Clinical trial NCT02926937
Conditions: Type 2 Diabetes Mellitus
Sponsor: Lexicon Pharmaceuticals
Start date: 2016-11-11; Completion date: 2019-05-17
Enrollment: 399 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To demonstrate the superiority of Sotagliflozin 400 milligrams (mg) versus placebo on hemoglobin A1c (HbA1c) reduction in participants with type 2 diabetes (T2D) who have inadequate glycemic control on diet and exercise.

Secondary Objectives:

* To compare Sotagliflozin 400 mg versus placebo based on:
* Change from baseline in 2-hour postprandial glucose (PPG) following a mixed meal.
* Change from baseline in fasting plasma glucose (FPG).
* Change from baseline in systolic blood pressure (SBP) for participants with baseline SBP ≥130 millimeter per mercury (mmHg).
* Change from baseline in SBP for all participants.
* Change from baseline in body weight.
* Proportion of participants with HbA1c \<6.5%, \<7.0%.
* To compare Sotagliflozin 200 mg versus placebo based on:
* Change from baseline in HbA1c.
* Change from baseline in 2-hour postprandial glucose (PPG) following a mixed meal.
* Change from baseline in body weight.
* Change from baseline in SBP for all participants.
* To evaluate the safety of Sotagliflozin 400 and 200 mg versus placebo.

Detailed description:
Up to 34 weeks, including a Screening Period consisting of a Screening Phase of up to 2 weeks and a 2-week single-blind placebo Run-in Phase, a 26-week double-blind Treatment Period, and a 4-week post-treatment Follow-up visit to collect safety information.

Arms: arm 1: Following a 2-week run-in period, participants were randomized to Sotagliflozin 400 milligrams (mg) administered as two 200 mg tablets, once daily (QD), before the first meal of the day in the double-blind treatment period for up to 26 weeks. arm 2: Following a 2-week run-in period, participants were randomized to Sotagliflozin 200 mg administered as 1 Sotagliflozin tablet and 1 matching placebo tablet, QD, before the first meal of the day in the double-blind treatment period for up to 26 weeks. arm 3: Following a 2-week run-in period, participants were randomized to matching placebo to sotagliflozin administered as 2 tablets, QD, before the first meal of the day in the double-blind treatment period for up to 26 weeks.
Interventions: intervention 1: Sotagliflozin (SAR439954) intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: tablet;

Route of administration: oral intervention 2: Pharmaceutical form: tablet;

Route of administration: oral

Protocol documents:
Prot_000.pdf: 
Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel-
group, Multicenter Study to Evaluate the Efficacy and Safety 
of Sotagliflozin as Monotherapy in Patients with Type 2 
Diabetes Mellitus Who Have Inadequate Glycemic Control 
  
NCT Number: NCT02926937 
  
Document Date: Protocol Amendment 2: 19-December-2017  
 


 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
 
 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 02 
COMPOUND: sotagliflozin/SAR439954 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study 
to Evaluate the Efficacy and Safety of Sotagliflozin as Monotherapy in Patients 
with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control 
STUDY NUMBER: EFC14833  
STUDY NAME: SOTA-MONO (SOTAgliflozin MONOtherapy) 
VERSION DATE / STATUS: 19-Dec-2017 / Approved 
Protocol Amendment 02 
Version number: 1 (electronic 1.0) 
Date : 19-Dec-2017 
Amended Clinical Trial Protocol 01 
Version number: 1 (electronic 1.0) 
Date : 11-Apr-2017 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 11-Apr-2017 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 27-Jul-2016 
EudraCT  
2016-001799-31 
IND Number(s) 
 
Version Number: 
1  
WHO universal trial number: 
U1111-1180-6169 
Date: 
19-Dec-2017 
Total number of pages: 
119 
 
 
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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.:  EFC14833  
TITLE 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin 
as Monotherapy in Patients with Type 2 Diabetes Who Have 
Inadequate Glycemic Control 
INVESTIGATOR/TRIAL LOCATION 
Multinational 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVES  
 
Primary objective:  
The primary objective of this study is to demonstrate the superiority of 
sotagliflozin 400 mg versus placebo on hemoglobin A1c (HbA1c) 
reduction at Week 26 in patients with type 2 diabetes (T2D) who have 
inadequate glycemic control on diet and exercise. 
Secondary objectives: 
• 
To compare sotagliflozin 400 mg versus placebo for:  
- 
Change from Baseline in 2-hour postprandial glucose 
(PPG) following a mixed meal at Week 26  
- 
Change from Baseline in fasting plasma glucose (FPG) 
at Week 26 
- 
Change from Baseline in body weight at Week 26 
- 
Change from Baseline in systolic blood pressure (SBP) 
at Week 12 for patients with Baseline SBP 
≥130 mmHg  
- 
Change from Baseline in SBP at Week 12 for all 
patients 
- 
Proportion of patients with HbA1c <6.5%, <7.0% at 
Week 26 
• 
To compare sotagliflozin 200 mg versus placebo for:  
- 
Change from Baseline in HbA1c at Week 26 
- 
Change from Baseline in 2-hour PPG following a 
mixed meal at Week 26  
- 
Change from Baseline in body weight at Week 26 
- 
Change from Baseline in SBP at Week 12 for all 
patients 
• 
To evaluate the safety of sotagliflozin 400 mg and 200 mg 
doses versus placebo 
Other: 
• 
To compare sotagliflozin 400 mg and 200 mg doses versus 
placebo with respect to change from Baseline for the 
following endpoints: 
- 
Urine albumin-creatinine ratio (ACR) 
- 
Urinary glucose excretion (UGE) and urine 
glucose-creatinine ratio (GCR)  
- 
Estimated glomerular filtration rate (eGFR) 
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- 
Reduction in body weight by ≥2%, ≥5%, and ≥10%  
• 
To compare sotagliflozin 200 mg versus placebo for: 
- 
Change from Baseline in FPG at Week 26 
- 
Change from Baseline in SBP at Week 12 for patients 
with baseline SBP ≥130 mmHg  
- 
Proportion of patients with HbA1c <6.5%, <7.0% at 
Week 26 
• 
To compare sotagliflozin 400 mg and 200 mg doses with 
placebo for change from Baseline in SBP at Week 26 for all 
patients and for patients with Baseline SBP ≥130 mmHg 
• 
To compare sotagliflozin 400 mg and 200 mg doses with 
placebo for the use of rescue medications for 
hyperglycemia 
• 
To assess plasma concentrations of sotagliflozin and its 
3-O-glucuronide metabolite in each sotagliflozin treatment 
group 
STUDY DESIGN 
This is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study that is anticipated to enroll a 
total of approximately 400 patients. This number includes patients 
randomized under the initial protocol, and patients to be randomized 
under the amended, current, version of this protocol (see below).  
Patients who previously managed their T2D with a single oral 
antidiabetic drug (OAD) may be eligible for screening if they have 
discontinued the OAD and been maintained on diet and exercise for 
at least 12 weeks before the Screening Visit. 
All patients will have a Screening Period comprised of an up to 
2 week Screening Phase and a 2-week, single-blind placebo Run-in 
Phase prior to randomization. In order to qualify for randomization, 
patients must demonstrate compliance during the single-blind placebo 
Run-in Phase based upon tablet count (≥80%).  
Randomization will be stratified by: 
• 
HbA1c at screening (≤8%, >8%) and 
• 
SBP at screening visit (<130 mmHg, ≥130 mmHg).  
Following randomization, patients will have a 26-week, double-blind 
Treatment Period, and an on-site 4-week post-treatment Follow-up 
visit. 
All patients will have PPG assessed following a mixed meal tolerance 
text (MMTT) at Weeks 0 and 26. 
In the original version of this protocol, it was planned for a total of 
240 patients ≥18 years of age to be randomly assigned 1:1 to the 
following 2 treatment groups: 
• 
Sotagliflozin 400 mg as two (2) 200-mg tablets, once daily 
• 
Placebo as two (2) placebo tablets (identical to sotagliflozin 
in appearance), once daily 
At the time of amendment to the current version of the protocol, 
approximately 100 patients had been randomized under this study 
design.  
In the amended, current, version of this protocol, approximately 
300 further patients ≥18 years of age will be randomly assigned 1:1:1 
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to the following 3 treatment groups: 
• 
Sotagliflozin 200 mg as one (1) 200 mg tablet and 
one (1) placebo tablet (identical to sotagliflozin in 
appearance), once daily 
• 
Sotagliflozin 400 mg as two (2) 200 mg tablets, once daily 
• 
Placebo as two (2) placebo tablets (identical to sotagliflozin 
in appearance), once daily 
The enrollment will be completed when each of the 3 treatment 
groups (placebo, sotagliflozin 200 mg, sotagliflozin 400 mg) reaches 
approximately 100 randomized patients. 
Hemoglobin A1c, FPG, and PPG (from MMTT assessment) will be 
masked to study sites and patients after randomization and until study 
end. To prevent partial unblinding, UGE and urine GCR results will be 
masked to study sites and patients. Additionally, urinalysis by dipstick 
will not include the measurement of urine glucose. Urine glucose, 
albumin, calcium and creatinine will be measured separately at all on-
site visits by the central laboratory. 
Early termination 
If a patient discontinues treatment with investigational medicinal 
product (IMP) early during the 26-week Treatment Period, the patient 
will have a Premature End-of-Treatment (EOT) Visit, and a Follow-up 
Visit 4 weeks after the last dose of IMP. In addition, every effort will 
be made to have all patients return to the site at the time 
corresponding to their scheduled visits, particularly the Week 26 Visit. 
If the patient does not agree to site visits, they will be contacted by 
telephone to inquire about their safety status, particularly at the time 
of the scheduled Week 26 Visit.  
The study design is presented graphically at the end of the synopsis. 
STUDY POPULATION  
 
Main selection criteria: 
Inclusion criteria: 
• 
Patients (male and female) with T2D, who are treated with 
diet and exercise only during the 12 weeks prior to 
screening  
• 
Signed written informed consent  
Major exclusion criteria: 
• 
Age <18 years at the Screening Visit or < legal age of 
majority, whichever is greater 
• 
Type 1 diabetes mellitus 
• 
Body Mass Index (BMI) ≤20 or >45 kg/m2 at Screening 
• 
HbA1c <7% or HbA1c >10% via central laboratory test at 
Screening 
• 
Fasting plasma glucose >15 mmol/L (270 mg/dL) measured 
by the central laboratory at screening (Visit 1) and 
confirmed by a repeat test (>15 mmol/L [270 mg/dL]) before 
randomization 
• 
Women of childbearing potential not willing to use highly 
effective method(s) of birth control during the study 
treatment period and the follow-up period, or who are 
unwilling or unable to be tested for pregnancy (see 
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Appendix A), during the study 
• 
Treated with an antidiabetic pharmacological agent within 
the 12 weeks prior to the Screening Visit 
• 
Previous use of any types of insulin for >1 month (at any 
time, except for treatment of gestational diabetes)  
• 
History of gastric surgical procedure including gastric 
banding within 3 years before the Screening Visit  
• 
History of diabetic ketoacidosis or nonketotic hyperosmolar 
coma within 12 weeks prior to the Screening Visit 
• 
Mean of 3 separate blood pressure measurements 
>180 mmHg (SBP) or >100 mmHg (diastolic blood pressure 
[DBP]) 
• 
History of hypertensive emergency within 12 weeks prior to 
Screening (1) 
• 
Patients with severe anemia, severe cardiovascular 
(including congestive heart failure New York Heart 
Association [NYHA] IV), respiratory, hepatic, neurological, 
psychiatric, or active malignant tumor or other major 
systemic disease or patients with short life expectancy that, 
according to the Investigator, will preclude their safe 
participation in this study, or will make implementation of the 
protocol or interpretation of the study results difficult 
• 
Aspartate aminotransferase and/or alanine 
aminotransferase: >3 times the upper limit of the normal 
laboratory range 
• 
Total bilirubin: >1.5 times the upper limit of the normal 
laboratory range (except in case of Gilbert’s syndrome) 
• 
Use of systemic glucocorticoids (excluding topical or 
ophthalmic application or inhaled forms) for more than 
10 consecutive days within 90 days prior to the Screening 
Visit 
• 
Patient who has taken other investigational drugs or 
prohibited therapy for this study within 12 weeks or 
5 half-lives from screening or randomization, whichever is 
longer. Current enrollment in any other clinical study 
involving an investigational study treatment or any other 
type of medical research. 
• 
Pregnant (confirmed by serum pregnancy test at Screening) 
or breastfeeding women 
• 
Severe renal disease as defined by eGFR of 
<30 mL/min/1.73m² at screening by the 4 variable 
Modification of Diet in Renal Disease (MDRD) equation. 
• 
Patient is unwilling or unable to perform self-monitoring of 
blood glucose (SMBG), complete the patient diary, or 
comply with study visits and other study procedures as 
required per protocol 
Total expected number of patients: 
 
Approximately 400. Including: 
• 
Approximately 100 patients randomized under the original 
protocol design (2-arm design sotagliflozin 400 mg and 
placebo) 
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• 
Approximately 300 patients to be randomized under the 
amended, current protocol design 
 
STUDY TREATMENT(s) 
 
Investigational medicinal product  
 
 
 
• 
Sotagliflozin 200 mg administered as one (1) 200 mg tablet 
and one (1) placebo tablet (identical to sotagliflozin 200 mg 
tablets in appearance), once daily, before the first meal of 
the day  
• 
Sotagliflozin 400 mg administered as two (2) 200 mg 
tablets, once daily, before the first meal of the day 
• 
Placebo administered as two (2) placebo tablets (identical 
to sotagliflozin 200 mg tablets in appearance), once daily, 
before the first meal of the day 
Noninvestigational medicinal Product 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rescue therapy 
The threshold values are defined as follows, depending on study 
period: 
• 
FPG >270 mg/dL (15.0 mmol/L) from Randomization up 
through the scheduled Week 8 visit 
• 
FPG >240 mg/dL (13.3 mmol/L) after the Week 8 visit up 
through the scheduled Week 12 visit 
• 
FPG >200 mg/dL (11.1 mmol/L) after the Week 12 visit 
through the end of the 26-week Treatment Period  
Routine fasting SMBG and central laboratory alerts on FPG are set 
up to ensure that glycemic parameter results remain under predefined 
thresholds. 
• 
If one fasting SMBG value exceeds the specific glycemic 
limit on one day, the patient checks it again during the two 
following days. If all the values in three consecutive days 
exceed the specific limit, the patient should contact the 
Investigator and a central laboratory FPG measurement be 
performed as soon as possible, preferably within 7 days, to 
confirm the hyperglycemia.  
• 
Upon receipt of a central laboratory rescue alert, a central 
laboratory re-test must be completed and confirmed as 
exceeding the threshold for rescue before rescue therapy is 
initiated. The re-test confirmation should be performed as 
soon as possible, but within 7 days of receipt, by 
unscheduled visit.  
In the event that a confirmatory FPG exceeds the threshold, the 
Investigator should ensure that no reasonable explanation exists for 
insufficient glucose control and in particular that: 
• 
The increased FPG has been tested at a fasting status (ie, 
no food intake for ≥8 hours) 
• 
Investigational medicinal product is given at the planned 
dose 
• 
There is no intercurrent disease, which may jeopardize 
glycemic control (eg, infectious disease) 
• 
Compliance to treatment is appropriate 
• 
Compliance to diet and lifestyle is appropriate 
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If any of the above can reasonably explain the insufficient glycemic 
control, the Investigator should consider not initiating rescue 
medication and should undertake appropriate action, ie: 
• 
Assess plasma glucose in fasting condition (ie, after at least 
8 hours fast) 
• 
Initiate an evaluation and treatment of intercurrent disease 
(to be reported in AE/concomitant medication parts of the 
e-CRF and the medical record) 
• 
Stress the absolute need to be compliant with treatment 
• 
Organize a specific interview with the patient and a 
Registered Dietician or other qualified nutrition professional 
to reinforce the absolute need to be compliant with diet and 
lifestyle recommendations, and schedule a FPG 
assessment at the next visit. 
If none of the above mentioned reasons can be found, or if 
appropriate action fails to decrease FPG under the threshold values, 
rescue medication may be introduced. 
Open label rescue medication(s) to treat hyperglycemia will be at the 
discretion of the investigator and in accordance with local standard of 
care and prescribing practice. Except for sodium-glucose 
cotransporter type 2 (SGLT2) inhibitors, any approved medication(s) 
including oral antidiabetic drugs or insulin can be prescribed to treat 
the hyperglycemia. For patients with renal impairment, 
contraindications to antihyperglycemic drugs should be taken into 
consideration. If a patient requires glycemic rescue, the IMP received 
during the randomized, double-blind Treatment Period should 
continue and must remain blinded until the end of the study. 
ENDPOINTS  
 
Primary efficacy endpoint: 
Comparison of sotagliflozin 400 mg versus placebo in change from 
Baseline to Week 26 in HbA1c  
Secondary efficacy endpoints: 
Comparison of sotagliflozin 400 mg versus placebo for:  
• 
Change from Baseline to Week 26 in 2-hour PPG following 
a mixed meal (MM) 
• 
Change from Baseline to Week 26 in FPG  
• 
Change from Baseline to Week 26 in body weight 
• 
Change from Baseline to Week 12 in SBP for patients with 
baseline SBP ≥130 mmHg  
• 
Change from Baseline to Week 12 in SBP for all patients 
• 
Proportion of patients with HbA1c <6.5%, <7.0% at 
Week 26 
Comparison of sotagliflozin 200 mg versus placebo for:  
• 
Change from Baseline to Week 26 in HbA1c 
• 
Change from Baseline to Week 26 in 2-hour PPG following 
an MM 
• 
Change from Baseline to Week 26 in body weight 
• 
Change from Baseline to Week 12 in SBP for all patients 
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Other efficacy endpoints: 
Comparison of sotagliflozin 400 mg and 200 mg doses versus 
placebo for:  
• 
Change from Baseline to Week 12 in SBP for patients with 
baseline SBP <130 mmHg 
• 
Changes from Baseline to Week 12 in diastolic blood 
pressure (DBP) 
• 
Proportion of patients achieving SBP <130 mmHg for those 
with Baseline SBP ≥130 mmHg  
• 
Proportion of patients achieving DBP <80 mmHg for those 
with Baseline DBP ≥80 mmHg 
• 
Change from Baseline in: 
- 
Urine albumin-creatinine ratio (ACR), urinary glucose 
excretion (UGE), and urine glucose-creatinine ratio 
(GCR)   
- 
Serum creatinine 
- 
eGFR 
• 
Proportion of patients with reduction in body weight by 
≥2%, ≥5%, and ≥10% from Baseline  
• 
Change from Baseline to Week 26 in SBP for all patients 
and for patients with Baseline SBP ≥130 mmHg 
• 
Proportion of patients requiring rescue for hyperglycemia 
Comparison of sotagliflozin 200 mg versus placebo for: 
• 
Change from baseline in FPG at Week 26 
• 
Change from baseline in SBP at Week 12 for patients with 
Baseline SBP ≥130 mmHg 
• 
Proportion of patients with HbA1c <6.5%, <7.0% at 
Week 26 
Safety endpoints: 
• 
Adverse events (AEs), hypoglycemia (all, severe, and/or 
documented symptomatic hypoglycemia), events of special 
interest (EOSIs), adverse events of special interest (AESIs), 
AEs leading to discontinuation from the IMP, SAEs, and 
deaths 
• 
Clinical laboratory results including fasting lipids, vital signs, 
and electrocardiogram (ECG) results 
• 
Markers of bone and calcium metabolism 
• 
Markers of intestinal transit and absorption 
Pharmacokinetic endpoints 
• 
Plasma concentrations of sotagliflozin and its metabolite 
predose at Weeks 4, 18 and 26 (End-of-treatment) and 
2 hours 30 minutes post-dose at Week 26 (End-of-
treatment) 
ASSESSMENT SCHEDULE 
See Study Flow Chart 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
In the original version of this protocol, the sample size/power 
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calculations were based on the primary variable, change from 
baseline to Week 26 in HbA1c. Assuming a common standard 
deviation (SD) of 1.2% and using a 2-sided test at a 0.05 α-level, 120 
patients per arm would have 95% power to detect a treatment 
difference of 0.6% in mean HbA1c change from Baseline to Week 26 
between sotagliflozin 400 mg and placebo. 
In the amended, current, version of this protocol, the sample 
size/power has been recalculated to account for the addition of the 
sotagliflozin 200 mg treatment group after enrollment had 
commenced. Assuming a common SD of 1.2% and using a 2-sided 
test at a 0.05 α-level, 100 patients per arm will have: 
• 
94% power to detect a treatment difference of 0.6% in 
mean HbA1c change from Baseline to Week 26 between 
sotagliflozin 400 mg and placebo, and  
• 
84% power to detect a treatment difference of 0.5% in 
mean HbA1c change from Baseline to Week 26 between 
sotagliflozin 200 mg and placebo. 
As a result, the total number of patients will include:  
• 
Approximately 100 patients from the initial randomization 
(1:1) according to the original protocol, balanced between 
placebo and sotagliflozin 400 mg, and 
• 
Approximately 300 patients from the subsequent 
randomization (1:1:1) according to the amended, current, 
protocol, balanced between placebo and the sotagliflozin 
200 mg and 400 mg doses.   
Analysis population: 
Efficacy analyses will be based on the intention to treat (ITT) 
population, defined as all randomized patients irrespective of 
compliance with the study protocol and procedures. Patients will be 
analyzed for efficacy analyses according to the treatment group to 
which they are randomized, that is, sotagliflozin 400 mg versus 
placebo (those randomized to placebo), and sotagliflozin 200 mg 
versus placebo (those randomized to placebo in the amended 
randomization only). 
Primary analysis: 
Analysis of the primary efficacy endpoint (change from Baseline to 
Week 26 in HbA1c) will be performed on the ITT population, using 
HbA1c measurements obtained during the study, including those 
obtained after IMP discontinuation or introduction of rescue therapy. 
The primary efficacy endpoint of change in HbA1c from baseline to 
Week 26 will be analyzed with missing values imputed by 
control-based multiple imputation method under the missing not at 
random frame work.  
• 
For placebo patients, missing data will be imputed based on 
the placebo group data, 
• 
For patients in the sotagliflozin 400 mg group, missing data 
will be imputed as if the patients were on placebo 
throughout the study, where all patients’ measurements 
including the on-treatment measurements will be 
considered as if the measurements were from the placebo 
group in the imputation model. 
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Each of the complete datasets will be analyzed by the Analysis of 
Covariance (ANCOVA) model with treatment groups (sotagliflozin 
400 mg, placebo), randomization stratum of HbA1c (≤8.0%, >8.0%), 
randomization stratum of SBP (<130, ≥130 mmHg), and country as 
fixed effects, and baseline HbA1c value as a covariate. Results from 
each complete dataset will be combined to provide the adjusted mean 
change in HbA1c from Baseline to Week 26 for each treatment group, 
as well as the between-group difference (comparing sotagliflozin 
400 mg vs placebo) and the 95% confidence intervals (CI) for the 
difference.  
 
Summary statistics (for screening value, baseline value, observed 
values, and observed changes from Baseline) at scheduled visits will 
be provided for each treatment group. The summary will include the 
number of observations, mean, SD, standard error (SE), minimum, 
median, and maximum. Graphical presentations will also be used to 
examine trends over time using mean values (±SE) and mean 
changes from baseline (±SE) at each of the scheduled visits (using 
observed cases [OC]).  
Analysis of secondary efficacy endpoints: 
The secondary endpoints will be analyzed using a similar approach to 
the primary efficacy endpoint, with missing values imputed by 
control-based multiple imputation method under the missing not at 
random frame work.  
For each of the continuous secondary endpoints, each of the 
complete datasets will be analyzed by the ANCOVA model. To 
compare sotagliflozin 400 mg versus placebo, the model will include 
treatment groups (400 mg sotagliflozin, placebo), randomization 
stratum of HbA1c (≤8.0%, >8.0%), randomization stratum of SBP 
(<130, ≥130 mmHg), and country as fixed effects, and baseline 
secondary endpoint value as a covariate. To compare sotagliflozin 
200 mg versus placebo, the model will include treatment groups 
(sotagliflozin 200 mg, placebo), randomization stratum of HbA1c 
(≤8.0%, >8.0%), randomization stratum of SBP (<130, ≥130 mmHg), 
and country as fixed effects, and baseline secondary endpoint value 
as a covariate. Results from each complete dataset will be combined 
to provide the adjusted mean change from Baseline to Week 26 for 
each treatment group, as well as the between-group difference 
(comparing each sotagliflozin group vs its corresponding placebo 
group) and the 95% CI for the difference. 
The categorical secondary efficacy variables of HbA1c <6.5%, <7% at 
Week 26 will be analyzed using a Cochran-Mantel-Haenszel method 
stratified by randomization stratum of HbA1c (≤8.0%, >8.0%), and 
randomization stratum of SBP (<130, ≥130 mmHg). 
Analysis of other efficacy endpoints 
The analysis of other endpoints will be descriptive with no formal 
testing. Summary statistics at scheduled visits using OC will be 
provided by each treatment group. Graphical presentations will also 
be used to illustrate trends over time. 
Analyses of safety data 
All safety summaries will be descriptive; no statistical significance 
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tests will be performed on safety data. These analyses will be based 
on the Safety Population, which is defined as all randomized patients 
who receive at least 1 dose of double-blind treatment, regardless of 
the amount of treatment administered. Patients will be analyzed for 
safety analyses according to the treatment actually received. 
DURATION OF STUDY PERIOD (per 
patient) 
Up to 34 weeks, including a Screening Period consisting of a 
Screening Phase of up to 2 weeks and a 2-week single-blind placebo 
Run-in Phase, a 26-week double-blind Treatment Period, and a 
4-week post-treatment Follow-up visit to collect safety information. 
STUDY COMMITTEES 
Steering committee:  
 Yes    
 No 
Data monitoring committee: 
 Yes    
 No 
Clinical endpoint committee(s):  
 Yes  
 No 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
Abbreviations: HbA1c: hemoglobin A1c; R: randomization; T2D: type 2 diabetes mellitus. 
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1.2 
STUDY FLOW CHART 
 
Screening Period 
 
Screening 
Run-in 
                        Double Blind Treatment Perioda 
Follow-
upb 
VISIT 
1 
2 
3 
(Randomization) 
4 
5 
6 
7 
8 
9 
10 
Week 
Up to -4 
-2 
0  
Baseline 
1 
4 
8 
12 
18 
26 
30 
Day (window [days]) 
 
(-7/+3) 
1 
7 (±3) 
28 (±3) 
56 (±3) 
84 (±3) 
126 (±3) 
182 (±3) 
210 (±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
Body weight, heightc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam: 
 
 
 
 
 
 
 
 
 
 
    complete 
X 
 
 
 
  
 
 
 
X 
 
    abbreviated 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Diet & exercise instruction 
 
X 
X 
 
 
 
 
 
X 
 
Instruction on basic genitourinary 
hygiene & hydration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Interactive response technology 
(IRT) contact 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Dispense glucose meter  
 
X 
 
 
 
 
 
 
 
 
Dispense diary  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect/review diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Instruction on diabetic 
ketoacidosis symptoms and 
glucose testing 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Dispense IMP  
 
X 
X 
 
X 
X 
X 
X 
 
 
IMP accounting & compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Screening Period 
 
Screening 
Run-in 
                        Double Blind Treatment Perioda 
Follow-
upb 
VISIT 
1 
2 
3 
(Randomization) 
4 
5 
6 
7 
8 
9 
10 
Week 
Up to -4 
-2 
0  
Baseline 
1 
4 
8 
12 
18 
26 
30 
Day (window [days]) 
 
(-7/+3) 
1 
7 (±3) 
28 (±3) 
56 (±3) 
84 (±3) 
126 (±3) 
182 (±3) 
210 (±3) 
Self-monitored blood glucosee 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
 
X 
 
 
 
 
 
X 
 
Standard mixed meal tolerance 
testg 
 
 
X 
 
 
 
 
 
X 
 
Laboratory testingh 
 
 
 
 
 
 
 
 
 
 
FPG 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
HbA1c 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Chemistry (including amylase 
and lipase) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
 
 
 
X 
 
X 
 
Fasting lipids 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Pregnancy test (WOCBP)i 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Serum follicle stimulating 
hormone and estradiol 
(menopausal women only)i 
X 
 
 
 
 
 
 
 
 
 
Plasma concentrationj 
 
 
 
 
X 
 
 
X 
X 
 
Markers of intestinal transit & 
absorptionk 
 
 
X 
 
 
 
 
 
X 
X 
Markers of bone & calcium 
metabolisml 
 
 
X 
 
 
 
 
 
X 
 
Urinalysis (dipstick and 
microscopy)m 
X 
 
X 
 
 
 
 
 
X 
 
Urine albumin, calcium, 
glucose & creatinine 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Evaluate for glycemic rescue 
 
 
 
To be assessed and reported throughout the treatment period 
 
Hypoglycemia 
To be assessed and reported throughout the study 
AEs/SAEs/AESIs/EOSIs 
To be assessed and reported throughout the studyp 
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a If a patient discontinues treatment with IMP early during the Treatment Period, the patient will have a Premature EOT Visit, and a Follow-up Visit 4 weeks after the last dose of IMP. However, every effort will be 
made to have all patients return to the site for all scheduled visits, in particular the Week 26 Visit. If the patient does not agree to a site visit, they will be contacted by telephone to inquire about safety status. If a 
patient discontinues (or completes) treatment and study at the same time, a single visit will be performed using the procedure normally planned for the EOT visit. 
b Four weeks after the last dose of IMP. 
c Height to be measured only at screening 
d Vital sign measurements (sitting BP and heart rate): 3 separate seated BP and heart rate measurements should be taken with at least 1 minute between readings, following a 5-minute rest period and prior to 
phlebotomy (see Section 9.2.1.4 and detailed instructions in Appendix D).  
e See Section 9.2.1.6 for details of SMBG measurements. Glucose meters used for SMBG display results as plasma glucose concentration. Patients should measure their fasting plasma glucose at least 3 times per 
week (including on day of each on-site study visit). 
f 
The 12-lead ECG recordings should be obtained prior to IMP administration. The ECG will be evaluated as “normal” or “abnormal”. 
g Postprandial plasma glucose will be assessed by central laboratory at Baseline and 2 hours after consuming a standard mixed liquid breakfast meal and via a mixed meal tolerance test (MMTT) on Day 1 and 
Week 26. If a patient withdraws from IMP early, please see Section 10.3.4. 
h All laboratory assessments occur prior to first dose of double-blind IMP. The first dose of double-blind IMP occurs after samples for the mixed liquid meal have been collected. All visit dates will be scheduled based 
on the date of randomization with a ±3 days visit window allowed during the treatment period. Serum chemistry parameters (clinical chemistry [including amylase and lipase], hematology, and other blood 
parameters) are listed in Table 2. 
i 
Serum pregnancy testing only at screening; urine pregnancy testing subsequently. Serum pregnancy test results must be reviewed prior to beginning the Run-in Phase for all women of childbearing potential 
(WOCBP). Any positive urine test results must be confirmed based on serum pregnancy test. The Investigator may perform additional tests at their discretion or as required by local regulations. For women of 
nonreproductive potential (Appendix A), follicle stimulating hormone (FSH) and/or estradiol levels should be tested if the definition of postmenopausal or premenopausal cannot be satisfied, eg, no medical 
document of hysterectomy or cessation of menses <12 months without an alternative medical cause. 
j 
Plasma concentration samples (ie, for sotagliflozin and sotagliflozin-3-O-glucuronide) on Weeks 4 and Week 18 should be drawn with the other laboratory assessments. For Week 26, plasma concentration 
samples should be drawn at predose and 2 hours 30 minutes, immediately after the respective glucose assessments during the MMTT. PK samples (except the 2 hours 30 minute sample during the MMTT) MUST 
be collected before administration of IMP. The date and time of the last intake of IMP prior to visits where PK samples are taken should be recorded by the patient in the patient diary. Patients should be reminded 
of this at visits preceding PK time points to ensure these details are captured. In the case of Premature IMP discontinuation, PK samples should not be drawn at the Premature EOT visit, nor at any subsequent 
visits. 
k The markers of intestinal transit and absorption include vitamins B6, B12, K, E, and A, serum folate, and ferritin. 
l 
Markers of bone and calcium metabolism include:  serum and urinary calcium, serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum and urinary phosphorus, serum parathyroid hormone, markers of 
bone resorption (serum NTX, serum β-CTX-1), and bone formation (serum P1NP). 
m Urinalysis includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte esterase. Microscopy includes detection 
of formed cellular elements, casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. In the event of abnormal urinalysis findings suspicious of urinary tract infection, urine culture should be 
performed. Positive urine culture determination will be based upon the criteria of the reporting laboratory. 
 
p All serious adverse events (SAEs), adverse events (AEs), AEs of special interest (AESIs), and Events of Special Interest (EOSIs) will be collected starting with signing informed consent and continue until the end 
of the study. All AEs that occur during treatment should be followed until study completion (or until patients leave the study) or until the event has resolved, the condition has stabilized, or the patient is lost to 
follow-up. All patients will have a follow-up contact 4 weeks after the last dose of IMP to collect safety information. 
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2 
TABLE OF CONTENTS 
 
1 
FLOW CHARTS.............................................................................................................................13 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................13 
1.2 
STUDY FLOW CHART ..................................................................................................................14 
2 
TABLE OF CONTENTS ................................................................................................................17 
2.1 
LIST OF TABLES...........................................................................................................................23 
2.2 
LIST OF FIGURES.........................................................................................................................23 
3 
LIST OF ABBREVIATIONS ..........................................................................................................24 
4 
INTRODUCTION AND RATIONALE.............................................................................................26 
4.1 
BACKGROUND:  SOTAGLIFLOZIN AND DISEASE ....................................................................26 
4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS ................................................................27 
4.3 
RATIONALE FOR CURRENT STUDY ..........................................................................................28 
4.3.1 
Rationale for selection of doses.....................................................................................................28 
4.3.2 
Rationale for study design and control groups ..............................................................................28 
4.4 
BENEFIT/RISK OF SOTAGLIFLOZIN...........................................................................................29 
5 
STUDY OBJECTIVES ...................................................................................................................31 
5.1 
PRIMARY.......................................................................................................................................31 
5.2 
SECONDARY ................................................................................................................................31 
5.3 
OTHER...........................................................................................................................................31 
6 
STUDY DESIGN ............................................................................................................................33 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................33 
6.1.1 
Screening period............................................................................................................................33 
6.1.1.1 
Screening Phase (Visit 1) ..............................................................................................................33 
6.1.1.2 
Run-in Phase (Visit 2) ....................................................................................................................33 
6.1.2 
Double-blind treatment period (Week 0 to Week 26).....................................................................34 
 
.........................................................................................................34 
6.1.4 
Follow-up period.............................................................................................................................35 
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6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................35 
6.2.1 
Duration of study participation for each patient .............................................................................35 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................35 
6.3 
INTERIM ANALYSIS......................................................................................................................35 
6.4 
STUDY COMMITTEES..................................................................................................................35 
6.4.1 
Data monitoring committee ............................................................................................................35 
6.4.2 
Clinical endpoint committee(s).......................................................................................................35 
6.4.3 
Safety adjudication of events requiring ongoing monitoring ..........................................................36 
6.4.4 
Steering Committee .......................................................................................................................36 
7 
SELECTION OF PATIENTS..........................................................................................................37 
7.1 
INCLUSION CRITERIA..................................................................................................................37 
7.2 
EXCLUSION CRITERIA ................................................................................................................37 
7.2.1 
Exclusion criteria related to study methodology ............................................................................37 
7.2.2 
Exclusion criteria related to diabetes history and treatment..........................................................38 
7.2.3 
Exclusion criteria related to the current knowledge of sotagliflozin ...............................................39 
7.2.4 
Additional exclusion criteria during or at the end of the Run-in phase before Randomization......39 
8 
STUDY TREATMENTS .................................................................................................................41 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................41 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................41 
8.2.1 
Rescue therapy..............................................................................................................................42 
8.3 
BLINDING PROCEDURES............................................................................................................44 
8.3.1 
Methods of blinding........................................................................................................................44 
8.3.2 
Randomization code breaking during the study.............................................................................44 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................45 
8.5 
PACKAGING AND LABELING ......................................................................................................45 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................46 
8.7 
RESPONSIBILITIES ......................................................................................................................46 
8.7.1 
Treatment accountability and compliance......................................................................................46 
8.7.2 
Return and/or destruction of treatments ........................................................................................47 
8.8 
CONCOMITANT MEDICATION.....................................................................................................47 
8.8.1 
Prohibited prior and concomitant medications...............................................................................47 
8.8.2 
Concomitant diabetes therapy .......................................................................................................48 
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8.9 
POSTSTUDY TREATMENT..........................................................................................................48 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................49 
9.1 
EFFICACY ENDPOINTS ...............................................................................................................49 
9.1.1 
Primary efficacy endpoint...............................................................................................................49 
9.1.2 
Secondary efficacy endpoints........................................................................................................49 
9.1.3 
Other efficacy endpoints ................................................................................................................49 
9.1.4 
Assessment methods of efficacy endpoints...................................................................................50 
9.1.4.1 
HbA1c ............................................................................................................................................50 
9.1.4.2 
Postprandial glucose and mixed meal tolerance test ....................................................................50 
9.1.4.3 
Fasting plasma glucose measurement ..........................................................................................51 
9.1.4.4 
Body weight measurement ............................................................................................................51 
9.1.4.5 
Blood pressure measurements ......................................................................................................52 
9.1.4.6 
Kidney function parameter measurement......................................................................................52 
9.1.4.7 
Proportion of patients requiring rescue for hyperglycemia ............................................................52 
9.2 
SAFETY ENDPOINTS ...................................................................................................................52 
9.2.1 
Assessment methods of safety endpoints .....................................................................................53 
9.2.1.1 
Adverse events ..............................................................................................................................53 
9.2.1.2 
Hypoglycemia.................................................................................................................................53 
9.2.1.3 
Laboratory safety variables............................................................................................................54 
9.2.1.4 
Vital signs and physical exam........................................................................................................56 
9.2.1.5 
Electrocardiogram variables ..........................................................................................................56 
9.2.1.6 
Self-monitoring of blood glucose....................................................................................................56 
9.2.1.7 
Diabetic ketoacidosis .....................................................................................................................57 
9.3 
OTHER ENDPOINTS.....................................................................................................................57 
9.3.1 
Pharmacokinetics...........................................................................................................................57 
9.3.1.1 
Sampling time ................................................................................................................................57 
9.3.1.2 
Pharmacokinetics handling procedure...........................................................................................58 
9.3.1.3 
Bioanalytical method......................................................................................................................58 
 
.........................................................................................58 
 
..............................................................................59 
9.6 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................59 
10 
STUDY PROCEDURES ................................................................................................................61 
10.1 
VISIT SCHEDULE..........................................................................................................................61 
10.1.1 
Screening Period............................................................................................................................61 
10.1.1.1 Screening Phase............................................................................................................................61 
10.1.1.2 Run-in Phase (Visit 2, Week -2).....................................................................................................63 
10.1.2 
Double-blind randomized treatment period....................................................................................64 
10.1.2.1 Treatment Period (Day 1 to Week 26) ...........................................................................................64 
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10.1.3 
Post-treatment Follow-up period....................................................................................................68 
10.1.3.1 On-site follow-up Visit 10 (Week 30) – End of Study.....................................................................68 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................69 
10.2.1 
Source data to be found in patient’s file.........................................................................................69 
10.2.2 
Source data verification requirements for screen failures .............................................................70 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................70 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................70 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................70 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................71 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................71 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................72 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................73 
10.4.1 
Definitions of adverse events.........................................................................................................73 
10.4.1.1 Adverse event ................................................................................................................................73 
10.4.1.2 Serious adverse event ...................................................................................................................73 
10.4.1.3 Adverse event of special interest...................................................................................................74 
10.4.1.4 Events of Special Interest ..............................................................................................................75 
10.4.2 
General guidelines for reporting adverse events ...........................................................................75 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................76 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................77 
10.4.5 
Guidelines for reporting events of special interest.........................................................................77 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................77 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................77 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................78 
10.6.1 
Hypoglycemia.................................................................................................................................78 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................80 
11 
STATISTICAL CONSIDERATIONS..............................................................................................81 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................81 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................81 
11.3 
ANALYSIS POPULATIONS...........................................................................................................82 
11.3.1 
Efficacy populations .......................................................................................................................82 
11.3.1.1 Intent-to-treat population................................................................................................................82 
11.3.2 
Safety population ...........................................................................................................................83 
11.4 
STATISTICAL METHODS .............................................................................................................83 
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11.4.1 
Extent of study treatment exposure and compliance.....................................................................84 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................84 
11.4.1.2 Compliance ....................................................................................................................................84 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................84 
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................84 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................86 
11.4.2.3 Analyses of other efficacy endpoints .............................................................................................87 
11.4.2.4 Multiplicity considerations ..............................................................................................................87 
11.4.3 
Analyses of safety data..................................................................................................................88 
11.4.3.1 Analysis of adverse events ............................................................................................................88 
11.4.3.2 Analyses of hypoglycemia .............................................................................................................89 
11.4.3.3 Analyses of adverse events of special interest..............................................................................90 
11.4.3.4 Analyses of events of special interest............................................................................................90 
11.4.3.5 Analyses of laboratory variables....................................................................................................90 
11.4.3.6 Analyses of vital sign variables ......................................................................................................90 
11.4.3.7 Analyses of 12 lead ECG status ....................................................................................................91 
11.4.4 
Analyses of pharmacokinetic variables..........................................................................................91 
11.5 
INTERIM ANALYSIS......................................................................................................................91 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................92 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................92 
12.2 
INFORMED CONSENT .................................................................................................................92 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................92 
13 
STUDY MONITORING...................................................................................................................94 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR............................................................................94 
13.2 
RESPONSIBILITIES OF THE SPONSOR OR SERVICE PROVIDER .........................................94 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................94 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................95 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................95 
14 
ADDITIONAL REQUIREMENTS...................................................................................................96 
14.1 
CURRICULUM VITAE....................................................................................................................96 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................96 
14.3 
CONFIDENTIALITY .......................................................................................................................96 
14.4 
PROPERTY RIGHTS.....................................................................................................................97 
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14.5 
DATA PROTECTION.....................................................................................................................97 
14.6 
INSURANCE COMPENSATION....................................................................................................98 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................98 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................98 
14.8.1 
By the Sponsor...............................................................................................................................98 
14.8.2 
By the Investigator .........................................................................................................................99 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................99 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................99 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................101 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................102 
17 
APPENDICES..............................................................................................................................104 
APPENDIX A GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION....................................................................................................105 
APPENDIX B TWO-HOUR STANDARDIZED MIXED MEAL ..................................................................108 
APPENDIX C RECOMMENDATIONS ON BASIC GENITOURINARY HYGIENE, MAINTAINING 
HYDRATION, AND RECOGNIZING DIABETIC KETOACIDOSIS..............................................110 
APPENDIX D MEASUREMENT OF BLOOD PRESSURE AND PULSE RATE......................................113 
APPENDIX E GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................114 
 
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2.1 
LIST OF TABLES 
Table 1 – Summary of investigational medicinal products............................................................................41 
Table 2 – Serum chemistry parameters ........................................................................................................54 
Table 3 – Samples identification ...................................................................................................................57 
 
2.2 
LIST OF FIGURES 
Figure 1 - Hypoglycemia classification in Study EFC14833..........................................................................79 
 
 
 
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3 
LIST OF ABBREVIATIONS 
 
ACR: 
albumin-creatinine ratio 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
Analysis of Covariance 
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
BP: 
blood pressure 
CEC: 
Clinical Endpoint Committee 
CI: 
confidence interval 
CRO: 
contract research organization 
CSR: 
clinical study report 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DILI: 
drug-induced liver injury 
DKA: 
diabetic ketoacidosis 
DMC: 
Data Monitoring Committee 
DRF: 
Discrepancy Resolution Form 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOSI: 
Events of Special Interest 
EOT: 
End-of-Treatment 
FPG: 
fasting plasma glucose 
FSH: 
follicle-stimulating hormone 
GCR: 
glucose-creatinine ratio 
GI: 
gastrointestinal 
GLP-1: 
glucagon-like peptide-1 
GU: 
genitourinary 
HbA1c: 
hemoglobin A1c 
HLGT: 
high-level group term 
HLT: 
high level term 
HRT: 
hormone replacement therapy 
IB: 
Investigator's Brochure 
ICF: 
informed consent form 
IEC: 
independent ethics committee 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
IRT: 
Interactive Response Technology 
ITT: 
intent-to-treat 
MACE: 
major adverse cardiovascular events 
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MI: 
myocardial infarction 
MM: 
mixed meal 
MMTT: 
mixed meal tolerance test 
NIMP: 
noninvestigational medicinal product 
OC: 
observed cases 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
P-gp: 
P-glycoprotein 
PI: 
Principal Investigator 
PK: 
pharmacokinetic 
PPG: 
postprandial glucose 
PT: 
preferred term 
PYY: 
peptide YY 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SC: 
Steering Committee 
SD: 
standard deviation 
SE: 
standard error 
SGLT: 
sodium-glucose cotransporter 
SGLT1: 
sodium-glucose cotransporter type 1 
SGLT2: 
sodium-glucose cotransporter type 2  
SMBG: 
self-monitoring of blood glucose 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
T1D: 
type 1 diabetes mellitus 
T2D: 
type 2 diabetes mellitus 
TEAE: 
treatment-emergent adverse events 
TG: 
triglycerides 
UGE: 
urinary glucose excretion 
ULN: 
upper limit of normal 
WOCBP: 
woman of child-bearing potential 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
BACKGROUND:  SOTAGLIFLOZIN AND DISEASE 
Sotagliflozin is a dual inhibitor of the sodium-glucose cotransporters type 1 and 2 (SGLT1 and 2) 
being developed for use in type 2 diabetes mellitus (T2D), a metabolic disorder characterized by 
hyperglycemia that results from a combination of increased insulin resistance and beta cell 
dysfunction. The microvascular complications of diabetes are well known and can result in 
impaired renal function, retinopathy and neuropathy. Other comorbidities that are frequently 
associated with diabetes are hypertension, obesity, and cardiovascular (CV) disease. Recently, the 
Centers for Disease Control and Prevention released a report stating that if current trends 
continue, 1 in 3 Americans will have diabetes by the year 2050. According to the most recent 
International Diabetes Federation Diabetes Atlas, the estimates in 2015 were that 1 in 11 adults 
have diabetes, which means 415 million people, estimated to rise to 642 million by 2040 (2). 
In 2010, 33 million people in the European Union had diabetes, 9% of the adult population. This 
number is projected to increase to 38 million by 2030 (3). While these numbers include both 
people with T2D and type 1 diabetes (T1D), over 90% of adults with diabetes have T2D. Diabetes 
is among the leading causes of death by disease and is a leading cause of heart disease, stroke, 
blindness, kidney disease, and amputation (2,3). Despite the fact that the population of people 
with diabetes is growing, none of the current therapies is curative and the results of treatment are 
variable. 
Although lifestyle changes, including diet, exercise, and education, are valuable components of 
diabetes treatment, the vast majority of people with T2D require pharmacological therapy to 
control the disease. In the United States and Europe, metformin is the standard first-line therapy in 
the absence of any contraindications or tolerability issues as per guidance from the American 
Association of Diabetes (4).  
Despite the numerous treatment options available, monotherapy fails in many patients as beta-cell 
function continues to deteriorate leading to progressively increasing hyperglycemia. Aggressive 
glycemic control with the currently available agents often leads to side effects, most notably 
weight gain and an increased frequency of hypoglycemia. These concerns emphasize the need to 
develop new agents that effectively and safely lower glucose in diabetic patients. 
In patients with diabetes, it is desirable to maintain blood glucose in the normal range without 
exhausting the ability of the pancreatic beta-cells to produce insulin. Glucose is transported across 
the cell membrane by 2 different types of glucose transporters:  glucose-facilitated transporters 
and sodium-glucose cotransporter (SGLT) proteins (5). In the kidney, after blood is filtered by the 
glomerulus, glucose passes into the urine, but 99% is reabsorbed, primarily via SGLT2, which is 
responsible for 90% of glucose reabsorption, while 10% is reabsorbed by SGLT1. When 
functional SGLT2 is lacking in humans, a significant amount of glucose remains in the urine and 
is removed from the body (6). This way of reducing blood glucose is not an insulin-dependent 
mechanism; therefore hyperglycemia may be reduced while the pancreas is spared from an 
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increased demand for insulin production that is caused by hyperglycemia. Since obesity is a 
significant comorbidity in T2D, and insulin resistance is increased in obesity, the caloric loss from 
glucose in the urine may represent an additional benefit resulting in decreased weight, which 
should result in decreased insulin resistance (6).  
The sodium-glucose cotransporter type 1 (SGLT1) is expressed predominantly in the 
gastrointestinal (GI) tract; SGLT1 is responsible for the majority of glucose absorption by the 
small intestine (7). Inhibition of SGLT1 in the GI tract prevents glucose from being absorbed. 
Additionally, there is accumulating evidence that SGLT1 inhibition stimulates secretion of 
glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), gut hormones involved in pancreatic 
beta-cell function and appetite control, respectively. Reduced glucose absorption in the proximal 
intestine leads to more glucose being delivered distally, which allows L cells in both the ileum 
and the colon to sense glucose and its byproducts, and as a result, they secrete GLP-1 and PYY. 
Although a complete lack of functional SGLT1 may be associated with symptoms of glucose and 
galactose malabsorption, (8) pharmacologic inhibition of SGLT1 by sotagliflozin has not 
produced these effects in preclinical models or patients with T2D. Selective inhibitors of the 
SGLT1 transporter are in early stages of development. 
Extensive clinical studies conducted for selective SGLT2 inhibitors have established this class as 
effective agents for the treatment of T2D (9,10,11) and have led to approvals by the US Food and 
Drug Administration (FDA) and the European Medicines Agency (EMA). Studies with 
sotagliflozin, a potent dual inhibitor of SGLT2 and SGLT1, have shown that this agent produces 
significant glucosuria in preclinical animal models, healthy human volunteers, and patients with 
T2D. Single- and multiple-dose administration of sotagliflozin to healthy human patients has 
resulted in dose-dependent increases in glucosuria. Multiple-dose (28-day) administration in 
diabetic patients produced improvements in several metabolic parameters, including urinary 
glucose excretion (UGE), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), GLP-1, and 
PYY. These data suggest that sotagliflozin should be of therapeutic benefit to patients with T2D.  
4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS 
Approximately 780 subjects (639 assigned to sotagliflozin and 141 assigned to placebo) have 
participated in completed clinical studies of sotagliflozin. No significant safety concerns have 
been identified in the sotagliflozin drug program, and sotagliflozin has been well-tolerated in all 
studies to date. Serious adverse events (SAEs) and discontinuations due to adverse events (AEs) 
have been infrequent and have been balanced between treatment and comparator groups. Reports 
of treatment-emergent adverse events (TEAE) across all sotagliflozin studies for which data are 
available were generally balanced between treatment and comparator groups. The most frequently 
reported TEAEs (≥2.0%) were headache, nausea, diarrhea, constipation, and dizziness, all of 
which were reported at a frequency greater than placebo. However, most were described as mild 
to moderate, and most resolved spontaneously.  
In completed and ongoing clinical trials, no safety issues in addition to those already described in 
the current Investigator Brochure were observed. In general, no significant imbalances of 
SAE/AEs between sotagliflozin and comparators were observed in completed studies. 
Cumulatively, during the clinical trial program 8 SAEs were reported by 6 patients (4 T2D and 
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2 T1D), all of which were assessed as unrelated to study drug; those reported by 4 T2D patients 
who received sotagliflozin included pulmonary embolism, deep vein thrombosis, bile duct stone, 
cholangitis and lower limb fracture, while a myocardial infarction (MI) was experienced by a 
patient receiving placebo. Two SAEs of diabetic ketoacidosis (DKA) were reported by 2 T1D 
patients receiving 400 mg once daily sotagliflozin in the Phase 2 T1D study LX4211.1 
203-TIDM; both SAEs were assessed as due to failure of insulin delivery via insulin pump. 
A drug interaction study with digoxin, a sensitive P-glycoprotein (P-gp) substrate, indicated that 
sotagliflozin acts as a weak P-gp inhibitor. 
More information on the safety of sotagliflozin and on the clinical program can be found in the 
Investigator Brochure (IB). 
4.3 
RATIONALE FOR CURRENT STUDY 
4.3.1 Rationale for selection of doses 
The selection of 400 mg and 200 mg once-daily doses is based on the results of the Phase 2b 
study LX4211.1-202-DM. In this study, doses of 75 mg once daily, 200 mg once daily, 200 mg 
twice daily, and 400 mg once daily sotagliflozin were tested over a 12-week, double-blind period. 
The 400 mg and 200 mg once daily doses were chosen for further evaluation based on their 
HbA1c-lowering effects and the overall safety and tolerability observed at these doses. At 
12 weeks, the 400 mg dose lowered HbA1c by a mean of 0.93% and the 200 mg dose by a mean 
of 0.48%, while placebo lowered HbA1c by a mean of 0.14%. Other doses did not have any 
advantages in efficacy, safety, or tolerability. The overall incidence of AEs in patients receiving 
400 mg or 200 mg once daily was similar to that seen with placebo. 
In healthy subjects sotagliflozin was well-tolerated following single doses up to 2000 mg, and in 
multiple doses up to 800 mg over 10 days. Furthermore, in a thorough QT study, single doses of 
sotagliflozin (800 mg and 2000 mg) were well tolerated and did not prolong the QT interval. 
Additionally, evaluation of metabolites in urine and plasma of healthy subjects resulted in no 
safety concerns following single doses of 400 mg sotagliflozin. Single doses of 400 mg in 
combination with sitagliptin, and multiple doses up to 400 mg in combination with metformin 
over 12 weeks were also well tolerated in patients with T2D.  
4.3.2 Rationale for study design and control groups 
This study is designed to demonstrate the efficacy and safety of sotagliflozin when used as 
monotherapy in patients with T2D who have inadequate glycemic control with diet and exercise. 
Sotagliflozin 200 mg and 400 mg will be compared to placebo, consistent with regulatory 
guidance. Based on the study design, the protocol stipulates that patients be provided antidiabetic 
agent rescue therapy according to a predefined algorithm. Safety, tolerability, pharmacokinetic 
(PK) and pharmacodynamic (PD) effects of sotagliflozin are supported by Phase 1 and Phase 2 
studies and toxicology data in rats up to 26 weeks and dogs up to 39 weeks as well as 2-year 
carcinogenicity data in rats.  
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To achieve balanced randomization for assessment of the primary endpoint, randomization will be 
stratified based on preexisting metabolic control (Screening HbA1c ≤8.0% versus >8.0%). 
Another stratification factor (systolic blood pressure [SBP] 130 < versus ≥130 mmHg) has been 
added to ensure balance in randomization for a secondary endpoint (change from baseline to 
12 weeks in SBP for patients with baseline SBP ≥130 mmHg). 
A placebo control will be used to allow for an unbiased assessment of treatment effects and safety 
data. Bias will be minimized by randomizing the patients to treatment groups, blinding the 
patients, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating the 
endpoints in a blinded fashion. 
A parallel-group, randomized placebo-controlled design was selected because trial participants are 
exposed to a single treatment and assignment to that treatment is based solely on chance. This 
design is free of the limitations of competing designs such as crossover in which there may be a 
carryover of effect from one treatment to the second treatment. Although this carryover effect can 
be minimized with a washout period, it is possible that some longer term effects may persist. 
While the sample size of the parallel group design is larger to account for more variability when 
participants cannot serve as their own control, the above-mentioned limitations of the crossover 
design have led the randomized controlled trial design to be the standard for therapeutic 
confirmatory trials for regulatory approval such as this trial. 
4.4 
BENEFIT/RISK OF SOTAGLIFLOZIN 
Sotagliflozin is currently being investigated as an adjunct to diet and exercise to improve 
glycemic control in adults with T2D. The study program will also provide efficacy and safety data 
for sotagliflozin in combination with other antidiabetic medications. In addition the study program 
will evaluate clinical outcomes in patients with high CV risk and in patients with renal 
impairment. The use of sotagliflozin in the treatment of T1D is also being studied in a separate 
development program. 
Sotagliflozin may benefit a wide variety of diabetic patients based on multiple potential beneficial 
effects of dual SGLT2/SGLT1 inhibition, and its insulin-independent mechanism of action. 
Improvements in HbA1c, FPG, and postprandial glucose (PPG) were observed with sotagliflozin 
in multiple studies. As anticipated from the mechanism of action, treatment with sotagliflozin 
resulted in increased UGE (from inhibition of SGLT2) as well as increased incretin levels (from 
inhibition of SGLT1). In addition, the improvements in body weight, blood pressure (BP), and 
triglycerides (TG) observed with sotagliflozin treatment have the potential to benefit patients with 
diabetes through their effects on common diabetic comorbidities.  
Overall, sotagliflozin has been well tolerated in all studies to date, with the majority of events 
assessed as mild to moderate; most of which resolved spontaneously. Serious adverse events and 
discontinuations due to AEs have been limited and balanced between treatment and comparator 
groups. Severe hypoglycemia, genital mycotic infections, urinary tract infections, DKA, volume 
depletion with serious consequence (orthostasis, falls, fractures), severe diarrhea, pancreatitis, 
bone fractures, venous thrombotic events, drug-induced liver injuries (DILI), severe renal events 
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and malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, prostate, 
and thyroid carcinoma) are monitored closely as identified and potential risks. 
The improvement in glycemic control, the reductions in weight and BP, and the tolerability and 
safety profile of sotagliflozin to date, demonstrate a favorable benefit-risk assessment for 
sotagliflozin.  
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY  
The primary objective of this study is to demonstrate the superiority of sotagliflozin 400 mg 
versus placebo on HbA1c reduction at Week 26 in patients with T2D who have inadequate 
glycemic control on diet and exercise. 
5.2 
SECONDARY  
• To compare sotagliflozin 400 mg versus placebo for:  
- 
Change from Baseline in 2-hour PPG following a mixed meal (MM) at Week 26 
- 
Change from Baseline in FPG at Week 26 
- 
Change from Baseline in body weight at Week 26 
- 
Change from Baseline in SBP at Week 12 for patients with baseline SBP ≥130 mmHg  
- 
Change from Baseline in SBP at Week 12 for all patients 
- 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
• To compare sotagliflozin 200 mg versus placebo for:  
- 
Change from Baseline in HbA1c at Week 26 
- 
Change from Baseline in 2-hour PPG following a mixed meal at Week 26  
- 
Change from Baseline in body weight at Week 26 
- 
Change from Baseline in SBP at Week 12 for all patients 
• To evaluate the safety of sotagliflozin 400 mg and 200 mg doses versus placebo 
5.3 
OTHER 
- 
Urine albumin-creatinine ratio (ACR) 
- 
Urinary glucose excretion (UGE) and urine glucose-creatinine ratio (GCR)  
- 
Estimated glomerular filtration rate (eGFR)  
- 
Reduction in body weight by ≥2%, ≥5%, and ≥10% 
- 
Change from Baseline in FPG at Week 26  
- 
Change from Baseline in SBP at Week 12 for patients with baseline SBP ≥130 mmHg 
- 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
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• To compare sotagliflozin 400 mg and 200 mg doses with placebo for change from 
Baseline in SBP at Week 26 for all patients and for patients with Baseline SBP 
≥130 mmHg 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This study is a Phase 3, multicenter and multinational, 1:1:1 randomized, double-blind, placebo 
controlled, parallel group study that is anticipated to enroll approximately 400 patients. This 
number includes approximately 100 patients enrolled under the original protocol study design, 
and approximately 300 patients to be enrolled under the amended, current, study design.  
The study will comprise a Screening period consisting of a Screening Phase and a single-blind 
placebo Run-in Period, a double-blind Treatment Period, and a Follow-up period.  
The study design is presented graphically at the end of the synopsis. 
6.1.1 Screening period 
6.1.1.1 Screening Phase (Visit 1) 
The Screening Phase will last up to 2 weeks. The period must be long enough to collect the data 
required to establish whether the patient satisfies the inclusion/exclusion criteria. 
Patients with T2D currently managed with diet and exercise alone are eligible for enrollment in 
this study. Patients who previously managed their T2D with a single oral antidiabetic drug (OAD) 
may be eligible for Screening if they have discontinued the OAD and been maintained on diet and 
exercise for at least 12 weeks before the screening visit.  
At the Screening Visit after signing of the informed consent form (ICF), eligibility criteria will be 
assessed and Screening assessment will be performed. Women of childbearing potential 
(WOCBP) not willing to use highly effective method(s) of birth control during the study treatment 
period and the follow-up period, or who are unwilling or unable to be tested for pregnancy will be 
excluded from the study; guidance on highly effective contraceptive methods and collection of 
pregnancy information is provided in Appendix A. If another contraceptive method is used (such 
as a barrier method), it should be used in combination with one of the highly effective methods in 
Appendix A (such as an oral contraceptive). 
The Interactive Response Technology (IRT; either Interactive Voice Response System or 
Interactive Web Response System) will be contacted at Visit 1 for notification of screening and 
for patient number allocation. 
6.1.1.2 Run-in Phase (Visit 2) 
The Run-in Phase will last 2 weeks. Patients will be treated in a single-blind manner with placebo 
(2 tablets) once daily during the Run-in Period, starting from Visit 2. 
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6.1.4 Follow-up period 
Following the last dose of IMP (either as scheduled or prematurely), a post treatment follow-up 
should be scheduled for all patients 4 weeks (±3 days) after permanent IMP discontinuation. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The duration of the study for each patient will include a Screening Phase of up to 2 weeks, a 
2-week Run-in Phase, and a 26-week double-blind treatment period. 
After completion of study treatment, each patient will enter a 4-week Follow-up Period. The total 
study duration for each patient will be up to 34 weeks. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is defined as being the “last patient last visit” planned with the protocol, 
including the follow-up visit. 
The Sponsor can terminate the trial prematurely based on the advice of the Independent Data 
Monitoring Committee (DMC) or other unforeseen developments. 
6.3 
INTERIM ANALYSIS 
No interim analysis is planned. 
6.4 
STUDY COMMITTEES 
6.4.1 Data monitoring committee 
A DMC with members who are independent from the Sponsor and the Investigators will meet on 
a regular basis, and will be responsible for: 
Safety data to be reviewed will be unblinded and include events and outcomes described below 
for adjudication, as well as any additional safety data considered relevant. Details describing the 
DMC processes and procedures are outlined in a separate DMC Charter. To maintain continuous 
blinding and study integrity, the analysis will be conducted by an independent statistician, and 
measures will be taken to ensure the validity of the data. 
6.4.2 Clinical endpoint committee(s) 
The Clinical Endpoint Committee(s) (CEC) is/are comprised of experts in cardiology and 
nephrology (and other appropriate medical specialties such as neurology and endocrinology, as 
needed) who are independent of the Sponsor and the contract research organization (CRO). The 
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CECs will review and adjudicate all deaths, major adverse cardiovascular events 
(MACE)/selected CV events (MI, stroke, unstable angina leading to hospitalization, and heart 
failure leading to hospitalization), selected renal events, bone fracture, and DKA. 
The details regarding the CEC processes and procedures will be outlined in the CEC Charter(s). 
6.4.3 Safety adjudication of events requiring ongoing monitoring  
Two independent committees will review safety events that require ongoing monitoring to ensure 
timing protocol amendments in case a safety signal is identified. These events are: 1) potential 
cases of DILI, and 2) cases of amputations. 
The two committees will review the cases in a treatment-blinded manner and will present their 
assessment to the DMC. 
The members, roles and responsibilities of the two committees will be described in separate 
Charters. 
6.4.4 Steering Committee 
The Steering Committee (SC) is composed of experts in diabetes and scientists with clinical and 
methodological expertise. 
This Committee, led by a Chair, in collaboration with the Sponsor, is responsible for producing 
and conducting a scientifically sound study and for ensuring accurate reporting of the study. In 
that capacity, the SC must address and resolve scientific issues encountered during the study. The 
members will remain blinded until completion of the study. 
Among its responsibilities, the SC will receive blinded study status reports from Sponsor, and will 
review the recommendations from the DMC throughout the study. The SC members will 
participate in face-to-face meetings at regular intervals throughout the study and in regularly 
scheduled teleconferences. 
Detailed activities and responsibilities of the SC are provided in the SC charter. 
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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 
Patients meeting all of the following inclusion criteria will be screened: 
I 01. Patients (male and female) with T2D currently treated with diet and exercise only during 
the 12 weeks prior to the screening  
I 02. Signed written informed consent 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 4 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Age <18 years at the time of Screening or < legal age of majority, whichever is greater 
E 02. Type 1 diabetes  
E 03. Body mass index (BMI) ≤20 or >45 kg/m² at Screening 
E 04. Previous use of any antidiabetic drug unless the drug has been discontinued for a period of 
at least 12 weeks before the Screening Visit 
E 05. Use of systemic glucocorticoids (excluding topical or ophthalmic application, nasal spray 
or inhaled forms) for more than 10 consecutive days within 90 days prior to the Screening 
Visit  
E 06. Use of weight loss medications within 12 weeks or weight change of 5 kg or more during 
the 12 weeks before screening 
E 07. Likelihood of requiring treatment during the study period with drugs not permitted by the 
study protocol (eg, long-term systemic glucocorticoids) and refusing or unable to take 
alternative treatment 
E 08. Patients who have previously participated in any clinical trial of sotagliflozin/LX4211 
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E 09. Patients with severe anemia, severe CV (including congestive heart failure New York 
Heart Association IV), respiratory, hepatic, neurological, psychiatric, or active malignant 
tumor or other major systemic disease or patients with short life expectancy that, according 
to the Investigator, will preclude their safe participation in this study, or will make 
implementation of the protocol or interpretation of the study results difficult 
E 10. Current diagnosis of chronic hepatitis and/or other clinically active liver disease requiring 
treatment 
E 11. Known presence of factors that interfere with the Central Lab HbA1c measurement (eg, 
genetic Hb variants) compromising the reliability of HbA1c assessment, or medical 
conditions that affect interpretation of HbA1c results (eg, blood transfusion or severe blood 
loss in the last 3 months prior to randomization, any condition that shortens erythrocyte 
survival) 
E 12. History of drug or alcohol abuse within 6 months prior to screening 
E 13. Patient is an employee of the Sponsor, or is the Investigator or any Sub-investigator, 
research assistant, pharmacist, study coordinator, other staff or relative thereof directly 
involved in conducting the study 
E 14. Patient who has taken other investigational drugs or prohibited therapy for this study 
within 12 weeks or 5 half-lives, whichever is longer, prior to the screening. Current 
enrollment in any other clinical study involving an investigational study treatment or any 
other type of medical research. 
E 15. Patients unwilling or unable to perform self-monitoring of blood glucose (SMBG), 
complete the patient diary, or comply with study visits and other study procedures as 
required per protocol 
7.2.2 Exclusion criteria related to diabetes history and treatment 
E 16. HbA1c <7% or >10% measured by the central laboratory at screening 
E 17. Fasting plasma glucose >15 mmol/L (270 mg/dL) measured by the central laboratory at 
screening (Visit 1) and confirmed by a repeat test (>15 mmol/L [270 mg/dL]) before 
randomization 
E 18. Previous use of any types of insulin for >1 month (at any time, except for treatment of 
gestational diabetes) 
E 19. Previous use of any antidiabetic medication(s) for >4 months at any time 
E 20. History of DKA or nonketotic hyperosmolar coma within 12 weeks prior to the Screening 
Visit 
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7.2.3 Exclusion criteria related to the current knowledge of sotagliflozin  
E 21. Pregnant (confirmed by serum pregnancy test at the screening) or breast-feeding women 
E 22. Women of childbearing potential (WOCBP) not willing to use highly effective method(s) 
of birth control during the study treatment period and the follow-up period, or who are 
unwilling or unable to be tested for pregnancy (see contraceptive guidance in Appendix 
A), during the study  
E 23. Mean of 3 separate blood pressure measurements >180 mmHg (SBP) or >100 mmHg 
(diastolic blood pressure [DBP]) 
E 24. History of hypertensive emergency within 12 weeks prior to Screening (1) 
E 25. History of gastric surgery, including gastric banding, within 3 years or inflammatory bowel 
disease 
E 26. Difficulty swallowing such that the patient cannot take the IMP 
E 27. Known allergies, hypersensitivity, or intolerance to SGLT2 inhibitor or any inactive 
component of sotagliflozin or placebo (ie, microcrystalline cellulose, croscarmellose 
sodium [disintegrant], talc, silicone dioxide, and magnesium stearate [nonbovine]), unless 
the reaction is deemed irrelevant to the study by the Investigator 
E 28. Laboratory findings with the central lab tests at Visit 1 
- 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x the upper 
limit of the normal laboratory range (ULN) 
- 
Total bilirubin >1.5 x ULN (except in case of Gilbert’s syndrome) 
- 
Neutrophils <1500/mm3 (or according to ethnic group; see Appendix E for details) 
and/or platelets <100 000/mm3 
- 
Amylase and/or lipase >3 x ULN 
E 29. Severe renal disease as defined by eGFR of <30 mL/min/1.73m² at screening by the 
4 variable Modification of Diet in Renal Disease (MDRD) equation  
E 30. Any country-related specific regulation that would prevent the patient from entering the 
study (eg, individuals committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities). 
7.2.4 Additional exclusion criteria during or at the end of the Run-in phase before 
Randomization 
E 31. Informed consent withdrawal before randomization (patient who is not willing to continue) 
or patient fails to return. 
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E 32. Any clinically significant abnormality identified on physical examination, laboratory tests, 
ECG or vital signs at the time of Screening or any AE during Screening period which, in 
the judgment of the Investigator or any Sub-investigator, would preclude safe completion 
of the study or constrains efficacy assessment. 
E 33. Patients insufficiently compliant during Run-in phase. Noncompliance will be based on 
tablet count (<80%) or based on the opinion of the Investigator. 
E 34. Lower extremity complications (such as skin ulcers, infection, osteomyelitis, and 
gangrene) identified during the Screening period, and still requiring treatment at 
Randomization. 
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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: 
- 
Placebo kits: 76 placebo tablets 
- 
Sotagliflozin 200 mg kits: 38 placebo tablets and 38 sotagliflozin 200 mg tablets 
- 
Sotagliflozin 400 mg kits: 76 sotagliflozin 200 mg tablets 
Table 1 provides a summary of each IMP.  
Table 1 – Summary of investigational medicinal products 
IMP: 
Sotagliflozin 200 mg 
Sotagliflozin 400 mg 
Placebo 
Name of the IMPs 
Sotagliflozin (SAR439954) 
Sotagliflozin (SAR439954) 
Placebo 
Pharmaceutical 
form 
Sotagliflozin (SAR439954) 
will be supplied as 200 mg 
tablets 
Placebo will be supplied as 
tablets (identical to 
sotagliflozin in appearance) 
Sotagliflozin (SAR439954) 
will be supplied as 200 mg 
tablets 
Placebo will be supplied as 
tablets (identical to 
sotagliflozin in appearance)  
Dose, timing and 
route of 
administration 
One sotagliflozin 200 mg 
tablet, and one placebo 
tablet, taken orally once daily, 
before first meal of the daya 
Two sotagliflozin 200 mg 
tablets, taken orally once 
daily, before first meal of the 
daya 
Two placebo tablets, taken 
orally once daily, before first 
meal of the daya 
Duration of 
treatment 
26 weeks following 
randomization. 
26 weeks following 
randomization. 
26 weeks following 
randomization. 
Storage conditions  
Store between +15°C and 
+30°C (59°F and 86°F) 
Store between +15°C and 
+30°C (59°F and 86°F) 
Store between +15°C and 
+30°C (59°F and 86°F) 
a On study visit days occurring on Day 1 (Visit 3) and Week 26 (Visit 9), IMP should be administered according to the 
schedule outlined in Appendix B. 
IMP: Investigational medicinal product 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
Non-IMP treatment is defined as the rescue medication(s) that will be used to treat hyperglycemia 
when a patient’s hyperglycemia reaches the rescue threshold (see Section 8.2.1 for details).  
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8.2.1 Rescue therapy 
The threshold values are defined as follows, depending on study period: 
Routine fasting SMBG (see Section 9.2.1.6) and central laboratory alerts on FPG are set up to 
ensure that glycemic parameter results remain under predefined thresholds.  
• To compare sotagliflozin 400 mg and 200 mg doses versus placebo with respect to change 
from Baseline for the following endpoints: 
• To compare sotagliflozin 200 mg versus placebo for:  
• To compare sotagliflozin 400 mg and 200 mg doses with placebo in the use of rescue 
medications for hyperglycemia  
• To assess plasma concentrations of sotagliflozin and its 3-O-glucuronide metabolite in 
each sotagliflozin treatment group 
• HbA1c at Screening (≤8%, >8%) 
• SBP at Screening (<130 mmHg, ≥130 mmHg)  
• Sotagliflozin 400 mg as two 200 mg tablets, once daily  
• Placebo as two placebo tablets (identical to sotagliflozin in appearance), once daily 
• Review of accumulating clinical study safety data by treatment 
• Making a recommendation to the Sponsor regarding the study following each meeting 
• Run in kit containing 1 wallet of 34 placebo tablets for the Run-in phase 
• Treatment kit containing 2 wallets of 38 tablets each will be dispensed as needed for the 
duration of the treatment period: 
• FPG >270 mg/dL (15.0 mmol/L) from Randomization up through the scheduled Week 8 
visit 
• FPG >240 mg/dL (13.3 mmol/L) after the Week 8 visit up through the scheduled Week 12 
visit 
• FPG >200 mg/dL (11.1 mmol/L) after the Week 12 visit through the end of the 26-week 
Treatment Period  
• If one fasting SMBG value exceeds the specific glycemic limit on one day, the patient 
checks it again during the two following days. If all the values in three consecutive days 
exceed the specific limit, the patient should contact the Investigator and a central 
laboratory FPG measurement be performed as soon as possible, preferably within 7 days, 
to confirm the hyperglycemia.  
• Upon receipt of a central laboratory rescue alert, a central laboratory re-test must be 
completed and confirmed as exceeding the threshold for rescue before rescue therapy is 
initiated. The re-test confirmation should be performed as soon as possible, but within 
7 days of receipt, by unscheduled visit.  
• The increased FPG has been tested at a fasting status (ie, no food intake for ≥8 hours) 
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• Investigational medicinal product is given at the planned dose 
• There is no intercurrent disease, which may jeopardize glycemic control (eg, infectious 
disease) 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
• Assess plasma glucose in fasting condition (ie, after at least 8 hours fast) 
• Initiate an evaluation and treatment of intercurrent disease (to be reported in 
AE/concomitant medication parts of the e-CRF and the medical record) 
• Stress the absolute need to be compliant with treatment 
• Organize a specific interview with the patient and a Registered Dietician or other qualified 
nutrition professional to reinforce the absolute need to be compliant with diet and lifestyle 
recommendations, and schedule a FPG assessment at the next visit. 
In the event that a confirmatory FPG exceeds the threshold, the Investigator should ensure that no 
reasonable explanation exists for insufficient glucose control and in particular that: 
If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider not initiating rescue medication and should undertake appropriate action, ie: 
If none of the above mentioned reasons can be found, or if appropriate action fails to decrease 
FPG under the threshold values, rescue medication may be introduced. 
Initiation of open-label rescue medication(s) to treat hyperglycemia will be at the discretion of the 
Investigator and in accordance with local standard of care and prescribing practice; except for 
SGLT2 inhibitors, any approved medication(s) including oral antidiabetic drugs or insulin can be 
prescribed to treat the hyperglycemia. The patient continues the study treatment (blinded) and 
stays in the study in order to collect efficacy and safety information. The planned visits and 
assessments should occur until the last scheduled visit. For patients with renal impairment, 
contraindications to antihyperglycemic drugs should be taken into consideration. If a patient 
requires glycemic rescue, the IMP received during the randomized, double-blind Treatment 
Period should continue and must remain blinded until the end of the study. 
Rescue therapy is considered a noninvestigational medicinal product (NIMP). Rescue therapy is 
to be reported in the e-CRF. This information should include specific drug name, dose, route of 
administration, and frequency. 
If not covered by health insurance, the cost of the rescue therapy will be reimbursed by the 
Sponsor where permitted by local regulations. 
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8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
To maintain blinding sotagliflozin and placebo tablets and packaging will be blinded and 
indistinguishable. 
During the double-blind Treatment Period each treatment package will be labeled with a number, 
which is generated by a computer program from Sanofi. Investigators will not have access to the 
randomization (treatment) code except under circumstances described in Section 8.3.2. 
The randomization and the treatment allocation will be performed centrally by an IRT. The study 
biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the patient 
randomization list from which it allocates treatment arms to the patients. 
Fasting glucose (plasma or serum), HbA1c, and PPG will be masked to study sites and patients 
after randomization and until study end. To prevent partial unblinding, UGE and GCR results will 
be masked to study sites and patients, and the central laboratory urine dipstick will not include the 
measurement of urine glucose. 
The CEC members will perform adjudication in a blinded manner. 
8.3.2 Randomization code breaking during the study 
In case of an AE, the randomization code should only be broken in circumstances when 
knowledge of the IMP is required for treating the patient.  
Code breaking can be performed at any time by using the proper module of the IRT and/or by 
calling any other phone number provided by the Sponsor for that purpose. Code breaking can be 
performed by a local study Investigator, sponsor physician or healthcare professional with direct 
responsibility for patient care. If the blind is broken, the Investigator should document the date, 
time of day, and reason for code breaking. The identity of the unblinded personnel, how the code 
was broken, and the treatment kit number should also be recorded. The Sponsor should also be 
informed. If the code is broken by the Investigator (or other medical doctor in an emergency 
situation), the patient must be withdrawn from IMP administration.  
Randomization code breaking will also be performed during the analysis of the Pharmacokinetic 
plasma concentration samples. Only the Project manager and lead scientist at the Bioanalytical 
laboratory will have access to the randomization code to allow for the sorting of the sotagliflozin 
plasma samples. The Bioanalytical lab and responsible personnel will follow the standard 
procedures to ensure the protection of the blind within the Sponsor’s clinical team. The 
randomization code or the individual analytical results will not be disclosed to any clinical team 
personnel prior to the database lock. 
Refer to Section 10.5 for suspected unexpected serious adverse drug reaction unblinding by the 
Sponsor. 
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Treatment labels will indicate the treatment number (used for treatment allocation and reported in 
the e-CRF). 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures. 
Control of IMP storage conditions, especially control of temperature and instructions for handling 
the Sanofi compound should be managed according to the rules provided by the Sponsor. 
The expiry date and storage conditions are written on the IMP labels. The IMP should be stored 
between 15°C and 30°C (59°F and 86°F) 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMPs will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor or Delegate. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor or Delegate, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for 
direct-to-patient shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in any 
other manner. 
8.7.1 Treatment accountability and compliance 
Accounting and compliance for IMPs will be performed at Visit 3 and all subsequent visits.  
The Investigator will check the compliance to the study treatments based on the patient diary and 
will then complete the appropriate Site treatment and patient treatment log forms. Returned IMP 
should be counted by site staff. In addition the dosing information will be recorded on the 
appropriate pages of the e-CRF. 
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If compliance is inadequate as determined by the Principal Investigator (PI), patients will be 
trained again and mentored. If suboptimal compliance continues after training and mentoring, 
patients may be discontinued at the discretion of the PI after discussion with the Sponsor’s 
medical monitor.  
8.7.2 Return and/or destruction of treatments 
Patients are to return all IMP (unused, in-use or used wallet[s]) at each on-site visit (see 
Section 1.2).  
At Visit 4 (Week 1), because no IMP re-supply is planned during this visit, patients will be sent 
home after this visit with the in-use wallet(s) dispensed at randomization. 
Patients are to return all the used, in-use and unused IMP at Visit 9 (or final assessment 
on-treatment visit in case of permanent premature discontinuation).  
All used, partially-used or unused IMPs will be retrieved by the Sponsor or Delegate. A detailed 
site and patient treatment log of the returned IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
The IMP includes placebo, sotagliflozin 400 mg and sotagliflozin 200 mg. 
All concomitant medications should be documented on the Medications page of the e-CRF. This 
includes all non–IMP treatments that are taken by the patients at any time during the clinical 
study, beginning at Visit 1. 
Additionally, all medications taken in the 3 months prior to Visit 1 and prior use of SGLT2 
inhibitors should be reported.  
8.8.1 Prohibited prior and concomitant medications 
During the study treatment period, the following medications are prohibited: 
• Initiation of any antidiabetic agents, including oral or injectable antihyperglycemic agents 
other than the IMP is not allowed before the rescue therapy 
• Systemic use of glucocorticoids is not allowed for more than 10 consecutive days (topical, 
ophthalmic, nasal spray or inhaled applications are allowed) 
• Initiation of any weight loss drugs (eg, phentermine, orlistat)  
• Investigational medicinal products in any other clinical study 
• SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin) are not allowed for 
rescue 
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Note: short term use (< 10 consecutive days) of the prohibited medication, eg, short-acting insulin 
for treatment of acute illness or surgery is allowed. 
Reduction of digoxin dose should be considered because sotagliflozin acts as a weak P-gp 
inhibitor and increases systemic exposure to digoxin. Patients taking sotagliflozin with 
concomitant digoxin should have digoxin concentrations monitored and doses reduced as needed. 
In addition, other P-gp substrates may be affected and the labels of P-gp substrate drugs should be 
consulted with regards to monitoring and dose adjustments. 
Other medications which are unlikely to interfere with the PK or PD of the IMP or confound 
interpretation of the study endpoints are allowed as needed and following discussion between the 
Investigator and the Sponsor. However, doses of chronically administered medicines should be 
kept fixed during the trial if at all possible. 
After premature permanent discontinuation of the IMPs, any treatments (other than SGLT2 
inhibitors) are permitted, as deemed necessary by the Investigator. 
The dose of all antihypertensive agents should be kept constant during the 12 weeks following 
randomization and no antihypertensive agents should be added or withdrawn for the 12 weeks 
following randomization unless it is considered necessary for safety reasons. 
8.8.2 Concomitant diabetes therapy 
Non-IMP treatment is defined as the rescue medication(s) that will be used to treat hyperglycemia 
when a patient’s hyperglycemia reaches the rescue threshold. Except for SGLT2 inhibitors, any 
approved medication(s) including oral antidiabetic drugs or insulin can be prescribed at the 
Investigator’s discretion to treat the hyperglycemia. The regimen of the rescue medications will be 
in accordance with local standard of care and prescribing practice. 
8.9 
POSTSTUDY TREATMENT 
Because sotagliflozin may reduce BP, adjustment of antihypertensive medication may be needed 
during the study in patients with hypertension. Conversely, monitoring for an increase in BP 
should be performed after withdrawal of study medication. If the BP is elevated after withdrawal 
of study treatment, the Investigator should consider adding or adjusting antihypertensive 
medication. 
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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 
• Comparison of sotagliflozin 400 mg versus placebo in change from Baseline to Week 26 
in HbA1c (%).  
9.1.2 Secondary efficacy endpoints 
The continuous secondary efficacy endpoints are: 
• Comparison of sotagliflozin 400 mg versus placebo for:  
- 
Change from Baseline to Week 26 in 2-hour PPG following a MM 
- 
Change from Baseline to Week 26 in FPG 
- 
Change from Baseline to Week 26 in body weight 
- 
Change from Baseline to Week 12 in SBP for patients with baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all patients 
- 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
• Comparison of sotagliflozin 200 mg versus placebo for:  
- 
Change from Baseline to Week 26 in HbA1c 
- 
Change from Baseline to Week 26 in 2-hour PPG following an MM 
- 
Change from Baseline to Week 26 in body weight 
- 
Change from Baseline to Week 12 in SBP for all patients 
9.1.3 Other efficacy endpoints 
Comparison of sotagliflozin 400 mg and 200 mg doses versus placebo for: 
• Change from Baseline to Week 12 in SBP for patients with baseline SBP <130 mmHg 
• Changes from Baseline to Week 12 in DBP 
• Proportion of patients achieving SBP <130 mmHg for those with Baseline 
SBP ≥130 mmHg 
• Proportion of patients achieving DBP <80 mmHg for those with Baseline DBP ≥80 mmHg 
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• Change from Baseline in: 
- 
Urine ACR, UGE, and urine GCR 
- 
Serum creatinine 
- 
eGFR 
• Proportion of patients with reduction in body weight by ≥2%, ≥5%, and ≥10% from 
Baseline  
• Change from Baseline to Week 26 in SBP for all patients and for patients with Baseline 
SBP ≥130 mmHg 
• Proportion of patients requiring rescue for hyperglycemia 
Comparison of sotagliflozin 200 mg versus placebo for: 
• Change from baseline in FPG at Week 26 
• Change from baseline in SBP at Week 12 for patients with Baseline SBP ≥130 mmHg 
• Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
9.1.4 Assessment methods of efficacy endpoints 
9.1.4.1 HbA1c 
Hemoglobin A1c will be assessed at Screening (Visit 1), Baseline (Visit 3), and all on-site visits 
during the double-blind treatment period with the exception of Week 1 (Visit 4). 
For the eligibility and efficacy assessments of the study, HbA1c is measured by a certified level I 
“National Glycohemoglobin Standardization Program” central laboratory to allow estimation of 
the change from Baseline to Week 26 in HbA1c and the proportion of patients with HbA1c 
<6.5%, <7.0% at Week 26. 
If a patient needs to receive rescue antidiabetic medication, assessment of HbA1c should be 
performed before the introduction of the rescue medication. 
9.1.4.2 Postprandial glucose and mixed meal tolerance test 
Patients will undergo assessment of PPG at Visit 3 (Baseline) and Visit 9 (Week 26) via a mixed 
meal tolerance test (MMTT) to allow estimation of change from Baseline to Week 26 in 2-hour 
PPG following a MM. Full details of the MMTT procedure at Baseline and Week 26 are 
presented in Appendix B. 
At Visit 3 (Baseline) and Visit 9 (Week 26), PPG values will be assessed by MMTT at baseline 
(fasting) and 2 hours after consuming a standard mixed liquid breakfast meal. 
The first dose of double-blind IMP on Day 1 (Baseline; Visit 3) will be given after completion of 
the 2-hour PPG collection. For the Week 26 standardized MM, the patient should take the dose of 
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double-blind IMP immediately after the fasting blood samples are obtained, and approximately 
30 minutes before ingestion of the standardized MM begins. 
Plasma concentration samples at Week 26 should be taken at the same times as the fasting blood 
sample and the 2-hour central laboratory plasma PPG collection (see Section 9.3.1.1). 
The composition and the quantity of the standard mixed liquid breakfast meal must be identical 
throughout the study; see Appendix B for further details.  
All patients should undergo the standardized MMTT at Visit 9 (Week 26), including those 
rescued before Visit 9. 
In case of permanent discontinuation of the treatment with IMP before Visit 9 (Week 26), every 
effort will be made to have the patient return to the site at the time of their Visit 9 (Week 26); 
however the MMTT should not be performed at this or any other visit following a Premature EOT 
visit. 
On the days of the MMTT, patients will come to the investigational site in the morning, in fasting 
conditions for at least 8 hours and must not eat any food or drink, except water, before the 
scheduled standardized meal test.  
The exact times of the IMP administration, standard mixed liquid breakfast meal intake, and the 
blood draws are to be documented. 
9.1.4.3 Fasting plasma glucose measurement 
Plasma glucose is measured in the fasting state at Screening (Visit 1) and all on-site visits during 
the treatment period. For the eligibility and efficacy assessments of the study, FPG is measured at 
a central laboratory to allow estimation of change from Baseline to Week 26 in FPG. 
9.1.4.4 Body weight measurement 
Body weight is measured at all on-site visits to allow the estimation of change from Baseline to 
Week 26 in body weight and reduction in body weight by ≥2%, ≥5%, and ≥10% from Baseline. 
Body weight should be obtained with the patient wearing undergarments or very light clothing 
and no shoes, and with an empty bladder. The same scale should be used throughout the study, 
and calibrated on a regular basis as recommended by the manufacturer. 
The same scale should be used throughout the study, and calibrated on a regular basis as 
recommended by the manufacturer. Calibration should be documented in source documents. The 
use of balance scales is recommended. The floor surface on which the scale rests must be hard and 
should not be carpeted or covered with other soft material. The scale should be balanced with both 
weights at zero and the balance bar aligned. The patient should stand in the center of the platform 
as standing off-center may affect measurement. The weights are moved until the beam balances 
(the arrows are aligned). The weight is read and recorded in the e-CRF and Source Data. Self-
reported weights are not acceptable; patients must not read the scales themselves. 
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9.1.4.5 Blood pressure measurements 
Systolic BP and DBP will be assessed at all on-site visits. Blood pressure measurements must be 
taken as described in Section 9.2.1.4 with details provided in Appendix D. 
9.1.4.6 Kidney function parameter measurement 
Urine albumin, creatinine and glucose, and serum creatinine are assessed at Baseline (Visit 3) and 
all subsequent on-site visits. A central laboratory will analyze samples and estimate change from 
Baseline in urine ACR, UGE, urine GCR, serum creatinine and eGFR (by the 4 variable MDRD 
equation). To prevent partial unblinding, UGE and GCR results will be masked to investigational 
sites. 
9.1.4.7 Proportion of patients requiring rescue for hyperglycemia 
The use of rescue medications for hyperglycemia will be assessed and reported throughout the 
treatment period. Routine alerts on FPG will be sent to the Investigator from the central laboratory 
to ensure that glycemic parameter results remain within predefined thresholds. For details and 
further actions should FPG values fall above thresholds, refer to Section 8.2.1. 
9.2 
SAFETY ENDPOINTS 
Assessments for safety include AEs, SMBG, clinical laboratory assessments, physical 
examination, electrocardiogram (ECG), weight, and vital signs. An independent DMC will meet 
on a regular basis to review accumulating clinical trial safety data. 
Adjudication of all deaths, MACE/other selected CV events (MI, stroke, unstable angina leading 
to hospitalization, and heart failure leading to hospitalization), selected renal events, bone 
fracture, and DKA will be performed in a blinded manner by a CEC(s) comprised of experts. 
Details will be provided in the charter of the CEC(s). Further details are available in Section 6.4.2. 
Two expert committees will review all potential cases of DILIs and cases of amputation in a 
treatment-blinded manner to evaluate causality. 
The following safety endpoints will be assessed: 
• Adverse events, AEs leading to discontinuation from the IMP, adverse events of special 
interest (AESIs), Events of Special Interest (EOSIs), SAEs and deaths 
• Hypoglycemia (all, severe, and/or documented symptomatic hypoglycemia) 
• Clinical laboratory results (including fasting lipids; see Section 9.2.1.3), vital signs and 
ECG results 
• Markers of bone and calcium metabolism  
• Markers of intestinal transit and absorption 
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Observation period of safety endpoints 
The observation period of safety data will be divided into 3 segments: 
• The pre-treatment period is defined as the time between the date of the informed consent 
and the first dose of double-blind IMP.  
• The on-treatment period (TEAE period) is defined as the time from the first dose of 
double-blind IMP up to 10 days (1 day for hypoglycemia) after the last dose of 
double-blind IMP, regardless of the introduction of rescue therapy. The 10-day interval is 
chosen based on the half-life of the IMP (approximately 5 times the half-life of 
sotagliflozin) in patients with moderate renal dysfunction.  
• The post-treatment period is defined as the time starting 11 days after the last dose of 
double-blind IMP (after the on-treatment period).  
The baseline value for safety endpoints in the safety population is the last available value (or the 
average of all values for creatinine or eGFR) prior to the first administration of the double-blind 
IMP. 
9.2.1 Assessment methods of safety endpoints 
9.2.1.1 Adverse events 
Adverse events including SAE, AESI and EOSI will be assessed. Refer to Section 10.4 to 
Section 10.6 for details. 
9.2.1.1.1 Adverse Events of Special Interest 
Adverse Events of Special Interest are listed in Section 10.4.1.3, reporting requirements for AESI 
are presented in Section 10.4.4. 
9.2.1.1.2 Events of Special Interest 
Events of Special Interest are separate from AESIs. For a list of events defined as EOSIs and their 
reporting requirements see Section 10.4.1.4 and Section 10.4.5, respectively. 
9.2.1.2 Hypoglycemia 
Hypoglycemia will be assessed from Visit 2 onwards and continue until 4 weeks after the last 
dose of IMP (note: for patients who discontinue treatment before Week 26, safety data will be 
collected until scheduled study end). Patients will also complete the hypoglycemia log (as part of 
the patient diary) from Visit 2 onwards, which will be regularly reviewed by Investigators. See 
Section 10.6.1 for further details. 
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9.2.1.3 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry, 
amylase, lipase, lipid profile) and urinalysis, according to the schedule presented in Section 1.2. 
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. Table 2 lists the hematology, clinical 
chemistry and other blood safety parameters to be assessed by the central laboratory. 
Alerts to the Investigator are set up for specific laboratory abnormalities. Investigators should 
review these alerts and follow-up if needed as per his/her medical judgement. Re-tests at central 
laboratory are acceptable if needed.  
In addition, for WOCBP a serum pregnancy test is performed at Screening and urine pregnancy 
tests are taken at all on-site visits during the double-blind Treatment Period excluding Visit 4 
(Week 1). Any positive urine test results must be confirmed by a serum pregnancy test. The 
Investigator may perform additional tests at their discretion or as required by local regulations. 
For women of nonreproductive potential (Appendix A), follicle-stimulating hormone (FSH) 
and/or estradiol levels should be tested if the definition of postmenopausal or premenopausal 
cannot be satisfied, eg, no medical document of hysterectomy or cessation of menses <12 months 
without an alternative medical cause. 
Table 2 – Serum chemistry parameters 
Clinical chemistry 
Hematology 
Other blood parameters 
Sodium 
Complete blood count (CBC) 
Lipid profile 
Potassium 
Differential 
Total cholesterol (TC) 
Chloride 
Platelet count 
High-density lipoprotein cholesterol (HDL-C) 
Carbon dioxide (bicarbonate) 
Hemoglobin 
Low-density lipoprotein cholesterol (LDL-C) will 
be calculated by Friedwald equation 
Blood urea nitrogen (BUN) 
Hematocrit 
Non-HDLC will be calculated as the difference 
between TC and HDLC 
Creatinine (eGFR will be calculated) 
 
Triglycerides (TG) 
Glucose (serum) 
 
Blood Markers of Intestinal Transit and 
Absorptiona 
Alanine aminotransferase (ALT) 
 
Vitamins: B6, B12, K, E, A 
Aspartate aminotransferase (AST) 
 
Serum folate 
Total bilirubin (TB) 
 
Ferritin 
Alkaline phosphatase (ALP) 
 
Markers of bone and calcium metabolismb 
Uric acid 
 
Calcium 
Calcium 
 
25-hydroxyvitamin D 
Phosphorus 
 
1,25-dihydroxyvitamin D 
Total protein 
 
Phosphorus 
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Clinical chemistry 
Hematology 
Other blood parameters 
Albumin 
 
Parathyroid hormone (PTH) 
Magnesium 
 
Markers of bone resorption: N-terminal telopeptide 
(NTX), beta-C-terminal telopeptide (β-CTX-1) 
Creatine phosphokinase (CPK) 
 
Marker of bone formation: type 1 procollagen 
N-terminal (P1NP) 
Lactic acid dehydrogenase (LDH)  
 
 
Amylase 
 
 
Lipase 
 
 
All assessments to be performed by central laboratory. 
All assessment measured in serum. 
a To be collected at Baseline (Visit 3), Week 26 (Visit 9), and Follow-up Visit (Visit 10). 
b To be collected at Baseline (Visit 3) and Week 26 (Visit 9). Urine markers of bone and calcium metabolism are listed in Section 9.2.1.3.1. 
9.2.1.3.1 Urinalysis 
Urinalysis (urine dipstick with microscopy) by central laboratory will be performed at Screening 
(Visit 1), Baseline (Visit 3) and Week 26 (Visit 9). To prevent partial unblinding, UGE results 
will be blinded to investigational sites and patients, and the central laboratory urine dipstick will 
not include the measurement of urine glucose. Central urinalysis includes: 
• Urine dipstick includes: specific gravity, pH, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, and leukocyte esterase 
• Urine microscopy includes, but is not limited to: detection of formed cellular elements, 
casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment 
In the event of abnormal urinalysis findings suspicious of urinary tract infection, urine culture 
should be performed. Positive urine culture determination will be based upon the criteria of the 
reporting laboratory. 
If the urine dipstick is positive for blood, the central laboratory will perform reflexive testing to 
include microscopy. Additional testing will be performed according to the judgment of the 
Investigator. Referral to urology/urologic evaluation is recommended for new or unexplained 
cases of confirmed hematuria (urology/urologic evaluation is not required where hematuria is 
considered to be related to diabetic nephropathy). 
In addition, urine albumin, calcium, glucose and creatinine will be assessed at Baseline (Visit 3) 
and all subsequent on-site visits. 
Urine markers of bone and calcium metabolism will be assessed at Baseline (Visit 3), and 
Week 26 (Visit 9), and include: calcium and phosphorus. Serum markers of bone and calcium 
metabolism are listed in Table 2. 
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9.2.1.4 Vital signs and physical exam 
A complete physical exam (including sitting blood pressure and heart rate, temperature and 
respiratory rate) will be performed at Visit 1 (Screening) and Visit 9 (Week 26); abbreviated 
physical exams (including sitting blood pressure and heart rate) will be performed at all other 
on-site visits. The abbreviated physical exam should focus on cardiac and respiratory systems, as 
well as any areas important for assessment of AEs if necessary. Three separate seated BP and 
heart rate measurements should be taken with at least 1 minute between measurements following 
a 5-minute rest period, and prior to phlebotomy. Full details and directions for the measurement of 
blood pressure are presented in Appendix D.  
9.2.1.5 Electrocardiogram variables 
The ECG assessment of “normal” or “abnormal” will be analyzed. 
A 12-lead ECG record is performed locally at Screening (Visit 1), Baseline (Visit 3) and Week 26 
(Visit 9). 
The 12-lead ECG should be performed after at least 10 minutes in supine position and prior to the 
morning IMP administration. The Investigator should review the ECG and document the 
interpretation, sign and date it on the ECG print out and report it in the e-CRF. Each ECG trace is 
analyzed in comparison with the screening recorded trace. All original traces are kept as source 
data. 
Note: Any new ECG abnormality should be rechecked for confirmation and reported as 
appropriate for that finding. 
9.2.1.6 Self-monitoring of blood glucose 
A meter for self-assessment of blood glucose will be dispensed at the Run-in visit (Visit 2). In 
addition to home measurements of self-monitored blood glucose, self-monitoring of blood glucose 
will be performed at Run-in (Visit 2) and all subsequent on-site visits. Glucose meters used for 
SMBG display results as plasma glucose concentration. 
Patients will also receive a patient diary at all on-site visits from Visit 1 to Visit 9. The diary will 
be reviewed at all on-site visits from Visit 2 to Visit 10. Self-assessed blood glucose levels will be 
entered in the patient diary. 
Patients will be asked to self-assess blood glucose levels at least 3 times a week from the run-in 
Visit (Visit 2) to Week 26. 
Patients will be requested to self-assess blood glucose levels in the fasted state and whenever they 
experience any illnesses (eg, cold, flu), or symptoms of hyperglycemia or hypoglycemia. 
Symptoms of hypoglycemia may include shakiness, dizziness, sweating, hunger, headache, pale 
skin color, sudden moodiness or behavior changes (such as crying for no apparent reason), clumsy 
or jerky movements, seizure, difficulty paying attention or confusion, or tingling sensations 
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around the mouth. Patients will be instructed to record the presence of absence of hypoglycemic 
episodes or hypoglycemic symptoms in the patient diary provided. 
Patients will also be instructed to record SMBG values that are ≤70 mg/dL (≤3.9 mmol/L) in the 
patient diary. Patients should be instructed to contact the site if fasting SMBG values over 
3 consecutive days are:  
• >270 mg/dL (15.0 mmol/L) from Randomization up through the scheduled Week 8 visit 
• >240 mg/dL (13.3 mmol/L) after the Week 8 visit up through the scheduled Week 12 visit  
• >200 mg/dL (11.1 mmol/L) after the Week 12 visit and through the end of the 26-week 
double-blind Treatment Period 
9.2.1.7 Diabetic ketoacidosis 
Patients will be provided with instructions on how to recognize the symptoms of DKA and 
instructed to contact the site (or seek emergency medical services if after business hours) if these 
symptoms develop. Patients should have a full clinical evaluation with laboratory testing for 
possible DKA by the Investigator or emergency medical services physician. If such evaluation 
and laboratory testing confirm the presence of metabolic acidosis, then appropriate treatment 
should be implemented and the “Possible DKA” e-CRF should be completed. See Appendix C for 
further details. 
9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacokinetics 
The PK endpoint is: 
• Plasma concentrations of sotagliflozin and its metabolite pre-dose at Weeks 4, 18 and 
26 and 2 hours 30 minutes post-dose at Week 26 
9.3.1.1 Sampling time 
At Weeks 4 and 18 (Visits 5 and 8, respectively), blood samples for PK assessment are to be 
drawn with the other laboratory assessments. At Week 26, PK samples should be drawn at 
pre-dose and at 2 hours 30 minutes postdose, immediately after the respective glucose 
assessments during the MMTT. Pharmacokinetic samples (with the exception of the 2 hours 
30 minute sample during the Week 26 MMTT) must be collected before administration of IMP. 
See Table 3 for the identification of samples.  
Table 3 – Samples identification  
Visit 
Week 
Relative to dosing 
PK 
Visit 5 
Week 4 
Pre-dose 
P00 
Visit 8 
Week 18 
Pre-dose 
P01 
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Improvements in FPG and PPG have been observed with sotagliflozin in multiple studies. 
Therefore assessment of both fasting and post-prandial glucose (after a MM) is relevant in this 
study. These 2 parameters are also considered by regulatory agencies to be supportive of efficacy 
of an antidiabetic agent. 
Phase 2 data indicated that sotagliflozin may reduce SBP by 10 to 15 mmHg in patients with 
SBP ≥130 mmHg at baseline, while having no significant effect in patients with SBP 
<130 mmHg, and did not induce hypotension. Since this could be of benefit to patients with T2D, 
this finding is being followed up as a secondary objective in this trial, as well as the potential in 
patients with DBP >80 mmHg. Although effects on BP in Phase 2 data were observed with the 
400 mg dose at 12 weeks, the effects will be examined at Weeks 12 and 26. 
Endpoints for evaluating renal function include eGFR, based on serum creatinine, and urine 
albumin to creatinine ratio as well as routine monitoring of urine via dipstick and microscopy. 
UGE and urine GCR are other valid markers of renal function, and will be assessed at appropriate 
time points in this study. 
Due to potential effects on bone and calcium metabolism, specific biomarkers for bone and 
calcium metabolism will be assessed at regular time points. In view of the SGLT1 inhibitory 
effects in the GI tract, specific markers of intestinal transit and absorption will also be measured. 
The other efficacy and safety assessments in this study are standard, well-established 
measurements for a Phase 3 study evaluating the treatment of T2D in adult participants.  
The length of the study is considered appropriate for detection of the primary endpoint given the 
power estimates (see Section 11). 
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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 10 on-site visits, although optional on-site and/or 
telephone visits can be scheduled at any time for any reason during the study whenever 
considered necessary by the Investigator. 
The patients need to be fasting for on-site visits V1 through V9 (Week -4 through Week 26), 
unless instructed otherwise by the Investigator. Throughout the study, “fasting” is defined as 
8 hours without food. Note: If the patient is not fasting at the visits specified above, the blood 
sample will not be collected and a new appointment should be given to the patient for the 
following day if possible, with instruction to be fasted.   
The Run-in visit can be performed as soon as the results of all screening tests are available and the 
patient is confirmed to be eligible for participation in the study. The visit window for visits V4 
through V10 should occur within ±3 days. If one visit date is changed, the next visit should occur 
according to the original schedule, ie calculated from the date of Baseline visit (Visit 3, Week 0). 
For a complete list of procedures scheduled for each study visit please refer to the Study Flow 
Chart (Section 1.2), which details the procedures to be performed.  
All data obtained during the trial visits will be reviewed by the Investigator and sub-investigators 
who are qualified in treatment of T2D and are trained on the study. 
10.1.1 Screening Period 
The Screening period is up to 4 weeks and includes the Screening Phase and the Run-in Phase. 
10.1.1.1 Screening Phase 
The duration of the Screening Phase is up to 2 weeks and includes only the Screening Visit 1 
(Week -4). The period must be long enough to collect the data to establish whether the patient 
satisfies the inclusion/exclusion criteria. 
Patients will undergo screening assessments at Visit 1 (Week -4) following signing of the ICF. 
Patients who meet the inclusion criteria as noted in Section 7.1 and have no exclusion criteria as 
noted in Section 7.2 will be randomized at Visit 3 (Day 1). 
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• The following laboratory testing (by the central laboratory) 
- 
Fasting plasma glucose 
- 
HbA1c 
- 
Serum pregnancy testing for WOCBP 
- 
Serum FSH and estradiol (for women of nonreproductive potential if definition of 
postmenopausal or premenopausal cannot be satisfied; see Appendix A). 
- 
Hematology 
- 
Clinical chemistry to include amylase and lipase 
- 
Fasting lipids 
- 
Urinalysis (dipstick and microscopy) 
• Patients are instructed to return to the site for Visit 2 (Week -2) in a fasted state.  
10.1.1.2 Run-in Phase (Visit 2, Week -2) 
The Run-in Phase is 2 weeks and includes Visit 2 (Week -2). 
10.1.1.2.1 On-site Visit 2 (Run-in, Week -2) 
The following procedures/assessments will be performed at Visit 2 (Week -2): 
• Measurement of body weight 
• Abbreviated physical examination including vital signs performed after the patient has 
been seated for at least 5 minutes (SBP and DBP, and heart rate). Systolic and diastolic BP 
and heart rate will be assessed 3 times with at least 1 minute between each measurement 
(see Appendix D for details)  
• Diet and exercise instruction 
• Instruction on basic GU hygiene and hydration (See Appendix C) 
• IRT to be notified 
• Patient diary is collected/reviewed. A new diary, including hypoglycemia log (as part of 
the diary), is dispensed and instructions/training are provided 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported, including those occurring 
since Visit 1 
• Run-in kit/placebo is dispensed 
• Blood glucose meter is dispensed and instructions/training is provided  
• Concomitant medication 
• Fasting SMBG is assessed 
• Patients are instructed to return to the site in the fasting state for Visit 3 (Randomization) 
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10.1.2 Double-blind randomized treatment period 
10.1.2.1 Treatment Period (Day 1 to Week 26) 
Upon successful completion of the Run-in Phase, patients will be randomly allocated to either 
sotagliflozin 400 mg, sotagliflozin 200 mg, or placebo for the double-blind treatment period 
lasting 26 weeks. All randomized patients will be followed at regular on-site visits for the duration 
of the treatment period. 
In addition to routine laboratory testing, the following will be performed at specified time points: 
plasma concentrations; markers of intestinal transit and absorption; markers of bone and calcium 
metabolism; urine albumin, calcium, glucose and creatinine.  
The date and time of the last intake of IMP prior to visits where PK samples are taken should be 
recorded by the patient in the patient diary. Patients should be reminded of this at visits preceding 
PK time points to ensure these details are captured. 
In the event of abnormal urinalysis findings suspicious of urinary tract infection, urine culture 
should be performed. Positive urine culture determination will be based upon the criteria of the 
reporting laboratory. 
In addition, PPG will be assessed at Baseline and 2 hours after consuming a standard mixed liquid 
breakfast meal vial a MMTT on Day 1 and at Week 26. On Day 1 the first dose of double-blind 
IMP will be given AFTER completion of the 2-hour PPG collection. For the Week 26 
standardized MM, the patient should take the dose of double-blind IMP immediately after the 
fasting blood samples are obtained, and approximately 30 minutes before ingestion of the 
standardized MM begins. 
10.1.2.1.1 Randomization Visit on Day 1 (Baseline; Week 0; Visit 3) 
The following procedures will be performed at this visit: 
• Exclusion criteria are to be reviewed, including assessment of compliance during Run-in 
Phase 
• Concomitant medications are assessed 
• Measurement of body weight 
• Abbreviated physical examination including vital signs performed after the patient has 
been seated for at least 5 minutes. Systolic and diastolic BP and heart rate will be assessed 
3 times with at least 1 minute between each measurement (see Appendix D for details). 
• IMP accounting and compliance for single-blind placebo Run-in phase 
• IRT is notified and randomization will occur 
• AEs/SAEs/AESIs/EOSIs and hypoglycemia (if any) are reported, including those 
occurring since Visit 2 
• Diet and exercise instruction 
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• Patient diary, including hypoglycemia log, is collected/reviewed and dispensed and 
instructions/training are provided as needed 
• Instruction on DKA symptoms (see Appendix C) is provided 
• Instruction on basic GU hygiene and hydration is provided (see Appendix C) 
• 12-lead ECG, prior to IMP administration 
• Fasting SMBG is assessed 
• Standard MMTT (2-hour PPG measurements) 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose 
- 
HbA1c 
- 
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test) 
- 
Hematology 
- 
Clinical chemistry to include amylase and lipase 
- 
Fasting lipids 
- 
Urinalysis (dipstick and microscopy) 
- 
Urine analysis for albumin, calcium, glucose, and creatinine 
• Additional laboratory testing at this visit: 
- 
Markers of intestinal transit and absorption (vitamins B6, B12, K, E, and A, serum 
folate, and ferritin) 
- 
Markers of bone and calcium metabolism (serum and urinary calcium, serum 
25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum and urinary 
phosphorus, serum PTH, markers of bone resorption [serum NTX, serum β-CTX-1], 
and bone formation [serum P1NP]) 
- 
 
- 
 
• IMP is dispensed 
• Patients are instructed to return to the site in the fasting state for V4 (Week 1). 
• For accountability and compliance purposes, patients are instructed to return to the site 
with their in-use wallet(s) dispensed during Visit 3. 
10.1.2.1.1.1 
On-site visits at Weeks 1, 4, 8, 12, and 18 (Visits 4 to 8) 
The following will be performed at these visits: 
• IRT is notified (all visits except Visit 4) 
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• IMP accounting and compliance 
• Patient diary, including hypoglycemia log, is collected/reviewed and dispensed and 
instructions/training are provided as needed 
• Concomitant medications are assessed 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• Patients are evaluated for glycemic rescue (see Section 9.1.4.7) 
• Measurement of body weight 
• Abbreviated physical examination including vital signs performed after the patient has 
been seated for at least 5 minutes. Systolic and diastolic BP and heart rate will be assessed 
3 times with at least 1 minute between each measurement (see Appendix D for details) 
• Instruction on DKA symptoms (see Appendix C) is provided 
• Instruction on basic GU hygiene and hydration (see Appendix C) 
• Fasting SMBG is assessed 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose (for all visits) 
- 
HbA1c (all visits except Visit 4) 
- 
Urine pregnancy testing for WOCBP (all visits except Visit 4; any positive urine test 
results must be confirmed by a serum pregnancy test) 
- 
Hematology (Visit 7 only) 
- 
Clinical chemistry to include amylase and lipase (all visits except Visit 4) 
- 
Fasting lipids (all visits except Visit 4) 
- 
Urine analysis for albumin, calcium, glucose, and creatinine (for all visits) 
• Pre-dose plasma concentration samples are collected and sent to the appropriate laboratory 
(Visits 5 and 8 only) 
• Patients should be reminded to record the time of IMP intake on the day before their next 
visit (reminders at Visits 4, 7 and 8 only) 
• IMP is dispensed (all visits except Visit 4) 
• Patients are instructed to return to the site in the fasting state for their next visit. 
• For accountability and compliance purposes, patients are instructed to return to the site 
with their wallet(s) at the next visit. 
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10.1.2.1.2 On-site Visit 9 at Week 26 – End-of-treatment 
The following will be performed at this visit: 
• IRT to be notified for EOT (if EOT visit is also last visit, IRT should be notified for end of 
study) 
• IMP accounting and compliance  
• Patient diary, including hypoglycemia log, is collected/reviewed and dispensed and 
instructions/training are provided as needed 
• Concomitant medications are assessed 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• Patients are evaluated for glycemic rescue (see Section 9.1.4.7) 
• Measurement of body weight 
• Complete physical examination including vital signs (SBP and DBP, temperature, heart 
rate, and respiratory rate). Three separate seated BP and heart rate measurements should be 
taken with at least 1 minute between measurements following a 5-minute rest period, and 
prior to phlebotomy (see Appendix D for details of BP procedure) 
• Diet and exercise instruction is provided 
• Instruction on DKA symptoms is provided 
• Instruction on basic GU hygiene and hydration is provided (see Appendix C) 
• 12-lead ECG, prior to the IMP administration 
• Fasting SMBG is assessed 
• Standard MMTT (2-hour PPG measurements) (not to be performed if patient has 
discontinued prior to Premature EOT visit; see Section 10.3.4) 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose 
- 
HbA1c 
- 
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test) 
- 
Hematology 
- 
Clinical chemistry to include amylase and lipase 
- 
Fasting lipids 
- 
Urinalysis (dipstick and microscopy) 
- 
Urine analysis for albumin, calcium, glucose, and creatinine 
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• Additional laboratory testing at this visit: 
- 
Markers of intestinal transit and absorption (vitamins B6, B12, K, E, and A, serum 
folate, and ferritin) 
• The patient is instructed to schedule future follow-up with their own personal physician. 
10.2 
DEFINITION OF SOURCE DATA 
10.2.1 Source data to be found in patient’s file 
Evaluations recorded in the e-CRF must be supported by appropriately signed source 
documentation related but not limited to the following: 
• Agreement and signature of ICF with the study identification 
• Study identification (name) 
• Patient number, confirmation of randomization, treatment batch number, dates and doses 
of study medication administration 
• Medical, surgical, diabetes history, including information on: 
- 
Demography, inclusion and exclusion criteria 
- 
Last participation in a clinical trial 
- 
Contraception method for WOCBP 
- 
Previous and concomitant medication 
• Dates and times of visits and assessments including examination results 
• Vital signs, height, body weight, Laboratory reports, Investigation results (eg, ECG traces, 
imaging reports) 
• Adverse events and follow-up: 
- 
In case of SAE, the site should file in the source documents at least copies of the 
hospitalization reports and any relevant examination reports documenting the follow- 
up of the SAE. 
• Date of premature treatment discontinuation (if any) and reason 
• Date of premature study discontinuation (if any) and reason 
• Nursing notes 
• Dietician’s notes 
• Physician’s notes 
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10.2.2 Source data verification requirements for screen failures 
For screen failure patients, the following source data must be verified: patient's identification 
details, the informed consent signed by the patient, the study identification (name), dates of study 
visits and the main reasons for screen failure. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the e-CRF. In any case, the 
patient should remain in the study and followed for the remainder of the study duration to collect 
vital safety status and endpoint data. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Lower extremity complications (such as skin ulcers, infection, osteomyelitis, and gangrene) 
requiring treatment should lead to temporary discontinuation of IMP. Reinitiating treatment with 
the IMP will be done under close and appropriate clinical and/or laboratory monitoring once the 
Investigator will have considered according to his/her best medical judgment that the occurrence 
of the concerned event was unlikely to be related to the IMP. 
It is in the interest of the patient to monitor blood glucose during the temporary discontinuation 
period, therefore regular determination of SMBG is to be performed and documented. 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the e-CRF when considered as confirmed. 
Temporary treatment discontinuation decided by the Investigator corresponds to more than 1 dose 
not administered to the patient. 
Use of any different anti-hyperglycemic medication during the time of temporary treatment 
discontinuation (ie, insulin during a hospitalization) is recorded as concomitant medication with 
the name and doses recorded in the e-CRF. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
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10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP at any time for any reason or this may be 
the Investigator’s decision. Patients should discuss stopping study medication with the site before 
doing so in order that questions can be addressed, glycemic therapy adjusted, and a follow-up 
assessment arranged. All efforts should be made to document the reasons for treatment 
discontinuation and this should be documented in the e-CRF. 
The following reasons lead to permanent discontinuation: 
• At the patient’s own request (ie, withdrawal of consent for treatment) 
• If, in the Investigator's opinion, continuation with the administration of the study treatment 
would be detrimental to the patient's well-being 
• Inter-current condition that requires permanent discontinuation of the study treatment as 
long as the abnormality persists and if the casual relationship of the concerned event and 
the IMP is possible (according to the Investigator’s best medical judgment) 
• Pregnancy (in female patients) 
• Specific request of the Sponsor 
Any abnormal laboratory value will be rechecked immediately for confirmation before making a 
decision of permanent discontinuation of the IMP for the concerned patient. 
For patients who prematurely discontinue the IMP, the assessments planned at EOT visit 
(Section 10.1.2.1.2) will be performed at the Premature EOT Visit, scheduled preferably prior to 
treatment discontinuation or as soon as possible after time of discontinuation the latest at the next 
on-site visit). Reason for IMP discontinuation will be clearly specified. This Premature EOT 
assessment may occur at a regularly scheduled visit or at an unscheduled visit. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Every effort should be made to maintain patients in the study. Patients should be followed up 
according to the study procedures as specified in this protocol up to the scheduled date of study 
completion, or up to recovery or stabilization of any AE to be followed-up as specified in this 
protocol, whichever comes last. 
If a patient prematurely discontinues study treatment, a Premature EOT visit (see 
Section 10.1.2.1.2) should be scheduled prior to treatment discontinuation, if possible. If not 
possible, the Premature EOT should be scheduled as soon as possible after treatment 
discontinuation. In the case of early discontinuation, no sample for measuring plasma 
concentration should be taken at the Premature EOT visit, nor at any subsequent visits. For 
patients who discontinue treatment but remain in the study, the remaining visits should occur as 
scheduled where possible. The IRT should be notified of EOT. 
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
10.4.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN 
- 
Suicide attempt or any event suggestive of suicidality 
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- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Cancers diagnosed during the study or aggravated during the study 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study  
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
The AESIs for this study: 
• Pregnancy of a female patient entered in a study as well as pregnancy occurring in a 
female partner of a male patient entered in a study with IMP/NIMP.  
- 
Pregnancy occurring in a female patient included in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.4.1.2), 
- 
In the event of pregnancy in a female patient, IMP should be discontinued,  
- 
Follow-up of the pregnancy in a female patient or in a female partner of a male patient 
is mandatory until the outcome has been determined (see Appendix A). 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
A symptomatic overdose (accidental or intentional) with the IMP/NIMP is an event 
suspected by the Investigator or spontaneously notified by the patient and resulting in 
clinical symptoms and/or signs accompanied by administration of more than twice the 
intended daily dose within a 24-hour period. It will be recorded in the e-CRF as an 
AESI with immediate notification “Symptomatic OVERDOSE (accidental or 
intentional)” in all cases and will be qualified as an SAE only if it fulfills the SAE 
criteria. 
(Please note that an Asymptomatic overdose with the IMP/NIMP, accidental or 
intentional, defined as administration of more than twice the intended daily dose 
within a 24-hour period, without clinical symptoms and/or signs, either suspected by 
the Investigator or spontaneously notified by the patient, not based on accountability 
assessment. It will be recorded as an AE “Asymptomatic OVERDOSE, accidental or 
intentional.”) 
• ALT increase >3X ULN (refer to related flow chart in Appendix E) 
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10.4.1.4 Events of Special Interest 
An EOSI is a serious or non-serious AE of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring may be appropriate. Such events 
may require further investigation in order to characterize and understand them. These events 
should be reported on the specific e-CRF page (where applicable) and will only qualify for 
expedited reporting when serious (fulfilling SAE criteria). 
The EOSIs for this study are: 
• Major adverse cardiovascular events (MACE [cardiovascular death, myocardial infarction, 
or stroke]) and other specific CV events (eg, heart failure leading to hospitalization) 
• Severe hypoglycemia (see Section 10.6.1) 
• Genital mycotic infections (to include vulvovaginal candidiasis in females and candidal 
balanitis in males) 
• Urinary tract infections 
• Clinically relevant volume depletion and events related/possibly related to volume 
depletion 
• Diarrhea 
• Pancreatitis 
• Bone fractures 
• Venous thrombotic events, to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism) 
• Diabetic ketoacidosis 
• Renal events, to include 50% decline in eGFR, end stage kidney disease, renal death 
• Malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, 
prostate, and thyroid cancer) 
• Adverse event leading to an amputation 
10.4.2 General guidelines for reporting adverse events 
• All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the ICF until the end of the study as defined by the protocol for that patient, 
are to be recorded on the corresponding page(s) or screen(s) of the e-CRF. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s).  
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• In this study, the use of concomitant medications including antidiabetic medications may 
make it difficult to assess the causal relationship, particularly for hypoglycemia. Global 
Safety Officer with input from other appropriate study team members will determine the 
causal relationship when it is not clearly provided by the Investigator. 
• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor.  
• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
• Laboratory, vital signs or ECG abnormalities are to be recorded as AEs if they are 
medically relevant based on the investigator’s medical judgment, eg,:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI or EOSI 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send the notification to the Monitoring team and 
Pharmacovigilance after approval of the Investigator within the e-CRF. 
• SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
• All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification. 
• A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work. 
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Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. 
10.4.5 Guidelines for reporting events of special interest 
If an EOSI fulfills the criteria of an SAE, reporting should be performed according to the 
instructions for reporting of SAEs (see Section 10.4.3). Otherwise, reporting should follow the 
instructions for an AE (see Section 10.4.2).  
10.4.6 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix E.   
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
• Neutropenia 
• Thrombocytopenia 
• Increase in ALT 
• Acute renal insufficiency 
• Suspicion of rhabdomyolysis 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction [SUSAR]),), to the regulatory authorities, independent 
ethics committees (IECs)/institutional review boards (IRBs) as appropriate and to the 
Investigators.   
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
• The following AESIs to those regulatory authorities who require such reporting: 
- 
Pregnancy 
- 
Symptomatic overdose 
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- 
ALT increase > 3 X ULN 
Adverse events that are considered expected will be specified by the reference safety information 
provided in the current Investigator’s Brochure.  
If required, unblinding of SUSARs will be the responsibility of the Sponsor. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Hypoglycemia 
During the study, patients are instructed to document any hypoglycemic episodes in their study 
diary. The hypoglycemia will be reported in the specific e-CRF page with onset date and time, 
symptoms and/or signs, the SMBG value if available, and the treatment. If the event fulfills SAE 
criteria, hypoglycemia will also be reported as an SAE.  
Hypoglycemia is categorized according to the ADA workgroup on hypoglycemia classification 
(12,13) and summarized in Figure 1. 
In addition to the threshold of ≤3.9 mmol/L (≤70 mg/dL), hypoglycemia episodes with a plasma 
glucose of <3.0 mmol/L (<54 mg/dL) will be analyzed separately. 
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Figure 1 - Hypoglycemia classification in Study EFC14833 
 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, intravenous glucose or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. 
Self-monitored plasma glucose values may not be available, but neurological recovery attributable 
to the restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. 
Note: “requiring assistance of another person” means that the patient could not help himself or 
herself to treat the hypoglycemia. Assisting a patient out of kindness, when assistance is not 
required, should not be considered a “requires assistance” incident. 
Any hypoglycemic event which leads to unconsciousness, coma, or seizure should also be 
reported as an SAE. 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L 
(≤70 mg/dL).  
Clinical symptoms that are considered to result from a hypoglycemic episode are eg, increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
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Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL).   
Note: low plasma glucose values without symptoms or signs should not be reported more than 
once within 30 minutes. Repeated low glucose values within a short period could be due to 
malfunction of the device, error testing or following up a low glucose reading. The Investigator 
should try not to document false low SMBG values or redundant low glucose values as 
asymptomatic hypoglycemic event. Further clarification with the patients is needed.     
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms of hypoglycemia are not 
accompanied by a plasma glucose determination, (but that was presumably caused by a plasma 
glucose concentration ≤3.9 mmol/L [≤70 mg/dL]), ie, symptoms treated with oral carbohydrate 
without a test of plasma glucose.  
Relative hypoglycemia 
Relative hypoglycemia, recently termed “pseudo-hypoglycemia” (14) is an event during which the 
patient reports typical symptoms of hypoglycemia, and interprets the symptoms as indicative of 
hypoglycemia, but with a measured plasma glucose concentration >3.9 mmol/L (>70 mg/dL). 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
In the original version of this protocol, the sample size/power calculations were performed based 
on the primary variable, change in HbA1c from baseline to Week 26. Assuming a common 
standard deviation (SD) of 1.2% and using a 2-sided test at a 0.05 α-level, 120 patients per arm 
would have 95% power to detect a treatment difference of 0.6% in mean HbA1c change from 
Baseline to Week 26 between sotagliflozin 400 mg and placebo. 
In the amended, current, version of this protocol, the sample size/power has been recalculated to 
account for the addition of the sotagliflozin 200 mg treatment group after enrollment had 
commenced. Assuming a common SD of 1.2% and using a 2-sided test at a 0.05 α-level, 
100 patients per arm will have: 
• 94% power to detect a treatment difference of 0.6% in mean HbA1c change from Baseline 
to Week 26 between sotagliflozin 400 mg and placebo, and  
• 84% power to detect a treatment difference of 0.5% in mean HbA1c change from Baseline 
to Week 26 between sotagliflozin 200 mg and placebo. 
As a result, the total number of patients will include:  
• Approximately 100 patients from the initial randomization (1:1) according to the original 
protocol, balanced between placebo and sotagliflozin 400 mg, and 
• Approximately 300 patients from the subsequent randomization (1:1:1) according to the 
amended protocol, balanced between placebo, sotagliflozin 200 mg and sotagliflozin 
400 mg. 
11.2 
DISPOSITION OF PATIENTS 
 
The total number of patients for each of the following categories will be presented in the CSR: 
 
• Screened patients: patients who have signed the ICF 
• Run-in patients 
• Randomized patients: patients with a treatment kit number allocated and recorded in IRT 
database, and regardless of whether the treatment kit was used or not 
• The safety population (ie, randomized and treated patients) 
• The intent-to-treat (ITT) population (as defined in Section 11.3.1.1 and analyzed as 
randomized) 
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• The randomization strata [HbA1c at Screening (≤8.0%, >8.0%) and SBP (<130, 
≥130 mmHg)]. The discrepancy between the strata assigned by IRT and the information 
reported on the e-CRF will be listed for all randomized patients 
• Patients who have completed the treatment period 
• Patients who discontinued the IMP during the 26-week treatment period, and the reasons 
for treatment discontinuation 
• Patients who have completed the study 
• Patients who discontinued the study, and the reasons for study discontinuation 
For all categories of patients except screened, percentages will be calculated using the number of 
randomized patients as denominator for each treatment group. 
A list of patients prematurely discontinued from the treatment, along with reasons for 
discontinuation, will be provided. Similarly, a list of patients prematurely discontinued from the 
study, along with reasons for discontinuation, will be provided. 
Patients treated but not randomized, patients randomized but not treated and patients randomized 
but not treated as randomized will be identified and described in separate listings. The safety 
experience of patients treated and not randomized will be reported separately, and these patients 
will not be in the safety population. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
Efficacy analyses will be based on the treatment group allocated by the IRT according to the 
randomization schedule at randomization visit (as randomized), irrespective of the treatment 
actually received. 
11.3.1.1 Intent-to-treat population 
Efficacy analyses will be based on the ITT population, defined as all randomized patients, 
irrespective of compliance with the study protocol and procedures. Patients will be analyzed for 
efficacy analyses according to the treatment group to which they are randomized, that is, 
sotagliflozin 400 mg versus placebo (those randomized to placebo), and sotagliflozin 200 mg 
versus placebo (those randomized to placebo in the amended randomization only). 
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11.3.2 Safety population 
Safety analyses will be based on the safety population, defined as all randomized patients who 
receive at least one dose of double-blind IMP (regardless of the amount of treatment 
administered). 
Patients will be analyzed for safety analyses according to the treatment actually received, that is, 
sotagliflozin 400 mg versus placebo, and sotagliflozin 200 mg versus placebo (those randomized 
in the amended randomization and exposed to placebo only). 
In addition: 
• Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately 
• Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized 
• When a patient is exposed to both sotagliflozin and placebo, the patient will be analyzed in 
the appropriate sotagliflozin group (depending on the treatment kits taken [400 mg or 
200 mg]) 
• When a patient is exposed to both sotagliflozin 400 mg (treatment kits) and 200 mg 
(treatment kits), the patient will be analyzed in the sotagliflozin 200 mg group 
• Randomized patients will be excluded from the safety population only if there is 
documented evidence (ie, all study dates recorded as no medication taken) that patients 
have not taken the study medication 
11.4 
STATISTICAL METHODS 
Continuous data will be summarized by treatment group using the number of observations 
available, mean, SD, minimum, median, and maximum. 
Categorical data will be summarized by treatment group using count and percentage. 
In general, descriptive statistics of quantitative efficacy and safety parameters (result and change 
from Baseline) by scheduled visits will be provided on observed cases (OC), ie, inclusion of only 
patients having non-missing assessments at a specific visit. 
The baseline value is defined generally as the last available value before the first dose of 
double-blind IMP or the last available value prior to randomization for patients who were 
randomized but never exposed to IMP. 
For serum creatinine and eGFR, the Baseline value is defined as the average of all values before 
the first dose of double-blind IMP for those randomized and exposed or before randomization for 
those who were randomized but never exposed to IMP. 
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Analysis of demographics and baseline characteristics, prior and concomitant medications will be 
provided in detail in the statistical analysis plan (SAP).  
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received in the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
The extent of study treatment exposure will be assessed by the duration of treatment exposure 
during the study.  
The duration of treatment exposure will be the total number of days of administration of the 
double-blind IMP, regardless of unplanned intermittent discontinuations. The duration of IMP 
exposure will be calculated as: 
(Date of the last double-blind IMP taken – Date of the first double-blind IMP taken) + 1. 
The number (%) of patients randomized and exposed to double-blind IMP will be presented by 
specific time periods for each treatment group. The time periods of interest will be defined in the 
SAP. 
Descriptive statistics of duration of treatment exposure (number, mean, SD, minimum, median, 
and maximum) and cumulative exposure in patient year will also be presented by treatment group 
in the safety population. 
11.4.1.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, mean, SD, median, min, and max). The percentage of patients with compliance 
<80% will be summarized. In addition, the number and percentage of patients with at least 1 
above-planned dosing administration will be given, as well as the number and percentage of 
patients with 0, >0 to 20%, and >20% under-planned dosing administrations. 
11.4.2 Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population. 
11.4.2.1 Analysis of primary efficacy endpoint 
The statistical test will be two-sided tests at a nominal 5% significance level. 
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Analysis of the primary efficacy endpoint (change from Baseline to Week 26 in HbA1c; see 
Section 9.1.1) will be performed on the ITT population, using HbA1c measurements obtained 
during the study, including those obtained after IMP discontinuation or introduction of rescue 
therapy. 
The primary efficacy endpoint of change in HbA1c from baseline to Week 26 will be analyzed 
with missing values imputed by control-based multiple imputation method under the missing not 
at random frame work.  
• For placebo patients, missing data will be imputed based on the placebo group data, 
• For patients in the sotagliflozin 400 mg group, missing data will be imputed as if the 
patients were on placebo throughout the study, where all patients’ measurements including 
the on-treatment measurements will be considered as if the measurements were from the 
placebo group in the imputation model. 
Each of the complete datasets will be analyzed by the Analysis of Covariance (ANCOVA) model 
with treatment groups (sotagliflozin 400 mg, placebo), randomization stratum of HbA1c (≤8.0%, 
>8.0%), randomization stratum of SBP (<130, ≥130 mmHg), and country as fixed effects, and 
baseline HbA1c value as a covariate. Results from each complete dataset will be combined to 
provide the adjusted mean change in HbA1c from Baseline to Week 26 for each treatment group, 
as well as the between-group difference (comparing sotagliflozin 400 mg vs placebo) and the 95% 
confidence interval (CI) for the difference.  
Summary statistics (for Screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided for each treatment group. The summary will 
include the number of observations, mean, SD, standard error (SE), minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from baseline (±SE) at each of the scheduled visits (using OC). 
Assessment of treatment effect by subgroup 
Descriptive analyses will be performed on the primary endpoint to summarize the treatment 
effects across subgroups defined by the following Baseline or Screening factors: 
• Race 
• Ethnicity (Hispanic, Not Hispanic) 
• Age group (<50, ≥50 to <65, ≥65 years) 
• Gender 
• Baseline BMI level (<30, ≥30 kg/m²) 
• Baseline HbA1c (≤8.0%, >8.0%) 
• Baseline HbA1c (≤8.5%, >8.5%)  
• Baseline SBP (<130 mmHg, ≥130 mmHg)  
• Country 
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The treatment effects across the subgroups defined for each of these factors will be estimated for 
the change from Baseline to Week 26 in HbA1c in the ITT population, and using a similar 
approach to the analysis for the primary efficacy endpoint. The adjusted estimates of treatment 
mean differences (sotagliflozin 400 mg versus placebo) with SE and 95% CIs will be provided as 
appropriate across the subgroups. 
In the case that the subgroup factor is identical or similar to a randomization strata factor 
(eg, baseline HbA1c category), only the subgroup factor will be included in the model in order to 
avoid the issue of collinearity in the analysis. 
11.4.2.2 Analyses of secondary efficacy endpoints 
The secondary endpoints (see Section 9.1.2) will be analyzed using a similar approach to the 
primary efficacy endpoint with missing values imputed by control-based multiple imputation 
method under the missing not at random frame work.  
To compare sotagliflozin 400 mg versus placebo (those randomized to placebo): 
• For placebo patients, missing data will be imputed based on the placebo group data, 
• For patients in the sotagliflozin 400 mg group, missing data will be imputed as if the 
patients were in the placebo group throughout the study, where all patients’ measurements 
including the on-treatment measurements will be considered as if the measurements were 
from the placebo group in the imputation model. 
To compare sotagliflozin 200 mg versus placebo (those randomized to placebo in the amended 
randomization only): 
• For placebo patients, missing data will be imputed based on the placebo group data, 
• For patients in the sotagliflozin 200 mg group, missing data will be imputed as if the 
patients were in the placebo group throughout the study, where all patients’ measurements 
including the on-treatment measurements will be considered as if the measurements were 
from the placebo group in the imputation model. 
For each of the continuous secondary endpoints, each of the complete datasets will be analyzed by 
an ANCOVA model. To compare sotagliflozin 400 mg versus placebo, the model will include 
treatment groups (sotagliflozin 400 mg, placebo), randomization stratum of HbA1c (≤8.0%, 
>8.0%), randomization stratum of SBP (<130, ≥130 mmHg), and country as fixed effects, and 
baseline secondary endpoint value as a covariate. To compare sotagliflozin 200 mg versus 
placebo, the model will include treatment groups (sotagliflozin 200 mg, placebo), randomization 
stratum of HbA1c (≤8.0%, >8.0%), randomization stratum of SBP (<130, ≥130 mmHg), and 
country as fixed effects, and baseline secondary endpoint value as a covariate. Results from each 
complete dataset will be combined to provide the adjusted mean change from Baseline to 
Week 26 (or Week 12 for SBP) for each treatment group, as well as the between-group difference 
(comparing each sotagliflozin group vs its corresponding placebo group) and the 95% CI for the 
difference. 
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The categorical secondary efficacy variables of HbA1c <6.5%, <7% at Week 26 will be analyzed 
using a Cochran-Mantel-Haenszel method stratified by randomization stratum of HbA1c (≤8.0%, 
>8.0%), and randomization stratum of SBP (<130, ≥130 mmHg). The proportion in each 
treatment group will be provided, as well as the difference of proportions between each 
sotagliflozin group and its corresponding placebo group with associated 2-sided 95% CI. For 
HbA1c responders at Week 26 (<6.5%, <7% respectively), all values at Week 26 will be used to 
determine whether a patient is a responder or not, even if they are measured after IMP 
discontinuation or rescue medication use. Patients who have no HbA1c measurement at Week 26 
will be treated as non-responders. 
For all secondary endpoints, summary statistics at scheduled visits will be provided for each 
treatment group. The summary will include the number of observations, mean, SD, SE, minimum, 
median, and maximum. Graphical presentations will also be used to examine trends over time 
using mean values (±SE) and mean changes from baseline (±SE) at each of the scheduled visits 
(using OC). 
11.4.2.3 Analyses of other efficacy endpoints 
The analysis of other endpoints (see Section 9.1.3) will be descriptive with no formal testing. 
Summary statistics at scheduled visits using OC will be provided by each treatment group. 
Graphical presentations will also be used to illustrate trends over time. 
11.4.2.4 Multiplicity considerations 
To control the family-wise type I error, a fixed-sequence testing procedure will be applied.   
Once the primary variable (change from Baseline to Week 26 in HbA1c) is statistically significant 
at α = 0.05 (2-sided), a hierarchical testing procedure will be performed to test the following 
secondary efficacy variables in the following prioritized order. The testing will stop as soon as an 
endpoint is found not to be statistically significant at α=0.05 (2-sided). 
• Comparing sotagliflozin 400 mg versus placebo: 
- 
Change from Baseline to Week 26 in 2-hour PPG following a MM 
- 
Change from Baseline to Week 26 in FPG 
- 
Change from Baseline to Week 26 in body weight 
- 
Change from Baseline to Week 12 in SBP for patients with baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all patients  
- 
Proportion of patients with HbA1c <7.0% at Week 26 
• Comparing sotagliflozin 200 mg versus placebo:  
- 
Change from Baseline to Week 26 in HbA1c 
- 
Change from Baseline to Week 26 in 2-hour PPG following a MM 
- 
Change from Baseline to Week 26 in body weight 
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- 
Change from Baseline to Week 12 in SBP for all patients 
No multiplicity adjustment will be made on other secondary efficacy variables than mentioned 
above.   
11.4.3 Analyses of safety data 
Safety endpoints are presented in Section 9.2. The summary of safety results will be presented by 
treatment group. All safety analyses will be performed on the Safety population as defined in 
Section 11.3.2 using the following common rules: 
The following definitions will be applied to laboratory parameters and vital signs: 
• The potentially clinically significant abnormality (PCSA) values for clinical laboratory 
tests and vital signs are defined as abnormal values considered medically important by the 
Sponsor’s Global Pharmacovigilance and Epidemiology department and in effect at the 
time of the final SAP approval. PCSA criteria for parameters not cited in the protocol as 
safety parameters will not be analyzed 
• PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage 
The “observation periods” defined in Section 9.2.1 are applicable for classification of AEs, 
determination of on-treatment PCSA values and the last on-treatment value for the laboratory, 
vital sign and ECG parameters. 
11.4.3.1 Analysis of adverse events 
Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
Treatment-emergent AEs (TEAEs) are AEs that developed or worsened (according to the 
Investigator’s opinion) or became serious during the on-treatment period. 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
The primary focus of AE reporting in the CSR will be on TEAEs. Pre- and post-treatment AEs 
will be described separately. 
All adverse events 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (n) and percentage 
(%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient 
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will be counted only once in the tables within a treatment phase. The denominator for 
computation of percentages is the safety population within each treatment group.  
Summaries of all TEAEs in each treatment group will include: 
• The overview of AEs, summarizing number (%) of patients with any 
- 
TEAE, 
- 
Serious TEAE, 
- 
TEAE leading to death, 
- 
TEAE leading to permanent treatment discontinuation. 
• The number (n) and percentage (%) of patients with at least one TEAE by primary SOC, 
HLGT, HLT and PT, 
• Summary of TEAEs by maximal severity (severe, moderate, mild), presented by primary 
SOC and PT, 
• Summary of TEAEs possibly related to IMP, presented by primary SOC, HLGT, HLT and 
PT. 
A detailed listing of TEAE summaries will be provided in the SAP. 
Death and serious adverse events 
Death and treatment-emergent SAEs will be summarized and presented as number and percent of 
patients in each treatment group. 
The following deaths summaries will be generated: 
• Number (%) of patients who died by study period (on-study, on-treatment, post-study) 
summarized on the safety population by treatment received 
• Death in nonrandomized patients or randomized and not treated patients 
• TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT 
Adverse events leading to permanent treatment discontinuation 
TEAEs leading to permanent treatment discontinuation will be summarized and presented as 
number and percent of patients in each treatment group. 
11.4.3.2 Analyses of hypoglycemia 
The number (%) of patients and rate in patient years (2 types: the number of patients with events 
or the total number of events per 100 patient-year) of all Investigator reported hypoglycemia, 
severe hypoglycemia, and documented symptomatic hypoglycemia will be summarized by 
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treatment group respectively. Their pattern of occurrence over time will also be assessed, as 
appropriate. 
11.4.3.3 Analyses of adverse events of special interest 
Pregnancy and overdose will be included in overall AE summaries if any are reported. ALT 
increase > 3 x ULN is included in laboratory PCSA summary if any. 
11.4.3.4 Analyses of events of special interest 
The number (%) of patients with each EOSI event will be summarized by treatment group. All 
events reported by the Investigators on the AE forms for special interests will be listed along with 
the adjudication outcome (if applicable). 
11.4.3.5 Analyses of laboratory variables 
The number and percentage of patients with PCSA or by the pre-defined categories (if no PCSA 
criterion is defined) at any evaluation during the on-treatment period will be summarized for each 
clinical laboratory test within each treatment group. The summaries will include patients in the 
safety population who have at least one laboratory test performed during the on-treatment period 
and, when required by the definition of the abnormality, with an available baseline value and 
available laboratory normal ranges. 
Descriptive statistics will be used to summarize the laboratory results and the changes from 
baseline by visit and for the last on-treatment value within each treatment group. Shift tables and 
other tabular and graphical methods may be used to present the results for laboratory tests of 
interest. Listings will be provided with flags indicating the out of laboratory range values as well 
as the PCSA values. 
The liver function tests, namely ALT, AST, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
postbaseline visit by baseline status will be displayed by treatment group for each parameter. 
11.4.3.6 Analyses of vital sign variables 
The number and percentage of patients with PCSA at any evaluation during the on-treatment 
period will be summarized for each vital sign parameter within each treatment group. The 
summaries will include patients in the safety population who have at least one parameter to be 
analyzed during the on-treatment period. Descriptive statistics will be used to summarize the 
results and the changes from baseline by visit and for the last on-treatment value within each 
treatment group. Tabular and graphical methods may be used to present the results for parameters 
of interest. Listings will be provided with flags indicating the PCSA values. 
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11.4.3.7 Analyses of 12 lead ECG status 
A shift table will be provided to present the ECG on-treatment status according to the baseline 
status within each treatment group. 
11.4.4 Analyses of pharmacokinetic variables 
The PK endpoint is presented in Section 9.3.1. Individual plasma concentrations of sotagliflozin 
and of its 3-O-glucuronide at nominal sampling times will be listed.  
Concentration data will be summarized by visit and, if appropriate, within visit by nominal 
sampling times (predose, 2 hours 30 minutes postdose), using descriptive statistics by N, 
geometric mean, coefficient of variation, median, minimum and maximum at each visit/nominal 
sampling time point for sotagliflozin-treated patients. 
11.5 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned for this study. The study will not be terminated 
early for excellent efficacy. 
An independent DMC will monitor and assess the safety of patients from this trial through 
periodic review of the accumulated safety data provided by an independent statistical group. 
Related details are provided in separate documents (DMC charter and DMC statistical analysis 
plan). 
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documents (summary of product characteristics, package insert), Investigator’s curriculum vitae 
[CV], etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC, before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the Investigator’s Brochure or 
labeling information, will be sent to the IRB/IEC and to health authorities (competent regulatory 
authority), as required by local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR OR SERVICE PROVIDER 
The Sponsor and/or service provider of this clinical trial is responsible to regulatory authorities for 
taking all reasonable steps to ensure the proper conduct of the clinical trial as regards ethics, 
clinical trial protocol compliance, and integrity and validity of the data recorded on the CRFs. 
Thus, the main duty of the monitoring team is to help the Investigator and the Sponsor maintain a 
high level of ethical, scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE and EOSI documentation, IMP allocation, 
patient compliance with the IMP regimen, IMP accountability, concomitant therapy use and 
quality of data.  
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
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personnel, the ethics committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor/service provider to record (according to Sponsor 
instructions) all observations and other data pertinent to the clinical investigation in a timely 
manner. All CRFs should be completed in their entirety in a neat, legible manner to ensure 
accurate interpretation of data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor/service provider may generate additional 
requests (DRF) to which the Investigator is obliged to respond by confirming or modifying the 
data questioned. The requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor/service provider and Investigator study files. 
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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 Subinvestigator will be signed, dated and provided to the Sponsor/service 
provider prior to the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
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the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). They may be further 
processed if they have been anonymized. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, good clinical practice, and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he/she will 
inform the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio 
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• Patient enrollment is unsatisfactory 
• The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon 
• Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP 
• The total number of patients are included earlier than expected 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
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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 
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2. International Diabetes Federation Diabetes Atlas 7th Edition.  
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3. American Diabetes Association. American Diabetes Association Applauds Two-Year Re 
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http://www.diabetes.org/newsroom/press-releases/2010/re-authorization-special-diabetes-
program.html. Accessed July 12, 2016. 
4. American Diabetes Association. Standards of Medical Care in Diabetes – 2013. Diabetes Care 
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5. Castaneda-Sceppa C, Castaneda F. Sodium-dependent glucose transporter protein as a 
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6. Mudalier S. Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal 
Glucose Transport; From Bench to Bedside. Diabetes Care 2015; 38: 2344–53. 
7. Hediger HA. Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. 
Nature 1987; 330:379-81. 
8. Wright EM. I. Glucose galactose malabsorption. Am J Physiol. 1998;275:G879-G882. 
9. Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M. Dapagliflozin, a novel, 
selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 
diabetes mellitus. Clinical Pharmacology & Therapeutics. 2009 May;85(5):513-9. 
10. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with 
dapagliflozin in type 2 diabetes. Diabetes care. 2009 Apr 1;32(4):650-7. 
11. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycemia in type 2 diabetes: a patient-centered approach position 
statement of the American Diabetes Association (ADA) and the European Association for the 
Study of Diabetes (EASD). Diabetes care. 2012 Jun;35(6):1364-79. 
12. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on 
Hypoglycemia. Diabetes Care. 2005 May;28(5):1245-9. 
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13. FDA Guidance for Industry:  Diabetes Mellitus - Developing Drugs and Therapeutic Biologics 
for Treatment and Prevention. Lines 1144 – 1215. Available from: 
http://www.fda.gov/downloads/ 
Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071624.pdf. Accessed 
July 12, 2016 
14. Seaquist ER, Anderson J, Childs B, Cryer P, Dagoga-Jack S, Fish L, et al. Hypoglycemia and 
Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95 
 
 
 
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17 
APPENDICES 
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Appendix A 
Guidance on contraceptive methods and collection of pregnancy 
information 
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy. 
1. Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.  
- 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Women of reproductive potential (WOCBP) must use a highly effective method of contraception 
during the treatment period and the post-treatment follow up period (28 ±3 days). If another 
contraceptive method is used (such as a barrier method), it should be used in combination with 
one of the highly effective methods (such as an oral contraceptive). 
Female patients: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 
− oral 
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− intravaginal 
− transdermal 
• Progestogen-only hormone contraception associated with inhibition of ovulation 
− oral 
− injectable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulation  
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method(s) of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.) 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the patient.) 
NOTE: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for patients 
participating in clinical studies. 
 
 
 
COLLECTION OF PREGNANCY INFORMATION 
Male patients with partners of reproductive potential who become pregnant  
• The Investigator will attempt to collect pregnancy information on any female partner of a 
male study patient who becomes pregnant while participating in this study. This applies 
only to patients who receive study treatment. 
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• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy  
• Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor.  
• Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure  
Female patients who become pregnant  
• The Investigator will collect pregnancy information on any female patient, who becomes 
pregnant while participating in this study  
• Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a patient’s pregnancy.  
• Patient will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on patient and neonate, which will be forwarded to the 
Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.  
• Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.  
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the study treatment by the Investigator, will be reported to the Sponsor as described in 
Section 10.4.1.2. While the Investigator is not obligated to actively seek this information in 
former study patients, he or she may learn of an SAE through spontaneous reporting.  
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Appendix B 
Two-hour standardized mixed meal 
A 2-hour PPG will be obtained after a standardized MM in all patients at Baseline (Day 1, Visit 3) 
and at Week 26 (Visit 9), or earlier if the patient terminates study participation before Week 26. 
Any patient who requires the addition of rescue medication should undergo the second 
standardized MMTT at Visit 9 (Week 26).  
The standardized MM must not be done while patients are temporarily off IMP; the Medical 
Monitor will address any episodes on a case-by-case basis and the standardized MM will be 
rescheduled when the patient can resume IMP, if applicable. 
The first dose of double-blind IMP on Day 1 (Visit 3) will be given AFTER completion of the 
2-hour PPG collection. For the Week 26 standardized MM, the patient should take the dose of 
double-blind IMP immediately after the fasting blood samples are obtained, and approximately 
30 minutes before ingestion of the standardized MM begins. 
Standard Meal for the Standardized Mixed Meal: 
The standard (breakfast) meal will be provided by the Sponsor as a liquid nutrition drink (Boost®, 
Ensure®, or similar), with ~40 g carbohydrate and ~240 calories per bottle (~8 ounces). The 
caloric composition of the meal is ~ 65% carbohydrate, ~15% protein, and ~20% fat. The amount 
given is 6 mL/kg body weight up to a maximum of 360 mL. Therefore for patients ≥60 kg, the 
standard meal consists of ~60 g carbohydrate and 360 calories.  
Patients are instructed to completely consume the meal within 15 minutes, and every effort should 
be made to complete the meal within 20 minutes after it is started. Water or noncaffeinated, 
zero-calorie beverages may be consumed ad libitum. No other food may be consumed until the 
2-hour postprandial plasma glucose sample has been collected. If the patient is unable to consume 
at least 50% of the standard meal during the MMTT at Baseline (Day 1, Visit 3), the patient 
should not be randomized. If a MMTT after randomization is not tolerated, effort should be made 
to repeat the testing at the discretion of the Investigator. If the patient cannot tolerate MMTT upon 
repeat testing, this should be documented in the e-CRF with the reason and the patient should 
continue in the study. If the patient is able to consume >50% of the standardized MM, the 
approximate amount should be recorded, and an equivalent amount should be consumed at the 
subsequent standardized MM. 
Baseline Visit (Day 1, Visit 3) Standardized MM: 
1. Record the amount and brand name of the standard meal liquid nutrition drink the patient 
is instructed to consume in the source documents 
2. Fasting blood samples are obtained, including Time 0 fasting FPG 
3. Record the time of blood sample collection in the source documents 
4. Immediately after the fasting blood samples are collected, the patient starts consuming the 
standard meal 
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5. Record the time the meal ingestion starts in the source documents 
6. The 2-hour countdown for the 2-hour plasma PPG starts immediately after the patient 
begins ingestion of the standard meal 
7. The patient is instructed to ingest the prescribed amount within 15 to 20 minutes. 
8. Record the time ingestion is completed, measure the portion of the meal not ingested (if 
any), and record the assessed percent of prescribed amount ingested in the source 
documents 
9. No blood samples for PK are collected at this visit 
10. Two hours after the meal ingestion starts, the 2-hour plasma PPG is collected 
11. Record the time the 2-hour plasma PPG is collected in source documents 
12. Double-blind IMP is administered after the blood sample is drawn at 120 minutes 
13. Record the time the double-blind IMP is administered in the source documents 
Week 26 Visit (Visit 9) Standardized MM: 
1. Record the amount and brand name of the standard meal liquid nutrition drink the patient 
is instructed to consume in the source documents 
2. Fasting blood samples are obtained, including Time 0 FPG and predose PK samples 
3. Record the time of blood sample collection in the source documents 
4. Double-blind IMP is administered after the fasting blood samples are obtained 
5. Record the time the double-blind IMP is administered in the source documents 
6. Thirty-minutes after the double-blind IMP is administered, the patient starts consuming the 
standard meal 
7. Record the time the meal ingestion starts in the source documents 
8. The 2-hour countdown for the 2-hour PPG starts immediately after the patient begins 
ingestion of the standard meal 
9. The patient is instructed to ingest the prescribed amount within 15 to 20 minutes 
10. Record the time ingestion is completed, measure the portion of the meal not ingested 
(if any), and record the assessed percent of prescribed amount ingested in the source 
documents 
11. Two hours after the meal ingestion starts, the 2-hour PPG and 2-hour 30 minute PK 
samples are collected 
12. Record the time the 2-hour postprandial blood samples are collected in the source 
documents 
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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 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 DKA 
Potential GI adverse events occurring with sotagliflozin may mask presenting symptoms of DKA. 
Patient communication cards will be printed with the following: 
“If you have any of these symptoms on the list, then contact your study site immediately for 
assistance with managing your diabetes: 
• Inability to maintain oral intake  
• Generalized weakness  
• Abdominal (belly) pain  
• Increased weight loss 
• Fever  
• Frequent urination, including at night 
• Fruity-scented breath 
• Confusion 
• Acute illness  
• Consistently elevated blood glucose  
• Feeling very thirsty or drinking a lot 
• Nausea or vomiting 
• Having trouble thinking clearly or feeling tired 
It is possible to have DKA even if your blood glucose is not elevated. Regardless of your blood 
glucose level, if you have any of these symptoms on the list, then contact your study site 
regarding the need to be evaluated for possible DKA, which will include specific blood testing. If 
your study site is closed and your study doctor is not available, go to the nearest emergency room 
for evaluation. 
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If you are scheduled for a procedure or surgery that requires you to not take any food or liquids, 
please contact your study doctor for instructions on continuing study drug. In such cases your 
study doctor may advise you NOT to take your study drug from the day prior to the procedure or 
surgery until after the procedure or surgery is complete, and you are taking food and liquids as 
you normally do.” 
Whenever AE data is collected or the patient reports DKA or intercurrent illness (including 
infections), generalized weakness, increased weight loss, gastrointestinal symptoms including 
nausea, vomiting, or abdominal pain or other symptoms or signs that the Investigator believes 
may be consistent with DKA, then the site will determine if an assessment for DKA is 
appropriate. If laboratory testing confirms presence of metabolic acidosis, then the “Possible 
DKA” e-CRF will be completed. 
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Appendix D 
Measurement of Blood Pressure and Pulse Rate 
The BP measurement device should be calibrated according to manufacturer instructions.  
Equipment 
1. Blood pressure measurements will be taken by an automated blood pressure monitor or a 
manual sphygmomanometer 
2. Bladder Length – Should nearly or completely encircle the patient’s arm. For many adults, 
the standard “adult” size bladder is not long enough and the “large” size bladder is 
recommended 
3. Bladder Width – Should be at least 40% of the bladder length 
Patient Factors 
Extraneous variables associated with the measurement of BP should be minimized. These include: 
1. Food intake, caffeine-containing beverages, cigarette smoking, or strenuous exercise 
within 2 hours prior to measurement 
2. Full urinary bladder 
3. The patient should not be allowed to talk while BP is being measured 
4. The patient should be placed in the examination room and the cuff should be placed on the 
patient’s nondominant arm. The proper sized cuff should fit snugly with the lower edge 2 
to 3 cm above the antecubital fossa. 
5. The patient should be allowed to sit quietly in a comfortably warm place (temperature 
around 25°C or 77°F) for 5 minutes with the arm supported at heart level, preferably with 
the cuff in place and with no restrictive clothing on the arm. The patient should be 
encouraged not to tense his or her muscles. 
Nondominant Arm 
The patient’s nondominant arm should be the arm declared by the patient as being nondominant. 
The nondominant arm should then be used for all seated BP measurements throughout the study. 
Measurement Technique 
Following the 5-minute rest period, 3 separate seated BPs should be measured with at least 
1 minute between BP measurements and with the cuff fully deflated between measurements. 
All 3 BPs will be recorded in the patient’s e-CRF. The mean of the 3 seated BPs will constitute 
the BP value for that visit. 
Three seated pulse rate measurements will be obtained. The mean of the 3 seated pulse rate 
measurements will constitute the pulse rate value for that visit. 
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Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.4.2 is met. 
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SAP_001.pdf: 
Official Title: 
A Randomized, Double-blind, Placebo-controlled Monotherapy in 
Patients with Type 2 Diabetes Mellitus Who Have Inadequate 
Glycemic Control, Parallel-group, Multicenter Study to Evaluate the 
Efficacy and Safety of Sotagliflozin as Monotherapy in Patients 
with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control 
NCT Number: NCT02926937 
Document Date: SAP Version 3: 22-November-2019 


COVANCE INC. CONFIDENTIAL 
 
                                           Page 1 of 85 
 
 
Lexicon Pharmaceuticals, Inc. 
Protocol No.: EFC14833 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study 
to Evaluate the Efficacy and Safety of Sotagliflozin as Monotherapy in Patients 
with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control 
Covance Study ID: 000000150524 
STATISTICAL ANALYSIS PLAN 
 
Version: 3.0 
Date of Issue: 21-Nov-2019 
Author:
 
 
 
 
 
 
 
 
Lexicon Pharmaceuticals, Inc. 
Covance Clinical Development Services 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
206 Carnegie Center 
Princeton, NJ 08540-6233  




Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov 2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                               Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
 
                                           Page 3 of 85 
TABLE OF CONTENTS 
List of abbreviations and definition of terms .................................................................................................... 5 
1                  OVERVIEW AND INVESTIGATIONAL PLAN ............................................................................. 7 
1.1             STUDY DESIGN AND RANDOMIZATION ................................................................................... 7 
1.2             OBJECTIVES ................................................................................................................................ 7 
1.2.1       Primary objectives ............................................................................................................................ 7 
1.2.2       Secondary objectives ....................................................................................................................... 8 
1.2.3       Other objectives ............................................................................................................................... 8 
1.3             DETERMINATION OF SAMPLE SIZE .......................................................................................... 9 
1.4             STUDY PLAN .............................................................................................................................. 10 
1.5             MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ............................. 11 
1.6             STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN (SAP) ........ 12 
2                  STATISTICAL AND ANALYTICAL PROCEDURES ................................................................. 15 
2.1             ANALYSIS ENDPOINTS ............................................................................................................. 15 
2.1.1       Demographic and baseline characteristics .................................................................................... 15 
2.1.2       Prior or concomitant medications ................................................................................................... 17 
2.1.3       Efficacy endpoints .......................................................................................................................... 18 
2.1.4       Safety endpoints ............................................................................................................................. 19 
2.1.5       Pharmacokinetic variables ............................................................................................................. 28 
2.2             DISPOSITION OF PATIENTS ..................................................................................................... 28 
2.2.1       Randomization and drug dispensing irregularities ......................................................................... 29 
2.3             ANALYSIS POPULATIONS ........................................................................................................ 30 
2.3.1       Efficacy populations ....................................................................................................................... 31 
2.3.2       Safety population ............................................................................................................................ 31 
2.3.3       PK population ................................................................................................................................. 32 
2.4             STATISTICAL METHODS ........................................................................................................... 32 
2.4.1       Demographics and baseline characteristics ................................................................................... 32 
2.4.2       Prior or concomitant medications ................................................................................................... 32 
2.4.3       Extent of investigational medicinal product exposure and compliance .......................................... 33 
2.4.4       Analyses of efficacy endpoints ....................................................................................................... 34 
2.4.5       Analyses of safety data .................................................................................................................. 41 
2.4.6       Analyses of pharmacokinetic variables .......................................................................................... 49 
2.5             DATA HANDLING CONVENTIONS ............................................................................................ 49 
2.5.1       General conventions ...................................................................................................................... 49 
2.5.2       Data handling conventions for secondary efficacy variables ......................................................... 50 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov 2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                               Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
 
                                           Page 4 of 85 
2.5.3       Missing data ................................................................................................................................... 51 
2.5.4       Windows for time points / Measurements for analyses .................................................................. 53 
2.5.5       Unscheduled visits ......................................................................................................................... 55 
2.5.6       Pooling of centers for statistical analyses ...................................................................................... 55 
2.5.7       Statistical technical issues .............................................................................................................. 56 
3                  INTERIM ANALYSIS ................................................................................................................. 57 
4                  DATABASE LOCK .................................................................................................................... 58 
5                  SOFTWARE DOCUMENTATION ............................................................................................. 59 
6                  REFERENCES .......................................................................................................................... 60 
7                  LIST OF APPENDICES ............................................................................................................. 61 
 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov 2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                               Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
 
                                           Page 5 of 85 
List of abbreviations and definition of terms 
ACR: 
albumin-creatinine ratio 
AESI: 
adverse events of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
ATC: 
anatomical therapeutic chemical 
BMI: 
body mass index 
BUN: 
blood urea nitrogen 
CI: 
confidence interval 
CMH: 
Cochran-Mantel-Haenszel 
CPK: 
creatine phosphokinase 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DCCT: 
Diabetes Control and Complications Trial  
DILI: 
drug-induced liver injury  
DMC: 
Data Monitoring Committee 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
eGFR: 
Estimated glomerular filtration rate 
EMA: 
European Medicines Agency 
EOSI: 
events of special interest 
FPG: 
fasting plasma glucose 
GCR: 
glucose-creatinine ratio 
HbA1c: 
hemoglobin A1c 
HDL-C: 
high density lipoprotein cholesterol 
HLGT: 
high level group term 
HLT: 
high level term 
HR: 
heart rate 
IFCC: 
International Federation of Clinical Chemistry and Laboratory Medicine  
IMP: 
investigational medicinal product 
IRT: 
Interactive Response Technology 
ITT: 
intent-to-treat 
KM: 
Kaplan-Meier 
LDH: 
Lactic acid dehydrogenase 
LDL-C: 
low density lipoprotein cholesterol 
LLT: 
lower level term 
MACE: 
Major adverse cardiovascular events 
MAR: 
Missing at random 
MDRD: 
Modification of Diet in Renal Disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MI: 
multiple imputation 
MM: 
mixed meal 
MNAR: 
missing not at random 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov 2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                               Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
 
                                           Page 6 of 85 
NIMP: 
noninvestigational medicinal product 
NTX: 
N-terminal telopeptide 
P1NP: 
type 1 procollagen N-terminal 
PCSA: 
Potentially Clinically Significant Abnormality 
PD: 
pharmacodynamic 
PK: 
pharmacokinetic 
PPG: 
postprandial glucose 
PRAC: 
Pharmacovigilance Risk Assessment Committee 
PT: 
preferred term 
PTH: 
Parathyroid hormone 
SAE: 
serious adverse events 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SD: 
standard deviation 
SE: 
standard error 
SOC: 
system organ class 
T2D: 
type 2 diabetes mellitus 
TC: 
total cholesterol 
TEAE: 
treatment-emergent adverse event 
TG: 
triglycerides 
UGE: 
Urinary glucose excretion 
ULN: 
upper limit of normal 
WHO-DD: 
World Health Organization-Drug Dictionary 
β-CTX-1: 
beta-C-terminal telopeptide 
 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov 2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                               Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
 
                                           Page 7 of 85 
1                  OVERVIEW AND INVESTIGATIONAL PLAN   
1.1             STUDY DESIGN AND RANDOMIZATION 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
stratified study. Under the original version of the protocol, patients were randomly assigned 1:1 to 
the following 2 treatment groups  
• 
Sotagliflozin 400 mg  
• 
Placebo  
The protocol was amended to include an additional dose group of sotagliflozin 200 mg after 
enrollment had commenced. Under Amendment 1, patients are to be randomly assigned 1:1:1 to 
the following 3 treatment groups  
• 
Sotagliflozin 400 mg  
• 
Sotagliflozin 200 mg 
• 
Placebo  
All patients will have a Screening Period comprised of an up to 2-week Screening Phase and a 
2-week, single-blind placebo Run-in Phase prior to randomization. Following randomization, 
patients will have a 26-week double-blind Treatment Period, and a 4-week post-treatment Follow-
up period (patients who prematurely discontinue the study treatment are expected to continue in 
the study). 
At the end of the screening period, eligible patients will be centrally randomized (using permuted 
block randomization schedule) via an Interactive Response Technology (IRT) in a 1:1:1 ratio 
(1:1 ratio in the initial randomization) to 1 of the 3 treatment groups (2 treatment group in the 
initial randomization). The randomization will be stratified by hemoglobin A1c (HbA1c) at the 
screening visit (≤8%, >8%) and mean systolic blood pressure (SBP) at the screening visit 
(<130 mmHg, ≥130 mmHg).  
It is anticipated to randomize a total of approximately 376 patients. This number includes patients 
randomized under the original protocol, and the patients to be randomized under Amendment 1. 
1.2             OBJECTIVES 
1.2.1       Primary objectives 
The primary objective of this study is to demonstrate the superiority of sotagliflozin 400 mg 
versus placebo on HbA1c reduction at Week 26 in patients with type 2 diabetes mellitus (T2D) 
who have inadequate glycemic control on diet and exercise. 


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1.2.2       Secondary objectives 
• 
To compare sotagliflozin 400 mg versus placebo for:  
-          Change from Baseline in 2-hour postprandial glucose (PPG) following a mixed meal 
(MM) at Week 26 
-          Change from Baseline in fasting plasma glucose (FPG)  at Week 26 
-          Change from Baseline in body weight at Week 26,  
-          Change from Baseline in SBP at Week 12 for patients with baseline SBP ≥130 
mmHg,  
-          Change from Baseline in SBP at Week 12 for all patients, 
-          Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
• 
To compare sotagliflozin 200 mg versus placebo for:  
-          Change from Baseline in HbA1c at Week 26 
-          Change from Baseline in 2-hour PPG following a MM at Week 26 
-          Change from Baseline in body weight at Week 26,  
-          Change from Baseline in SBP at Week 12 for all patients. 
• 
To evaluate the safety of sotagliflozin 400 mg and 200 mg doses versus placebo 
1.2.3       Other objectives 
• 
To compare sotagliflozin 400 mg and 200 mg doses versus placebo with respect to change 
from Baseline for the following endpoints:   
-          Urine albumin-creatinine ratio (ACR) 
-          Urinary glucose excretion (UGE) and urine glucose-creatinine ratio (GCR) 
-          Estimated glomerular filtration rate (eGFR) 
-          Reduction in body weight by ≥2%, ≥5%, and ≥10% 
• 
To compare sotagliflozin 200 mg versus placebo for: 
-          Change from baseline in FPG at Week 26 
-          Change from baseline in SBP at Week 12 for patients with Baseline SBP ≥130 mmHg 
-          Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
• 
To compare sotagliflozin 400 mg and 200 mg doses with placebo for change from 
Baseline in SBP at Week 26 for all patients and for patients with Baseline SBP ≥130 
mmHg 
• 
To compare sotagliflozin 400 mg and 200 mg doses with placebo in the use of rescue 
medications for hyperglycemia  
• 
To assess plasma concentrations of sotagliflozin and its 3-O-glucuronide metabolite in 
each sotagliflozin treatment group. 


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1.3             DETERMINATION OF SAMPLE SIZE 
In the original version of the protocol, the sample size/power calculations were performed based 
on the primary variable, change in HbA1c from baseline to Week 26. Assuming a common 
standard deviation (SD) of 1.2% and using a 2-sided test at a 0.05 α-level, 120 patients per arm 
would have 95% power to detect a treatment difference of 0.6% in mean HbA1c change from 
Baseline to Week 26 between sotagliflozin 400 mg and placebo. 
In Amendment 1, the sample size/power has been recalculated to account for the addition of the 
sotagliflozin 200 mg treatment group after enrollment had commenced. Assuming a common 
standard deviation (SD) of 1.2% and using a 2-sided test at a 0.05 α-level, 100 patients per arm 
will have 
• 
94% power to detect a treatment difference of 0.6% in mean HbA1c change from Baseline 
to Week 26 between sotagliflozin 400 mg and placebo, and  
• 
84% power to detect a treatment difference of 0.5% in mean HbA1c change from Baseline 
to Week 26 between sotagliflozin 200 mg and placebo. 
As a result, the total number of patients will include:  
• 
76 patients randomized (1;1) under the original protocol, balanced between placebo and 
sotagliflozin 400 mg, and 
• 
Approximately 300 patients to be randomized (1:1:1) under Amendment 1, balanced 
among placebo, sotagliflozin 200 mg and sotagliflozin 400 mg doses. 


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1.4             STUDY PLAN 
 
 
The study flowchart can be found in Appendix E. 




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Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
2 
19-Dec-2017 
5 half-lives of sotagliflozin 
prolonged to 10 days considering 
patients with moderate renal 
dysfunction  
5 half-lives of IMP updated from 5 days to 10 
days; TEAE period updated accordingly 
2 
19-Dec-2017 
Baseline eGFR defined as 
recommended by CDISC 
Therapeutic Area Data Standards 
User Guide for Diabetic Kidney 
Disease 
For serum creatinine and eGFR, the 
baseline value is defined as the average of 
all values before the first dose of 
double-blind IMP for those randomized and 
exposed or before randomization for those 
who were randomized but never exposed to 
IMP. 
2 
19-Dec-2017 
The effect in body weight 
considered more closely associated 
with the planned indication. 
the order of secondary objectives / endpoints 
/ multiplicity adjustment updated 
 
1.6             STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
(SAP) 
The statistical analysis plan history table below gives the timing, rationale, and key details for 
major changes to the statistical analysis features in the statistical analysis plan.  Changes also 
incorporated in a protocol amendment are cross-referenced to Table 1.  






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2                  STATISTICAL AND ANALYTICAL PROCEDURES 
2.1             ANALYSIS ENDPOINTS 
2.1.1       Demographic and baseline characteristics 
The baseline value (with the exception of serum creatinine and eGFR) is defined as the last 
available value before the first dose of double-blind investigational medicinal product (IMP) or 
the last available value prior to randomization for patients who were randomized but never 
exposed to IMP. 
For serum creatinine and eGFR, the baseline value is defined as the average of all values before 
the first dose of double-blind IMP for those randomized and exposed or before randomization for 
those who were randomized but never exposed to IMP. 
Baseline safety and efficacy parameters are presented along with the summary statistics for safety 
and efficacy sections (Section 2.4.5 and Section 2.4.4).  
Demographic characteristics 
Demographic characteristics to be summarized are: 
• 
Age (years) derived as: (Year of informed consent - Year of birth), 
• 
Age categories (<50, ≥50 to <65, ≥65 to < 75, ≥75 years), 
• 
Gender (Male, Female), 
• 
Race (White, Black or African American, Asian, American Indian or Alaska native, 
Native Hawaiian or other pacific islander, Multiple, Unknown), 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown), 
• 
HbA1c (%) at screening visit, 
• 
Randomization strata of HbA1c (≤8%, >8%) at screening visit (data from IRT), 
• 
Mean SBP at screening visit, 
• 
Randomization strata of mean SBP (<130 mmHg, ≥130 mmHg) at screening visit (data 
from IRT), 
• 
Baseline body mass index (BMI) (kg/m2) derived as: (Weight in kg)/(Height in meters)2, 
• 
Baseline BMI categories (<30, ≥30 kg/m2), 
• 
Country. 
 


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Disease characteristics at screening or baseline 
Disease history includes: 
• 
Duration of diabetes (years) derived as: (Date of informed consent – Date of diagnosis of 
diabetes + 1)/365.25, 
• 
Age at diagnosis of diabetes (years) derived as: Year of diagnosis of diabetes – Year of 
birth, 
• 
Baseline diabetic microvascular complications (Yes, No) [ie, diabetic retinopathy, diabetic 
neuropathy, diabetic nephropathy, diabetic peripheral neuropathy (sensory or motor), 
diabetic autonomic neuropathy, diabetic foot infection], 
• 
Baseline urine ACR categories (<30 mg/g [Normal], ≥30 to <300 mg/g 
[Microalbuminuria], and ≥300 mg/g [Macroalbuminuria]), 
• 
eGFR at screening (mL/min/1.73m2), 
• 
eGFR categories at screening (<15 mL/min/1.73m2 [End stage renal disease], ≥15 to 
<30 mL/min/1.73m2 [Severe decrease in GFR], ≥30 to <60 mL/min/1.73m2 [Moderate 
decrease in GFR], ≥60 to <90 mL/min/1.73m2 [Mild decrease in GFR], and 
≥90 mL/min/1.73m2 [Normal]). 
• 
Prior antihypertensive medication identified by therapeutic class as agents acting on the 
renin-angiotensin system, beta blocking agents, diuretics (a sub-category: loop diuretics 
identified by pharmacological class as high-ceiling diuretics), calcium channel blockers, 
and antihypertensives according to World Health Organization-Drug Dictionary (WHO-
DD). 
Medical or surgical history  
Medical history and medical findings include: 
• 
Physical examination, 
• 
Medical or surgical history, 
• 
Medical history cardiovascular, 
• 
Surgical history amputation, 
• 
Alcohol habits, 
• 
Tobacco smoking habits. 
Medical and surgical history will be coded to a “lower level term (LLT)”, “preferred term (PT)”, 
“high level term (HLT)”, “high level group term (HLGT)”, and associated primary “system organ 
class (SOC)” using the version of Medical Dictionary for Regulatory Activities (MedDRA) 
currently in effect at Covance at the time of database lock. 
Any technical details related to computation, dates, and imputations for missing dates are 
described in Section 2.5. 


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2.1.2       Prior or concomitant medications 
All medications taken within 3 months before the screening visit (any time for prior SGLT2) and 
until the end of the study are to be reported in the electronic case report form (e-CRF). 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Covance at the time of database lock. 
• 
Prior medications are those the patient used prior to first administration of double-blind 
IMP.  Prior medications can be discontinued before first administration or can be ongoing 
during treatment phase.   
• 
Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, from the 1st administration of double-blind IMP to the date of last administration + 
10 days.  A given medication can be classified both as a prior medication and as a 
concomitant medication.   
• 
Posttreatment medications are those the patient took in the period running from the 11th 
day after the last administration of double-blind IMP up to the end of the study. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.2.1      Rescue therapy 
Except for SGLT2 inhibitors, any approved medication(s) including oral antidiabetic drugs or 
insulin can be prescribed to treat the hyperglycemia at the discretion of the investigator. Rescue 
therapy is considered a noninvestigational medicinal product (NIMP). 
2.1.2.2      Prohibited prior and concomitant medications 
During the study treatment period, the following medications are prohibited: 
• 
Initiation of any antidiabetic agents, including oral or injectable antihyperglycemic agents 
other than the IMP is not allowed before the rescue therapy 
• 
Systemic use of glucocorticoids is not allowed for more than 10 consecutive days (topical, 
ophthalmic, nasal spray or inhaled applications are allowed) 
• 
Initiation of any weight loss drugs (eg, phentermine, orlistat)  
• 
Investigational medicinal products in any other clinical study 
• 
SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin) are not allowed for 
rescue. 
Note: short term use (<10 consecutive days) of the prohibited medication, eg, short-acting insulin 
for treatment of acute illness or surgery is allowed. 
Reduction of digoxin dose should be considered because sotagliflozin acts as a weak P-gp 
inhibitor and increases systemic exposure to digoxin.  


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Other medications which are unlikely to interfere with the pharmacokinetic (PK) or 
pharmacodynamic (PD) of the IMP or confound interpretation of the study endpoints are allowed 
as needed and following discussion between the Investigator and the Sponsor. However, doses of 
chronically administered medicines should be kept fixed during the trial if at all possible. 
After premature permanent discontinuation of the IMPs, any treatments (other than SGLT2 
inhibitors) are permitted, as deemed necessary by the Investigator. 
The dose of all antihypertensive agents should be kept constant during the 12 weeks following 
randomization and no antihypertensive agents should be added or withdrawn for the 12 weeks 
following randomization unless it is considered necessary for safety reasons. 
2.1.3       Efficacy endpoints 
All efficacy measurements collected during the study will be considered for analyses, including 
those obtained after IMP discontinuation or introduction of rescue therapy (see Section 2.5.4). 
HbA1c, 2-hour PPG, FPG, urine ACR, UGE, urine GCR, serum creatinine, and eGFR are 
measured/calculated in a central laboratory (see study flowchart in ). Body weight, SBP and DBP 
(see Section 2.1.4.5) are measured at on-site visits by the investigator. Patients requiring rescue 
are identified as those with the reason for treatment ticked “rescue therapy” in e-CRF 
“Medication” page. 
Efficacy variables will be summarized in both standard international units and conventional units 
when applicable. 
2.1.3.1      Primary efficacy endpoint(s) 
Comparison of sotagliflozin 400 mg versus placebo in change from baseline to Week 26 in 
HbA1c (%).  
2.1.3.2      Secondary efficacy endpoint(s) 
The secondary efficacy endpoints are: 
• 
Comparison of sotagliflozin 400 mg versus placebo for, 
-          Change from Baseline to Week 26 in 2-hour PPG following a MM 
-          Change from Baseline to Week 26 in FPG 
-          Change from Baseline to Week 26 in body weight 
-          Change from Baseline to Week 12 in SBP for patients with baseline SBP ≥130 mmHg 
-          Change from Baseline to Week 12 in SBP for all patients  
-          Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 


Statistical Analysis Plan 
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• 
Comparison of sotagliflozin 200 mg versus placebo for, 
-          Change from Baseline to Week 26 in HbA1c 
-          Change from Baseline to Week 26 in 2-hour PPG following a MM 
-          Change from Baseline to Week 26 in body weight 
-          Change from Baseline to Week 12 in SBP for all patients. 
2.1.3.3      Other efficacy endpoint(s) 
Comparison of sotagliflozin 400 mg and 200 mg doses versus placebo for, 
• 
Change from Baseline to Week 12 in SBP for patients with baseline SBP <130 mmHg 
• 
Changes from Baseline to Week 12 in diastolic blood pressure (DBP) 
• 
Proportion of patients achieving SBP <130 mmHg for those with Baseline 
SBP ≥130 mmHg  
• 
Proportion of patients achieving DBP <80 mmHg for those with Baseline DBP ≥80 mmHg 
• 
Change from Baseline in:  
-          Urine ACR, UGE, and urine GCR 
-          Serum creatinine 
-          eGFR 
• Proportion of patients with reduction in body weight by ≥2%, ≥5%, and ≥10% from 
Baseline  
• Change from Baseline to Week 26 in SBP for all patients and for patients with Baseline 
SBP  ≥130 mmHg 
• Proportion of patients requiring rescue for hyperglycemia 
Comparison of sotagliflozin 200 mg versus placebo for, 
• 
Change from baseline in FPG at Week 26 
• 
Change from baseline in SBP at Week 12 for patients with Baseline SBP ≥130 mmHg 
• 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
2.1.4       Safety endpoints 
The safety analysis will be based on the reported adverse events, hypoglycemia, and other safety 
information, such as clinical laboratory data, vital signs, electrocardiogram (ECG), and physical 
examination, etc.  


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Observation period  
The observation period will be divided into 4 epochs: 
• 
The screening epoch is defined as the time from the signed informed consent date up to 
the first administration of the double-blind IMP.  
• 
The treatment epoch is defined as the time from the first administration of the double-
blind IMP to the last administration of the double-blind IMP. 
• 
The residual treatment epoch is defined as the time from the last administration of the 
double-blind IMP up to 10 days (1 day for hypoglycemia) after the last administration of 
the double-blind IMP. 
The treatment-emergent adverse event (TEAE) period will include both treatment and 
residual treatment epochs. 
• 
The posttreatment epoch is defined as the period of time starting the day after the end of 
the treatment-emergent adverse event period up to the last protocol-planned visit or the 
resolution/stabilization of all serious adverse events (SAE), adverse events of special 
interest (AESI) and events of special interest (EOSI), whichever is later. 
The on-study observation period is defined as the time from start of double-blind treatment until 
the end of the study (defined as the last scheduled visit for those who completed the study and the 
date collected on e-CRF page “Completion of End of Study/Follow-up” for those who did not 
complete the study). 
The post-study observation period is defined as the time from the day after the end of the study 
until the resolution/stabilization of all SAE, AESI and EOSI if applicable. 
2.1.4.1      Hypoglycemia 
Hypoglycemia will be identified as events recorded on the dedicated e-CRF “Hypoglycemic event 
information” page, and will be categorized as follows (see study protocol for further details): 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, intravenous glucose or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. 
Self-monitored plasma glucose values may not be available, but neurological recovery attributable 
to the restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. 
Severe hypoglycemia is identified in e-CRF “Hypoglycemic event information” page as those 
documented as, 
1. To the question “Countermeasure Administration”, ticked the option “Subject was Not 
Capable of Treating Self and Required Assistance”, and  


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2. To the question “Were Symptoms Present”, ticked “Yes”. 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L 
(≤70 mg/dL). 
Clinical symptoms that are considered to result from a hypoglycemic episode are eg, increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
Documented symptomatic hypoglycemia is identified in e-CRF “Hypoglycemic event 
information” page as those documented as, 
1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and  
2. To the question “Were Symptoms Present”, ticked “Yes”, and  
3. With a plasma glucose value before countermeasure ≤3.9 mmol/L (≤70 mg/dL).  
Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL). 
Asymptomatic hypoglycemia is identified in e-CRF “Hypoglycemic event information” page as 
those documented as, 
1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and 
2. To the question “Were Symptoms Present”, ticked “No”, and  
3. With a plasma glucose value before countermeasure ≤3.9 mmol/L (≤70 mg/dL).  
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms of hypoglycemia are not 
accompanied by a plasma glucose determination, (but that was presumably caused by a plasma 
glucose concentration ≤3.9 mmol/L [≤70 mg/dL]), ie, symptoms treated with oral carbohydrate 
without a test of plasma glucose. 
Probable symptomatic hypoglycemia is identified in e-CRF “Hypoglycemic event information” 
page as those documented as, 
1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and 
2. To the question “Were Symptoms Present”, ticked “Yes”, and 
3. With no plasma glucose value before countermeasure, and  


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4. To the question “Did this countermeasure lead a significant improvement or prompt 
recovery?”, ticked “Yes”. 
Relative hypoglycemia 
Relative hypoglycemia, recently termed “pseudo-hypoglycemia” is an event during which the 
patient reports typical symptoms of hypoglycemia, and interprets the symptoms as indicative of 
hypoglycemia, but with a measured plasma glucose concentration >3.9 mmol/L (>70 mg/dL). 
Relative hypoglycemia is identified in e-CRF “Hypoglycemic event information” page as those 
documented as, 
1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance” 
2. To the question “Were Symptoms Present”, ticked “Yes”, and  
3. With a plasma glucose value before countermeasure >3.9 mmol/L (>70 mg/dL).  
In addition of the threshold of ≤3.9 mmol/L (≤70 mg/dL), hypoglycemia episodes with a plasma 
glucose of <3.0 mmol/L (<54 mg/dL) will be analyzed separately.  
Any hypoglycemic event fulfilling the criteria of a SAE or leading to unconsciousness, coma, or 
seizure will also be recorded as a SAE (see Section 2.1.4.2). 
2.1.4.2      Adverse events variables 
Adverse event observation period  
• 
Pretreatment adverse events are adverse events that developed or worsened or became 
serious from the signed informed consent date up to first administration of double-blind 
IMP. 
• 
Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the treatment-emergent adverse event period. 
• 
Posttreatment adverse events are adverse events that developed or worsened or became 
serious during the posttreatment period. 
All adverse events (including SAE, AESI and EOSI will be coded to a lower-level term (LLT), 
preferred term (PT), high-level term (HLT), high-level group term (HLGT), and associated 
primary system organ class (SOC) using the version of MedDRA currently in effect at Covance at 
the time of database lock. 
The occurrence of adverse events (including SAE, AESI and EOSI) will be recorded from the 
time of signed informed consent until the end of the study (see Section 2.1.4) or the 
resolution/stabilization of all SAE, AESI and EOSI. 
AESI include: 
• 
Pregnancy 


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• 
Symptomatic overdose with IMP/NIMP 
• 
Alanine aminotransferase (ALT) increase > 3 times upper limit of normal (ULN) 
EOSI include:  
• 
Major adverse cardiovascular events (MACE [cardiovascular death, myocardial infarction, 
or stroke]) and other specific cardiovascular (CV) events (eg, heart failure requiring 
hospitalization)   
• 
Severe hypoglycemia 
• 
Genital mycotic infections (to include vulvovaginal candidiasis in females and candida 
balanitis in males) 
• 
Urinary tract infection 
• 
Clinically relevant volume depletion and events related/possibly related to volume 
depletion 
• 
Diarrhea 
• 
Pancreatitis 
• 
Bone fractures 
• 
Venous thrombotic events, to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism) 
• 
Diabetic ketoacidosis 
• 
Renal events, to include 50% decline in eGFR, end stage kidney disease, renal death 
• 
Malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, 
prostate, and thyroid cancer) 
• 
Adverse event leading to an amputation. 
A Clinical Endpoint Committee(s) (CEC) will in a blinded manner review and adjudicate all 
deaths, myocardial infarction, stroke, unstable angina requiring hospitalization, and heart failure 
requiring hospitalization, selected renal events, bone fracture, and diabetic ketoacidosis. 
Two independent committees will review safety events that require ongoing monitoring to ensure 
timing protocol amendments in case a safety signal is identified. These events are: 1) potential 
cases of drug-induced liver injury (DILI), and 2) cases of amputations. The two committees will 
review the cases in a treatment-blinded manner and will present their assessment to the DMC. 
AESI and EOSI will be identified based on criteria in Table 3.  
Table 3 - Criteria for AESI and EOSI  
 


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AE Grouping 
Criteria 
AESI 
 
Pregnancy 
eCRF “Pregnancy” 
Symptomatic overdose 
with IMP/NIMP  
“Overdose of IMP” or “Overdose of NIMP” checked and “Symptomatic 
overdose” checked in eCRF “Overdose” 
ALT increase > 3X ULN 
eCRF “ALT increase” 
EOSI adjudicated 
Cardiovascular death 
Positively adjudicated by CEC: “Cardiovascular” or “Undetermined” as 
the primary cause of death 
Myocardial infarction, 
Unstable Angina requiring 
hospitalization 
Positively adjudicated by CEC: Yes to the question “Does the event 
meet the definition of an MI for this study?”, or Yes to the question “If 
event is not an MI, does the event meet the definition of an UA 
Requiring admission to hospital or emergency room, for this study?” 
Stroke 
Positively adjudicated by CEC: Yes to the question “Does the event 
meet the definition of a Stroke for this study?” 
Heart failure requiring 
hospitalization 
Positively adjudicated by CEC: Yes to the question “Does the event 
meet the definition of a Heart Failure Event for this study?”  
Bone fractures 
Positively adjudicated by CEC: Yes to the question “Did the Fracture 
occur?” 
Diabetic ketoacidosis 
Positively adjudicated by CEC: Yes to the question “Does this event 
meet the criteria to be a DKA event?” 
EOSI Renal events where select events adjudicated 
Sustained ≥50% decrease 
in eGFR 
(1) For ≥50% decrease in eGFR from baseline, 
      (1a) confirmed ≥50% decrease in GFR for ≥30 days with no 
reversible cause as recorded in eCRF “eGFR decrease”, OR  
      (1b) positively adjudicated by CEC: Yes to the question “Does the 
subject meet the criteria of CKD progression” for ≥50% decrease in 
eGFR. 
Sustained eGFR <15 
mL/min/1.73 m2 
(2) For eGFR <15 mL/min/1.73 m2, 
      (2a) confirmed eGFR <15 mL/min/1.73 m2 for ≥30 days with no 
reversible cause as recorded in eCRF “eGFR decrease”, OR 
       (2b) positively adjudicated by CEC: Yes to the question “Does the 
subject meet the criteria of CKD progression”. 
Chronic dialysis 
(3) For dialysis,  
      (3a) dialysis lasted for ≥90 days (e.g. end date – start date+ 1 ≥90) 
as recorded in eCRF “Renal Event – Dialysis”, OR 


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AE Grouping 
Criteria 
      (3b) positively adjudicated by CEC: Yes to the question “. Does the 
subject meet the criteria for ESRD”. 
Renal transplant * 
(4) “Renal transplant” captured in eCRF “Other procedure form”, where 
adjudication is not required. PTs of Renal transplant (10038533), Renal 
and pancreas transplant (10052278), Renal and liver transplant 
(10052279) based on MedDRA v22.0. 
Renal death 
(5) Renal death as positively adjudicated by CEC: “Death - Non-
Cardiovascular (Renal)” as the primary cause of death 
EOSI not adjudicated * 
 
Severe hypoglycemia 
algorithm specified in Section 2.1.4.1 based on eCRF “Hypoglycemic 
Events” 
Genital mycotic infections 
PTs in Appendix C 
Urinary tract infections 
PTs in Appendix C 
Clinically relevant volume 
depletion and events 
related/possibly related to 
volume depletion 
PTs in Appendix C 
Diarrhea 
Narrow search on “Noninfectious diarrhoea (SMQ)” [20000218] plus 
the following PTs (MedDRA v22.0):  Gastroenteritis (10017888), 
Antidiarrhoeal supportive care (10055660), Enteritis (10014866), 
Enteritis leukopenic (10014877), Enterocolitis (10014893), Enterocolitis 
haemorrhagic (10014896) 
Pancreatitis 
PTs in Appendix C 
Venous thrombotic events 
PTs in Appendix C 
Malignancies of special 
interest 
Breast cancer: Narrow search on “Breast neoplasms, malignant and 
unspecified (SMQ)” [20000149] 
Prostate cancer: Narrow search on “Prostate neoplasms, malignant 
and unspecified (SMQ)” [20000152] 
Leydig-cell cancer: PTs of Leydig cell tumour of the testis (10024407) 
and Ovarian Sertoli-Leydig cell tumour (10073270) based on MedDRA 
v22.0 
Thyroid cancer: PTs in Appendix C 
Renal cell cancer: PTs in Appendix C 
Pancreatic cancer: PTs in Appendix C 
Bladder cancer: PTs in Appendix C 
EOSI AE leading to an amputation 


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AE Grouping 
Criteria 
Adverse event leading to 
an amputation 
“AE Correction” as the reason for amputation in eCRF “Other 
Procedures related to Amputation”  
AE potentially leading to an 
amputation * 
PTs in Appendix C 
*  Search terms will be updated using the MedDRA version currently in effect at Covance at the time of database lock for EOSI identified by 
them. 
AE potentially leading to an amputation: not an EOSI per individual protocol; analyzed due to their relevance to lower limb complication and 
amputations as a requirement from health authorities. 
2.1.4.3      Deaths 
The deaths observation period are per the observation periods defined above.  
• 
Death on-study:  deaths occurring during the on-study observation period 
• 
Death on-treatment:  deaths occurring during the TEAE period  
• 
Death post-study:  deaths occurring after the end of the study  
2.1.4.4      Laboratory safety variables 
Clinical laboratory data consists of blood analysis (including hematology, clinical chemistry, 
amylase, lipase and lipid profile) and urinalysis.  Clinical laboratory values will be summarized in 
both standard international units and conventional units when applicable. 
Blood samples for clinical laboratories will be collected at designated visits (see study flowchart 
in Appendix E). The following laboratory data will be measured at a central laboratory:  
• 
Hematology  
-          Red blood cells and platelets:  hemoglobin, hematocrit, red blood cell, platelets 
count  
-          White blood cells:  white blood cell, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils 
• 
Clinical chemistry  
-          Metabolism:  glucose (serum), creatine phosphokinase (CPK),        
-          Electrolytes and minerals:  sodium, potassium, chloride, bicarbonate (ie, carbon 
dioxide), calcium, phosphorus, magnesium  
-          Renal function:  blood urea nitrogen (BUN), creatinine, uric acid,         
-          Liver function:  total protein, albumin, ALT, aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), total bilirubin, Lactic acid dehydrogenase (LDH)       
• 
Lipid parameters (fasting): total cholesterol (TC), high density lipoprotein cholesterol 
(HDL-C), low density lipoprotein cholesterol (LDL-C) (calculated by Friedwald equation, 
See Section 2.5.1), Non-HDL-C (calculated as the difference between TC and HDL-C), 
triglycerides (TG). 


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• 
Pancreatic enzymes: lipase, amylase. 
• 
Markers of Intestinal Transit and Absorption: Vitamins: B6, B12, K, E and A, Serum 
folate, and Ferritin  
• 
Markers of bone and calcium metabolism  
-          Calcium,  
-          25-hydroxyvitamin D,  
-          1,25-dihydroxyvitamin D,  
-          Phosphorus,  
-          Parathyroid hormone (PTH),  
-          Markers of bone resorption: N-terminal telopeptide (NTX), beta-C-terminal 
telopeptide (β-CTX-1),  
-          Marker of bone formation: type 1 procollagen N-terminal (P1NP) 
Urine samples will be collected at designated visits (see study flowchart in Appendix E). The 
following laboratory data will be measured at a central laboratory:  
• 
Urine dipstick includes: specific gravity, pH, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, and leukocyte esterase 
• 
Urine microscopy includes, but is not limited to: detection of formed cellular elements, 
casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment 
• 
Urine markers of bone and calcium metabolism: calcium and phosphorus. 
• 
Urine albumin, calcium, glucose and creatinine 
Serum glucose, UGE, calculated urine ACR and calculated urine GCR will be presented as 
efficacy parameters in Section 2.4.4. For creatinine and calculated eGFR, PCSA summaries will 
be presented in the safety section while descriptive summaries in the efficacy section. 
Technical formulas are described in Section 2.5.1. 
2.1.4.5      Vital signs variables 
Vital signs include:  heart rate (HR), systolic and diastolic blood pressure, temperature, and 
respiratory rate (see study flowchart in Appendix E for designated visits).  They will be performed 
after the patient has been seated for at least 5 minutes. Blood pressure and HR will be assessed 
3 times with at least 1 minute between each measurement following the 5-minute rest period. The 
mean of the 3 measurements will be analyzed for each vital sign variable (HR, SBP, and DBP). 
2.1.4.6      Physical examination 
A complete physical exam will be performed at Visit 1 (Screening) and Visit 9 (Week 26). 
“Normal”, “Abnormal” or “Not done” as determined by the Investigator will be reported in the 
e-CRF by body system. 


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2.1.4.7      Electrocardiogram variables 
12-lead ECGs will be performed at Visit 1 (Screening), Visit 3 (Randomization) and Visit 9 
(Week 26). ECG status of “normal” or “abnormal” will be reported in the e-CRF as determined by 
the investigator. 
2.1.5       Pharmacokinetic variables  
Pharmacokinetic variables include the concentration of sotagliflozin and its 3-O-glucuronide 
metabolite in the sotagliflozin group.  
2.2             DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as all patients who have signed the informed consent.   
Randomized patients consist of all patients with a signed informed consent form who have had a 
treatment kit number allocated and recorded in the IRT database, regardless of whether the 
treatment kit was used or not. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary tables: 
• 
Screened patients 
• 
Run in patients: patients who had a run-in record in IRT, 
• 
Screen failure patients (including failures during run-in) and reasons for screen failure (see 
Appendix A  for details on the mapping of inclusion and exclusion criteria under the 
original protocol and Amendments) 
• 
Nonrandomized but treated patients 
• 
Randomized patients 
• 
Randomized but not treated patients 
• 
Randomized and treated patients 
• 
Patients who have completed the 26-week double-blind treatment period as scheduled 
• 
Patients who did not complete the 26-week double-blind treatment period as scheduled 
and the reasons for permanent treatment discontinuation 
• 
Patients who have completed the study as scheduled 
• 
Patients who did not complete the study as scheduled and the reasons for study 
discontinuation 


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• 
Patients’ end of study status (completed, not completed) and corresponding end of 
treatment status (completed, not completed) 
• 
Status at last study contact. 
For screened, run in, screen failure, and nonrandomized but treated patients, percentages will be 
calculated using the number of screened patients as the denominator. All other categories of 
patients will be presented by treatment group and the percentages will be calculated using the 
number of randomized patients within each treatment group as the denominator.  Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages by treatment 
group.  Patients prematurely discontinued from treatment and/or study, along with reasons for 
discontinuation, will also be listed.  
A summary of the distribution of patients by country and center will also be provided (overall 
number of patients screened, run-in, randomized, and treated, as well as number of patients 
randomized, discontinued from study treatment, and discontinued from study for each treatment 
group). 
Patients treated but not randomized, patients randomized but not treated and patients randomized 
but not treated as randomized will be identified and described in separate listings. The patients of 
the third category (randomized and not treated as randomized) will be part of efficacy and safety 
analyses (see Section 2.3). Patients randomized but not treated will be included in efficacy 
analysis. Safety data of patients treated but not randomized will be reported separately. 
The randomization strata [HbA1c at Screening (≤8.0%, >8.0%) and mean SBP (<130, 
≥130 mmHg)] assigned by IRT will be summarized. The percentages will be calculated using the 
number of randomized patients as the denominator. The discrepancy between the strata assigned 
by IRT and the information reported on e-CRF will be listed for all randomized patients. 
Kaplan-Meier (KM) plots of the cumulative incidence of double-blind IMP discontinuations due 
to any reason and due to AEs will be provided for the double-blind treatment period separately 
(see Section 2.5.4). A listing of these patients, along with the reason for discontinuation of 
treatment, study completion status and the reason for discontinuation study, will be provided.  
All important deviations including randomization and drug-dispensing irregularities will be 
summarized in tables giving numbers and percentages of deviations by randomized treatment 
group. 
Additionally, the analysis populations for safety, efficacy, and pharmacokinetics defined in 
Section 2.3 will be summarized in a table by number of patients in the randomized population.  
• 
Efficacy population: intent-to-treat (ITT) population  
• 
Safety population 
• 
PK population. 
2.2.1       Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 


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


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As described in Section 1.3, 76 patients were randomized 1:1 to receive sotagliflozin 400 mg or 
placebo under the original protocol and approximate 300 patients are to be randomized 1:1:1 to 
receive sotagliflozin 400 mg, sotagliflozin 200 mg, or placebo under Amendment 1. To ensure an 
unbiased comparison, the statistical analysis is planned so as to compare each sotagliflozin dose 
group with its matching placebo (1:1) within the same randomization, that is, sotagliflozin 400 mg 
versus placebo pooled under the original protocol and Amendment 1, and sotagliflozin 200 mg 
versus placebo under Amendment 1 only.   
2.3.1       Efficacy populations 
Efficacy analyses will be based on the treatment group allocated by the IRT according to the 
randomization schedule at randomization visit (as randomized), irrespective of the treatment 
actually received. 
2.3.1.1      Intent–to-treat population  
Efficacy analyses will be based on the ITT population, defined as all randomized patients, 
irrespective of compliance with the study protocol and procedures. Patients will be analyzed for 
efficacy according to the treatment group to which they are randomized, that is, sotagliflozin 
400 mg versus placebo under the original protocol and Amendment 1, and sotagliflozin 200 mg 
versus placebo under Amendment 1.  
2.3.2       Safety population 
Safety analyses will be based on the safety population, defined as all randomized patients who 
receive at least one dose of double-blind IMP (regardless of the amount of treatment 
administered). Patients will be analyzed according to the treatment actually received, that is, 
sotagliflozin 400 mg versus placebo under the original protocol and Amendment 1, and 
sotagliflozin 200 mg versus placebo under Amendment 1.  
In addition:  
• 
Nonrandomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately 
• 
Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized 
• 
When a patient is exposed to both sotagliflozin and placebo, the patient will be analyzed in 
the appropriate sotagliflozin group (depending on the treatment kits taken [400 mg or 
200 mg]) 
• 
When a patient is exposed to both sotagliflozin 400 mg (treatment kits) and 200 mg 
(treatment kits), the patient will be analyzed in the sotagliflozin 200 mg group 
• 
Randomized patients will be excluded from the safety population only if there is 
documented evidence (ie, all study dates recorded as no medication taken) that patients 
have not taken the study treatment. If a patient is dispensed double-blind IMP and is lost to 
follow-up without any documented evidence, the patient will be considered exposed. 


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2.3.3       PK population 
For PK analyses, the PK population is defined as all safety patients who contribute with at least 
1 valid plasma concentration of sotagliflozin or its 3-O-glucuronide metabolite. The PK data will 
be analyzed according to the treatment actually received (see Section 2.3.2).  
2.4             STATISTICAL METHODS 
2.4.1       Demographics and baseline characteristics 
Continuous data will be summarized using the number of observations available, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group.  Categorical and 
ordinal data will be summarized using the count and percentage of patients in each treatment 
group. 
Parameters will be summarized based on the randomized population analyzed in the treatment 
group to which they were randomized, that is, sotagliflozin 400 mg versus placebo under the 
original protocol and Amendment 1, and sotagliflozin 200 mg versus placebo under Amendment 
1.  Analyses for the safety population will be included in the appendices if the size of the safety 
population is different (>10%) from the size of that in the primary analysis population (ie, 
randomized patients) for any treatment group. 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall (pooled 
across treatment groups) using descriptive statistics.  
P-values on the treatment difference for the demographic and baseline characteristic data will not 
be calculated.  
In general, no specific description of the safety parameters will be provided at baseline.  If 
relevant, the baseline values will be described along with each safety analysis. 
In general, no specific description of the efficacy parameters will be provided at baseline.  If 
relevant, the baseline values will be described along with each efficacy analysis.  
2.4.2       Prior or concomitant medications  
The prior, concomitant and posttreatment medications will be presented in the randomized 
population for each treatment group (and overall for the summary of prior medications), using 
counts and percentages. No statistical test for the between-group difference will be performed. 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomical therapeutic chemical (ATC) class (anatomic category) 
and the first 3 digits of the ATC class (therapeutic category).  A given medication may be 
classified in more than 1 ATC class. All ATC codes corresponding to a medication will be 
summarized, and a patient will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. Therefore a patient may be counted several times for the same 
medication.  


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Prior medications will be presented by anatomic and therapeutic categories and sorted by 
decreasing frequency of ATC based on the overall incidence across treatment groups.  In case of 
equal frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be 
used. 
Concomitant and posttreatment medications will be presented by anatomic and therapeutic 
categories and sorted by decreasing frequency of ATC based on the incidence in the sotagliflozin 
400 mg group. In case of equal frequency regarding ATCs (anatomic or therapeutic categories), 
alphabetical order will be used.  
2.4.3       Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2). 
2.4.3.1      Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure. 
Duration of IMP exposure is defined as last dose date of double-blind IMP – first dose date of 
double-blind IMP + 1 day, regardless of unplanned intermittent discontinuations (see Section 
2.5.3 for calculation in case of missing or incomplete data).   
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number of 
patients exposed, mean, SD, median, minimum, and maximum).  In addition, duration of 
treatment exposure will also be summarized categorically by numbers and percentages for each of 
the following categories and cumulatively according to these categories:  
• 
1 to 28 days,  
• 
29 to 56 days,  
• 
57 to 84 days,  
• 
85 to 126 days,  
• 
127 to 182 days,  
• 
>182 days. 
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient years. 
Number and percentage of patients by final dose at the end of the treatment will also be presented 
by each treatment group. 


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2.4.3.2      Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Percentage of compliance for a patient will be defined as the number of days that the patient was 
compliant divided by the total number of days that the patient was planned to take during the 
treatment epoch defined in Section 2.1.4 (ie, from the first date to the last date of double-blind 
IMP administration).  
Above-planned dosing percentage for a patient will be defined as the number of days that the 
patient took a higher dose than planned divided by the total number of days that the patient was 
planned to take during the treatment epoch.  
Under-planned dosing percentage for a patient will be defined as the number of days that the 
patient took a lower dose than planned divided by the total number of days that the patient was 
planned to take during the treatment epoch.  
Treatment compliance, above-planned, and under-planned dosing percentages will be summarized 
descriptively as quantitative variables (number, mean, SD, median, minimum, and maximum). 
The percentage of patients whose compliance is <80% will be summarized. In addition, numbers 
and percentages of patients with at least 1 day above-planned dose will be provided, as well as 
numbers and percentages of patients with (0, 20%], and >20% of days under-planned dose. 
Cases of overdose (see study protocol for further details) will constitute AEs/SAEs and be 
analyzed as such. More generally, dosing irregularities will be listed in Section 2.2.1. 
2.4.4       Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population using the efficacy assessments 
collected during the study, including those obtained after IMP discontinuation or introduction of 
rescue therapy, unless otherwise specified. 
Missing data for efficacy analyses is identified through steps described in Section 2.5.4.  
2.4.4.1      Analysis of primary efficacy endpoint(s) 
The statistical tests will be two-sided tests at a nominal 5% significance level. 
Primary analysis 
The primary efficacy endpoint of change in HbA1c from baseline to Week 26 will be analyzed by 
an Analysis of Covariance (ANCOVA) model using HbA1c values measured at baseline and 
Week 26 (observed or imputed). The missing data at endpoint will be imputed by multiple 
imputation (MI) methods in 2 parts as detailed below. To be concise, the following texts related to 
imputation are generalized to accommodate primary as well as continuous secondary efficacy 
endpoints. 


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Missing endpoint data at Week 26 (or Week 12 for SBP) visit will be imputed using a model built 
separately in each treatment group and estimated from the patients in the same treatment group 
who prematurely discontinue the IMP before the Week 26 (or Week 12 for SBP) visit but have the 
measurement for the endpoint (ie, retrieved dropouts). The imputation model will include the 
randomization strata and the corresponding baseline value. In cases of non-convergence during 
the imputations, the offending stratum will be identified and then will be dropped from the model. 
Considering that the number of retrieved dropout patients in each treatment group is expected to 
be small, a simple imputation model based on regression will be used with baseline measurement 
included as the predictor. This will serve as the primary method of imputation for missing data 
should sampling criteria be satisfied (see below). 
An alternative (back-up) imputation method will be used if the number of patients who 
prematurely discontinue the IMP before the Week 26 (or Week 12 for SBP) visit but have the 
measurement for the endpoint is < 5 in any treatment groups (ie, an insufficient number of 
retrieved dropouts to support the imputation method described above). This criterion will be 
assessed for each primary or continuous secondary efficacy endpoint. 
In the back-up imputation method, missing post-baseline endpoint values at Week 26 (or Week 12 
for SBP) will be imputed by the washout Multiple Imputation (MI) method under the missing not 
at random (MNAR) framework.  
Missing endpoint data at the Week 26 (or Week 12 for SBP) in all treatment groups (sotagliflozin 
400 mg, sotagliflozin 200 mg and placebo) are imputed from a model estimated from patients in 
the placebo group who have the endpoint data available.  
For patients in the sotagliflozin group with missing data at Week 26 (or Week 12 for SBP), their 
missing values will be imputed using observed baseline and the observed primary endpoint data 
from placebo completers; no intermittent values from either placebo or the active treatment 
groups will be used.  
For placebo patients, missing data will be imputed based on the placebo group data. Intermittent 
observed values will be used while imputing missing values at Week 26 (or Week 12 for SBP). In 
cases that a non-monotone missing data pattern occurs at the intermediate visits, these data points 
will be first imputed in the placebo group using the Markov Chain Monte Carlo (MCMC) option 
in PROC MI to achieve a monotone missing pattern for all placebo patients.  The Week 26 (or 
Week 12 for SBP) endpoint values will be subsequently imputed from the multiple copies of the 
original dataset where each copy will have a monotone missing pattern. 
The imputation models for the washout MI method will include the randomization strata and the 
corresponding baseline value. Missing data will be imputed using the regression method.  
In cases of non-convergence during the imputations, especially for the MCMC application in the 
placebo non-monotone datasets, graphical measures (eg, trace and autocorrelation plots) will be 
used to identify the offending variable and once detected, that variable(s) will be dropped from the 
model and the imputations will be re-run. These re-run models will use the same seed number and 
number of imputations as used in the original models.          
Using either imputation method, missing endpoint data will be imputed 2000 times to generate 
multiple data sets with complete data. Other details of the imputation procedures such as the seed 


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number and sort ordering are specified in the SAS programs. The HbA1c change from baseline to 
Week 26 will be derived from observed and imputed HbA1c values at Week 26.  
To impute the missing values for the primary endpoint, the imputation for the two doses of 
sotagloflozin will be performed separately.  To compare sotagliflozin 400 mg  and placebo, 
imputations will be performed using the pooled dataset of patients randomized to placebo and 
sotagliflozin 400 mg under the Original protocol plus the Amendment 1. However, for the placebo 
and sotagliflozin 200 mg, patients randomized to the two doses under the protocol Amendment 1 
will be used for imputing missing values. 
Each of the completed datasets after the imputation will be analyzed using the Analysis of 
Covariance (ANCOVA) model for the placebo and sotagliflozin 400 mg patients randomized 
under the original protocol and Amendment 1, or for the placebo and sotagliflozin 200 mg 
patients randomized under the protocol Amendment 1. The model will include treatment groups 
(sotagliflozin 400 mg and placebo; or sotagliflozin 200 mg, and placebo), randomization stratum 
of HbA1c (≤8.0%, >8.0%), randomization stratum of SBP (<130 mmHg, ≥130 mmHg), and 
country as fixed factors, and baseline HbA1c value as a covariate. Results from each analysis will 
be combined using Rubin’s formula to provide the adjusted mean change in HbA1c from Baseline 
to Week 26 for sotagliflozin 400 mg and placebo (under the original protocol and Amendment 1) 
and for sotagliflozin 200 mg and placebo (under the Amendment 1), as well as the between-group 
differences and its associated 95% confidence interval (CI).  
 
Sensitivity analyses 
Tipping point analysis based on the same MI method as applied to the primary analysis will be 
performed to examine the robustness of the results from the primary analysis. Patients who were 
randomized to sotagliflozin 400 mg group and had no HbA1c data at Week 26 will be given a 
penalty. The penalty will be gradually increased to evaluate at which level the conclusion of the 
analyses in terms of statistical significance is changed. The tipping point is the penalty level, at 
which the magnitude of efficacy reduction in patients without HbA1c data at Week 26 creates a 
shift in the treatment effect of sotagliflozin 400 mg from being statistically significantly better 
than placebo to a non-statistically significant effect. LS mean difference between sotagliflozin 
400 mg and placebo and its associated p-value for superiority will be provided for each penalty 
level. The steps to perform the tipping point analysis are as follows: 
1. Missing data will be imputed using the same MI method as applied to the primary 
analysis, 
2. The imputed HbA1c value at Week 26 in the sotagliflozin 400 mg group will be penalized  
by adding a penalty δ (eg, δ = 0.1%) in each complete dataset, 
3. Change from baseline at Week 26 in HbA1c will be analyzed using the same ANCOVA 
model as specified in the primary analysis in each complete dataset, 
4. Results will be combined across complete datasets using Rubin’s formula, 
5. Steps 2 to 4 will be repeated with incremental penalty at δ (ie, δ, 2δ, 3δ, ……) until the p-
value for treatment effect of sotagliflozin 400 mg compared to placebo estimated in Step 4 
is >0.05.  


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The above tipping point analysis will be replicated to examine the robustness of the treatment 
effect of sotagliflozin 200 mg (ie, adding penalty to the sotagliflozin 200 mg group in Step 2) for 
the patients randomized to placebo and sotagliflozin 200 mg under the protocol Amendment 1. 
The tipping point analysis will be performed for the primary variable only if that variable (change 
from baseline to Week 26 in HbA1c) is statistically significant at α = 0.05 (2-sided). 
In addition to the tipping point analyses, if the retrieved dropout imputation is applied to the 
primary analysis, the analysis based on the washout imputation method (ie, the backup imputation 
method) will be presented as a sensitivity analysis. 
Patients in this study have undergone sampling for plasma levels of sotagliflozin and its main 
active metabolite in order to perform population PK analysis.  Patients may be identified as those 
who have no detectable levels of active study drug or metabolite in their samples (ie, Below Limit 
of Quantification or BLOQ).  When sample analysis has been completed and the study has been 
unblinded, explanations for some of these patients may be found: known non-compliance or 
sampling occurring after treatment had been discontinued.  In other cases, drug intake history 
relative to the randomization assignment may not be fully explained.  The ITT-based analyses 
specified in this document provides for a conservative assessment of the efficacy data should 
patients have been subjected to these unexplained non-compliance findings or PK ‘anomalies’. To 
provide a broader perspective on the impact of these apparent errors in compliance, additional 
sensitivity analyses of the primary efficacy endpoint and continuous efficacy endpoints may be 
conducted. The need to perform such analyses, their specifics, and results will be provided in the 
Clinical Study Report (CSR), if applicable. The analysis methods applied to the patient 
subpopulations defined by the occurrence of the PK anomalies (eg, exclusion of patients with PK 
anomalies from the ITT dataset) will include the ANCOVA model using the retrieved dropout 
and/or washout MI methods previously specified in this section. 
 
Assessment of treatment effect by subgroup  
Descriptive analyses will be performed on the primary endpoint to summarize the treatment 
effects across subgroups defined by the following Baseline or Screening factors: 
• 
Race (White, Black or African American, Asian, Other) (any race groups with fewer than 
5 patients may be combined with “Other” category as appropriate),  
• 
Ethnicity (Hispanic, Not Hispanic), 
• 
Age group (<50, ≥50 to <65, ≥65 years) (any category with fewer than 5 patients may be 
combined with another category as appropriate), 
• 
Gender (Male, Female), 
• 
Baseline BMI level (<30, ≥30 kg/m²), 
• 
Baseline HbA1c (≤8.0%, >8.0%), 
• 
Baseline HbA1c (≤8.5%, >8.5%), 


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• 
Baseline mean SBP (<130 mmHg, ≥130 mmHg), 
• 
Baseline eGFR (≥30 to <60 mL/min/1.73m2 [Moderate decrease in GFR], ≥60 to 
<90 mL/min/1.73m2 [Mild decrease in GFR], and ≥90 mL/min/1.73m2 [Normal]) 
• 
Country. 
The treatment effect (sotagliflozin 400 mg versus placebo under the original protocol and 
Amendment 1 or sotagliflozin 200 mg versus placebo under the Amendment 1) across the 
subgroups defined for each of these factors will be estimated for the change from Baseline to 
Week 26 in HbA1c in the ITT population, and using the same MI method as applied to the 
primary analysis. The ANCOVA model will include treatment groups (sotagliflozin 400 mg and 
placebo; or sotagliflozin 200 mg and placebo), randomization stratum of HbA1c (≤8.0%, >8.0%), 
randomization stratum of SBP (<130 mmHg, ≥130 mmHg), subgroup factor, treatment-by-
subgroup factor, and country as fixed factors and using baseline HbA1c value as a covariate. The 
adjusted estimates of treatment mean differences (sotagliflozin 400 mg versus placebo or 
sotagliflozin 200 mg versus placebo) with standard error (SE) and 95% CIs will be provided as 
appropriate across the subgroups. A graphical presentation of the results (ie, forest plot) will also 
be provided. 
In the case that the subgroup factor is identical or similar to a randomization strata factor (eg, 
baseline HbA1c or baseline mean SBP category), only the subgroup factor (as a single factor or an 
interaction term) will be included in the model in order to avoid the issue of collinearity in the 
analysis. The corresponding strata factor will not be included in the model. 
Summary statistics at scheduled visits 
Summary statistics (for screening value, baseline value, observed post-baseline value and its 
changes from baseline) at scheduled visits will be provided for each treatment group. The 
summary will include the number of observations, mean, SD, SE, minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from baseline (±SE) at each of the scheduled visits. 
Similar presentations will be provided excluding measurements after rescue therapy during the 
26-week double-blind treatment period. 
2.4.4.2      Analyses of secondary efficacy endpoints 
For continuous secondary efficacy parameters  (see Section 2.1.3) with missing data at baseline, 
missing data will be imputed using MI under the missing at random (MAR) assumption. Missing 
data at baseline will be imputed using regression method that includes randomization stratum of 
HbA1c (≤8.0%, >8.0%), randomization stratum of SBP (<130 mmHg, ≥130 mmHg), and baseline 
value in the imputation model. 
Each continuous secondary efficacy endpoint (Section 2.1.3) will be analyzed using a similar 
ANCOVA model including the measurements at baseline and endpoint (observed or imputed). 
The missing data at endpoint will be imputed by the retrieved dropouts if there are at least 5 
patients in each study treatment group who discontinued but have the endpoint. Otherwise, the 


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washout imputation method will be used according to the criterion described in Section 2.4.1. 
After the imputation, each of the complete datasets will be analyzed by an ANCOVA model.  
• 
To compare sotagliflozin 400 mg versus placebo under the original protocol and 
Amendment 1, the ANCOVA model will include treatment groups (sotagliflozin 400 mg,  
placebo), randomization stratum of HbA1c (≤8.0%, >8.0%), randomization stratum of 
SBP (<130 mmHg, ≥130 mmHg), and country as fixed effects, and the corresponding 
baseline value as a covariate.  
• 
To compare sotagliflozin 200 mg versus placebo under Amendment 1, the ANCOVA 
model will include treatment groups (sotagliflozin 200 mg, placebo), randomization 
stratum of HbA1c (≤8.0%, >8.0%), randomization stratum of SBP (<130 mmHg, 
≥130 mmHg), and country as fixed effects, and the corresponding baseline value as a 
covariate. 
For the analysis of SBP in patients with baseline SBP ≥130 mmHg, the randomization stratum of 
SBP will not be included in the ANCOVA model. Results from each complete dataset will be 
combined using Rubin’s formula to provide the adjusted mean change from Baseline to Week 26 
(or Week 12 for SBP) for each treatment group, as well as the between-group difference 
(comparing each sotagliflozin dose group vs its corresponding placebo group) and the 95% CI for 
the difference. 
Sensitivity analyses will be performed to compare sotagliflozin 200 mg and placebo under 
Amendment 1 for selected other endpoints such as FPG, SBP and HbA1c responders. 
For all continuous secondary endpoints, summary statistics at scheduled visits will be provided for 
each treatment group. The summary will include the number of observations, mean, SD, SE, 
minimum, median, and maximum. Graphical presentations will also be used to examine trends 
over time using mean values (±SE) and mean changes from baseline (±SE) at each of the 
scheduled visits. In addition, SBP will be summarized descriptively at each visit for those with 
baseline SBP ≥140 mmHg. 
The categorical secondary efficacy variables of HbA1c <6.5%, <7% at Week 26 will be analyzed 
respectively using a Cochran-Mantel-Haenszel (CMH) method stratified by randomization 
stratum of HbA1c (≤8.0%, >8.0%), and randomization stratum of SBP (<130 mmHg, ≥130 
mmHg). The proportion in each treatment group will be provided, as well as the difference 
between each sotagliflozin group and its corresponding placebo group with the associated 2-sided 
95% CI. For HbA1c responders at Week 26 (<6.5%, <7% respectively), all values at Week 26 will 
be used to determine whether a patient is a responder or not, even if they are measured after IMP 
discontinuation or rescue medication use. Patients who have no HbA1c measurement at Week 26 
will be treated as non-responders. Summary tables and graphs will also be provided by treatment 
group at scheduled visits.  
For between-group comparison, a sensitivity analysis will be performed respectively for HbA1c 
<6.5% responder analysis by excluding patients whose HbA1c values at baseline are <6.5%, and 
for HbA1c <7% responder analysis by excluding patients whose HbA1c values at baseline are 
<7% using the same CMH test mentioned above. Similarly, by-visit summary may also be 
provided excluding those patients. 


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Sensitivity analyses 
Tipping point analysis, similar to what is described in Section 2.4.4.1, will be performed to 
examine the robustness of the treatment effect of sotagliflozin 200 mg on HbA1c, using the same 
imputation method and ANCOVA model as described above for comparing sotagliflozin 200 mg 
versus placebo under Amendment 1. The tipping point analysis  will be performed only if the 
secondary endpoint change from baseline to Week 26 in HbA1c for comparing sotagliflozin 200 
mg versus placebo is statistically significant at α = 0.05 (2-sided). 
Similar to what is described in Section 2.4.4.1, the treatment effects (sotagliflozin 200 mg versus 
placebo under Amendment 1) across the subgroups (see Section 2.4.4.1) will be estimated for the 
change from Baseline to Week 26 in HbA1c in the ITT population, and using the same imputation 
method described above for comparing sotagliflozin 200 mg versus placebo under Amendment 1 
in the full analysis dataset. The ANCOVA model will include treatment groups (sotagliflozin 200 
mg, placebo), randomization stratum of HbA1c (≤8.0%, >8.0%), randomization stratum of SBP 
(<130 mmHg, ≥130 mmHg), subgroup factor, treatment-by-subgroup factor, and country as fixed 
factors and using baseline HbA1c value as a covariate. The adjusted estimates of treatment mean 
differences (sotagliflozin 200 mg versus placebo) with SE and 95% CIs will be provided as 
appropriate across the subgroups. A graphical presentation of the results (ie, forest plot) will also 
be provided. 
2.4.4.3      Analyses of other efficacy endpoints 
The analysis of other endpoints (see Section 2.1.3) will be descriptive with no formal testing. 
Summary statistics at scheduled visits based on observed value will be provided by each treatment 
group. Graphical presentations will also be used to illustrate trends over time as appropriate.  
The number (%) of patients who used rescue therapy and a KM curve for the time to first rescue 
therapy will be provided by treatment group. A list of patients who used rescue therapy will also 
be provided (see Section 2.5.4).  
Urine ACR will be log-transformed at patient level. Summary statistics of urine ACR in log scale 
will then be calculated for each treatment group at each visit and back-transformed to provide the 
geometric mean and its associated percent change of urine ACR from baseline. 
Shift tables will be provided for urine ACR at Week 26 using the pre-defined categories. That is, 
the number (%) of patients with progression from one category at baseline to another category at 
Week 26 will be provided by treatment group. The pre-defined categories are, for urine ACR, 
<30 mg/g creatinine [Normal], ≥30 to <300 mg/g creatinine [Microalbuminuria], and ≥300 mg/g 
creatinine [Macroalbuminuria].  
The analysis of the 2-hour PPG endpoint will be based on a Time 0 adjusted value (ie, the 2-hour 
PPG value minus the Time 0 value, FPG sample) at both the Baseline and Week 26 time points. 
These Time 0 adjusted values will be used to derive the Week 26 minus Baseline scores, which 
will serve as the measure of interest for comparative purposes. 


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2.4.4.4      Multiplicity issues 
To control the family-wise type I error, a fixed-sequence procedure will be applied. 
Once the primary variable (change from Baseline to Week 26 in HbA1c) is statistically significant 
at α = 0.05 (2-sided), the following secondary efficacy variables will be tested in the following 
prioritized order. The testing will stop as soon as an endpoint is found not to be statistically 
significant at α=0.05 (2-sided). 
• 
Comparing sotagliflozin 400 mg versus placebo,  
-          Change from Baseline to Week 26 in 2-hour PPG following an MM 
-          Change from Baseline to Week 26 in FPG 
-          Change from Baseline to Week 26 in body weight 
-          Change from Baseline to Week 12 in SBP for patients with baseline SBP ≥130 mmHg 
-          Change from Baseline to Week 12 in SBP for all patients 
-          Proportion of patients with HbA1c <7.0% at Week 26 
• 
Comparing sotagliflozin 200 mg versus placebo,  
-          Change from Baseline to Week 26 in HbA1c 
-          Change from Baseline to Week 26 in 2-hour PPG following an MM 
-          Change from Baseline to Week 26 in body weight 
-          Change from Baseline to Week 12 in SBP for all patients. 
No multiplicity adjustment will be made on efficacy variables other than those mentioned above. 
2.4.5       Analyses of safety data 
The summary of safety results will be presented by treatment group.  
The “observation period” defined in Section 2.1.4 is applicable in all safety analyses for the 
classification of AEs, determination of treatment-emergent Potentially Clinically Significant 
Abnormality (PCSA) values and the last on-treatment value for the laboratory, vital sign and 
ECG. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• 
Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately. 
• 
The baseline value  (with the exception of serum creatinine and eGFR) is defined as the 
last available value before the first dose of double-blind IMP. For serum creatinine and 


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eGFR, the baseline value is defined as the average of all values before the first dose of 
double-blind IMP. 
• 
PCSA values are defined as abnormal values considered medically important by the 
Sponsor according to predefined criteria/thresholds based on literature review and defined 
by the Sponsor for clinical laboratory tests, vital signs, and ECG [Appendix B]. 
• 
PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during the TEAE period, including 
nonscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the treatment-emergent PCSA percentage. 
• 
The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter during the TEAE period by 
treatment group in the safety population. 
• 
For laboratory parameters cited in the protocol as efficacy endpoints (including HbA1c 
and plasma glucose etc.), PCSA summaries will not be provided. These parameters will be 
summarized in efficacy Section 2.4.4. For creatinine and eGFR, PCSA summaries will be 
presented in safety Section 2.4.5 while descriptive summaries in efficacy Section 2.4.4. 
• 
For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group.  Summaries will include the last on-treatment value.  The last 
on-treatment value is commonly defined as the value collected at the same day/time of the 
last administration of IMP.  If this value is missing, this last on-treatment value will be the 
closest value prior to the last dose administration.   
• 
The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned. Relative risks versus placebo and their 95% CIs may be provided, if 
relevant.  
• 
Selected safety analyses will be summarized by age, gender, racial subgroups, and other 
pertinent subgroups (see details in Section 2.4.5.1 and Section 2.4.5.2). 
2.4.5.1      Analyses of hypoglycemia  
Analyses of hypoglycemia will be performed on the TEAE period as defined in Section 2.1.4. 
Hypoglycemia will be classified as severe hypoglycemia, documented symptomatic 
hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia or relative 
hypoglycemia (see Section 2.1.4.1).  
The number (%) of patients with any hypoglycemia, severe hypoglycemia and documented 
symptomatic hypoglycemia will be summarized respectively by treatment group during the TEAE 
period, as well as the incidence rate in patient years. Two types of incidence rates will be 
presented: the number of patients with at least 1 event per 100 patient-years (calculated as the 
number of patients with at least 1 event / total exposure in 100 patient-years), and the number of 
events per 100 patient-years (calculated as the total number of events / total exposure in 100 
patient-years). Note: here exposure (in days) is the duration of TEAE period, ie, duration of IMP 
treatment in days +1 (see Section 2.1.4). 


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The summary of frequency and incidence rate in patient years for severe hypoglycemia or 
documented symptomatic hypoglycemia will be provided as appropriate by gender (Male, 
Female), age group (<50, ≥50 to <65, ≥65 years), race (White, Black or African American, Asian, 
Other). 
A KM curve will also be provided by treatment group for the time to first severe hypoglycemia or 
documented symptomatic hypoglycemia during the TEAE period (see Section 2.5.4). 
Documented symptomatic hypoglycemia maybe presented by ≤3.9 mmol/L (≤70 mg/dL) and 
<3.0 mmol/L (<54 mg/dL) respectively, as appropriate. 
A listing of patients for all events reported on the dedicated e-CRF “Hypoglycemic event 
information” page will be provided with each category flagged (ie, severe hypoglycemia, 
documented symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic 
hypoglycemia and relative hypoglycemia). 
2.4.5.2      Analyses of adverse events 
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.  
Pretreatment and posttreatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, treatment-
emergent, or posttreatment.  The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pretreatment or posttreatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will be presented by SOC, HLGT, HLT, and PT, sorted by the 
internationally agreed order for SOCs and alphabetic order for HLGT, HLT and PT within a SOC, 
the number (n) and percentage (%) of patients experiencing an adverse event.  Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a 
treatment phase.  The denominator for computation of percentages is the safety population within 
each treatment group. 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pretreatment, treatment-emergent, and posttreatment).  For that purpose, the 
table of all treatment-emergent adverse events presented by primary SOC and PT (sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs in the 
sotagliflozin 400 mg group) will define the presentation order for all other similar tables unless 
otherwise specified. In case of equal frequency regarding PTs, alphabetical order will be used.  


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Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
• 
Overview of treatment-emergent adverse events, summarizing number (%) of patients 
with any 
-          TEAE 
-          Serious TEAE 
-          TEAE leading to death 
-          TEAE leading to permanent treatment discontinuation 
• 
All treatment-emergent adverse events by primary SOC, showing number (%) of patients 
with at least 1 treatment-emergent adverse event, sorted by internationally agreed order of 
primary system organ class  
• 
All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the 
SOC internationally agreed order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical 
order 
• 
Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing 
incidence of PT in the sotagliflozin 400 mg group 
• 
All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC in the 
sotagliflozin 400 mg group.  This sorting order will be applied to all other similar tables, 
unless otherwise specified 
• 
All treatment-emergent adverse events regardless of relationship and related to IMP by 
primary SOC, HLGT, HLT and PT, showing the number (%) of patients with at least 
1 treatment-emergent adverse event, sorted by the internationally agreed SOC order.  The 
other levels (HLGT, HLT, PT) will be presented in alphabetical order 
• 
All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (ie, mild, moderate, or severe), sorted by the sorting order defined above 
• 
Common TEAEs (PTs with an incidence ≥2% in any treatment group) by primary SOC, 
HLGT, HLT, and PT, sorted by internationally agreed order of SOCs. The other levels 
(HLGT, HLT, PT) will be presented in alphabetic order.  
• 
Common TEAEs (PTs with an incidence ≥2% in any treatment group) will be provided as 
appropriate by primary SOC and PT and by demographic factors including gender (Male, 
Female), age group (<50, ≥50 to <65, ≥65 years of age), race (White, Black or African 
American, Asian, other), baseline SBP category (<130 mmHg, ≥130 mmHg), and baseline 
eGFR category (≥30 to <60 mL/min/1.73m2 [Moderate decrease in GFR], ≥60 to <90 
mL/min/1.73m2 [Mild decrease in GFR], and ≥90 mL/min/1.73m2 [Normal]). SOC will be 


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sorted by internationally agreed order and the PT by decreasing incidence within each 
SOC in the sotagliflozin 400 mg group, as described above. 
• 
TEAEs (PTs with an incidence ≥5% in any treatment group) by primary SOC, HLGT, 
HLT, and PT, sorted by internationally agreed order of SOCs. The other levels (HLGT, 
HLT, PT) will be presented in alphabetic order.  
Analysis of all treatment emergent serious adverse event(s) 
• 
All treatment-emergent SAE by primary SOC, HLGT, HLT, and PT, showing the number 
(%) of patients with at least 1 serious treatment-emergent adverse event, sorted by the 
internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical 
order 
• 
All treatment-emergent SAE regardless of relationship and related to IMP, by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of patients with at least 1 serious 
treatment-emergent adverse event, sorted by the internationally agreed SOC order.  The 
other levels (HLGT, HLT, PT) will be presented in alphabetical order 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• 
All treatment-emergent adverse events leading to treatment discontinuation, by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of patients sorted by the 
internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical 
order 
Analysis of adverse events of special interest 
Pregnancy and overdose will be included in overall AE summaries if any are reported. ALT 
increase >3 x ULN is included in laboratory PCSA summary if any.  
In addition, the number (%) of patients with an AESI will be summarized by PT and by treatment 
group. Corresponding listings will be provided as appropriately. 
Analysis of events of special interest  
CV events, bone fracture and DKA  
For EOSIs that are adjudicated (ie, deaths, myocardial infarction, stroke, and unstable angina 
requiring hospitalization, heart failure requiring hospitalization, bone fracture, and diabetic 
ketoacidosis), the number (%) of patients with an EOSI positively adjudicated by CEC will be 
summarized by treatment group. All EOSIs sent for adjudication and/or reported by the 
investigators in the specific AE forms will be listed along with the adjudication outcome. 
Renal events 
For the EOSI renal events where selected events are adjudicated, the number (%) of patients with 
any renal events identified in Table 3 in Section 2.1.4.2 will be summarized by treatment group.  


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The following renal events will be listed along with the adjudication outcome if applicable, 
including events,  
i. 
recorded in eCRF “GFR decrease”,  
ii. 
recorded in eCRF “Renal Event – Dialysis”,  
iii. 
identified as “Renal transplant” in eCRF “Other procedure”,  
Renal death will be part of all deaths specified above. 
Other EOSIs  
For EOSIs that are not adjudicated, the number (%) of patients with at least one event will be 
summarized by treatment group and by PT (as identified in Table 3 in Section 2.1.4.2).  
Severe hypoglycemia will be included in the summary of hypoglycemia (See Section 2.4.5.1). 
AE leading to an amputation is described in the section below. 
Analysis of Amputation 
The number (%) of patients with amputation will be summarized by treatment group and by PT 
and LLT during the study (ie, regardless of on- or post-treatment). Amputation is a procedure 
recorded in eCRF “Other Procedures related to Amputation”. Patients who had a procedure 
related to amputation will be listed. 
The number (%) of patients with an “AE leading to an amputation” will be summarized by 
treatment group and by PT.  The “AE leading to an amputation” is determined by the AE 
identifier recorded in eCRF “Other Procedures related to Amputation” when “AE correction” is 
chosen as the reason for the amputation procedure.  
In addition, the number (%) of patients with an “AE potentially leading to an amputation” will be 
summarized by treatment group and by PT (as identified in Table 3 in Section 2.1.4.2). These PTs 
in Table 3 were requested by the European Medicines Agency (EMA)/ Pharmacovigilance Risk 
Assessment Committee (PRAC) Assessment Report, 9 February 2017). The associated list will be 
provided as well, with patients who had an amputation procedure flagged. “AE potentially leading 
to an amputation” represents the condition that may potentially lead to the amputation procedure, 
but not in all cases an amputation has occurred. 
Analysis of pretreatment and posttreatment adverse events  
• 
All pretreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 pretreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC in the sotagliflozin 400 mg 
group 
• 
All posttreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 posttreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC in the sotagliflozin 400 mg 
group. 


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Listings 
Supportive AE listings will be provided for all AEs, SAEs, death, AEs leading to treatment 
discontinuation and/or death, and EOSI as appropriate. Listing of all AEs, SAEs and AEs leading 
to treatment discontinuation and/or death, sorted by treatment, patient identification, and onset 
date, will include the following information: treatment, patient identification, country, age, 
gender, race, BMI, primary SOC, PT, reported term, onset date, study day (relative day to the start 
date of double-blind treatment), AE duration, duration of exposure, intensity, corrective treatment, 
action taken with IMP, date of treatment discontinuation (if relevant), relationship to IMP or 
NIMP, outcome, date of death (if any), seriousness, seriousness criteria, and AE status ( “E” for a 
TEAE; and “P” for an on-study post-treatment AE). 
2.4.5.3      Deaths 
The following summaries of deaths will be generated. 
• 
Number (%) of patients who died by study period (on-study, on-treatment, post-study) 
• 
Deaths in nonrandomized patients or randomized but not treated patients 
• 
Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC , HLGT, 
HLT, and PT showing number (%) of patients sorted by internationally agreed SOC order, 
with HLGT, HLT, and PT presented in alphabetical order within each SOC.  
2.4.5.4      Analyses of laboratory variables  
Laboratory parameters will be grouped and summarized by biological function as described in 
Section 2.1.4.4. 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all laboratory variables (central laboratory values and changes from baseline) 
will be calculated for each applicable visit or study assessment (screening, baseline, postbaseline 
time points, last on-treatment value) by treatment group.   
The incidence of PCSAs (list provided in Appendix B) at any time during the TEAE period will 
be summarized for each laboratory test by biological function and treatment group whatever the 
baseline level and/or according to the following baseline status categories:  
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria. 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
All measurements collected during the TEAE period, including values from unscheduled visits, 
will be considered for the PCSA summaries. These summaries will include patients in the safety 
population who have at least 1 assessment performed during the TEAE period. When a PCSA 


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definition involves a change from baseline value, patients must also have a baseline value to be 
included in the summaries, and when required by the definition of the abnormality, patients must 
also have available laboratory normal ranges. 
A listing of patients with at least 1 post-baseline PCSA (or out of normal range when no PCSA 
criterion is defined) will be provided which will display the entire patients’ profile across time for 
all parameters belonging to the corresponding biological function. Individual data listings will 
include the following flags when applicable: 
• 
Baseline values will be flagged “B”. 
• 
Normal laboratory ranges, available for most laboratory parameters, will be identified as 
ULN and LLN. Baseline, last on-treatment value, and individual data will be flagged “L” 
if the value is below the LLN and will be flagged “H” if it is above the ULN. 
• 
Laboratory PCSA criteria will be used for the corresponding laboratory parameters. 
Values reaching a PCSA limit will be flagged (+, ++, -, or -- depending upon the direction 
and level of the abnormality). Flags for WBC and differential counts will be determined 
using data expressed in international units. 
For parameters whose PCSA criteria are multiples of the ULN, the parameter’s value will also be 
expressed as a multiple of the ULN in the individual data provided. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity.  The proportion of patients with PCSA values at any 
postbaseline visit by baseline status will be displayed by treatment group for each parameter.  The 
proportion of patients with PCSA values at any postbaseline visit will also be displayed by 
duration of exposure for each treatment group (only if a tabulation summary is necessary).  
Listing of possible Hy’s law cases identified by treatment group (eg, patients with any elevated 
ALT>3 x ULN, and associated with an increase in bilirubin ≥2 x ULN) with ALT, AST, alkaline 
phosphatase, total bilirubin, and the following complementary parameters (if available):  
conjugated bilirubin and prothrombin time/international normalized ratio, creatine phosphokinase, 
serum creatinine, complete blood count, anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA 
, anti-CMV IgM and anti-HEV IgM antibodies, auto-antibodies: anti-nuclear, anti-DNA, anti-
smooth muscle, Epstein-Barr virus, herpes viruses, and anti-LKM. 
2.4.5.5      Analyses of vital sign variables 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of heart rate, temperature and respiratory rate (observed values or mean of 
observed values, and changes from baseline) will be calculated for each applicable visit or study 
assessment (baseline, post-baseline time points, last on-treatment value) by treatment group.   
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group for SBP, DBP and HR. All measurements collected during the TEAE period, including 




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IFCC-HbA1c (mmol/mol) = [DCCT-HbA1c (%) - 2.15] x 10.929. 
Renal function formulas  
The estimated GFR (mL/min/1.73 m2) will be calculated using the 4 variable Modification of Diet 
in Renal Disease (MDRD) formula:  
Standard unit: eGFR (mL/min/1.73 m2) = 175 x [Serum Creatinine (µmol/L)/88.4] -1.154 x Age 
(year) -0.203 x 1.212 (if Black) x 0.742 (if female) 
Conventional unit: eGFR (mL/min/1.73 m2) = 175 x Serum Creatinine (mg/dL) -1.154 x Age (year) 
-0.203 x 1.212 (if Black) x 0.742 (if Female) 
Urine ACR 
Standard unit: Urine ACR (mg/g) = Urine Albumin (mg/dL) / [Urine Creatinine (mmol/L) x 
11.31] x 1000 
Conventional unit: Urine ACR (mg/g) = Urine Albumin (mg/dL) / Urine Creatinine (mg/dL) x 
1000 
Urine GCR 
Standard unit: Urine GCR = Urine Glucose (mmol/L) / Urine Creatinine (mmol/L) 
Conventional unit: Urine GCR = Urine Glucose (mg/dL) / Urine Creatinine (mg/dL) 
Calculation of LDL-C 
When TG is lower than or equal to 4.52 mmol/L (400 mg/dL), LDL-C is calculated using the 
Friedewald equation as: 
• 
in standard unit (mmol/L), TC – HDL-C – TG/2.17; 
• 
in conventional unit (mg/dL), TC – HDL-C – TG/5. 
2.5.2       Data handling conventions for secondary efficacy variables 
Scheduled measurements (see Section 2.5.4) of continuous efficacy variables collected during the 
study will be used in the analyses including those obtained after IMP discontinuation or 
introduction of rescue therapy. Continuous secondary efficacy endpoints will be analyzed with 
missing values imputed by the retrieved dropouts & washout imputation method or by the control-
based copy reference imputation method according to the criterion described in Section 2.4.4.1.   
For the categorical secondary efficacy endpoints, data handling conventions are described in 
Section 2.4.4.2. 


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


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Handling of adverse events/hypoglycemia when date and time of first IMP administration is 
missing 
When the date and time of the first double-blind IMP administration is missing, the day of 
randomization should be considered as the start date of TEAE period (see Section 2.1.4).  The 
exposure duration should be kept as missing. 
Handling of adverse events/hypoglycemia when IMP end of treatment date is missing 
For the purpose of defining TEAE period, the date of the last administration of double-blind IMP 
is equal to the date of the last administration reported on the e-CRF “Treatment Status Library” 
page.  
If the date of last administration reported on the e-CRF “Treatment Status Library” page is  
• 
Partially missing, it will be imputed with a date as late as possible before or on the date of 
last available information on eCRF “Completion of End of Study/Follow-up”.  
• 
Completely missing, it will be imputed with the date of last available information on eCRF 
“Completion of End of Study/Follow-up” page.  
If the date of last available information on eCRF “Completion of End of Study/Follow-up” page is  
• 
Partially missing, it will be imputed with a date as late as possible. 
• 
Completely missing, all adverse events occurred on or after the first administration of 
double-blind IMP will be considered as treatment emergent adverse events.  
Handling of missing assessment of relationship of adverse events to IMP  
If the assessment of the relationship to IMP is missing, the relationship to IMP has to be assumed 
and the adverse event considered as such in the frequency tables of possibly related adverse 
events, but no imputation should be done at the data level. 
Handling of missing severity/grades of adverse events 
If the severity/grade is missing for 1 of the treatment-emergent occurrences of an adverse event, 
the maximal severity on the remaining occurrences will be considered.  If the severity is missing 
for all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 


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For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   
Linked adverse events that worsened or became serious 
An AE that worsened or became serious will have a separate record in the data from the original 
event record with an AE identification number that links the new record to the original record. An 
AE that worsened or became serious will be considered a new recurring AE in the summary of 
recurrent events or in the summary of events by time intervals. 
Handling of missing data for continuous efficacy endpoints 
Please see Section 2.4.4.1 and Section 2.4.4.2. 
Handling of missing data for categorical secondary efficacy endpoints 
Please see Section 2.4.4.2. 
2.5.4       Windows for time points / Measurements for analyses 
The following steps will decide how the scheduled and/or unscheduled visits will be used in the 
analyses on efficacy variables and the by-visit summaries for safety variables (clinical laboratory 
data in Section 2.1.4.4 and vital signs in Section 2.1.4.5). 
Step 1 A scheduled measurement will be used if it is available; otherwise, an unscheduled 
measurement (including the end of treatment/study visit for those prematurely discontinued) will 
be used if it happens to be on the same date as the date of the scheduled visit. 
Step 2 After Step 1, if there are still no measurement for a given parameter at a scheduled visit, 
the analysis window below (Table 4) will be applied to re-allocate a post-baseline unscheduled 
measurement to a scheduled measurement. 
 
 
Table 4 - Analyses window definition 
Scheduled visit post baseline 
Targeted study day 
Analysis window in study days 
Week 1 (Visit 4) 
7 
2 to 17 
Week 4 (Visit 5) 
28 
18 to 41 
Week 8 (Visit 6) 
56 
42 to 69 
Week 12 (Visit 7) 
84 
70 to 104 
Week 18 (Visit 8) 
126 
105 to 153 


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Scheduled visit post baseline 
Targeted study day 
Analysis window in study days 
Week 26 (Visit 9) 
182 
≥154  
Study days are calculated from the day of first administration of double-blind IMP; the day of first administration of IMP (or the day of 
randomization if not exposed) is Day 1. 
After applying the above time windows, if multiple assessments are associated to the same time 
point, the closest from the targeted study day will be used. In case of equality, the last 
measurement will be used. Re-allocated scheduled visits (ie, visit numbers) should be sequential if 
ordered by the date of measurement. 
After Step 2, if there are still no measurement for a given parameter at a scheduled visit, data is 
considered missing for efficacy analyses, where multiple imputation would be applied as 
appropriately as described in Section 2.4.4.  
Reference day 
The reference day for the calculation of extent of exposure, time to onset, and relative days will be 
the day of the first administration of double-blind IMP or the day of randomization if not exposed 
to double-blind IMP, denoted as Day 1. 
Baseline definition for efficacy/safety data 
For the safety analyses, the baseline for a given parameter is defined as the last available 
measurement (or the average of all measurements for creatinine and eGFR), including 
unscheduled assessments, assessed prior to the first administration of double-blind IMP. For the 
efficacy analyses, the baseline for a given parameter is defined as the last available measurement 
(or the average of all measurements for creatinine and eGFR), including unscheduled assessments, 
assessed prior to the first administration of double-blind IMP or the last available value (or the 
average of all measurements for creatinine and eGFR) before randomization if not treated with 
double-blind IMP.  
Summary statistics by visit for continuous efficacy endpoints 
Summary statistics (number, mean, SD, SE, minimum, median, maximum) of continuous efficacy 
endpoints (observed data and change from baseline) will be provided at scheduled visits as per 
protocol. Summaries showing data by visit will be presented according to the visit number (or re-
allocated visit number, see Section 2.5.4) and labeled with the targeted approximate day/week.  
Last on-treatment value for laboratory variables and vital signs 
The last on-treatment value is the final measurement assessed during the treatment epoch, 
regardless of the introduction of rescue therapy, including measurements at unscheduled visits. 
Please see details in Section 2.1.4 and Section 2.4.5. 
Display of safety data by visit (laboratory variables and vital signs)  
Descriptive statistics (number, mean, SD, minimum, median, maximum) of quantitative 
laboratory variables and vital signs (observed data and change from baseline) during the TEAE 


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period will be provided at scheduled visits. In addition, these summaries will also include a row 
for the ‘last value on-treatment’ to describe the last available on-treatment value (see above). 
Summaries showing data by visit will be presented according to the visit number (or re-allocated 
visit number, see Section 2.5.4) and labeled with the targeted approximate day/week. 
As specified in the study protocol, laboratory data from scheduled visits are reported by central 
laboratories. The local results will not be used in the efficacy analyses or in the definition of 
baseline for both safety and efficacy analyses. In the safety analyses, for parameters with PCSA 
defined based on normal range, local results will only be used in the PCSA summary if they are 
accompanied by a local laboratory normal range. For parameters with PCSA not defined based on 
normal range, local results will be used in the PCSA summary as appropriate. 
When a patient has more than 1 measurement from the central laboratory for the same laboratory 
parameter on the same date, the average of the measurements will be used. For the same 
laboratory parameter, if a patient has more than 1 measurement on different dates for the same 
scheduled visit, the value closest to the date of the visit will be used for the scheduled visit. When 
the values for the same scheduled visit are equidistant, the last value should be used for the 
scheduled visit. Similar rules will be applicable to a patient who has more than 1 set of 
measurements for the same vital sign parameter (ie, SBP, DBP, or HR) on the same date. 
Time to event analysis  
For time to event analysis/KM plot, time to event (eg, treatment discontinuation, rescue therapy, 
hypoglycemia, etc) is defined as the number of days from the date of the first administration of 
double-blind IMP (or the date of randomization if not exposed) to the start date of the first 
occurrence of the event during the 26-week double-blind treatment period.  
Patients who did not experience any event during the 26-week double-blind treatment period are 
considered censored observations. For time to treatment discontinuation/rescue therapy, censoring 
date is the date of EOT. For time to severe or documented hypoglycemia, censoring date is date of 
EOT+1 or date of EOS, whichever is the earliest. Date of EOS will be used if date of EOT is not 
available. Last contact date will be used if date of EOS is not available. 
2.5.5       Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline, the last on-treatment value, PCSAs, and the shift summaries for safety or 
efficacy. They will be included in the by-visit summaries if they are re-allocated to scheduled 
visits (see Section 2.5.4). 
2.5.6       Pooling of centers for statistical analyses 
Center will not be included in the statistical models for efficacy analyses. However, all centers 
within a country will be pooled, and country will be included as a fixed effect in a parametric 
statistical model (eg, ANCOVA etc) for primary and secondary efficacy endpoints. Countries with 
fewer than 5 randomized patients will be grouped, if patients from grouped countries are still 


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fewer than 5, they will then be further grouped with the country with the lowest number of 
patients that is 5 or more.  
2.5.7       Statistical technical issues 
None. 
 


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3                  INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned for this study. The study will not be terminated 
early for excellent efficacy. 
An independent Data Monitoring Committee (DMC) will be used to monitor and assess the safety 
of patients from this trial through periodic review of the accumulated safety data provided by an 
independent statistical group. Related details are provided in separate documents (DMC charter 
and DMC SAP). 
 


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4                  DATABASE LOCK 
The database is planned to be locked approximately 4 weeks after the last patient last visit. 
 


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


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6                  REFERENCES 
None. 


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7                  LIST OF APPENDICES 
 
Appendix A 
Mapping of inclusion and exclusion criteria under the original protocol and 
Amendments  
Appendix B 
Potentially clinically significant abnormalities criteria 
Appendix C 
List of PTs for select EOSIs (MedDRA v22.0) 
Appendix D 
Summary of statistical analyses 
Appendix E 
Study flow chart 


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Appendix A        Mapping of inclusion and exclusion criteria under the original 
protocol and Amendments  
Order 
Original Protocol 
Amendment 1 
Amendment 2 
CSR Display 
1 
I01 
 
 
I01 
2 
I02 
 
 
I02 
3 
E01 
E01 
 
E01/E01A1 
4 
E02 
 
 
E02 
5 
E03 
 
 
E03 
6 
E04 
 
 
E04 
7 
E05 
 
 
E05 
8 
E06 
E06 
 
E06/E06A1 
9 
E07 
 
 
E07 
10 
E08 
 
 
E08 
11 
E09 
E09 
E09 
E09/E09A1/E09A2 
12 
E10 
E10 
E10 
E10/E10A1/E10A2 
13 
E11 
E11 
 
E11/E11A1 
14 
E12 
 
 
E12 
15 
E13 
 
 
E13 
16 
E14 
 
E14 
E14/E14A2 
17 
E15 
E15 
 
E15/E15A1 
18 
E16 
E33 
 
E16/E33A1 
19 
E17 
E16 
 
E17/E16A1 
20 
E18 
E17 
 
E18/E17A1 
21 
E19 
  
 
E19 
22 
E20 
E18 
 
E20/E18A1 
23 
E21 
E19 
 
E21/E19A1 
24 
E22 
E20 
 
E22/E20A1 
25 
E23 
E21 
 
E23/E21A1 
26 
E24 
E22 
E22 
E24/E22A1/E22A2 
27 
E25 
E23 
 
E25/E23A1 
28 
E26 
E24 
 
E26/E24A1 
29 
E27 
E25 
 
E27/E25A1 
30 
E28 
E26 
 
E28/E26A1 
31 
E29 
E27 
 
E29/E27A1 
32 
E30 
  
 
E30 
33 
E31 
E28 
 
E31/E28A1 
34 
E32 
E29 
 
E32/E29A1 
35 
E33 
  
 E33 
E33/E33A2 
36 
E34 
  
  
E34 
37 
E35 
E30 
E30 
E35/E30A1/E30A2 
38 
  
E31 
 
E31A1 
39 
  
E32 
 
E32A1 
40 
 
 
E34 
E34A2 


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Appendix B Potentially clinically significant abnormalities criteria  
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
 Parameter 
PCSA 
Comments 
 Clinical Chemistry 
 ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
 AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
 Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
 Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
 Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
 ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, whatever 
the interval between measurement. 
 CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
CLcr (mL/min) 
(Estimated creatinine 
clearance based on the 
Cokcroft-Gault equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-
study design, data analysis, and impact on dosing and 
labeling 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 64 of 85            
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
 Parameter 
PCSA 
Comments 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based 
on an MDRD equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-
study design, data analysis, and impact on dosing and 
labeling 
 Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
 Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
 Blood Urea Nitrogen 
≥17 mmol/L 
 
 Chloride 
<80 mmol/L 
>115 mmol/L 
 
 Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
 Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
 Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
 Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
 Lipasemia 
≥3 ULN 
 
 Amylasemia 
≥3 ULN 
 
 Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
 HbA1c 
>8% 
 
 Albumin 
≤25 g/L 
 
 CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
 Hematology 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 65 of 85            
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
 Parameter 
PCSA 
Comments 
 WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
 Lymphocytes 
>4.0 Giga/L 
 
 Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
FDA criteria. 
 Monocytes 
>0.7 Giga/L 
 
 Basophils 
>0.1 Giga/L 
 
 Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
 Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other categories for 
decrease from baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
 Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
 RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
 Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
 Urinalysis 
 pH 
≤4.6 
≥8 
 
 Vital signs 
 HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) except 
STANDING. 
 SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) except 
STANDING. 
 DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) except 
STANDING. 
 Orthostatic Hypotension 
Orthostatic SDB 
 
 
≤-20 mmHg 
 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 66 of 85            
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
 Parameter 
PCSA 
Comments 
Orthostatic DBP 
≤-10 mmHg 
 Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
 ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), and 
Cardiac Safety Research Consortium White Paper on PR 
and QRS (Nada et al. Am Heart J. 2013; 165(4) : 489-500) 
 HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
 PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
 QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
 QT 
>500 ms 
 
 QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and ∆QTc>60 ms are the 2 PCSA categories 
to be identified in individual subjects/patients listings. 
 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 67 of 85            
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
 Parameter 
PCSA 
Comments 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
  
 
  
 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 68 of 85            
Appendix C List of PTs for select EOSIs (MedDRA v22.0) 
EOSI 
Preferred term code 
Preferred term 
Genital Mycotic Infections 
10004074 
Balanitis candida 
Genital Mycotic Infections 
10018143 
Genital candidiasis 
Genital Mycotic Infections 
10047784 
Vulvovaginal candidiasis 
Genital Mycotic Infections 
10061180 
Genital infection fungal 
Genital Mycotic Infections 
10064899 
Vulvovaginal mycotic infection 
Genital Mycotic Infections 
10065582 
Urogenital infection fungal 
Genital Mycotic Infections 
10071209 
Candida cervicitis 
Genital Mycotic Infections 
10079521 
Fungal balanitis 
Urinary tract infections 
10011781 
Cystitis 
Urinary tract infections 
10011790 
Cystitis escherichia 
Urinary tract infections 
10011797 
Cystitis klebsiella 
Urinary tract infections 
10011799 
Cystitis pseudomonal 
Urinary tract infections 
10017525 
Fungal cystitis 
Urinary tract infections 
10018185 
Genitourinary chlamydia infection 
Urinary tract infections 
10023424 
Kidney infection 
Urinary tract infections 
10037584 
Pyelitis 
Urinary tract infections 
10037596 
Pyelonephritis 
Urinary tract infections 
10037597 
Pyelonephritis acute 
Urinary tract infections 
10037601 
Pyelonephritis chronic 
Urinary tract infections 
10037603 
Pyelonephritis mycoplasmal 
Urinary tract infections 
10037653 
Pyonephrosis 
Urinary tract infections 
10038351 
Renal abscess 
Urinary tract infections 
10044828 
Tuberculosis of genitourinary system 
Urinary tract infections 
10046424 
Urethral abscess 
Urinary tract infections 
10046480 
Urethritis 
Urinary tract infections 
10046482 
Urethritis chlamydial 
Urinary tract infections 
10046483 
Urethritis gonococcal 
Urinary tract infections 
10046490 
Urethritis ureaplasmal 
Urinary tract infections 
10046571 
Urinary tract infection 
Urinary tract infections 
10046572 
Urinary tract infection enterococcal 
Urinary tract infections 
10046704 
Urogenital trichomoniasis 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 69 of 85            
EOSI 
Preferred term code 
Preferred term 
Urinary tract infections 
10048302 
Tubulointerstitial nephritis 
Urinary tract infections 
10048709 
Urosepsis 
Urinary tract infections 
10048837 
Cystitis glandularis 
Urinary tract infections 
10049059 
Urinary tract infection fungal 
Urinary tract infections 
10049100 
Pyelocystitis 
Urinary tract infections 
10051250 
Ureteritis 
Urinary tract infections 
10051350 
Cytomegalovirus urinary tract infection 
Urinary tract infections 
10051959 
Urinary bladder abscess 
Urinary tract infections 
10052238 
Escherichia urinary tract infection 
Urinary tract infections 
10054088 
Urinary tract infection bacterial 
Urinary tract infections 
10056351 
Emphysematous cystitis 
Urinary tract infections 
10058523 
Bladder candidiasis 
Urinary tract infections 
10058596 
Renal cyst infection 
Urinary tract infections 
10059517 
Bacterial pyelonephritis 
Urinary tract infections 
10061181 
Genitourinary tract gonococcal infection 
Urinary tract infections 
10061182 
Genitourinary tract infection 
Urinary tract infections 
10061395 
Ureter abscess 
Urinary tract infections 
10062279 
Urinary tract infection pseudomonal 
Urinary tract infections 
10062280 
Urinary tract infection staphylococcal 
Urinary tract infections 
10064825 
Urinary tract infection viral 
Urinary tract infections 
10064921 
Urinary tract inflammation 
Urinary tract infections 
10065197 
Cystitis viral 
Urinary tract infections 
10065198 
Cystitis bacterial 
Urinary tract infections 
10065199 
Cystitis helminthic 
Urinary tract infections 
10065213 
Pyelonephritis viral 
Urinary tract infections 
10065214 
Pyelonephritis fungal 
Urinary tract infections 
10065582 
Urogenital infection fungal 
Urinary tract infections 
10065583 
Urogenital infection bacterial 
Urinary tract infections 
10066757 
Urinary tract abscess 
Urinary tract infections 
10068822 
Emphysematous pyelonephritis 
Urinary tract infections 
10070300 
Streptococcal urinary tract infection 
Urinary tract infections 
10074409 
Escherichia pyelonephritis 
Urinary tract infections 
10075063 
Urethritis mycoplasmal 
Urinary tract infections 
10078665 
Bacterial urethritis 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 70 of 85            
EOSI 
Preferred term code 
Preferred term 
Urinary tract infections 
10081163 
Fungal urethritis 
Urinary tract infections 
10081262 
Candida urethritis 
Urinary tract infections 
10082040 
Nephritis bacterial 
Volume depletion 
10005697 
Blood osmolarity increased 
Volume depletion 
10005731 
Blood pressure ambulatory decreased 
Volume depletion 
10005734 
Blood pressure decreased 
Volume depletion 
10005737 
Blood pressure diastolic decreased 
Volume depletion 
10005748 
Blood pressure immeasurable 
Volume depletion 
10005758 
Blood pressure systolic decreased 
Volume depletion 
10005761 
Blood pressure systolic inspiratory decreased 
Volume depletion 
10007979 
Central venous pressure decreased 
Volume depletion 
10009192 
Circulatory collapse 
Volume depletion 
10012174 
Dehydration 
Volume depletion 
10013578 
Dizziness postural 
Volume depletion 
10021097 
Hypotension 
Volume depletion 
10021137 
Hypovolaemia 
Volume depletion 
10021138 
Hypovolaemic shock 
Volume depletion 
10026983 
Mean arterial pressure decreased 
Volume depletion 
10031127 
Orthostatic hypotension 
Volume depletion 
10036653 
Presyncope 
Volume depletion 
10037327 
Pulmonary arterial wedge pressure decreased 
Volume depletion 
10042772 
Syncope 
Volume depletion 
10046640 
Urine flow decreased 
Volume depletion 
10047235 
Venous pressure decreased 
Volume depletion 
10047239 
Venous pressure jugular decreased 
Volume depletion 
10047689 
Volume blood decreased 
Volume depletion 
10050760 
Blood urea nitrogen/creatinine ratio increased 
Volume depletion 
10050905 
Decreased ventricular preload 
Volume depletion 
10053356 
Blood pressure orthostatic decreased 
Volume depletion 
10059895 
Urine output decreased 
Volume depletion 
10060089 
Left ventricular end-diastolic pressure decreased 
Volume depletion 
10060231 
Pulmonary arterial pressure decreased 
Volume depletion 
10063080 
Postural orthostatic tachycardia syndrome 
Volume depletion 
10063927 
Orthostatic intolerance 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 71 of 85            
EOSI 
Preferred term code 
Preferred term 
Volume depletion 
10066077 
Diastolic hypotension 
Volume depletion 
10069431 
Orthostatic heart rate response increased 
Volume depletion 
10069583 
Pulse volume decreased 
Volume depletion 
10072370 
Prerenal failure 
Pancreatitis 
10033625 
Pancreatic haemorrhage 
Pancreatitis 
10033635 
Pancreatic pseudocyst 
Pancreatitis 
10033636 
Pancreatic pseudocyst drainage 
Pancreatitis 
10033645 
Pancreatitis 
Pancreatitis 
10033647 
Pancreatitis acute 
Pancreatitis 
10033649 
Pancreatitis chronic 
Pancreatitis 
10033650 
Pancreatitis haemorrhagic 
Pancreatitis 
10033654 
Pancreatitis necrotising 
Pancreatitis 
10033657 
Pancreatitis relapsing 
Pancreatitis 
10048984 
Pancreatic abscess 
Pancreatitis 
10052400 
Oedematous pancreatitis 
Pancreatitis 
10056277 
Pancreatorenal syndrome 
Pancreatitis 
10056975 
Pancreatic phlegmon 
Pancreatitis 
10056976 
Hereditary pancreatitis 
Pancreatitis 
10056977 
Alcoholic pancreatitis 
Pancreatitis 
10058096 
Pancreatic necrosis 
Pancreatitis 
10065189 
Pancreatitis helminthic 
Pancreatitis 
10066127 
Ischaemic pancreatitis 
Pancreatitis 
10069002 
Autoimmune pancreatitis 
Pancreatitis 
10074894 
Traumatic pancreatitis 
Pancreatitis 
10076058 
Haemorrhagic necrotic pancreatitis 
Venous thrombotic events 
10003192 
Arteriovenous fistula thrombosis 
Venous thrombotic events 
10003880 
Axillary vein thrombosis 
Venous thrombotic events 
10006537 
Budd-Chiari syndrome 
Venous thrombotic events 
10007830 
Cavernous sinus thrombosis 
Venous thrombotic events 
10008138 
Cerebral venous thrombosis 
Venous thrombotic events 
10014522 
Embolism venous 
Venous thrombotic events 
10019713 
Hepatic vein thrombosis 
Venous thrombotic events 
10023237 
Jugular vein thrombosis 
Venous thrombotic events 
10027402 
Mesenteric vein thrombosis 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 72 of 85            
EOSI 
Preferred term code 
Preferred term 
Venous thrombotic events 
10034272 
Pelvic venous thrombosis 
Venous thrombotic events 
10034324 
Penile vein thrombosis 
Venous thrombotic events 
10036206 
Portal vein thrombosis 
Venous thrombotic events 
10037377 
Pulmonary embolism 
Venous thrombotic events 
10037421 
Pulmonary microemboli 
Venous thrombotic events 
10037437 
Pulmonary thrombosis 
Venous thrombotic events 
10037459 
Pulmonary venous thrombosis 
Venous thrombotic events 
10038547 
Renal vein embolism 
Venous thrombotic events 
10038548 
Renal vein thrombosis 
Venous thrombotic events 
10038908 
Retinal vein thrombosis 
Venous thrombotic events 
10041659 
Splenic vein thrombosis 
Venous thrombotic events 
10042567 
Superior sagittal sinus thrombosis 
Venous thrombotic events 
10043570 
Thrombophlebitis 
Venous thrombotic events 
10043581 
Thrombophlebitis migrans 
Venous thrombotic events 
10043595 
Thrombophlebitis superficial 
Venous thrombotic events 
10043605 
Thrombosed varicose vein 
Venous thrombotic events 
10044457 
Transverse sinus thrombosis 
Venous thrombotic events 
10047193 
Vena cava embolism 
Venous thrombotic events 
10047195 
Vena cava thrombosis 
Venous thrombotic events 
10047249 
Venous thrombosis 
Venous thrombotic events 
10048591 
Post thrombotic syndrome 
Venous thrombotic events 
10049446 
Subclavian vein thrombosis 
Venous thrombotic events 
10050216 
Paget-Schroetter syndrome 
Venous thrombotic events 
10050902 
Postoperative thrombosis 
Venous thrombotic events 
10051055 
Deep vein thrombosis 
Venous thrombotic events 
10053182 
Arteriovenous graft thrombosis 
Venous thrombotic events 
10061251 
Intracranial venous sinus thrombosis 
Venous thrombotic events 
10061408 
Venous thrombosis limb 
Venous thrombotic events 
10063363 
Brachiocephalic vein thrombosis 
Venous thrombotic events 
10063909 
Post procedural pulmonary embolism 
Venous thrombotic events 
10066881 
Deep vein thrombosis postoperative 
Venous thrombotic events 
10067270 
Thrombosis corpora cavernosa 
Venous thrombotic events 
10069909 
Metastatic pulmonary embolism 
Venous thrombotic events 
10072059 
Ovarian vein thrombosis 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 73 of 85            
EOSI 
Preferred term code 
Preferred term 
Venous thrombotic events 
10074349 
Ophthalmic vein thrombosis 
Venous thrombotic events 
10077623 
Portosplenomesenteric venous thrombosis 
Venous thrombotic events 
10077829 
Visceral venous thrombosis 
Venous thrombotic events 
10078810 
Hepatic vein embolism 
Thyroid cancer 
10002240 
Anaplastic thyroid cancer 
Thyroid cancer 
10016935 
Follicular thyroid cancer 
Thyroid cancer 
10027105 
Medullary thyroid cancer 
Thyroid cancer 
10033701 
Papillary thyroid cancer 
Thyroid cancer 
10043744 
Thyroid neoplasm 
Thyroid cancer 
10055107 
Thyroid cancer metastatic 
Thyroid cancer 
10066136 
Huerthle cell carcinoma 
Thyroid cancer 
10066474 
Thyroid cancer 
Thyroid cancer 
10070567 
Thyroid cancer stage 0 
Thyroid cancer 
10071027 
Thyroid cancer stage I 
Thyroid cancer 
10071028 
Thyroid cancer stage II 
Thyroid cancer 
10071029 
Thyroid cancer stage III 
Thyroid cancer 
10071030 
Thyroid cancer stage IV 
Thyroid cancer 
10072162 
Thyroid cancer recurrent 
Thyroid cancer 
10072613 
Thyroid B-cell lymphoma 
Thyroid cancer 
10073153 
Familial medullary thyroid cancer 
Thyroid cancer 
10076603 
Poorly differentiated thyroid carcinoma 
Renal cell cancer 
10038389 
Renal cancer 
Renal cell cancer 
10038390 
Renal cancer recurrent 
Renal cell cancer 
10038391 
Renal cancer stage I 
Renal cell cancer 
10038392 
Renal cancer stage II 
Renal cell cancer 
10038393 
Renal cancer stage III 
Renal cell cancer 
10038394 
Renal cancer stage IV 
Renal cell cancer 
10038410 
Renal cell carcinoma recurrent 
Renal cell cancer 
10038411 
Renal cell carcinoma stage I 
Renal cell cancer 
10038412 
Renal cell carcinoma stage II 
Renal cell cancer 
10038413 
Renal cell carcinoma stage III 
Renal cell cancer 
10038414 
Renal cell carcinoma stage IV 
Renal cell cancer 
10050018 
Renal cancer metastatic 
Renal cell cancer 
10050513 
Metastatic renal cell carcinoma 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 74 of 85            
EOSI 
Preferred term code 
Preferred term 
Renal cell cancer 
10061482 
Renal neoplasm 
Renal cell cancer 
10067944 
Hereditary leiomyomatosis renal cell carcinoma 
Renal cell cancer 
10067946 
Renal cell carcinoma 
Renal cell cancer 
10073251 
Clear cell renal cell carcinoma 
Renal cell cancer 
10078493 
Papillary renal cell carcinoma 
Pancreatic cancer 
10018404 
Glucagonoma 
Pancreatic cancer 
10022498 
Insulinoma 
Pancreatic cancer 
10025997 
Malignant neoplasm of islets of Langerhans 
Pancreatic cancer 
10029341 
Neurotensinoma 
Pancreatic cancer 
10033609 
Pancreatic carcinoma 
Pancreatic cancer 
10033610 
Pancreatic carcinoma metastatic 
Pancreatic cancer 
10033613 
Pancreatic carcinoma recurrent 
Pancreatic cancer 
10041329 
Somatostatinoma 
Pancreatic cancer 
10047430 
Vipoma 
Pancreatic cancer 
10051709 
Gastrinoma malignant 
Pancreatic cancer 
10052747 
Adenocarcinoma pancreas 
Pancreatic cancer 
10055006 
Pancreatic sarcoma 
Pancreatic cancer 
10055007 
Carcinoid tumour of the pancreas 
Pancreatic cancer 
10059320 
Pancreatic carcinoma stage 0 
Pancreatic cancer 
10059321 
Pancreatic carcinoma stage I 
Pancreatic cancer 
10059322 
Pancreatic carcinoma stage II 
Pancreatic cancer 
10059323 
Pancreatic carcinoma stage III 
Pancreatic cancer 
10059326 
Pancreatic carcinoma stage IV 
Pancreatic cancer 
10061902 
Pancreatic neoplasm 
Pancreatic cancer 
10067517 
Pancreatic neuroendocrine tumour 
Pancreatic cancer 
10068909 
Pancreatic neuroendocrine tumour metastatic 
Pancreatic cancer 
10069345 
Solid pseudopapillary tumour of the pancreas 
Pancreatic cancer 
10073363 
Acinar cell carcinoma of pancreas 
Pancreatic cancer 
10073364 
Ductal adenocarcinoma of pancreas 
Pancreatic cancer 
10073365 
Intraductal papillary-mucinous carcinoma of 
pancreas 
Pancreatic cancer 
10073367 
Pancreatoblastoma 
Bladder cancer 
10004986 
Bladder adenocarcinoma recurrent 
Bladder cancer 
10004987 
Bladder adenocarcinoma stage 0 
Bladder cancer 
10004988 
Bladder adenocarcinoma stage I 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 75 of 85            
EOSI 
Preferred term code 
Preferred term 
Bladder cancer 
10004989 
Bladder adenocarcinoma stage II 
Bladder cancer 
10004990 
Bladder adenocarcinoma stage III 
Bladder cancer 
10004991 
Bladder adenocarcinoma stage IV 
Bladder cancer 
10004992 
Bladder adenocarcinoma stage unspecified 
Bladder cancer 
10005003 
Bladder cancer 
Bladder cancer 
10005005 
Bladder cancer recurrent 
Bladder cancer 
10005006 
Bladder cancer stage 0, with cancer in situ 
Bladder cancer 
10005007 
Bladder cancer stage 0, without cancer in situ 
Bladder cancer 
10005008 
Bladder cancer stage I, with cancer in situ 
Bladder cancer 
10005009 
Bladder cancer stage I, without cancer in situ 
Bladder cancer 
10005010 
Bladder cancer stage II 
Bladder cancer 
10005011 
Bladder cancer stage III 
Bladder cancer 
10005012 
Bladder cancer stage IV 
Bladder cancer 
10005056 
Bladder neoplasm 
Bladder cancer 
10005075 
Bladder squamous cell carcinoma recurrent 
Bladder cancer 
10005076 
Bladder squamous cell carcinoma stage 0 
Bladder cancer 
10005077 
Bladder squamous cell carcinoma stage I 
Bladder cancer 
10005078 
Bladder squamous cell carcinoma stage II 
Bladder cancer 
10005079 
Bladder squamous cell carcinoma stage III 
Bladder cancer 
10005080 
Bladder squamous cell carcinoma stage IV 
Bladder cancer 
10005081 
Bladder squamous cell carcinoma stage 
unspecified 
Bladder cancer 
10005084 
Bladder transitional cell carcinoma 
Bladder cancer 
10051690 
Urinary bladder sarcoma 
Bladder cancer 
10057352 
Metastatic carcinoma of the bladder 
Bladder cancer 
10066749 
Bladder transitional cell carcinoma stage 0 
Bladder cancer 
10066750 
Bladder transitional cell carcinoma recurrent 
Bladder cancer 
10066751 
Bladder transitional cell carcinoma stage I 
Bladder cancer 
10066752 
Bladder transitional cell carcinoma stage IV 
Bladder cancer 
10066753 
Bladder transitional cell carcinoma stage II 
Bladder cancer 
10066754 
Bladder transitional cell carcinoma stage III 
Bladder cancer 
10071664 
Bladder transitional cell carcinoma metastatic 
Bladder cancer 
10078341 
Neuroendocrine carcinoma of the bladder 
Potentially leading to amputation 
10003084 
Areflexia 
Potentially leading to amputation 
10003178 
Arterial thrombosis 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 76 of 85            
EOSI 
Preferred term code 
Preferred term 
Potentially leading to amputation 
10003210 
Arteriosclerosis 
Potentially leading to amputation 
10003222 
Arteriosclerotic gangrene 
Potentially leading to amputation 
10006784 
Burning sensation 
Potentially leading to amputation 
10007904 
Cellulitis enterococcal 
Potentially leading to amputation 
10007905 
Cellulitis gangrenous 
Potentially leading to amputation 
10007921 
Cellulitis staphylococcal 
Potentially leading to amputation 
10007922 
Cellulitis streptococcal 
Potentially leading to amputation 
10012174 
Dehydration 
Potentially leading to amputation 
10012665 
Diabetic gangrene 
Potentially leading to amputation 
10012679 
Diabetic neuropathic ulcer 
Potentially leading to amputation 
10012680 
Diabetic neuropathy 
Potentially leading to amputation 
10017711 
Gangrene 
Potentially leading to amputation 
10020937 
Hypoaesthesia 
Potentially leading to amputation 
10021137 
Hypovolaemia 
Potentially leading to amputation 
10021519 
Impaired healing 
Potentially leading to amputation 
10021784 
Infected skin ulcer 
Potentially leading to amputation 
10022562 
Intermittent claudication 
Potentially leading to amputation 
10024774 
Localised infection 
Potentially leading to amputation 
10028862 
Necrosis ischaemic 
Potentially leading to amputation 
10029331 
Neuropathy peripheral 
Potentially leading to amputation 
10031149 
Osteitis 
Potentially leading to amputation 
10031252 
Osteomyelitis 
Potentially leading to amputation 
10031253 
Osteomyelitis acute 
Potentially leading to amputation 
10031256 
Osteomyelitis chronic 
Potentially leading to amputation 
10031262 
Osteomyelitis salmonella 
Potentially leading to amputation 
10031264 
Osteonecrosis 
Potentially leading to amputation 
10033775 
Paraesthesia 
Potentially leading to amputation 
10034568 
Peripheral coldness 
Potentially leading to amputation 
10034576 
Peripheral ischaemia 
Potentially leading to amputation 
10034620 
Peripheral sensory neuropathy 
Potentially leading to amputation 
10034636 
Peripheral vascular disorder 
Potentially leading to amputation 
10036155 
Poor peripheral circulation 
Potentially leading to amputation 
10036410 
Postoperative wound infection 
Potentially leading to amputation 
10040026 
Sensory disturbance 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 77 of 85            
EOSI 
Preferred term code 
Preferred term 
Potentially leading to amputation 
10040840 
Skin erosion 
Potentially leading to amputation 
10040872 
Skin infection 
Potentially leading to amputation 
10040943 
Skin ulcer 
Potentially leading to amputation 
10042343 
Subcutaneous abscess 
Potentially leading to amputation 
10043607 
Thrombosis 
Potentially leading to amputation 
10048031 
Wound dehiscence 
Potentially leading to amputation 
10048038 
Wound infection 
Potentially leading to amputation 
10049927 
Dry gangrene 
Potentially leading to amputation 
10050473 
Abscess limb 
Potentially leading to amputation 
10050502 
Neuropathic ulcer 
Potentially leading to amputation 
10051548 
Burn infection 
Potentially leading to amputation 
10052428 
Wound 
Potentially leading to amputation 
10052949 
Arterial therapeutic procedure 
Potentially leading to amputation 
10053692 
Wound complication 
Potentially leading to amputation 
10053716 
Wound necrosis 
Potentially leading to amputation 
10054044 
Diabetic microangiopathy 
Potentially leading to amputation 
10056340 
Diabetic ulcer 
Potentially leading to amputation 
10056418 
Arterial bypass operation 
Potentially leading to amputation 
10056673 
Peripheral sensorimotor neuropathy 
Potentially leading to amputation 
10057518 
Peripheral artery angioplasty 
Potentially leading to amputation 
10057525 
Peripheral artery occlusion 
Potentially leading to amputation 
10058041 
Wound sepsis 
Potentially leading to amputation 
10058042 
Wound abscess 
Potentially leading to amputation 
10059245 
Angiopathy 
Potentially leading to amputation 
10059385 
Extremity necrosis 
Potentially leading to amputation 
10059442 
Wound infection staphylococcal 
Potentially leading to amputation 
10059444 
Wound infection pseudomonas 
Potentially leading to amputation 
10060734 
Diabetic foot 
Potentially leading to amputation 
10060803 
Diabetic foot infection 
Potentially leading to amputation 
10060963 
Arterial disorder 
Potentially leading to amputation 
10060965 
Arterial stenosis 
Potentially leading to amputation 
10061627 
Amputation 
Potentially leading to amputation 
10061655 
Arterial graft 
Potentially leading to amputation 
10061657 
Arterial stent insertion 


Statistical Analysis Plan 
Version: 3                                                                                                                             Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                              Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                       Page 78 of 85            
EOSI 
Preferred term code 
Preferred term 
Potentially leading to amputation 
10061666 
Autonomic neuropathy 
Potentially leading to amputation 
10061815 
Diabetic vascular disorder 
Potentially leading to amputation 
10062198 
Microangiopathy 
Potentially leading to amputation 
10062255 
Soft tissue infection 
Potentially leading to amputation 
10062585 
Peripheral arterial occlusive disease 
Potentially leading to amputation 
10062599 
Arterial occlusive disease 
Potentially leading to amputation 
10062610 
Ischaemic limb pain 
Potentially leading to amputation 
10062932 
Wound treatment 
Potentially leading to amputation 
10064250 
Staphylococcal osteomyelitis 
Potentially leading to amputation 
10064601 
Iliac artery occlusion 
Potentially leading to amputation 
10065237 
Osteomyelitis bacterial 
Potentially leading to amputation 
10065239 
Osteomyelitis fungal 
Potentially leading to amputation 
10065240 
Wound infection bacterial 
Potentially leading to amputation 
10065242 
Wound infection fungal 
Potentially leading to amputation 
10068653 
Bone abscess 
Potentially leading to amputation 
10069379 
Peripheral arterial reocclusion 
Potentially leading to amputation 
10072170 
Skin wound 
Potentially leading to amputation 
10072557 
Peripheral artery restenosis 
Potentially leading to amputation 
10072560 
Peripheral endarterectomy 
Potentially leading to amputation 
10072561 
Peripheral artery bypass 
Potentially leading to amputation 
10072562 
Peripheral artery stent insertion 
Potentially leading to amputation 
10072563 
Peripheral artery stenosis 
Potentially leading to amputation 
10072564 
Peripheral artery thrombosis 
Potentially leading to amputation 
10074396 
Penetrating atherosclerotic ulcer 
Potentially leading to amputation 
10075118 
Subperiosteal abscess 
Potentially leading to amputation 
10075714 
Vasculitic ulcer 
Potentially leading to amputation 
10076246 
Spontaneous amputation 
 
 
 


Statistical Analysis Plan 
Version: 3                                                                                                                                                                                                                          Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                                                                                                            Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                                                                                                               Page 79 of 85 
 
Appendix D Summary of statistical analyses 
EFFICACY ANALYSIS 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoint 
HbA1c: Change from 
baseline at Week 26, 
(sotagliflozin 400 mg vs 
placebo)  
 
ITT 
ANCOVA (with missing values 
imputed by the retrieved dropouts 
& washout imputation method or 
by control-based copy reference 
MI method under MNAR 
framework): treatment, 
randomization stratum (HbA1c / 
SBP at screening), and country as 
fixed effects, and baseline HbA1c 
value as a covariate, under the 
original protocol and Amendment 1 
Tipping point analysis; 
ANCOVA (with missing 
values imputed by the 
retrieved dropouts & 
washout imputation method 
or by control-based copy 
reference MI method under 
MNAR framework) under 
original protocol and 
Amendment 1 
Subgroups: 
race, ethnicity, 
age, gender, 
baseline BMI, 
baseline HbA1c, 
baseline SBP, 
baseline eGFR  
and country. 
 
Summary statistics for observed values and 
changes from baseline by visit. 
Graphical presentations for mean changes from 
baseline (±SE) and mean values (±SE) by visit. 
By-visit summary and graph excluding 
measurments after rescue therapy. 
 
Secondary endpoints 
 
 
 
 
 
HbA1c, 2-hour PPG, FPG, 
body weight: Change from 
Baseline to Week 26;  
SBP (for patients with 
baseline SBP ≥130 mmHg, 
all patients): Change from 
Baseline to Week 12 
ITT 
ANCOVA (with missing values 
imputed by the retrieved dropouts 
& washout imputation method or 
by control-based copy reference 
MI Method under MNAR 
framework): treatment, 
randomization stratum (HbA1c / 
SBP at screening), and country as 
fixed effects, and baseline HbA1c 
value as a covariate, comparing 
sotagliflozin 400 mg vs placebo 
under the original protocol and 
Amendment 1, and comparing 
sotagliflozin 200 mg vs placebo 
ANCOVA (with missing 
values imputed by the 
retrieved dropouts & 
washout imputation method 
or by control-based copy 
reference MI method under 
MNAR framework) 
comparing sotagliflozin 200 
mg (for selected other 
endpoints) vs placebo under 
Amendment 1; Tipping point 
analysis on HbA1c. 
Subgroups on 
HbA1c: race, 
ethnicity, age, 
gender, baseline 
BMI, baseline 
HbA1c, baseline 
SBP, baseline 
eGFR  and 
country. 
 
Summary statistics for observed values and 
changes from baseline by visit. 
Graphical presentations for mean changes from 
baseline (±SE) and mean values (±SE) by visit. 


Statistical Analysis Plan 
Version: 3                                                                                                                                                                                                                          Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                                                                                                            Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                                                                                                               Page 80 of 85 
 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
under Amendment 1. 
Proportion of patients with 
HbA1c <6.5%, <7.0% at 
Week 26 
ITT 
CMH method stratified on 
randomization strata (HbA1c / SBP 
at screening), comparing 
sotagliflozin 400 mg vs placebo 
under the original protocol and 
Amendment 1, and comparing 
sotagliflozin 200 mg vs placebo 
under Amendment 1. 
CMH method stratified on 
randomization strata (HbA1c 
/ SBP at screening): 
excluding patients with 
baseline HbA1c values 
<6.5% (for <6.5% 
responders) or <7% (for 
<7% responders) 
respectively 
No 
By-visit summary and graphs of HbA1c responders 
(<6.5%, <7%). 
By-visit frequency summary and graphs of HbA1c 
responders (<6.5%, <7%) excluding patients with 
baseline HbA1c values <6.5% or <7% respectively. 
Other endpoints 
SBP (for patients with 
baseline SBP <130 mmHg), 
DBP, Urine ACR, UGE, and 
urine GCR, Serum 
creatinine, eGFR: change 
from baseline 
ITT 
Summary statistics for observed values 
and changes from baseline by visit. 
No 
No 
Graphical presentations for mean changes from 
baseline (±SE) and mean values (±SE) by visit as 
appropriate. 
Proportion of patients, with 
reduction in body weight by 
≥2%, ≥5%, and ≥10% from 
Baseline; achieving SBP 
<130 mmHg with baseline 
SBP ≥130 mmHg; 
achieving DBP <80 mmHg 
with baseline DBP 
≥80 mmHg  
ITT 
By-visit frequency summary 
No 
No 
By-visit graphical presentation as appropriate 
Proportion of patients 
requiring rescue for 
hyperglycemia 
 
Summary statistics 
No 
No 
KM plot; List of patients rescued 


Statistical Analysis Plan 
Version: 3                                                                                                                                                                                                                          Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                                                                                                            Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                                                                                                               Page 81 of 85 
 
SAFETY ANALYSES 
Endpoint 
Analysis 
Population 
Primary 
analysis 
Supportive 
Analysis 
Subgroup 
analysis 
Other 
analyses 
hypoglycemia 
Safety 
Follow safety guidelines 
Number (%) of patients with any 
hypoglycemia, severe 
hypoglycemia, documented 
symptomatic hypoglycemia during 
TEAE period, and incidence rates in 
100 patient-years. 
 
Severe hypoglycemia or 
documented symptomatic 
hypoglycemia by subgroups: 
race, age, gender 
KM plot time to first event of severe hypoglycemia 
or documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia maybe 
presented by <54 mg/dL (3.0 mmol/L) as 
appropriate. 
Adverse Events 
Safety 
Follow safety guidelines 
No 
Common TEAEs by 
subgroups: race, age, gender, 
baseline SBP, baseline eGFR  
 
Clinical laboratory 
data 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
Vital signs 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
ECG, Physical 
examination 
Safety 
Follow safety guidelines 
Frequency 
summary 
No 
No 
 


Statistical Analysis Plan 
Version: 3                                                                                                                                                                                                                          Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                                                                                                            Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                                                                                                               Page 82 of 85 
 
Appendix E Study flow chart 
 
Screening Period 
                        Double Blind Treatment Perioda 
Follow-
upb 
Screening 
Run-in 
VISIT 
1 
2 
3 
(Randomization) 
4 
5 
6 
7 
8 
9 
10 
Week 
Up to -4 
-2 
0  
Baseline 
1 
4 
8 
12 
18 
26 
30 
Day (window [days]) 
 
(-7/+3) 
1 
7 (±3) 
28 (±3) 
56 (±3) 
84 (±3) 
126 (±3) 
182 (±3) 
210 (±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
Body weight, heightc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam: 
 
 
 
 
 
 
 
 
 
 
    complete 
X 
 
 
 
  
 
 
 
X 
 
    abbreviated 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Diet & exercise instruction 
 
X 
X 
 
 
 
 
 
X 
 
Instruction on basic genitourinary 
hygiene & hydration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Interactive response technology 
(IRT) contact 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Dispense glucose meter  
 
X 
 
 
 
 
 
 
 
 
Dispense diary  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect/review diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Instruction on diabetic 
ketoacidosis symptoms and 
glucose testing 
 
 
X 
X 
X 
X 
X 
X 
X 
 


Statistical Analysis Plan 
Version: 3                                                                                                                                                                                                                          Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                                                                                                            Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                                                                                                               Page 83 of 85 
 
 
Screening Period 
                        Double Blind Treatment Perioda 
Follow-
upb 
Screening 
Run-in 
VISIT 
1 
2 
3 
(Randomization) 
4 
5 
6 
7 
8 
9 
10 
Week 
Up to -4 
-2 
0  
Baseline 
1 
4 
8 
12 
18 
26 
30 
Day (window [days]) 
 
(-7/+3) 
1 
7 (±3) 
28 (±3) 
56 (±3) 
84 (±3) 
126 (±3) 
182 (±3) 
210 (±3) 
Dispense IMP  
 
X 
X 
 
X 
X 
X 
X 
 
 
IMP accounting & compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-monitored blood glucosee 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
 
X 
 
 
 
 
 
X 
 
Standard mixed meal tolerance 
testg 
 
 
X 
 
 
 
 
 
X 
 
Laboratory testingh 
 
 
 
 
 
 
 
 
 
 
FPG 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
HbA1c 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Chemistry (including amylase 
and lipase) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
 
 
 
X 
 
X 
 
Fasting lipids 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Pregnancy test (WOCBP)i 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Serum follicle stimulating 
hormone and estradiol 
(menopausal women only)i 
X 
 
 
 
 
 
 
 
 
 
Plasma concentrationj 
 
 
 
 
X 
 
 
X 
X 
 
Markers of intestinal transit & 
absorptionk 
 
 
X 
 
 
 
 
 
X 
X 
Markers of bone & calcium 
metabolisml 
 
 
X 
 
 
 
 
 
X 
 
Urinalysis (dipstick and 
microscopy)m 
X 
 
X 
 
 
 
 
 
X 
 


Statistical Analysis Plan 
Version: 3                                                                                                                                                                                                                          Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                                                                                                            Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                                                                                                               Page 84 of 85 
 
 
Screening Period 
                        Double Blind Treatment Perioda 
Follow-
upb 
Screening 
Run-in 
VISIT 
1 
2 
3 
(Randomization) 
4 
5 
6 
7 
8 
9 
10 
Week 
Up to -4 
-2 
0  
Baseline 
1 
4 
8 
12 
18 
26 
30 
Day (window [days]) 
 
(-7/+3) 
1 
7 (±3) 
28 (±3) 
56 (±3) 
84 (±3) 
126 (±3) 
182 (±3) 
210 (±3) 
Urine albumin, calcium, 
glucose & creatinine 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluate for glycemic rescue 
 
 
 
To be assessed and reported throughout the treatment period 
 
Hypoglycemia 
To be assessed and reported throughout the study 
AEs/SAEs/AESIs/EOSIs 
To be assessed and reported throughout the studyp 
a      If a patient discontinues treatment with IMP early during the Treatment Period, the patient will have a Premature EOT Visit, and a Follow-up Visit 4 weeks after the last dose of IMP. However, every effort will be 
made to have all patients return to the site for all scheduled visits, in particular the Week 26 Visit. If the patient does not agree to a site visit, they will be contacted by telephone to inquire about safety status. If a 
patient discontinues (or completes) treatment and study at the same time, a single visit will be performed using the procedure normally planned for the EOT visit. 
b      Four weeks after the last dose of IMP. 
c      Height to be measured only at screening 
d      Vital sign measurements (sitting BP and heart rate): 3 separate seated BP and heart rate measurements should be taken with at least 1 minute between readings, following a 5-minute rest period and prior to 
phlebotomy (see protocol Section 9.2.1.4 and detailed instructions in protocol Appendix D).  
e      See protocol Section 9.2.1.6 for details of SMBG measurements. Glucose meters used for SMBG display results as plasma glucose concentration. Patients should measure their fasting plasma glucose at least 3 
times per week (including on day of each on-site study visit). 
f       The 12-lead ECG recordings should be obtained prior to IMP administration. The ECG will be evaluated as “normal” or “abnormal”. 
g      Postprandial plasma glucose will be assessed by central laboratory at Baseline and 2 hours after consuming a standard mixed liquid breakfast meal and via a mixed meal tolerance test (MMTT) on Day 1 and 
Week 26. If a patient withdraws from IMP early, please see protocol Section 10.3.4. 
h      All laboratory assessments occur prior to first dose of double-blind IMP. The first dose of double-blind IMP occurs after samples for the mixed liquid meal have been collected. All visit dates will be scheduled 
based on the date of randomization with a ±3 days visit window allowed during the treatment period. Serum chemistry parameters (clinical chemistry [including amylase and lipase], hematology, and other blood 
parameters) are listed in protocol Table 2. 
i       Serum pregnancy testing only at screening; urine pregnancy testing subsequently. Serum pregnancy test results must be reviewed prior to beginning the Run-in Phase for all women of childbearing potential 
(WOCBP). Any positive urine test results must be confirmed based on serum pregnancy test. The Investigator may perform additional tests at their discretion or as required by local regulations. For women of 
nonreproductive potential (protocol Appendix A), follicle stimulating hormone (FSH) and/or estradiol levels should be tested if the definition of postmenopausal or premenopausal cannot be satisfied, eg, no medical 
document of hysterectomy or cessation of menses <12 months without an alternative medical cause. 


Statistical Analysis Plan 
Version: 3                                                                                                                                                                                                                          Date of Issue: 21-Nov-2019 
Lexicon Pharmaceuticals Protocol No.  EFC14833                                                                                                                            Covance Study ID: 000000150524 
COVANCE INC. CONFIDENTIAL 
                                                                                                                                                                                                                                                               Page 85 of 85 
 
j       Plasma concentration samples (ie, for sotagliflozin and sotagliflozin-3-O-glucuronide) on Weeks 4 and Week 18 should be drawn with the other laboratory assessments. For Week 26, plasma concentration 
samples should be drawn at predose and 2 hours 30 minutes, immediately after the respective glucose assessments during the MMTT. PK samples (except the 2 hours 30 minute sample during the MMTT) MUST 
be collected before administration of IMP. The date and time of the last intake of IMP prior to visits where PK samples are taken should be recorded by the patient in the patient diary. Patients should be reminded 
of this at visits preceding PK time points to ensure these details are captured. In the case of Premature IMP discontinuation, PK samples should not be drawn at the Premature EOT visit, nor at any subsequent 
visits. 
k      The markers of intestinal transit and absorption include vitamins B6, B12, K, E, and A, serum folate, and ferritin. 
l       Markers of bone and calcium metabolism include:  serum and urinary calcium, serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum and urinary phosphorus, serum parathyroid hormone, markers of 
bone resorption (serum NTX, serum β-CTX-1), and bone formation (serum P1NP). 
m    Urinalysis includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte esterase. Microscopy includes detection 
of formed cellular elements, casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. In the event of abnormal urinalysis findings suspicious of urinary tract infection, urine culture should be 
performed. Positive urine culture determination will be based upon the criteria of the reporting laboratory. 
p      All serious adverse events (SAEs), adverse events (AEs), AEs of special interest (AESIs), and Events of Special Interest (EOSIs) will be collected starting with signing informed consent and continue until the end 
of the study. All AEs that occur during treatment should be followed until study completion (or until patients leave the study) or until the event has resolved, the condition has stabilized, or the patient is lost to 
follow-up. All patients will have a follow-up contact 4 weeks after the last dose of IMP to collect safety information.