Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 770
Healthy volunteers: no

Brief summary:
The purpose of the study is to demonstrate the superiority of sotagliflozin versus placebo on hemoglobin A1c (HbA1c) reduction in participants with type 2 diabetes (T2D) who have inadequate glycemic control on a DPP4(i) with or without metformin.

Detailed description:

Arms:
arm 1: Following a 2-week run-in period, sotagliflozin 400 mg (milligrams) administered as two 200 mg tablets and one placebo capsule (identical to the empagliflozin capsule in appearance), once daily before the first meal of the day for up to 26 weeks. arm 2: Following a 2-week run-in period, placebo matching sotagliflozin administered as two tablets (identical to sotagliflozin in appearance) and one capsule of empagliflozin 25 mg, once daily before the first meal of the day for up to 26 weeks. arm 3: Following a 2-week run-in period, placebo was given as two placebo tablets (identical to sotagliflozin) and one placebo capsule (identical to empagliflozin) once daily before the first meal of the day for up to 26 weeks.

Interventions: intervention 1: Sotagliflozin intervention 2: Empagliflozin intervention 3: Placebo intervention 4: Placebo
Intervention descriptions: intervention 1: Sotagliflozin 400 mg was administered as two tablets, once daily before the first meal of the day. intervention 2: Empagliflozin 25 mg capsule was administered, once daily before the first meal of the day. intervention 3: Placebo was administered as two tablets (identical to sotagliflozin in appearance), once daily before the first meal of the day. intervention 4: Placebo was administered as one capsule (identical to the empagliflozin capsule in appearance), once daily before the first meal of the day.

Protocol document:
Prot_000.pdf: 
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.
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
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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 
(electronic 
 
 
 
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(electronic 
 
 
 
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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
(electronic 
 
 
 
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(electronic 
 
 
 
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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
(electronic 
 
 
 
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(electronic 
 
 
 
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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.
(electronic 
 
 
 
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(electronic 
 
 
 
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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
(electronic 
 
 
 
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(electronic 
 
 
 
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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)
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
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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.
(electronic 
 
 
 
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(electronic 
 
 
 
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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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BIBLIOGRAPHIC REFERENCES
1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: 
perspectives on the past, present, and future Lancet. 2014;383:1068-83.
2. Fowler MJ. Microvascular and Macrovascular Complications of Diabetes. Clinical Diabetes. 
2008;26(2):77-82.
3. Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 
burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and 
prediabetes prevalence. Popul Health Metr. 2010;8:29.
4. International Diabetes Federation. IDF Diabetes Atlas, 7th ed. Brussels, Belgium: 
International Diabetes Federation, 2015. Available from URL: http://www.diabetesatlas.org. 
[Accessed November 2016].
5. World Health Organization, Regional Office for Europe, Data and Statistics. Available from 
URL: http://www.euro.who.int/en/health-topics/noncommunicable-diseases/diabetes/data-
andstatistics. [Accessed November 2016].
6. Hediger HA, Coady MJ, Ikeda TS, Wright EM. Expression cloning and cDNA sequencing of 
the Na+/glucose co-transporter. Nature. 1987;330(6146):379-81.
7. Wright EM. I. Glucose galactose malabsorption. Am J Physiol. 1998;275(5 Pt 1):G879-82.
8. Mudalier S, Polidori D, Zambrowicz B, Henry RR.  Sodium–glucose cotransporter inhibitors: 
Effects on renal and intestinal glucose transport:  from bench to bedside. Diabetes Care. 
2015;38:2344–53.
9. Raskin P. Sodium–glucose cotransporter inhibition:  therapeutic potential for the treatment of 
type 2 diabetes mellitus.  Diabetes Metab Res Rev. 2013;29(5):347–56.
10. Canagliflozin [package insert]. Titusville, NJ, Janssen Pharmaceuticals, Inc.;July 2016. p 1-15.
11. Dapagliflozin [package insert]. Wilmington, DE, AstraZeneca Pharmaceuticals LP;June 2016. 
p 1-10.
12. Empagliflozin [package insert]. Ridgefield, CT, Boehringer Ingelheim Pharmaceuticals, Inc., 
and Indianapolis, IN, Eli Lilly and Company;July 2016. p 1-25.
13. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl U, Woerle H. Empagliflozin 
reduces blood pressure in patients With type 2 diabetes and hypertension. Diabetes Care. 2015 
Mar;38(3):420-8.
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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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17
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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SAP_001.pdf: 
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: 
SAP Version 3: 15-November-2019 


 
Lexicon Pharmaceuticals, Inc. 
Sotaglifozin/ LX4211 
Protocol No.: EFC14867 
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 
Covance Study ID: 000000155204 
Statistical Analysis Plan  
Version: 3 
DATE OF ISSUE: 15-Nov-2019 
Author: 
 
 
 
 
 
 
 
Lexicon Pharmaceuticals, Inc.  
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Covance Clinical Development Services 
206 Carnegie Center 
Princeton, NJ 08540-6233 




Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals, inc. Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 6 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 8 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 8 
1.2 
OBJECTIVES ................................................................................................................................... 8 
1.2.1 
Primary objectives ............................................................................................................................ 8 
1.2.2 
Secondary objectives ....................................................................................................................... 8 
1.2.3 
Other objectives ............................................................................................................................... 9 
1.2.4 
Objectives of ABPM substudy ........................................................................................................ 10 
1.3 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 10 
1.4 
STUDY PLAN ................................................................................................................................. 11 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 11 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 12 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 15 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 15 
2.1.1 
Demographic and baseline characteristics .................................................................................... 15 
2.1.2 
Prior or concomitant medications ................................................................................................... 17 
2.1.2.1 
Rescue therapy .............................................................................................................................. 18 
2.1.2.2 
Prohibited prior and concomitant medications ............................................................................... 18 
2.1.3 
Efficacy endpoints .......................................................................................................................... 19 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 19 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 19 
2.1.3.3 
Other efficacy endpoint(s) .............................................................................................................. 19 
2.1.3.4 
ABPM substudy efficacy endpoint(s) ............................................................................................. 20 
2.1.4 
Safety endpoints ............................................................................................................................ 20 
2.1.4.1 
Hypoglycemia ................................................................................................................................. 21 
2.1.4.2 
Adverse events variables ............................................................................................................... 23 
2.1.4.3 
Deaths ............................................................................................................................................ 26 
2.1.4.4 
Laboratory safety variables ............................................................................................................ 26 
2.1.4.5 
Vital signs variables ....................................................................................................................... 27 
2.1.4.6 
Physical examination ..................................................................................................................... 28 
2.1.4.7 
Electrocardiogram variables .......................................................................................................... 28 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 28 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 28 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 30 


Statistical Analysis Plan 
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Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals, inc. Protocol No. EFC14867 
  
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COVANCE INC. CONFIDENTIAL 
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2.3 
ANALYSIS POPULATIONS ........................................................................................................... 31 
2.3.1 
Efficacy populations ....................................................................................................................... 31 
2.3.1.1 
Intent-to-treat population ................................................................................................................ 32 
2.3.1.2 
ABPM substudy population ............................................................................................................ 32 
2.3.1.3 
Completers population ................................................................................................................... 32 
2.3.2 
Safety population ........................................................................................................................... 32 
2.3.3 
PK population ................................................................................................................................. 33 
2.4 
STATISTICAL METHODS ............................................................................................................. 33 
2.4.1 
Demographics and baseline characteristics .................................................................................. 33 
2.4.2 
Prior or concomitant medications ................................................................................................... 33 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 34 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 35 
2.4.3.2 
Compliance .................................................................................................................................... 35 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 36 
2.4.4.1 
Analysis of primary efficacy endpoint............................................................................................. 36 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 40 
2.4.4.3 
Analyses of other efficacy endpoints ............................................................................................. 42 
2.4.4.4 
Analysis of ABPM substudy efficacy endpoints ............................................................................. 42 
2.4.4.5 
Multiplicity issues ........................................................................................................................... 43 
2.4.5 
Analyses of safety data .................................................................................................................. 44 
2.4.5.1 
Analyses of hypoglycemia ............................................................................................................. 45 
2.4.5.2 
Analyses of adverse events ........................................................................................................... 46 
2.4.5.3 
Deaths ............................................................................................................................................ 50 
2.4.5.4 
Analyses of laboratory variables .................................................................................................... 50 
2.4.5.5 
Analyses of vital sign variables ...................................................................................................... 51 
2.4.5.6 
Analyses of electrocardiogram variables ....................................................................................... 52 
2.4.5.7 
Analyses of physical examination variables .................................................................................. 52 
2.4.6 
Analyses of pharmacokinetic variables .......................................................................................... 52 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 52 
2.5.1 
General conventions ...................................................................................................................... 52 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 53 
2.5.3 
Missing data ................................................................................................................................... 53 
2.5.4 
Windows for time points /Measurements for analyses .................................................................. 56 
2.5.5 
Unscheduled visits ......................................................................................................................... 59 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 59 
2.5.7 
Statistical technical issues ............................................................................................................. 59 
3 
INTERIM ANALYSIS ..................................................................................................................... 60 
4 
DATABASE LOCK ........................................................................................................................ 61 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals, inc. Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
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5 
SOFTWARE DOCUMENTATION ................................................................................................. 62 
6 
REFERENCES ............................................................................................................................... 63 
7 
LIST OF APPENDICES ................................................................................................................. 64 
APPENDIX A 
AMBULATORY BLOOD PRESSURE MONITORING SUBSTUDY .................................... 65 
APPENDIX B 
ABPM SUBSTUDY EFFICACY VARIABLE DERIVATION ................................................. 68 
APPENDIX C 
LIST OF PTS FOR SELECT EOSIS (MEDDRA V22.0) ...................................................... 70 
APPENDIX D 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 79 
APPENDIX E 
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 85 
APPENDIX F 
STUDY FLOW CHART ........................................................................................................ 90 


Statistical Analysis Plan 
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Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABPM: 
ambulatory blood pressure monitoring 
ACR: 
albumin-creatinine ratio 
AEs: 
adverse events 
AESI: 
adverse events of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
ATC: 
anatomical therapeutic chemical 
BMI: 
body mass index 
BP: 
blood pressure 
BUN: 
blood urea nitrogen 
CEC: 
clinical endpoint committee 
CI: 
confidence interval 
CMH: 
Cochran-Mantel-Haenszel 
CPK: 
creatine phosphokinase 
CSR: 
clinical study report 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DCCT: 
diabetes control and complications trial  
DILI: 
drug-induced liver injury  
DMC: 
Data monitoring Committee 
DPP4(i): 
dipeptidyl peptidase 4 inhibitor  
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EMA/PRAC: 
European Medicines Agency/ Pharmacovigilance Risk Assessment Committee 
EOSI: 
events of special interest 
FPG: 
fasting plasma glucose 
GCR: 
glucose-creatinine ratio 
HbA1c: 
hemoglobin A1c 
HDL-C: 
high density lipoprotein cholesterol 
HLGT: 
high level group term 
HLT: 
high level term 
HR: 
heart rate 
IFCC: 
International Federation of Clinical Chemistry and Laboratory Medicine  
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 


Statistical Analysis Plan 
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Date of Issue: 15-Nov-2019 
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KM: 
Kaplan-Meier 
LDH: 
lactic acid dehydrogenase 
LDL-C: 
low density lipoprotein cholesterol 
LLT: 
lower level term 
MACE: 
major adverse cardiovascular events 
MAR: 
missing at random 
MDRD: 
modification of diet in renal disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MI: 
multiple imputation 
MMTT: 
mixed meal tolerance test 
MNAR: 
missing not at random 
NIMP: 
noninvestigational medicinal product 
PCSA: 
potentially clinically significant abnormality 
PPG: 
postprandial glucose 
PRA: 
plasma renin activity 
PT: 
preferred term 
SAE: 
serious adverse events 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SOC: 
system organ class 
T2D: 
type 2 diabetes mellitus 
TC: 
total cholesterol 
TEAE: 
treatment-emergent adverse event 
TG: 
triglycerides 
UGE: 
urinary glucose excretion 
ULN: 
upper limit of normal 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
 


Statistical Analysis Plan 
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Date of Issue: 15-Nov-2019 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a Phase 3, multicenter and multinational, double blind, placebo- and active-controlled, 
parallel-group study. Patients will be randomly assigned 2:2:1 to the following 3 treatment groups: 
• Sotagliflozin 400 mg. 
• Empagliflozin 25 mg. 
• Placebo. 
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 
Period, and a 4-week post-treatment Follow-up Period. 
At the end of the screening period, eligible patients will be centrally randomized (using permuted 
block randomization schedule) via an Interactive Response Technology (IRT). The randomization 
will be stratified by: 
• Hemoglobin A1c (HbA1c) at Screening (≤8.5%, >8.5%). 
• Metformin use at Screening (Yes, No). 
• Systolic blood pressure (SBP) at Screening (<130 mmHg, ≥130 mmHg). 
It is anticipated to randomize a total of approximately 700 patients. 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 preselected study sites participating in the ABPM substudy, approximately 180 of the 
700 enrolled patients are expected to participate in an Ambulatory Blood Pressure Monitoring 
(ABPM) substudy where patients will have blood pressure measured by a validated ABPM device.  
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to demonstrate the superiority of sotagliflozin 400 mg versus 
placebo on HbA1c reduction at Week 26 in patients with type 2 diabetes mellitus (T2D) who have 
inadequate glycemic control on a DPP4(i) with or without metformin. 
1.2.2 Secondary objectives 
The secondary objectives of this study are to demonstrate: 


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Date of Issue: 15-Nov-2019 
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• 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 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. 
1.2.3 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-creatinine ratio (GCR), 
- 
Urine albumin-creatinine ratio (ACR) for all patients and patients with urine 
ACR>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: 


Statistical Analysis Plan 
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Date of Issue: 15-Nov-2019 
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- 
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. 
1.2.4 Objectives of ABPM 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 blood pressure (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. 
Full details of the ABPM substudy are provided in Appendix A. 
1.3 
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).  


Statistical Analysis Plan 
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Date of Issue: 15-Nov-2019 
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1.4 
STUDY PLAN 
The study plan is presented graphically as follows. 
 
The study flowchart can be found in Appendix F. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled).   
The protocol history table below gives the timing, rationale, and key details of major changes to 
the protocol statistical section.  
The first patient was enrolled on 27-Nov-2017. There were no planned interim analyses. 


Statistical Analysis Plan 
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Date of Issue: 15-Nov-2019 
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Table 1 - Protocol amendment statistical changes 
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
2 
11-April-2018 
The actigraphy capacity of the 
ABPM device will be used to 
measure the patient’s activity levels, 
ie, when he/she is awake or asleep. 
This will provide a more accurate 
assessment of awake time and 
sleeping time BP, because not all 
patients have the same 
activity/sleeping patterns. 
Objectives and endpoints of ABPM substudy 
updated: 
Average adjusted awake time BP and 
sleeping time BP modified as measured by 
SBP and DBP with adjustment based on 
actigraphy  
2 
11-April-2018 
Baseline eGFR defined as 
recommended by CDISC 
Therapeutic Area Data Standards 
User Guide for Diabetic Kidney 
Disease 
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. 
2 
11-April-2018 
For some sites the standard meal 
supplies are not approved by the 
local regulatory agency, the patients 
will not participate in the MMTT. 
Those patients in the sites of specific region 
will not be included in the efficacy population 
for MMTT analyses. No such specific region 
exists, so this amendment does not change 
the statistical analysis. See Section 1.6. 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
The statistical analysis plan (SAP) history table below gives the timing, rationale, and key details 
for major changes to the statistical analysis features in the statistical analysis plan. Changes also 
incorporated in a protocol amendment are cross-referenced to Table 1. 


Statistical Analysis Plan 
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Date of Issue: 15-Nov-2019 
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Table 2 - Statistical analysis plan statistical changes 
SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
1 
04-Oct-2018 
The actigraphy capacity of the ABPM 
device will be used to measure the 
patient’s activity levels, ie, when 
he/she is awake or asleep. This will 
provide a more accurate assessment 
of awake time and sleeping time BP, 
because not all patients have the 
same activity/sleeping patterns. 
Objectives and endpoints of ABPM substudy 
updated: 
Average adjusted awake time BP and sleeping 
time BP modified as measured by SBP and 
DBP with adjustment based on actigraphy* 
1 
04-Oct-2018 
Baseline eGFR defined as 
recommended by CDISC Therapeutic 
Area Data Standards User Guide for 
Diabetic Kidney Disease 
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* 
1 
04-Oct-2018 
Clarification on EOSI renal events  
Details specified on renal events to be 
consistent with outcome studies in Section 
2.1.4.2. 
1 
04-Oct-2018 
 
  
 
 
1 
04-Oct-2018 
 
 
  
 
1 
04-Oct-2018 
No such sites that the standard meal 
supplies are not approved by the local 
regulatory agency. 
Remove the statement that those patients in the 
specific region will not be included in the 
efficacy population for MMTT analyses. Efficacy 
population will be used for MMTT analyses 
1 
04-Oct-2018 
Updating the wording to be 
consistency with CEC charter 
Unstable angina leading to hospitalization 
changed to Unstable angina requiring 
hospitalization 
2 
11-Jun-2019 
 
 
 
 
 
 
 
2 
11-Jun-2019 
Number of iterations for multiple 
imputation was changed 
Number of iterations for multiple imputation was 
changed from 10 000 to 2000 
2 
11-Jun-2019 
Wording change to be consistent with 
CEC charter 
”Heart failure leading to hospitalization” 
changed to ”Heart failure requiring 
hospitalization” 
2 
11-Jun-2019 
MedDRA version and dictionary 
updated 
MedDRA version was updated to V22.0 and list 
of PTs for selected EOSI was updated 
2 
11-Jun-2019 
To add high and low doses of 
vildagliptin for baseline characteristics 
Label recommended high and low doses added 
for vildagliptin 


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SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
3 
This version 
 
 
 
 
 
 
 
3 
This version 
 
 
3 
This version 
 
 
 
3 
This version 
 
 
 
 
3 
This version 
Assess robustness on the ITT-based 
analyses 
Identify possible need to conduct sensitivity 
analyses for PK anomalies 
3 
This version 
Compare treatment groups for 
important pharmacodynamic 
measures 
Addition of inferential analyses for UGE and 
UGCR endpoints 
3 
This version 
Maximize number of null hypotheses 
to reject, include/omit clinically 
meaningful hypotheses to test 
Analyses of some secondary endpoints are 
omitted from the statistical testing hierarchy: 
FPG reduction at week 26 (superiority 
comparison of sotaglifozin 400 versus placebo), 
 HbA1c responder analysis (HbA1c < 7.0% at 
Week 26 / superiority comparison of sotaglifozin 
400 versus placebo), 
Sitting SBP reduction at Week 12 (superiority 
comparison of sotaglifozin 400 versus placebo) 
Addition of 2-Hour PPG reduction at Week 26 
as a secondary endpoint to statistical testing 
hierarchy (superiority comparison of sotagliflozin 
400 mg versus empagliflozin 25 mg) 
 * Change made in Protocol Amendment 2 dated 11-April-2018. 
 


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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value (with the exception of serum creatinine and eGFR) is defined as the last 
available value before the first dose of double-blind investigational medicinal product (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. 
Baseline safety and efficacy parameters are presented along with the summary statistics in the 
safety and efficacy sections (Section 2.4.5 and Section 2.4.4). 
Demographic characteristics 
Demographic characteristics to be summarized are: 
• Age (years) derived as: (Year of informed consent - Year of birth). 
• Age categories:  (<50, ≥50 to <65, ≥65 to <75, ≥75 years). 
• Gender (Male, Female). 
• Race (White, Black or African American, Asian, American Indian or Alaska native, 
Native Hawaiian or other pacific islander, Multiple, Unknown). 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown). 
• HbA1c (%) at screening visit. 
• Randomization strata of HbA1c (≤8.5%, >8.5%) at screening (data from IRT). 
• Randomization strata of metformin use (Yes, No) at screening (data from IRT). 
• Mean SBP at screening. 
• Randomization strata of SBP (<130 mmHg, ≥130 mmHg) at screening (data from IRT). 
• Baseline body mass index (BMI) (kg/m2) derived as: (Weight in kg)/(Height in meters)2. 
• Baseline BMI categories (<30, ≥30 kg/m2). 
• Country. 


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Disease characteristics at screening or baseline 
Disease history includes:  
• Duration of diabetes (years) derived as: (Date of informed consent – Date of diagnosis of 
diabetes + 1)/365.25. 
• Duration of diabetes categories: (<10, ≥10 years). 
• Age at diagnosis of diabetes (years): (Year of diagnosis of diabetes – Year of birth). 
• Metformin use at screening (Yes, No). 
• Duration of metformin treatment (for those patients who used metformin at screening) 
(years): (date of informed consent - date of first intake of metformin +1)/365.25. 
• Daily dose of metformin (mg) at baseline (for those patients who used metformin at 
screening). 
• Categorized daily dose of metformin at baseline for those patients who used metformin at 
screening (<1500, ≥ 1500  to <2500, ≥2500 mg). 
• Duration of DPP4(i) treatment (years): (date of informed consent - date of first intake of 
DPP4(i) +1)/365.25. 
• Categorized daily dose of DPP4(i) at baseline:  
- 
At label recommended high dose, 
- 
At label recommended low dose, 
- 
Other doses. 
where the label recommended high dose for sitagliptin is 100 mg, alogliptin is 25 mg, 
saxagliptin is 5 mg, linagliptin is 5 mg and vildagliptin is 100 mg, and label recommended 
low dose for sitagliptin is 50/25 mg, alogliptin is 12.5 mg, saxagliptin is  
2.5 mg and vildagliptin is 50 mg. 
• Baseline diabetic microvascular complications (Yes, No) [ie, diabetic retinopathy, diabetic 
neuropathy, diabetic nephropathy, diabetic peripheral neuropathy (sensory or motor), 
diabetic autonomic neuropathy, diabetic foot infection]. 
• Baseline urine ACR categories (<30 mg/g [Normal], ≥30 to <300 mg/g 
[Microalbuminuria], and ≥300 mg/g [Macroalbuminuria]). 
• eGFR at screening (mL/min/1.73m2). 
• eGFR categories at screening (<15 mL/min/1.73m2 [End stage renal disease], ≥15 to 
<30 mL/min/1.73m2 [Severe decrease in GFR], ≥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]). 
• Prior antihypertensive medication identified by therapeutic class as agents acting on the 
renin-angiotensin system, beta blocking agents, diuretics (a sub-category: loop diuretics 
identified by pharmacological class as high-ceiling diuretics), calcium channel blockers, 


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Date of Issue: 15-Nov-2019 
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Covance Study ID: 000000155204  
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and antihypertensives according to World Health Organization-Drug Dictionary 
(WHO-DD). 
Medical or surgical history 
Medical history and medical findings include: 
• Physical examination. 
• Medical or surgical history. 
• Medical history cardiovascular. 
• Surgical history amputation. 
• Alcohol habits. 
• Tobacco smoking habits. 
Medical and surgical history will be coded to a “lower level term (LLT)”, “preferred term (PT)”, 
“high level term (HLT)”, “high level group term (HLGT)”, and associated primary “system organ 
class (SOC)” using the version of Medical Dictionary for Regulatory Activities (MedDRA) 
currently in effect at Covance at the time of database lock. 
Any technical details related to computation, dates, and imputations for missing dates are 
described in Section 2.5. 
2.1.2 Prior or concomitant medications 
All medications taken within 3 months before the screening visit (any time for prior SGLT2) and 
until the end of the study are to be reported in the electronic case report form (e-CRF). 
All medications will be coded using the WHO-DD using the version currently in effect at 
Covance at the time of database lock. 
• Prior medications are those the patient used prior to first administration of the 
double-blind IMP.  Prior medications can be discontinued before first administration or 
can be ongoing during treatment phase. 
• Concomitant medications are any treatments received by the patient concomitantly to any 
IMP, from first administration of double-blind IMP to the date of last administration 
+ 10 days.  A given medication can be classified both as a prior medication and as a 
concomitant medication. 
• Posttreatment medications are those the patient took in the period running from the 
11th day after the last administration of double-blind IMP up to the end of the study. 
Background DPP4(i) and metformin are considered as noninvestigational medicinal products 
(NIMP).  


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Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.2.1 Rescue therapy 
If rescue thresholds are reached, 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. Rescue therapy is considered a NIMP. 
2.1.2.2 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.  
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. 


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2.1.3 Efficacy endpoints 
All efficacy measurements collected during the study will be considered for analyses, including 
those obtained after IMP discontinuation or introduction of rescue therapy (see Section 2.5.4). 
HbA1c, 2-hour PPG, FPG, urine ACR, UGE, urine GCR, serum creatinine, eGFR and 
hemodynamic markers are measured/calculated in a central laboratory (see study flowchart in 
Appendix F). Body weight, SBP and DBP (see Section 2.1.4.4) are measured at on-site visits by 
the investigator. Patients requiring rescue are identified as those with the reason for treatment 
ticked “rescue therapy” in e-CRF “Medication” page. 
Efficacy variables will be summarized in both standard international units and conventional units 
when applicable. 
2.1.3.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is the change from Baseline to Week 26 in HbA1c (%). 
2.1.3.2 Secondary efficacy endpoint(s) 
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. 
2.1.3.3 Other efficacy endpoint(s) 
Other efficacy endpoints include: 
• Change from Baseline in: 
- 
eGFR, 
- 
Serum creatinine, 
- 
UGE and urine GCR, 
- 
Urine ACR for all patients and patients with Urine ACR >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, 


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- 
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. 
• Plasma concentration of sotagliflozin and sotagliflozin-3-O-glucuronide for patients 
receiving sotagliflozin. 
• Hemodynamic markers (including PRA, aldosterone, angiotensinogen 1, angiotensinogen 
2 and glucagon). 
2.1.3.4 ABPM substudy efficacy endpoint(s)  
The ABPM endpoints are changes from Baseline to Week 12 and Week 26 for all patients 
participating 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. 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events (AEs), hypoglycemia, and other 
safety information, such as clinical laboratory data, vital signs, electrocardiogram (ECG), and 
physical examination, etc.  
Observation period  
The observation period will be divided into 4 epochs: 
• The screening epoch is defined as the time from the signed informed consent date up to 
the first administration of the double-blind IMP.  
• The treatment epoch is defined as the time from the first administration of the 
double-blind IMP to the last administration of the double-blind IMP. 
• The residual treatment epoch is defined as the time from the last administration of the 
double-blind IMP up to 10 days (1 day for hypoglycemia) after the last administration of 
the double-blind IMP. 
The treatment-emergent adverse event (TEAE) period will include both treatment and 
residual treatment epochs. 


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• The posttreatment epoch is defined as the period of time starting the day after the end of 
the treatment-emergent adverse event period up to the last protocol-planned visit or the 
resolution/stabilization of all serious adverse events (SAE), adverse events of special 
interest (AESI) and events of special interest (EOSI), whichever is later. 
The on-study observation period is defined as the time from start of double-blind treatment until 
the end of the study (defined as the last scheduled visit for those who completed the study and the 
date collected on e-CRF page “Completion of End of Study/Follow-up” for those who did not 
complete the study). 
The post-study observation period is defined as the time from the day after the end of the study 
until the resolution/stabilization of all SAE, AESI and EOSI if applicable. 
2.1.4.1 Hypoglycemia 
Hypoglycemia will be identified as events recorded on the dedicated e-CRF “Hypoglycemic event 
information” page, and will be categorized as follows (see study protocol for further details): 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, intravenous glucose or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. 
Self-monitored plasma glucose values may not be available, but neurological recovery attributable 
to the restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. 
Severe hypoglycemia is identified in e-CRF “Hypoglycemic event information” page as those 
documented as, 
1. To the question “Countermeasure Administration”, ticked the option “Subject was Not 
Capable of Treating Self and Required Assistance”, and  
2. To the question “Were Symptoms Present”, ticked “Yes”. 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L 
(≤70 mg/dL). 
Clinical symptoms that are considered to result from a hypoglycemic episode are eg, increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 


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Documented symptomatic hypoglycemia is identified in e-CRF “Hypoglycemic event 
information” page as those documented as, 
1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and  
2. To the question “Were Symptoms Present”, ticked “Yes”, and  
3. With a plasma glucose value before countermeasure ≤3.9 mmol/L (≤70 mg/dL).  
Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL). 
Asymptomatic hypoglycemia is identified in e-CRF “Hypoglycemic event information” page as 
those documented as, 
1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and 
2. To the question “Were Symptoms Present”, ticked “No”, and  
3. With a plasma glucose value before countermeasure ≤3.9 mmol/L (≤70 mg/dL).  
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms of hypoglycemia are not 
accompanied by a plasma glucose determination, (but that was presumably caused by a plasma 
glucose concentration ≤3.9 mmol/L [≤70 mg/dL]), ie, symptoms treated with oral carbohydrate 
without a test of plasma glucose. 
Probable symptomatic hypoglycemia is identified in e-CRF “Hypoglycemic event information” 
page as those documented as, 
1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and 
2. To the question “Were Symptoms Present”, ticked “Yes”, and 
3. With no plasma glucose value before countermeasure, and  
4. To the question “Did this countermeasure lead a significant improvement or prompt 
recovery?”, ticked “Yes”. 
Relative hypoglycemia 
Relative hypoglycemia, recently termed “pseudo-hypoglycemia” is an event during which the 
patient reports typical symptoms of hypoglycemia, and interprets the symptoms as indicative of 
hypoglycemia, but with a measured plasma glucose concentration >3.9 mmol/L (>70 mg/dL). 
Relative hypoglycemia is identified in e-CRF “Hypoglycemic event information” page as those 
documented as, 


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1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, 
2. To the question “Were Symptoms Present”, ticked “Yes”, and  
3. With a plasma glucose value before countermeasure >3.9 mmol/L (>70 mg/dL).  
In addition of the threshold of ≤3.9 mmol/L (≤70 mg/dL), hypoglycemia episodes with a plasma 
glucose of <3.0 mmol/L (<54 mg/dL) will be analyzed separately.  
Any hypoglycemic event fulfilling the criteria of a SAE or leading to unconsciousness, coma, or 
seizure will also be recorded as a SAE (see Section 2.1.4.1). 
2.1.4.2 Adverse events variables 
Adverse event observation period  
• Pretreatment adverse events are adverse events that developed or worsened or became 
serious from the signed informed consent date up to first administration of double-blind 
IMP. 
• Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the treatment-emergent adverse event period. 
• Posttreatment adverse events are adverse events that developed or worsened or became 
serious during the posttreatment period. 
All adverse events (including SAE, AESI and EOSI) will be coded to a lower-level term (LLT), 
preferred term (PT), high-level term (HLT), high-level group term (HLGT), and associated 
primary system organ class (SOC) using the version of MedDRA currently in effect at Covance at 
the time of database lock. 
The occurrence of adverse events (including SAE, AESI and EOSI) will be recorded from the 
time of signed informed consent until the end of the study (see Section 2.1.4) or the 
resolution/stabilization of all SAE, AESI and EOSI. 
AESI include: 
• Pregnancy. 
• Symptomatic overdose with IMP/NIMP. 
• Alanine aminotransferase (ALT) increase >3 × upper limit of normal (ULN). 
EOSI include:  
• Major adverse cardiovascular events (MACE [cardiovascular death, myocardial infarction, 
or stroke]) and other specific cardiovascular (CV) events (eg, heart failure requiring 
hospitalization).   
• Severe hypoglycemia. 


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• Genital mycotic infections (to include vulvovaginal candidiasis in females and candida 
balanitis in males). 
• Urinary tract infection. 
• Clinically relevant volume depletion and events related/possibly related to volume 
depletion. 
• Diarrhea. 
• Pancreatitis. 
• Bone fractures. 
• Venous thrombotic events, to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism). 
• Diabetic ketoacidosis. 
• Renal events, to include 50% decline in eGFR, end stage kidney disease, renal death. 
• Malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, 
prostate, and thyroid cancer). 
• Adverse event leading to an amputation. 
A Clinical Endpoint Committee (CEC) will, in a blinded manner, review and adjudicate all 
deaths, myocardial infarction, stroke, unstable angina requiring hospitalization, and heart failure 
requiring hospitalization, selected renal events, bone fracture, and diabetic ketoacidosis. 
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. 
AESI and EOSI will be identified based on criteria in Table 3.  
Table 3 - Criteria for AESI and EOSI 
AE Grouping 
Criteria 
AESI 
 
Pregnancy 
e-CRF “Pregnancy” 
Symptomatic overdose with 
IMP/NIMP 
“Overdose of IMP” or “Overdose of NIMP” checked and “Symptomatic overdose” checked in 
e-CRF “Overdose” 
ALT increase >3 × ULN 
e-CRF “ALT increase” 
EOSI adjudicated 
Cardiovascular death 
Positively adjudicated by CEC: “Cardiovascular” or “Undetermined” as the primary cause of 
death 
Myocardial infarction, Unstable 
Angina requiring hospitalization 
Positively adjudicated by CEC: Yes to the question “Does the event meet the definition of 
an MI for this study?”, or Yes to the question “If event is not an MI, does the event meet the 
definition of an UA Requiring admission to hospital or emergency room, for this study?” 


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AE Grouping 
Criteria 
Stroke 
Positively adjudicated by CEC: Yes to the question “Does the event meet the definition of a 
Stroke for this study?” 
Heart failure requiring 
hospitalization 
Positively adjudicated by CEC: Yes to the question “Does the event meet the definition of a 
Heart Failure Event for this study?”  
Bone fractures 
Positively adjudicated by CEC: Yes to the question “Did the Fracture occur?” 
Diabetic ketoacidosis 
Positively adjudicated by CEC: Yes to the question “Does this event meet the criteria to be 
a DKA event?” 
EOSI Renal events where select events adjudicated 
Sustained ≥50% decrease in 
eGFR 
(1) For ≥50% decrease in eGFR from baseline, 
(1a) confirmed ≥50% decrease in GFR for ≥30 days with no reversible cause as 
recorded in e-CRF “eGFR decrease”, OR  
(1b) positively adjudicated by CEC: Yes to the question “Does the subject meet the 
criteria of CKD progression” for ≥50% decrease in eGFR. 
Sustained eGFR <15 
mL/min/1.73 m² 
(2) For eGFR <15 mL/min/1.73 m², 
(2a) confirmed eGFR <15 mL/min/1.73 m2 for ≥30 days with no reversible cause as 
recorded in e-CRF “eGFR decrease”, OR 
(2b) positively adjudicated by CEC: Yes to the question “Does the subject meet the 
criteria of CKD progression”. 
Chronic dialysis 
(3) For dialysis,  
(3a) dialysis lasted for ≥90 days (eg, end date – start date+ 1 ≥90) as recorded in e-
CRF “Renal Event – Dialysis”, OR 
(3b) positively adjudicated by CEC: Yes to the question “. Does the subject meet the 
criteria for ESRD”. 
Renal transplant* 
(4) “Renal transplant” captured in e-CRF “Other procedure form”, where adjudication is not 
required. PTs of Renal transplant (10038533), Renal and pancreas transplant (10052278), 
Renal and liver transplant (10052279) based on MedDRAv22.0. 
Renal death 
(5) Renal death as positively adjudicated by CEC: “Death - Non-Cardiovascular (Renal)” as 
the primary cause of death 
EOSI not adjudicated* 
 
Severe hypoglycemia 
Algorithm specified in Section 2.1.4.1 based on e-CRF “Hypoglycemic Events” 
Genital mycotic infections 
PTs in Appendix C 
Urinary tract infections 
PTs in Appendix C 
Clinically relevant volume depletion 
and events related/possibly related 
to volume depletion 
PTs in Appendix C 
Diarrhea 
Narrow search on “Noninfectious diarrhoea (SMQ)” [20000218] plus the following PTs 
(MedDRA v22.0:  Gastroenteritis (10017888), Antidiarrhoeal supportive care (10055660), 
Enteritis (10014866), Enteritis leukopenic (10014877), Enterocolitis (10014893), 
Enterocolitis haemorrhagic (10014896) 
Pancreatitis 
PTs in Appendix C 


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AE Grouping 
Criteria 
Venous thrombotic events 
PTs in Appendix C 
Malignancies of special interest 
Breast cancer: Narrow search on “Breast neoplasms, malignant and unspecified (SMQ)” 
[20000149] 
Prostate cancer: Narrow search on “Prostate neoplasms, malignant and unspecified (SMQ)” 
[20000152] 
Leydig-cell cancer: PTs of Leydig cell tumour of the testis (10024407) and Ovarian 
Sertoli-Leydig cell tumour (10073270) based on MedDRA v22.0 
Thyroid cancer: PTs in Appendix C 
Renal cell cancer: PTs in Appendix C 
Pancreatic cancer: PTs in Appendix C 
Bladder cancer: PTs in Appendix C 
EOSI AE leading to an amputation 
AE leading to an amputation 
“AE Correction” as the reason for amputation in e-CRF “Other Procedures related to 
Amputation”  
AE potentially leading to an 
amputation ** 
PTs in Appendix C 
* Search terms will be updated using the MedDRA version currently in effect at Covance at the time of database lock for EOSI identified by 
them. 
** AE potentially leading to amputation: not one of EOSI defined in protocol, included and analyzed due to their relevance in regards to lower 
limb complications and amputations as a requirement from health authorities. 
2.1.4.3 Deaths 
The deaths observation period are per the observation periods defined above.  
• Death on-study:  deaths occurring during the on-study observation period. 
• Death on-treatment:  deaths occurring during the TEAE period. 
• Death post-study:  deaths occurring after the end of the study. 
2.1.4.4 Laboratory safety variables 
Clinical laboratory data consists of blood analysis (including hematology, clinical chemistry, 
amylase, lipase and lipid profile) and urinalysis.  Clinical laboratory values will be summarized in 
both standard international units and conventional units when applicable. 
Blood samples for clinical laboratories will be collected at designated visits (see study flowchart 
in Appendix F). The following laboratory data will be measured at a central laboratory:  
• Hematology: 
- 
Red blood cells and platelets: hemoglobin, hematocrit, red blood cell, platelets count,  
- 
White blood cells: white blood cell, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils. 


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• Clinical chemistry: 
- 
Metabolism: glucose (serum), creatine phosphokinase (CPK),        
- 
Electrolytes and minerals: sodium, potassium, chloride, bicarbonate (ie, carbon 
dioxide), calcium, phosphorus, magnesium,  
- 
Renal function: blood urea nitrogen (BUN), creatinine, uric acid,         
- 
Liver function: total protein, albumin, ALT, aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), total bilirubin, Lactic acid dehydrogenase (LDH).       
• Lipid parameters (fasting): total cholesterol (TC), high density lipoprotein cholesterol 
(HDL-C), low density lipoprotein cholesterol (LDL-C) (calculated by Friedwald equation, 
See Section 2.5.1), Non-HDL-C (calculated as the difference between TC and HDL-C), 
triglycerides (TG). 
• Pancreatic enzymes: lipase, amylase. 
Urine samples will be collected at designated visits (see study flowchart in Appendix F). The 
following laboratory data will be measured at a central laboratory:  
• Urine dipstick includes: specific gravity, pH, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, and leukocyte esterase 
• Urine microscopy includes, but is not limited to: detection of formed cellular elements, 
casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment 
• Urine albumin, total protein, calcium, glucose, creatinine, phosphorus, and magnesium 
Serum glucose, UGE, calculated urine ACR and calculated urine GCR will be presented as 
efficacy parameters in Section 2.4.4. For creatinine and calculated eGFR, PCSA summaries will 
be presented in the safety section while descriptive summaries in the efficacy section. 
Technical formulas are described in Section 2.5.1. 
2.1.4.5 Vital signs variables 
Vital signs include:  heart rate (HR), systolic and diastolic blood pressure, temperature, and 
respiratory rate (see study flowchart in Appendix F for designated visits).  They will be performed 
after the patient has been seated for at least 5 minutes. Blood pressure and HR will be assessed 
3 times with at least 1 minute between each measurement following the 5-minute rest period, and 
prior to phlebotomy. The mean of the 3 measurements will be analyzed for each vital sign 
variable (HR, SBP, and DBP). 


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2.1.4.6 Physical examination 
A complete physical exam will be performed at Visit 1 (Screening) and Visit 8 (Week 26). 
“Normal”, “Abnormal” or “Not done” as determined by the Investigator will be reported in the 
e-CRF by body system. 
2.1.4.7 Electrocardiogram variables 
12-lead ECGs will be performed at Visit 2 (Run-in) and Visit 8 (Week 26). ECG status of 
“normal” or “abnormal” will be reported in the e-CRF as determined by the Investigator. 
2.1.5 Pharmacokinetic variables  
Pharmacokinetic variables include the plasma concentration of sotagliflozin and its 
3-O-glucuronide metabolite in the sotagliflozin group.  
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as all patients who have signed the informed consent.   
Randomized patients consist of all patients with a signed informed consent form who have had a 
treatment kit number allocated and recorded in the IRT database, regardless of whether the 
treatment kit was used or not. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report (CSR) using a flowchart diagram or summary tables: 
• Screened patients. 
• Run in patients: patients who had a run-in record in IRT. 
• Screen failure patients (including failures during run-in) and reasons for screen failure. 
• Nonrandomized but treated patients. 
• Randomized patients. 
• Randomized but not treated patients. 
• Randomized and treated patients. 
• Patients who have completed the 26-week double-blind treatment period as scheduled. 
• Patients who did not complete the 26-week double-blind treatment period as scheduled 
and the reasons for permanent treatment discontinuation. 


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• Patients who have completed the study as scheduled. 
• Patients who did not complete the study as scheduled and the reasons for study 
discontinuation. 
• Patients’ end of study status (completed, not completed) and corresponding end of 
treatment status (completed, not completed). 
• Status at last study contact.  
For screened, run in, screen failure, and nonrandomized but treated patients, percentages will be 
calculated using the number of screened patients as the denominator. All other categories of 
patients will be presented by treatment group and the percentages will be calculated using the 
number of randomized patients within each treatment group as the denominator.  Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages by treatment 
group.  Patients prematurely discontinued from treatment and/or study, along with reasons for 
discontinuation, will also be listed.  
A summary of the distribution of patients by country and center will also be provided (overall 
number of patients screened, run-in, randomized, and treated, as well as number of patients 
randomized, discontinued from study treatment, and discontinued from study for each treatment 
group). 
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 patients of 
the third category (randomized and not treated as randomized) will be part of efficacy and safety 
analyses (see Section 2.3). Patients randomized but not treated will be included in efficacy 
analysis. Safety data of patients treated but not randomized will be reported separately. 
The randomization strata [HbA1c at Screening (≤8.5%, >8.5%), metformin use at Screening 
(Yes, No) and mean SBP at Screening (<130, ≥130 mmHg)] assigned by IRT will be summarized. 
The percentages will be calculated using the number of randomized patients as the denominator. 
The discrepancy between the strata assigned by IRT and the information reported on e-CRF will 
be listed for all randomized patients. 
Kaplan-Meier (KM) plots of the cumulative incidence of double-blind IMP discontinuations due 
to any reason and due to AEs will be provided for the double-blind treatment period separately 
(see Section 2.5.4). A listing of these patients, along with the reason for discontinuation of 
treatment, study completion status and the reason for discontinuation study, will be provided.  
For ABPM sub-study, the number of patients in each of the following categories will be 
summarized: 
• Patients who consented to ABPM substudy.  
• Patients not entering ABPM substudy and the reason for not entering.   
• Patients who randomized and entered ABPM substudy (ie, ABPM substudy population, 
see Section 2.3.1.2). 


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• Patients who completed ABPM substudy.  
• Patients who discontinued ABPM substudy and the reason for discontinuation: 
- 
Adverse Event, 
- 
Study Terminated by Sponsor, 
- 
At patient’s own request, 
- 
Lost to follow-up, 
- 
Poor compliance to Protocol, 
- 
Other. 
For patients not entering ABPM substudy, percentages will be calculated using the number of 
patients consented to substudy as the denominator. All other categories of patients will be 
presented by treatment group and the percentages will be calculated using the number of patients 
randomized and entered substudy within each treatment group as the denominator.  Reasons for 
ABPM substudy discontinuation will be supplied in tables giving numbers and percentages by 
treatment group. Patients prematurely discontinued the substudy, along with reasons for 
discontinuation, will also be listed. Patients who consented but did not enter ABPM substudy, 
along with reasons for not entering, will also be presented.  
All important deviations including randomization and drug-dispensing irregularities will be 
summarized in tables giving numbers and percentages of deviations by randomized treatment 
group. 
Additionally, the analysis populations for safety, efficacy, ABPM substudy, and pharmacokinetics 
defined in Section 2.3 will be summarized in a table by number of patients in the randomized 
population.  
• Efficacy population: ITT population, completers population.  
• Efficacy population for substudy: ABPM substudy population. 
• Safety population. 
• PK population. 
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, c) a patient is randomized twice, or d) in a dynamic randomization 
scheme the treatment assignment is, in fact, not random, due to a computer program error.  
 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 


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randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report. If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages).  Nonrandomized, treated patients will be described separately. Listings with 
additional, relevant details will be provided in appendices. 
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
Randomization and drug allocation irregularities 
Kit dispensation without IRT transaction 
Erroneous kit dispensation 
Kit not available 
Randomization by error 
Patient randomized twice 
Stratification error 
Patient switched to another site 
2.3 
ANALYSIS POPULATIONS 
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population.   
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
2.3.1 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. 


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2.3.1.1 Intent-to-treat population  
Efficacy analyses will be based on the ITT population, defined as all randomized patients, 
irrespective of compliance with the study protocol and procedures. Patients will be analyzed for 
efficacy according to the treatment group to which they are randomized. 
2.3.1.2 ABPM substudy population  
ABPM efficacy analysis will be based on ABPM substudy population which defined as all 
randomized patients having: 
1. Signed the informed consent for ABPM substudy 
2. Baseline ABPM measurement at Visit 3A with Good Quality (see Appendix A) 
2.3.1.3 Completers population 
The completers population is a subset of the ITT population who complete the 26-week 
double-blind treatment period and without starting rescue therapy. A sensitivity analysis for 
noninferiority comparison will be conducted on this population. 
2.3.2 Safety population 
Safety analyses will be based on the safety population, defined as all randomized patients who 
receive at least one dose or part of a dose of double-blind IMP (regardless of the amount of 
treatment administered). Patients will be analyzed according to the treatment actually received. 
In addition: 
• Nonrandomized but treated patients will not be part of the safety population, however, 
their safety data will be presented separately. 
• Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population 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 the study treatment. If a patient is dispensed double-blind IMP and is lost to 
follow-up without any documented evidence, the patient will be considered exposed. 


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2.3.3 PK population 
For PK analyses, the PK population is defined as all safety patients who contribute with at least 
1 valid plasma concentration of sotagliflozin or its 3-O-glucuronide metabolite. The PK data will 
be analyzed according to the treatment actually received (see Section 2.3.2).  
2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
Continuous data will be summarized using the number of observations available, mean, SD, 
median, minimum, and maximum for each treatment group. Categorical and ordinal data will be 
summarized using the count and percentage of patients in each treatment group.  
Parameters will be summarized based on the randomized population analyzed in the treatment 
group to which they were randomized.  Analyses for the safety population will be included in the 
appendices if the size of the safety population is different (>10%) from the size of that in the 
primary analysis population (ie, randomized patients) for any treatment group. 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall (pooled 
across treatment groups) using descriptive statistics.  
P-values on the treatment difference for the demographic and baseline characteristic data will not 
be calculated.  
In general, no specific description of the safety parameters will be provided at baseline.  If 
relevant, the baseline values will be described along with each safety analysis. 
In general, no specific description of the efficacy parameters will be provided at baseline.  If 
relevant, the baseline values will be described along with each efficacy analysis. 
2.4.2 Prior or concomitant medications 
The prior, concomitant and posttreatment medications will be presented in the randomized 
population for each treatment group (and overall for the summary of prior medications), using 
counts and percentages. No statistical test for the between-group difference will be performed. 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomical therapeutic chemical (ATC) class (anatomic category) 
and the first 3 digits of the ATC class (therapeutic category).  A given medication may be 
classified in more than 1 ATC class. All ATC codes corresponding to a medication will be 
summarized, and a patient will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. Therefore, a patient may be counted several times for the same 
medication.  


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Prior medications will be presented by anatomic and therapeutic categories and sorted by 
decreasing frequency of ATC based on the overall incidence across treatment groups.  In case of 
equal frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be 
used. 
Concomitant and posttreatment medications will be presented by anatomic and therapeutic 
categories and sorted by decreasing frequency of ATC based on the incidence in the sotagliflozin 
400mg group. In case of equal frequency regarding ATCs (anatomic or therapeutic categories), 
alphabetical order will be used. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2).  


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2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure. 
Duration of IMP exposure is defined as last dose date of double-blind IMP – first dose date of 
double-blind IMP + 1 day, regardless of unplanned intermittent discontinuations 
(see Section 2.5.3 for calculation in case of missing or incomplete data).   
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number of 
patients exposed, mean, SD, median, minimum, and maximum).  In addition, duration of 
treatment exposure will also be summarized categorically by numbers and percentages for each of 
the following categories and cumulatively according to these categories:  
• 1 to 28 days. 
• 29 to 56 days. 
• 57 to 84 days. 
• 85 to 126 days. 
• 127 to 182 days. 
• >182 days. 
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient years. 
Number and percentage of patients by final dose at the end of the treatment will also be presented 
by each treatment group.  
2.4.3.2 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 will be calculated and presented for 
sotagliflozin or matching placebo (Tablet) and empagliflozin or matching placebo (Capsule) 
separately by treatment group. 
Percentage of compliance for a patient will be defined as the number of days that the patient was 
compliant to Capsule or Tablet, respectively, divided by the total number of days that the patient 
was planned to take IMP during the treatment epoch defined in Section 2.1.4 (ie, from the first 
date to the last date of double-blind IMP administration).  
Above-planned dosing percentage for a patient will be defined as the number of days that the 
patient took a higher dose to Capsule or Tablet than planned, respectively, divided by the total 
number of days that the patient was planned to take during the treatment epoch.  
Under-planned dosing percentage for a patient will be defined as the number of days that the 
patient took a lower dose to Capsule or Tablet than planned, respectively, divided by the total 
number of days that the patient was planned to take during the treatment epoch.  


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Treatment compliance, above-planned, and under-planned dosing percentages will be summarized 
for Capsule and Tablet separately and descriptively as quantitative variables (number, mean, SD, 
median, minimum, and maximum). The percentage of patients whose compliance is <80% will be 
summarized. In addition, numbers and percentages of patients with at least 1 day above-planned 
dose will be provided, as well as numbers and percentages of patients with (0, 20%], and >20% of 
days under-planned dose. 
Cases of overdose (see study protocol for further details) will constitute AEs/SAEs and be 
analyzed as such. More generally, dosing irregularities will be listed in Section 2.2.1. 
2.4.4 Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population using the efficacy assessments 
collected during the study, including those obtained after IMP discontinuation or introduction of 
rescue therapy, unless otherwise specified. 
Missing data for efficacy analyses is identified through steps described in Section 2.5.4. 
2.4.4.1 Analysis of primary efficacy endpoint 
The statistical test will be two-sided tests at a nominal 5% significance level. 
Primary analysis 
The primary efficacy endpoint of change in HbA1c from baseline to Week 26 will be analyzed by 
an Analysis of Covariance (ANCOVA) model using HbA1c values measured at baseline and 
Week 26 (observed or imputed). The missing data at endpoint will be imputed by multiple 
imputation (MI) methods as detailed below. To be concise, the following texts related to 
imputation are generalized to accommodate primary as well as continuous secondary efficacy 
endpoints. 
Missing endpoint data at Week 26 (or Week 12 for SBP) visit will be imputed using a model built 
separately in each treatment group and estimated from the patients in the same treatment group 
who prematurely discontinue the IMP before the Week 26 (or Week 12 for SBP) visit but have the 
measurement for the endpoint (ie, retrieved dropouts). The imputation model will include the 
randomization strata and the corresponding baseline value. In cases of non-convergence during 
the imputations, the offending stratum will be identified and then will be dropped from the model. 
Considering that the number of retrieved dropout patients in each treatment group is expected to 
be small, a simple imputation model based on regression will be used with baseline measurement 
included as the predictor. This will serve as the primary model of imputation for missing data 
should sampling criteria be satisfied (see below). 
An alternative (back-up) imputation method will be used if the number of patients who 
prematurely discontinue the IMP before the Week 26 (or Week 12 for SBP) visit but have the 
measurement for the endpoint is < 5 in any treatment groups (ie, insufficient number of retrieved 


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dropouts to support the imputation method described above). This criterion will be assessed for 
each primary or continuous secondary efficacy endpoint. 
In the back-up imputation method, missing post-baseline endpoint values at Week 26 (or Week 12 
for SBP) will be imputed by the washout Multiple Imputation (MI) method under the missing not 
at random (MNAR) framework.  
Missing endpoint data at the Week 26 (or Week 12 for SBP) in all treatment groups (sotagliflozin 
400 mg, empagliflozin 25 mg and placebo) are imputed from a model estimated from patients in 
the placebo group who have the endpoint data available.  
For patients in the sotagliflozin 400 mg and empagliflozin 25 mg groups with missing data at Week 
26 (or Week 12 for SBP), their missing values will be imputed using observed baseline and the 
observed primary endpoint data from placebo completers; no intermittent values from either 
placebo or the active treatment groups will be used.  
For placebo patients, missing data will be imputed based on the placebo group data. Intermittent 
observed values will be used while imputing missing values at Week 26 (or Week 12 for SBP). In 
cases that a non-monotone missing data pattern occurs at the intermediate visits, these data points 
will be first imputed in the placebo group using the Markov Chain Monte Carlo (MCMC) option in 
PROC MI to achieve a monotone missing pattern for all placebo patients.  The Week 26 (or Week 
12 for SBP) endpoint values will be subsequently imputed from the multiple copies of the original 
dataset where each copy will have a monotone missing pattern. 
The imputation models for the washout MI method will include the randomization strata and the 
corresponding baseline value. Missing data will be imputed using the regression method. 
In cases of non-convergence during the imputations, especially for the MCMC application in the 
placebo non-monotone datasets, graphical measures (eg, trace and autocorrelation plots) will be 
used to identify the offending variable and once detected, that variable(s) will be dropped from the 
model and the imputations will be re-run. These re-run models will use the same seed number and 
number of imputations as used in the original models.          
 
Using either imputation method, missing endpoint data will be imputed 2000 times to generate 
multiple data sets with complete data. Other details of the imputation procedures such as the seed 
number and sort ordering are specified in the SAS programs. The HbA1c change from baseline to 
Week 26 (or Week 12 for SBP) will be derived from observed and imputed HbA1c values at 
Week 26 (or Week 12 for SBP). Each of the completed datasets after the imputation will be 
analyzed using the Analysis of Covariance (ANCOVA) model with treatment groups 
(sotagliflozin 400 mg, empagliflozin 25 mg and placebo), randomization stratum of HbA1c 
(≤8.5%, >8.5%), randomization stratum of metformin use at screening (Yes, No), randomization 
stratum of SBP (<130 mmHg, ≥130 mmHg), and country as fixed factors, and baseline HbA1c 
value as a covariate . Results from each analysis will be combined using Rubin’s formula, to 
provide the adjusted mean change in HbA1c from Baseline to Week 26 (or Week 12 for SBP) for 
each treatment group, as well as the between-group difference (comparing sotagliflozin 400 mg 
versus placebo) and its associated 95% confidence interval (CI).  


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Sensitivity analyses 
Tipping point analysis based on the same MI method as applied to the primary analysis will be 
performed to examine the robustness of the results from the primary analysis. Patients who were 
randomized to sotagliflozin 400 mg group and had no HbA1c data at Week 26 will be given a 
penalty. The penalty will be gradually increased to evaluate at which level the conclusion of the 
analyses in terms of statistical significance is changed. The tipping point is the penalty level, at 
which the magnitude of efficacy reduction in patients without HbA1c data at Week 26 creates a 
shift in the treatment effect of sotagliflozin 400 mg from being statistically significantly better 
than placebo to a non-statistically significant effect. LS mean difference between sotagliflozin 
400 mg and placebo and its associated p-value for superiority will be provided for each penalty 
level. The steps to perform the tipping point analysis are as follows: 
1. Missing data will be imputed using the same MI method as applied to the primary 
analysis, 
2. The imputed HbA1c value at Week 26 in the sotagliflozin 400 mg group will be penalized 
by adding a penalty δ (eg, δ = 0.1%) in each complete dataset, 
3. Change from baseline at Week 26 in HbA1c will be analyzed using the same ANCOVA 
model as specified in the primary analysis in each complete dataset, 
4. Results will be combined across complete datasets using Rubin’s formula, 
5. For superiority of sotagliflozin 400 mg versus placebo on HbA1c reduction, steps 2 to  
4 will be repeated with incremental penalty at δ (ie, δ, 2δ, 3δ, ……) until the p-value for 
treatment effect of sotagliflozin 400 mg compared to placebo estimated in Step 4 is >0.05.  
6. For noninferiority of sotagliflozin 400 mg versus empagliflozin 25 mg on HbA1c 
reduction, Steps 2 to 4 will be repeated with incremental penalty at δ (ie, δ, 2δ, 3δ, ……) 
until the upper bound of the 2-sided 95% CI for the adjusted mean difference is >0.3. The 
range of penalty values will include the non-inferiority margin of 0.3% to evaluate bias 
toward the null. 
The tipping point analysis will be performed on the ITT population and completer’s population. 
The tipping point analysis will be performed for the primary variable only if that variable (change 
from baseline to Week 26 in HbA1c comparing sotagliflozin 400 mg versus placebo) is 
statistically significant at α = 0.05 (2-sided). Similarly, the tipping point analysis will be 
conducted for the sotaglifozin 400 mg versus empaglifozin 25 mg non-inferiority endpoint only if 
the primary efficacy endpoint analysis yields a statistically significant finding and the upper 
bound of the 2-sided 95% CI associated with the non-inferiority test is < 0.3%. 
In addition to the tipping point analyses, if the retrieved dropout imputation is applied to the 
primary analysis, the analysis based on the washout imputation method (ie, the backup imputation 
method) will be presented as a sensitivity analysis. 
Patients in this study have undergone sampling for plasma levels of sotagliflozin and its main active 
metabolite in order to perform population PK analysis.  Patients may be identified who have no 
detectable levels of active study drug or metabolite in their samples (ie, Below Lower Limit of 


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Quantification or BLLOQ).  When sample analysis has been completed and the study has been 
unblinded, explanations for some of these patients may be found: known non-compliance or 
sampling occurring after treatment had been discontinued.  In other cases, drug intake history 
relative to the randomization assignment may not be fully explained.  The ITT-based analyses 
specified in this document provides for a conservative assessment of the efficacy data should 
patients have been subjected to these unexplained non-compliance findings or PK ‘anomalies’. To 
provide a broader perspective on the impact of these apparent errors in compliance, additional 
sensitivity analyses of the primary efficacy endpoint and continuous efficacy endpoints may be 
conducted. The need to perform such analyses, their specifics, and results will be provided in the 
Clinical Study Report (CSR), if applicable. The analysis methods applied to the patient 
subpopulations defined by the occurrence of the PK anomalies (eg., exclusion of patients with PK 
anomalies from the ITT dataset) will include the ANCOVA model using the retrieved dropout 
and/or washout MI methods previously specified in this section. 
 
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 (White, Black or African American, Asian, Other) (any race groups with fewer than 
5 patients may be combined with “Other” category as appropriate). 
• Ethnicity (Hispanic, Not Hispanic). 
• Age group (<50, ≥50 to <65, ≥65 years) (any category with fewer than 5 patients may be 
combined with another category as appropriate). 
• Gender (Male, Female). 
• Baseline BMI level (<30, ≥30 kg/m²). 
• Baseline HbA1c (≤8.5%, >8.5%). 
• Metformin use at Screening (Yes, No). 
• Baseline mean SBP (<130 mmHg, ≥130 mmHg). 
• 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). 
• Country. 
The treatment effects (sotagliflozin 400 mg versus placebo) 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 the retrieved dropout method if there are at least 5 patients in each 
study treatment group who discontinued but have the endpoint. Otherwise, the washout 
imputation method will be used. The ANCOVA model will include treatment groups 


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(sotagliflozin 400 mg, empagliflozin 25 mg, placebo), randomization stratum of HbA1c (≤8.5%, 
>8.5%), randomization stratum of metformin use at screening (Yes, No), randomization stratum 
of SBP at screening (<130 mmHg, ≥130 mmHg), subgroup factor, treatment-by-subgroup factor, 
and country as fixed factors and using baseline HbA1c value as a covariate. The adjusted 
estimates of treatment mean differences (sotagliflozin 400 mg versus placebo) with SE and 95% 
CIs will be provided as appropriate across the subgroups. A graphical presentation of the results 
(ie, forest plot) will also be provided.  
In the case that the subgroup factor is identical or similar to a randomization strata factor 
(eg, baseline HbA1c, metformin use at screening, or baseline mean SBP category), only the 
subgroup factor (as a single factor or an interaction term) will be included in the model in order to 
avoid the issue of collinearity in the analysis. The corresponding strata factor will not be included 
in the model. 
Summary statistics at scheduled visits 
Summary statistics (for screening value, baseline value, observed post-baseline value and its 
changes from baseline) at scheduled visits will be provided for each treatment group. The 
summary will include the number of observations, mean, SD, SE, minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from baseline (±SE) at each of the scheduled visits. 
Similar presentations will be provided excluding measurements after rescue therapy during the 
26-week double-blind treatment period. 
2.4.4.2 Analyses of secondary efficacy endpoints 
For continuous secondary efficacy parameters (Section 2.1.3) with missing data at baseline, 
missing baseline data will be imputed using MI under the missing at random (MAR) assumption. 
Missing data at baseline will be imputed using regression method that includes randomization 
stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of metformin use at Screening (Yes, 
No), randomization stratum of SBP (<130 mmHg, ≥130 mmHg), and baseline value in the 
imputation model . 
Each continuous secondary efficacy endpoint (Section 2.1.3) will be analyzed using a similar 
ANCOVA model including the measurements at baseline and endpoint (observed or imputed). 
The missing data at endpoint will be imputed by the retrieved dropouts if there are at least 5 
patients in each study treatment group who discontinued but have the endpoint. Otherwise, the 
washout imputation method will be used. After the imputation, each of the complete datasets will 
be analyzed by an ANCOVA model.  
The ANCOVA model will include treatment groups (sotagliflozin 400 mg, empagliflozin 25 mg 
and placebo), randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of 
metformin use at Screening (Yes, No), randomization stratum of SBP (<130 mmHg, 
≥130 mmHg), and country as fixed effects, and the corresponding baseline secondary endpoint 


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value as a covariate. For the analysis of SBP in patients with baseline SBP ≥130 mmHg, the 
randomization stratum of SBP will not be included. Results from each complete dataset will be 
combined using Rubin’s formula to provide the adjusted mean change from Baseline to Week 26 
(or Week 12 for SBP) for each treatment group, as well as the between-group differences and the 
95% CIs for the differences.  
For all continuous secondary endpoints, summary statistics at scheduled visits will be provided for 
each treatment group. The summary will include the number of observations, mean, SD, SE, 
minimum, median, and maximum. Graphical presentations will also be used to examine trends 
over time using mean values (±SE) and mean changes from baseline (±SE) at each of the 
scheduled visits. In addition, SBP will be summarized descriptively at each visit for those patients 
with baseline SBP ≥140 mmHg.  
The categorical secondary efficacy variables of HbA1c <6.5%, <7% at Week 26 will be analyzed 
respectively using a Cochran-Mantel-Haenszel (CMH) method stratified by randomization 
stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of metformin use at Screening 
(Yes, No), and randomization stratum of SBP (<130 mmHg, ≥130 mmHg). The proportion in 
each treatment group will be provided, as well as the difference of proportions between 
sotagliflozin 400 mg and placebo with associated 2-sided 95% CI. For HbA1c responders at 
Week 26 (<6.5%, <7% respectively), all values at Week 26 will be used to determine whether a 
patient is a responder or not, even if they are measured after IMP discontinuation or rescue 
medication use. Patients who have no HbA1c measurement at Week 26 will be treated as 
non-responders. Summary tables and graphs will also be provided by treatment group at 
scheduled visits. 
For between-group comparison, a sensitivity analysis will be performed respectively for HbA1c 
<6.5% responder analysis by excluding patients whose HbA1c values at baseline are <6.5%, and 
for HbA1c <7% responder analysis by excluding patients whose HbA1c values at baseline are 
<7% using the same CMH test mentioned above. Similarly, by-visit summary may also be 
provided excluding those patients. 
Noninferiority on HbA1c reduction  
Tipping point analysis, described in Section 2.4.4.1, will be performed to examine the robustness 
of the noninferiority of sotagliflozin 400 mg versus empagliflozin 25 mg on HbA1c reduction 
using the same imputation method and ANCOVA model as described in Section 2.4.4.1. LS mean 
difference between sotagliflozin 400 mg and empagliflozin 25 mg will be provided for each 
penalty level.  The tipping point analysis will be performed only if the primary endpoint analysis 
is positive with an observed p-value ≤ 0.05 and the secondary endpoint analysis of the 
noninferiority of sotagliflozin 400 mg versus empagliflozin 25 mg on HbA1c reduction at Week 
26 is positive; ie, the upper bound of the 2-sided 95% CI is < 0.3%. 
The treatment effects (sotagliflozin 400 mg versus empagliflozin 25 mg) across the subgroups 
(defined in Section 2.4.4.1) will be estimated for the change from Baseline to Week 26 in HbA1c 
in the ITT population, and using the same approach described in Section 2.4.4.1. The adjusted 
estimates of treatment mean differences (sotagliflozin 400 mg versus empagliflozin 25 mg) with 


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SE and 95% CIs will be provided as appropriate across the subgroups. A graphical presentation of 
the results (ie, forest plot) will also be provided. 
A sensitivity analysis will be conducted with the treatment completers (ie, all patients who 
complete the 26-week double-blind treatment period and do not start rescue therapy) for 
noninferiority of sotagliflozin 400 mg versus empagliflozin 25 mg on HbA1c reduction using the 
same ANCOVA model described in Section 2.4.4.1. The washout imputation method will be 
used, where missing endpoint data in all treatment groups are imputed from a model estimated 
from patients in the placebo group who have the endpoint data available. The imputation model 
will include the randomization strata and the corresponding baseline value. Missing data will be 
imputed using the regression method. 
2.4.4.3 Analyses of other efficacy endpoints 
The analysis of other endpoints (see Section 2.1.3) will be descriptive with no formal testing. 
Summary statistics at scheduled visits based on observed value will be provided by each treatment 
group. Graphical presentations will also be used to illustrate trends over time as appropriate. The 
exception to this plan is for UGE, urine GCR, and the originally listed secondary endpoints re-
categorized as ‘Other’ endpoints (see Section 2.4.4.5). The sotagliflozin 400 mg versus placebo 
and sotagliflozin 400 mg versus empagliflozin 25 mg comparisons for these variables will be 
subjected to statistical analyses as described in Section 2.4.4.2. 
The number (%) of patients who used rescue therapy and a KM curve for the time to first rescue 
therapy will be provided by treatment group. A list of patients who used rescue therapy will also 
be provided (see Section 2.5.4).  
Urine ACR will be log-transformed at patient level. Summary statistics of urine ACR in log scale 
will then be calculated for each treatment group at each visit and back-transformed to provide the 
geometric mean and its associated percent change of urine ACR from baseline. 
Shift tables will be provided for urine ACR at Week 26 using the pre-defined categories. That is, 
the number (%) of patients with progression from one category at baseline to another category at 
Week 26 will be provided by treatment group. The pre-defined categories are, for urine ACR, 
<30 mg/g creatinine [Normal], ≥30 to <300 mg/g creatinine [Microalbuminuria], and 
≥300 mg/g creatinine [Macroalbuminuria].  
The analysis of the 2-hour PPG endpoint will be based on a Time 0 adjusted value (ie, the 2-hour 
PPG value minus the Time 0 value, FPG sample) at both the Baseline and Week 26 time points. 
These Time 0 adjusted values will be used to derive the Week 26 minus Baseline scores, which 
will serve as the measure of interest for comparative purposes. 
2.4.4.4 Analysis of ABPM substudy efficacy endpoints  
Analyses of ABPM substudy efficacy endpoints will be performed on the ABPM population using 
all assessment collected up to Week 26. All ABPM substudy efficacy endpoints will be 


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summarized by descriptive statistics at scheduled visits (Baseline (Visit 3A, Week -1), Visit 6A 
(Week 12), and Visit 8A (Week 26)). The descriptive statistics will include number, mean, 
standard deviation, Q1, Q3, minimum, maximum. In addition, analyses will be done for those 
patients with baseline Mean 24-hour SBP ≥130 mmHg and those patients with baseline Mean 
24-hour SBP <130 mmHg separately.  
Please refer to Appendix A and Appendix B for ABPM substudy efficacy variable derivation. 
2.4.4.5 Multiplicity issues 
To control for the family-wise type I error, a fixed-sequence 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 statistically significant for the primary efficacy 
endpoint, the following secondary hypothesis based on change from Baseline scores will be tested 
in the following prioritized order: 
1. The noninferiority of sotagliflozin 400 mg versus empagliflozin 25 mg on HbA1c 
reduction at Week 26, 
The superiority of sotagliflozin 400 mg versus placebo on: 
2. 2-hour PPG reduction at Week 26, 
3. Body weight reduction at Week 26, 
4. Sitting SBP reduction at Week 12 in patients with Baseline SBP ≥130 mmHg, 
The superiority of sotagliflozin 400 mg versus empagliflozin 25 mg on: 
5. 2-hour PPG reduction at Week 26, 
6. HbA1c reduction at Week 26, 
7. Sitting SBP reduction at Week 12 in patients with Baseline SBP ≥130 mmHg, 
8. 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 
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). This 
hierarchy differs from the ordering provided in the study protocol and that is likewise reflected in 
Section 1.2.2 of this SAP. The Sponsor elected to modify the contents/testing order to maximize 


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the number of rejected null hypotheses. These modifications were made before unblinding of the 
database. 
The secondary endpoints omitted from the original testing hierarchy will still be subjected to the 
analysis methods specified in Section 2.4.4.2. However, these variables will be labeled as ‘Other’ 
endpoints and not secondary endpoints. 
No multiplicity adjustment will be made on efficacy variables other than those mentioned above. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group.  
The “observation period” defined in Section 2.1.4 is applicable in all safety analyses for the 
classification of AEs, determination of treatment-emergent Potentially Clinically Significant 
Abnormality (PCSA) values and the last on-treatment value for the laboratory, vital sign and 
ECG. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately. 
• The baseline value (with the exception of serum creatinine and eGFR) is defined as the 
last available value before the first dose of double-blind 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. 
• PCSA values are defined as abnormal values considered medically important by the 
Sponsor according to predefined criteria/thresholds based on literature review and defined 
by the Sponsor for clinical laboratory tests, vital signs, and ECG Appendix C. 
• PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during the TEAE period, including 
nonscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the treatment-emergent PCSA percentage. 
• The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter during the TEAE period by 
treatment group in the safety population. 
• For laboratory parameters cited in the protocol as efficacy endpoints (including HbA1c 
and plasma glucose etc.), PCSA summaries will not be provided. These parameters will be 
summarized in efficacy Section 2.4.4. For creatinine and eGFR, PCSA summaries will be 
presented in safety Section 2.4.5 while descriptive summaries in efficacy Section 2.4.4. 


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• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group.  Summaries will include the last on-treatment value. The last on-
treatment value is commonly defined as the value collected at the same day/time of the last 
administration of IMP.  If this value is missing, this last on-treatment value will be the 
closest value prior to the last dose administration.   
• The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned. Relative risks versus placebo and empagliflozin, and their 95% CIs may 
be provided, if relevant.  
• Selected safety analyses will be summarized by age, gender, racial subgroups, and other 
pertinent subgroups (see details in Section 2.4.5.1 and Section 2.4.5.2). 
2.4.5.1 Analyses of hypoglycemia 
Analyses of hypoglycemia will be performed on the TEAE period as defined in Section 2.1.4. 
Hypoglycemia will be classified as severe hypoglycemia, documented symptomatic 
hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia or relative 
hypoglycemia (see Section 2.1.4.1).  
The number (%) of patients with any hypoglycemia, severe hypoglycemia and documented 
symptomatic hypoglycemia will be summarized respectively by treatment group during the TEAE 
period, as well as the incidence rate in patient years. Two types of incidence rates will be 
presented: the number of patients with at least 1 event per 100 patient-years (calculated as the 
number of patients with at least 1 event / total exposure in 100 patient-years), and the number of 
events per 100 patient-years (calculated as the total number of events / total exposure in 
100 patient-years). Note: here exposure (in days) is the duration of TEAE period, ie, duration of 
IMP treatment in days +1 (see Section 2.1.4). 
The summary of frequency and incidence rate in patient years for severe hypoglycemia or 
documented symptomatic hypoglycemia will be provided as appropriate by gender 
(Male, Female), age group (<50, ≥50 to <65, ≥65 years), race (White, Black or African American, 
Asian, Other) and metformin use at Screening (Yes, No).  
A KM curve will also be provided by treatment group for the time to first severe hypoglycemia or 
documented symptomatic hypoglycemia during the TEAE period (see Section 2.5.4). 
Documented symptomatic hypoglycemia maybe presented by ≤3.9 mmol/L (≤70 mg/dL) 
and (<3.0 mmol/L (<54 mg/dL) respectively, as appropriate. 
A listing of patients for all events reported on the dedicated e-CRF “Hypoglycemic event 
information” page will be provided with each category flagged (ie, severe hypoglycemia, 


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documented symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic 
hypoglycemia and relative hypoglycemia). 
2.4.5.2 Analyses of adverse events 
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.  
Pretreatment and posttreatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, treatment-
emergent, or posttreatment.  The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pretreatment or posttreatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will be presented by SOC, HLGT, HLT, and PT, sorted by the 
internationally agreed order for SOCs and alphabetic order for HLGT, HLT and PT within a SOC, 
the number (n) and percentage (%) of patients experiencing an adverse event.  Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a 
treatment phase.  The denominator for computation of percentages is the safety population within 
each treatment group. 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pretreatment, treatment-emergent, and posttreatment).  For that purpose, the 
table of all treatment-emergent adverse events presented by primary SOC and PT (sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs in the 
sotagliflozin 400 mg group) will define the presentation order for all other similar tables unless 
otherwise specified. In case of equal frequency regarding PTs, alphabetical order will be used.  
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
• Overview of treatment-emergent adverse events, summarizing number (%) of patients 
with any: 
- 
TEAE, 
- 
Serious TEAE, 
- 
TEAE leading to death, 
- 
TEAE leading to permanent treatment discontinuation. 
• All treatment-emergent adverse events by primary SOC, showing number (%) of patients 
with at least 1 treatment-emergent adverse event, sorted by internationally agreed order of 
primary system organ class.  


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• All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the 
SOC internationally agreed order. The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
• Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing 
incidence of PT in the sotagliflozin 400 mg group. 
• All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC in the 
sotagliflozin 400 mg group.  This sorting order will be applied to all other similar tables, 
unless otherwise specified. 
• All treatment-emergent adverse events regardless of relationship and related to IMP by 
primary SOC, HLGT, HLT and PT, showing the number (%) of patients with at least 
1 treatment-emergent adverse event, sorted by the internationally agreed SOC order. The 
other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
• All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (ie, mild, moderate, or severe), sorted by the sorting order defined above. 
• Common TEAEs (PTs with an incidence ≥2% in any treatment group) by primary SOC, 
HLGT, HLT, and PT, sorted by internationally agreed order of SOCs. The other levels 
(HLGT, HLT, PT) will be presented in alphabetic order.  
• Common TEAEs (PTs with an incidence ≥2% in any treatment group) will be provided as 
appropriate by primary SOC and PT and by demographic factors including gender (Male, 
Female), age group (<50, ≥50 to <65, ≥65 years of age), race (White, Black or African 
American, Asian, other), baseline SBP category (<130 mmHg, ≥130 mmHg), and baseline 
eGFR category (≥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]). 
SOC will be sorted by internationally agreed order and the PT by decreasing incidence 
within each SOC in the sotagliflozin 400 mg group, as described above. 
• TEAEs (PTs with an incidence ≥5% in any treatment group) by primary SOC, HLGT, 
HLT, and PT, sorted by internationally agreed order of SOCs. The other levels 
(HLGT, HLT, PT) will be presented in alphabetic order.  
Analysis of all treatment emergent serious adverse event(s) 
• All treatment-emergent SAE by primary SOC, HLGT, HLT, and PT, showing the number 
(%) of patients with at least 1 serious treatment-emergent adverse event, sorted by the 
internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
• All treatment-emergent SAE regardless of relationship and related to IMP, by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of patients with at least 1 serious 


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treatment-emergent adverse event, sorted by the internationally agreed SOC order.  The 
other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All treatment-emergent adverse events leading to treatment discontinuation, by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of patients sorted by the 
internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
Analysis of adverse events of special interest 
Pregnancy and overdose will be included in overall AE summaries if any are reported. 
ALT increase >3 x ULN is included in laboratory PCSA summary if any.  
In addition, the number (%) of patients with an AESI will be summarized by PT and by treatment 
group. Corresponding listings will be provided as appropriately. 
Analysis of events of special interest  
CV events, bone fracture and DKA  
For EOSIs that are adjudicated (ie, deaths, myocardial infarction, stroke, and unstable angina 
requiring hospitalization, heart failure requiring hospitalization, bone fracture, and diabetic 
ketoacidosis), the number (%) of patients with an EOSI positively adjudicated by CEC will be 
summarized by treatment group. All EOSIs sent for adjudication and/or reported by the 
investigators in the specific AE forms will be listed along with the adjudication outcome. 
Renal events 
For the EOSI renal events where selected events are adjudicated, the number (%) of patients with 
any renal events identified in Table 3 in Section 2.1.4.2 will be summarized by treatment group.  
The following renal events will be listed along with the adjudication outcome if applicable, 
including events,  
i. 
recorded in e-CRF “GFR decrease”,  
ii. 
recorded in e-CRF “Renal Event – Dialysis”,  
iii. 
identified as “Renal transplant” in e-CRF “Other procedure”. 
Renal death will be part of all deaths specified above. 
Other EOSIs  
For EOSIs that are not adjudicated, the number (%) of patients with at least one event will be 
summarized by treatment group and by PT (as identified in Table 3 Section 2.1.4.2).  
Severe hypoglycemia will be included in the summary of hypoglycemia (See Section 2.4.5.1). 


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AE leading to an amputation is described in the section below. 
Analysis of Amputation 
The number (%) of patients with amputation will be summarized by treatment group and by 
PT and LLT during the study (ie, regardless of on- or post-treatment). Amputation is a procedure 
recorded in e-CRF form “Other Procedures related to Amputation”. Patients who had a procedure 
related to amputation will be listed. 
The number (%) of patients with an “AE leading to an amputation” will be summarized by 
treatment group and by PT.  The “AE leading to an amputation” is determined by the AE 
identifier recorded in e-CRF “Other Procedures related to Amputation” when “AE correction” is 
chosen as the reason for the amputation procedure.   
In addition, the number (%) of patients with an “AE potentially leading to an amputation” will be 
summarized by treatment group and by PT (as identified in Table 3 in Section 2.1.4.2; these PTs 
in Table 3 were requested by the European Medicines Agency/ Pharmacovigilance Risk 
Assessment Committee[EMA/PRAC] Assessment Report 9 February 2017). Associated list will 
be provided as well, with patients who had an amputation procedure flagged. “AE potentially 
leading to an amputation” represents the condition that may potentially lead to the amputation 
procedure, but not in all cases an amputation has occurred (as per the EMA/PRAC request). 
Analysis of pretreatment and posttreatment adverse events  
• All pretreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 pretreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC in the sotagliflozin 
400 mg group. 
• All posttreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 posttreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC in the sotagliflozin 
400 mg group. 
Listings 
Supportive AE listings will be provided for all AEs, SAEs, death, AEs leading to treatment 
discontinuation and/or death, and EOSI as appropriate. Listing of all AEs, SAEs and AEs leading 
to treatment discontinuation and/or death will include at least the following information, sorted by 
treatment, patient identification, and onset date: treatment, patient identification, country, age, 
gender, race, BMI, primary SOC, PT, reported term, onset date, study day (relative day to the start 
date of double-blind treatment), AE duration, duration of exposure, intensity, corrective treatment, 
action taken with IMP, date of treatment discontinuation (if relevant), relationship to IMP 
(sotagliflozin/matching placebo tablet and empagliflozin/matching capsule) or NIMP, outcome, 
date of death (if any), seriousness, seriousness criteria, and AE status ( “E” for a TEAE; and “P” 
for an on-study post-treatment AE). 


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2.4.5.3 Deaths 
The following summaries of deaths will be generated. 
• Number (%) of patients who died by study period (on-study, on-treatment, post-study). 
• Deaths in nonrandomized patients or randomized but not treated patients. 
• Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event e-CRF page as reported by the Investigator) by primary SOC , HLGT, HLT, and PT 
showing number (%) of patients sorted by internationally agreed SOC order, with HLGT, 
HLT, and PT presented in alphabetical order within each SOC.  
2.4.5.4 Analyses of laboratory variables  
Laboratory parameters will be grouped and summarized by biological function as described in 
Section 2.1.4.4. 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all laboratory variables (central laboratory values and changes from baseline) 
will be calculated for each applicable visit or study assessment (screening, baseline, postbaseline 
time point, last on-treatment value) by treatment group.   
The incidence of PCSAs (list provided in Appendix D) at any time during the TEAE period will 
be summarized for each laboratory test by biological function and treatment group whatever the 
baseline level and/or according to the following baseline status categories:  
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
All measurements collected during the TEAE period, including values from unscheduled visits, 
will be considered for the PCSA summaries. These summaries will include patients in the safety 
population who have at least 1 assessment performed during the TEAE period. When a PCSA 
definition involves a change from baseline value, patients must also have a baseline value to be 
included in the summaries, and when required by the definition of the abnormality, patients must 
also have available laboratory normal ranges. 
A listing of patients with at least 1 post-baseline PCSA (or out of normal range when no PCSA 
criterion is defined) will be provided and will display the entire patients’ profile across time for all 
parameters belonging to the corresponding biological function. Individual data listings will 
include the following flags when applicable: 
• Baseline values will be flagged “B”. 
• Normal laboratory ranges, available for most laboratory parameters, will be identified as 
ULN and LLN. Baseline, last on-treatment value, and individual data will be flagged “L” 
if the value is below the LLN and will be flagged “H” if it is above the ULN. 


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• Laboratory PCSA criteria will be used for the corresponding laboratory parameters. 
Values reaching a PCSA limit will be flagged (+, ++, -, or -- depending upon the direction 
and level of the abnormality). Flags for WBC and differential counts will be determined 
using data expressed in international units. 
For parameters whose PCSA criteria are multiples of the ULN, the parameter’s value will also be 
expressed as a multiple of the ULN in the individual data provided. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity.  The proportion of patients with PCSA values at any 
postbaseline visit by baseline status will be displayed by treatment group for each parameter.  
The proportion of patients with PCSA values at any postbaseline visit will also be displayed by 
duration of exposure for each treatment group (only if a tabulation summary is necessary).  
Listing of possible Hy’s law cases identified by treatment group (eg, patients with any elevated 
ALT>3 x ULN, and associated with an increase in bilirubin ≥2 x ULN) with ALT, AST, alkaline 
phosphatase, total bilirubin, and the following complementary parameters (if available):  
conjugated bilirubin and prothrombin time/international normalized ratio, creatine phosphokinase, 
serum creatinine, complete blood count, anti-HAV IgM, anti-HBc IgM, anti-HCV and 
HCV RNA, anti-CMV IgM and anti-HEV IgM antibodies, auto-antibodies: anti-nuclear, 
anti-DNA, anti-smooth muscle, Epstein-Barr virus, herpes viruses, and anti-LKM. 
2.4.5.5 Analyses of vital sign variables 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of heart rate, temperature and respiratory rate (observed values or mean of 
observed values, and changes from baseline) will be calculated for each applicable visit or study 
assessment (baseline, post-baseline time points, last on-treatment value) by treatment group.   
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group for SBP, DBP and HR. All measurements collected during the TEAE period, including 
values from unscheduled visits, will be considered for the PCSA summaries. The summaries will 
include patients in the safety population who have at least 1 assessment performed during the 
TEAE period. When a PCSA definition involves a change from baseline value, patients must also 
have a baseline value to be included in the summaries. 
A listing of patients with at least 1 post-baseline PCSA will be provided and will display the 
patient’s profile over time of all vital sign parameters. Individual data listings will include the 
following flags: 
• Baseline values will be flagged “B”. 
• Parameter values reaching a PCSA limit will be flagged (+, or - depending of the 
direction). 


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2.4.5.6 Analyses of electrocardiogram variables 
Shift tables will be provided to present ECG status according to baseline status (Normal/Missing, 
Abnormal) for each treatment group during the TEAE period. Supportive listings of patients with 
abnormal ECG status at any post-baseline visit will be provided. 
2.4.5.7 Analyses of physical examination variables 
Shift tables will be provided to present physical examination findings by body system according 
to baseline status (Normal/Missing, Abnormal) for each treatment group during the TEAE period. 
Supportive listings of patients with abnormal findings at any post-baseline visit will be provided. 
2.4.6 Analyses of pharmacokinetic variables 
Plasma concentrations of sotagliflozin and its 3-O-glucuronide metabolite will be summarized by 
visit and nominal sampling time (pre-dose at Weeks 4, 18 and 26 and 3 hours post-dose at 
Week 26) in the PK population (see Section 2.3.3) in the sotagliflozin group, using descriptive 
statistics such as number, geometric mean, coefficient of variation, median, minimum and 
maximum. Individual plasma concentrations of sotagliflozin and its 3-O-glucuronide metabolite at 
nominal sampling times will also be listed. 
 
 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
HbA1c 
The formula to convert HbA1c from Diabetes Control and Complications Trial (DCCT) aligned 
value to International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) 
standardized value is, 
IFCC-HbA1c (mmol/mol) = [DCCT-HbA1c (%) - 2.15] x 10.929. 
Renal function formulas  
The estimated GFR (mL/min/1.73 m2) will be calculated using the 4 variable Modification of Diet 
in Renal Disease (MDRD) formula:  
Standard unit: eGFR (mL/min/1.73 m2) = 175 x [Serum Creatinine (µmol/L)/88.4] -1.154 x Age 
(year) -0.203 x 1.212 (if Black) x 0.742 (if female) 


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Conventional unit: eGFR (mL/min/1.73 m2) = 175 x Serum Creatinine (mg/dL) -1.154 x Age (year) 
-0.203 x 1.212 (if Black) x 0.742 (if Female) 
Urine ACR 
Standard unit: Urine ACR (mg/g) = Urine Albumin (mg/dL) / [Urine Creatinine (mmol/L) x 
11.31] x 1000 
Conventional unit: Urine ACR (mg/g) = Urine Albumin (mg/dL) / Urine Creatinine (mg/dL) x 
1000 
Urine GCR 
Standard unit: Urine GCR = Urine Glucose (mmol/L) / Urine Creatinine (mmol/L) 
Conventional unit: Urine GCR = Urine Glucose (mg/dL) / Urine Creatinine (mg/dL) 
Calculation of LDL-C 
When TG is lower than or equal to 4.52 mmol/L (400 mg/dL), LDL-C is calculated using the 
Friedewald equation as: 
• In standard unit (mmol/L), TC – HDL-C – TG/2.17. 
• In conventional unit (mg/dL), TC – HDL-C – TG/5. 
2.5.2 Data handling conventions for secondary efficacy variables 
Scheduled measurements (see Section 2.5.4) of continuous efficacy variables collected during the 
study will be used in the analyses including those obtained after IMP discontinuation or 
introduction of rescue therapy. Continuous secondary efficacy endpoints will be analyzed with 
missing values imputed by retrieved dropout MI method (if there are at least 5 patients in each 
study treatment group who discontinued but have the endpoint) or washout MI method according 
to the criterion described in Section 2.4.4.1. 
For the categorical secondary efficacy endpoints, data handling conventions are described in 
Section 2.4.4.2. 
2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Derived variables will be considered missing if any of the original variables required to calculate 
them are missing. For example, if either a baseline assessment or an endpoint assessment is 
missing for a particular patient, then change from baseline at endpoint will be missing. Depending 


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upon the assessment, analyses may not include all patients in the analysis population, because 
certain patients in the intended population may have missing data. 
Incomplete date of first administration of double-blind IMP 
Date/time of first administration is the first non-missing start date/time of double-blind IMP 
completed in the e-CRF “First dose IMP” module. 
For patients who are randomized and dispensed a double-blind treatment kit but who are lost to 
follow-up just after Visit 3 (eg. only the treatment kit number is reported in the e-CRF 
“Exposure - treatment period” module without any dose information), the date of first 
administration will be imputed using the date of randomization. When a patient is randomized but 
not exposed, “Not taken” should be ticked in the e-CRF “First dose IMP” module.  
Handling of computation of treatment duration if IMP end of treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of double-blind IMP is equal 
to the date of last administration reported on the e-CRF “Treatment status library” page.  If this 
date is missing, the exposure duration should be left as missing.  
The last dose administration should be clearly identified in the e-CRF and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Handling of adverse events/hypoglycemia with missing or partial date/time of onset 
Missing or partial adverse event/hypoglycemia onset dates and times will be imputed so that if the 
partial adverse event/hypoglycemia onset date/time information does not indicate that the adverse 
event/hypoglycemia started prior to treatment or after the treatment-emergent adverse event 
period, the adverse event/hypoglycemia will be classified as treatment-emergent.  No imputation 
of adverse event end dates/times will be performed.  These data imputations are for categorization 
purpose only and will not be used in listings.  No imputation is planned for date/time of adverse 
event resolution. 
Handling of adverse events/hypoglycemia when date and time of first IMP administration is 
missing 
When the date and time of the first double-blind IMP administration is missing, the day of 
randomization should be considered as the start date of TEAE period (Section 2.1.4).  
The exposure duration should be kept as missing. 


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Handling of adverse events/hypoglycemia when IMP end of treatment date is missing 
For the purpose of defining TEAE period, the date of the last administration of double-blind IMP 
is equal to the date of the last administration reported on the e-CRF “Treatment Status Library” 
page.  
If the date of last administration reported on the e-CRF “Treatment Status Library” page is  
• Partially missing, it will be imputed with a date as late as possible before or on the date of 
last available information on e-CRF “Completion of End of Study/Follow-up”.  
• Completely missing, it will be imputed with the date of last available information on 
e-CRF “Completion of End of Study/Follow-up” page.  
If the date of last available information on e-CRF “Completion of End of Study/Follow-up” page 
is  
• Partially missing, it will be imputed with a date as late as possible. 
• Completely missing, all adverse events occurred on or after the first administration of 
double-blind IMP will be considered as treatment emergent adverse events.  
Handling of missing assessment of relationship of adverse events to IMP (Capsule or Tablet) 
If the assessment of the relationship to sotagliflozin or matching placebo (Tablet) is missing, the 
relationship to sotagliflozin or matching placebo (Tablet) has to be assumed. If the assessment of 
the relationship to empagliflozin or matching placebo (Capsule) is missing, the relationship to 
empagliflozin or matching placebo (Capsule) has to be assumed. The adverse event has to be 
considered as such in the frequency tables of possibly related adverse events, but no imputation 
should be done at the data level.   
Handling of missing severity/grades of adverse events 
If the severity/grade is missing for 1 of the treatment-emergent occurrences of an adverse event, 
the maximal severity on the remaining occurrences will be considered.  If the severity is missing 
for all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 


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Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   
Linked adverse events that worsened or became serious 
An AE that worsened or became serious will have a separate record in the data from the original 
event record with an AE identification number that links the new record to the original record. An 
AE that worsened or became serious will be considered a new recurring AE in the summary of 
recurrent events or in the summary of events by time intervals. 
Handling of missing data for continuous efficacy endpoints 
Please see Section 2.4.4.1 and Section 2.4.4.2. 
Handling of missing data for categorical efficacy endpoints 
Please see Section 2.4.4.2. 
2.5.4 Windows for time points /Measurements for analyses 
The following steps will decide how the scheduled and/or unscheduled visits will be used in the 
analyses for efficacy variables and the by-visit summaries for safety variables (clinical laboratory 
data in Section 2.1.4.4 and vital signs in Section 2.1.4.5). 
Step 1 A scheduled measurement will be used if it is available; otherwise, an unscheduled 
measurement (including the end of treatment/study visit for those prematurely discontinued) will 
be used if it happens to be on the same date as the date of the scheduled visit. 
Step 2 After Step 1, if there are still no measurement for a given parameter at a scheduled visit, 
the analysis window below (Table 4) will be applied to re-allocate a post-baseline unscheduled 
measurement to a scheduled measurement. 
Table 4 - Analyses window definition 
Scheduled visit post baseline 
Targeted study day 
Analysis window in study days 
Main study 
 
 
Week 4 (Visit 4) 
28 
2 to 41 
Week 8 (Visit 5) 
56 
42 to 69 
Week 12 (Visit 6) 
84 
70 to 104 
Week 18 (Visit 7) 
126 
105 to 153 
Week 26 (Visit 8) 
182 
≥154 
ABPM substudy 
 
 
Week 12 (Visit 6A) 
83 
70 to 133 


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Scheduled visit post baseline 
Targeted study day 
Analysis window in study days 
Main study 
 
 
Week 26 (Visit 8A 
181 
≥134 
Study days are calculated from the day of first administration of double-blind IMP; the day of first administration of IMP (or the day of 
randomization if not exposed) is Day 1. 
After applying the above time windows, if multiple assessments are associated to the same time 
point, the closest from the targeted study day will be used. In case of equality, the last 
measurement will be used. Re-allocated scheduled visits (ie, visit numbers) should be sequential if 
ordered by the date of measurement. 
After Step 2, if there are still no measurement for a given parameter at a scheduled visit, data is 
considered missing for efficacy analyses, where multiple imputation would be applied as 
appropriately as described in Section 2.4.4.  
Reference day 
The reference day for the calculation of extent of exposure, time to onset, and relative days will be 
the day of the first administration of double-blind IMP or the day of randomization if not exposed 
to double-blind IMP, denoted as Day 1. 
Baseline definition for efficacy/safety data 
For the safety analyses, the baseline for a given parameter is defined as the last available 
measurement (or the average of all measurements for creatinine and eGFR), including 
unscheduled assessments, assessed prior to the first administration of double-blind IMP. For the 
efficacy analyses, the baseline for a given parameter is defined as the last available measurement 
(or the average of all measurements for creatinine and eGFR), including unscheduled assessments, 
assessed prior to the first administration of double-blind IMP or the last available value (or the 
average of all measurements for creatinine and eGFR) before randomization if not treated with 
double-blind IMP.  


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Summary statistics by visit for continuous efficacy endpoints 
Summary statistics (number, mean, SD, SE, minimum, median, maximum) of continuous efficacy 
endpoints (observed data and change from baseline) will be provided at scheduled visits as per 
protocol. Summaries showing data by visit will be presented according to the visit number 
(or re-allocated visit number, see Section 2.5.4) and labeled with the targeted approximate 
day/week.  
Last on-treatment value for laboratory variables and vital signs 
The last on-treatment value is the final measurement assessed during the treatment epoch, 
regardless of the introduction of rescue therapy, including measurements at unscheduled visits. 
Please see details in Section 2.1.4 and Section 2.4.5. 
Display of safety data by visit (laboratory variables and vital signs)  
Descriptive statistics (number, mean, SD, minimum, median, maximum) of quantitative 
laboratory variables and vital signs (observed data and change from baseline) during the TEAE 
period will be provided at scheduled visits. In addition, these summaries will also include a row 
for the ‘last value on-treatment’ to describe the last available on-treatment value (see above). 
Summaries showing data by visit will be presented according to the visit number (or re-allocated 
visit number, see Section 2.5.4) and labeled with the targeted approximate day/week. 
As specified in the study protocol, laboratory data from scheduled visits are reported by central 
laboratories. The local results will not be used in the efficacy analyses or in the definition of 
baseline for both safety and efficacy analyses. In the safety analyses, for parameters with PCSA 
defined based on normal range, local results will only be used in the PCSA summary if they are 
accompanied by a local laboratory normal range. For parameters with PCSA not defined based on 
normal range, local results will be used in the PCSA summary as appropriately. 
When a patient has more than 1 measurement from the central laboratory for the same laboratory 
parameter on the same date, the average of the measurements will be used. For the same 
laboratory parameter, if a patient has more than 1 measurement on different dates for the same 
scheduled visit, the value closest to the date of the visit will be used for the scheduled visit. When 
the values for the same scheduled visit are equidistant, the last value should be used for the 
scheduled visit. Similar rules will be applicable to a patient who has more than 1 set of 
measurements for the same vital sign parameter (ie, SBP, DBP, or HR) on the same date. 
Time to event analysis  
For time to event analysis/KM plot, time to event (eg, treatment discontinuation, rescue therapy, 
hypoglycemia, etc) is defined as the number of days from the date of the first administration of 
double-blind IMP (or the date of randomization if not exposed) to the start date of the first 
occurrence of the event during the 26-week double-blind treatment period.  


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Patients who did not experience any event during the 26-week double-blind treatment period are 
considered censored observations. For time to treatment discontinuation/rescue therapy, censoring 
date is the date of EOT. For time to severe or documented hypoglycemia, censoring date is the 
date of EOT+1 or the date of EOS, whichever is the earliest. Date of EOS will be used if the date 
of EOT is not available. Last contact date will be used if date of EOS is not available. 
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline, the last on-treatment value, PCSAs and the shift summaries for safety or 
efficacy. They will be included in the by-visit summaries if they are re-allocated to scheduled visit 
(see Section 2.5.4). 
2.5.6 Pooling of centers for statistical analyses 
Center will not be included in the statistical models for efficacy analyses. However, all centers 
within a country will be pooled, and country will be included as a fixed effect in a parametric 
statistical model (eg, ANCOVA etc) for primary and secondary efficacy endpoints. Countries with 
fewer than 5 randomized patients will be grouped, if patients from grouped countries are still 
fewer than 5, they will then be further grouped with the country with the lowest number of 
patients that is 5 or more.  
2.5.7 Statistical technical issues 
None. 


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3 
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 Data Monitoring Committee (DMC) will be used to 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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4 
DATABASE LOCK 
The database lock was on 05Aug2019. 


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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS Version 9.2 or higher. 


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6 
REFERENCES 
1. 
O’Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al. European Society of 
Hypertension position paper on ambulatory blood pressure monitoring. Journal of hypertension. 
2013;31(9):1731-68. 
 


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7 
LIST OF APPENDICES 
 
 
 
Appendix A  
Ambulatory blood pressure monitoring substudy  
Appendix B  
ABPM substudy efficacy variable derivation  
Appendix C  
List of PTs for select EOSIs (MedDRA v22.0)  
Appendix D  
Potentially clinically significant abnormalities criteria  
Appendix E  
Summary of statistical analyses  
Appendix F 
Study Flow Chart 


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Appendix A 
Ambulatory blood pressure monitoring substudy  
Background 
A Phase 2 trial of sotagliflozin (LX4211.1-202) provided evidence that sotagliflozin reduced both 
SBP and DBP in patients with elevated SBP and DBP at baseline but not 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 ABPM assessed for 24 hours via ambulatory BP monitoring technology at baseline, 
Week 12, and Week 26 to provide a more systematic assessment of the SBP and DBP lowering 
efficacy of sotagliflozin. 
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. 
• 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.  


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• 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. 
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. 
Sub-study objectives 
The objective of the ABPM substudy is to compare the effect of sotagliflozin, empagliflozin and 
placebo for 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.  
Sub-study endpoints 
The ABPM endpoints are changes from Baseline to Week 12 and Week 26 for all patients 
participating 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. 


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• Average adjusted sleeping time BP as measured by SBP and DBP with adjustment based 
on actigraphy. 
Statistical analyses 
The quality of a visit recording will be considered insufficient if the visit recording does not meet 
the criteria below (1): 
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. 
Analyses of ABPM substudy efficacy endpoints will be performed on the ABPM population using 
all assessment collected up to Week 26. All ABPM substudy efficacy endpoints will be 
summarized by descriptive statistics by scheduled visits (Baseline (Visit 3A, Week -1), Visit 6A 
(Week 12), and Visit 8A (Week 26)). The descriptive statistics will include number, mean, 
standard deviation, Q1, Q3, minimum, maximum. In addition, analyses will be done for those 
patients with baseline Mean 24-hour SBP ≥130 mmHg and those patients with baseline Mean 
24-hour SBP <130 mmHg separately. 


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Appendix B 
ABPM substudy efficacy variable derivation 
All following derivation of the efficacy variables for ABPM substudy will be performed and 
provided by vendor 
 (specialized in ABPM device) by using validated software 
 
 and following 
 Project Requirement Specifications as 
follows:  
All ABPM substudy efficacy measurements will be recorded by validated ABPM 
Ambulo 2400 device. The device’s inflation plan is set up to collect patient’s BP measurements 
every 20 minutes during 8:00-21:59 and every 30 minutes during 22:00 -7:59 over at least  
24-hour time interval. The device will start recording patient’s blood pressure after its inflation is 
initiated, which composes a patient’s visit recording. All individual measurements will be 
analyzed by 
 and be assigned a status of successful included, successful excluded manual 
inflations, error or event.   
Successful excluded measurements are valid device log entries related to manual device initiation 
of inflation by the patient and will be excluded from analysis. Error measurements are any 
attempted inflation that results in a 0 value for one of the four values the device captures: systolic, 
diastolic, mean atrial pressure, or pulse pressure. Examples of errors are "cuff leak," device error, 
movement error, etc. These errors could be the result of a hole in the hose or patient movement 
(during inflation or deflation of the cuff). Events refer to non-inflation events which appear in the 
data with 0 values for systolic, diastolic, mean atrial pressure, and pulse pressure. Examples of 
these events are USB disconnect, sequence trigger, and power on reset. Usually, occurrence of 
events will not impact the quality of the recording. Both events and errors are excluded from 
analysis. Successful included measurements are device log entries during the time interval after 
device automatic initiation based on the inflation plan (daytime, nighttime, or 24-hour period) that 
are neither successful excluded manual inflation plan, error, nor event. The successful included 
measurement captured systolic, diastolic, mean atrial pressure, and pulse pressure. 
The quality of each recording at each visit will be considered Not Good Quality and not 
acceptable for analysis if the visit recording meets the criteria below:  
1. Visit Recording does not contain greater than or equal to 17 non-consecutive hours of 
data where each hour has at least one valid BP measurement.  
2. Visit Recording has less than 44 total measurements. 
A valid measurement is a measurement having non-missing values for systolic, diastolic, pulse 
pressure and mean arterial pressure (MAP). 
 will analyze the recording from the first valid 
inflation (after device initiated) up to 24 hours thereafter to determine the quality of the recording.  
If the quality of the visit recording is of Not Good Quality, the efficacy variable of the patient at 
that visit will be considered as missing value. Otherwise, the efficacy variable of the patient at the 
visit will be calculated as follow:  
Summing over all successful included systolic/diastolic measurements collected during the time 
interval (24-hour, actigraphy reported sleep time or actigraphy reported wake time), then divide 
the total by number of successful included measurements. 


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The actigraphy can detect the patient’s sleep or wake time based on the patient’s activity intensity. 
If the patient has interruptive sleep periods, the actigraphy will report the first inactivity period of 
the patient as the patient’s sleep time. Wake time will be the time outside the sleep interval.  Each 
patient will only have one sleep time and one wake time reported by the device.  
 


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Appendix C 
List of PTs for select EOSIs (MedDRA v22.0) 


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EOSI 
Preferred 
Term Code 
Preferred Term  
Genital Mycotic Infections 
10004074 
Balanitis candida 
Genital Mycotic Infections 
10018143 
Genital candidiasis 
Genital Mycotic Infections 
10047784 
Vulvovaginal candidiasis 
Genital Mycotic Infections 
10061180 
Genital infection fungal 
Genital Mycotic Infections 
10064899 
Vulvovaginal mycotic infection 
Genital Mycotic Infections 
10065582 
Urogenital infection fungal 
Genital Mycotic Infections 
10071209 
Candida cervicitis 
Genital Mycotic Infections 
10079521 
Fungal balanitis 
Urinary tract infections 
10011781 
Cystitis 
Urinary tract infections 
10011790 
Cystitis escherichia 
Urinary tract infections 
10011797 
Cystitis klebsiella 
Urinary tract infections 
10011799 
Cystitis pseudomonal 
Urinary tract infections 
10017525 
Fungal cystitis 
Urinary tract infections 
10018185 
Genitourinary chlamydia infection 
Urinary tract infections 
10023424 
Kidney infection 
Urinary tract infections 
10037584 
Pyelitis 
Urinary tract infections 
10037596 
Pyelonephritis 
Urinary tract infections 
10037597 
Pyelonephritis acute 
Urinary tract infections 
10037601 
Pyelonephritis chronic 
Urinary tract infections 
10037603 
Pyelonephritis mycoplasmal 
Urinary tract infections 
10037653 
Pyonephrosis 
Urinary tract infections 
10038351 
Renal abscess 
Urinary tract infections 
10044828 
Tuberculosis of genitourinary system 
Urinary tract infections 
10046424 
Urethral abscess 
Urinary tract infections 
10046480 
Urethritis 
Urinary tract infections 
10046482 
Urethritis chlamydial 
Urinary tract infections 
10046483 
Urethritis gonococcal 
Urinary tract infections 
10046490 
Urethritis ureaplasmal 
Urinary tract infections 
10046571 
Urinary tract infection 
Urinary tract infections 
10046572 
Urinary tract infection enterococcal 
Urinary tract infections 
10046704 
Urogenital trichomoniasis 
Urinary tract infections 
10048302 
Tubulointerstitial nephritis 
Urinary tract infections 
10048709 
Urosepsis 
Urinary tract infections 
10048837 
Cystitis glandularis 
Urinary tract infections 
10049059 
Urinary tract infection fungal 
Urinary tract infections 
10049100 
Pyelocystitis 
Urinary tract infections 
10051250 
Ureteritis 
Urinary tract infections 
10051350 
Cytomegalovirus urinary tract infection 
Urinary tract infections 
10051959 
Urinary bladder abscess 
Urinary tract infections 
10052238 
Escherichia urinary tract infection 
Urinary tract infections 
10054088 
Urinary tract infection bacterial 
Urinary tract infections 
10056351 
Emphysematous cystitis 
Urinary tract infections 
10058523 
Bladder candidiasis 
Urinary tract infections 
10058596 
Renal cyst infection 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 72 of 94 
Urinary tract infections 
10059517 
Bacterial pyelonephritis 
Urinary tract infections 
10061181 
Genitourinary tract gonococcal infection 
Urinary tract infections 
10061182 
Genitourinary tract infection 
Urinary tract infections 
10061395 
Ureter abscess 
Urinary tract infections 
10062279 
Urinary tract infection pseudomonal 
Urinary tract infections 
10062280 
Urinary tract infection staphylococcal 
Urinary tract infections 
10064825 
Urinary tract infection viral 
Urinary tract infections 
10064921 
Urinary tract inflammation 
Urinary tract infections 
10065197 
Cystitis viral 
Urinary tract infections 
10065198 
Cystitis bacterial 
Urinary tract infections 
10065199 
Cystitis helminthic 
Urinary tract infections 
10065213 
Pyelonephritis viral 
Urinary tract infections 
10065214 
Pyelonephritis fungal 
Urinary tract infections 
10065582 
Urogenital infection fungal 
Urinary tract infections 
10065583 
Urogenital infection bacterial 
Urinary tract infections 
10066757 
Urinary tract abscess 
Urinary tract infections 
10068822 
Emphysematous pyelonephritis 
Urinary tract infections 
10070300 
Streptococcal urinary tract infection 
Urinary tract infections 
10074409 
Escherichia pyelonephritis 
Urinary tract infections 
10075063 
Urethritis mycoplasmal 
Urinary tract infections 
10078665 
Bacterial urethritis 
Urinary tract infections 
10081163 
Fungal urethritis 
Urinary tract infections 
10081262 
Candida urethritis 
Urinary tract infections 
10082040 
Nephritis bacterial 
Volume depletion 
10005697 
Blood osmolarity increased 
Volume depletion 
10005731 
Blood pressure ambulatory decreased 
Volume depletion 
10005734 
Blood pressure decreased 
Volume depletion 
10005737 
Blood pressure diastolic decreased 
Volume depletion 
10005748 
Blood pressure immeasurable 
Volume depletion 
10005758 
Blood pressure systolic decreased 
Volume depletion 
10005761 
Blood pressure systolic inspiratory decreased 
Volume depletion 
10007979 
Central venous pressure decreased 
Volume depletion 
10009192 
Circulatory collapse 
Volume depletion 
10012174 
Dehydration 
Volume depletion 
10013578 
Dizziness postural 
Volume depletion 
10021097 
Hypotension 
Volume depletion 
10021137 
Hypovolaemia 
Volume depletion 
10021138 
Hypovolaemic shock 
Volume depletion 
10026983 
Mean arterial pressure decreased 
Volume depletion 
10031127 
Orthostatic hypotension 
Volume depletion 
10036653 
Presyncope 
Volume depletion 
10037327 
Pulmonary arterial wedge pressure decreased 
Volume depletion 
10042772 
Syncope 
Volume depletion 
10046640 
Urine flow decreased 
Volume depletion 
10047235 
Venous pressure decreased 
Volume depletion 
10047239 
Venous pressure jugular decreased 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 73 of 94 
Volume depletion 
10047689 
Volume blood decreased 
Volume depletion 
10050760 
Blood urea nitrogen/creatinine ratio increased 
Volume depletion 
10050905 
Decreased ventricular preload 
Volume depletion 
10053356 
Blood pressure orthostatic decreased 
Volume depletion 
10059895 
Urine output decreased 
Volume depletion 
10060089 
Left ventricular end-diastolic pressure decreased 
Volume depletion 
10060231 
Pulmonary arterial pressure decreased 
Volume depletion 
10063080 
Postural orthostatic tachycardia syndrome 
Volume depletion 
10063927 
Orthostatic intolerance 
Volume depletion 
10066077 
Diastolic hypotension 
Volume depletion 
10069431 
Orthostatic heart rate response increased 
Volume depletion 
10069583 
Pulse volume decreased 
Volume depletion 
10072370 
Prerenal failure 
Pancreatitis 
10033625 
Pancreatic haemorrhage 
Pancreatitis 
10033635 
Pancreatic pseudocyst 
Pancreatitis 
10033636 
Pancreatic pseudocyst drainage 
Pancreatitis 
10033645 
Pancreatitis 
Pancreatitis 
10033647 
Pancreatitis acute 
Pancreatitis 
10033649 
Pancreatitis chronic 
Pancreatitis 
10033650 
Pancreatitis haemorrhagic 
Pancreatitis 
10033654 
Pancreatitis necrotising 
Pancreatitis 
10033657 
Pancreatitis relapsing 
Pancreatitis 
10048984 
Pancreatic abscess 
Pancreatitis 
10052400 
Oedematous pancreatitis 
Pancreatitis 
10056277 
Pancreatorenal syndrome 
Pancreatitis 
10056975 
Pancreatic phlegmon 
Pancreatitis 
10056976 
Hereditary pancreatitis 
Pancreatitis 
10056977 
Alcoholic pancreatitis 
Pancreatitis 
10058096 
Pancreatic necrosis 
Pancreatitis 
10065189 
Pancreatitis helminthic 
Pancreatitis 
10066127 
Ischaemic pancreatitis 
Pancreatitis 
10069002 
Autoimmune pancreatitis 
Pancreatitis 
10074894 
Traumatic pancreatitis 
Pancreatitis 
10076058 
Haemorrhagic necrotic pancreatitis 
Venous thrombotic events 
10003192 
Arteriovenous fistula thrombosis 
Venous thrombotic events 
10003880 
Axillary vein thrombosis 
Venous thrombotic events 
10006537 
Budd-Chiari syndrome 
Venous thrombotic events 
10007830 
Cavernous sinus thrombosis 
Venous thrombotic events 
10008138 
Cerebral venous thrombosis 
Venous thrombotic events 
10014522 
Embolism venous 
Venous thrombotic events 
10019713 
Hepatic vein thrombosis 
Venous thrombotic events 
10023237 
Jugular vein thrombosis 
Venous thrombotic events 
10027402 
Mesenteric vein thrombosis 
Venous thrombotic events 
10034272 
Pelvic venous thrombosis 
Venous thrombotic events 
10034324 
Penile vein thrombosis 
Venous thrombotic events 
10036206 
Portal vein thrombosis 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 74 of 94 
Venous thrombotic events 
10037377 
Pulmonary embolism 
Venous thrombotic events 
10037421 
Pulmonary microemboli 
Venous thrombotic events 
10037437 
Pulmonary thrombosis 
Venous thrombotic events 
10037459 
Pulmonary venous thrombosis 
Venous thrombotic events 
10038547 
Renal vein embolism 
Venous thrombotic events 
10038548 
Renal vein thrombosis 
Venous thrombotic events 
10038908 
Retinal vein thrombosis 
Venous thrombotic events 
10041659 
Splenic vein thrombosis 
Venous thrombotic events 
10042567 
Superior sagittal sinus thrombosis 
Venous thrombotic events 
10043570 
Thrombophlebitis 
Venous thrombotic events 
10043581 
Thrombophlebitis migrans 
Venous thrombotic events 
10043595 
Thrombophlebitis superficial 
Venous thrombotic events 
10043605 
Thrombosed varicose vein 
Venous thrombotic events 
10044457 
Transverse sinus thrombosis 
Venous thrombotic events 
10047193 
Vena cava embolism 
Venous thrombotic events 
10047195 
Vena cava thrombosis 
Venous thrombotic events 
10047249 
Venous thrombosis 
Venous thrombotic events 
10048591 
Post thrombotic syndrome 
Venous thrombotic events 
10049446 
Subclavian vein thrombosis 
Venous thrombotic events 
10050216 
Paget-Schroetter syndrome 
Venous thrombotic events 
10050902 
Postoperative thrombosis 
Venous thrombotic events 
10051055 
Deep vein thrombosis 
Venous thrombotic events 
10053182 
Arteriovenous graft thrombosis 
Venous thrombotic events 
10061251 
Intracranial venous sinus thrombosis 
Venous thrombotic events 
10061408 
Venous thrombosis limb 
Venous thrombotic events 
10063363 
Brachiocephalic vein thrombosis 
Venous thrombotic events 
10063909 
Post procedural pulmonary embolism 
Venous thrombotic events 
10066881 
Deep vein thrombosis postoperative 
Venous thrombotic events 
10067270 
Thrombosis corpora cavernosa 
Venous thrombotic events 
10069909 
Metastatic pulmonary embolism 
Venous thrombotic events 
10072059 
Ovarian vein thrombosis 
Venous thrombotic events 
10074349 
Ophthalmic vein thrombosis 
Venous thrombotic events 
10077623 
Portosplenomesenteric venous thrombosis 
Venous thrombotic events 
10077829 
Visceral venous thrombosis 
Venous thrombotic events 
10078810 
Hepatic vein embolism 
Thyroid cancer 
10002240 
Anaplastic thyroid cancer 
Thyroid cancer 
10016935 
Follicular thyroid cancer 
Thyroid cancer 
10027105 
Medullary thyroid cancer 
Thyroid cancer 
10033701 
Papillary thyroid cancer 
Thyroid cancer 
10043744 
Thyroid neoplasm 
Thyroid cancer 
10055107 
Thyroid cancer metastatic 
Thyroid cancer 
10066136 
Huerthle cell carcinoma 
Thyroid cancer 
10066474 
Thyroid cancer 
Thyroid cancer 
10070567 
Thyroid cancer stage 0 
Thyroid cancer 
10071027 
Thyroid cancer stage I 
Thyroid cancer 
10071028 
Thyroid cancer stage II 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 75 of 94 
Thyroid cancer 
10071029 
Thyroid cancer stage III 
Thyroid cancer 
10071030 
Thyroid cancer stage IV 
Thyroid cancer 
10072162 
Thyroid cancer recurrent 
Thyroid cancer 
10072613 
Thyroid B-cell lymphoma 
Thyroid cancer 
10073153 
Familial medullary thyroid cancer 
Thyroid cancer 
10076603 
Poorly differentiated thyroid carcinoma 
Renal cell cancer 
10038389 
Renal cancer 
Renal cell cancer 
10038390 
Renal cancer recurrent 
Renal cell cancer 
10038391 
Renal cancer stage I 
Renal cell cancer 
10038392 
Renal cancer stage II 
Renal cell cancer 
10038393 
Renal cancer stage III 
Renal cell cancer 
10038394 
Renal cancer stage IV 
Renal cell cancer 
10038410 
Renal cell carcinoma recurrent 
Renal cell cancer 
10038411 
Renal cell carcinoma stage I 
Renal cell cancer 
10038412 
Renal cell carcinoma stage II 
Renal cell cancer 
10038413 
Renal cell carcinoma stage III 
Renal cell cancer 
10038414 
Renal cell carcinoma stage IV 
Renal cell cancer 
10050018 
Renal cancer metastatic 
Renal cell cancer 
10050513 
Metastatic renal cell carcinoma 
Renal cell cancer 
10061482 
Renal neoplasm 
Renal cell cancer 
10067944 
Hereditary leiomyomatosis renal cell carcinoma 
Renal cell cancer 
10067946 
Renal cell carcinoma 
Renal cell cancer 
10073251 
Clear cell renal cell carcinoma 
Renal cell cancer 
10078493 
Papillary renal cell carcinoma 
Pancreatic cancer 
10018404 
Glucagonoma 
Pancreatic cancer 
10022498 
Insulinoma 
Pancreatic cancer 
10025997 
Malignant neoplasm of islets of Langerhans 
Pancreatic cancer 
10029341 
Neurotensinoma 
Pancreatic cancer 
10033609 
Pancreatic carcinoma 
Pancreatic cancer 
10033610 
Pancreatic carcinoma metastatic 
Pancreatic cancer 
10033613 
Pancreatic carcinoma recurrent 
Pancreatic cancer 
10041329 
Somatostatinoma 
Pancreatic cancer 
10047430 
Vipoma 
Pancreatic cancer 
10051709 
Gastrinoma malignant 
Pancreatic cancer 
10052747 
Adenocarcinoma pancreas 
Pancreatic cancer 
10055006 
Pancreatic sarcoma 
Pancreatic cancer 
10055007 
Carcinoid tumour of the pancreas 
Pancreatic cancer 
10059320 
Pancreatic carcinoma stage 0 
Pancreatic cancer 
10059321 
Pancreatic carcinoma stage I 
Pancreatic cancer 
10059322 
Pancreatic carcinoma stage II 
Pancreatic cancer 
10059323 
Pancreatic carcinoma stage III 
Pancreatic cancer 
10059326 
Pancreatic carcinoma stage IV 
Pancreatic cancer 
10061902 
Pancreatic neoplasm 
Pancreatic cancer 
10067517 
Pancreatic neuroendocrine tumour 
Pancreatic cancer 
10068909 
Pancreatic neuroendocrine tumour metastatic 
Pancreatic cancer 
10069345 
Solid pseudopapillary tumour of the pancreas 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 76 of 94 
Pancreatic cancer 
10073363 
Acinar cell carcinoma of pancreas 
Pancreatic cancer 
10073364 
Ductal adenocarcinoma of pancreas 
Pancreatic cancer 
10073365 
Intraductal papillary-mucinous carcinoma of 
pancreas 
Pancreatic cancer 
10073367 
Pancreatoblastoma 
Bladder cancer 
10004986 
Bladder adenocarcinoma recurrent 
Bladder cancer 
10004987 
Bladder adenocarcinoma stage 0 
Bladder cancer 
10004988 
Bladder adenocarcinoma stage I 
Bladder cancer 
10004989 
Bladder adenocarcinoma stage II 
Bladder cancer 
10004990 
Bladder adenocarcinoma stage III 
Bladder cancer 
10004991 
Bladder adenocarcinoma stage IV 
Bladder cancer 
10004992 
Bladder adenocarcinoma stage unspecified 
Bladder cancer 
10005003 
Bladder cancer 
Bladder cancer 
10005005 
Bladder cancer recurrent 
Bladder cancer 
10005006 
Bladder cancer stage 0, with cancer in situ 
Bladder cancer 
10005007 
Bladder cancer stage 0, without cancer in situ 
Bladder cancer 
10005008 
Bladder cancer stage I, with cancer in situ 
Bladder cancer 
10005009 
Bladder cancer stage I, without cancer in situ 
Bladder cancer 
10005010 
Bladder cancer stage II 
Bladder cancer 
10005011 
Bladder cancer stage III 
Bladder cancer 
10005012 
Bladder cancer stage IV 
Bladder cancer 
10005056 
Bladder neoplasm 
Bladder cancer 
10005075 
Bladder squamous cell carcinoma recurrent 
Bladder cancer 
10005076 
Bladder squamous cell carcinoma stage 0 
Bladder cancer 
10005077 
Bladder squamous cell carcinoma stage I 
Bladder cancer 
10005078 
Bladder squamous cell carcinoma stage II 
Bladder cancer 
10005079 
Bladder squamous cell carcinoma stage III 
Bladder cancer 
10005080 
Bladder squamous cell carcinoma stage IV 
Bladder cancer 
10005081 
Bladder squamous cell carcinoma stage 
unspecified 
Bladder cancer 
10005084 
Bladder transitional cell carcinoma 
Bladder cancer 
10051690 
Urinary bladder sarcoma 
Bladder cancer 
10057352 
Metastatic carcinoma of the bladder 
Bladder cancer 
10066749 
Bladder transitional cell carcinoma stage 0 
Bladder cancer 
10066750 
Bladder transitional cell carcinoma recurrent 
Bladder cancer 
10066751 
Bladder transitional cell carcinoma stage I 
Bladder cancer 
10066752 
Bladder transitional cell carcinoma stage IV 
Bladder cancer 
10066753 
Bladder transitional cell carcinoma stage II 
Bladder cancer 
10066754 
Bladder transitional cell carcinoma stage III 
Bladder cancer 
10071664 
Bladder transitional cell carcinoma metastatic 
Bladder cancer 
10078341 
Neuroendocrine carcinoma of the bladder 
Potentially leading to amputation 
10003084 
Areflexia 
Potentially leading to amputation 
10003178 
Arterial thrombosis 
Potentially leading to amputation 
10003210 
Arteriosclerosis 
Potentially leading to amputation 
10003222 
Arteriosclerotic gangrene 
Potentially leading to amputation 
10006784 
Burning sensation 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 77 of 94 
Potentially leading to amputation 
10007904 
Cellulitis enterococcal 
Potentially leading to amputation 
10007905 
Cellulitis gangrenous 
Potentially leading to amputation 
10007921 
Cellulitis staphylococcal 
Potentially leading to amputation 
10007922 
Cellulitis streptococcal 
Potentially leading to amputation 
10012174 
Dehydration 
Potentially leading to amputation 
10012665 
Diabetic gangrene 
Potentially leading to amputation 
10012679 
Diabetic neuropathic ulcer 
Potentially leading to amputation 
10012680 
Diabetic neuropathy 
Potentially leading to amputation 
10017711 
Gangrene 
Potentially leading to amputation 
10020937 
Hypoaesthesia 
Potentially leading to amputation 
10021137 
Hypovolaemia 
Potentially leading to amputation 
10021519 
Impaired healing 
Potentially leading to amputation 
10021784 
Infected skin ulcer 
Potentially leading to amputation 
10022562 
Intermittent claudication 
Potentially leading to amputation 
10024774 
Localised infection 
Potentially leading to amputation 
10028862 
Necrosis ischaemic 
Potentially leading to amputation 
10029331 
Neuropathy peripheral 
Potentially leading to amputation 
10031149 
Osteitis 
Potentially leading to amputation 
10031252 
Osteomyelitis 
Potentially leading to amputation 
10031253 
Osteomyelitis acute 
Potentially leading to amputation 
10031256 
Osteomyelitis chronic 
Potentially leading to amputation 
10031262 
Osteomyelitis salmonella 
Potentially leading to amputation 
10031264 
Osteonecrosis 
Potentially leading to amputation 
10033775 
Paraesthesia 
Potentially leading to amputation 
10034568 
Peripheral coldness 
Potentially leading to amputation 
10034576 
Peripheral ischaemia 
Potentially leading to amputation 
10034620 
Peripheral sensory neuropathy 
Potentially leading to amputation 
10034636 
Peripheral vascular disorder 
Potentially leading to amputation 
10036155 
Poor peripheral circulation 
Potentially leading to amputation 
10036410 
Postoperative wound infection 
Potentially leading to amputation 
10040026 
Sensory disturbance 
Potentially leading to amputation 
10040840 
Skin erosion 
Potentially leading to amputation 
10040872 
Skin infection 
Potentially leading to amputation 
10040943 
Skin ulcer 
Potentially leading to amputation 
10042343 
Subcutaneous abscess 
Potentially leading to amputation 
10043607 
Thrombosis 
Potentially leading to amputation 
10048031 
Wound dehiscence 
Potentially leading to amputation 
10048038 
Wound infection 
Potentially leading to amputation 
10049927 
Dry gangrene 
Potentially leading to amputation 
10050473 
Abscess limb 
Potentially leading to amputation 
10050502 
Neuropathic ulcer 
Potentially leading to amputation 
10051548 
Burn infection 
Potentially leading to amputation 
10052428 
Wound 
Potentially leading to amputation 
10052949 
Arterial therapeutic procedure 
Potentially leading to amputation 
10053692 
Wound complication 
Potentially leading to amputation 
10053716 
Wound necrosis 
Potentially leading to amputation 
10054044 
Diabetic microangiopathy 
Potentially leading to amputation 
10056340 
Diabetic ulcer 
Potentially leading to amputation 
10056418 
Arterial bypass operation 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 78 of 94 
Potentially leading to amputation 
10056673 
Peripheral sensorimotor neuropathy 
Potentially leading to amputation 
10057518 
Peripheral artery angioplasty 
Potentially leading to amputation 
10057525 
Peripheral artery occlusion 
Potentially leading to amputation 
10058041 
Wound sepsis 
Potentially leading to amputation 
10058042 
Wound abscess 
Potentially leading to amputation 
10059245 
Angiopathy 
Potentially leading to amputation 
10059385 
Extremity necrosis 
Potentially leading to amputation 
10059442 
Wound infection staphylococcal 
Potentially leading to amputation 
10059444 
Wound infection pseudomonas 
Potentially leading to amputation 
10060734 
Diabetic foot 
Potentially leading to amputation 
10060803 
Diabetic foot infection 
Potentially leading to amputation 
10060963 
Arterial disorder 
Potentially leading to amputation 
10060965 
Arterial stenosis 
Potentially leading to amputation 
10061627 
Amputation 
Potentially leading to amputation 
10061655 
Arterial graft 
Potentially leading to amputation 
10061657 
Arterial stent insertion 
Potentially leading to amputation 
10061666 
Autonomic neuropathy 
Potentially leading to amputation 
10061815 
Diabetic vascular disorder 
Potentially leading to amputation 
10062198 
Microangiopathy 
Potentially leading to amputation 
10062255 
Soft tissue infection 
Potentially leading to amputation 
10062585 
Peripheral arterial occlusive disease 
Potentially leading to amputation 
10062599 
Arterial occlusive disease 
Potentially leading to amputation 
10062610 
Ischaemic limb pain 
Potentially leading to amputation 
10062932 
Wound treatment 
Potentially leading to amputation 
10064250 
Staphylococcal osteomyelitis 
Potentially leading to amputation 
10064601 
Iliac artery occlusion 
Potentially leading to amputation 
10065237 
Osteomyelitis bacterial 
Potentially leading to amputation 
10065239 
Osteomyelitis fungal 
Potentially leading to amputation 
10065240 
Wound infection bacterial 
Potentially leading to amputation 
10065242 
Wound infection fungal 
Potentially leading to amputation 
10068653 
Bone abscess 
Potentially leading to amputation 
10069379 
Peripheral arterial reocclusion 
Potentially leading to amputation 
10072170 
Skin wound 
Potentially leading to amputation 
10072557 
Peripheral artery restenosis 
Potentially leading to amputation 
10072560 
Peripheral endarterectomy 
Potentially leading to amputation 
10072561 
Peripheral artery bypass 
Potentially leading to amputation 
10072562 
Peripheral artery stent insertion 
Potentially leading to amputation 
10072563 
Peripheral artery stenosis 
Potentially leading to amputation 
10072564 
Peripheral artery thrombosis 
Potentially leading to amputation 
10074396 
Penetrating atherosclerotic ulcer 
Potentially leading to amputation 
10075118 
Subperiosteal abscess 
Potentially leading to amputation 
10075714 
Vasculitic ulcer 
Potentially leading to amputation 
10076246 
Spontaneous amputation 
 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 79 of 94 
Appendix D 
Potentially clinically significant abnormalities criteria  
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in 
ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in 
ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in 
ULN, not in IU/L. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L 
or mg/L. Categories are cumulative. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN Conjugated bilirubin dosed on a 
case-by-case basis. 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment 
phase, whatever the interval between 
measurement. 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 80 of 94 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 
CLcr (mL/min) 
(Estimated 
creatinine 
clearance based on 
the Cockcroft-Gault 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with 
impaired renal function-study design, data 
analysis, and impact on dosing and 
labeling 
eGFR 
(mL/min/1.73m2) 
(Estimate of GFR 
based on an 
MDRD equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with 
impaired renal function-study design, data 
analysis, and impact on dosing and 
labeling 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 81 of 94 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L 
(fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not 
provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L 
(Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential 
count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L 
(Black) 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from 
baseline are more relevant than based on 
absolute value. Other categories for 
decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular 
drug development, the analysis is 
redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 82 of 94 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline 
≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
To be applied for all positions (including 
missing) except STANDING. 
SBP 
≤95 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline 
≥20 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline 
≥10 mmHg 
≥110 mmHg and increase from baseline 
≥10 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 83 of 94 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
ECG 
Ref.: ICH E14 guidance (2005) and E14 
Q&A (2012), and Cardiac Safety Research 
Consortium White Paper on PR and QRS 
(Nada et al. Am Heart J. 2013; 165(4) : 
489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline 
≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline 
≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline 
≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline 
≥20bpm 
>100 bpm  
>100 bpm and increase from baseline 
≥20bpm 
>120 bpm  
>120 bpm and increase from baseline 
≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline 
≥25% 
>220 ms 
>220 ms and increase from baseline 
≥25% 
>240 ms 
>240 ms and increase from baseline 
≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline 
≥25% 
>120 ms 
>120 ms and increase from baseline 
≥25% 
Categories are cumulative 


Statistical Analysis Plan 
Version:3 
 
Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
Covance Study ID: 000000155204  
COVANCE INC. CONFIDENTIAL 
Page 84 of 94 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and QTc>60 ms are the 
2 PCSA categories to be identified in 
individual patients listings. 
 
 


Statistical Analysis Plan 
Version:3 
 
 
            Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
 
Covance Study ID: 000000155204 
 
COVANCE INC. CONFIDENTIAL 
Page 85 of 94 
Appendix E 
Summary of statistical analyses 
EFFICACY ANALYSIS 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoint 
HbA1c: Change from baseline at Week 26, 
(sotagliflozin versus placebo)  
ITT 
ANCOVA (with missing 
values imputed by the 
retrieved dropouts or 
washout imputation method 
under MNAR framework): 
treatment, randomization 
stratum (HbA1c /metformin 
use/SBP at screening), and 
country as fixed effects, 
and baseline HbA1c value 
as a covariate 
Tipping point 
analysis; 
 
Subgroups: race, 
ethnicity, age, 
gender, baseline 
BMI, baseline 
HbA1c, baseline 
SBP, metformin use 
at screening, 
baseline eGFR, 
Duration of diabetes, 
and country 
 
Summary statistics for observed values and 
changes from baseline by visit. 
Graphical presentations for mean changes from 
baseline (±SE) and mean values (±SE) by visit. 
By-visit summary and graph excluding 
measurements after rescue therapy. 
 
Secondary endpoints 
HbA1c(sotagliflozin versus empagliflozin); 2-
hour PPG reduction, body weight 
(sotagliflozin versus placebo only): Change 
from baseline to Week 26;  
SBP (for patients with baseline SBP 
≥130 mmHg): Change from baseline to Week 
12; SBP any baseline (sotagliflozin versus 
empagliflozin only): Change from baseline to 
Week 12 
ITT 
ANCOVA (with missing 
values imputed by the 
retrieved dropouts or 
washout imputation method 
under MNAR framework): 
treatment, randomization 
stratum (HbA1c /metformin 
use /SBP at screening), 
and country as fixed 
effects, and baseline value 
as a covariate 
Tipping point 
analysis and 
Completer 
analysis for 
HbA1c 
(sotagliflozin 
versus 
empagliflozin) 
For HbA1c 
(sotagliflozin versus 
empagliflozin): 
similar to primary 
endpoint subgroups 
Summary statistics for observed values and 
changes from baseline by visit. 
Graphical presentations for mean changes from 
baseline (±SE) and mean values (±SE) by visit. 
SBP will be summarized descriptively at each visit 
for those with baseline SBP ≥140 mmHg 


Statistical Analysis Plan 
Version:3 
 
 
            Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
 
Covance Study ID: 000000155204 
 
COVANCE INC. CONFIDENTIAL 
Page 86 of 94 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Other endpoints 
 
 
 
 
 
SBP (for patients with baseline SBP <130 
mmHg), DBP, Serum creatinine, eGFR, 
UGE, UGCR, UACR, hemodynamic markers: 
change from Baseline 
ITT 
Summary statistics for 
observed values and 
changes from baseline by 
visit. In addition for UGE 
and UGCR, ANCOVA (with 
missing values imputed by 
the retrieved dropouts or 
washout imputation method 
under MNAR framework): 
treatment, randomization 
stratum (HbA1c /metformin 
use /SBP at screening), 
and country as fixed 
effects, and baseline value 
as a covariate  
No 
No 
Graphical presentations for mean changes from 
baseline (±SE) and mean values (±SE) by visit as 
appropriate. 


Statistical Analysis Plan 
Version:3 
 
 
            Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
 
Covance Study ID: 000000155204 
 
COVANCE INC. CONFIDENTIAL 
Page 87 of 94 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Proportion of patients with HbA1c <6.5%, 
<7.0% at Week 26 
 
ITT 
CMH method stratified on 
randomization strata 
(HbA1c /metformin 
use/SBP at screening),  
CMH method 
stratified on 
randomization 
strata (HbA1c 
/metformin 
use/ SBP at: 
excluding 
patients with 
baseline HbA1c 
values <6.5% 
(for <6.5% 
responders) or 
<7% (for <7% 
responders) 
respectively 
No 
By-visit summary and graphs of HbA1c responders 
(<6.5%, <7%). 
By-visit frequency summary and graphs of HbA1c 
responders (<6.5%, <7%) excluding patients with 
baseline HbA1c values <6.5% or <7% respectively. 
Proportion of patients, with reduction in body 
weight by ≥2%, ≥5%, and ≥10% from 
Baseline  
ITT 
By-visit frequency summary 
No 
No 
By-visit graphical presentation as appropriate 
Proportion of patients requiring rescue for 
hyperglycemia 
ITT 
Summary statistics 
No 
No 
KM plot; List of patients rescued 


Statistical Analysis Plan 
Version:3 
 
 
            Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
 
Covance Study ID: 000000155204 
 
COVANCE INC. CONFIDENTIAL 
Page 88 of 94 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
ABPM Substudy 
 
 
 
 
 
Changes from Baseline to Week 12 and 
Week 26 in: 
Average 24-hour SBP and DBP, average 
adjusted awake time BP as measured by 
SBP and DBP with adjustment based on 
actigraphy, average adjusted awake time BP 
as measured by SBP and DBP with 
adjustment based on actigraphy for all 
patients participating substudy, patients with 
baseline average 24-hour SBP≥130 mmHg 
and patients with baseline average 24-hour 
SBP<130 mmHg. 
 
ABPM 
population    
Summary statistics for 
observed values and 
changes from baseline by 
visit. 
No 
No 
 
 


Statistical Analysis Plan 
Version:3 
 
 
            Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
 
Covance Study ID: 000000155204 
 
COVANCE INC. CONFIDENTIAL 
Page 89 of 94 
SAFETY ANALYSES 
Endpoint 
Analysis 
Population 
Primary 
analysis 
Supportive 
Analysis 
Subgroup 
analysis 
Other 
analyses 
Hypoglycemia 
Safety 
Follow safety guidelines 
Number (%) of patients with any 
hypoglycemia, severe 
hypoglycemia, documented 
symptomatic hypoglycemia 
during TEAE period, and 
incidence rates in 100 patient-
years. 
 
Severe hypoglycemia or 
documented symptomatic 
hypoglycemia by subgroups: race, 
age, gender, metformin use 
KM plot time to first event of severe 
hypoglycemia or documented 
symptomatic hypoglycemia 
Documented symptomatic 
hypoglycemia maybe presented by 
<3.0 mmol/L (<54 mg/dL) as 
appropriate. 
Adverse Events 
Safety 
Follow safety guidelines 
No 
Common TEAEs by subgroups: 
race, age, gender, baseline SBP, 
metformin use, baseline eGFR  
 
Clinical laboratory data 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
Vital signs 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
ECG, Physical examination 
Safety 
Follow safety guidelines 
Frequency summary 
No 
No 
 


Statistical Analysis Plan 
Version:3 
 
 
            Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
 
Covance Study ID: 000000155204 
 
COVANCE INC. CONFIDENTIAL 
Page 90 of 94 
Appendix F 
Study Flow Chart 
 
Screening Period 
Double-blind Treatment Perioda 
Follow-
upb 
Screenin
g 
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 
 


Statistical Analysis Plan 
Version:3 
 
 
            Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
 
Covance Study ID: 000000155204 
 
COVANCE INC. CONFIDENTIAL 
Page 91 of 94 
 
Screening Period 
Double-blind Treatment Perioda 
Follow-
upb 
Screenin
g 
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) 
Instruction on basic 
genitourinary (GU) hygiene and 
hydration 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
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 
 


Statistical Analysis Plan 
Version:3 
 
 
            Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
 
Covance Study ID: 000000155204 
 
COVANCE INC. CONFIDENTIAL 
Page 92 of 94 
 
Screening Period 
Double-blind Treatment Perioda 
Follow-
upb 
Screenin
g 
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) 
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 
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 
 


Statistical Analysis Plan 
Version:3 
 
 
            Date of Issue: 15-Nov-2019 
Lexicon Pharmaceuticals Protocol No. EFC14867 
  
 
Covance Study ID: 000000155204 
 
COVANCE INC. CONFIDENTIAL 
Page 93 of 94 
 
Screening Period 
Double-blind Treatment Perioda 
Follow-
upb 
Screenin
g 
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) 
Collection of home overnight 
urine for albumin, total protein, 
creatinine, calcium, phosphorus, 
magnesium, and glucosepp 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Urine NMP-22 and cytologyqq 
To be assessed as clinically indicated 
Evaluate for glycemic rescue 
 
 
 
To be assessed and reported throughout the treatment period 
 
Hypoglycemia 
To be assessed and reported throughout the studyt 
AEs/SAEs/AESI/EOSI 
To be assessed and reported throughout the studyt 
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. 
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 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. 


Statistical Analysis Plan 
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            Date of Issue: 15-Nov-2019 
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Covance Study ID: 000000155204 
 
COVANCE INC. CONFIDENTIAL 
Page 94 of 94 
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 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.  
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 the Run-in Phase for all women 
of childbearing potential. 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 non-productive potentials, follicle-stimulating hormone [FSH] and/or estradiol levels should be tested in case the definition of postmenopausal or premenopausal can’t be satisfied, eg, no medical 
document of hysterectomy or cessation of menses without an alternative medical cause is <12 months. 
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 e-CRF. 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 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. 
q Urine NMP-22 and cytology should only be performed when clinically indicated in cases of unexplained hematuria, and should be assessed by the central laboratory. 
 
 
 
t 
All SAEs, AEs, AESI, and EOSI will be collected starting from signing informed consent and continue until the end of the study (Note: For patients who discontinue treatment >2 weeks before Week 26, safety data 
will be collected until scheduled study end). 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, whichever comes earlier. All patients will have a Follow-up visit 4 weeks ± 5 days after the last dose of IMP to collect safety information.