROL GROUPS..................................................31
4.5
BENEFIT/RISK OF SOTAGLIFLOZIN...........................................................................................32
5
STUDY OBJECTIVES ...................................................................................................................33
5.1
PRIMARY.......................................................................................................................................33
5.2
SECONDARY ................................................................................................................................33
5.3
OTHER...........................................................................................................................................33
5.4
AMBULATORY BLOOD PRESSURE MONITORING SUBSTUDY ..............................................34
6
STUDY DESIGN ............................................................................................................................35
6.1
DESCRIPTION OF THE STUDY...................................................................................................35
6.1.1
Screening Period............................................................................................................................35
6.1.1.1
Screening Phase............................................................................................................................35
6.1.1.2
Single-blind Placebo Run-in Phase ...............................................................................................35
6.1.2
Double-blind Treatment Period......................................................................................................36
6.1.3
Ambulatory blood pressure monitoring substudy...........................................................................36
6.1.4
Follow-up period.............................................................................................................................37
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6.2
DURATION OF STUDY PARTICIPATION ....................................................................................37
6.2.1
Duration of study participation for each patient .............................................................................37
6.2.2
Determination of end of clinical trial (all patients) ..........................................................................37
6.3
INTERIM ANALYSIS......................................................................................................................37
6.4
STUDY COMMITTEES..................................................................................................................37
6.4.1
Steering Committee .......................................................................................................................37
6.4.2
Data Monitoring Committee ...........................................................................................................38
6.4.3
Clinical Endpoint Committee..........................................................................................................38
6.4.4
Safety adjudication of events requiring ongoing monitoring ..........................................................38
7
SELECTION OF PATIENTS..........................................................................................................39
7.1
INCLUSION CRITERIA..................................................................................................................39
7.2
EXCLUSION CRITERIA ................................................................................................................39
7.2.1
Exclusion criteria related to study methodology ............................................................................39
7.2.2
Exclusion criteria related to mandatory background therapies......................................................40
7.2.3
Exclusion criteria related to the current knowledge of sotagliflozin and empagliflozin..................41
7.2.4
Additional exclusion criteria during or at the end of screening before randomization ...................42
8
STUDY TREATMENTS .................................................................................................................43
8.1
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................43
8.2
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................43
8.2.1
Background medications................................................................................................................44
8.2.2
Rescue therapy..............................................................................................................................44
8.3
BLINDING PROCEDURES............................................................................................................46
8.3.1
Methods of blinding........................................................................................................................46
8.3.2
Randomization code breaking during the study.............................................................................46
8.4
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................47
8.5
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING .............................47
8.6
STORAGE CONDITIONS AND SHELF LIFE................................................................................48
8.7
RESPONSIBILITIES ......................................................................................................................48
8.7.1
Treatment accountability and compliance......................................................................................48
8.7.2
Return and/or destruction of treatments ........................................................................................49
8.8
CONCOMITANT MEDICATION.....................................................................................................49
8.8.1
Prohibited prior and concomitant medications...............................................................................49
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8.9
POSTSTUDY TREATMENT..........................................................................................................50
9
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................51
9.1
EFFICACY ENDPOINT..................................................................................................................51
9.1.1
Primary efficacy endpoint...............................................................................................................51
9.1.2
Secondary efficacy endpoints........................................................................................................51
9.1.3
Other efficacy endpoints ................................................................................................................51
9.1.4
Assessment methods of efficacy endpoints...................................................................................52
9.1.4.1
Hemoglobin A1c.............................................................................................................................52
9.1.4.2
Blood pressure...............................................................................................................................52
9.1.4.3
Postprandial glucose via MMTT.....................................................................................................52
9.1.4.4
Fasting plasma glucose .................................................................................................................53
9.1.4.5
Body weight....................................................................................................................................53
9.1.4.6
Kidney function parameters ...........................................................................................................53
9.1.4.7
Use of rescue medications for hyperglycemia ...............................................................................54
9.2
SAFETY ENDPOINTS ...................................................................................................................54
9.2.1
Assessment methods of safety endpoints .....................................................................................55
9.2.1.1
Adverse events ..............................................................................................................................55
9.2.1.2
Hypoglycemia.................................................................................................................................55
9.2.1.3
Laboratory safety variables............................................................................................................55
9.2.1.4
Urinalysis........................................................................................................................................56
9.2.1.5
Vital signs and physical examination .............................................................................................57
9.2.1.6
Electrocardiogram variables ..........................................................................................................58
9.2.1.7
Self-monitored blood glucose ........................................................................................................58
9.3
OTHER ENDPOINTS.....................................................................................................................59
9.3.1
Pharmacokinetics of sotagliflozin...................................................................................................59
9.3.1.1
Sampling time ................................................................................................................................59
9.3.1.2
Pharmacokinetics handling procedure...........................................................................................59
9.3.1.3
Bioanalytical method......................................................................................................................59
60
60
9.3.3
Hemodynamic markers ..................................................................................................................60
9.3.4
Ambulatory blood pressure monitoring substudy...........................................................................61
61
9.5
APPROPRIATENESS OF MEASUREMENTS ..............................................................................61
10
STUDY PROCEDURES ................................................................................................................63
10.1
VISIT SCHEDULE..........................................................................................................................63
10.1.1
Screening Period............................................................................................................................63
10.1.1.1 Screening phase ............................................................................................................................63
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10.1.1.2 Run-in Phase .................................................................................................................................65
10.1.2
Double-blind Randomized Treatment Period (Day 1 to Week 26) ................................................66
10.1.2.1 Visit 3, Randomization, Day 1 (Baseline; Week 0) ........................................................................66
10.1.2.2 Week 4 to Week 18 (Visit 4 to Visit 7)............................................................................................68
10.1.2.3 Week 26 (Visit 8) - End of Treatment.............................................................................................69
10.1.3
Post-treatment Follow-up Period ...................................................................................................70
10.2
DEFINITION OF SOURCE DATA..................................................................................................70
10.2.1
Source data to be found in patient’s file.........................................................................................70
10.2.2
Source data verification requirements for screen failures .............................................................71
10.3
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................71
10.3.1
Temporary treatment discontinuation with investigational medicinal product(s) ...........................72
10.3.2
Permanent treatment discontinuation with investigational medicinal product(s) ...........................72
10.3.3
List of criteria for permanent treatment discontinuation.................................................................72
10.3.4
Handling of patients after permanent treatment discontinuation ...................................................73
10.3.5
Procedure and consequence for patient withdrawal from study....................................................74
10.4
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................74
10.4.1
Definitions of adverse events.........................................................................................................74
10.4.1.1 Adverse event ................................................................................................................................74
10.4.1.2 Serious adverse event ...................................................................................................................75
10.4.1.3 Adverse event of special interest...................................................................................................76
10.4.1.4 Events of special Interest...............................................................................................................76
10.4.2
General guidelines for reporting adverse events ...........................................................................77
10.4.3
Instructions for reporting serious adverse events ..........................................................................78
10.4.4
Guidelines for reporting adverse events of special interest...........................................................78
10.4.5
Guidelines for reporting events of special interest.........................................................................79
10.4.6
Guidelines for management of specific laboratory abnormalities ..................................................79
10.4.7
Guidelines for reporting product complaints (IMP/NIMP) ..............................................................79
10.5
OBLIGATIONS OF THE SPONSOR .............................................................................................79
10.6
SAFETY INSTRUCTIONS .............................................................................................................80
10.6.1
Hypoglycemia.................................................................................................................................80
10.7
ADVERSE EVENTS MONITORING..............................................................................................82
11
STATISTICAL CONSIDERATIONS..............................................................................................83
11.1
DETERMINATION OF SAMPLE SIZE...........................................................................................83
11.2
DISPOSITION OF PATIENTS .......................................................................................................83
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11.3
ANALYSIS POPULATIONS...........................................................................................................84
11.3.1
Efficacy populations .......................................................................................................................84
11.3.2
Intent–to-treat population ...............................................................................................................84
11.3.3
Safety population ...........................................................................................................................84
11.4
STATISTICAL METHODS .............................................................................................................85
11.4.1
Extent of study treatment exposure and compliance.....................................................................85
11.4.1.1 Extent of investigational medicinal product exposure....................................................................85
11.4.1.2 Compliance ....................................................................................................................................86
11.4.2
Analyses of efficacy endpoints.......................................................................................................86
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................86
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................88
11.4.2.3 Analysis of other efficacy endpoints...............................................................................................88
11.4.2.4 Multiplicity considerations ..............................................................................................................89
11.4.3
Analyses of safety data..................................................................................................................89
11.4.3.1 Analysis of adverse events ............................................................................................................90
11.4.3.2 Analyses of hypoglycemia .............................................................................................................91
11.4.3.3 Analyses of adverse events of special interest..............................................................................91
11.4.3.4 Analyses of events of special interest............................................................................................91
11.4.3.5 Analyses of laboratory variables....................................................................................................92
11.4.3.6 Analyses of vital sign variables ......................................................................................................92
11.4.3.7 Analysis of 12-lead electrocardiogram status ................................................................................92
11.4.4
Analyses of other endpoints...........................................................................................................92
11.4.4.1 Pharmacokinetic.............................................................................................................................92
11.4.4.2 Hemodynamic markers ..................................................................................................................93
11.4.4.3 Ambulatory blood pressure monitoring substudy...........................................................................93
11.5
INTERIM ANALYSIS......................................................................................................................93
12
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................94
12.1
ETHICAL AND REGULATORY STANDARDS ..............................................................................94
12.2
INFORMED CONSENT .................................................................................................................94
12.3
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................94
13
STUDY MONITORING...................................................................................................................96
13.1
RESPONSIBILITIES OF THE INVESTIGATOR............................................................................96
13.2
RESPONSIBILITIES OF THE SPONSOR OR SERVICE PROVIDER .........................................96
13.3
SOURCE DOCUMENT REQUIREMENTS....................................................................................96
13.4
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................97
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13.5
USE OF COMPUTERIZED SYSTEMS..........................................................................................97
14
ADDITIONAL REQUIREMENTS...................................................................................................98
14.1
CURRICULUM VITAE....................................................................................................................98
14.2
RECORD RETENTION IN STUDY SITES ....................................................................................98
14.3
CONFIDENTIALITY .......................................................................................................................98
14.4
PROPERTY RIGHTS.....................................................................................................................99
14.5
DATA PROTECTION.....................................................................................................................99
14.6
INSURANCE COMPENSATION..................................................................................................100
14.7
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................100
14.8
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................100
14.8.1
By the Sponsor.............................................................................................................................100
14.8.2
By the Investigator .......................................................................................................................101
14.9
CLINICAL TRIAL RESULTS ........................................................................................................101
14.10
PUBLICATIONS AND COMMUNICATIONS ...............................................................................101
15
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................103
16
BIBLIOGRAPHIC REFERENCES...............................................................................................104
17
APPENDICES..............................................................................................................................106
APPENDIX A
CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .................................................................................................................107
APPENDIX B
AMBULATORY BLOOD PRESSURE MONITORING SUBSTUDY ..................................110
APPENDIX C
TWO-HOUR STANDARDIZED MIXED MEAL..................................................................112
APPENDIX D
RECOMMENDATIONS ON BASIC GENITOURINARY HYGIENE, MAINTAINING 
HYDRATION AND RECOGNIZING DIABETIC KETOACIDOSIS....................................114
APPENDIX E
MEASUREMENT OF BLOOD PRESSURE AND HEART RATE......................................117
APPENDIX F
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI.........................................................................................118
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2.1
LIST OF TABLES
Table 1 - Summary of investigational medicinal products during Treatment Period.....................................43
Table 2 - Blood safety parameters ................................................................................................................56
Table 3 - Sotagliflozin samples identification ................................................................................................59
Table 4 - Highly Effective Contraceptive Methods ......................................................................................108
2.2
LIST OF FIGURES
Figure 1 - Hypoglycemia classification in Study EFC14867..........................................................................80
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3
LIST OF ABBREVIATIONS
ABPM:
ambulatory blood pressure monitoring
AE:
adverse event(s)
AESI:
adverse event(s) 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
DNA:
deoxyribonucleic acid
DPP4(i):
dipeptidyl peptidase 4 inhibitor
ECG:
electrocardiogram
eCRF:
electronic case report form
eGFR:
estimated glomerular filtration rate
EOSI:
event(s) of special interest
EOT:
End of Treatment
FDA:
Food and Drug Administration
FPG:
fasting plasma glucose
FSH:
follicle-stimulating hormone
GCP:
Good Clinical Practice
GI:
gastrointestinal
GLP-1:
glucagon-like peptide-1
GU:
genitourinary
HbA1c:
hemoglobin A1C
HLGT:
high level group term
HLT:
high level term
HR:
heart rate
HRT:
hormone replacement therapy
IB:
Investigator’s Brochure
ICF:
informed consent form
ICH:
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ID:
identification
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IEC:
Independent Ethics Committee
IMP:
investigational medicinal product
IRB:
Institutional Review Board
IRT:
Interactive Response Technology
ITT:
intent-to-treat
MACE:
major adverse cardiovascular event(s)
MI:
myocardial infarction
NIMP:
noninvestigational medicinal product
OC:
observed cases
PCSA:
potentially clinically significant abnormality
P-gp:
P-glycoprotein
PK:
pharmacokinetic
PPG:
postprandial glucose
PRA:
plasma renin activity
PT:
preferred term
PYY:
peptide YY
SAE:
serious adverse event(s)
SAP:
statistical analysis plan
SBP:
systolic blood pressure
SC:
Steering Committee
SD:
standard deviation
SE:
standard error
SGLT1:
sodium-glucose cotransporter type 1
SGLT2:
sodium-glucose cotransporter type 2
SMBG:
self-monitoring of blood glucose
SOC:
system organ class
T1D:
type 1 diabetes
T2D:
type 2 diabetes
TEAE:
treatment-emergent adverse event(s)
UACR:
urine albumin to creatinine ratio
UGCR:
urine glucose to creatinine ratio
UGE:
urinary glucose excretion
ULN:
upper limit of normal
US:
United States
UTI:
urinary tract infection
WOCBP:
women of childbearing potential
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4
INTRODUCTION AND RATIONALE
4.1
BACKGROUND: SOTAGLIFLOZIN AND DISEASE
Sotagliflozin is a dual inhibitor of the sodium-glucose cotransporters Type 1 and 2 (SGLT-1 and 
2) being developed for use in Type 2 diabetes (T2D), a metabolic disorder characterized by 
hyperglycemia that results from a combination of increased insulin resistance and beta-cell 
dysfunction (1). 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 (2). 
The Centers for Disease Control and Prevention released a report in 2010 stating that if current 
trends continue, 1 in 3 Americans will have diabetes by the year 2050 (3). 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 and is estimated to be 642 million by 
2040 (4).
According to the World Health Organization, there are about 60 million people with diabetes in 
the European Region, or about 10.3% of men and 9.6% of women aged 25 years and over (5). 
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 (4, 5).
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 (6). Inhibition of SGLT1 in the GI tract delays 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 that are 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 (7), pharmacologic inhibition of SGLT1 by sotagliflozin has 
not produced these effects in preclinical models or in patients with T2D. Selective inhibitors of 
the SGLT1 transporter are in early stages of development.
Extensive clinical studies conducted for selective sodium-glucose cotransporter type 2 (SGLT2) 
inhibitors have established this class as effective agents for the treatment of T2D (8, 9, 10, 11, 12, 
13) and have led to approvals by the United States (US) Food and Drug Administration (FDA) 
and the European Medicines Agency. 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 (14). These data suggest that 
sotagliflozin should be of therapeutic benefit to patients with T2D.
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In Study LX4211.1-202-DM, patients with systolic blood pressure (SBP) ≥130 mmHg at Baseline
had reduction in SBP after 12 weeks of treatment with sotagliflozin (15). The reduction noted in
patients with Baseline SBP ≥130 mmHg (a target based on guidelines for management of blood 
pressure (BP) in diabetic patients and used by several SGLT2 inhibitors) was 1, 3, 10, 16, and 
17 mmHg, respectively, in placebo, 75 mg once daily, 200 mg once daily, 400 mg once daily, and 
200 mg twice daily of sotagliflozin. Similar to other parameters, the sotagliflozin 400-mg daily 
dose has optimal effect on the SBP reduction.
Empagliflozin is shown to reduce BP and HbA1c. Patients (N = 825) with T2D and mean seated 
SBP of 130 to 159 mmHg and diastolic blood pressure (DBP) of 80 to 99 mmHg were 
randomized (double-blind) to 10 mg or 25 mg empagliflozin or placebo once daily for 12 weeks. 
At Week 12, adjusted mean difference versus placebo in change from Baseline in mean 24-hour
SBP (ambulatory blood pressure monitoring [ABPM]) was -3.44 mmHg (95% confidence interval 
[CI]: -4.78, -2.09) with 10 mg empagliflozin and -4.16 mmHg (95% CI: -5.50, -2.83) with 25 mg
empagliflozin (both p <0.001). At Week 12, adjusted mean difference versus placebo in change 
from Baseline in mean 24-hour DBP (ABPM) was -1.36 mmHg (95% CI: -2.15, -0.56) with 
10 mg empagliflozin and -1.72 mmHg (95% CI -2.51, -0.93) with 25 mg empagliflozin 
(both p <0.001). Changes in office BP were consistent with ABPM. Adjusted mean difference 
versus placebo in change from Baseline to Week 12 in HbA1c was -0.62% (95% CI: -0.72, -0.52) 
(-6.8 mmol/mol [95% CI: -7.9, -5.7]) with 10 mg empagliflozin and -0.65% 
(95% CI: -0.75, -0.55) (-7.1 mmol/mol [95% CI: -8.2, -6.0]) with 25 mg empagliflozin (both 
p <0.001) (13).
Based on the glucose-lowering and BP-lowering effects of sotagliflozin and empagliflozin, the 
purpose of this trial is to evaluate the effects of sotagliflozin (a SGLT1/2 inhibitor) compared with 
empagliflozin (a SGLT2 inhibitor) and placebo. In addition, patients in this study will be taking 
concomitant dipeptidyl peptidase 4 inhibitor (DPP4[i]), which will enable the investigation of the 
increase in medium chain fatty acid and sodium excretion in patients treated with sotagliflozin 
compared with patients treated with empagliflozin.
4.2
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS
Approximately 840 subjects (698 assigned to sotagliflozin and 229 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 AEs (TEAEs) 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, dizziness, and upper respiratory 
tract infection, all of which were reported at a greater frequency with sotagliflozin than with 
placebo. However, most were described as mild to moderate, and most resolved spontaneously 
and without discontinuation of the study drug.
In completed and ongoing clinical trials, no safety issues in addition to those already described in 
the current Investigator’s Brochure (IB) have been observed. In general, no significant imbalances 
of SAE/AEs between sotagliflozin and comparators were observed in completed studies. 
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Cumulatively, across the completed studies 8 SAEs were reported in 6 patients (4 patients with 
T2D and 2 patients with T1D), all of which were assessed as unrelated to study drug; those 
reported in 4 patients with T2D 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 in 2 patients with T1D receiving 400 mg once daily 
sotagliflozin in the Phase 2 T1D study LX4211.1-203-TIDM (16); both SAEs were assessed as 
due to failure of insulin delivery via insulin pump.
Study LX4211.1-114-NRM, a drug interaction study with digoxin, a sensitive P-glycoprotein 
(P-gp) substrate, indicated that sotagliflozin acts as a weak P-gp inhibitor. Thus, sotagliflozin 
increases systemic exposure of digoxin and other substrates of P-gp (17).
The efficacy of sotagliflozin has been shown in other studies in T2D patients. Study 
LX4211.1-202-DM, which was also described in Section 4.1, was a Phase 2, multicenter, 
randomized, double-blind, placebo-controlled, parallel-group study evaluating the safety and 
efficacy of sotagliflozin in combination with metformin in patients with T2D who had inadequate 
glycemic control on metformin monotherapy (N = 299) (15). The primary objective of this 
dose-ranging study was to evaluate the change from Baseline to Week 12 in HbA1c of 4 different 
dosing regimens of sotagliflozin (75 mg once daily, 200 mg once daily, 400 mg once daily, and 
200 mg twice daily given as tablets) versus placebo in combination with metformin. Prespecified 
secondary efficacy endpoints were proportion of subjects achieving an HbA1c value of <7.0% at 
Week 12, change from Baseline in FPG and 3-hour oral glucose tolerance test, and changes from 
Baseline in body weight, BP, and triglycerides. Sotagliflozin reduced mean HbA1c from Baseline
to Week 12 to a statistically and clinically significant degree for all four dose regimens compared 
to placebo (p = 0.025, p = 0.018, p <0.001, and p <0.001), respectively. The arithmetic mean 
change from Baseline in HbA1c was greatest for the 400 mg once daily group (-0.92%), followed 
by the 200 mg twice daily group (-0.80%). The least squares (LS) mean difference from placebo 
was also greatest for the 400 mg once daily group (-0.79%; p <0.001), followed by the 200 mg
twice daily group (-0.61%; p <0.001). The LS mean differences from placebo were similar for the 
200 mg once daily group (-0.34%) and the 75 mg once daily group (-0.33%).
More information on the safety of sotagliflozin and on the clinical program can be found in the 
IB.
4.3
RATIONALE FOR SELECTION OF DOSE
The proposed 400 mg once daily dosage is based on the results of the Phase 2b study 
LX4211.1-202-DM (15). In this study, dosages 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 once daily dosage was chosen for further evaluation based on its HbA1c lowering 
effect and the overall safety and tolerability observed at this dose. At 12 weeks, the 400 mg once 
daily dosage lowered HbA1c by a mean of 0.92%, while placebo lowered HbA1c by a mean of 
0.09%. Lower doses were less effective than the 400-mg dose and did not have any advantages in 
safety or tolerability. The overall incidence of AEs at the 400 mg once daily dosage was similar to 
placebo. In addition for this active controlled trial, it is appropriate to compare the projected 
maximum dose for sotagliflozin versus the approved maximum dose for the comparator
(empagliflozin) (12).
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In Study LX4211.202, patients with SBP ≥130 mmHg at Baseline had a reduction in SBP after 
12 weeks of treatment with sotagliflozin (15). The reduction noted in patients with Baseline
SBP ≥130 mmHg was 1, 3, 10, 16, and 17 mmHg, respectively, in placebo, sotagliflozin 75 mg
once daily, sotagliflozin 200 mg once daily, sotagliflozin 400 mg once daily, and sotagliflozin 
200 mg twice daily. Similar to other parameters, the sotagliflozin 400 mg daily dose has optimal 
effect on the SBP reduction.
From a safety perspective, sotagliflozin was well tolerated across studies. In healthy subjects,
sotagliflozin was well tolerated following single doses up to 2 000 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. In patients with T2D, 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. Additional details on these studies are available in the IB.
4.4
RATIONALE FOR STUDY DESIGN AND CONTROL GROUPS
This study is designed to demonstrate the efficacy in lowering HbA1c, lowering BP and safety of 
sotagliflozin when used as add-on therapy in patients with T2D who have inadequate glycemic 
control. 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 effects of sotagliflozin are supported by Phase 1 and Phase 2 studies 
and animal toxicology data in rats up to 26 weeks and dogs up to 39 weeks as well as 2-year 
carcinogenicity data in rats.
The study will be a double-blind design. There will be 3 arms in this study: placebo, 
empagliflozin, and sotagliflozin. The control group will be treated with the maximum tolerated 
dose of empagliflozin (SGLT2 inhibitor) or placebo, and the double-blind design will 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, the Sponsor, and the 
service provider to the treatment allocations; and by adjudicating the endpoints in a blinded 
fashion. A placebo arm was included to support the primary objective of demonstrating benefit of 
sotagliflozin as add-on therapy to patients inadequately controlled on a DPP4(i) with or without 
metformin.
A parallel-group, randomized, 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.
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4.5
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 program will also provide efficacy and safety data for 
sotagliflozin in combination with other antidiabetic medications. 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, BP, and triglycerides
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 AEs and 
discontinuations due to AEs have been limited and balanced between treatment and comparator 
groups. Based on an evaluation of the cumulative safety data for the sotagliflozin clinical 
program, genital infections are monitored closely as an important identified risk. However, reports 
of these events have been infrequent and have responded to standard treatment.
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.
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5
STUDY OBJECTIVES
5.1
PRIMARY
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 T2D who have 
inadequate glycemic control on a DPP4(i) with or without metformin.
5.2
SECONDARY
The secondary objectives of this study are to demonstrate:

Noninferiority of sotagliflozin 400 mg versus empagliflozin on HbA1c reduction from 
Baseline at Week 26

Superiority of sotagliflozin 400 mg versus placebo with respect to:
-
Change from Baseline in 2-hour PPG reduction following a mixed meal tolerance test 
(MMTT) at Week 26
-
Change from Baseline in FPG reduction at Week 26
-
Change from Baseline in Body weight reduction at Week 26
-
Proportion of patients with HbA1c <6.5% and <7.0% at Week 26
-
Change from baseline in sitting SBP reduction at Week 12 in Patients with SBP
≥130 mmHg at Baseline
-
Change from baseline in sitting SBP reduction at Week 12 in all patients

Superiority of sotagliflozin 400 mg versus empagliflozin with respect to change from 
baseline in:
-
HbA1c reduction at Week 26
-
Sitting SBP reduction at Week 12 in patients with SBP ≥130 mmHg at Baseline
-
Sitting SBP reduction at Week 12 in all patients

To evaluate the safety of sotagliflozin 400 mg versus empagliflozin 25 mg, and placebo,
throughout the 26-week trial.
5.3
OTHER
Other objectives of this study are:

To compare sotagliflozin versus empagliflozin and placebo with respect to change from 
Baseline in:
-
Estimated glomerular filtration rate (eGFR)
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-
Serum creatinine
-
Urinary glucose excretion and urine glucose to creatinine ratio (UGCR)
-
Urine albumin to creatinine (UACR) for all patients and patients with UACR
>30 mg/g at Baseline
-
Sitting SBP for patients with Baseline SBP <130 mmHg at Weeks 12 and 26
-
Sitting SBP for patients with Baseline SBP ≥130 mmHg at Week 26
-
Sitting SBP for all patients at Week 26
-
Sitting DBP for patients with Baseline SBP ≥130 mmHg at Weeks 12 and 26
-
Reduction in body weight by ≥2%, ≥5%, and ≥10%

To compare sotagliflozin versus empagliflozin with respect to change from Baseline in:
-
2-hour PPG reduction following an MMTT at Week 26
-
FPG reduction at Week 26
-
Body weight reduction at Week 26

To compare the use of rescue medications for hyperglycemia in the sotagliflozin and 
empagliflozin treatment groups

To assess plasma levels of sotagliflozin and sotagliflozin-3-O-glucuronide in the 
sotagliflozin treatment arm

To compare hemodynamic markers (including plasma renin activity [PRA], aldosterone, 
angiotensinogen 1, angiotensinogen 2 and glucagon) in the sotagliflozin and empagliflozin 
treatment groups.
5.4
AMBULATORY BLOOD PRESSURE MONITORING SUBSTUDY
The objective of the ABPM substudy is to compare the effect of sotagliflozin, empagliflozin, and
placebo in a subset of patients based on:

24-hour average SBP and DBP

Average adjusted awake time BP as measured by SBP and DBP with adjustment based on 
actigraphy

Average adjusted sleeping time BP as measured by SBP and DBP with adjustment based 
on actigraphy.
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6
STUDY DESIGN
6.1
DESCRIPTION OF THE STUDY
This study is a Phase 3, multicenter and multinational, 2:2:1 randomized, double-blind
(single-blind Run-in Phase), placebo- and active-controlled, double-dummy, parallel-group study 
that is anticipated to enroll approximately 700 patients.
The study comprises an up to 4-week 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 
Phase, and a 4-week post-treatment Follow-up visit. To qualify for randomization, patients must 
demonstrate compliance based upon tablet and capsule count (≥80%) during the Run-in Phase.
The study design is presented graphically in Section 1.1.
6.1.1
Screening Period
6.1.1.1
Screening Phase
The Screening Phase will last up to 2 weeks. It must be long enough to collect the data required to 
establish whether the patient satisfies the inclusion/exclusion criteria.
Patients with T2D who have inadequate glycemic control on DPP4(i) with or without metformin 
for at least 12 weeks prior to Screening are eligible for enrollment in this study. To ensure an 
approximately equal number of patients have Screening SBP <130 mmHg or SBP ≥130 mmHg, 
the number of patients enrolled in each category will be limited to 60% of all patients 
(≤420 patients).
At the Screening Visit (Visit 1) after signing the informed consent form (ICF), eligibility criteria 
will be assessed and Screening assessments will be performed.
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
Single-blind Placebo Run-in Phase
The Run-in Phase will last 2 weeks. Patients will be treated in a single-blind manner with placebo 
(identical to sotagliflozin 200 mg and empagliflozin 25 mg in appearance) administered once 
daily during the Run-in Phase, starting from Visit 2, to assess patients’ compliance to the study 
medication.
During the Run-in Phase, patients will receive a glucose meter and study diary. Patients will be 
trained to perform blood glucose measurements and complete the study diary correctly.  
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6.1.2
Double-blind Treatment Period
Eligible patients will be randomized on Day 1 (Visit 3). To qualify for randomization, patients
must also demonstrate compliance during the single-blind placebo Run-in Phase based upon tablet 
and capsule count (≥80%) and, as assessed, at the Investigator’s discretion.
Randomization will be stratified by:

HbA1c at Screening (≤8.5%, >8.5%)

SBP at Screening (<130 mmHg, ≥130 mmHg)

Metformin use at Screening (Yes, No).
Following randomization, patients will be treated in a double-blind manner for 26 weeks. 
Approximately 700 patients will be randomly assigned 2:2:1 to the following 3 treatment groups 
on top of DPP4(i) with or without metformin:

Sotagliflozin arm (estimated N = 280): sotagliflozin 400 mg, given as two (2) 200 mg
tablets and one (1) placebo capsule (identical to empagliflozin capsule), once daily before 
the first meal of the day

Empagliflozin arm (estimated N = 280): placebo, given as two (2) placebo tablets 
(identical to sotagliflozin in appearance) and one capsule of empagliflozin 25 mg, once 
daily before the first meal of the day

Placebo arm (estimated N = 140): placebo, given as two (2) placebo tablets (identical to 
sotagliflozin) and one placebo capsule (identical to empagliflozin), once daily before the 
first meal of the day.
The doses of the OADs (DPP4[i]) and/or metformin should be held constant throughout the entire 
26-week double-blind Treatment Period (ie, not changed except for safety reasons), and the dose 
of all antihypertensive medications should be held constant for the first 12 weeks except for safety 
reasons.
6.1.3
Ambulatory blood pressure monitoring substudy
In several preselected study sites, approximately 180 patients will participate in a substudy of 
ABPM to further assess BP changes over time. In sites participating in the ABPM substudy, 
patients must consent to conducting ABPM to participate in this study until the planned number of 
subset patients has been reached (sites will be informed).
Baseline ABPM will be measured starting at an additional study visit 1 week before 
Randomization (Visit 3A). Postrandomization ABPM will take place at 2 additional in-person 
study visits 1 day prior to the Week 12 (Visit 6A) and Week 26 (Visit 8A) visits. The details of 
the ABPM substudy procedures are provided in Appendix B.
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6.1.4
Follow-up period
Following the last dose of the investigational medicinal product (IMP; either as scheduled or 
prematurely), a post-treatment Follow-up Visit should be scheduled for all patients 28 days
(4 weeks) ±5 days after permanent IMP discontinuation to collect safety information.
6.2
DURATION OF STUDY PARTICIPATION
6.2.1
Duration of study participation for each patient
The total duration of the study for each patient will be up to 34 weeks and will include a 
Screening Phase of up to 2 weeks, a 2 week Run-in Phase, a 26-week double-blind Treatment 
Period, and a 4-week Follow-up Period after completion of study treatment.
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) (Section 6.4.2) or other unforeseen developments.
6.3
INTERIM ANALYSIS
No interim analysis is planned.
6.4
STUDY COMMITTEES
6.4.1
Steering Committee
The Steering Committee (SC) will be composed of experts in diabetes and scientists with clinical 
and methodological expertise.
This Committee, led by a Chair, will be responsible for producing and conducting a scientifically 
sound study and for ensuring accurate reporting of the study. In that capacity, the SC will need to
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.
Details of the activities and responsibilities of the SC are provided in a separate SC Charter.
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6.4.2
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:

Review of accumulating clinical study safety data by treatment

Make a recommendation to the Sponsor regarding the study following each meeting.
Safety data to be reviewed will be unblinded and include events and outcomes described in 
Section 6.4.3 for adjudication, as well as any additional safety data considered relevant. 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.
Details of the DMC processes and procedures are outlined in a separate DMC Charter.
6.4.3
Clinical Endpoint Committee
The Clinical Endpoint Committees (CECs) 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 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).
6.4.4
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 drug-induced liver injury (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.
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7
SELECTION OF PATIENTS
Note: A patient must 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.
For study sites participating in the ABPM substudy, patients must also consent to the ABPM to 
participate in this study until the planned the number of participants has been reached.
7.1
INCLUSION CRITERIA
I 01.
Patients with Type 2 Diabetes on DPP4(i) with or without metformin at a stable dose for at 
least 12 weeks prior to Screening Visit. Metformin dose will be ≥1500 mg per day 
(or maximum tolerated dose [documented]). DPP4(i) dose must be the appropriate dose per 
local label.
I 02.
Signed written informed consent.
7.2
EXCLUSION CRITERIA
Patients who have met all the inclusion criteria listed in Section 7.1 will be screened for exclusion 
criteria.
7.2.1
Exclusion criteria related to study methodology
E 01. At the time of Screening age <18 years or less than legal age of majority, whichever is 
greater
E 02. Body mass index (BMI) ≤20 kg/m2 or >45 kg/m2 at Screening
E 03. Use of systemic glucocorticoids (excluding topical, ophthalmic, nasal spray or inhaled 
applications) for more than 10 consecutive days within 90 days prior to the Screening Visit
E 04. Use of weight loss medications or weight change of 5 kg or more during the 12 weeks
before Screening
E 05. Likelihood of requiring treatment during the study period with drugs not permitted by the 
study protocol (eg, long-term systemic glucocorticoids) and refusing to or unable to take 
alternative treatment
E 06. Patients who have previously participated in any clinical trial of sotagliflozin/LX4211
E 07. 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
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E 08. Known presence of factors that interfere with the central laboratory 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 Visit, any condition that shortens 
erythrocyte survival)
E 09. History of drug or alcohol abuse within 6 months prior to Screening
E 10. 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 11. At the sites with participating ABPM patients, patients work night (third) shift (defined as
11:00 PM [23:00] to 7:00 AM [07:00])
E 12. Patient has an upper arm circumference <24 cm or >42 cm
E 13. 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 mandatory background therapies
E 14. Type 1 diabetes mellitus
E 15. HbA1c <7.0% or >11.0% at Screening Visit (central laboratory)
E 16. FPG >270 mg/dL (>15.0 mmol/L) measured by the central laboratory at Screening 
(Visit 1), and confirmed by a repeat test (>270 mg/dL [>15.0 mmol/L]) before 
Randomization Visit
E 17. Use of any antidiabetic drug other than DPP4(i) and metformin within 12 weeks preceding 
the Screening Visit
E 18. Previous use of any types of insulin for >1 month (except for treatment of gestational 
diabetes)
E 19. History of DKA or nonketotic hyperosmolar coma within 12 weeks prior to the Screening 
Visit
E 20. Use of a selective SGLT2 inhibitor (eg, canagliflozin, dapagliflozin, or empagliflozin) 
within 3 months prior to Screening Visit
E 21. Patient who has taken other investigational drugs or prohibited therapy for this study 
within 12 weeks or 5 half-lives from prior to Screening, whichever is longer
E 22. Patients with contraindication to metformin as per local labeling.
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7.2.3
Exclusion criteria related to the current knowledge of sotagliflozin and 
empagliflozin
E 23. Patients with contraindication to empagliflozin as per local labeling.
E 24. Pregnant (confirmed by serum pregnancy test at Screening) or breast-feeding women.
E 25. Women of childbearing potential (WOCBP) not willing to use highly effective method(s) 
of birth control during the study treatment period and follow-up period, or who are 
unwilling or unable to be tested for pregnancy (see Appendix A), during the study.
E 26. Mean of 3 separate BP measurements >180 mmHg (SBP) or >100 mmHg (DBP).
E 27. History of hypertensive crisis resulting in emergency medical care within 12 weeks prior to 
Screening Visit.
E 28. History of gastric surgery including history of gastric banding or inflammatory bowel 
disease within 3 years prior to the Screening Visit.
E 29. Known allergies, hypersensitivity, or intolerance to SGLT2 inhibitor or any inactive 
component or placebo (ie, microcrystalline cellulose, croscarmellose sodium [disintegrant], 
talc, silicone dioxide, and magnesium stearate [nonbovine]), or intolerance of 
empagliflozin unless the reaction is deemed irrelevant to the study by the Investigator.
E 30. Laboratory findings with the central laboratory tests at Visit 1
-
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the 
upper limit of the normal laboratory range (x ULN)
-
Total bilirubin >1.5 x ULN (except in case of Gilbert’s syndrome)
-
Neutrophils <1500/mm3 (or according to ethnic group) and/or platelets <100 000/mm3
-
Amylase and/or lipase >3 x ULN
-
Patients with renal impairment as defined by the eGFR criterion that precludes
initiation of empagliflozin as per the approved local label (eg, <45 mL/min/1.73 m2 in 
US; <60 mL/min/1.73 m2 in EU).
E 31. Secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, 
Cushing's syndrome)
E 32. For patients on hypertensive medications, the antihypertensive has changed in the 8 weeks
prior to Screening (new drug or new dose).
E 33. Current diagnosis of chronic hepatitis, and/or other clinically active liver disease requiring 
treatment.
E 34. 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).
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7.2.4
Additional exclusion criteria during or at the end of screening before randomization
E 35. Patients insufficiently compliant during Run-in Phase. Noncompliance will be based on
tablet and capsule count (<80%) or based on the opinion of the Investigator
E 36. Patient withdraws informed consent before randomization (patient who is not willing to 
continue) or patient fails to return
E 37. Any clinically significant abnormality identified on physical examination, laboratory tests, 
electrocardiogram (ECG) , or vital signs at the time of Screening Period 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 38. Lower extremity complications (such as skin ulcers, infection, osteomyelitis and gangrene) 
identified during the Screening period, and still requiring treatment at Randomization.
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8
STUDY TREATMENTS
8.1
INVESTIGATIONAL MEDICINAL PRODUCT(S)
The IMPs are sotagliflozin 400 mg, empagliflozin 25 mg, and matching placebo. Patients will be 
provided with kits containing wallets of sotagliflozin or empagliflozin, or their 
sotagliflozin-matching placebo (supplied as tablets identical to sotagliflozin 200 mg tablets in 
appearance) or empagliflozin-matched placebo (supplied as capsules identical to empagliflozin 
25 mg capsules in appearance). Each patient will be supplied with the appropriate number of kits, 
on a schedule according to the dispensing scheme indicated in the study flow chart 
(See Section 1.2).
Table 1 provides a summary of the IMP (dose and timing).
Table 1 - Summary of investigational medicinal products during Treatment Period
Treatment group
Sotagliflozin 400 mg group
Empagliflozin 25 mg group
Placebo group
Name of IMP
Sotagliflozin (SAR439954)
Empagliflozin
Placebo
Pharmaceutical form
Sotagliflozin (SAR439954) 
will be supplied as 200 mg
tablets
Empagliflozin will be supplied 
as 25 mg capsules
Placebo will be supplied as 
tablets (identical to 
sotagliflozin in appearance)
and capsules (identical to 
empagliflozin in 
appearance)
Dose, timing, and route of 
administration
Two 200-mg tablets, taken 
orally once daily, before first 
meal of the day
One placebo capsule
One 25 mg capsule, taken 
orally once daily, before first 
meal of the day
Two placebo tablets
Two placebo tablets and 
one placebo capsule, taken 
orally once daily, before 
first meal of the day 
Duration of treatment
26-week double-blind 
Treatment Period following 
randomization
26-week double-blind 
Treatment Period following 
randomization
2 weeks Run-in and 
26 weeks following 
randomization
Storage conditions
Store between +15°C and +30°C (59°F and 86°F)
IMP = investigational medicinal product
No dose reductions are planned.
8.2
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)
Noninvestigational medicinal product (NIMP) treatment is defined as the rescue medication(s) 
that will be used to treat hyperglycemia when a patient’s hyperglycemia reaches the rescue 
threshold. It also includes the background medications DPP4(i) and metformin.
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8.2.1
Background medications
Patients will be enrolled with a background therapy consisting of their existing DPP4(i) treatment 
and metformin treatment (for patients on metformin at Screening). Background metformin and 
DPP4(i) are considered to be NIMPs.
Metformin (commercial formulation) will be administered orally according to the Investigator’s 
recommendation and the locally approved label. The metformin dose must be ≥1500 mg per day 
(or maximum tolerated dose [documented]). The dose of metformin must be stable for at least 
12 weeks before Screening. The metformin dose should remain unchanged during the 26-week 
treatment period unless down-titration or discontinuation is required for safety reasons, or the 
patient’s requirement for rescue medication.
The DPP4(i) will be administered orally at the appropriate dose per local label. The dose of 
DPP4(i) must be stable for at least 12 weeks before the Screening Visit and should remain 
unchanged during the 26-week treatment period unless as needed for safety reasons, or the 
patient’s requirement for rescue medication.
Metformin and DPP4(i) treatment will be reported in the electronic case report form (eCRF). This 
information should include specific drug name, dose, route of administration, and frequency.
The cost of the background treatment metformin and DPP4(i) not covered by health insurance will 
be reimbursed where permitted by local regulations.
Rescue therapies (see Section 8.2.2) will also be considered as NIMPs.
8.2.2
Rescue therapy
The threshold values for rescue are defined as follows, depending on the study period:

From Baseline Visit (Visit 3, Day 1) to Visit 5 (Week 8) (including value at Visit 5): 
FPG >270 mg/dL (>15.0 mmol/L)

From Visit 5 (Week 8) to Visit 6 (Week 12) (including value at Visit 6): FPG >240 mg/dL 
(>13.3 mmol/L)

From Visit 6 (Week 12) up to the end of the treatment period Visit 8 (Week 26): FPG 
>200 mg/dL (>11.1 mmol/L) or HbA1c ≥8.5%. 
Note: The 8.5% criterion does not apply if the HbA1c decrease from Baseline was 
≥1.0%).
Routine fasting SMBG and central laboratory alerts on FPG (and HbA1c after Week 12 and 
onwards) are set up to ensure that glycemic parameter results remain within predefined thresholds.

If one fasting SMBG value exceeds the specific glycemic limit on 1 day, the patient will 
check it again during the 2 following days. If all the values in 3 consecutive days exceed 
the specific limit, the patient should contact the Investigator and a central laboratory FPG 
measurement (and HbA1c after Week 12 and onwards) will be performed as soon as 
possible, preferably within 7 days to confirm the hyperglycemia.
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
Upon receipt of a central laboratory rescue alert a central laboratory retest must be 
completed and confirmed as exceeding the criterion for rescue before rescue therapy is 
initiated. The retest confirmation should be performed as soon as possible, but within 
7 days of receipt by unscheduled visit.
In the event that a confirmatory FPG and/or HbA1c exceed 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 and drink [with the 
exception of water] intake for ≥8 hours)

IMP 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.
If any of the above can reasonably explain 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 eCRF 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 and to reinforce on the absolute need to be compliant to diet and 
lifestyle recommendations, and schedule a FPG/HbA1c assessment at the next visit 
(in case the next visit is a phone call, it should be replaced by an on-site visit).
If none of the above mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, rescue medication may be introduced:

Sulfonylurea (eg, glimepiride) should be added first, unless there is a contraindication to 
sulfonylurea treatment per label. In case of contraindication to sulfonylurea, another 
rescue medication (oral or injectable) can be added at the Investigator’s decision except 
for SGLT2 inhibitors

The patient continues the study treatment (blinded) and stays in the study to collect 
efficacy and safety information. The planned visits and assessments should occur until the 
last scheduled visit

Rescue therapy is considered a NIMP. Rescue therapy is to be reported in the eCRF. This 
information should include specific drug name, dose, route of administration, and 
frequency.
If not covered by health insurance, the cost of rescue therapy will be reimbursed where permitted 
by local regulations.
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8.3
BLINDING PROCEDURES
8.3.1
Methods of blinding
To maintain blinding sotagliflozin, empagliflozin, and their matching placebo tablets (including 
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.
To prevent partial unblinding, results of laboratory assessments of HbA1c, FPG, PPG, UGE, and 
UGCR will be masked to study centers and patients after randomization and until study end. 
Additionally urinalysis by dipstick will not include the measurement of urine glucose. Urine 
glucose, albumin, calcium, and creatinine will be measured separately at Visit 3, 6, and 8 by the 
central laboratory.
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 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 laboratory and responsible personnel will follow standard 
operating 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.
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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 compounds should be managed according to the rules provided by the Sponsor.
The expiry date and storage conditions are written on the IMP labels. The IMPs should be stored 
between +15ºC and +30ºC (59ºF and 86ºF).
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 IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained.
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc.) must be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure.
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, to recall the IMP and eliminate potential hazards.
Under no circumstances will the Investigator supply IMP to a third party allow the IMP to be used 
other than as directed by this clinical trial protocol, or dispose of IMP in any other manner.
8.7.1
Treatment accountability and compliance
Accounting and compliance for IMPs will be performed at Visit 3 (Treatment Day 1) and all 
subsequent on-treatment visits.
The Investigator will check the compliance to the study treatments based on the patient diary and 
will 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 eCRF.
Rescue therapy (Section 8.2.2) is to be reported in the eCRF. This information should include 
specific drug name, dose, route of administration, and frequency.
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If compliance is inadequate as determined by the Investigator, patients will be trained again and 
mentored. If suboptimal compliance continues after training and mentoring, patients may be 
discontinued at the discretion of the Investigator after discussion with the Sponsor’s/CRO’s 
medical monitor.
8.7.2
Return and/or destruction of treatments
Patients are to return all IMP (unused, in-use, or empty wallet[s]) at each on-site visit, or at on-site 
visits after premature treatment discontinuation, as described in Section 1.2.
Patients are to return all the used, in-use and unused IMP at Visit 8 (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 log 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.
For NIMP not provided by the Sponsor (ie, rescue therapy), tracking and reconciliation is to be 
undertaken by the Investigator (or pharmacist if appropriate) according to the system proposed by 
the CRO.
8.8
CONCOMITANT MEDICATION
A concomitant medication is any treatment received by the patient concomitantly to any IMP. 
The IMP includes sotagliflozin 400 mg, empagliflozin 25 mg, and placebo.
All concomitant medications should be documented on the Medications pages of the eCRF. This 
includes all NIMP 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 any prior use of SGLT2
inhibitor 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. The existing background 
medication (NIMP) should not be modified before the rescue
Note: Short term use (<10 consecutive days) of the prohibited medication, eg, short-acting insulin 
for treatment of acute illness or surgery, is allowed

Systemic use of glucocorticoids is not allowed for more than 10 consecutive days within 
90 days prior to the Screening Visit.
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Note: Topical, ophthalmic, nasal spray, or inhaled applications are allowed.

SGLT2 inhibitors (eg, canagliflozin, dapagliflozin) are not allowed for rescue or post-IMP 
treatment until the planned end of the study (Visit 9, Week 30)

Modification of antihypertensive medication before Week 12 is not allowed unless for 
safety reasons

Use of investigational medication in any other clinical study

Initiation of any weight loss drugs (eg, phentermine, orlistat)

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 PKs or pharmacodynamics of the IMP 
or confound interpretation of the study endpoints are allowed as needed, following discussion 
between the Investigator and the Sponsor/CRO. However, doses of chronically administered 
medicines should be kept fixed during the trial if at all possible.
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.
8.9
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.
Sotagliflozin will not be provided after End of Treatment (EOT). Patient’s further treatment, for 
diabetes and other pathologies, will be at the Investigator’s discretion based on his/her clinical 
judgment.
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9
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT
9.1
EFFICACY ENDPOINT
The methods of assessment of efficacy endpoints are detailed in Section 9.1.4.
9.1.1
Primary efficacy endpoint
The primary efficacy endpoint is the change from Baseline to Week 26 in HbA1c.
9.1.2
Secondary efficacy endpoints
The secondary efficacy endpoints are:

Change from Baseline to Week 26 in 2-hour PPG following an MMTT

Change from Baseline to Week 26 in FPG

Change from Baseline to Week 26 in body weight

Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 (HbA1c responders)

Change from Baseline to Week 12 in sitting SBP in patients with SBP ≥130 mmHg at 
Baseline

Change from Baseline to Week 12 in sitting SBP in all patients.
9.1.3
Other efficacy endpoints
Other efficacy endpoints include:

Change from Baseline in:
-
eGFR
-
Serum creatinine
-
UGE and UGCR
-
UACR for all patients and patients with UACR >30 mg/g
-
Sitting SBP for patients with Baseline SBP <130 mmHg at Weeks 12 and 26
-
Sitting SBP for patients with Baseline SBP ≥130 mmHg at Week 26
-
Sitting SBP for all patients at Week 26
-
Sitting DBP for patients with Baseline SBP ≥130 mmHg at Weeks 12 and 26
-
Reduction in body weight ≥2%, ≥5%, and ≥10%.

Use of rescue medications for hyperglycemia in the sotagliflozin and empagliflozin 
treatment groups
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
Plasma concentration of sotagliflozin and sotagliflozin-3-O-glucuronide for patients 
receiving sotagliflozin

Hemodynamic markers (including plasma renin activity [PRA], aldosterone, 
angiotensinogen 1, angiotensinogen 2 and glucagon).
9.1.4
Assessment methods of efficacy endpoints
9.1.4.1
Hemoglobin A1c
Hemoglobin A1c will be assessed at Screening (Visit 1), Baseline (Visit 3), Week 8 (Visit 5), 
Week 12 (Visit 6), and Week 26 (Visit 8), measured by a certified Level I “National 
Glycohemoglobin Standardization Program” central laboratory.
9.1.4.2
Blood pressure
Blood pressure is measured as part of the vital signs assessment that is performed at all study 
visits, except for ABPM substudy visits, for both safety and efficacy endpoints. At Screening, BP
will be measured on both arms to identify and select the appropriate arm for future measurements. 
Full details and directions for the measurement of BP and heart rate (HR) are presented in 
Appendix E. The investigator will assess for volume contraction and correct volume status if 
indicated before randomization.
9.1.4.3
Postprandial glucose via MMTT
Postprandial glucose will be assessed at Baseline (Visit 3, Week 0) and at Visit 8 (Week 26) via 
MMTT to allow estimation of change from Baseline to Week 26 in 2-hour PPG following a mixed 
meal. For the efficacy assessments of the study, PPG will be measured at a central laboratory. Full 
details of the MMTT procedure at Baseline and Week 26 are presented in Appendix C. At 
Baseline (Visit 3) and Visit 8 (Week 26), PPG 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 (and dosing with DPP4[i] and metformin, if applicable) on 
Day 1 (Visit 3) will be given after collection of the 2-hour PPG sample is completed.
For the Week 26 (Visit 8) standardized MMTT, 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 mixed meal begins. At Week 26, DPP4(i) and metformin (if 
applicable) dosing will occur after collection of the 2-hour PPG sample and 3-hour PK sample is 
completed.
Plasma concentration samples at Week 26 (Visit 8) should be taken at the same time as the fasting 
blood sample and 3 hours postdose (30 minutes after the 2-hour PPG sample 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 C for further details. In some study sites, for which the 
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standard meal supplies are not approved by the local regulatory agency, the patients will not 
participate in the MMTT. Any patient who requires the addition of rescue medication prior to 
Week 26 should still have the standardized MMTT performed as scheduled.
In case of permanent discontinuation of the treatment with IMP before Week 26, every effort will 
be made to have the patient return to the site at the time of their Week 26 visit; however, the 
MMTT should not be performed at these 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 fasted
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.
9.1.4.4
Fasting plasma glucose
Fasting plasma glucose will be assessed at all study visits except at the Run-in Phase Visit 
(Week -2, Visit 2), the Follow-up Visit (Week 30, Visit 9), and ABPM substudy visits. Fasting is 
defined as no food and drink (with the exception of water) intake for ≥8 hours. The FPG 
assessment is performed on the morning of the visit. For the efficacy assessments of the study, 
FPG is measured at a central laboratory.
9.1.4.5
Body weight
Body weight is measured at every study visit. 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. Calibration should be documented in source documents. The use of balance 
scales is recommended; if digital scales are used, testing with standard weights is of particular 
importance. The floor surface on which the scale rests must be hard and should not be carpeted or 
covered with other soft material. The scale should be balanced with both weights at zero and the 
balance bar aligned. The patient should stand in the center of the platform, as standing off-center 
may affect measurement. The weights are moved until the beam balances (the arrows are aligned). 
The weight is read and recorded in the eCRF and source data. Self-reported weights are not 
acceptable; patients must not read the scales themselves.
9.1.4.6
Kidney function parameters
Serum creatinine will be assessed at Screening (Visit 1), Baseline (Visit 3), Week 4 (Visit 4),
Week 12 (Visit 6), Week 26 (Visit 8), and the Follow-up Visit (Visit 9). Home-collected urine 
albumin, total protein, creatinine, calcium, phosphorus, magnesium, and glucose will be assessed 
at Baseline (Visit 3), Week 12 (Visit 6), Week 26 (Visit 8), and the Follow-up Visit (Visit 9)
(Section 1.2). Details of urine collection and analysis are provided in Section 9.2.1.4.
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9.1.4.7
Use of rescue medications for hyperglycemia
The use of rescue medications for hyperglycemia will be assessed and reported throughout the 
double-blind Treatment Period. Routine alerts on FPG and/or HbA1c 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 8.2.2.
9.2
SAFETY ENDPOINTS
Assessments for safety include AEs, SMBG, clinical laboratory assessments, physical 
examination, ECG, weight, and vital signs. An independent DMC will meet on a regular basis to 
review accumulating clinical trial safety data by treatment.
Adjudication of all deaths, MACE, and other selected CV events, selected renal events, bone 
fracture, and DKA will be performed in a blinded manner by a CEC. Further details are available 
in Section 6.4.3 and in the CEC Charter.
Two expert committees will review all potential cases of DILIs and cases of amputation in a 
treatment-blinded manner.
The following safety endpoints will be assessed throughout the 26-week double-blind Treatment 
Period:

Adverse events, hypoglycemia (all, severe, and/or documented symptomatic 
hypoglycemia), events of special interest (EOSI), adverse events of special interest 
(AESI), AEs leading to discontinuation from the IMP, SAEs, and deaths

Acute renal failure (see Section 9.1.4.6)

Clinical laboratory results, (including fasting lipids; see Section 9.2.1.3), vital signs, and 
ECG results.
Observation period of safety endpoints
The observation period of safety data will be divided into 3 segments:

The pretreatment 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).
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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 SAEs, AESI, and EOSI will be assessed. Refer to Section 10.4 to 
Section 10.7 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 a separate category from AESI. For a list of events defined as EOSI 
and their reporting requirements see Section 10.4.1.4 and Section 10.4.4, respectively.
9.2.1.2
Hypoglycemia
Hypoglycemia events (all, severe, and/or documented symptomatic hypoglycemia) will be 
assessed starting with signing of the ICF 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 patient diary, which will be regularly reviewed by 
Investigators. See Section 10.6.1 for further details.
9.2.1.3
Laboratory safety variables
The clinical laboratory data consist of blood analysis (including clinical chemistry, hematology 
amylase, lipase, fasting lipid profile, and additional evaluations) and urinalysis, according to the 
schedule presented in Section 1.2. Clinical laboratory values will be evaluated after conversion 
into standard international units. International units will be used in all listings and tables. Table 2
lists the blood safety parameters to be assessed by the central laboratory. Urinalysis parameters 
are presented in Section 9.2.1.4.
In addition, for WOCBP, a serum pregnancy test is performed at Screening (Visit 1, Week -4) and 
urine pregnancy tests are taken at all visits during the double-blind Treatment Period (there is no 
pregnancy testing at the Run-in Phase Visit (Visit 2, Week -2). Any positive urine test result must 
be confirmed by a serum pregnancy test. The Investigator may perform additional pregnancy 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 documentation of hysterectomy or cessation of menses 
<12 months without an alternative medical cause.
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Table 2 - Blood safety parameters
Clinical chemistry
Hematology
Other parameters
Sodium
Complete blood count (CBC)
Fasting lipid profile
Potassium
Differential WBC
Total cholesterol (TC)
Chloride
Platelet count
High-density lipoprotein cholesterol (HDL-C)
Carbon dioxide (bicarbonate)
Hemoglobin
Low-density lipoprotein cholesterol (LDL-C)b
Blood urea nitrogen (BUN)
Hematocrit
Non–HDL-Cc
Creatinine (for eGFR calculationa)
Erythrocyte count
Triglycerides (TG)
Glucose (serum)
Alanine aminotransferase (ALT)
Other tests
Aspartate aminotransferase (AST)
Amylase
Total bilirubin (TB)
Lipase
Alkaline phosphatase (ALP)
Uric acid
Phosphorus
Total protein
Albumin
Magnesium
Creatine phosphokinase (CPK)
Lactic acid dehydrogenase (LDH)
All assessments to be performed by central laboratory. All assessment measured in serum.
a
The eGFR will be calculated. The recommended equation for estimating eGFR from serum creatinine is the 4-variable Modification of Diet in 
Renal Disease (MDRD) Study equation (18, 19). The IDMS-traceable version of the MDRD Study equation will be used. Either equation 
below may be used based on whether the laboratory reports conventional units or Standardized International (SI) units.
Conventional Units (for use predominantly in the US): http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-conventional-unit.asp
SI Units (for use predominantly outside the US): http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-SI-units.asp.
b
LDL-C will be calculated by Friedwald equation.
c
Non–HDL-C will be calculated as the difference between TC and HDL-C.
9.2.1.4
Urinalysis
Urinalysis (urine dipstick with microscopy) will be performed at the Screening Visit (Visit 1), 
Baseline Visit (Visit 3), and at the end of the Double-Blind Treatment Period (Visit 8, Week 26). 
Central laboratory urinalysis includes:

Urine dipstick will include: specific gravity, pH, protein, blood, ketones, bilirubin, 
urobilinogen, Nitrite, and leukocyte esterase

Urine microscopy will include, but will not be limited to: detection of formed cellular 
elements, casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment.
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To prevent partial unblinding, the central laboratory urine dipstick will not include the 
measurement of urine glucose.
In the event of abnormal urinalysis findings suspicious of urinary tract infection (UTI), urine 
culture should be performed. Positive urine culture determination will be based upon the criteria 
of the reporting laboratory. Additionally, urine culture should be performed if at any point the 
Investigator suspects the presence of a UTI.
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).
Serum creatinine will be assessed at Screening (Visit 1), Baseline (Visit 3), Week 4 (Visit 4),
Week 12 (Visit 6), Week 26 (Visit 8), and the Follow-up Visit (Visit 9). Home-collected urine 
albumin, total protein, creatinine, calcium (adjusted for creatinine), phosphorus (adjusted for 
serum phosphorus and creatinine), magnesium (adjusted for serum magnesium and urinary 
creatinine), and glucose will be assessed at Baseline (Visit 3), Week 12 (Visit 6), and Week 26 
(Visit 8) (Section 1.2).
Patients will collect home overnight urine samples during the night prior to Visits 3 (Week 0), 
6 (Week 12) and 8 (Week 26). The urine sample before the sleep will be discarded and all urine 
during sleep and the first urine after getting up the next morning will be collected. 
A central laboratory will analyze samples and estimate change from Baseline in UACR, UGE, 
UGCR, serum creatinine, and eGFR. To prevent partial unblinding, results of laboratory 
assessments of HbA1c, FPG, PPG, UGE, and UGCR will be masked to study centers and patients 
after randomization and until study end.
9.2.1.5
Vital signs and physical examination
Vital signs, including sitting BP and HR, will be assessed at all study visits, except for ABPM 
substudy visits, for safety and efficacy endpoints. Full details and directions for the measurement 
of BP and HR are presented in Appendix E.
Physical examinations will be performed at every study visit.
A complete physical examination will be performed at Visit 1 (Screening) and Visit 8 (Week 26). 
Body weight measurements are discussed in Section 9.1.4.5. The complete physical examination 
will include recording height, body weight, and vital signs. Height will be measured only at 
Screening Visit, for BMI calculations.
An abbreviated physical examination will be performed at the Run-in Phase Visit (Visit 2, 
Week -2), at every visit during the Double-blind Treatment Period except for Visit 8, and at the 
Follow-up or Premature EOT Visit (within 4 weeks of the last dose of IMP or after patient 
withdraws early from treatment). The abbreviated physical examination should focus on cardiac 
and respiratory systems, as well as any areas important for assessment of AEs, if necessary.
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9.2.1.6
Electrocardiogram variables
Twelve-lead ECG recording will be performed locally at the Run-in Visit (Visit 2), and at 
Week 26 (Visit 8).
The 12-lead ECG should be performed after the patient has spent at least 10 minutes in supine 
position and prior to IMP administration. The Investigator should review the ECG trace and 
document the interpretation, sign and date the ECG print out, and report the interpretation in the 
eCRF. Each subsequent ECG trace will be analyzed in comparison to the Screening ECG trace. 
All original ECG traces are retained as source data.
The ECG results will be evaluated as “normal” or “abnormal”.
Note: Any new ECG abnormality should be rereviewed for confirmation and reported as 
appropriate for that finding.
9.2.1.7
Self-monitored blood glucose
A meter for the self-assessment of blood glucose will be dispensed at the start of Run-in (Visit 2). 
Patients will receive a patient diary at each visit except for the Follow-up Visit (Week 30) and 
ABPM substudy visits. The patient will enter SMBG levels into this diary. The diary will be 
collected and reviewed by investigators and study staff at each visit (except ABPM substudy 
visits).
Patients will be asked to self-assess blood glucose levels 3 times a week (at least 3 times in the 
week prior to a study visit) from the Run-in Visit (Visit 2) through the end of the study (Visit 9).
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 
around the mouth. Patients will be instructed to record the presence or 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. 
SMBG for hyperglycemia: 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 Baseline Visit (Visit 3, Day 1) to Visit 5 (Week 8) 
(including value at Visit 5)

>240 mg/dL (13.3 mmol/L) from Visit 5 (Week 8) to Visit 6 (Week 12) (including value 
at Visit 6)

>200 mg/dL (11.1 mmol/L) from Visit 6 (Week 12) to Visit 8 (Week 26) (including value 
at Visit 8).
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9.3
OTHER ENDPOINTS
9.3.1
Pharmacokinetics of sotagliflozin
The PK endpoint for sotagliflozin is the plasma levels of sotagliflozin and 
sotagliflozin-3-O-glucuronide in the sotagliflozin treatment arms.
Pharmacokinetic sotagliflozin data may be subjected to a population PK analysis, which will be 
reported separately from the clinical study report (CSR).
9.3.1.1
Sampling time
At Weeks 4, 18, and 26 (Visits 4, 7, and 8, respectively), blood samples for PK assessment are to 
be drawn with the other laboratory assessments, prior to administration of IMP. An additional 
blood sample will be drawn at Week 26 (Visit 8), 3 hours after administering the dose of IMP
(30 minutes after the 2-hour PPG sample collection). The time of the last intake of study drug 
prior to visits PK samples were 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, or at subsequent visits. See Table 3 for identification of samples.
Table 3 - Sotagliflozin samples identification
Visit
Week
Relative to dosing
PK
Visit 4
Week 4
Predose
P00
Visit 7
Week 18
Predose
P01
Visit 8
Week 26
Predose
P02
Visit 8
Week 26
3 hours postdose
P03
PK: pharmacokinetic
9.3.1.2
Pharmacokinetics handling procedure
Detailed procedures for sample preparation, storage, and shipment are described in the laboratory 
manual developed by the central laboratory.
9.3.1.3
Bioanalytical method
Concentration of sotagliflozin and its 3-O-glucuronide metabolite
Plasma samples will be analyzed at Covance US using validated high performance liquid 
chromatography-tandem mass spectrometry, with a lower limit of quantification of 2 ng/mL for 
sotagliflozin and a lower limit of quantification of 10 ng/mL for sotagliflozin-3-O-glucuronide.
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The concentration of HbA1c reflects the glycemic history of the previous 120 days and is thus an 
index of mean glycemia, documenting glycemic control over the past 2 to 3 months. 
Hemoglobin A1c has also been shown to correlate with the development of long-term 
complications of diabetes, and reduction of HbA1c is known to reduce the risk of long-term 
microvascular complications. Therefore, HbA1c is considered an appropriate primary endpoint for 
assessing the effect of a treatment on glycemic control. The duration of study treatment (26 weeks
for the primary HbA1c endpoint) is considered to be sufficient for achieving stable conditions 
with IMP and for enabling an adequate assessment of time-dependent changes in HbA1c.
The problem of weight gain in T2D is widely recognized. More than 80% of individuals with T2D 
are overweight, many at the time of diagnosis. Consequently, iatrogenic weight gain is not only 
unwelcome, but represents an important clinical issue that can become a barrier to the successful 
management of glycemic control. Therefore, in this study, assessing change in body weight from 
Baseline to Week 26 is a secondary endpoint.
Improvements in FPG have been observed with sotagliflozin in multiple studies. Therefore,
assessment of FPG is relevant in this study. This parameter is 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 in normotensive patients. 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.
To further evaluate the diurnal effect of sotagliflozin on SBP compared with the comparator arms 
(placebo and empagliflozin) and to avoid the white-coat effect, a subset of patients (180 patients) 
similar to the full study population in BP levels (ie, equal distribution in SBP <130 mmHg or 
≥130 mmHg) will be evaluated by ABPM.
Safety analyses focus on the TEAEs include occurrences with SAE, AESI, EOSI, AE leading to 
IMP discontinuation, and hypoglycemic events. Other standard safety parameters such as vital 
signs, ECG and laboratory measurements will also be evaluated. 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).
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10
STUDY PROCEDURES
10.1
VISIT SCHEDULE
The visit schedule and procedures and 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 and 
assessments should be performed.
This is an out-patient study and consists of 9 on-site visits (a total of 12 on-site visits for patients 
participating in the ABPM substudy).
The patients need to arrive at the study site in a fasting state for Visit 1 through Visit 8
(Week -4/Screening through Week 26/end of double-blind Treatment Period), 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. Other procedures can be performed as scheduled. With the exception 
of PPG, all laboratory assessments will occur prior to IMP administration on the day of the visit.
The Run-in Visit (Visit 2) can be performed up to 2 weeks after the Screening Visit and once the 
results of all Screening tests are available and the patient is confirmed to be eligible for 
participation in the study. The visit windows for the Double-blind Treatment Period visits will be 
as follows: Visit 4 through Visit 6 should occur at the schedule ±3 days; Visit 7 through Visit 8
should occur at the schedule ±5 days. For the Follow-up Visit (Visit 9), the visit window should 
occur within ±5 days, 4 weeks after last dose of IMP.
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 study visits are 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 a Screening Phase and a Run-in Phase.
10.1.1.1 Screening phase
The Screening Phase will be up to 2 weeks in duration and includes Visit 1 (Week -4) only. The 
Screening Phase must be long enough to collect the data to establish whether the patient satisfies 
the inclusion/exclusion criteria.
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
The following laboratory testing (by the central laboratory):
-
FPG
-
HbA1c
-
Serum pregnancy testing for WOCBP or serum FSH and/or estradiol (for women of 
nonreproductive potential if definition of postmenopausal or premenopausal cannot be 
satisfied; see Appendix A)
-
Clinical chemistry (including amylase, lipase, and uric acid) and hematology.

AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported.

Urinalysis (dipstick and microscopy).

Patients will be instructed to return to the site in the fasting state for Visit 2 (Week -2).
10.1.1.2 Run-in Phase
The Run-in Phase is 2 weeks and includes Visit 2 (Week -2).
10.1.1.2.1Run-in Visit, Visit 2 (Week -2)
The following procedures and assessments will be performed at Visit 2 (Week -2):

Measurement of body weight

Abbreviated physical examination:
-
The abbreviated physical examination should focus on cardiac and respiratory systems, 
as well as any areas important for assessment of AEs, if necessary) and vital signs 
(SBP and DBP, and HR). After 5 minutes of rest, seated SBP, DBP, and HR will be 
assessed 3 times with at least 1 minute between each measurement (see Appendix E for 
details on BP and HR measurement).

Diet and exercise instruction will be provided

Instructions on basic GU hygiene and hydration is provided

Patient diary is dispensed and instructions/training are provided

Blood glucose meter is dispensed and instructions/training are provided

Fasting SMBG is assessed.

Instructions on DKA symptoms, glucose testing, basic genitourinary (GU) hygiene, and 
hydration (see Appendix D)

The IRT is notified for registration of Run-in Visit and allocation of single-blind Run-in 
kit

The AEs/SAEs/AESI/EOSI and hypoglycemia occurring since Visit 1 (if any) are reported

Run-in kit/placebo is dispensed

Changes in concomitant medication are reported

12-lead ECG is conducted
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
Patients are instructed to return to the site in the fasting state with used/not-used 
single-blind Run-in kit for Visit 3 (Randomization).
10.1.1.2.2Ambulatory Blood Pressure Monitoring visit (Week -1)
A subset of patients (180 patients) will complete ABPM. The first ABPM visit will occur 1 week 
before Randomization (Visit 3A, Week -1). Patients will return the ABPM device by mail after 
24-hour monitoring is complete. At least 70% recording of the expected BP recording is needed in 
each 24-hour period. The measurement will be done on the nondominant arm. Additional details 
on ABPM procedures are provided in Appendix B.
10.1.2 Double-blind Randomized 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, empagliflozin 25 mg, or matching placebo for the 26-week Double-Blind 
Treatment Period. 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: 
PK samples for sotagliflozin and sotagliflozin metabolite plasma concentration; collection of 
home overnight urine for assessment of albumin, total protein, creatinine, calcium (adjusted for 
creatinine), phosphorus (adjusted for serum phosphorus and creatinine), magnesium (adjusted for 
serum magnesium and urinary creatinine), and glucose.
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 for UTI, urine culture should be 
performed. Positive urine culture determination will be based upon the criteria of the reporting 
laboratory. Additionally, urine culture should be performed if at any point the Investigator 
suspects the presence of a UTI.
10.1.2.1 Visit 3, Randomization, Day 1 (Baseline; Week 0)
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 and vital signs

IMP accountability and compliance with single-blind placebo Run-in treatment

IRT to be notified and randomization to occur
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
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported

Diet and exercise instruction

Patient diary collected and reviewed and a new one is dispensed. Instructions/training are 
provided as needed

Instructions on DKA symptoms, glucose testing, basic GU hygiene, and hydration is 
provided

Fasting SMBG is assessed

Patients are evaluated for glycemic rescue (see Section 9.1.4.7)

The following laboratory testing (by the central laboratory):
-
FPG
-
HbA1c
-
Urine pregnancy testing for WOCBP
-
Clinical chemistry (including amylase, lipase, and fasting lipids)
-
Hematology
-
Hemodynamic markers
-
Urinalysis (dipstick and microscopy)
-
Collection of home overnight urine for albumin, total protein, creatinine, calcium 
(adjusted for creatinine), phosphorus (adjusted for serum phosphorus and creatinine), 
magnesium (adjusted for serum magnesium and urinary creatinine), and glucose.

Collection of samples for additional laboratory testing:
-
-

PPG assessment via MMTT 2 hours after consuming a standard mixed liquid breakfast 
meal

IMP is dispensed

Patients are instructed to return to the site in the fasting state for their next visit (Visit 4; 
Week 4)

Patients should be reminded to record the time of study drug intake on the day before their 
next visit

For accountability and compliance purposes, patients are instructed to return to the site 
with their used, in-use and not-used wallet(s) dispensed during Visit 3.
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10.1.2.2 Week 4 to Week 18 (Visit 4 to Visit 7)
The following procedures will be performed at Visit 4 (Week 4), Visit 5 (Week 8), Visit 6
(Week 12), and Visit 7 (Week 18), except as specified:

Concomitant medications will be assessed

Measurement of body weight

Abbreviated physical examination and vital signs

IMP accountability and compliance for double-blind IMP

IRT will be notified IMP for resupply

AEs/SAEs/AESI/EOSI and hypoglycemia (if any) occurring since the previous visit will 
be reported

Patients will be evaluated for glycemic rescue

Patient diary will be collected and reviewed and a new one will be dispensed. 
Instructions/training will be provided as needed

Instructions on DKA symptoms, glucose testing, basic GU hygiene, and hydration will be 
provided

Fasting SMBG will be assessed

Central laboratory testing:
-
FPG: all visits
-
HbA1c: Visit 5 (Week 8) and Visit 6 (Week 12)
-
Clinical chemistry, including amylase and lipase: Visit 4 (Week 4) and Visit 6 
(Week 12)
-
Hematology: Visit 4 (Week 4) and Visit 6 (Week 12)
-
Pregnancy test (WOCBP): all visits
-
FSH and/or estradiol: as needed
-
Predose PK (plasma concentration samples for sotagliflozin and 
sotagliflozin-3-O-glucuronide): Visit 4 (Week 4), Visit 7 (Week 18)
-
Hemodynamic markers: Visit 6 (Week 12)
-
Collection of home overnight urine for albumin, total protein, creatinine, calcium 
(adjusted for creatinine), phosphorus (adjusted for serum phosphorus and creatinine), 
magnesium (adjusted for serum magnesium and urinary creatinine), and glucose will 
be done prior to Visit 6 (Week 12)
-
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
Patients participating in the ABPM assessments will have an additional visit 1 day before 
the Week 12 visit (Visit 6A) for placement of the ABPM device. The ABPM device will 
be returned at the Week 12 visit (Visit 6) the following day

IMP is dispensed

Patients are instructed to return to the site in the fasting state for each subsequent visit

Patients should be reminded to record the time of study drug intake on the day before their 
next visit

For accountability and compliance purposes, patients are instructed to return to the site 
with their kit(s) dispensed during the previous visit.
10.1.2.3 Week 26 (Visit 8) - End of Treatment
The following procedures will be performed at this visit:

Concomitant medications are assessed

Measurement of body weight

Complete physical examination including vital signs

IMP accountability and compliance

Diet and exercise instruction

Instructions on DKA symptoms, glucose testing, basic GU hygiene, and hydration

IRT will be notified

AEs/SAEs/AESI/EOSI and hypoglycemia (if any) occurring since the previous visit will 
be reported

Patients evaluated for glycemic rescue

Patient diary will be collected and reviewed and a new one will be dispensed. 
Instructions/training will be provided as needed

12-lead ECG

Fasting SMBG will be assessed.

The following laboratory testing (by the central laboratory):
-
FPG
-
HbA1c
-
Clinical chemistry (including amylase, lipase, and fasting lipids)
-
Hematology
-
Hemodynamic markers
-
Urine pregnancy testing for WOCBP
-
Urinalysis sample collection (dipstick and microscopy)
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-
Collection of home overnight urine for albumin, total protein, creatinine, calcium 
(adjusted for creatinine), phosphorus (adjusted for serum phosphorus and creatinine), 
magnesium (adjusted for serum magnesium and urinary creatinine), and glucose.
-
-
Predose PK (plasma concentration sample for sotagliflozin and 
sotagliflozin-3-O-glucuronide) and postdose PK (collected 3 hours after IMP 
administration.

PPG assessment via MMTT 2 hours after consuming a standard mixed liquid breakfast 
meal

Patients participating in the ABPM assessments will have an additional visit 1 day before 
the Week 26 visit (Visit 8A) for placement of the ABPM device. The ABPM device will 
be returned at the Week 26 visit (Visit 8) the following day

Patients are to return all the used, in-use, and unused IMP at Visit 8 (or final assessment 
on-treatment visit in case of permanent premature discontinuation).
10.1.3 Post-treatment Follow-up Period
The post-treatment Follow-up Period will include an on-site visit, 4 weeks ± 5 days after the last 
dose of IMP.
The following procedures will be performed at this visit:

Concomitant medications will be assessed.

Measurement of body weight.

Abbreviated physical examination including vital signs.

IRT to be notified.

AEs/SAEs/AESI/EOSI and hypoglycemia (if any) since the previous visit will be reported.

Collect glucose meter.

Patient diary is collected and reviewed.

Central laboratory testing:
-
Clinical chemistry (including amylase and lipase).
10.2
DEFINITION OF SOURCE DATA
10.2.1 Source data to be found in patient’s file
Evaluations recorded in the eCRF must be supported by appropriately signed source 
documentation related but not limited to the following:

Agreement and signature of ICF with the study ID
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
Study ID (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)

AEs 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.
10.2.2 Source data verification requirements for screen failures
For screen failure patients, the following source data must be verified: patient’s ID details, the 
informed consent signed by the patient, the study ID (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 must be fully documented in the eCRF. In any case, the 
patient should remain in the study and followed for the remainder of the study to collect vital 
safety status and endpoint data.
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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 has considered, according to his/her best medical judgment, that the occurrence of the 
concerned event was unlikely to be related to the IMP.
Since the IMP received is blinded, patients must return to the site and IRT will be contacted for 
IMP reinitiation.
It is in the interest of the patient to monitor their blood glucose during the temporary 
discontinuation period, therefore regular determination of SMBG is to be performed and 
documented (see Section 9.2.1.7).
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the eCRF 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 other antihyperglycemic medication during the time of temporary treatment 
discontinuation (ie, insulin during a hospitalization) will be recorded as concomitant medication 
with the name and dose recorded in the eCRF.
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s)
Permanent treatment discontinuation is defined as any treatment discontinuation associated with 
the definitive decision from the Investigator or the patient not to re-expose the patient to the IMP 
at any time.
10.3.3 List of criteria for permanent treatment discontinuation
Patients may withdraw from treatment with the IMP if they decide to do so, at any time, and 
irrespective of the reason, or this may be the Investigator’s decision. Patients should discuss 
stopping study medication with the site before doing so, to allow for questions to be addressed, 
glycemic therapy to be adjusted, and a follow-up assessment to be arranged. All efforts should be 
made to document the reasons for treatment discontinuation; this reason should be documented in 
the eCRF.
The following reasons can 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
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10.3.5 Procedure and consequence for patient withdrawal from study
Patients may withdraw from the study before study completion if they decide to do so, at any time 
and irrespective of the reason. Withdrawal of consent for treatment should be distinguished from 
withdrawal of consent for follow-up visits. Patients will be told that they are free to withdraw 
from the study at any time without any adverse effect on their care. However, if they no longer 
wish to take the IMP, they will be encouraged to remain in the study and attend the remaining 
study visits. The value of all their study data collected during their continued involvement will be 
emphasized as important to the public health value of the study.
If possible, the patients are assessed using the procedure normally planned for the Week 26 (EOT)
visit.
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. 
All confirmed study withdrawals should be recorded by the Investigator in the appropriate screens 
of the eCRF and in the patient’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented.
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator should make the best effort to recontact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts (3 phone call attempts followed by a 
certified letter) to contact such patients must be documented in the patient’s records (eg, times and 
dates of attempted telephone contact, receipt for sending a registered letter).
Patients who have withdrawn from the study cannot be rerandomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.
10.4
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING
10.4.1 Definitions of adverse events
10.4.1.1 Adverse event
An 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 the IMP.
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10.4.1.2 Serious adverse event
An 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; or

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
-
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).
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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 to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment.
The AESI for this study are:

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 entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.4.1.2)
-
In the event of pregnancy in a female participant, IMP should be discontinued
-
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (see Appendix A).

Symptomatic overdose with IMP/NIMP:
-
A symptomatic overdose (accidental or intentional) with the IMP/NIMP is an event 
suspected by the Investigator or spontaneously notified by the patient 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 eCRF 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.
Note: An asymptomatic overdose with the IMP/NIMP, accidental or intentional, is 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 >3 x ULN (refer to related flowchart, Appendix F).
10.4.1.4 Events of special Interest
An EOSI is a serious or nonserious 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 to characterize and understand them. These events should be reported on the 
specific eCRF page (where applicable) and will only qualify for expedited reporting when serious 
(fulfilling SAE criteria).
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The EOSI for this study are:

MACE (CV death, MI, 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)

UTIs

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)

DKA

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)

AEs 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 pages of the eCRF

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)

In this study, the use of concomitant medications including antidiabetic medications, as 
well as metformin and DPP4(i), may make it difficult to assess the causal relationship, 
particularly for hypoglycemia. The 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, 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.
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
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 sign, 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 eCRF; the system will automatically send a notification to the monitoring team and 
pharmacovigilance after approval of the Investigator within the eCRF

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 e-mail 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 eCRF 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) must be available and should be used when 
the eCRF system does not work.
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team.
10.4.4 Guidelines for reporting adverse events of special interest
For AESI, 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 eCRF.
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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 F.
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in Appendix F.

Neutropenia

Thrombocytopenia

ALT increase

Acute renal insufficiency

Suspicion of rhabdomyolysis.
10.4.7 Guidelines for reporting product complaints (IMP/NIMP)
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines.
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE.
10.5
OBLIGATIONS OF THE SPONSOR
During the course of the study, the Sponsor will report in an expedited manner:

All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, Independent Ethics Committee (IECs)/Institutional Review 
Board (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 AESI to those regulatory authorities who require such reporting:
-
Pregnancy
-
Symptomatic overdose
-
ALT increase >3 times ULN.
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Adverse events that are considered expected will be specified by the reference safety information 
provided in the current IB.
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 CSR.
10.6
SAFETY INSTRUCTIONS
10.6.1 Hypoglycemia
During the study, patients are instructed to document any hypoglycemic episodes in their study 
diary. Hypoglycemia will be reported in the specific eCRF 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 American Diabetes Association workgroup on 
hypoglycemia classification (20, 21) and summarized in Figure 1.
In addition to the threshold of ≤70 mg/dL (≤3.9 mmol/L), hypoglycemia episodes with a plasma 
glucose of <54 mg/dL (<3.0 mmol/L) will be analyzed separately.
Figure 1 - Hypoglycemia classification in Study EFC14867
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PG = plasma glucose; SAE = serious adverse event.
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 blood 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 ≤70 mg/dL
(≤3.9 mmol/L).
Clinical symptoms that are considered to result from a hypoglycemic episode include increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma.
Asymptomatic hypoglycemia
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L).
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 events. 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 ≤70 mg/dL [≤3.9 mmol/L]), ie, symptoms treated with oral carbohydrate 
without a test of plasma glucose.
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Relative hypoglycemia
Relative hypoglycemia, recently termed “pseudo-hypoglycemia” (22), 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 >70 mg/dL (>3.9 mmol/L).
10.7
ADVERSE EVENTS MONITORING
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final CSR.
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11
STATISTICAL CONSIDERATIONS
11.1
DETERMINATION OF SAMPLE SIZE
The sample size/power calculations were performed based on the primary endpoint.
A sample size of 280 patients in the sotagliflozin group and 140 patients in the placebo group will 
provide more than 90% power to detect a difference of 0.6% for change from Baseline to 
Week 26 in HbA1c between sotagliflozin and placebo (standard deviation [SD]=1.1%; 5% 
significance level 2-sided).
A sample size of 280 patients in the sotagliflozin group and 280 patients in the empagliflozin 
group will ensure that the upper bound of the 2-sided 95% CI of the adjusted mean difference 
would not exceed 0.3% with more than 80% power to show noninferiority for intent-to-treat (ITT) 
analysis and for completer analysis considering 15% dropout. This calculation assumes a common 
SD of 1.1%, and the true difference between sotagliflozin and empagliflozin is zero for change 
from Baseline to Week 26 in HbA1c.
The total sample size will be approximately 700 patients to be randomized (sotagliflozin group: 
280; empagliflozin group: 280; placebo group: 140).
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, regardless of whether the treatment kit was used or not

The safety population (ie, randomized and treated patients)

The ITT population

The randomization strata (HbA1c at Screening [≤8.5%, >8.5%], SBP at Screening 
[<130 mmHg, ≥130 mmHg], and metformin use at Screening [Yes, No]). Any discrepancy 
between the strata assigned by IRT and the information reported on eCRF will be listed for 
all randomized patients.

Patients who have completed the 26-week Double-Blind Treatment Period

Patients who discontinued the IMP during the 26-week Double-Blind 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.
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For all categories of patients except screened, percentages will be calculated using the number of 
randomized patients as denominator for each treatment group.
A listing of patients prematurely discontinued from the treatment, along with reasons for 
discontinuation, will be provided. Similarly, a listing 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 included 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.
11.3.2 Intent–to-treat population
Efficacy analyses (with the exception of MMTT 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.
For some sites for which the standard meal supplies are not approved by the local regulatory 
agency, the patients will not participate in the MMTT. Those patients in the specific region will 
not be included in the efficacy population for MMTT analyses (change from Baseline to Week 26 
in 2-hour PPG following an MMTT).
11.3.3 Safety population
Safety analyses will be based on the safety population, defined as all randomized patients who 
receive at least 1 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.
In addition:

Nonrandomized, but treated, patients will not be part of the safety population, but their 
safety data will be presented separately
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
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 active treatment group and placebo, the patient will be 
analyzed in the corresponding active treatment group

When a patient is exposed to both sotagliflozin and empagliflozin, the patient will be 
analyzed in the sotagliflozin 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 at least 1 dose of double-blind IMP.
11.4
STATISTICAL METHODS
Continuous data will be summarized by treatment group using the number of observations 
available (N), 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 (OCs), ie, inclusion of only
patients having nonmissing 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.
Analysis of demographics and Baseline characteristics, prior and concomitant medications will be 
provided in detail in the 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 within 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.
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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 day 
above-planned dose, as well as numbers and percentages of patients with 0 to 20% and >20% of 
days under-planned dose.
11.4.2 Analyses of efficacy endpoints
Efficacy analyses will be performed on the ITT population. Statistical testing will be performed 
for primary endpoint and secondary endpoints at Week 26 (or Week 12 for SBP).
11.4.2.1 Analysis of primary efficacy endpoint
The statistical test will be two-sided tests at a nominal 5% significance level (α level).
Analysis of the primary efficacy endpoint (change from Baseline to Week 26 in HbA1c 
comparing sotagliflozin 400 mg versus placebo) will be performed on the ITT population, using 
HbA1c measurements obtained from visits during the study, including those obtained after IMP 
discontinuation or introduction of rescue therapy.
The primary efficacy endpoint of change from Baseline to Week 26 in HbA1c will be analyzed 
with missing post-baseline values imputed by placebo control-based copy reference multiple 
imputation method under the missing not at random framework:

For placebo patients, missing data will be imputed based on the placebo group data

For patients in the active arms (sotagliflozin and empagliflozin), missing data will be 
imputed as if the patients were on placebo throughout the study, where all patients' 
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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, empagliflozin, placebo), randomization strata of Screening 
HbA1c (≤8.5%, >8.5%), randomization strata of Screening SBP (<130 mmHg, ≥130 mmHg) and 
metformin use at Screening (Yes, No) 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% CI for the 
between-group 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 OCs).
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 years, ≥50 to <65 years, ≥65 years)

Gender

Baseline BMI level (<30 kg/m2, ≥30 kg/m2)

Baseline HbA1c (≤8.5%, >8.5%)

Baseline SBP (<130 mmHg, ≥130 mmHg)

Country

Metformin use at Screening (Yes, No)

Baseline eGFR (≥30 to <60 mL/min/1.73m2 [Moderate decrease in GFR], ≥60 to 
<90 mL/min/1.73m2 [Mild decrease in GFR], and ≥90 mL/min/1.73m2 [Normal])

Duration of diabetes (<10, ≥10 years).
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 (comparing sotagliflozin 400 mg versus empagliflozin and placebo) with SE and 
95% CIs will be provided as appropriate across the subgroups using contrast statements.
In the event that the subgroup factor is identical or similar to a randomization strata factor 
(eg, Baseline HbA1c category); only the subgroup factor (as a single factor and/or an interaction 
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term) will be included in the model to avoid the issue of co-linearity in the analysis. The 
corresponding strata factor will not be included in the model.
11.4.2.2 Analyses of secondary efficacy endpoints
For each of the continuous secondary endpoints, a similar approach to the primary efficacy 
endpoints will be used, with missing values imputed by placebo control-based copy reference 
multiple imputation method under the missing not at random framework:

For patients receiving placebo, missing data will be imputed based on the placebo group 
data

For patients in the active arms (sotagliflozin and empagliflozin) missing data will be 
imputed as if the patients were on 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.
Each of the complete datasets will be analyzed by the ANCOVA model with treatment groups 
(sotagliflozin, empagliflozin, placebo), randomization strata of Screening HbA1c (≤8.5%, >8.5%), 
randomization strata of Screening SBP (<130 mmHg, ≥130 mmHg) and metformin use at 
Screening (Yes, No) and country as fixed effects, and Baseline value as a covariate. For analysis 
in patients with Baseline SBP ≥130 mmHg, the randomization stratum of SBP will not be 
included in the ANCOVA model. Results from each complete dataset will be combined to provide 
the adjusted mean change from Baseline to Week 12/Week 26 for each treatment group, as well as 
the between-group differences and the 95% CIs for the differences.
Categorical secondary endpoints such as HbA1c responders (<6.5%, <7.0%) at Week 26 will be 
analyzed using a Cochran-Mantel-Haenszel method stratified by randomization strata of 
Screening HbA1c (≤8.5%, >8.5%), Screening SBP (<130 mmHg, ≥130 mmHg) and metformin 
use at Screening (Yes, No). The proportion in each treatment group will be provided, as well as 
the difference of proportions between sotagliflozin and placebo with associated 2-sided 95% CI. 
For HbA1c responders at Week 26, 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 
nonresponders.
A sensitivity analysis to noninferiority test will be conducted with the 26-week treatment 
completers using the Week 26 values and the same ANCOVA model described above.
11.4.2.3 Analysis of other efficacy endpoints
The analysis of other endpoints will be descriptive with no formal testing. Summary statistics at 
scheduled visits using OCs will be provided by each treatment group. Graphical presentations will 
also be used to illustrate trends over time.
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11.4.2.4 Multiplicity considerations
To control for the family-wise Type I error, a fixed-sequence testing procedure will be applied.
Once the primary hypothesis (superiority of the change from Baseline to Week 26 in HbA1c 
comparing sotagliflozin 400 mg versus placebo) is established statistically significant for the 
primary efficacy endpoint, the following secondary hypotheses will be tested in the following 
prioritized order:
1. The noninferiority of sotagliflozin versus empagliflozin on HbA1c reduction at Week 26
2. The superiority of sotagliflozin versus placebo on 2-hour PPG reduction at Week 26
3. The superiority of sotagliflozin versus placebo on FPG reduction at Week 26
4. The superiority of sotagliflozin versus placebo on body weight reduction at Week 26
5. The superiority of sotagliflozin versus placebo on HbA1c responder analysis 
(HbA1c<7.0% at Week 26)
6. The superiority of sotagliflozin versus placebo on sitting SBP reduction at Week 12 in
patients with Baseline SBP ≥130 mmHg
7. The superiority of sotagliflozin versus placebo on sitting SBP reduction at Week 12
8. The superiority of sotagliflozin versus empagliflozin on HbA1c reduction at Week 26
9. The superiority of sotagliflozin versus empagliflozin on sitting SBP reduction at Week 12 
in patients with Baseline SBP ≥130 mmHg
10. The superiority of sotagliflozin versus empagliflozin on sitting SBP reduction at Week 12.
If any hypothesis is found to be not statistically significant, the testing procedure will be stopped 
and the following hypotheses will not be tested. The noninferiority hypothesis will be declared 
statistically significant if the upper bound of the 2-sided 95% CI for the adjusted mean difference 
is <0.3. The superiority hypothesis will be declared statistically significant at α = 0.05 (2-sided).
No multiplicity adjustment will be made on efficacy variables other than those mentioned above.
11.4.3 Analyses of safety data
The summary of safety results will be presented by treatment group. All safety summaries will be 
descriptive; no statistical significance tests will be performed on safety data.
Safety endpoints are presented in Section 9.1.2. These analyses will be based on the Safety 
Population as defined in Section 11.3.3. Patients will be analyzed for safety analyses according to 
the treatment actually received. All safety analyses will be performed on the safety population as 
defined in Section 11.3.3 using the following common rules:
The following definitions will be applied to laboratory parameters and vital signs:

Potentially clinically significant abnormality (PCSA) values for clinical laboratory tests 
and vital signs will be defined as abnormal values considered medically important by the 
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Sponsor’s Global Pharmacovigilance and Epidemiology department and in effect at the 
time of the final SAP approval. The PCSA criteria for parameters not cited in the protocol 
as safety parameters will not be analyzed

The PCSA criteria will determine which patients had at least 1 PCSA during the 
Double-blind Treatment Period, taking into account all evaluations performed during the 
Double-blind 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 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
Pretreatment AEs are AEs that developed or worsened or became serious during the 
pretreatment period.
Treatment-emergent AEs 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 
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
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
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 (n) and percentage (%) of patients who died by study period (on-study, 
on-treatment, poststudy) 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 eCRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT, and PT showing number (n) and percentage 
(%) of patients sorted by internationally agreed order of SOC and alphabetic order of 
HLGT, HLT, and PT.
Adverse events leading to permanent treatment discontinuation
Treatment-emergent AEs leading to permanent treatment discontinuation will be summarized and 
presented as number (n) and percentage (%) of patients in each treatment group.
11.4.3.2 Analyses of hypoglycemia
The number (n) and percentage (%) of patients and rate in patient-years (2 types: the number of 
patients with events or the total number of events per 100 patient-years) of all hypoglycemia, 
severe hypoglycemia, and documented symptomatic hypoglycemia will be summarized by 
treatment group, respectively. In addition, documented hypoglycemia will also be analyzed by 
using a threshold of plasma glucose of <54 mg/dL (<3.0 mmol/L) if applicable. 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. Any ALT 
increase of >3 x ULN will be included in laboratory PCSA summary.
11.4.3.4 Analyses of events of special interest
The number (n) and percentage (%) 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).
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11.4.3.5 Analyses of laboratory variables
The number (n) and percentage (%) of patients with PCSA or by the predefined 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 out of laboratory range values and PCSA 
values.
The liver function tests, namely ALT, AST, ALP, and total bilirubin, are used to assess possible 
drug-induced liver toxicity (DILI). The proportion of patients with PCSA values at any 
post-Baseline visit by Baseline status will be displayed by treatment group for each parameter.
11.4.3.6 Analyses of vital sign variables
The number (n) 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.
11.4.3.7 Analysis of 12-lead electrocardiogram status
A shift table will be provided to present the ECG on-treatment status according to the Baseline 
status, by treatment group.
11.4.4 Analyses of other endpoints
11.4.4.1 Pharmacokinetic
The PK endpoints are presented in Section 9.3.1. Pharmacokinetic sotagliflozin data may be 
subjected to a population PK analysis, which will be reported separately.
Individual plasma concentrations of sotagliflozin and of sotagliflozin-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, 3 hours postdose), using descriptive statistics by N, geometric mean, 
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coefficient of variation, median, minimum and maximum at each visit/nominal sampling time 
point for sotagliflozin-treated patients.
11.4.4.2 Hemodynamic markers
The hemodynamic marker endpoints are presented in Section 9.3.3.
Hemodynamic markers including PRA, aldosterone, angiotensinogen 1, angiotensinogen 2, and 
glucagon will be checked to provide better characterization of hemodynamic markers in relation 
to sotagliflozin treatment.
11.4.4.3 Ambulatory blood pressure monitoring substudy
The analysis of ABPM endpoints will be descriptive with no formal testing. Summary statistics at 
scheduled visits using OC of sufficient quality will be provided by each treatment group.
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 SAP).
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12
ETHICAL AND REGULATORY CONSIDERATIONS
12.1
ETHICAL AND REGULATORY STANDARDS
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Sub-investigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
guidelines for good clinical practice (GCP), all applicable laws, rules and regulations.
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.
12.2
INFORMED CONSENT
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand.
Prior to a patient’s participation in the clinical trial, the written ICF should be signed, name filled 
in and personally dated by the patient or by the patient’s legally acceptable representative, and by 
the person who conducted the informed consent discussion. A copy of the signed and dated 
written ICF will be provided to the patient.
Separate informed consent will be sought for participation in the ABPM substudy.
The ICF used by the Investigator for obtaining the patient’s informed consent must be reviewed 
and approved by the Sponsor prior to submission to the appropriate ethics committee (IRB/IEC) 
for approval/favorable opinion
12.3
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition.
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, IB with any addenda or labeling documents, summary of 
product characteristics, package insert, Investigator’s curriculum vitae, etc.) and the date of the 
review should be clearly stated on the written (IRB/IEC) approval/favorable opinion.
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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 IB 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.
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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 eCRF, Discrepancy Resolution Form, or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives.
If any circuit includes transfer of data, particular attention should be paid to the confidentiality of 
the patient's data to be transferred.
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Sub-investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The 
Sub-investigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information.
13.2
RESPONSIBILITIES OF THE SPONSOR 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 regarding ethics, 
clinical trial protocol compliance, and integrity and validity of the data recorded on the eCRFs. 
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
(including rescue therapy), and quality of data.
13.3
SOURCE DOCUMENT REQUIREMENTS
According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the preidentified source data directly recorded in the eCRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
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ethics committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the eCRFs (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 eCRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All eCRFs
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 eCRF 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 eCRF.
The computerized handling of the data by the Sponsor or 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 eCRF.
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 trial master file.
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ADDITIONAL REQUIREMENTS
14.1
CURRICULUM VITAE
A current copy of the CV describing the experience, qualification, and training of each 
Investigator and Sub-investigator will be signed, dated, and provided to the Sponsor or service 
provider prior to the beginning of the clinical trial.
14.2
RECORD RETENTION IN STUDY SITES
The Investigator must maintain confidentiality for 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 eCRF, the IB, and the results obtained during 
the course of the clinical trial, is confidential, prior to the publication of results. The Investigator 
and any person under his/her authority agree to undertake to keep confidential and not to disclose 
the information to any third party without the prior written approval of the Sponsor.
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality.
The Sub-investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-investigators of the confidential nature of the clinical trial.
The Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party’s account.
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14.6
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, GCP, 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 are bound by professional secrecy, and 
as such will not disclose any personal identity or personal medical information.
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents.
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection.
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections.
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor.
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections.
14.8
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE
14.8.1 By the Sponsor
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including, but not limited to, the following:

The information on the product leads to doubt as to the benefit/risk ratio

Patient enrollment is unsatisfactory
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
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 Sub-investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP

The total number of patients is included earlier than expected.
In any case the Sponsor will notify the Investigator of its decision by written notice.
14.8.2 By the Investigator
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements.
14.9
CLINICAL TRIAL RESULTS
The Sponsor will be responsible for preparing a CSR and providing 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 12 months of the completion of this study at all sites, the Investigator shall have 
the right to publish or present independently the results of this study in agreement with other 
Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of any such
presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
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shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s).
The Sponsor has the right at any time to publish the results of the study.
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CLINICAL TRIAL PROTOCOL AMENDMENTS
All appendices attached hereto and referred to herein are made part of this clinical trial protocol.
The Investigator should not implement any deviation from, or changes 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.
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14. Zambrowicz B, Freiman J, Brown PM, Frazier KS, Turnage A, Bronner J, et al. LX4211, a 
dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a 
randomized, placebo-controlled trial. Clin Pharmacol Ther. 2012;92(2):158-169.
15. Rosenstock J, Cefalu WT, Lapuerta P, Zambrowicz B, Ogbaa I, Banks P, Sands A. Greater 
dose-ranging effects on A1C levels than on glucosuria with LX4211, a dual inhibitor of 
SGLT1 and SGLT2, in patients with type 2 diabetes on metformin monotherapy. Diabetes 
Care. 2015 Mar;38(3):431-8.
16. Sands AT, Zambrowicz BP, Rosenstock J, Lapuerta P, Bode BW, Garg SK, Buse JB, Banks P, 
Heptulla R, Rendell M, Cefalu WT, Strumph P. Sotagliflozin, a Dual SGLT1 and SGLT2
Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes. Diabetes Care. 2015 
Jul;38(7):1181-8.
17. Lexicon Pharmaceuticals, Inc., Clinical Study Report for: A Phase 1, Randomized, Double 
blind, Placebo controlled, Ascending Single and Multiple Dose Study to Determine the Safety 
and Tolerability of Orally Administered LX4211 in Healthy Human Subjects (LX4211.1-114-
NRM).
18. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-70.
19. Florkowski CM, Chew-Harris JS. Methods of Estimating GFR - Different Equations Including 
CKD-EPI. Clin Biochem Rev. 2011;32(2):75-9.
20. 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;28(5):1245-9.
21. 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.
22. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95.
23. Mancia G, Fagard R, Narkiewicz K,  Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC 
guidelines for the management of arterial hypertension: the Task Force for the Management of 
Arterial Hypertension of the European Society of Hypertension (ESH) and of the European 
Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159–219.
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APPENDICES
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Appendix A
Contraceptive guidance and collection of pregnancy information
DEFINITIONS
Woman of childbearing potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy.
3. Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high 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 one 
of the nonhormonal 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 enrollment.
CONTRACEPTION GUIDANCE
Female participants
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 ±5 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).
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Table 4 - Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods that are User Dependenta
Failure rate of <1% per year when used consistently and correctly

Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulation:
-
Oral
-
Intravaginal
-
Transdermal.

Progestogen-only hormone contraception associated with inhibition of ovulation:
-
oral
-
injectable.
Highly Effective Methods that are User Independenta

Implantable progestogen-only hormonal contraception associated with inhibition of ovulation:
-
Intrauterine device 
-
Intrauterine hormone-releasing system.

Bilateral tubal occlusion.
Vasectomized partner
A vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.
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 treatment. 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 participant.
NOTES:
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 participants participating in clinical studies.
COLLECTION OF PREGNANCY INFORMATION
Male participants with partners who become pregnant

The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study treatment
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
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. The 
female 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, the 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 participants who become pregnant 

The Investigator will collect pregnancy information on any female participant 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 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate, and the information 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
Any pregnancy complication or elective termination of a pregnancy will be reported as an 
adverse event (AE) or serious adverse event (SAE). A spontaneous abortion is always 
considered to be an SAE and will be reported as such. Any poststudy pregnancy-related 
SAE considered reasonably related to the study treatment by the Investigator will be 
reported to the Sponsor as described in Section 10.4.3. While the Investigator is not 
obligated to actively seek this information in former study participants, he or she may 
learn of an SAE through spontaneous reporting

Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment or be withdrawn from the study.
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Appendix B
Ambulatory blood pressure monitoring substudy
Background
A Phase 2 trial of sotagliflozin (LX4211.1-202) provided evidence that sotagliflozin reduced both 
systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with elevated SBP 
and DBP at Baseline, but not in normotensive patients. In this substudy of approximately 
180 patients, patients with similar Baseline BP distribution as the full study population (ie, equal 
numbers of patients with SBP <130 mmHg or ≥130 mmHg) will have ambulatory blood pressure 
monitoring (ABPM) assessed for 24 hours via ambulatory blood pressure (BP) monitoring 
technology. The ABPM substudy includes 3 sets of assessments, at 1 week before the 
Randomization Visit, and the days before the Week 12 and 26 visits, respectively, to provide a 
more systematic assessment of the SBP and DBP lowering efficacy of sotagliflozin.
Ambulatory blood pressure monitoring will be performed with a validated device provided by the 
Sponsor or Sponsor representative. The ABPM data process will be facilitated by a vendor,
 
(
, USA).
Substudy procedures
At the preselected study sites participating in the ABPM substudy, patients must consent to be a 
part of the substudy to participate in the main study until the planned number of patients for 
substudy has been achieved.
At Visit 1, patients will be provided with information on the ABPM substudy and separate written 
consent will be taken before ABPM substudy-specific procedures are performed. Patients who 
work a night (third) shift (defined as 11:00 PM [23:00] to 7:00 AM [07:00]) will be excluded 
from the ABPM substudy.
Patients in the ABPM substudy will have 3 additional visits to the site for placement of the ABPM 
device. These will be Visits 3A, 6A, and 8A. Visit 3A will occur at Week -1, 1 week before the 
Randomization Visit. Visit 6A, and Visit 8A will occur the day before Visit 6 (Week 12) and Visit 
8 (Week 26). Patients do not need to be fasting at these 3 visits.
Patients who discontinued the Investigational Medicinal Product (IMP) during the study before 
the visit for ABPM will not continue in the ABPM substudy post-IMP discontinuation. Patients 
who receive rescue therapy but remain on IMP will continue on the ABPM substudy as planned.
On the 3 visit days (Visits 3A, 6A, and 8A) each recording will start in the morning, preferably 
between 08:00 and 10:00 immediately after the administration of study medication, and will end 
after at least 24 hours of recording on the following day.

Investigator and/or designee will help patients wear the ambulant BP monitor and the 
appropriate BP cuff (depending on the patient’s arm size) on the nondominant upper arm
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
Patients should be aware that the device will automatically inflate the cuff and measure the 
BP every 20 minutes during the day-time (08:00 and 21:59) and every 30 minutes during 
the sleeping time (22:00 and 07:59) over a 24-hour period

During the ABPM period, patients should continue their daily activities and concomitant 
medications, but avoid activities that may interfere with functioning of the device such as 
vigorous exercise, bathing, or taking a shower

When the cuff starts to inflate, the patient should remain still and avoid arm movement.

Patients will record the time of sleep and any unusual events or poor sleep quality during 
the ABPM recording period in their study diary

Patients will be instructed to remove the BP device after 24-hour wearing the ABPM 
device:
-
Once the ABPM device has been placed at Visit 3A, patients will be instructed to 
remove it 24 hours later and return it to the site by mail in appropriate packaging 
provided by the site
-
Twenty-four hours after Visits 6A and 8A, patients will return to the site in a fasting 
state at Visits 6 and 8, respectively, and the device will be removed at the site.
All ABPM data will be reviewed following return of the device to ensure quality of the recording. 
The quality of a visit recording will be considered insufficient if the visit recording does not meet 
the criteria below:
1. Visit recording does not contain ≥17 nonconsecutive hours of data where each hour has at
least one valid BP measurement
2. Visit recording has <44 total measurements.
Patients with ABPM data not of sufficient quality will be asked to repeat the process as soon as 
possible. Patients with ABPM data not of sufficient quality at Visit 3A should not be randomized 
until the Baseline ABPM recording has been repeated, and the Randomization Visit (Visit 3) will 
be postponed correspondingly.
Patients must be well trained to understand the importance of the ABPM performance and 
compliance of the instruction. Technique support via a 24/7 help-line service for troubleshooting 
will be provided by 
. The patients should immediately contact the sites if they encounter any 
device-related events (malfunction) or any questions about the ABPM. The investigator or site 
staff will help patients contact the 
 service line for problem solving.
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Appendix C
Two-hour standardized mixed meal
A 2-hour postprandial glucose (PPG) will be obtained after a standardized mixed meal in all 
patients at Baseline (Day 1, Visit 3) and at Week 26 (Visit 8). Patients requiring rescue therapy
prior to Week 26 (see Section 9.1.4.3) should still have the standardized mixed meal tolerance test 
(MMTT) performed at Week 26. Patients who permanently discontinued the Investigational 
Medicinal Product (IMP) before Week 26 will not perform the MMTT at the planned Visit 8
(Week 26).
The standardized MMTT must not be performed while patients are temporarily off IMP; the 
Medical Monitor will address any episodes on a case-by-case basis and the standardized MMTT 
will be rescheduled when the patient can resume IMP, if applicable.
The first dose of double-blind investigational medicinal product (IMP; and dosing with dipeptidyl 
peptidase 4 inhibitor [DPP4(i)] and metformin, if applicable) on Day 1 (Visit 3) will be given 
after completion of the 2-hour PPG collection. For the Week 26 standardized MMTT, 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 mixed meal begins. 
At Week 26, DPP4(i) and metformin (if applicable) dosing will occur after collection of the 
2-hour PPG sample and 3 hour PK sample are completed.
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 approximately 40 g carbohydrate and approximately 240 calories per 
bottle (approximately 8 ounces). The caloric composition of the meal is approximately 65% 
carbohydrate, approximately 15% protein, and approximately 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 approximately 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 
PPG plasma sample has been collected. If the patient is unable to consume at least 50% of the 
standard mixed meal, the MMTT should not be completed and the subsequent standardized 
MMTT should not be performed. If the patient is able to consume >50% of the standardized 
mixed meal, the approximate amount should be recorded, and an equivalent amount should be 
consumed at the subsequent standardized mixed meal.
Baseline Visit (Day 1, Visit 3) Standardized MMTT:
1. Record in the source documents the amount and brand name of the standard meal liquid 
nutrition drink the patient is instructed to consume
2. Fasting blood samples are obtained, including Time 0 fasting FPG
3. Record the time of blood sample collection in the source documents
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4. Immediately after the fasting blood samples are collected, the patient starts consuming the 
standard meal
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 (and DPP4[i] and metformin, if applicable) are 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 8) Standardized MMTT:
1. Record in the source documents the amount and brand name of the standard meal liquid 
nutrition drink the patient is instructed to consume
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 sample is collected
12. Two hours and 30 minutes after the meal ingestion starts, the 3-hour PK sample is 
collected
13. DPP4(i) and metformin (if applicable) are administered after the PK blood sample is 
drawn
14. Record in the source documents the time the 2-hour postprandial blood samples are 
collected.
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Appendix D
Recommendations on basic genitourinary hygiene, maintaining 
hydration and recognizing diabetic ketoacidosis
Basic genitourinary hygiene
Patients with Type 2 diabetes are at risk for developing genitourinary (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 systolic 
blood pressure, 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 Type 2 diabetes:
“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
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
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 diabetic ketoacidosis
Potential gastrointestinal (GI) adverse events occurring with sotagliflozin may mask presenting 
symptoms of diabetic ketoacidosis (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. 
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If your study site is closed and your study doctor is not available, go to the nearest emergency 
room for evaluation.
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 adverse event data are collected or the patient reports DKA or intercurrent illness 
(including infections), generalized weakness, increased weight loss, GI 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” electronic case report form will be completed.
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Appendix E
Measurement of blood pressure and heart rate
Equipment
1. Blood pressure measurements will be taken by an automated blood pressure (BP) 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 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.
Determination of the arm with the highest blood pressure
At the Screening Visit (Visit 1, Week -4), BP will be measured on both arms to identify and select 
the appropriate arm for future measurements. Seated BP should be measured in both arms after 
5-minute rest period, and then again after 1 minute in both arms in seated position. The arm with 
the highest SBP will be determined at this visit, and BP should be measured in this arm 
throughout the study.
Measurement Technique (23)
At the Screening Visit (Visit 1, Week -4), immediately following arm selection, with the patient in 
the same position, an additional seated BP should be measured in the selected arm (at least 
1 minute after last measurement).
At all other visits, following the 5-minute rest period, 3 separate seated BPs should be measured 
in the arm selected at Visit 1, 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 eCRF. The mean of the 3 seated BPs will constitute the 
BP value for that visit.
Three seated HR measurements will also be obtained. The mean of the 3 seated HR measurements 
will constitute the HR value for that visit.
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