A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control on Basal Insulin Alone or in Addition to Oral Antidiabetes Drugs (OADs)
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Lexicon Pharmaceuticals

Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-
week Multicenter Study to Evaluate the Efficacy and Safety of 
Sotagliflozin in Patients with Type 2 Diabetes Who Have Inadequate 
Glycemic Control on Basal Insulin Alone or in Addition to Oral 
Antidiabetes Drugs (OADs) 
NCT Number: NCT03285594 
         Document Date: Protocol Version 3: 12-March-2018 

 
 
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affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
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consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
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direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
 
 
Page 1 
 
AMENDED CLINICAL TRIAL PROTOCOL NO. 02 
 
COMPOUND: sotagliflozin/SAR439954 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week 
Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin in Patients 
with Type 2 Diabetes Who Have Inadequate Glycemic Control on Basal Insulin 
Alone or in Addition to Oral Antidiabetes Drugs (OADs) 
STUDY NUMBER: EFC14868 
STUDY NAME: SOTA-INS 
VERSION DATE / STATUS: Approval date (06-Mar-2018) / Approved 
Protocol Amendment 03 
Version number: 1 (electronic 1.0) 
Date : 06-Mar-2018 
Amended protocol 01 
Version number: 1 (electronic 1.0) 
Date : 27-Sep-2017 
Protocol Amendment 02 
Version number: 1 (electronic 1.0) 
Date : 27-Sep-2017 
Protocol Amendment 01 (GB) 
Version number: 1 (electronic 1.0) 
Date : 11-Sep-2017 
Clinical Trial Protocol 
Version number: 1 (electronic 3.0) 
Date : 22-May-2017 
EudraCT  
2016-001804-43 
IND Number(s) 
 
Version Number: 
1  
WHO universal trial number: 
U1111-1190-7567 
Date: 
06-Mar-2018  
Total number of pages: 
133 
 
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Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: sotagliflozin/SAR439954 
STUDY No.: EFC14868  
STUDY NAME: SOTA-INS 
TITLE 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 
52-week Multicenter Study to Evaluate the Efficacy and Safety of 
Sotagliflozin in Patients with Type 2 Diabetes Who Have Inadequate 
Glycemic Control on Basal Insulin Alone or in Addition to Oral 
Antidiabetes Drugs (OADs) 
INVESTIGATOR/TRIAL LOCATION 
Multinational 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVES 
Primary objective: 
To demonstrate the superiority of sotagliflozin 400 mg versus 
placebo with respect to hemoglobin A1c (HbA1c) reduction at 
Week 18 in patients with type 2 diabetes (T2D) who have inadequate 
glycemic control on basal insulin alone or with OADs. 
Secondary objectives: 
• 
To assess the effects of sotagliflozin 400 mg versus placebo 
on: 
- 
Change from Baseline to Week 18 in fasting plasma 
glucose (FPG) 
- 
Change from Baseline to Week 18 in body weight (BW) 
- 
Change from Baseline to Week 12 in systolic blood 
pressure (SBP) for patients with Baseline SBP 
≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all 
patients 
- 
Change form baseline to Week 52 in HbA1c 
- 
Change from baseline to Week 52 in BW 
• 
To assess the effects of sotagliflozin 200 mg versus placebo 
on: 
- 
Change from Baseline to Week 18 in HbA1c 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 12 in SBP for patients 
with Baseline SBP ≥130 mmHg 
- 
Change form baseline to Week 52 in HbA1c 
- 
Change from baseline to Week 52 in BW 
• 
To evaluate the safety of sotagliflozin 400 mg and 200 mg 
versus placebo throughout the 52-week trial 
Other objectives: 
• 
To assess the effects of sotagliflozin 400 mg versus placebo 
on the proportion of patients with HbA1c <7.0% or HbA1c 
<6.5% at Weeks 18, 26, and 52 
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• 
To assess the effects of sotagliflozin 200 mg versus placebo 
on the proportion of patients with HbA1c <7.0% or HbA1c 
<6.5% at Weeks 18, 26, and 52 
• 
To assess the effects of sotagliflozin 200 mg versus placebo 
on the change from Baseline to Week 12 in SBP for all 
patients 
• 
To assess the effects of sotagliflozin 400 mg and 200 mg 
versus placebo on: 
- 
Change from baseline to Week 26 in HbA1c 
- 
Change from Baseline to Weeks 26 and 52 in SBP in 
all patients and the subset of patients with Baseline 
SBP ≥130 mmHg 
- 
Change from Baseline to Weeks 12, 26, and 52 in SBP 
in patients with Baseline SBP <130 mmHg 
- 
Change from Baseline to Weeks 12, 26, and 52 in 
diastolic blood pressure (DBP) for all patients and the 
subset of patients with Baseline DBP ≥80 mmHg 
- 
Change from Baseline to Week 52 in the total daily 
insulin dose 
- 
Proportion of patients requiring rescue therapy during 
the 52-week double-blind Treatment Period 
- 
Change from Baseline to Week 18 and Week 52  on 
7-point Self-Monitored Blood Glucose (SMBG) profile 
(mean daily value at each time point)  
- 
Change from Baseline on estimated glomerular 
filtration rate (eGFR) 
- 
Change from Baseline in urinary albumin creatinine 
ratio (UACR) 
- 
Patient Qualitative Assessment of Treatment (PQAT) 
during the 52-week Treatment Period 
- 
Patient perception of treatment impact and satisfaction 
using the Treatment Related Impact Measure - 
Diabetes (TRIM-D) during the 52-week Treatment 
Period 
• 
To assess plasma concentrations of sotagliflozin and its 
3-O-glucuronide metabolite. 
Continuous Glucose Monitoring (CGM) substudy: 
In the United States, a substudy employing Continuous Glucose 
Monitoring (CGM) technology will be performed to assess detailed 
glycemic profiles. The details of the CGM substudy procedures, 
endpoints and statistical analyses will be provided in a separate 
substudy protocol document. 
STUDY DESIGN 
This is a Phase 3, multicenter, randomized, double-blind (with 
single-blind Run-in Phase), placebo-controlled, parallel-group study. 
Patients with T2D will be included in this study if at Screening they 
have inadequate glycemic control (as demonstrated by a mean 
HbA1c ≥7.5% or HbA1c ≤10.5%), despite use of basal insulin (at a 
total daily dose that has been stable within ±20% of the dose at 
Screening for 8 weeks, inclusive). Patients may also be using up to 
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2 OADs which may include metformin at a dose of at least 
1500 mg/day or the maximum tolerated dose (documented). Patients 
who satisfy the entry criteria will be switched to Lantus® (1:1 dose 
conversion from basal insulin being used at Screening). 
The trial will consist of 3 periods: 
• 
An up to 6-week Screening Period comprised of: 
- 
An up to 2-week Screening phase 
- 
A 4-week Lantus titration/single-blind placebo Run-in 
Phase. 
• 
A 52-week double-blind Treatment Period comprised of: 
- 
An initial 18-week fixed-dose phase during which 
Lantus dose is held constant except for safety reasons 
- 
Subsequent 34 weeks during which Lantus can be 
titrated. 
• 
A 2-week, post-treatment Follow-up Period. 
Screening Period 
Up to 2-week Screening phase (see Section 1.2) 
4-week Lantus titration/single-blind placebo Run-in Phase 
If the patient satisfies the entry criteria, their basal insulin will be 
converted to Lantus supplied by the Sponsor (1:1 conversion based 
on units) and a 4-week Lantus optimization phase will commence at 
Week -4 (Visit 2). 
Lantus titration: The target range of fasting SMBG is 80-100 mg/dL 
(4.4-5.6 mmol/L). The titration will be based on SMBG readings 
performed before the first meal of the day for at least 5 days per 
week. The Lantus dose will be adjusted based on the mean of the 
3 most recent fasting SMBG values according to the following 
titration rule: 
• 
≥140 mg/dL (≥7.8 mmol/L): increase Lantus by 4 units, or 
split to 2 x 2 units 
• 
≥120 mg/dL (≥6.7 mmol/L) but <140 mg/dL (<7.8 mmol/L): 
increase Lantus by 2 units 
• 
>100 mg/dL (>5.6 mmol/L) but <120 mg/dL (<6.7 mmol/L): 
increase Lantus by 1 unit 
• 
80-100 mg/dL (4.4-5.6 mmol/L), inclusive: no change in 
dose 
• 
<80 mg/dL (<4.4 mmol/L): decrease Lantus by 2 units. 
Lantus dose adjustment will occur every 3 days (twice a week). The 
dose adjustments will be made in consultation with the study site 
either at site visits, phone visits, or unscheduled phone contacts. In 
case of hypoglycemia, insulin titration may be withheld according to 
the Investigator’s medical judgment. 
During the 4-week Lantus titration/single-blind placebo Run-in 
Phase, patients will also take single-blind placebo, given as two (2) 
placebo tablets (identical to sotagliflozin 200 mg in appearance), 
once daily before the first meal of the day. In order to qualify for 
randomization, patients must demonstrate compliance at the end of 
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the Run-in Phase, based upon tablet count (≥80%) and the 
Investigator’s discretion. 
Patients will not initiate any new antidiabetic medication. The 
pre-existing OAD should remain stable without any changes. 
Monitoring for serum ketones: At Visit 2, patients will be provided 
meters and test strips for monitoring capillary blood 
beta-hydroxybutyrate (BHB). Patients will be instructed to measure 
their BHB levels by fingerstick if they experience any symptoms 
consistent with ketosis/ketoacidosis throughout the entire study 
period. Patients will be instructed on how to respond (seek help, 
hydrate, ingest carbohydrates, etc) if they present with possible 
ketoacidosis symptoms and the BHB value is abnormal (>0.6 mM/L). 
Randomized Core Treatment Period: Weeks 0 to18 
Randomization: To be randomized, patients must have HbA1c 
value ≥7% based on value obtained at Week -1 (Visit 5). 
Patients will be randomly assigned at a ratio of 2:1:1 respectively to 
one of 3 arms: 
• 
Sotagliflozin 400 mg, given as two (2) 200-mg tablets, once 
daily before the first meal of the day 
• 
Sotagliflozin 200 mg, given as one (1) 200-mg tablet and 
one (1) placebo tablet (identical to sotagliflozin 200 mg in 
appearance), once daily before the first meal of the day 
• 
Placebo, given as two (2) placebo tablets (identical to 
sotagliflozin 200 mg in appearance), once daily before the 
first meal of the day. 
Randomization will be stratified by the following 3 binary factors: 
HbA1c at Week -1 (≤8.5%, >8.5%) and SBP at Week -1 
(<130 mmHg, ≥130 mmHg), sulfonylureas use at Week -1 (yes, no). 
Administration of blinded investigational medicinal product (IMP) 
begins at Randomization (Day 1). 
Lantus dose: The dose of Lantus should be held constant for the 
first 18 weeks unless glycemic rescue criteria are satisfied (see 
below). 
In addition, the doses of the two OADs (if applicable) should be held 
constant throughout the entire 52-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 (until Visit 11) except for safety reasons. 
Hyperglycemic rescue: For the first 18 weeks, the total daily insulin 
should remain stable (< ±10% from randomization dose, or 
<±4 units, whichever is less). Patients requiring glycemic rescue 
may initiate rescue therapy with prandial insulin, or glucagon-like 
peptide-1 (GLP-1) agonists, or another antidiabetic medication 
(except sodium-glucose cotransporter type 2 [SGLT2] inhibitors), 
according to the Investigator’s clinical judgment and in accordance 
with the treatment guidelines. Criteria for hyperglycemic rescue have 
been set for different phases of the study (see STUDY 
TREATMENTS, Rescue Therapy) and are consistent with accepted 
treatment goals for diabetic therapy. 
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The dose of double-blind study treatment (sotagliflozin or placebo) 
will not be adjusted throughout the study. 
Weeks 19 to 52 Treatment Period 
Lantus Titration: Lantus titration resumes after Visit 12 (Week 18). 
During Weeks 19 to 52, SMBG values will be reviewed with site staff 
at site visits as well as extemporaneously if the patient calls site due 
to low or high SMBG readings. The same titration rule as described 
above (for the 4 week pre-Randomization Lantus titration period) will 
be followed. The Lantus dose will be adjusted based on the mean of 
the 3 most recent fasting SMBG values according to the following 
titration rule: 
• 
≥140 mg/dL (≥7.8 mmol/L): increase Lantus by 4 units, or 
split to 2 x 2 units 
• 
≥120 mg/dL (≥6.7 mmol/L) but <140 mg/dL (<7.8 mmol/L): 
increase Lantus by 2 units, or split to 2 x 1 unit 
• 
>100 mg/dL (>5.6 mmol/L) but <120 mg/dL (<6.7 mmol/L): 
increase Lantus by 1 unit 
• 
80-100 mg/dL (4.4-5.6 mmol/L), inclusive: no change in 
dose 
• 
<80 mg/dL (<4.4 mmol/L): decrease Lantus by 2 units. 
The doses of the two OADs (if applicable) should be held constant 
throughout the entire 52-week double-blind Treatment Period (ie, not 
changed except for safety reasons). 
In case of hypoglycemia, insulin titration may be withheld according 
to the Investigator’s medical judgment. 
Hyperglycemic rescue: During Weeks 19 to 52, patients exceeding 
glucose rescue limits may have their Lantus dose up-titrated without 
a maximum limit as a first approach. If up-titration of the Lantus 
regimen, based on the previously described titration rules, has been 
unsuccessful (ie, increase in basal insulin is associated with low 
FPG values despite high HbA1c or elevated post-prandial values), it 
is appropriate to initiate rescue therapy with prandial insulin, or a 
GLP-1 agonist, or another antidiabetic medication (except SGLT2 
inhibitors), according to the Investigator’s clinical judgment and in 
accordance with the treatment guidelines. 
Hyperglycemia rescue criteria: Rescue is defined by the criteria 
described below (see STUDY TREATMENTS, Rescue Therapy). 
2-Week, Post-treatment Follow-up Visit 
Blood pressure (BP) and laboratory values will be assessed, and 
safety information including adverse events (AEs) will be collected. 
The HbA1c and centrally measured FPG will be masked to study 
sites and patients after Randomization and until study end. 
Additionally, urinalysis by dipstick will not include the measurement 
of urine glucose. 
Early Termination 
If a patient discontinues treatment with IMP any time during the 
Treatment Period, the patient will have a Premature End of 
Treatment (EOT) Visit, and a Follow-up Visit 2 weeks after the last 
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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 visits at Week 18 (Visit 12) and 
Week 52 (Visit 15). If the patient does not agree to site visits, the 
patient will be contacted by respective sites by telephone to inquire 
about safety status. If a patient discontinues (or completes) 
treatment and study at the same time, a single visit for both EOT and 
end of study (EOS) will be performed. 
The study design is presented graphically in Section 1.1. The CGM 
substudy will be detailed in a sub-protocol. 
STUDY POPULATION 
Main selection criteria 
Inclusion criteria: 
• 
Patients with T2D using any types of basal insulin alone or in 
combination with up to 2 OADs 
• 
Patient has given written informed consent to participate in 
the study in accordance with local regulations. 
Major exclusion criteria: 
• 
At the time of Screening age <18 years or <legal age of 
majority, whichever is greater 
• 
Type 1 diabetes mellitus 
• 
OAD dose not stable for 8 weeks before Screening 
• 
Use of basal insulin therapy (eg, insulin glargine, Neutral 
Protamine Hagedorn [NPH], detemir, or degludec) for less 
than 6 months before Screening 
• 
Dose of basal insulin (eg, insulin glargine, NPH, detemir, or 
degludec) not stable for 8 weeks before Screening (ie, total 
daily insulin dose increased or decreased by more than 
20%) 
• 
Use of injectable diabetes drugs other than basal insulin (eg, 
insulin glargine, NPH, detemir, or degludec), ie, prandial or 
rapid-acting insulins, short-acting insulins, GLP-1 receptor 
agonists, or inhaled prandial insulin (Afrezza) within 8 weeks 
of Screening 
• 
Use of a selective SGLT2 inhibitor (eg, canagliflozin, 
dapagliflozin, or empagliflozin) within 3 months prior to the 
trial 
• 
Use of systemic glucocorticoids (excluding topical, 
intra-articular, or ophthalmic application, nasal spray or 
inhaled forms) for more than 10 consecutive days within 
90 days prior to the Screening Visit 
• 
Patients with severe anemia, severe cardiovascular 
(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 
• 
Known presence of factors that interfere with the Central Lab 
HbA1c measurement (eg, genetic Hb variants) 
compromising the reliability of HbA1c assessment or 
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medical conditions that affect interpretation of HbA1c results 
(eg, blood transfusion or severe blood loss in the last 3 
months prior to randomization, any condition that shortens 
erythrocyte survival) 
• 
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 unwilling or unable to perform SMBG 
(Section 8.2.1.4), complete the patient diary or comply with 
study visits and other study procedures as required per 
protocol 
• 
HbA1c <7.5% or HbA1c >10.5% measured by the central 
laboratory at Screening 
• 
HbA1c <7% measured by the central laboratory at Visit 5 
(Week -1) 
• 
History of diabetic ketoacidosis or nonketotic hyperosmolar 
coma within 12 weeks prior to the Screening Visit 
• 
Pregnant (confirmed by serum pregnancy test at screening) 
or breastfeeding women 
• 
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 gastric surgery including history of gastric banding 
or inflammatory bowel disease within 3 years prior to the 
Screening Visit. Note: Patients who have had bariatric 
surgery or gastric banding more than 3 years prior to the 
Screening Visit must have a stable weight (±10%) for 
6 months prior to the Screening Visit. 
• 
Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 times the upper limit of normal 
(ULN) laboratory range 
• 
Total bilirubin >1.5 times the ULN (except in case of Gilbert’s 
syndrome). 
Total expected number of patients: 
560 randomized patients in the main study. 
STUDY TREATMENTS 
 
Investigational medicinal products 
Sotagliflozin 400 mg 
• 
200 mg tablets 
• 
Oral 
• 
400 mg, given as two (2) 200-mg tablets, once daily before 
the first meal of the day. 
 
Sotagliflozin 200 mg 
• 
200 mg tablets 
• 
Oral 
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• 
200 mg, given as one (1) 200-mg tablet and one (1) placebo 
tablet (identical to sotagliflozin 200 mg in appearance), once 
daily before the first meal of the day. 
 
Placebo 
• 
Tablets identical in appearance to sotagliflozin 200 mg 
• 
Oral 
• 
Two (2) placebo tablets, once daily before the first meal of 
the day. 
Noninvestigational medicinal product(s) 
Lantus (insulin glargine, 100 U/mL) 
• 
Prefilled pen (3.0 mL solution) 
• 
Subcutaneous injection 
• 
Lantus to be provided by the Sponsor at the beginning of the 
Lantus titration phase. Patients who are receiving any basal 
insulin other than Lantus before screening will switch to 
Lantus. For patients who are using long-acting insulin 
analogs other than Lantus (eg, Levemir, Tresiba, Basaglar), 
the existing basal insulin will be converted to an equivalent 
dose of Lantus on a 1:1 unit basis (ie, the same dose on the 
day before Visit 2). If the patient is using Toujeo® (glargine 
U-300/mL), the initial Lantus dose is 80% of the existing 
Toujeo dose as recommended in the Lantus label. If the 
patient is using NPH twice daily, it’s recommended that the 
converted Lantus dose should be reduced by 20% and given 
once daily. If using NPH once a day, it can be converted to 
Lantus unit-to-unit. 
• 
Metformin (optional) tablets to be administered as per 
Principal Investigator and in accordance with local labeling 
• 
Other OADs (up to 2 in total, including metformin) to be 
administered as per Principal Investigator and in accordance 
with local labeling, with the exception of SGLT2 inhibitors. 
 
Rescue Therapy 
The threshold values for rescue are defined as follows, depending 
on study period: 
• 
From Baseline Visit (Visit 6, Day 1) to Visit 10 (Week 8) 
(including value at Visit 10): FPG >270 mg/dL (15.0 mmol/L) 
• 
From Visit 10 (Week 8) to Visit 11 (Week 12) (including 
value at Visit 11): FPG >240 mg/dL (13.3 mmol/L) 
• 
From Visit 11 (Week 12) up to Visit 12 (Week 18): 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 
≥1.5%) 
• 
From Visit 12 (Week 18) up to the EOT, Visit 15 (Week 52): 
FPG >170 mg/dL (9.4 mmol/L) or HbA1c ≥8.0% (the 8.0% 
criteria does not apply if the HbA1c decrease from Baseline 
was ≥1.5%). 
Routine fasting SMBG and central laboratory alerts on FPG (and 
HbA1c at Week 12 and onwards) are set up to ensure that glycemic 
parameter results remain within predefined thresholds.  
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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 
re-test must be completed and confirmed.  
Likewise, patients are instructed to contact the sites for a 
confirmatory FPG test via central lab in case of consecutive 3 days 
high readings in fasting SMBG. Hyperglycemia must be confirmed as 
exceeding the criterion for rescue before rescue therapy is initiated. 
The central Lab FPG confirmation should be performed as soon as 
possible preferably within 7 days by unscheduled visit. 
The recommended approach to rescue if rescue thresholds have 
been reached despite up-titration of the Lantus dose includes 
initiating a prandial dose of short-acting insulin, or GLP-1 agonist, or 
another antidiabetic medication (except SGLT2 inhibitors) 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 EOS. 
ENDPOINTS 
 
Primary endpoint (Sotagliflozin 400 mg dose): 
Change from Baseline to Week 18 in HbA1c. 
Secondary endpoints (Sotagliflozin 400 mg dose): 
• 
Change from Baseline to Week 18 in FPG 
• 
Change from Baseline to Week 18 in BW. 
• 
Change from Baseline to Week 12 in SBP for patients with 
Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 12 in SBP for all patients 
• 
Change from Baseline to Week 52 in HbA1c 
• 
Change from Baseline to Week 52 in BW 
Secondary endpoints (Sotagliflozin 200 mg dose): 
• 
Change from Baseline to Week 18 in HbA1c 
• 
Change from Baseline to Week 18 in BW. 
• 
Change from Baseline to Week 18 in FPG 
• 
Change from Baseline to Week 12 in SBP for patients with 
Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 52 in HbA1c 
• 
Change from Baseline to Week 52 in BW 
Other efficacy endpoints (Sotagliflozin 400 mg and 200 mg): 
• 
Proportion of patients with HbA1c <7.0% or HbA1c <6.5% at 
Weeks 18, 26, and 52 
• 
Change from Baseline to Week 26 in HbA1c 
• 
Change from Baseline to Week 12 in SBP for all patients in 
the sotagliflozin 200 mg arm, and from Baseline to 
Weeks 26 and 52 in SBP for all patients and the subset of 
patients with Baseline SBP ≥130 mmHg in the sotagliflozin 
400 mg and 200 mg arms 
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• 
Change from Baseline to Weeks 12, 26, and 52 in SBP in 
patients with Baseline SBP <130 mmHg 
• 
Change from Baseline to Weeks 12, 26, and 52 in DBP for 
all patients and for the subset of patients with Baseline DBP 
≥80 mmHg 
• 
Change from Baseline to Week 52 in total daily insulin dose 
• 
Proportion of patients requiring rescue therapy during the 
52-week double-blind Treatment Period 
• 
Change from Baseline to Weeks 18 and 52 in 7-point SMBG 
profile (mean daily value and at each time point) 
• 
Change from Baseline in eGFR 
• 
Change from Baseline in UACR during the 52-week 
Treatment Period 
• 
PQAT at Weeks 18 and 52 
• 
Change in TRIM-D from Baseline to Week 52 for total score 
and 5 domain scores. 
Safety endpoints: 
• 
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 
• 
Markers of calcium metabolism 
• 
Safety laboratory results, vital signs results, and 12-lead 
electrocardiogram (ECG) results. 
Pharmacokinetic endpoints: 
Plasma concentrations of sotagliflozin and its 3-O-glucuronide 
metabolite. 
CGM substudy endpoints: 
The list of endpoints will be outlined in a separate substudy protocol. 
ASSESSMENT SCHEDULE 
See Section 1.2 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
The sample size/power calculations were performed based on the 
primary endpoint. Assuming a common standard deviation (SD) of 
1.2% and using a 2-sided test at a 0.05 α-level, 280 patients in the 
sotagliflozin 400 mg arm and 140 patients in the placebo arm will 
provide at least 95% power to detect a treatment difference of 0.5% 
in mean HbA1c change from Baseline to Week 18 between 
sotagliflozin 400 mg and placebo. 
A sample size of 140 patients in the sotagliflozin 200 mg arm and 
140 patients in the placebo arm will provide 80% power to detect a 
treatment difference of 0.4% in mean HbA1c change from Baseline 
to Week 18 between sotagliflozin 200 mg and placebo (SD 1.2%; 5% 
significance level 2-sided). 
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Page 13 
The total sample size will be 560 patients to be randomized 
(280 patients in the sotagliflozin 400 mg arm; 140 patients in the 
sotagliflozin 200 mg arm; 140 patients in the placebo arm). 
Analysis population: 
Efficacy analyses will be based on the intention to treat (ITT) 
population, defined as all randomized patients irrespective of 
compliance with the study protocol and procedures. Patients will be 
analyzed according to the treatment group to which they are 
randomized. 
Analysis of the primary efficacy endpoint: 
Analysis of the primary efficacy endpoint (change from Baseline to 
Week 18 in HbA1c) will be performed using the ITT population, using 
HbA1c measurements obtained during the study, including those 
obtained after IMP discontinuation or introduction of rescue therapy. 
The primary efficacy endpoint of change in HbA1c from Baseline to 
Week 18 will be analyzed with missing values imputed by 
control-based 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 sotagliflozin groups, 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 analysis of 
covariance (ANCOVA) model with treatment groups (sotagliflozin 
400 mg, sotagliflozin 200 mg, placebo), randomization strata of 
Week -1 HbA1c (≤8.5%, >8.5%), randomization strata of Week -1 
SBP (<130 mmHg, ≥130 mmHg), randomization strata of 
sulfonylureas use at Week -1 (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 18 for the sotagliflozin 
400 mg arm and placebo arm, as well as the between-group 
difference (comparing sotagliflozin 400 mg arm versus placebo) and 
the 95% confidence interval (CI) using contrast statements. 
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]). 
Baseline definition: 
The Baseline value is defined generally as the last available value 
before the first dose of double-blind IMP or the last available value 
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Page 14 
prior to Randomization for patients who were randomized but never 
exposed to IMP. 
Analysis of secondary efficacy endpoints: 
The secondary endpoints will be analyzed using a similar approach 
to the primary efficacy endpoint, with missing values imputed by the 
control-based multiple imputation method under the missing not at 
random framework. For each of the continuous secondary endpoints, 
each of the complete datasets will be analyzed by the ANCOVA 
model with treatment groups (sotagliflozin 400 mg, sotagliflozin 
200 mg, placebo), randomization strata of Week -1 HbA1c (≤8.5%, 
>8.5%), randomization strata of Week -1 SBP (<130 mmHg, 
≥130 mmHg), randomization strata of sulfonylureas use at Week -1 
(yes, no), and country as fixed effects, and Baseline secondary 
endpoint value as a covariate. Results from each complete dataset 
will be combined to provide the adjusted mean change from Baseline 
to Week 18 (Week 12 for SBP endpoints) for each treatment group, 
as well as the between-group difference (comparing each 
sotagliflozin group versus placebo) and the 95% CI using contrast 
statements. For HbA1c endpoint, results from each complete dataset 
will be combined to provide the adjusted mean change from Baseline 
to Week 18 for sotagliflozin 200 mg arm and placebo arm, as well as 
the between-group difference (comparing the sotagliflozin 200 mg 
arm versus placebo arm) and the 95% CI using contrast statements. 
The categorical secondary efficacy variables of HbA1c <6.5% or 
<7% at Week 18 will be analyzed using a Cochran-Mantel-Haenszel 
method stratified by randomization strata of Week -1 HbA1c (≤8.5%, 
>8.5%), randomization strata of Week -1 SBP (<130 mmHg, 
≥130 mmHg), and randomization strata of sulfonylureas use at 
Week -1 (yes, no). For the HbA1c <7% or <6.5% analysis, patients 
with missing HbA1c data at Week 18 will be considered 
non-responders in the ITT population. 
Summary statistics for the secondary endpoints at scheduled visits 
will be provided for each treatment group. 
Analysis of other efficacy endpoints: 
Except for patient reported outcome (PRO) 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. 
For TRIM-D scores (total and domain scores), descriptive statistics 
will be presented by treatment group per visit. The change from 
Baseline to endpoint will be analyzed using a similar approach as the 
primary efficacy endpoint with missing values imputed by 
control-based multiple imputation method under the missing not at 
random framework. 
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 IMP, regardless of the 
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Page 15 
amount of treatment administered. Patients will be analyzed for 
safety analyses according to the treatment actually received. The 
safety analyses will be provided for the 18-week randomized 
Treatment Period and for the entire 52-week double-blind Treatment 
Period. 
DURATION OF STUDY PERIOD (per 
patient) 
Up to 60 weeks, including an up to 6-week Screening Period 
(comprised of an up to 2-week Screening phase and a 4-week, 
Lantus titration/single-blind placebo Run-in Phase), a 52-week 
double-blind Treatment Period, and a 2-week post-treatment 
Follow-up Visit. 
STUDY COMMITTEES 
Steering committee: 
 Yes 
 No 
Data monitoring committee: 
 Yes 
 No 
Adjudication committee: 
 Yes 
 No 
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Page 16 
1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
Abbreviations: CGM = continuous glucose monitoring; HbA1c = hemoglobin A1c; MMTT = mixed-meal tolerance test; R = Randomization; T2D = type 2 diabetes. 
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Page 17 
1.2 
STUDY FLOW CHART 
Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
 
Screen-
ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight, heightd 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signse 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examination: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Abbreviatedf 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
Concomitant Medication 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Diet & exercise instruction 
 
X 
 
 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Instruction on basic GU 
hygiene & hydration 
 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Interactive response 
technology (IRT) contact 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
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Page 18 
Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
 
Screen-
ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense glucose meter, 
Beta-hydroxybutyrate (BHB) 
meter 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense glucose test strips 
and BHB strips 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Measurement of capillary 
BHB at the site 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
Dispense diary 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Collect/review diary 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Instruction on diabetic 
ketoacidosis symptoms, 
glucose testing 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Dispense IMP and Lantus 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
IMP and Lantus accounting & 
compliance 
 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Review results of SMBG and 
recommend Lantus dose 
adjustments as necessaryg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record results of a 7-point 
SMBGh 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
12-lead ECGi 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
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Page 19 
Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
 
Screen-
ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
Laboratory Assessmentsj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FPGk 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
BHB 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
HbA1c 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Clinical Chemistry l 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
Fasting lipids 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Pregnancy test (WOCBP)m 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
FSH and/or estradiol as 
neededm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma concentrationn 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Markers of calcium 
metabolismo 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Urinalysis w/microscopyp 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Collection of home 
overnight urine for albumin, 
protein, creatinine, calcium, 
phosphorus, magnesium, 
glucose, and albumin-
creatinine ratioq 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
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Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
 
Screen-
ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
PRO: PQATt 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
PRO: TRIM-Dt 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
Evaluate for glycemic rescue 
 
 
 
 
 
To be assessed and reported throughout the Treatment Period 
 
Hypoglycemia 
To be assessed and reported throughout the study 
AEs/SAEs/AESI/EOSIu 
To be assessed and reported throughout the study 
a If a patient discontinues treatment with IMP early during the Treatment Period, the patient will have a Premature EOT Visit, and a Follow-up Visit 2 weeks after the last dose of IMP. However, every effort will be 
made to have the patients return to the site for all scheduled visits, in particular the visits at Week 18 (Visit 12) and Week 52 (Visit 15). If the patient does not agree to a site visits, the patient will be contacted by 
telephone to inquire about safety status. If a patient discontinues (or completes) treatment and study at the same time, a single visit for both EOT and EOS will be performed. 
b To ensure effective Lantus dose titration during the Run-in Phase, patients will be instructed to call the Investigator to discuss the necessary adjustments in Lantus dose if they have 2 or more SMBG 
measurements above 100 mg/dL or below 80 mg/dL. 
c Two weeks after the last dose of IMP. 
d Height to be measured only at Screening. 
e Vital sign measurements (sitting blood pressure [BP], heart rate): 3 separate seated BP and heart rate measurements should be taken with at least 1 minute between readings, following a 5-minute rest period and 
prior to phlebotomy (if applicable). 
f 
The abbreviated physical exam should focus on cardiac and respiratory systems, as well as any areas important for assessment of AEs if necessary. 
g Fasting (pre-breakfast/pre-injection if available) SMBG: during the 4-week Run-in Lantus titration period, fasting SMBG should be performed daily. Thereafter, the number of fasting SMBG checks can be reduced 
according to the Investigator’s judgment, however at least 3 fasting (pre-breakfast) SMBG measurements per week should be done from Weeks 0 to 18 and 3 measurements during the week prior to study visits 
from Weeks 19 to 52 (Section 8.2.1.4). Patients will review SMBG values with site staff either at site visits, phone visits or extemporaneously if patient feels high or low SMBG values may necessitate a dose 
adjustment. See Table 2 for permitted adjustments. Patients should be advised to check SMBG whenever they experience any symptoms of hypoglycemia, if possible, before taking the treatment. Note: Units in 
table represent plasma glucose values as glucometers used for SMBG display results already adjusted to plasma concentration and no conversion is required. 
h 7-point SMBG profile (before [pre-injection after randomization] and 2 hours after breakfast, lunch and dinner, and bedtime): at least ONE day during the weeks prior to Weeks 0 (Visit 6), 18 (Visit 12), and 52 
(Visit 15). 
i 
The 12-lead ECG recordings should be obtained after at least 10 minutes in a supine position and prior to IMP administration. The ECG will be evaluated as “normal” or “abnormal”. 
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Page 22 
2 
TABLE OF CONTENTS 
 
AMENDED CLINICAL TRIAL PROTOCOL NO. 02.......................................................................................1 
1 
FLOW CHARTS.............................................................................................................................16 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................16 
1.2 
STUDY FLOW CHART ..................................................................................................................17 
2 
TABLE OF CONTENTS ................................................................................................................22 
2.1 
LIST OF TABLES...........................................................................................................................28 
2.2 
LIST OF FIGURES.........................................................................................................................28 
3 
LIST OF ABBREVIATIONS ..........................................................................................................29 
4 
INTRODUCTION AND RATIONALE.............................................................................................31 
4.1 
BACKGROUND: SOTAGLIFLOZIN AND DISEASE .....................................................................31 
4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS ................................................................32 
4.3 
RATIONALE FOR SELECTION OF DOSE ...................................................................................33 
4.4 
RATIONALE FOR STUDY DESIGN AND CONTROL GROUPS..................................................34 
4.5 
BENEFIT/RISK OF SOTAGLIFLOZIN...........................................................................................35 
5 
STUDY OBJECTIVES ...................................................................................................................37 
5.1 
PRIMARY.......................................................................................................................................37 
5.2 
SECONDARY ................................................................................................................................37 
5.3 
OTHER...........................................................................................................................................37 
6 
STUDY DESIGN ............................................................................................................................39 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................39 
6.1.1 
Screening period............................................................................................................................39 
6.1.1.1 
Screening phase (Visit 1)...............................................................................................................39 
6.1.1.2 
Run-in phase (Visits 2 to 5)............................................................................................................40 
6.1.2 
Double-blind Treatment Period (Day 1 to Week 52)......................................................................40 
6.1.3 
Follow-up period.............................................................................................................................41 
 
41 
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6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................41 
6.2.1 
Duration of study participation for each patient .............................................................................41 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................41 
6.3 
STUDY COMMITTEES..................................................................................................................41 
6.3.1 
Steering committee ........................................................................................................................41 
6.3.2 
Data monitoring committee ............................................................................................................42 
6.3.3 
Clinical endpoint committee(s).......................................................................................................42 
6.3.4 
Safety adjudication of events requiring ongoing monitoring ..........................................................42 
7 
SELECTION OF PATIENTS..........................................................................................................43 
7.1 
INCLUSION CRITERIA..................................................................................................................43 
7.2 
EXCLUSION CRITERIA ................................................................................................................43 
7.2.1 
Exclusion criteria related to study methodology ............................................................................43 
7.2.2 
Exclusion criteria related to the diabetes history and treatment....................................................44 
7.2.3 
Exclusion criteria related to the current knowledge of sotagliflozin ...............................................45 
7.2.4 
Additional exclusion criteria during or at the end of the Run-in Phase before Randomization .....46 
8 
STUDY TREATMENTS .................................................................................................................47 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................47 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT .......................................................................47 
8.2.1 
Lantus (insulin glargine 100 U/mL) ................................................................................................48 
8.2.1.1 
Dosage schedule ...........................................................................................................................48 
8.2.1.2 
Starting dose..................................................................................................................................48 
8.2.1.3 
Dose titration and modification.......................................................................................................49 
8.2.1.4 
Self-monitoring of blood glucose (SMBG) .....................................................................................51 
8.2.2 
Metformin .......................................................................................................................................52 
8.2.3 
Other oral antidiabetes drugs.........................................................................................................52 
8.2.4 
Rescue therapy..............................................................................................................................53 
8.3 
BLINDING PROCEDURES............................................................................................................55 
8.3.1 
Methods of blinding........................................................................................................................55 
8.3.2 
Randomization code breaking during the study.............................................................................55 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................56 
8.5 
PACKAGING AND LABELING ......................................................................................................56 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................57 
8.7 
RESPONSIBILITIES ......................................................................................................................57 
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8.7.1 
Treatment accountability and compliance......................................................................................58 
8.7.2 
Return and/or destruction of treatments ........................................................................................58 
8.8 
CONCOMITANT MEDICATION.....................................................................................................59 
8.8.1 
Prohibited prior and concomitant medications...............................................................................59 
8.8.2 
Concomitant diabetes therapy .......................................................................................................60 
8.9 
POST-STUDY TREATMENT.........................................................................................................60 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................61 
9.1 
EFFICACY ENDPOINTS ...............................................................................................................61 
9.1.1 
Primary efficacy endpoint (sotagliflozin 400 mg dose) ..................................................................61 
9.1.2 
Secondary efficacy endpoints........................................................................................................61 
9.1.3 
Other efficacy endpoints (sotagliflozin 400 mg and 200 mg doses)..............................................61 
9.1.4 
Assessment methods of efficacy endpoints...................................................................................62 
9.1.4.1 
Hemoglobin A1c.............................................................................................................................62 
9.1.4.2 
Fasting plasma glucose measurement ..........................................................................................62 
9.1.4.3 
Blood pressure measurements ......................................................................................................62 
9.1.4.4 
Body weight measurement ............................................................................................................63 
9.1.4.5 
Kidney function parameter measurement......................................................................................63 
9.1.4.6 
7-point SMBG profiles....................................................................................................................63 
9.1.4.7 
Proportion of patients starting rescue therapy...............................................................................63 
9.1.4.8 
Insulin dose....................................................................................................................................64 
9.2 
SAFETY ENDPOINTS ...................................................................................................................64 
9.2.1 
Assessment methods of safety endpoints .....................................................................................65 
9.2.1.1 
Adverse events ..............................................................................................................................65 
9.2.1.2 
Hypoglycemia.................................................................................................................................65 
9.2.1.3 
Laboratory safety variables............................................................................................................65 
9.2.1.4 
Urinalysis........................................................................................................................................67 
9.2.1.5 
Vital signs.......................................................................................................................................67 
9.2.1.6 
Electrocardiogram variables ..........................................................................................................67 
9.2.1.7 
Diabetic ketoacidosis .....................................................................................................................68 
9.3 
OTHER ENDPOINTS.....................................................................................................................68 
9.3.1 
Pharmacokinetics...........................................................................................................................68 
9.3.1.1 
Sampling time ................................................................................................................................68 
9.3.1.2 
Pharmacokinetic handling procedure.............................................................................................69 
9.3.1.3 
Bioanalytical method......................................................................................................................69 
 
69 
 
69 
9.3.3 
Patient reported outcomes assessments.......................................................................................70 
9.3.3.1 
Patient’s qualitative assessment of treatment ...............................................................................70 
9.3.3.2 
Treatment related impact measure for diabetes (TRIM-D)............................................................71 
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71 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................72 
10 
STUDY PROCEDURES ................................................................................................................74 
10.1 
VISIT SCHEDULE..........................................................................................................................74 
10.1.1 
Screening Period............................................................................................................................74 
10.1.1.1 Screening phase (Visit 1)...............................................................................................................74 
10.1.1.2 Run-in phase (Visits 2 to 5)............................................................................................................76 
10.1.2 
Double-blind Treatment Period (Day 1 to Week 52)......................................................................77 
10.1.2.1 On-site Visits 6, 8, 10, 11, 12, 13, and 14 (Weeks 0, 4, 8, 12, 18, 26, and 39).............................78 
10.1.2.2 Telephone Visits 7 and 9 (Weeks 2 and 6)....................................................................................80 
10.1.2.3 On-site Visit 15 (Week 52) - end of treatment ...............................................................................80 
10.1.3 
Post-treatment follow-up period.....................................................................................................81 
10.1.3.1 On-site Follow-up Visit 16 (Week 54) ............................................................................................81 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................82 
10.2.1 
Source data to be found in patient’s file.........................................................................................82 
10.2.2 
Source data verification requirements for screen failures .............................................................82 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................82 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product................................83 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................83 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................83 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................84 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................84 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................85 
10.4.1 
Definitions of adverse events.........................................................................................................85 
10.4.1.1 Adverse event ................................................................................................................................85 
10.4.1.2 Serious adverse event ...................................................................................................................85 
10.4.1.3 Adverse event of special interest...................................................................................................86 
10.4.1.4 Events of special interest ...............................................................................................................87 
10.4.2 
General guidelines for reporting adverse events ...........................................................................88 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................88 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................89 
10.4.5 
Guidelines for reporting events of special interest.........................................................................89 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................89 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................90 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................90 
10.6.1 
Hypoglycemia.................................................................................................................................90 
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10.7 
ADVERSE EVENTS MONITORING..............................................................................................92 
11 
STATISTICAL CONSIDERATIONS..............................................................................................93 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................93 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................93 
11.3 
ANALYSIS POPULATIONS...........................................................................................................94 
11.3.1 
Efficacy populations .......................................................................................................................94 
11.3.2 
Intent-to-treat population................................................................................................................94 
11.3.3 
Safety population ...........................................................................................................................94 
11.4 
STATISTICAL METHODS .............................................................................................................95 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................95 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................95 
11.4.1.2 Compliance ....................................................................................................................................96 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................96 
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................96 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................98 
11.4.2.3 Analysis of other efficacy endpoints...............................................................................................98 
11.4.2.4 Multiplicity considerations ..............................................................................................................99 
11.4.3 
Analyses of safety data................................................................................................................100 
11.4.3.1 Analysis of adverse events ..........................................................................................................100 
11.4.3.2 Analysis of hypoglycemia.............................................................................................................101 
11.4.3.3 Analysis of adverse events of special interest .............................................................................102 
11.4.3.4 Analysis of events of special interest...........................................................................................102 
11.4.3.5 Analysis of laboratory variables ...................................................................................................102 
11.4.3.6 Analyses of vital sign variables ....................................................................................................102 
11.4.3.7 Analyses of 12-lead electrocardiogram status.............................................................................103 
11.4.3.8 Analyses of pharmacokinetic variables........................................................................................103 
11.5 
INTERIM ANALYSIS....................................................................................................................103 
12 
ETHICAL AND REGULATORY CONSIDERATIONS.................................................................104 
12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................104 
12.2 
INFORMED CONSENT ...............................................................................................................104 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE .................................................................................................................104 
13 
STUDY MONITORING.................................................................................................................106 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS .......................................................................106 
13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................106 
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13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................106 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST ...........107 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................107 
14 
ADDITIONAL REQUIREMENTS.................................................................................................108 
14.1 
CURRICULUM VITAE..................................................................................................................108 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................108 
14.3 
CONFIDENTIALITY .....................................................................................................................108 
14.4 
PROPERTY RIGHTS...................................................................................................................109 
14.5 
INSURANCE COMPENSATION..................................................................................................109 
14.6 
DATA PROTECTION...................................................................................................................109 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................110 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................111 
14.8.1 
By the Sponsor.............................................................................................................................111 
14.8.2 
By the Investigator .......................................................................................................................111 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................111 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................111 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................113 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................114 
17 
APPENDICES..............................................................................................................................116 
APPENDIX A 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION....................................................................................................117 
APPENDIX B 
TREATMENT RELATED IMPACT MEASURE - DIABETES (TRIM-D) ............................120 
APPENDIX C RECOMMENDATIONS ON BASIC GENITOURINARY HYGIENE, MAINTAINING 
HYDRATION, AND RECOGNIZING DIABETIC KETOACIDOSIS..............................................122 
APPENDIX D MEASUREMENT OF BLOOD PRESSURE AND HEART RATE .....................................125 
APPENDIX E 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................127 
APPENDIX F PATIENT QUALITATIVE ASSESSMENT OF TREATMENT (PQAT) ...............................132 
 
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2.1 
LIST OF TABLES 
Table 1 – Summary of investigational medicinal products............................................................................47 
Table 2 – Lantus titration regimen.................................................................................................................50 
Table 3 – Instruction for SMBG performed during the study.........................................................................51 
Table 4 – Blood safety parameters ...............................................................................................................66 
Table 5 – Samples identification ...................................................................................................................69 
 
2.2 
LIST OF FIGURES 
Figure 1 - Hypoglycemia classification in Study EFC14868..........................................................................91 
 
 
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3 
LIST OF ABBREVIATIONS 
 
AE: 
adverse event 
AESI: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
BHB: 
beta-hydroxybutyrate 
BMI: 
body mass index 
BP: 
blood pressure 
BW: 
body weight 
CEC: 
Clinical Endpoint Commitee 
CGM: 
continuous glucose monitoring 
CI: 
confidence interval 
CRF: 
case report form 
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 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOS: 
end of study 
EOSI: 
events 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 
HRT: 
hormone replacement therapy 
IB: 
Investigator's Brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
ID: 
identification 
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IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ITT: 
intention-to-treat 
MACE: 
major adverse cardiac event 
MDRD: 
Modification of Diet in Renal Disease 
MI: 
myocardial infarction 
N: 
number (of observations) 
NIMP: 
noninvestigational medicinal product 
NPH: 
Neutral Protamine Hagedorn 
OAD: 
oral antidiabetes drug 
OC: 
observed cases 
PCSA: 
potentially clinically significant abnormality  
P-gp: 
P-glycoprotein 
PK: 
pharmacokinetic 
PQAT: 
Patient Qualitative Assessment of Treatment 
PRO: 
patient reported outcome 
PT: 
preferred term 
PYY: 
peptide YY 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SC: 
Steering Committee 
SD: 
standard deviation 
SE: 
standard error 
SGLT: 
sodium-glucose cotransporter 
SGLT1: 
sodium-glucose cotransporter type 1 
SGLT2: 
sodium-glucose cotransporter type 2 
SMBG: 
self-monitored blood glucose 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
T1D: 
type 1 diabetes 
T2D: 
type 2 diabetes 
TEAE: 
treatment-emergent adverse event 
TRIM-D: 
Treatment Related Impact Measure - Diabetes 
UACR: 
urinary albumin creatinine ratio 
ULN: 
upper limit of normal 
US: 
United States 
UTI: 
urinary tract infection 
VTE: 
venous thrombotic event 
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 (SGLT) type 1 and 2 
(SGLT1 and SGLT2). Sotagliflozin is 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, while results 
of macrovascular complications are coronary artery disease, peripheral arterial disease, and stroke 
(2). Other comorbidities that are frequently associated with diabetes are hypertension, obesity, and 
cardiovascular (CV) disease. According to the most recent International Diabetes Federation 
Diabetes Atlas, it was estimated in 2015 that 1 in 11 adults have diabetes, equivalent to 
415 million people, which is estimated to rise to 642 million adults by 2040 (3). 
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 (4). 
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 (3, 4). Despite 
the fact that the population of people with diabetes is growing, none of the current therapies is 
curative and the results of treatment are variable. 
Although lifestyle changes, including diet, exercise, and education, are valuable components of 
diabetes treatment, the vast majority of people with T2D must receive pharmacological therapy to 
control the disease. In the United States (US) and Europe, metformin is the standard first-line 
therapy in the absence of any contraindications or tolerability issues, as per guidance from the 
American Diabetes Association (5). 
Despite the numerous treatment options available, monotherapy fails in many patients as beta cell 
function continues to deteriorate leading to progressively increasing hyperglycemia. Aggressive 
glycemic control with the currently available agents often leads to side effects, most notably 
weight gain and an increased frequency of hypoglycemia. These concerns emphasize the need to 
develop new agents that effectively and safely lower glucose in diabetic patients (6). 
In patients with diabetes, it is desirable to maintain blood glucose in the normal range without 
exhausting the ability of the pancreatic beta-cells to produce insulin. Glucose is transported across 
the cell membrane by 2 different types of glucose transporters: glucose-facilitated transporters and 
SGLT proteins (7). In the kidney, after blood is filtered by the glomerulus, glucose passes into the 
urine, but 99% is reabsorbed, primarily via SGLT2, which is responsible for 90% of glucose 
reabsorption, while 10% is reabsorbed by SGLT1. When functional SGLT2 is lacking in humans, 
a significant amount of glucose remains in the urine and is removed from the body (8). This way 
of reducing blood glucose is an insulin-independent mechanism and therefore hyperglycemia may 
be reduced while the pancreas is spared from an increased demand for insulin production that is 
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caused by hyperglycemia. Since obesity is a significant comorbidity in T2D, and insulin 
resistance is increased in obesity, the caloric loss from glucose in the urine may represent an 
additional benefit resulting in decreased weight, which should result in decreased insulin 
resistance (8). 
SGLT1 is expressed predominantly in the gastrointestinal (GI) tract and is responsible for the 
majority of glucose absorption by the small intestine (9). Inhibition of SGLT1 in the GI tract 
delays glucose absorption and lowers peak postprandial glucose levels (8). Additionally, there is 
accumulating evidence that SGLT1 inhibition stimulates secretion of glucagon-like peptide-1 
(GLP-1) and peptide YY (PYY), gut hormones involved in pancreatic beta cell function and 
appetite control, respectively. Reduced glucose absorption in the proximal intestine leads to more 
glucose being delivered distally, which allows L cells in both the ileum and the colon to sense 
glucose and its byproducts and, as a result, they secrete GLP-1 and PYY. Although a complete 
lack of functional SGLT1 may be associated with symptoms of glucose and galactose 
malabsorption (10), pharmacologic inhibition of SGLT1 by sotagliflozin has not produced these 
effects in preclinical models or patients with T2D. Selective inhibitors of the SGLT1 transporter 
are in early stages of development. 
Extensive clinical studies conducted for selective SGLT2 inhibitors have established this class as 
effective agents for the treatment of T2D (6, 11) and have led to approvals by the US Food and 
Drug Administration (FDA) and the European Medicines Agency. Studies with sotagliflozin, a 
dual inhibitor of SGLT1 and SGLT2, 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, 
fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), GLP-1, and PYY (12). These data 
suggest that sotagliflozin should be of therapeutic benefit to patients with T2D. 
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 adverse events (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 frequency greater than placebo. 
However, the majority were described as mild to moderate, and most resolved spontaneously and 
without discontinuation of the study drug. 
In completed and ongoing clinical trials, no additional safety issues beside those already described 
in the current Investigator’s Brochure (IB) have been observed. In general, no significant 
imbalances of SAEs/AEs between sotagliflozin and comparators were observed in completed 
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studies. Cumulatively, across the completed studies, 8 SAEs were reported in 6 patients 
(4 patients with T2D and 2 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 patient 
receiving placebo had a myocardial infarction (MI). Two SAEs of diabetic ketoacidosis (DKA) 
were reported in 2 patients with T1D in the ongoing (blinded) Phase 2 T1D study (LX4211.1-203-
TIDM) using insulin pumps; in each case basal insulin was within 7% of Baseline, and both SAEs 
were assessed as due to failure of insulin delivery via insulin pump. Both cases were associated 
with high blood glucose readings >300 mg/dL, a finding expected in DKA and notable in that this 
value did not appear to be masked by sotagliflozin treatment. 
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 could also increase the exposure of other P-gp substrates. 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. 
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. 
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 
Both the 200 mg and 400 mg doses are being developed in the Phase 3 program for sotagliflozin 
for the treatment of T2D. These doses are being tested in several Phase 3 trials, including the 
current trial in patients with T2D and inadequate glycemic control. 
The proposed sotagliflozin 200 mg and 400 mg once daily doses are based on the results of the 
Phase 2b study LX4211.1-202-DM. In this study sotagliflozin doses of 75 mg once daily, 200 mg 
once daily, 200 mg twice daily, and 400 mg once daily were tested over a 12-week, double-blind 
period. The sotagliflozin 200 mg and 400 mg once daily doses were chosen for further evaluation 
based on their HbA1c lowering effects and the overall safety and tolerability observed at these 
doses. At 12 weeks, the 200 mg and 400 mg once daily doses lowered HbA1c by a mean of 0.52% 
and 0.93%, respectively (p <0.001 for both arms), while placebo lowered HbA1c by a mean of 
0.14%. Sotagliflozin also produced statistically significant reductions in body weight (BW) 
(200 mg and 400 mg doses) and systolic blood pressure (SBP) (400 mg dose). 
The overall incidences of AEs on sotagliflozin 200 mg and 400 mg once daily doses were similar 
to placebo. 
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From a safety perspective, sotagliflozin was well-tolerated across studies. In healthy subjects, 
sotagliflozin was well-tolerated following single doses up to 2000 mg, and in multiple doses up to 
800 mg over 10 days. Furthermore, in a thorough QT study, single doses of sotagliflozin (800 mg 
and 2000 mg) were well-tolerated and did not prolong the QT interval. Additionally, evaluation of 
metabolites in urine and plasma of healthy subjects resulted in no safety concerns following single 
doses of 400 mg sotagliflozin. 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. 
4.4 
RATIONALE FOR STUDY DESIGN AND CONTROL GROUPS 
This study is designed to assess the efficacy and safety of sotagliflozin (compared to placebo) 
when used as add-on therapy to basal insulin (Lantus), alone or in combination with oral 
antidiabetes drugs (OADs). Patients will be switched from their current basal insulin to Lantus 
(1:1 dose conversion, or 20% reduction if on treatment with Toujeo or Neutral Protamine 
Hagedorn [NPH] twice daily) and will have a 4-week dose titration period to improve their basal 
insulin dose prior to Randomization, utilizing a standard titration algorithm. During this period, 
compliance with the algorithm will be reviewed by an internal group blinded to the treatment 
assignment and investigators will be contacted as needed to encourage adherence to titration 
algorithm. During this Lantus titration period, the dose of concomitant OADs should stay 
unchanged, except if decreases are needed due to hypoglycemia. 
The primary endpoint is HbA1c reduction from Baseline to Week 18 because it is expected that 
sotagliflozin can provide significant additional glycemic efficacy even in an advanced T2D 
population with presumed beta cell failure. During the first 18 weeks no adjustment of Lantus is 
permitted (except for safety reasons or if rescue criteria are met) to enable the assessment of the 
effect of randomized treatment drug on top of a stable background therapy of insulin ±OADs. 
After Week 18, titration of Lantus may resume following the same titration algorithm utilized 
during the Run-in period. This will enable the assessment of the effect of the randomized study 
drug in a context of total dose of insulin being simultaneously adjusted and more typical of a 
real-world setting. Prandial insulin or GLP-1 agonists will be the recommended rescue therapy for 
patients on a stable regimen of oral antihyperglycemic agents who cannot adequately achieve 
glycemic control by up-titrating their Lantus dose, as per international diabetes treatment 
guidelines (13, 14). However, the investigator will be allowed to choose from any antidiabetic 
agent (with the exception of the SGLT2 inhibitors class) according to their clinical judgment and 
in line with the local standard of care. The protocol stipulates that patients be provided rescue 
therapy according to increasingly stringent hyperglycemia criteria (based on FPG and/or HbA1c) 
as aligned with regulatory guidance (15). 
Randomization will be stratified based on HbA1c at Week -1 (≤8.5%, >8.5%), SBP at Week -1 
(<130 mmHg, ≥130 mmHg), and use of sulfonylureas at Week -1 (yes, no), to achieve balanced 
randomization for assessment of the primary and main secondary study endpoints. 
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A placebo control will be used to allow for an unbiased assessment of treatment effects and safety 
data. Bias will be minimized by randomizing the patients to treatment groups, blinding the 
patients, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating 
endpoints in a blinded fashion. 
Two Patient Reported Outcomes (PROs) will be assessed in this trial. The Patient Qualitative 
Assessment of Treatment (PQAT) will be assessed at Week 18 and at the final on-treatment visit 
(Week 52). This instrument includes a 7-point Likert Scale for the patient to evaluate his/her 
subjective response to the treatment (-3 to +3 including 0 for a neutral response) and 2 free-text 
response questions to describe key advantages and disadvantages. The Treatment Related Impact 
Measure – Diabetes (TRIM-D) includes questions related to satisfaction with weight and 
hypoglycemia; it will be assessed at Screening, at Baseline (after the Lantus titration phase), and 
at several visits during the Treatment Period. 
A continuous glucose monitoring (CGM) substudy is planned to include a subset of patients. This 
study will allow assessing the impact of sotagliflozin on additional parameters of glucose control 
and variability over 24 hours which cannot be inferred by the HbA1c as an aggregate measure of 
overall glycemic control. The details of the CGM substudy are specified in the separate substudy 
protocol. 
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 development program will also provide efficacy and 
safety data for sotagliflozin in combination with other antidiabetes medications. In addition, the 
program will evaluate clinical outcomes in patients with high CV risk and in patients with renal 
impairment. The use of sotagliflozin in the treatment of T1D is also being studied in a separate 
development program. 
Sotagliflozin may benefit a wide variety of diabetic patients based on multiple potential beneficial 
effects of dual SGLT1/SGLT2 inhibition, and its insulin-independent mechanism of action. 
Improvements in HbA1c, FPG, and postprandial glucose were observed with sotagliflozin in 
multiple studies. As anticipated from the mechanism of action, treatment with sotagliflozin 
resulted in increased urinary glucose excretion (from inhibition of SGLT2) as well as increased 
levels of the intestinal peptides GLP-1 and PYY (from inhibition of SGLT1). In addition, the 
improvements in BW and blood pressure (BP) observed with sotagliflozin treatment have the 
potential to benefit patients with diabetes through their effects on common diabetic comorbidities. 
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. 
Additionally, the insulin-independent glucose lowering mechanism can result in an insulin sparing 
effect and consequently reduce the insulin requirements of patients managed with basal insulin. 
This outcome can result in a clinical benefit in patients on insulin therapy by lowering the risk of 
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hypoglycemia and weight gain associated with higher insulin doses. Also, the reduction in glucose 
levels can also delay the need for initiation of rescue treatment, which can include prandial insulin 
and GLP-1 receptor agonists. 
SGLT2 inhibitors class have been associated with small decreases of glomerular filtration rate and 
increased rate of genital infections, which are usually mild and well tolerated in clinical trials. 
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. 
Events of special interest (EOSI) are evaluated based on either their potential link to the drug’s 
mechanism of action, events that occur in other SGLT-inhibitor drugs, or regulatory 
interest/guidance for diabetes products, but found not to be in imbalance in clinical trials. In 
addition to the identified and potential risks (genital mycotic infections [male and female], 
metabolic acidosis, DKA, urinary tract infections [UTIs], volume depletion, severe hypoglycemia) 
for the sotagliflozin program, other EOSI have been defined. These EOSI are: major adverse 
cardiac events (MACEs) and other CV events, venous thrombotic events (VTEs), drug-induced 
liver injuries (DILIs)/alanine aminotransferase (ALT) increase >3 times the upper limit of normal 
(ULN), diarrhea, pancreatitis, bone fractures, renal events, malignancies of special interest 
(including but not limited to: breast, bladder, renal cell, Leydig cell, pancreatic, prostate and 
thyroid cancer), and AEs leading to amputation. 
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 
To demonstrate the superiority of sotagliflozin 400 mg versus placebo with respect to HbA1c 
reduction at Week 18 in patients with T2D who have inadequate glycemic control on basal insulin 
alone or with OADs. 
5.2 
SECONDARY 
• 
To assess the effects of sotagliflozin 400 mg versus placebo on: 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all patients 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
• 
To assess the effects of sotagliflozin 200 mg versus placebo on: 
- 
Change from Baseline to Week 18 in HbA1c 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 18 in FPG. 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
• 
To evaluate the safety of sotagliflozin 400 mg and 200 mg versus placebo throughout the 
52-week trial. 
5.3 
OTHER 
• 
To assess the effects of sotagliflozin 400 mg versus placebo on the proportion of patients 
with HbA1c <7.0% or HbA1c <6.5% at Weeks 18, 26, and 52 
• 
To assess the effects of sotagliflozin 200 mg versus placebo on the proportion of patients 
with HbA1c <7.0% or HbA1c <6.5% at Weeks 18, 26, and 52 
• 
To assess the effects of sotagliflozin 200 mg versus placebo on the change from Baseline 
to Week 12 in SBP for all patients 
• 
To assess the effects of sotagliflozin 400 mg and 200 mg versus placebo on: 
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- 
Change from baseline to Week 26 in HbA1c 
- 
Change from Baseline to Weeks 26 and 52 in SBP in all patients and the subset of 
patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Weeks 12, 26, and 52 in SBP in patients with Baseline SBP 
<130 mmHg 
- 
Change from Baseline to Weeks 12, 26, and 52 in diastolic blood pressure (DBP) for 
all patients and the subset of patients with Baseline DBP ≥80 mmHg 
- 
Change from Baseline to Week 52 in the total daily insulin dose 
- 
Proportion of patients requiring rescue therapy during the 52-week double-blind 
Treatment Period 
- 
Change from Baseline to Weeks 18 and 52 on 7-point Self-Monitored Blood Glucose 
(SMBG) profile (mean daily value at each time point)  
- 
Change from Baseline on estimated glomerular filtration rate (eGFR) 
- 
Change from Baseline in urinary albumin creatinine ratio (UACR) 
- 
Patient Qualitative Assessment of Treatment (PQAT) during the 52-week Treatment 
Period 
- 
Patient perception of treatment impact and satisfaction using the TRIM-D during the 
52-week Treatment Period. 
• 
To assess plasma concentrations of sotagliflozin and its 3-O-glucuronide metabolite. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This study is a Phase 3, multicenter, randomized, double-blind (with single-blind Run-in Phase), 
placebo-controlled, parallel-group study that is anticipated to enroll approximately 560 patients. 
The study will consist of 3 periods: 1) an up to 6-week Screening Period comprised of a Screening 
phase of up to 2 weeks and a 4-week Lantus titration/single-blind placebo titration Run-in Phase; 
2) a 52-week double-blind Treatment Period; and 3) a 2-week, post-treatment Follow-up Period. 
The study design is presented graphically in Section 1.1. 
In the United States, a substudy employing CGM technology will be performed to assess detailed 
glycemic profiles. The details of the CGM substudy procedures, endpoints and statistical analyses 
will be provided in a separate substudy protocol. 
6.1.1 Screening period 
6.1.1.1 Screening phase (Visit 1) 
The Screening phase will last up to 2 weeks. The period must be long enough to collect the data 
required to establish whether the patient satisfies the inclusion/exclusion criteria. 
Patients with T2D (16) will be included in this study if at Screening they have inadequate 
glycemic control (as demonstrated by a mean HbA1c ≥7.5% or HbA1c ≤10.5%), despite use of 
basal insulin (at a total daily dose that has been stable within ±20% of the dose at Screening for 
8 weeks inclusive). Patients may also be using up to any 2 OADs which may include metformin at 
a dose of at least 1500 mg/day or the maximum tolerated dose (documented). 
At the Screening Visit after signing of the informed consent form (ICF), eligibility criteria will be 
assessed, and Screening assessments will be performed. Women of childbearing potential 
(WOCBP) not willing to use highly effective contraceptive method(s), and/or who are 
unwilling or unable to be tested for pregnancy during the study will be excluded; guidance on 
highly effective contraceptive methods and collection of pregnancy information is provided in 
Appendix A. If another contraceptive method is used (such as a barrier method), it should be used 
in combination with one of the highly effective methods described in Appendix A (such as an oral 
contraceptive). 
The interactive response technology (IRT; either Interactive Voice Response System or 
Interactive Web Response System) will be contacted at Visit 1 for notification of Screening and 
for patient number allocation. 
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6.1.1.2 Run-in phase (Visits 2 to 5) 
The Lantus titration/single-blind placebo Run-in Phase will last 4 weeks. If the patient satisfies 
the entry criteria during the Screening phase, the basal insulin that the patient is currently taking 
will be replaced by Lantus (Section 8.2.1) provided by the Sponsor. A 4-week Lantus 
optimization phase will commence. 
During the 4-week Lantus titration/single-blind placebo Run-in Phase, patients will also take 
single-blind placebo (2 tablets, identical to sotagliflozin 200 mg in appearance) once daily before 
the first meal of the day, starting from Visit 2. 
6.1.2 Double-blind Treatment Period (Day 1 to Week 52) 
Eligible patients will be randomized on Day 1 (Visit 6). In order to qualify for randomization, 
patients must have an HbA1c value ≥7.0% at Week -1 (Visit 5) and must demonstrate compliance 
at the end of the single-blind placebo Run-in Phase based upon tablet count (≥80%), and as 
assessed at the Investigator’s discretion. 
Randomization will be stratified by: 
• 
HbA1c at Week -1 (≤8.5%, >8.5%) 
• 
SBP at Week -1 (<130 mmHg, ≥130 mmHg) 
• 
Sulfonylureas use at Week -1 (yes, no). 
Following randomization, patients will be treated in a double-blind manner for 52 weeks. A total 
of 560 patients ≥18 years of age (or ≥legal age of majority if greater) will be randomly assigned 
2:1:1 to the following 3 treatment groups: 
• 
Sotagliflozin 400 mg, given as two (2) 200-mg tablets, once daily before the first meal of 
the day (N = 280 patients) 
• 
Sotagliflozin 200 mg, given as one (1) 200-mg tablet and one (1) placebo tablet (identical 
to sotagliflozin 200 mg in appearance), once daily before the first meal of the day 
(N = 140 patients) 
• 
Placebo, given as two (2) placebo tablets (identical to sotagliflozin 200 mg in appearance), 
once daily before the first meal of the day (N = 140 patients). 
The doses of the OADs (if applicable) should be held constant throughout the entire 52-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 (until Visit 11) except 
for safety reasons. 
The dose of Lantus should be held constant for the first 18 weeks unless glycemic rescue criteria 
are satisfied (Section 8.2.1.4). Insulin titration resumes after Visit 12. 
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Detailed activities and responsibilities for the SC are provided in the SC Charter. 
6.3.2 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 trial safety data by treatment 
• 
Making a recommendation to the Sponsor regarding the study following each meeting. 
Safety data to be reviewed will include events and outcomes described below for adjudication, as 
well as any additional safety data considered relevant. Details describing the DMC processes and 
procedures are outlined in a separate DMC Charter. To maintain continuous blinding and study 
integrity, the analysis will be conducted by an independent statistician, and measures will be taken 
to ensure the validity of the data. 
6.3.3 Clinical endpoint committee(s) 
The Clinical Endpoint Committees (CECs) is/are comprised of experts in cardiology and 
nephrology (and other appropriate medical specialties such as neurology and endocrinology as 
needed) who are independent of the Sponsor and the contract research organization (CRO). The 
CEC(s) will review and adjudicate all deaths, 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). 
6.3.4 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 DILI, and 2) cases of amputations.  
The 2 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 a separate 
Charter. 
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7 
SELECTION OF PATIENTS 
Note: A patient should not be randomized more than once. In cases where original screen failure 
was due to reasons expected to change at rescreening and based upon the Investigator’s clinical 
judgment, the patient can be rescreened once prior to entering Run-in for this study. 
7.1 
INCLUSION CRITERIA 
I 01. Patients with T2D using any types of basal insulin alone or in combination with up to 
2 OADs 
I 02. Patient has given written informed consent to participate in the study in accordance with 
local regulations. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 4 subsections: 
7.2.1 Exclusion criteria related to study methodology 
E 01. At the time of Screening age <18 years or <legal age of majority, whichever is greater. 
E 02. Body Mass Index (BMI) ≤20 or >45 kg/m2 at the Screening Visit. 
E 03. Use of systemic glucocorticoids (excluding topical, intra-articular, or ophthalmic 
application, nasal spray or inhaled forms) for more than 10 consecutive days within 
90 days prior to the Screening Visit. 
E 04. Use of weight loss medications within 12 weeks 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 or unable to take 
alternative treatment. 
E 06. Patients who have previously been randomized 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. Current diagnosis of chronic hepatitis, and/or other clinically active liver disease requiring 
treatment. 
E 09. Known presence of factors that interfere with the Central Lab HbA1c measurement (eg, 
genetic Hb variants) compromising the reliability of HbA1c assessment or medical 
conditions that affect interpretation of HbA1c results (eg, blood transfusion or severe 
blood loss in the last 3 months prior to randomization, any condition that shortens 
erythrocyte survival). 
E 10. History of drug or alcohol abuse within 6 months prior to Screening. 
E 11. 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 12. 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.  
7.2.2 Exclusion criteria related to the diabetes history and treatment 
E 13. Type 1 diabetes mellitus. 
E 14. HbA1c <7.5% or HbA1c >10.5% measured by the central laboratory at Screening. 
E 15. Use of a selective SGLT2 inhibitor (eg, canagliflozin, dapagliflozin, or empagliflozin) 
within 3 months prior to the trial. 
E 16. History of DKA or nonketotic hyperosmolar coma within 12 weeks prior to the Screening 
Visit. 
E 17. History of severe hypoglycemia resulting in unconsciousness, seizure or hospitalization 
within 6 months prior to the Screening Visit. 
E 18. For patients using metformin or other OADs, contraindication to metformin or the other 
OADs as per local labeling. 
E 19. Use of injectable diabetes drugs other than basal insulin (eg, insulin glargine, NPH, 
detemir, or degludec), ie, prandial or rapid-acting insulins, short-acting insulins, GLP-1 
receptor agonists, or inhaled prandial insulin (Afrezza) within 8 weeks of Screening. 
E 20. OAD dose not stable for 8 weeks before Screening. 
E 21. Use of basal insulin therapy (eg, insulin glargine, NPH, detemir, or degludec) for less than 
6 months before Screening. 
E 22. Dose of basal insulin (eg, insulin glargine, NPH, detemir, or degludec) not stable for 
8 weeks before Screening (ie, total daily insulin dose increased or decreased by more than 
20%). 
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E 23. Known unstable proliferative diabetic retinopathy or any other rapidly progressive 
diabetic retinopathy or macular edema that is likely to require laser, surgical treatment 
during study period. 
7.2.3 Exclusion criteria related to the current knowledge of sotagliflozin 
E 24. Pregnant (confirmed by serum pregnancy test at Screening) or breastfeeding women. 
E 25. Women of childbearing potential 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 emergency within 12 weeks prior to Screening. 
E 28. History of gastric surgery including history of gastric banding or inflammatory bowel 
disease within 3 years prior to the Screening Visit. Note: Patients who have had bariatric 
surgery or gastric banding more than 3 years prior to the Screening Visit must have a 
stable weight (±10%) for 6 months prior to the Screening Visit. 
E 29. Difficulty swallowing such that the patient cannot take the IMP. 
E 30. Known allergies, hypersensitivity, or intolerance to SGLT2 inhibitor or any inactive 
component of sotagliflozin or placebo (ie, microcrystalline cellulose, croscarmellose 
sodium [disintegrant], talc, silicone dioxide, and magnesium stearate [nonbovine]), unless 
the reaction is deemed irrelevant to the study by the Investigator. 
E 31. Renal disease as defined by eGFR of <30 mL/min/1.73m2 at Screening by the 4 variable 
Modification of Diet in Renal Disease (MDRD) equation. 
E 32. Laboratory findings with the central lab tests at Visit 1 
• 
ALT or aspartate aminotransferase (AST) >3 times the ULN laboratory range 
• 
Total bilirubin >1.5 times the 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 times the ULN. 
E 33. 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 the Run-in Phase before 
Randomization 
E 34. Patients unwilling or unable to perform SMBG (failure to perform at least 3 fasting 
SMBG per week during Run-in), complete the patient diary, or comply with study visits 
and other study procedures as required per protocol. 
E 35. HbA1c <7% measured by the central laboratory at Visit 5 (Week -1). 
E 36. Informed consent withdrawal before randomization (patient who is not willing to continue 
or 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 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. Patient insufficiently compliant during Run-in Phase based upon tablet count (<80%) or 
in the opinion of the Investigator. 
E 39. 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 PRODUCTS 
The IMPs are sotagliflozin 400 mg, sotagliflozin 200 mg, and matching placebo. Patients will be 
provided with kits containing wallets of sotagliflozin or sotagliflozin-matching placebo (supplied 
as tablets identical to sotagliflozin 200 mg in appearance). 
Each patient will be supplied with the appropriate number of kit according to the dispensing 
scheme indicated in the study flowchart (see Section 1.2).  
A summary of the IMP (dose and timing) is provided in Table 1. 
Table 1 – Summary of investigational medicinal products 
IMP: 
Sotagliflozin 200 mg 
Sotagliflozin 400 mg 
Placebo group 
Name of IMP 
Sotagliflozin (SAR439954) 
Sotagliflozin (SAR439954) 
Placebo 
Pharmaceutical 
form 
Sotagliflozin (SAR439954) will 
be supplied as 200-mg tablets 
Sotagliflozin (SAR439954) will 
be supplied as 200-mg tablets 
Placebo will be supplied as 
tablets (identical to sotagliflozin 
200 mg in appearance) 
Dose, timing, and 
route of 
administration 
Sotagliflozin 200 mg group: 
One 200-mg tablet, taken orally 
once daily, before the first meal 
of the day 
One placebo tablet, taken orally 
once daily, before the first meal 
of the day 
Sotagliflozin 400 mg group: 
Two 200-mg tablets, taken orally 
once daily, before the first meal 
of the day 
Placebo group: 
Two placebo tablets, taken orally 
once daily, before the first meal 
of the day 
Duration of 
treatment 
52-week double-blind Treatment 
Period following randomization 
52-week double-blind Treatment 
Period following randomization 
4 weeks Run-in and 52 weeks 
following randomization 
Storage conditions 
Store between +15°C and +30°C (59°F and 86°F) 
IMP = Investigational medicinal product 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT 
Noninvestigational medicinal product (NIMP) treatment is defined as the rescue medication that 
will be used to treat hyperglycemia when a patient’s hyperglycemia reaches the rescue threshold 
and the mandatory background therapy (Lantus [see Section 8.2.1]), and/or the patients’ existing 
OADs (metformin [see Section 8.2.2]; other OADs [see Section 8.2.3]). The recommended rescue 
medication is the initiation of prandial injection of short-acting insulin or GLP-1 agonists, or 
another antidiabetic agent (except SGLT2 inhibitors) as per the Investigator’s discretion and in 
line with local treatment guidelines (see Section 8.2.4). 
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8.2.1 Lantus (insulin glargine 100 U/mL) 
All patients will use the study provided basal insulin, Lantus (insulin glargine 100 U/mL), starting 
from Visit 2 (beginning of the single-blind Run-in Phase) and continuing throughout the entire 
Run-in Phase and double-blind Treatment Period. Lantus will be supplied as a sterile, 
non-pyrogenic, clear, colorless solution in the marketed Lantus SoloStar prefilled (disposable) pen 
(insulin glargine 100 U/mL solution for subcutaneous injection) specifically labeled for use in this 
study. The disposable self-injector prefilled pens will be provided to each patient entering in the 
single-blind Run-in Phase at Visit 2. 
Each Lantus SoloStar contains 300 units of insulin glargine (3.0 mL of 100 U/mL insulin glargine 
solution) in total. This pen allows dose setting in the range of 1 to 80 units with a minimum 
increment of 1 unit. Dosing and dose adjustments should be performed according to details 
provided in Section 8.2.1.1, Section 8.2.1.2, Section 6.1.1.2 and Section 6.1.2. Each patient will 
be supplied with the appropriate number of pens according to the dispensing scheme indicated in 
the study flow chart (see Section 1.2). (Patients will be provided with kit containing 5 prefilled 
pens.) 
Pen-device related issues (malfunctions) should be reported to the Sponsor by the means of a 
procedure on Product Technical Complaint forms, which are described in a separate manual. 
8.2.1.1 Dosage schedule 
Lantus will be administered once a day. Patients should keep their existing basal insulin 
administration time (eg, morning or evening dosing) for Lantus dosing time. If a dose greater than 
80 units is required, it may be given as two or more consecutive subcutaneous injections at the 
same dosing time with daily dose split in equal or close to equal doses. Patients who are receiving 
NPH (or any other basal insulin) twice daily prior to Screening should administer Lantus once a 
day either in the morning or evening, following the Investigator’s advice since the beginning of 
Run-In. However, once the NIMP Lantus starts, the patients should not change the injection time 
during the study course. Lantus should be given at the same time daily within a ±1 hour window, 
which should be maintained for the duration of the study. 
Lantus should be administered by deep subcutaneous injection, alternating between the left and 
right anterolateral and left and right posterolateral abdominal wall or thighs or upper arms. Within 
a given area, location should be changed (rotated) at each time to prevent injection site skin 
reactions. 
8.2.1.2 Starting dose 
From Visit 2 (start of the single-blind Run-in period) all patients will receive Lantus as basal 
insulin. Patients who are already receiving Lantus prior to the study will start Run-in (Visit 2) at 
their pre-study dose level. 
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Patients who are receiving any basal insulin other than Lantus before Screening will switch to 
Lantus once a day. For patients who are using long-acting insulin analogs other than Lantus (eg, 
Levemir, Tresiba, Basaglar) the existing basal insulin will be converted to an equivalent dose of 
Lantus on a 1:1 unit basis (ie, the same dose on the day before Visit 2). If the patient is using 
Toujeo (glargine U-300/mL), the initial Lantus dose is 80% of the existing Toujeo dose as 
recommended in the Lantus label. If the patient is using NPH twice daily, it’s recommended that 
the converted Lantus dose should be reduced by 20% and given once daily. (If using NPH once a 
day, it can be converted to Lantus unit-to-unit.) 
8.2.1.3 Dose titration and modification 
Lantus will be titrated during the 4-week single-blind Run-in Phase and if necessary after 
18 weeks of the core Treatment Period to reach and maintain the target fasting glucose. 
The target range for fasting (pre-breakfast/pre-injection if available) blood glucose is 
80-100 mg/dL (4.4 to 5.6 mmol/L) avoiding hypoglycemia. 
During Run-in (Week -4 to Week -1): after initiating the study provided basal insulin, Lantus, 
the insulin dose will be up-titrated every 3 days (twice per week) until the patient reaches the 
target fasting blood glucose according to the recommended regimen (Table 2). The dose 
adjustments will be made in consultation with the study site either at site visits, phone visits, or 
unscheduled phone contacts. At the end of Run-in, patients with HbA1c ≥7.0% measured at 
Visit 5 (Week -1) are eligible to be randomized to receive the IMP treatment (sotagliflozin 
200 mg, sotagliflozin 400 mg or placebo) on top of Lantus.  
During the randomized core Treatment Period (Weeks 0 to 18): no insulin titration should be 
implemented.  
For patients with HbA1c <7.5% measured at Week-1, a 10% reduction in the Lantus dose at the 
randomization may be considered by the Investigator as needed, to reduce a potential risk of 
hypoglycemia. 
Lantus daily dose will remain stable (< ±10% from the dose at randomization, or < ±4 units, 
whichever is less) unless it is deemed necessary by the investigator to reduce or increase the dose 
for safety reasons (ie, severe hypoglycemia or AE/SAE) or the patient has met the hyperglycemic 
threshold for rescue therapy. In such a case, rescue assessment will apply and be implemented 
(Section 8.2.4). Increase and optimization in Lantus dose will be the first step of rescue therapy 
prior to initiation of prandial insulin or GLP-1 receptor agonists. 
After the core Treatment Period (Weeks 19 to 52): if the target fasting SMBG level is not 
achieved at the end of Week 18, insulin dose should be continuously up-titrated to maintain the 
fasting SMBG in the target range until the EOT. Titration will be done on a weekly basis, or as 
frequently as deemed necessary by the Investigator. 
Lantus dose adjustment is based on fasting SMBG values using study glucose meter that displays 
results already converted to plasma glucose concentration. Regular self-monitoring of plasma 
glucose is very important in order to achieve the blood glucose targets. It is recommended to 
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perform daily fasting/pre-breakfast SMBG to support Lantus titration process during the 4-week 
Run-in period and less frequent afterward during the Treatment Period (Section 8.2.1.4 and 
Table 3). 
The recommended Lantus titration regimen is outlined in Table 2, based on the mean of the 
3 most recent fasting pre-breakfast SMBG values, as measured by the patients. 
Table 2 – Lantus titration regimen 
Mean of 3 most recent fasting SMBG valuesa 
Lantus dose adjustments (IU/day) 
≥140 mg/dL (≥7.8 mmol/L) 
Increase Lantus by 4 units, or split to 2 x 2 units 
≥120 mg/dL and <140 mg/dL (≥6.7 mmol/L and <7.8 mmol/L) 
Increase Lantus by 2 units 
>100 mg/dL and <120 mg/dL (>5.6 mmol/L and <6.7 mmol/L) 
Increase Lantus by 1 unit 
80 mg/dL and 100 mg/dL (4.4 and 5.6 mmol/L), inclusive 
No change in dose 
<80 mg/dL (<4.4 mmol/L) 
Decrease Lantus by 2 units 
a The glucometers, used for SMBG, display results already calibrated to plasma glucose concentrations, thus no conversion is required. 
SMBG = self-monitored blood glucose 
In addition: 
1. Lantus dose titration may be withheld for a week or reduced in a patient who experiences 
two or more episodes of symptomatic hypoglycemia (with symptoms of hypoglycemia and 
an SMBG reading ≤70 mg/dL [≤3.9 mmol/L]) or one episode of severe hypoglycemia 
(patient required assistance from others to treat the hypoglycemic event; see  
Section 10.6.1). 
2. In both Run-in phase or post-Week 18 Treatment Phase, Investigators are allowed to 
modulate or stop titration or temporarily reduce dosage if they believe further titration 
would be hazardous to the patient (eg, due to age, comorbid conditions, individual patient 
considerations, other than hypoglycemia). In such a case the reason for the exceptions 
should be recorded in the source document. 
Good clinical judgment is to be exercised while titrating the insulin dose. For example, when 
implementing the weekly Lantus titration dose, a dose increase could be split into two incremental 
increases over the course of the week, rather than implementing the entire dose increase at one 
time, if it was concluded by the investigator or medically qualified designee to be in the best 
interest of the patient to do so. 
Patients will be familiarized with the titration schedule so that they would be able to monitor the 
titration with the assistance of the investigator or medically qualified designee. All dose 
adjustments must be discussed between the patient and appropriate site personnel. 
Patients who experienced mild to moderate hypoglycemia as a result of a missed meal, unusual 
exercise, or alcohol use will be counseled on the correction of those behaviors and may not need 
to have their insulin dose decreased. 
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8.2.1.4 Self-monitoring of blood glucose (SMBG) 
Self-monitoring of blood glucose measured by patients will be used for investigators to guide 
Lantus dose modification and monitor for hypoglycemia or hyperglycemia. 
A meter for self-assessment of blood glucose will be dispensed at the Week -4 Run-in visit 
(Visit 2). Patients will be trained on how to accurately measure plasma glucose values with the 
blood glucose meter. The study provided glucose meter will be used over the course of the study 
period. The investigator or site study staff will explain the need to measure glucose at the times 
requested for profiles and how to correctly record the values and times in the diary. Training is 
repeated as often as necessary at the study visits and the site study staff reviews the patient’s diary 
at each on-site visit. 
Patients will also receive a patient diary at all on-site visits with the exception of Visit 5 and 
Follow-up (Visit 16). The diary will be reviewed at all on-site visits from Visit 2 to Visit 16. 
The performance of SMBG is outlined in Table 3 and is also specified in Section 1.2. 
Table 3 – Instruction for SMBG performed during the study 
Frequency 
SMBG 
Definition 
Recommended 
Mandatory 
Weeks/Visits 
Fasting SMBG 
Overnight fasting pre-breakfast 
and before Lantus injection or 
any OAD intake 
Daily until achieving 
fasting SMBG target 
Daily SMBG 
Week -4 to Week -1 
 
 
5 days per week 
5 days per week 
until achieving 
fasting SMBG target 
3 days per week 
3 days during the week 
prior to study visit 
Week 0 to Week 18 
Week 19 to Week 52 
7-points 
Before and 2 hours after 
breakfast, lunch and dinner, 
and bedtime 
As needed 
1 day during the weeks 
prior to Weeks 0, 18, 
and 52 
Visit 6, 12, and 15 
OAD = oral antidiabetes drugs; SMBG = self-monitored blood glucose. 
Fasting SMBG readings will be used to guide the Lantus dose modification to reach and maintain 
the glucose targets. The investigators should review the SMBG records at each study visit 
including the phone visits so that they can provide instruction to the patients for appropriate 
insulin dose adjustment. 
Fasting SMBG 
Fasting SMBG should be tested in the morning before breakfast and before Lantus injection (for 
morning regimen) and taking any antidiabetic oral medications (if applicable). Patients should be 
instructed to check the fasting SMBG without food intake (except for water) for at least 8 hours 
(overnight) if possible. Patients should also be advised that a SMBG value should be excluded for 
insulin dose titration if the data were measured after taking food. 
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SMBG during hypoglycemic event 
Patients will also be requested to self-assess blood glucose levels whenever they experience any 
illnesses (eg, cold, flu), 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 should be instructed to 
measure blood glucose prior to carbohydrate intake/administration of glucose whenever 
symptomatic hypoglycemia is suspected, unless safety considerations necessitate immediate 
carbohydrate/glucose rescue prior to confirmation with the SMBG. 
Patients will be instructed to record the presence or absence of hypoglycemic episodes or 
hypoglycemic symptoms in the patient diary provided. 
All hypoglycemia episodes will be documented on the “hypoglycemia specific form” in the 
electronic case report form (eCRF). This includes all symptomatic hypoglycemia events and 
asymptomatic hypoglycemia. 
Hypoglycemia events fulfilling the criteria of a SAE will be documented on the SAE form in the 
eCRF. 
SMBG for monitoring hyperglycemia 
Patients should be instructed to contact the site if the fasting SMBG values over 3 consecutive 
days are: 
• 
From Baseline Visit (Visit 6, Day 1) to Visit 10 (Week 8): fasting SMBG >270 mg/dL 
(15.0 mmol/L) 
• 
From Visit 10 (Week 8) to Visit 11 (Week 12): fasting SMBG >240 mg/dL (13.3 mmol/L) 
• 
From Visit 11 (Week 12) up to Visit 12 (Week 18): fasting SMBG >200 mg/dL 
(11.1 mmol/L) 
• 
From Visit 12 (Week 18) up to the EOT Period Visit 15 (Week 52): fasting SMBG 
>170 mg/dL (9.4 mmol/L) 
8.2.2 Metformin 
Patients may use metformin at a dose of ≥1500 mg/day or maximum tolerated dose (as 
documented). Use of metformin is not required but the dose should be stable throughout the study; 
a dose decrease is allowed only for safety reasons. 
Metformin tablets are administered as per Investigator and in accordance with local labeling. 
8.2.3 Other oral antidiabetes drugs 
Patients may use up to 2 OADs (including metformin). Other OADs are administered as per 
Investigator and administered in accordance with local labeling. Doses of OADs should be kept 
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constant during the trial, but decrease for safety reasons during the insulin titration period is 
allowed. 
8.2.4 Rescue therapy 
If a patient needs to receive rescue antidiabetes medication, assessment of HbA1c should be 
performed before the introduction of the rescue medication. 
The threshold values for FPG and HbA1c are defined as follows, depending on study period: 
• 
From Baseline Visit (Visit 6, Day 1) to Visit 10 (Week 8) (including value at Visit 10): 
FPG >270 mg/dL (15.0 mmol/L) 
• 
From Visit 10 (Week 8) to Visit 11 (Week 12) (including value at Visit 11): FPG 
>240 mg/dL (13.3 mmol/L) 
• 
From Visit 11 (Week 12) up to Visit 12 (Week 18): 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 
≥1.5%) 
• 
From Visit 12 (Week 18) up to the EOT Period Visit 15 (Week 52): FPG >170 mg/dL 
(9.4 mmol/L) or HbA1c ≥8.0% (the 8.0% criteria does not apply if the HbA1c decrease 
from Baseline was ≥1.5%). 
Routine fasting SMBG and central laboratory alerts on FPG (and HbA1c at 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 one day, the patient will 
check again during the two 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 at Week 12 and onwards) will be performed as soon as 
possible, preferably within 7 days, to confirm the hyperglycemia. 
• 
Likewise, upon receipt of a central laboratory rescue alert, a central laboratory re-test 
must be completed and confirmed as exceeding the criterion for rescue before rescue 
therapy is initiated. The re-test confirmation should be performed as soon as possible, but 
within 7 days of receipt, by unscheduled visit. 
In the event that a confirmatory FPG 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 intake for ≥8 hours) 
• 
IMP is given at the maximum planned dose and the basal insulin is titrated according to 
the titration algorithm 
• 
Lantus is appropriately titrated, according to the titration algorithm, during the Run-in 
Phase and from Week 18 to EOT 
• 
There is no intercurrent disease, which may jeopardize glycemic control (eg, infectious 
disease) 
• 
Compliance to treatment is appropriate 
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• 
Compliance to diet and lifestyle is appropriate. During these phases, increase in Lantus 
dose is the first choice prior to initiating prandial insulin or a GLP-1 receptor agonist. 
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-hour 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. Increase in Lantus dose is the first 
choice prior to initiating prandial insulin 
• 
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 an 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. However, patients 
exceeding glucose rescue limits should have their Lantus dose up-titrated without a maximum 
limit as a first approach. If up-titration of the Lantus regimen has been unsuccessful (ie, increase 
in basal insulin is associated with low FPG values despite high HbA1c or elevated post-prandial 
values), it is appropriate to initiate rescue therapy. 
The recommended approach to rescue, if rescue thresholds have reached despite up-titration of the 
Lantus dose, is to initiate a prandial insulin, or a GLP-1 agonist or another antidiabetic agent 
(except SGLT2 inhibitors) as per the Investigator’s discretion and in line with local treatment 
guidelines. The prandial insulin can be any injectable short-acting insulin including fast-acting 
insulin analogs (such as, Humalog, Novolog, Apidra, and Fiasp) or regular insulin (eg, Humulin) 
or inhaled insulin (Afrezza). 
If a patient requires glycemic rescue, the IMP received during the randomized, double-blind 
Treatment Period should continue and must remain blinded until the EOS. The dose of the 
existing OAD may be adjusted after rescue therapy. 
Rescue therapy is considered an 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 by the Sponsor 
where permitted by local regulations. 
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8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
To maintain blinding, sotagliflozin and the matching placebo tablets and packaging will be 
blinded and indistinguishable. 
During the double-blind Treatment Period, each treatment package will be labeled with a number, 
which is generated by a computer program from Sanofi. Investigators will not have access to the 
randomization (treatment) code except under circumstances described in Section 8.3.2. 
The randomization and the treatment allocation will be performed centrally by an IRT. The study 
biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the patient 
randomization list from which it allocates treatment arms to the patients. 
Fasting glucose (plasma or serum) and HbA1c will be masked to study sites and patients after 
randomization and until study end. Additionally, the central laboratory urinalysis by dipstick will 
not include the measurement of urine glucose. 
The CEC members will perform adjudication in a blinded manner. 
8.3.2 Randomization code breaking during the study 
In case of an AE, the 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. 
Refer to Section 10.5 for suspected unexpected serious adverse reaction (SUSAR) unblinding by 
the Sponsor. 
Randomization code breaking will also be performed during the analysis of the Pharmacokinetic 
plasma concentration samples.  Only the Project manager and lead scientist at the Bioanalytical 
laboratory will have access to the randomization code to allow for the sorting of the sotagliflozin 
plasma samples. The Bioanalytical lab and responsible personnel will follow the standard 
procedures (SOP) 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 and 
Lantus in a secure and safe place in accordance with local regulations, labeling specifications, 
policies, and procedures. 
Control of IMP and Lantus storage conditions, especially control of temperature (eg, refrigerated 
storage) and information on in-use stability and instructions for handling the Sanofi compound 
should be managed according to the rules provided by the Sponsor. 
The expiry date and storage conditions are written on the IMP and Lantus labels. 
The treatment kit containing sotagliflozin 400 mg, sotagliflozin 200 mg, or placebo should be 
stored between +15°C and +30°C (59°F and 86°F). 
For the Lantus, prior to the first use, the disposable pens are to be stored between +2°C and +8°C, 
protected from light, and must not be frozen. In-Use Lantus disposable pens are to be stored 
below +25°C (not refrigerated) protected from light. Each pen should not be used for more than 
28 days after the first use. 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP and Lantus supplied by sponsor will be responsible for ensuring that the IMP and Lantus 
used in the clinical trial is securely maintained as specified by the Sponsor and in accordance with 
applicable regulatory requirements. 
All IMPs and Lantus 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 and Lantus issued and 
returned is maintained. 
Any quality issue noticed with the receipt or use of an IMP and Lantus (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) should be promptly notified 
to the Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP and Lantus may be subject to initiation of a recall 
procedure by the Sponsor. In this case, the Investigator will be responsible for promptly 
addressing any request made by the Sponsor or Delegate, in order to recall the IMP and Lantus 
and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP and Lantus to a third party (except for 
direct-to-patient shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP and Lantus to be used other than as directed by this clinical trial protocol, or dispose of 
IMP in any other manner. 
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8.7.1 Treatment accountability and compliance 
Accounting and compliance for IMPs and Lantus will be performed at Visit 5 and all subsequent 
on-treatment visits (excluding telephone visits). 
The Investigator will check the compliance to the study treatments based on the patient diary and 
will then complete the appropriate site treatment and patient treatment log forms. Returned IMP 
and Lantus NIMP (unused, in-use, or used wallets and pens) should be counted by site staff. In 
addition, the dosing information will be recorded on the appropriate pages of the eCRF. 
An internal group will review compliance with the fasting SMBG algorithm for Lantus titration in 
a blinded manner during the study. Mean fasting SMBG and insulin doses over time will be used 
to identify the out of the target values (within the range of 4.4 to 5.6 mmol/L [80-100 mg/dL]) via 
a pre-set program. The identified issues will be sent to the Investigators for their actions on the 
refinement of the titration schedule as needed. 
For other NIMPs (metformin, and other OADs), name, start and end date of treatment, total daily 
dose, etc, will be documented in the source documents. Compliance to NIMPs will be checked by 
interviewing the patient and reviewing diary at each on-treatment visit and be documented in the 
source documents and in the eCRF. 
If compliance is inadequate as determined by the Principal Investigator, patients will be trained 
again and mentored. If sub-optimal compliance continues after training and mentoring, patients 
may be discontinued at the discretion of the Investigator after discussion with the Sponsor’s 
medical monitor. 
8.7.2 Return and/or destruction of treatments 
Patients are to return all IMP and Lantus NIMP (unused, in-use, or used wallets and pens) at each 
on-site visit (or final assessment on-treatment visit, in the case of permanent premature 
discontinuation), as described in Section 1.2). IMP accounting is not required at telephone visits. 
Patients are to return all IMP and Lantus NIMP (unused, in-use, or used wallets and pens) at 
Visit 15 (or final assessment on-treatment visit, in the case of permanent premature 
discontinuation). 
All used wallets and pens, partially-used, or unused IMPs, and basal Lantus NIMP will be 
retrieved by the sponsor or delegate. A detailed site and patient treatment log of the returned IMP 
and basal Lantus NIMP will be established with the Investigator and countersigned by the 
Investigator and the monitoring team. 
For NIMP not provided by the Sponsor (ie, metformin or other OAD), tracking and reconciliation 
is to be undertaken by the Investigator (or pharmacist if appropriate) according to the system 
proposed by the CRO. 
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8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
The IMP includes placebo and sotagliflozin 400 mg and 200 mg. 
All concomitant medications should be documented on the Medications page 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 in the 3 months prior to Visit 1 and prior use of SGLT1/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, inhaled, or injectable 
antihyperglycemic agents other than the IMP and NIMP is not allowed before the rescue 
therapy. The existing background medication (NIMP) should not be modified before the 
rescue. 
• 
SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin) are not allowed for 
rescue. 
• 
Systemic use of glucocorticoids for more than 10 consecutive days (topical, intra-articular, 
ophthalmic, nasal spray, or inhaled applications are allowed). 
• 
IMPs in any other clinical study. 
• 
Modification of any antihypertensive medication before Week 12 is not allowed unless for 
safety reasons. 
• 
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. 
Note: short-term use (<10 consecutive days) of the prohibited medication, eg, short-acting insulin 
for treatment of acute illness or surgery is allowed. 
Other medications which are unlikely to interfere with the PK or pharmacodynamics of the IMP 
or confound interpretation of the study endpoints are allowed as needed and 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. During the Run-in 
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Phase, adjustments to antihypertensive therapy can be made as needed. After randomization, 
antihypertensive regimen should be kept constant during the following 12 weeks. 
8.8.2 Concomitant diabetes therapy 
Noninvestigational medicinal product (see Section 8.2) treatment is defined as the rescue 
medication that will be used to treat hyperglycemia when a patient’s hyperglycemia reaches the 
rescue threshold, plus the protocol-specified background therapy (Lantus), and/or up to 2 OADs 
(metformin and/or other OADs). The recommended approach to rescue, if rescue thresholds have 
been reached despite up-titration of the Lantus dose, is to initiate a prandial insulin, or a GLP-1 
agonist or another antidiabetic agent (except SGLT2 inhibitors) as per the Investigator’s discretion 
and in line with local treatment guidelines. 
8.9 
POST-STUDY TREATMENT 
As sotagliflozin may reduce BP, decrease 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 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 ENDPOINTS 
The methods of assessment of efficacy endpoints are detailed in Section 9.1.4. 
9.1.1 Primary efficacy endpoint (sotagliflozin 400 mg dose) 
• 
Change from Baseline to Week 18 in HbA1c. 
9.1.2 Secondary efficacy endpoints 
Continuous secondary efficacy endpoints for the sotagliflozin 400 mg dose: 
• 
Change from Baseline to Week 18 in FPG 
• 
Change from Baseline to Week 18 in BW 
• 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 12 in SBP for all patients 
• 
Change from Baseline to Week 52 in HbA1c 
• 
Change from Baseline to Week 52 in BW 
Continuous secondary efficacy endpoints for the sotagliflozin 200 mg dose: 
• 
Change from Baseline to Week 18 in HbA1c 
• 
Change from Baseline to Week 18 in BW 
• 
Change from Baseline to Week 18 in FPG 
• 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 52 in HbA1c 
• 
Change from Baseline to Week 52 in BW 
9.1.3 Other efficacy endpoints (sotagliflozin 400 mg and 200 mg doses) 
• 
The proportion of patients with HbA1c <7.0% or HbA1c <6.5% at Weeks 18, 26, and 52 
• 
Change from baseline to Week 26 in HbA1c 
• 
Change from Baseline to Week 12 in SBP for all patients in the sotagliflozin 200 mg arm, 
and from Baseline to Weeks 26 and 52 in SBP for all patients and the subset of patients 
with Baseline SBP ≥130 mmHg in the sotagliflozin 400 mg and 200 mg arms 
• 
Change from Baseline to Weeks 12, 26, and 52 in SBP in patients with Baseline SBP 
<130 mmHg 
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• 
Change from Baseline to Weeks 12, 26, and 52 in DBP for all patients and for the subset 
of patients with Baseline DBP ≥80 mmHg 
• 
Change from Baseline to Week 52 in total daily insulin dose 
• 
Proportion of patients requiring rescue therapy during the 52-week double-blind Treatment 
Period 
• 
Change from Baseline to Weeks 18 and 52 in 7-point SMBG profile (mean daily value and 
at each time point) 
• 
Change from Baseline in eGFR 
• 
Change from Baseline in UACR during the 52-week Treatment Period 
• 
PQAT at Weeks 18 and 52 
• 
Change in TRIM-D from Baseline to Week 52 for total score and 5 domain scores. There 
will be a particular focus on the Diabetes Management domain score, to evaluate patient 
satisfaction of ability of treatment to control diabetes and its effects. 
9.1.4 Assessment methods of efficacy endpoints 
9.1.4.1 Hemoglobin A1c 
Hemoglobin A1c will be assessed at Screening (Visit 1), Week -1 (Visit 5), and all on-site visits 
during the double-blind Treatment Period. 
For the eligibility and efficacy assessments of the study, HbA1c is measured by a certified level I 
“National Glycohemoglobin Standardization Program” central laboratory to allow estimation of 
the change from Baseline to Week 18 in HbA1c and the proportion of patients with HbA1c 
<6.5%, <7.0% at Week 18. 
If a patient needs to receive rescue antidiabetes medication, assessment of HbA1c should be 
performed before the introduction of the rescue medication. 
9.1.4.2 Fasting plasma glucose measurement 
Plasma glucose is measured in the fasting state at Screening (Visit 1) and all on-site visits during 
the Treatment Period. Fasting plasma glucose will be performed in fasting state, ie, without any 
food intake (except for water) for at least 8 hours. For the eligibility and efficacy assessments of 
the study, FPG is measured at a central laboratory to allow estimation of change from Baseline to 
Week 18 in FPG. 
9.1.4.3 Blood pressure measurements 
Systolic BP and DBP will be assessed at all on-site visits. Blood pressure measurements taken as 
described in Section 9.2.1.5 with details provided in Appendix D. 
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9.1.4.4 Body weight measurement 
Body weight is measured at all on-site visits to allow the estimation of change from Baseline to 
Week 52 in BW. Change from Baseline to Week 18 in BW will also be assessed (secondary 
endpoint). 
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. 
9.1.4.5 Kidney function parameter measurement 
Serum creatinine will be assessed at Screening (Visit 1), Week -1 (Visit 5), Baseline (Visit 6), and 
all subsequent on-site visits. 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 from overnight urine 
samples taken at Weeks 0, 12, 26, and 52. A central laboratory will analyze samples and estimate 
change from Baseline in serum UACR. 
9.1.4.6 7-point SMBG profiles 
Before (pre-injection after randomization) and 2 hours after breakfast; before and 2 hours after 
lunch; before and 2 hours after dinner and at bedtime: at least one day in the week before the 
Baseline visit (Visit 6), and before Visit 12 (Week 18) and Visit 15 (Week 52). 
Note: Patients should be reminded at the preceding visit to perform at least one day 7-point 
SMBG in the week prior to above study visits. If found missing performance (or any missing 
point), the visit should be postponed to allow the patient for repeating the performance. 
9.1.4.7 Proportion of patients starting rescue therapy 
The use of rescue medication for hyperglycemia will be assessed and reported throughout the 
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 8.2.4. 
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9.1.4.8 Insulin dose 
Patients will record their Lantus daily dose in the diary since Visit 2 at the beginning of Run-in 
and throughout the Treatment Period. In case of rescue therapy with prandial insulin, the meal-
time insulin will also be recorded in the patient’s diary. The insulin doses will be reviewed and 
verified by the investigator and site study staff, and then be documented onto the eCRF. 
The total daily insulin dose (Lantus and prandial, if applicable) will be analyzed by treatment 
groups. 
9.2 
SAFETY ENDPOINTS 
Assessments for safety include AEs, SMBG, clinical laboratory assessments, physical 
examination, 12-lead ECG, weight, and vital signs. An independent DMC will meet on a regular 
basis to review accumulating clinical trial safety data. 
Adjudication of all deaths, MACE/other selected CV events, selected renal events, bone fracture, 
and DKA will be performed in a blinded manner by a CEC(s) comprised of experts. Details will 
be provided in the charter of the CEC(s). Further details are available in Section 6.3.3. 
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 52-week double-blind Treatment 
Period: 
• 
Adverse events, AEs leading to discontinuation from the IMP, adverse events of special 
interest (AESI), EOSI, SAEs, and deaths 
• 
Hypoglycemia (all, severe and/or documented symptomatic) 
• 
Markers of calcium metabolism 
• 
Safety laboratory results (including amylase, lipase, and fasting lipids; see  
Section 9.2.1.3), vital signs results, and 12-lead ECG results. 
Observation period of safety endpoints 
The observation period of safety data will be divided into 3 segments: 
• 
The pre-Treatment Period is defined as the time between the date of 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 separate from AESI. For a list of events defined as EOSI and their 
reporting requirements see Section 10.4.1.4 and Section 10.4.5, respectively. 
9.2.1.2 Hypoglycemia 
Hypoglycemia (all, severe and/or documented symptomatic hypoglycemia) will be assessed 
starting with signing of the ICF and continue until 2 weeks after the last dose of IMP (Note: for 
patients who discontinue treatment >2 weeks before Week 52, safety data will be collected until 
scheduled study end). Patients will also complete the patient diary, which will be regularly viewed 
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 hematology, clinical chemistry, 
amylase, lipase, and fasting lipids) and urinalysis, according to the schedule presented in  
Section 1.2. Clinical laboratory values will be analyzed after conversion into standard 
international units. International units will be used in all listings and tables. Table 4 lists the 
hematology, clinical chemistry, and other blood safety parameters to be assessed by the central 
laboratory. 
In addition, for WOCBP a serum pregnancy test is performed at Screening and urine pregnancy 
tests are taken at all on-site visits during the double-blind Treatment Period. Any positive urine 
test results must be confirmed by a serum pregnancy test. The Investigator may perform 
additional tests at their discretion or as required by local regulations. 
For women of nonreproductive potential (Appendix A), follicle-stimulating hormone (FSH) 
and/or estradiol levels should be tested if the definition of postmenopausal or premenopausal 
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cannot be satisfied, eg, no medical document of hysterectomy or cessation of menses <12 months 
without an alternative medical cause. 
Table 4 – Blood safety parameters 
Clinical chemistry 
Hematology 
Other blood parameters 
Sodium 
Complete blood count (CBC) 
Lipid profile 
Potassium 
Differential 
Total cholesterol (TC) 
Calcium  
Chloride 
Platelet count 
High-density lipoprotein cholesterol (HDL-C) 
Carbon dioxide (bicarbonate) 
Hemoglobin 
Low-density lipoprotein cholesterol (LDL-C) will be 
calculated by Friedwald equation 
Blood urea nitrogen (BUN) 
Hematocrit 
Non-HDLC will be calculated as the difference 
between TC and HDLC 
Creatinine (eGFR will be 
calculateda) 
 
Triglycerides (TG) 
Glucose (serum) 
 
 
Alanine aminotransferase (ALT) 
 
Markers of calcium metabolismb 
Aspartate aminotransferase (AST) 
 
25-hydroxyvitamin D 
Total bilirubin (TB) 
 
1,25-dihydroxyvitamin D 
Alkaline phosphatase (ALP) 
 
Parathyroid hormone (PTH) 
Uric acid 
 
 
Phosphorus 
 
 
Total protein 
 
 
Albumin 
 
 
Magnesium 
 
 
Creatine phosphokinase (CPK) 
 
 
Lactic acid dehydrogenase (LDH)  
 
 
Amylase 
 
 
Lipase 
 
 
Beta-hydroxybutyrate (BHB)c 
 
 
All assessments to be performed by central laboratory. All assessments measured in serum. 
a The recommended equation for estimating eGFR from serum creatinine is the 4 variable MDRD study equation (17, 18). The isotope 
dilution mass spectrometry (IDMS)-traceable version of the MDRD Study equation is 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 predominately outside the US): http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-SI-units.asp. 
b To be collected at Baseline (Visit 6) and Week 26 (Visit 13). 
c Serum BHB to be assessed (central lab determination) at Baseline (Visit 6), Week 4 (Visit 8), Week 8 (Visit 10), Week 18 (Visit 12), 
Week 26 (Visit 13), Week 39 (Visit 14), and Week 52 (Visit 15). 
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9.2.1.4 Urinalysis 
Urinalysis (urine dipstick with microscopy) will be performed by central laboratory at Screening 
(Visit 1), Baseline (Visit 6), and Week 26 (Visit 13). To prevent partial unblinding the central 
laboratory urinalysis by dipstick will not include the measurement of urine glucose. Central 
urinalysis includes: 
• 
Urine dipstick includes: specific gravity, pH, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, and leukocyte esterase 
• 
Urine microscopy includes, but is not limited to: detection of formed cellular elements, 
casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. 
In the event of abnormal urinalysis findings suspicious of 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 Principal 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). 
9.2.1.5 Vital signs 
A complete physical exam (including sitting BP and heart rate, temperature and respiratory rate) 
will be performed at Visit 1 (Screening) and Week 26 (Visit 13). Abbreviated physical exams 
(including sitting BP and heart rate) will be performed at all other on-site visits. The abbreviated 
physical exam should focus on cardiac and respiratory systems, as well as any areas important for 
assessment of AEs if necessary. 
Three separate seated BPs and heart rate measurements should be taken with at least 1 minute 
between measurements following a 5-minute rest period, and prior to phlebotomy. Full details and 
directions for the measurement of BP are presented in Appendix D. 
9.2.1.6 Electrocardiogram variables 
The ECG assessment of “normal” or “abnormal” will be analyzed. 
A 12-lead ECG record is performed locally at Screening (Visit 1), Baseline (Visit 6), and 
Week 26 (Visit 13). 
The 12-lead ECG should be performed after at least 10 minutes in a supine position and prior to 
the morning IMP administration. The Investigator should review the ECG and the document the 
interpretation, and sign and date it on the ECG print out and on the eCRF. Each ECG trace is 
analyzed in comparison with the Screening recorded trace. All original traces are kept as source 
data. 
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Note: any new ECG abnormality should be rechecked for confirmation and reported as 
appropriate for that finding. 
9.2.1.7 Diabetic ketoacidosis 
During the Run-in Phase patients will be provided meters and test strips for monitoring capillary 
blood beta-hydroxybutyrate (BHB). Patients will be instructed to measure their BHB levels by 
fingerstick if they experience any symptoms consistent with ketosis/ketoacidosis throughout the 
Lantus titration phase/Run-in Phase and randomized Treatment Period. Patients will be instructed 
on how to respond (seek help, hydrate, ingest carbohydrates, etc) if they present with possible 
ketoacidosis symptoms and the BHB value is abnormal (>0.6 mM/L) (see Appendix C). 
Patients will be provided with instructions on how to recognize the symptoms of DKA and 
perform the BHB measurement at home in these situations, and will be instructed to contact the 
site (or seek emergency medical services if after business hours) if these symptoms develop. 
Patients should have a full clinical evaluation with laboratory testing for possible DKA by the 
Investigator or emergency medical services physician. If such an evaluation and laboratory testing 
confirm the presence of metabolic acidosis, then appropriate treatment should be implemented 
and the “Possible DKA” eCRF should be completed. 
In addition, serum BHB will be assessed at the study site via a central lab determination at 
Baseline (Visit 6), Week 4 (Visit 8), Week 8 (Visit 10), Week 18 (Visit 12), Week 26 (Visit 13), 
Week 39 (Visit 14), and Week 52 (Visit 15) and a capillary BHB measurement will also be done 
at the study site at these same visits. An alert will be sent to the investigator if the serum BHB 
measured by central lab value is ≥1.5 mM/L. Upon receiving the alert, investigator/designees 
should call the patient to assess if the patient experiences a suspected DKA, insulin dosing 
compliance, and any action to take, eg, seek urgent care or unscheduled site visit for further 
evaluation. 
9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacokinetics 
The PK endpoint for sotagliflozin is: 
• 
Plasma concentrations of sotagliflozin and its 3-O-glucuronide metabolite. 
Pharmacokinetic sotagliflozin data may be subjected to a population PK analysis, which will be 
reported separately to the clinical study report (CSR). 
9.3.1.1 Sampling time 
At Weeks 4, 18, 26, and 52 (Visits 8, 12, 13, and 15, respectively) blood samples for PK 
assessment are to be drawn with the other laboratory assessments, prior to administration of IMP. 
Pharmacokinetic samples must be collected before administration of IMP. The date and time of 
the last intake of study drug prior to visits when PK samples are taken should be recorded by the 
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9.5 
APPROPRIATENESS OF MEASUREMENTS 
The addition of sotagliflozin to background therapy consisting of Lantus with or without up to 
2 OADs (which may include metformin) is expected to lower HbA1c over 18 weeks of treatment 
(primary efficacy analysis). Sotagliflozin treatment for 18 weeks is likely to be of sufficient 
duration to observe effects on reduction of HbA1c, FPG, BP, and BW, and is therefore selected as 
the time point for assessment of the primary endpoint HbA1c. Treatment up to 52 weeks will 
provide additional long-term data on safety and efficacy. 
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 considered an appropriate primary endpoint for assessing the 
effect of a treatment on glycemic control. The duration of study treatment (18 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 BW from Baseline 
to Week 18 is a secondary endpoint. 
Potential therapeutic effect of sotagliflozin on BP reduction will be assessed in all trial patients 
and in patients with a mean SBP ≥130 mmHg at Baseline. To avoid confounding factors, 
modification of antihypertensive medications is not allowed during the first 12 weeks of 
Treatment Period (Section 8.8.1). The beneficial effect of sotagliflozin to patients with 
inadequately controlled hypertension could be best assessed by the key secondary endpoint, “the 
change in the SBP from Baseline to Week 12 for patients with Baseline SBP ≥ 130 mmHg”. In 
addition, the effect of sotagliflozin on BP will be evaluated in all patients, including normotensive 
individuals. 
Improvement in FPG has 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 the efficacy of an antidiabetes agent. 
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 patients. Safety 
laboratory parameters include BHB (beta-hydroxybutyrate), which is considered as a sensitive 
indicator for DKA diagnosis and monitoring (20). The values measured during study course will 
be analyzed between the treatment groups. 
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The length of the study is considered appropriate for detection of efficacy endpoints given the 
power estimates (see Section 11). 
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, 26, and 52. 
Because of potential effects on calcium metabolism, specific biomarkers for calcium metabolism 
will be assessed at regular time points. 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The visit schedule and procedures/assessments are listed in the Study Flow Chart (Section 1.2). 
The aim of this section is to provide details on how some of the procedures/assessments should be 
performed. 
This is an out-patient study and consists of 12 on-site visits and 4 telephone visits, although 
optional on-site and/or telephone visits can be scheduled at any time for any reason during the 
study whenever considered necessary by the Investigator. 
The patients need to be fasting for on-site visits Visit 1 through Visit 15 (Week -6 through 
Week 52), unless otherwise instructed by the Investigator. Throughout the study, “fasting” is 
defined as at least 8 hours without any food intake (except for water). 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). The first Run-in Visit (Visit 2) can be performed as 
soon as the results of all Screening tests are available and the patient is confirmed to be eligible 
for participation in the study. The visit window for Visit 5 is ±2 days, and Visits 7 through 13 
should occur within ±3 days. Visits 14 and 15 should occur at the scheduled time point ±7 days. 
Visit 15 (EOT) should occur from Day 357 to Day 371. For the Follow-up Visit (Visit 16), the 
visit should occur within a window of ±3 days, 2 weeks after the last dose of IMP. If one date is 
changed, the next visit should occur according to the original schedule, ie, calculated from the 
date of Baseline Visit (Visit 6, Day 1). 
For a complete list of procedures scheduled for each study visit, please refer to the Study Flow 
Chart (Section 1.2), which details the procedures to be performed. 
All data obtained during the trial visits are reviewed by the Investigator and/or Sub-investigators 
who are qualified in the treatment of T2D and are trained on the study. 
10.1.1 Screening Period 
The Screening Period is up to 6 weeks in duration and includes the Screening phase and the 
Run-in phase. 
10.1.1.1 Screening phase (Visit 1) 
The Screening phase will be up to 2 weeks in duration and includes Visit 1 (Week -6) only. It 
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): 
- 
HbA1c 
- 
Safety laboratory, including amylase and lipase 
- 
Hematology 
- 
Serum pregnancy testing for WOCBP or serum FSH and estradiol (for women of 
nonreproductive potential if definition of postmenopausal or premenopausal cannot be 
satisfied; see Appendix A) 
- 
Urinalysis (dipstick and microscopy) 
• 
PRO: TRIM-D 
• 
Patients are instructed to return to the site in the fasting state for Visit 2 (Week -4). 
10.1.1.2 Run-in phase (Visits 2 to 5) 
The Run-in phase is 4 weeks in duration and includes Visits 2 to 5 (Weeks -4 to -1, inclusive). 
10.1.1.2.1 On-site Visit 2 (Run-in, Week -4) 
The following procedures/assessments will be performed at Visit 2 (Week -4): 
• 
Assessment of exclusion criteria 
• 
Measurement of BW 
• 
Abbreviated physical examination including vital signs (SBP, DBP, and heart rate). After 
5 minutes resting, seated SBP, DBP, and heart rate will be assessed 3 times with at least 
1 minute between each measurement (see Appendix D for details). 
• 
Diet and exercise instruction 
• 
Blood glucose and BHB meters are dispensed and instructions/training is provided 
• 
Glucose test strips and BHB strips are dispensed 
• 
IRT to be notified (registration of Run-in, allocation of single-blind placebo Run-in kit and 
Lantus kit) 
• 
Instruction on DKA symptoms and glucose testing is provided 
• 
Patient diary is collected and reviewed and a new one dispensed. Instructions/training are 
provided as needed. 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia occurring since Visit 1 (if any) are reported 
• 
Run-in kit/placebo (IMP) and Lantus are dispensed 
• 
Treatment with study provided Lantus is started either on evening of Visit 2 (if evening 
dose) or the following morning (if morning dose) 
• 
Changes in concomitant medication are reported 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary 
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• 
Patients are instructed to return to the site for Visit 5. 
10.1.1.2.2 Telephone Visits 3 and 4 (Run-in Weeks -3 and -2) 
The following will be performed at this visit: 
• 
Assessment of exclusion criteria 
• 
Fasting SMBG is reviewed from diary and Lantus dose adjustments are made as necessary 
(Section 8.2) 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are instructed to return to the site for Visit 5. 
10.1.1.2.3 On-site Visit 5 (Run-in, Week -1) 
The following procedures/assessments will be performed at Visit 5 (Week -1): 
• 
Assessment of exclusion criteria 
• 
Measurement of BW 
• 
Abbreviated physical examination including vital signs (SBP, DBP, and heart rate). After 
5 minutes resting, seated SBP, DBP, and heart rate will be assessed 3 times with at least 
1 minute between each measurement (see Appendix D for details). 
• 
Diet and exercise instruction 
• 
Instruction on DKA symptoms, glucose testing, and basic genitourinary (GU) hygiene and 
hydration (see Appendix C) is provided 
• 
Patient diary is collected/reviewed. Instructions/training are provided as needed. 
• 
IMP and Lantus accountability and compliance 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Changes in concomitant medication are reported 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary  
(Section 8.2) 
• 
Patients are instructed to return to the site in the fasting state for Visit 6 (Randomization) 
• 
The following laboratory testing (by the central laboratory): 
- 
HbA1c 
- 
Clinical chemistry, including amylase and lipase. 
10.1.2 Double-blind Treatment Period (Day 1 to Week 52) 
Upon successful completion of the Run-in phase, patients will be randomly allocated to 
sotagliflozin 400 mg, sotagliflozin 200 mg, or placebo for the double-blind Treatment Period. All 
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randomized patients will be followed at regular on-site visits for the duration of the Treatment 
Period. Visit 7 (Week 2) and Visit 9 (Week 6) are telephone visits.  
Patients will be instructed that their Lantus dose should remain unchanged (< ±10% of the 
randomization dose, or < ±4 units, whichever is less) until after Week 18 unless for safety reasons 
(eg, hypoglycemia, during treatment of an SAE) or meet the rescue criteria. After Week 18, 
Lantus dose may be adjusted if deemed necessary by the Investigator. 
In addition to routine laboratory testing, the following will be performed at specified time points: 
plasma concentration, serum and capillary BHB, hematology, fasting lipids, urinalysis, complete 
physical examination, diet and exercise instruction, 
, PQAT, and TRIM-D. 
The date and time of the last intake of IMP prior to visits where PK samples are taken should be 
recorded by the patient in the patient diary. Patients should be reminded of this at visits preceding 
PK time points to ensure these details are captured. 
In the event of abnormal urinalysis findings suspicious of 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 Principal Investigator suspects 
the presence of a UTI. 
10.1.2.1 On-site Visits 6, 8, 10, 11, 12, 13, and 14 (Weeks 0, 4, 8, 12, 18, 26, and 39) 
The following procedures will be performed at these visits: 
• 
Exclusion criteria are to be reviewed, including assessment of compliance during the 
Run-in phase (Visit 6 only) 
• 
Randomization (Visit 6 only) 
• 
Measurement of BW (all visits) 
• 
Abbreviated physical examination including vital signs (SBP and DBP, and heart rate). 
After 5 minutes resting, seated SBP, DBP, and heart rate will be assessed 3 times with at 
least 1 minute between each measurement (see Appendix D for details) (all visits except 
Visit 13, where a complete physical examination will be performed). 
• 
Concomitant medications are assessed (all visits) 
• 
Glucose test strips and BHB strips are dispensed (all visits) 
• 
Measurement of capillary BHB (all visits, except Visit 11) 
• 
Diet and exercise instruction (Visits 6 and 13 only) 
• 
Instruction on DKA symptoms, glucose testing, and basic GU hygiene and hydration (see 
Appendix C) is provided (all visits) 
• 
IRT to be notified, IMP and Lantus for resupply (all visits) 
• 
Patient diary is collected/ reviewed and new diary dispensed. Instructions/training are 
provided as needed (all visits). 
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• 
IMP and Lantus are dispensed (all visits) 
• 
IMP and Lantus accountability and compliance (all visits) 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary (all visits) 
• 
Record results of 7-point SMBG (Visits 6 and 12 only) 
• 
Patients are evaluated for glycemic rescue (see Section 9.1.4.7) (all visits) 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
The following laboratory testing (by the central laboratory): 
- 
FPG (all visits) 
- 
BHB (all visits except Visit 11) 
- 
HbA1c (all visits) 
- 
Clinical chemistry, including amylase and lipase (all visits) 
- 
Hematology (Visits 6, 11, 13, and 14 only) 
- 
Fasting lipids (Visits 6, and 12 only) 
- 
Urine pregnancy testing for WOCBP (all visits) 
- 
Pre-dose plasma concentration samples are collected and sent to the appropriate 
laboratory (Visits 8, 12, and 13 only) 
- 
Markers of calcium metabolism (Visits 6 and 13 only) 
- 
Urinalysis (dipstick and microscopy) (Visits 6 and 13 only) 
- 
Overnight urine collection for albumin, protein, creatinine, calcium, phosphorus, 
magnesium, glucose, and albumin-creatinine ratio (Visits 6, 11, and 13 only) 
 
 
 
 
• 
PRO: PQAT (Visit 12 only) 
• 
PRO: TRIM-D (Visits 6, 12, 13, and 14 only) 
• 
12-lead ECG (Visits 6 and 13 only) 
• 
Patients are instructed to return to the site in the fasting state for their next visit (all visits 
except Visits 6 and 8, which precede telephone visits). They should be reminded to record 
in the diary the date and time of IMP intake on the day before their next visit (reminder at 
Visits 7, 11, and 12 only). 
• 
For accountability and compliance purposes, patients are instructed to return to the site 
with their unused, in-use, and used wallets and pens at the next on-site visit (all visits). 
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10.1.2.2 Telephone Visits 7 and 9 (Weeks 2 and 6) 
The following will be performed at this visit: 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are evaluated for glycemic rescue (see Section 9.1.4.7) 
• 
Patients are instructed to return to the site in the fasting state for Visits 8 and 10. 
10.1.2.3 On-site Visit 15 (Week 52) - end of treatment 
The following procedures will be performed at this visit: 
• 
Measurement of BW 
• 
Abbreviated physical examination including vital signs (SBP and DBP, and heart rate). 
After 5 minutes resting, seated SBP, DBP, and heart rate will be assessed 3 times with at 
least 1 minute between each measurement (see Appendix D for details). 
• 
Concomitant medications are assessed 
• 
Glucose test strips and BHB strips are dispensed 
• 
Diet and exercise instruction 
• 
Instruction on DKA symptoms, glucose testing, and basic GU hygiene and hydration (see 
Appendix C) is provided 
• 
IRT to be notified 
• 
Patient diary is collected and reviewed and new diary dispensed. Instructions/training are 
provided as needed 
• 
IMP and Lantus accountability and compliance 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary 
• 
Record results of 7-point SMBG 
• 
Measurement of capillary BHB at the site using the meter 
• 
Patients are evaluated for glycemic rescue (see Section 9.1.4.7) 
• 
The following laboratory testing (by the central laboratory): 
- 
FPG 
- 
BHB 
- 
HbA1c 
- 
Clinical chemistry, including amylase and lipase 
- 
Hematology 
- 
Fasting lipids 
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- 
Urine pregnancy testing for WOCBP 
- 
Plasma concentration of sotagliflozin and its 3 O-glucuronide metabolite 
- 
Overnight urine collection for albumin, protein, creatinine, calcium, phosphorus, 
magnesium, glucose, and albumin-creatinine ratio 
 
 
• 
PRO: PQAT 
• 
PRO: TRIM-D 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are instructed to return to the site in the fasting state for their next visit (Visit 16) 
• 
For accountability and compliance purposes, patients are instructed to return to the site 
with their unused, in-use, and used wallets and pens at the next visit. 
10.1.3 Post-treatment follow-up period 
The post-treatment Follow-up Period (EOS) will include an on-site visit 14 days (2 weeks) 
±3 days after the last dose of IMP. 
10.1.3.1 On-site Follow-up Visit 16 (Week 54) 
The following will be performed at this visit: 
• 
Measurement of BW 
• 
IRT notified for EOS 
• 
Patient diary is collected and reviewed 
• 
Concomitant medications are assessed 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Abbreviated physical examination including vital signs (SBP, DBP, and heart rate). After 
5 minutes resting, seated SBP, DBP and heart rate will be assessed 3 times with at least 
1 minute between each measurement (see Appendix D for details). 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary. 
• 
The following laboratory testing (by the central laboratory): 
- 
Clinical chemistry, including amylase and lipase. 
• 
The patient is instructed to schedule future follow-up with their own personal physician. 
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10.2 
DEFINITION OF SOURCE DATA 
10.2.1 Source data to be found in patient’s file 
Evaluations recorded in the eCRF must be supported by appropriately signed source 
documentation related but not limited to the following: 
• 
Agreement and signature of ICF with the study identification 
• 
Study identification (name) 
• 
Patient number, confirmation of randomization, treatment batch number, dates, and doses 
of study medication administration 
• 
Medical, surgical, diabetes history, including information on: 
- 
Demography, inclusion, and exclusion criteria 
- 
Last participation in a clinical trial 
- 
Contraception method for WOCBP 
- 
Previous and concomitant medication. 
• 
Dates and times of visits and assessments including examination results 
• 
Vital signs, height, BW, laboratory reports, Investigation results (eg, ECG traces, imaging 
reports) 
• 
Adverse events and follow-up: 
- 
In case of an 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 identification (name), dates of study visits, and 
the main reasons for screen failure. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporary; permanent IMP discontinuation should be a 
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last resort. Any IMP discontinuation should 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. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Low extremity complications (such as skin ulcers, infection, osteomyelitis and gangrene) 
requiring treatment should lead to temporary discontinuation of IMP.  Re-initiation of treatment 
with the IMP will be done under close and appropriate clinical and/or laboratory monitoring once 
the Investigator will have considered according to his/her best medical judgment, that the 
occurrence of the concerned event was unlikely to be related to the IMP. 
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 8.2.1.4). 
For all temporary treatment discontinuations, the duration should be recorded by the Investigator 
in the appropriate pages of the eCRF when considered as confirmed. 
Temporary treatment discontinuation, as 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) is recorded as concomitant medication with 
the name and doses 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 at any time for any reason or this may be the 
Investigator’s decision. Patients should discuss stopping study medication with the site before 
doing so in order that questions can be addressed, glycemic therapy adjusted, and a follow-up 
assessment arranged. All efforts should be made to document the reasons for treatment 
discontinuation and this should be documented in the eCRF. 
The following reasons lead to permanent discontinuation: 
• 
At the patient’s own request (ie, withdrawal of consent for treatment) 
• 
If, in the Investigator’s opinion, continuation with the administration of the study 
treatment would be detrimental to the patient’s well-being 
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• 
Intercurrent condition that requires permanent discontinuation of the study treatment as 
long as the abnormality persists and if the causal relationship of the concerned event and 
the IMP is possible (according to the Investigator’s best medical judgment) 
• 
Pregnancy (in female patients) 
• 
Specific request of the Sponsor. 
Any abnormal laboratory value will be immediately rechecked to confirm the result before a 
decision is made to permanently discontinue IMP for the concerned patient. 
For patients who prematurely discontinue the IMP, the assessments planned at the EOT Visit (see 
Section 10.1.2.3) will be performed at the Premature EOT Visit scheduled preferably prior to 
treatment discontinuation or as soon as possible after the time of discontinuation (at the latest at 
the next scheduled on-site visit). In the case of premature IMP discontinuation, PK samples 
should not be drawn at the Premature EOT Visit, or at any subsequent visit. The reason(s) for IMP 
discontinuation will be clearly specified. This EOT assessment may occur at a regularly scheduled 
or unscheduled visit. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Every effort should be made to maintain patients in the study. Patients should be followed-up 
according to the study procedures specified in this protocol up to the scheduled date of study 
completion, or up to recovery or stabilization of any AE to be followed up as specified in this 
protocol, whichever comes last. 
If a patient decides to discontinue study treatment early, a Premature EOT Visit (see  
Section 10.1.2.3) should be scheduled prior to treatment discontinuation, if possible. If not 
possible, the Premature EOT Visit should be scheduled as soon as possible after treatment 
discontinuation. In the case of premature IMP discontinuation, PK samples should not be drawn at 
the Premature EOT Visit, or at any subsequent visits. For patients that discontinue treatment but 
remain in the study, remaining study visits should occur as scheduled where possible. The IRT 
should be notified of EOT. 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the eCRF. 
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 EOT Visit. 
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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. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing. 
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 re-contact 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 re-randomized (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 this treatment. 
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. 
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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 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase >10 × 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) or aggravated during the study. 
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid notification by the 
Investigator to the Sponsor may be appropriate. Such events may require further investigation in 
order to characterize and understand them. Adverse events of special interest may be added, 
modified, or removed during a study by protocol amendment. 
The 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). 
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• 
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 
- 
(Please note that an asymptomatic overdose with the IMP/NIMP, accidental or 
intentional, defined 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 × ULN (refer to related flow chart, Appendix E). 
10.4.1.4 Events of special interest 
An EOSI is a serious or non-serious AE of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring may be appropriate. Such events 
may require further investigation in order to characterize and understand them. These events 
should be reported on the specific eCRF page and will only qualify for expedited reporting when 
serious (fulfilling SAE criteria). 
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 9.2.1.2) 
• 
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 
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• 
Malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, 
prostate, and thyroid carcinoma) 
• 
Adverse events leading to an amputation. 
10.4.2 General guidelines for reporting adverse events 
• 
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the ICF until the end of the study as defined by the protocol for that patient, 
are to be recorded on the corresponding page(s) or screen(s) of the 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 antidiabetes medications 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, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
• 
When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
• 
Laboratory, vital signs, or ECG abnormalities are to be recorded as AEs if they are 
medically relevant based on the investigator’s’ medical judgment, eg: 
- 
Symptomatic, and/or 
- 
Requiring either corrective treatment or consultation, and/or 
- 
Leading to IMP discontinuation or modification of dosing, and/or 
- 
Fulfilling a seriousness criterion, and/or 
- 
Defined as an AESI or EOSI. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the 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 
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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 case report form [CRF] process) is 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. 
10.4.5 Guidelines for reporting events of special interest 
If an EOSI fulfills the criteria of an SAE, reporting should be performed according to the 
instructions for reporting of SAEs (see Section 10.4.3). Otherwise, reporting should follow the 
instructions for an AE (see Section 10.4.2). 
10.4.6 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix E. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices. 
• 
Neutropenia 
• 
Thrombocytopenia 
• 
Increase in ALT 
• 
Acute renal insufficiency 
• 
Suspicion of rhabdomyolysis. 
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10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• 
All SAEs that are both unexpected and at least reasonably related to the IMP (SUSARs), 
to the regulatory authorities, and 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 × ULN. 
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 the presence or absence of hypoglycemic 
episodes or hypoglycemic symptoms in their study diary. The 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 (21) and summarized in Figure 1. 
In addition to the threshold of ≤3.9 mmol/L (≤70 mg/dL), hypoglycemia episodes with a plasma 
glucose of <3.0 mmol/L (<54 mg/dL) will be analyzed separately. 
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Figure 1 - Hypoglycemia classification in Study EFC14868 
 
PG = plasma glucose; SAE = serious adverse event 
 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate (sugar), glucagon, intravenous glucose, or other resuscitative actions. These 
episodes may be associated with sufficient neuroglycopenia to induce seizure, unconsciousness, 
or coma. Self-monitored plasma glucose values may not be available, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient evidence that 
the event was induced by a low plasma glucose concentration. 
Note: “Requiring assistance of another person” means that the patient could not help himself or 
herself to treat the hypoglycemia. Assisting a patient out of kindness, when assistance is not 
required, should not be considered a “requires assistance” incident. 
Any hypoglycemic event which leads to unconsciousness, coma, or seizure should also be 
reported as an SAE. 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L 
(≤70 mg/dL). 
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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 ≤3.9 mmol/L (≤70 mg/dL). 
Note: low plasma glucose values without symptoms or signs should not be reported more than 
once within 30 minutes. Repeated low glucose values within a short period could be due to 
malfunction of the device, error testing or following up a low glucose reading. The Investigator 
should try not to document false low SMBG values or redundant low glucose values as 
asymptomatic hypoglycemic 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 ≤3.9 mmol/L [≤70 mg/dL]), ie, symptoms treated with oral carbohydrate 
without a test of plasma glucose. 
Relative hypoglycemia 
Relative hypoglycemia recently termed “pseudo-hypoglycemia” (21) is an event during which the 
patient reports typical symptoms of hypoglycemia, and interprets the symptoms as indicative of 
hypoglycemia, but with a measured plasma glucose concentration >3.9 mmol/L (>70 mg/dL). 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final 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. Assuming a 
common standard deviation (SD) of 1.2% and using a 2-sided test at a 0.05 α-level, 280 patients 
in the sotagliflozin 400 mg arm and 140 patients in the placebo arm will provide at least 95% 
power to detect a treatment difference of 0.5% in mean HbA1c change from Baseline to Week 18 
between sotagliflozin 400 mg and placebo. 
A sample size of 140 patients in the sotagliflozin 200 mg arm and 140 patients in the placebo arm 
will provide 80% power to detect a treatment difference of 0.4% in mean HbA1c change from 
Baseline to Week 18 between sotagliflozin 200 mg and placebo (SD 1.2%; 5% significance level 
2-sided). 
The total sample size will be 560 patients to be randomized (280 patients in the sotagliflozin 
400 mg arm; 140 patients in the sotagliflozin 200 mg arm; 140 patients in the placebo arm). 
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 intention to treat (ITT) population (as defined in Section 11.3.2 and analyzed as 
randomized) 
• 
The randomization strata (HbA1c at Week -1 [≤8.5%, >8.5%], SBP at Week -1 
[<130 mmHg, ≥130 mmHg], and sulfonylureas use at Week -1 [yes, no]). The 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 18-week randomized core Treatment Period 
• 
Patients who discontinued the IMP during the 18-week randomized core Treatment Period, 
and the reasons for treatment discontinuation 
• 
Patients who have completed the entire 52-week double-blind Treatment Period 
• 
Patients who discontinued the IMP during the entire 52-week double-blind Treatment 
Period, and the reasons for treatment discontinuation 
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• 
Patients who have completed the study 
• 
Patients who discontinued the study, and the reasons for study discontinuation. 
For all categories of patients except screened, percentages will be calculated using the number of 
randomized patients as denominator for each treatment group. 
A list of patients prematurely discontinued from the treatment, along with reasons for 
discontinuation, will be provided. Similarly, a list of patients prematurely discontinued from the 
study, along with reasons for discontinuation, will be provided. 
Patients treated but not randomized, patients randomized but not treated and patients randomized 
but not treated as randomized will be identified and described in separate listings. The safety 
experience of patients treated and not randomized will be reported separately, and these patients 
will not be in the safety population. 
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 
schedule at Randomization Visit (as randomized), irrespective of the treatment group actually 
received. 
11.3.2 Intent-to-treat population 
Efficacy analyses will be based on the ITT population, defined as all randomized patients 
irrespective of compliance with the study protocol and procedures. Patients will be analyzed for 
efficacy analyses according to the treatment group to which they are randomized. 
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: 
• 
Non-randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately. 
• 
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
• 
When a patient is exposed to both sotagliflozin and placebo, the patient will be analyzed in 
the sotagliflozin group (depending on the treatment kit taken [400 mg or 200 mg]). 
• 
When a patient is exposed to both sotagliflozin 400 mg (treatment kit) and 200 mg 
(treatment kit), the patient will be analyzed in the sotagliflozin 200 mg group. 
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• 
Randomized patients will be excluded from the safety population only if there is 
documented evidence (ie, all study dates recorded as no medication taken) that patients 
have not taken the study medication. 
11.4 
STATISTICAL METHODS 
Continuous data will be summarized by treatment group using the number of observations 
available (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 (OC), ie, inclusion of only 
patients having non-missing assessments at a specific visit. 
The Baseline value is defined generally as the last available value before the first dose of 
double-blind IMP or the last available value prior to Randomization for patients who were 
randomized but never exposed to IMP. 
For serum creatinine and eGFR, the Baseline value is defined as average of all values before the 
first dose of double-blind IMP for those patients randomized and exposed or before randomization 
for those patients 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 in the Safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
The extent of study treatment exposure will be assessed by the duration of treatment exposure 
during the study. 
The duration of treatment exposure will be the total number of days of administration of the 
double-blind IMP, regardless of unplanned intermittent discontinuations. The duration of IMP 
exposure will be calculated as: 
(Date of the last double-blind IMP taken – Date of the first double-blind IMP taken) + 1 
The number (%) of patients randomized and exposed to double-blind IMP will be presented by 
specific time periods for each treatment group. The time periods of interest will be defined in the 
SAP. 
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Descriptive statistics of duration of treatment exposure (number, mean, SD, minimum, median, 
and maximum) and cumulative exposure in patient year will also be presented by treatment group 
in the Safety population. 
11.4.1.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, mean, SD, median, min, and max). The percentage of patients with compliance 
<80% will be summarized. In addition, the number and percentage of patients with at least 
1 above-planned dosing administration will be given, as well as the number and percentage of 
patients with 0, 0 to 20%, and >20% under-planned dosing administrations. 
11.4.2 Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population. 
Statistical testing will be performed for primary endpoint at Week 18, and at Week 12 (for SBP) 
and Week 18 and Week 52 (for HbA1c and BW) for secondary endpoints. All other efficacy 
variables will only be summarized by descriptive statistics without formal statistical testing. 
11.4.2.1 Analysis of primary efficacy endpoint 
The statistical test will be two-sided tests at a nominal 5% significance level. 
Analysis of the primary efficacy endpoint (change from Baseline to Week 18 in HbA1c) will be 
performed using 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 in HbA1c from Baseline to Week 18 will be analyzed 
with missing values imputed by control-based 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 sotagliflozin groups, 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 analysis of covariance (ANCOVA) model 
with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), randomization strata 
of Week -1 HbA1c (≤8.5%, >8.5%), randomization strata of Week -1 SBP (<130 mmHg, 
≥130 mmHg), randomization strata of sulfonylureas use at Week -1 (yes, no), and country as fixed 
effects, and Baseline HbA1c value as a covariate. Results from each complete dataset will be 
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combined to provide the adjusted mean change in HbA1c from Baseline to Week 18 for the 
sotagliflozin 400 mg arm and placebo arm, as well as the between-group difference (comparing 
sotagliflozin 400 mg arm versus placebo) and the 95% confidence interval (CI) using contrast 
statements. 
Summary statistics (for Screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided for each treatment group. The summary will 
include the number of observations, mean, SD, standard error (SE), minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from Baseline (±SE) at each of the scheduled visits (using OC). 
Assessment of treatment effect by subgroup 
Descriptive analyses will be performed on the primary endpoint to summarize the treatment 
effects across subgroups defined by the following Baseline or Screening factors: 
• 
Race 
• 
Ethnicity (Hispanic, Not Hispanic) 
• 
Age group (<50 years, ≥50 to <65 years, ≥65 years) 
• 
Gender 
• 
Baseline BMI level (<30, ≥30 kg/m2) 
• 
Baseline HbA1c (≤8.5%, >8.5%) 
• 
Baseline SBP (<130 mmHg, ≥130 mmHg) 
• 
Country 
• 
Use of sulfonylureas at Week -1 (yes, no). 
The treatment effects across the subgroups defined for each of these factors will be estimated for 
the change from Baseline to Week 18 in HbA1c in the ITT population, and using a similar 
approach to the analysis for the primary efficacy endpoint. The adjusted estimates of treatment 
mean differences (sotagliflozin 400 mg versus placebo) with SE and 95% CIs will be provided as 
appropriate across the subgroups. 
In the event that the subgroup factor is identical or similar to a randomization strata factor (eg, 
Baseline HbA1c category, Baseline SBP category, or sulfonylurea use), only the subgroup factor 
will be included in the model in order to avoid the issue of co-linearity in the analysis. 
Baseline definition 
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. 
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11.4.2.2 Analyses of secondary efficacy endpoints 
The secondary endpoints (Section 9.1.2) will be analyzed using a similar approach to the primary 
efficacy endpoint, with missing values imputed by the control-based 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 sotagliflozin groups, 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. 
For each of the continuous secondary endpoints, each of the complete datasets will be analyzed by 
the ANCOVA model with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), 
randomization strata of Week -1 HbA1c (≤8.5%, >8.5%), randomization strata of Week -1 SBP 
(<130 mmHg, ≥130 mmHg), randomization strata of sulfonylureas use at Week -1 (yes, no), and 
country as fixed effects, and Baseline secondary endpoint value as a covariate. Results from each 
complete dataset will be combined to provide the adjusted mean change from Baseline to 
Week 18 (Week 12 for SBP endpoints) for each treatment group, as well as the between-group 
difference (comparing each sotagliflozin group versus placebo) and the 95% CI using contrast 
statements. For HbA1c endpoint, results from each complete dataset will be combined to provide 
the adjusted mean change from Baseline to Week 18 for sotagliflozin 200 mg arm and placebo 
arm, as well as the between group difference (comparing the sotagliflozin 200 mg arm versus 
placebo arm) and the 95% CI using contrast statements. 
Summary statistics for the secondary endpoints at scheduled visits will be provided for each 
treatment group. The summary will include the number of observations, mean, SD, SE, minimum, 
median, and maximum. Graphical presentations will also be used to examine trends over time 
using mean values (± SE) and mean changes from Baseline (± SE) at each of the scheduled visits 
(using OC). 
11.4.2.3 Analysis of other efficacy endpoints 
Except for PRO endpoints, the analysis of other endpoints (see Section 9.1.3) will be descriptive 
with no formal testing. Summary statistics at scheduled visits using OC will be provided by each 
treatment group. Graphical presentations will also be used to illustrate trends over time. 
The analysis of the TRIM-D PRO scores will be conducted on the ITT population. 
For TRIM-D scores (total and domain scores), descriptive statistics will be presented by treatment 
group per visit. The change in TRIM-D scores from Baseline to endpoint will be analyzed using a 
similar approach to the primary efficacy endpoint, with missing values imputed by control-based 
multiple imputation method under the missing not at random framework. 
Each of the complete datasets will be analyzed by the ANCOVA model with treatment groups 
(sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), randomization strata of Week -1 HbA1c 
(≤8.5%, >8.5%), randomization strata of Week -1 SBP (<130 mmHg, ≥130 mmHg), and 
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randomization strata of sulfonylureas use at Week -1 (yes, no), and country as fixed effects, and 
TRIM-D scores at Baseline as a covariate. Results from each complete dataset will be combined 
to provide the adjusted mean change from Baseline to Week 52 for each treatment group, as well 
as the between-group difference (comparing sotagliflozin group versus placebo) and the 95% CI 
using contrast statements. 
The number (%) of patients achieving HbA1c response (<6.5%, <7% at Week 18 and Week 52, 
respectively) will be descriptive summarized at each scheduled visit. 
Sensitivity analysis may be performed as appropriate. 
11.4.2.4 Multiplicity considerations 
To control for the family wise type I error, a fixed-sequence testing procedure will be applied to 
the primary and key secondary endpoints to the following order: 
Once the main study primary variable (change from Baseline to Week 18 in HbA1c comparing 
sotagliflozin 400 mg versus placebo) is statistically significant at α = 0.05 (2-sided), a hierarchical 
testing procedure will be performed to test the following main study secondary efficacy variables 
by the following prioritized order. The testing will stop as soon as an endpoint is found to be not 
statistically significant at α = 0.05 (2-sided). 
• 
Comparing sotagliflozin 400 mg versus placebo: 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all patients 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
• 
Comparing sotagliflozin 200 mg versus placebo: 
- 
Change from Baseline to Week 18 in HbA1c 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
No multiplicity adjustment will be made on other secondary efficacy variables than mentioned 
above. 
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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 9.2. 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. The safety analyses will be provided for the 18-week randomized 
core Treatment Period and for the entire 52-week double-blind Treatment Period, unless specified 
otherwise. 
The following definitions will be applied to laboratory parameters and vital signs: 
• The potentially clinically significant abnormality (PCSA) values for clinical laboratory 
tests and vital signs are defined as abnormal values considered medically important by the 
Sponsor’s Global Pharmacovigilance and Epidemiology department and in effect at the 
time of the final SAP approval. 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 
on-treatment period, taking into account all evaluations performed during the on-treatment 
period, including unscheduled or repeated evaluations. The number of all such patients 
will be the numerator for the on-treatment PCSA percentage. 
The “observation periods” defined in Section 9.2 are applicable for classification of AEs, 
determination of on-treatment PCSA values and the last on-treatment value for the laboratory, 
vital sign and ECG parameters. 
11.4.3.1 Analysis of adverse events 
Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-Treatment Period. 
Treatment-emergent AEs 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 N and percentage (%) of 
patients experiencing an AE. Multiple occurrences of the same event in the same patient will be 
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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 N and percentage (%) of patients with at least one TEAE by primary SOC, HLGT, 
HLT, and PT 
• 
Summary of TEAEs by maximal severity (severe, moderate, mild), presented by primary 
SOC and PT 
• 
Summary of TEAEs possibly related to IMP, presented by primary SOC, HLGT, HLT, 
and PT. 
A detailed listing of TEAE summaries will be provided in the SAP. 
Death and serious adverse events 
Death and treatment-emergent SAEs will be summarized and presented as number and percent of 
patients in each treatment group. 
The following deaths summaries will be generated: 
• Number (%) of patients who died by study period (on-study, on-treatment, post-study) 
summarized on the safety population by treatment received 
• Death in non-randomized 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 (%) 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 and percent of patients in each treatment group. 
11.4.3.2 Analysis of hypoglycemia 
The number (%) of patients and rate in patient years (2 types: the number of patients with events 
or the number of events per 100 patient-years) of all, severe and/or documented symptomatic 
hypoglycemia, will be summarized by treatment group respectively. In addition, documented 
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hypoglycemia will also be analyzed by using a threshold of plasma glucose of <54 mg/dL 
(3.0 mmol/L).  
Their pattern of occurrence over time will also be assessed, as appropriate. 
11.4.3.3 Analysis of adverse events of special interest 
Pregnancy and overdose will be included in overall AE summaries if any are reported. Alanine 
aminotransferase increase >3 × ULN is included in laboratory PCSA summary, if any. 
11.4.3.4 Analysis of events of special interest 
The number (%) of patients with each EOSI event will be summarized by treatment group. All 
events reported by the Investigators on the AE forms for special interest will be listed along with 
the adjudication outcome (if applicable). 
11.4.3.5 Analysis of laboratory variables 
The number 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 the out of laboratory range values as well 
as the PCSA values. 
The liver function tests, namely ALT, AST, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
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 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. 
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11.4.3.7 Analyses of 12-lead electrocardiogram status 
A shift table will be provided to present the ECG on-treatment status according to the Baseline 
status within each treatment group. 
11.4.3.8 Analyses of pharmacokinetic variables 
The PK endpoint is presented in Section 9.3.1. Individual plasma concentrations of sotagliflozin 
and of its 3-O-glucuronide at nominal sampling times will be listed. 
Concentration data will be summarized by visit and, if appropriate, within visit by nominal 
sampling times (pre-dose), using descriptive statistics by N, geometric mean, coefficient of 
variation, median, minimum, and maximum at each visit/nominal sampling time point for 
sotagliflozin-treated patients. 
11.5 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned for this study. The study will not be terminated 
early for excellent efficacy. 
An independent DMC will monitor and assess the safety of patients from this trial through 
periodic review of the accumulated safety data provided by an independent statistical group. 
Related details are provided in separate documents (DMC charter and DMC SAP). 
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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. 
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 INVESTIGATORS 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the 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 
The Sponsor and/or service provider of this clinical trial is responsible to regulatory authorities for 
taking all reasonable steps to ensure the proper conduct of the clinical trial as regards ethics, 
clinical trial protocol compliance, and integrity and validity of the data recorded on the 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, 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 pre-identified 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 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 will be 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/service provider may generate additional 
requests (Discrepancy Resolution Form) 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/service provider and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification, and training of 
each Investigator and Sub-investigator will be signed, dated, and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation and take measures to prevent 
accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee. 
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to the clinical trial 
protocol, personal data in relation to the patients, the eCRFs, 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. 
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The Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party’s account. 
14.4 
PROPERTY RIGHTS 
All information, documents, and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Sub-investigator not to 
mention any information or the product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents, and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market, or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Sub-Investigators shall provide all assistance 
required by the Sponsor, at the Sponsor’s expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
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. 
14.6 
DATA PROTECTION 
• 
The patient’s personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations 
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party 
• 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Patient race and ethnicity (race: American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, not reported, unknown; ethnicity: 
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14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor 
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following: 
• 
The information on the product leads to doubt as to the benefit/risk ratio 
• 
Patient enrollment is unsatisfactory 
• 
The Investigator has received from the Sponsor all 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 to provide a summary of study results to 
the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
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or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights. 
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes 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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16 
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(9922):1068-83. 
2. Fowler MJ. Microvascular and Macrovascular Complications of Diabetes. Clinical Diabetes. 
2008;26(2):77-82. 
3. International Diabetes Federation. IDF Diabetes Atlas, 7th ed. Brussels, Belgium: 
International Diabetes Federation, 2015.  http://www.diabetesatlas.org. Accessed: 19 Mar 
2017. 
4. World Health Organization, Regional Office for Europe, Data and Statistics. 
http://euro.who.int/en/health-topics/noncommunicable-diseases/diabetes/data-and-statistics. 
Accessed: 17 Mar 2017. 
5. American Diabetes Association. Standards of Medical Care in Diabetes - 2013. Diabetes Care. 
2013;36(Supplement 1):S11-S66. 
6. Bailey CJ. The Current Drug Treatment Landscape for Diabetes and Perspectives for the 
Future. Clin Pharmacol Ther. 2015;98(2):170-84. 
7. Castaneda-Sceppa C, Castaneda F. Sodium-dependent glucose transporter protein as a 
potential therapeutic target for improving glycemic control in diabetes. Nutr Rev. 
2011;69(12):720-9. 
8. Mudaliar S. Sodium-Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal 
Glucose Transport: From Bench to Bedside. Diabetes Care. 2015;38(12):2344-53. 
9. Hediger HA, Coady MJ, Ikeda TS, Wright EM. Expression cloning and cDNA sequencing of 
the Na+/glucose cotransporter. Nature. 1987;330(6146):379-81. 
10. Wright EM. I. Glucose galactose malabsorption. Am J Physiol. 1998;275(5 Pt 1):G879-82. 
11. Raskin P. Sodium-glucose cotransporter inhibition: therapeutic potential for treatment of type 
2 diabetes mellitus. Diabetes Metab Res Rev. 2013;29(5):347-56. 
12. 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):158-69. 
13. American Diabetes Association. Pharmacologic approaches to glycemic treatment. Sec. 8. In 
Standards of Medical Care in Diabetes - 2017. Diabetes Care. 2017;40(Suppl. 1):S64–S74. 
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14. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update 
to a position statement of the American Diabetes Association and the European Association 
for the Study of Diabetes. Diabetes Care. 2015;38(1):140-9. 
15. U.S. Department of Health and Human Services. Food and Drug Administration. Center for 
Drug Evaluation and Research (CDER). Guidance for Industry. Diabetes Mellitus: Developing 
Drugs and Therapeutic Biologics for Treatment and Prevention. February 2008. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM071624.pdf. Accessed: 11 Apr 2017. 
16. American Diabetes Association. Standards of Medical Care in Diabetes – 2017. Diabetes 
Care. 2017;40(Suppl 1):S1-S135. 
17. 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. 
18. Florkowski CM, Chew-Harris JS. Methods of Estimating GFR - Different Equations Including 
CKD-EPI. Clin Biochem Rev. 2011;32(2):75-9 
19. Brod M, Hammer M, Christensen T, Lessard S, Bushnell DM. Understanding and assessing 
the impact of treatment in diabetes: the Treatment-Related Impact Measures for Diabetes and 
Devices (TRIM-Diabetes and TRIM-Diabetes Device). Health Qual Life Outcomes. 
2009;7:83. 
20. Brooke J, Stiell M, Ojo O. Evaluation of the Accuracy of Capillary Hydroxybutyrate 
Measurement Compared with Other Measurements in the Diagnosis of Diabetic Ketoacidosis: 
A Systematic Review. Int J Environ Res Public Health. 2016;13(9). pii:E837. 
21. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and The Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95. 
 
 
 
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APPENDICES 
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Appendix A 
Guidance on contraceptive methods and collection of pregnancy 
information 
DEFINITIONS 
Non-reproductive potential 
• Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy. 
• Postmenopausal 
- 
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 1 of 
the highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Women of reproductive potential (WOCBP) must use a highly effective method of contraception 
during the treatment period and the post-treatment follow up period (14 ± 3 days). If another 
contraceptive method is used (such as a barrier method), it should be used in combination with 
one of the highly effective methods (such as an oral contraceptive).  
 
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Female patients: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 
- 
Oral 
- 
Intravaginal 
- 
Transdermal. 
• Progestogen-only hormone contraception associated with inhibition of ovulation 
− Oral 
− Injectable. 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method(s) of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.) 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the patient.) 
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 patients participating in clinical studies. 
 
 
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COLLECTION OF PREGNANCY INFORMATION 
Male patients with partners of reproductive potential who become pregnant 
• The Investigator will attempt to collect pregnancy information on any female partner of a 
male study patient who becomes pregnant while participating in this study. This applies 
only to patients who receive study treatment 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy 
• Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor 
• Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure. 
Female patients who become pregnant 
• The Investigator will collect pregnancy information on any female patient, who becomes 
pregnant while participating in this study 
• Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant’s pregnancy 
• Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which will be forwarded to 
the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date 
• Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE 
• A spontaneous abortion is always considered to be an SAE and will be reported as such 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the study treatment by the Investigator, will be reported to the Sponsor as described in  
Section 10.4.3. While the Investigator is not obligated to actively seek this information in former 
study patients, he/she may learn of an SAE through spontaneous reporting. 
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Appendix C 
Recommendations on basic genitourinary hygiene, maintaining 
hydration, and recognizing diabetic ketoacidosis 
Patients with T2D 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 SBP, or if 
receiving diuretics, angiotensin-converting-enzyme inhibitors, or angiotensin receptor blockers. 
All patients will be advised to maintain proper fluid intake and to consider increasing it if they 
sense greater thirst, more urine production, or if they feel dizzy or faint. 
Patient communication cards will be printed with the following for patients with T2D: 
“The following advice may be useful in helping you to maintain proper hydration and prevent 
dehydration: 
• 
Dehydration is when your body loses too much fluid, frequently due to diarrhea or 
increased urination 
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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 GI AEs occurring with sotagliflozin may mask presenting symptoms of DKA. Patients 
will be provided with the BHB meter and instructions for use at the start of the Run-in Phase at 
Visit 2 (Week -4). Patients will be instructed to measure their BHB levels by fingerstick if they 
experience any symptoms consistent with ketosis/ketoacidosis throughout the entire study period. 
Patients will be instructed on how to respond (seek help, hydrate, ingest carbohydrates, etc) if they 
present with potential ketoacidosis symptoms and the BHB value is abnormal (>0.6 mM/L). 
Patient communication cards will be printed with the following: 
“If you have any of these symptoms on the list, measure your glucose and BHB by fingerstick, 
and 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. 
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It is possible to have DKA even if your blood glucose is not elevated. Regardless of your blood 
glucose level, if you have any of these symptoms on the list, then contact your study site 
regarding the need to be evaluated for possible DKA, which will include specific blood testing. If 
your study site is closed and your study doctor is not available, go to the nearest emergency room 
for evaluation. 
If your blood BHB reading is >0.6 mM/L and you have symptoms of ketoacidosis, seek help, 
hydrate, ingest carbohydrates, etc, as described above. 
If you are scheduled for a procedure or surgery that requires you to not take any food or liquids, 
please contact your study doctor for instructions on continuing study drug. In such cases your 
study doctor may advise you NOT to take your study drug from the day prior to the procedure or 
surgery until after the procedure or surgery is complete, and you are taking food and liquids as 
you normally do.” 
Whenever AE data is collected or the patient reports DKA or intercurrent illness (including 
infections), generalized weakness, increased weight loss, 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” eCRF will 
be completed. 
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Appendix D 
Measurement of blood pressure and heart rate 
Equipment 
1. Blood pressure measurements will be taken by an automated BP monitor or a manual 
sphygmomanometer. Same equipment should be used throughout the study and should be 
calibrated as per manufacturer recommendation. 
2. Bladder Length – Should nearly or completely encircle the patient’s arm. For many adults, 
the standard “adult” size bladder is not long enough and the “large” size bladder is 
recommended. 
3. Bladder Width – Should be at least 40% of the bladder length. 
Patient factors 
Extraneous variables associated with the measurement of BP should be minimized. These include: 
1. Food intake, caffeine-containing beverages, cigarette smoking, or strenuous exercise 
within 2 hours prior to measurement. 
2. Full urinary bladder. 
3. The patient should not be allowed to talk while BP is being measured. 
4. The patient should be placed in the examination room and the cuff should be placed on the 
patient’s nondominant arm. The proper sized cuff should fit snugly with the lower edge 
2 to 3 cm above the antecubital fossa. 
5. The patient should be allowed to sit quietly in a comfortably warm place (temperature 
around 25°C or 77°F) for 5 minutes with the arm supported at heart level, preferably with 
the cuff in place and with no restrictive clothing on the arm. The patient should be 
encouraged not to tense his/her muscles. 
Determination of the reference arm 
At Visit 1 (Week -6), 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 always in this same arm throughout the study. 
Measurement technique 
At Visit 1, 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 on-site visits, following the 5-minute rest period, 3 separate seated BPs should be 
measured in the selected arm with at least 1 minute between BP measurements and with the cuff 
fully deflated between measurements. 
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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 heart rate measurements will be obtained. The mean of the 3 seated heart rate 
measurements will constitute the pulse rate value for that visit. 
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Appendix F 
Patient Qualitative Assessment of Treatment (PQAT) 
Week 18 Assessment 
The following questions ask for your opinion on the drug you received during this clinical study. 
There are no right or wrong answers; we would like to better understand your own experience of the drug. 
 
1. 
During this trial, so far, what were the main benefits you experienced with the drug you 
received? 
 
 
 
 
 
 
2. 
During this trial, so far, what were the main disadvantages you experienced with the drug you 
received? 
 
 
 
 
 
 
3. 
After this trial, would you be willing to continue using the drug you received during this trial? 
Yes   
No  
Please explain why? 
 
 
 
 
 
4. 
Based on your own experience in this trial so far, please select a response on the scale 
below 
The 
disadvantages of 
the drug I 
received 
significantly 
outweigh the 
benefits 
 
 
There were 
equal benefits 
and 
disadvantages 
of the drug I 
received 
 
 
The benefits of 
the drug I 
received 
significantly 
outweigh the 
disadvantages 
 
- 3 
 
- 2 
 
- 1 
 
0 
 
1 
 
2 
 
3 
 
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Week 52 Assessment 
The following questions ask for your opinion on the drug you received during this clinical study. 
There are no right or wrong answers; we would like to better understand your own experience of the drug. 
 
1. 
In the past 6 months, what were the main benefits you experienced with the drug you 
received? 
 
 
 
 
 
 
2. 
In the past 6 months, what were the main disadvantages you experienced with the drug you 
received?  
 
 
 
 
 
 
3. 
After this trial, would you be willing to continue using the drug you received during this trial?  
Yes   
No  
Please explain why? 
 
 
 
 
 
4. 
Based on your own experience in the past 6 months, please select a response on the scale 
below 
The 
disadvantages of 
the drug I 
received 
significantly 
outweigh the 
benefits 
 
 
There were 
equal benefits 
and 
disadvantages 
of the drug I 
received 
 
 
The benefits of 
the drug I 
received 
significantly 
outweigh the 
disadvantages 
 
- 3 
 
- 2 
 
- 1 
 
0 
 
1 
 
2 
 
3 
 
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