Conditions: Type 2 Diabetes Mellitus Chronic Kidney Disease Stage 4
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 277
Healthy volunteers: no

Brief summary:
Primary Objective:

To demonstrate the superiority of sotagliflozin 400 milligrams (mg) versus placebo with respect to hemoglobin A1c (HbA1c) reduction at Week 26 in participants with Type 2 diabetes who have inadequate glycemic control and severe renal impairment

Secondary Objectives:

* To assess the effects of sotagliflozin 200 mg versus placebo based on change from baseline in HbA1c
* To assess the effects of sotagloflozin 400 mg and 200 mg versus placebo
* To evaluate the safety of sotagliflozin 400 mg and 200 mg versus placebo

Detailed description:
The study duration is up to 60 weeks including 4 weeks prior to randomization, 52 weeks of randomized treatment and a visit 4 weeks after completion of the randomized treatment period.

Arms:
arm 1: Following a 2-week run-in phase, participants received two placebo tablets (identical to sotagliflozin 200 milligrams \[mg\] in appearance) orally once daily for up to 56 weeks. arm 2: Following a 2-week run-in phase, participants received two tablets, one sotagliflozin 200 mg tablet and one placebo tablet (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 56 weeks. arm 3: Following a 2-week run-in phase, participants received sotagliflozin 400 mg, administered as 2 sotagliflozin 200 mg tablets, orally once daily for up to 56 weeks.

Interventions: intervention 1: Placebo intervention 2: Sotagliflozin
Intervention descriptions: intervention 1: Placebo tablet (identical to sotagliflozin 200 mg in appearance) orally, once daily. intervention 2: Sotagliflozin 200 mg, tablet, orally, once daily.

Protocol document:
Prot_000.pdf: 
Official Title: A Randomized, Double-blind, Placebo-controlled, 3-arm, Parallel-
group, 52-week Multicenter Study to Evaluate the Efficacy and Safety 
of Sotagliflozin in Patients with Type 2 Diabetes Mellitus and Severe 
Renal Impairment who have Inadequate Glycemic Control 
NCT Number: NCT03242018 
Document Date: Protocol Version 01: 15-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. 01 
 
COMPOUND: sotagliflozin/SAR439954 
A Randomized, Double-blind, Placebo-controlled, 3-arm, Parallel-group, 52-week 
Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin in Patients 
with Type 2 Diabetes Mellitus and Severe Renal Impairment who have Inadequate 
Glycemic Control 
STUDY NUMBER: EFC15166 
STUDY NAME: SOTA-CKD4 
VERSION DATE / STATUS: Approval date (13-Dec-2017) / Approved 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 13-Dec-2017 
Clinical Trial Protocol 
Version number: 1 (electronic 3.0) 
Date : 10-May-2017 
EudraCT: 
2016-004906-32 
IND Number: 
 
Version Number: 
1  
WHO universal trial number: 
U1111-1190-7589 
Date: 
13-Dec-2017 
Total number of pages: 
128 
 
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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.: EFC15166 
TITLE 
A randomized, double-blind, placebo-controlled, 3-arm, parallel-group, 
52-week multicenter study to evaluate the efficacy and safety of 
sotagliflozin in patients with type 2 diabetes mellitus and severe renal 
impairment 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 with respect to hemoglobin A1c 
(HbA1c) reduction at Week 26 in patients with type 2 diabetes (T2D) 
who have inadequate glycemic control and severe renal impairment. 
Secondary objectives: 
The secondary objectives of this study are: 
• 
To assess the effects of sotagliflozin 200 mg versus placebo 
based on: Change from Baseline in HbA1c at Week 26 
• 
To assess the effects of sotagliflozin 400 mg and 200 mg 
versus placebo, based on: 
- 
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 
- 
Percentage change in urine albumin:creatinine ratio 
(UACR) from baseline to Week 26 (for patients with 
baseline UACR >30 mg/g) 
- 
The proportion of patients with HbA1c <6.5%, <7.0% at 
Week 26 
• 
To evaluate the safety of sotagliflozin 400 mg and 200 mg 
versus placebo over the 52 weeks of treatment. 
Other: 
To compare sotagliflozin 400 mg and 200 mg versus placebo with 
respect to: 
• 
Change from Baseline in SBP at Weeks 26 and 52 for patients 
with Baseline SBP ≥130 mmHg 
• 
Change from Baseline in SBP at Weeks 26 and 52 for all 
patients 
• 
Change from Baseline in HbA1c at Week 52 
• 
Change from Baseline in FPG at Week 52 
• 
Change from Baseline in body weight at Week 52 
• 
Change from Baseline in estimated glomerular filtration rate 
(eGFR) 
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• 
Change from baseline on the following endpoints 
- 
Cystatin C 
- 
Urinary glucose excretion (UGE) 
- 
Urine glucose:creatinine ratio (UGCR) 
- 
Fructosamine 
- 
N-terminal prohormone of brain natriuretic peptide (NT-
proBNP) 
• 
Progression of kidney disease, based upon changes in eGFR 
or albuminuria 
• 
Change from Baseline in additional measures of sitting blood 
pressure (BP) 
• 
The proportion of patients requiring rescue for hyperglycemia 
during the 26-week double-blind Treatment Period 
• 
To assess plasma levels of sotagliflozin and sotagliflozin-3-O-
glucuronide in the sotagliflozin treatment arms 
STUDY DESIGN 
This is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study. 
Patients with T2D will be included in this study if at Screening they have 
a HbA1c level between 7% and 11%, inclusive, and severe renal 
impairment (defined as a screening modification of diet in renal disease 
[MDRD] eGFR of ≥15 to <30 mL/min/1.73 m2). Any background 
antidiabetic therapy (oral or injected including insulin) is permitted with 
the exception of other sodium-glucose cotransporter type 2 (SGLT2) 
inhibitors. During the double-blind Treatment Period, the type and the 
dose of background therapy should not be changed unless for safety 
concerns. 
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%) and as assessed at the Investigator’s 
discretion. 
Randomization will be stratified by: 
• 
HbA1c at screening (≤8.5% and >8.5%)  
• 
SBP at screening (<130 mmHg and ≥130 mmHg). 
To ensure safety, all randomized patients will be monitored weekly for 
their laboratories and safety for the first 4 weeks. When 10 patients in 
each group are exposed for 4 weeks there will be a formal evaluation by 
Data Monitoring Committee (DMC). 
Following randomization, patients will have a 26-week double-blind 
Treatment Period, a 26-week double-blind Extension Period, and a 
4-week, post-treatment Follow-up Visit to collect safety information. 
Patients will be monitored throughout the double-blind Treatment Period 
and Extension Period for signs of deterioration in renal function (eg, 
decrease in eGFR) as well as other routine clinical and laboratory 
findings (see Study Flowchart, Section 1.2). If at any visit after 
randomization up to Week 8 there is a rise in creatinine level (ie, >50% 
increase from baseline level, where baseline level is defined as the 
mean of creatinine values obtained at Screening and Randomization) or 
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if at any visit after Week 8 there is a rise of >50% above the mean of 
creatinine values from the previous 2 visits, the Investigator should 
ensure that no reasonable explanation exists for creatinine increase and 
in particular the following causes: 
• 
Medications that increase creatinine 
• 
Decrease in cardiac output 
• 
Obstructive uropathy 
• 
Urinary tract infection 
• 
Volume depletion 
If addressing these causes does not reduce the creatinine level below 
the above stated threshold, the investigational medicinal product (IMP) 
will be stopped for 2 weeks. If at creatinine recheck the patient has 
returned to below the threshold, then IMP will be restarted at a reduced 
dose (ie, dose reduced via interactive response technology (IRT) to 
200 mg for those randomized to 400 mg; maintained to 200 mg for 
those randomized to 200 mg, and to placebo for those randomized to 
placebo). If the creatinine does not return to below the threshold, the 
IMP will be permanently discontinued but the patient will be asked to 
continue attending all study visits.  
Patients will be randomly assigned 1:1:1 to 1 of 3 treatment groups: 
A. Placebo; 
B. Sotagliflozin 200 mg 
C. Sotagliflozin 400 mg 
The HbA1c and FPG results will be masked to study sites and patients 
after randomization and until study end. To prevent partial unblinding, 
UGE and urine glucose:creatinine ratio (UGCR) results will be also 
masked to study sites and patients.  
Additionally, urinalysis by dipstick will not include the measurement of 
urine glucose. Quantitative urine glucose, albumin, calcium, and 
creatinine will be measured separately at selected on-site visits by the 
central laboratory. 
Early Termination 
If a patient discontinues treatment with IMP early during the 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 Weeks 26 and 
52 visits.  
If the patient does not agree to site visits, they will be contacted by 
telephone to enquire about safety status, particularly at the time of the 
initially scheduled end of study. 
The study design is presented graphically in Section 1.1. 
STUDY POPULATION  
Main selection criteria: 
Inclusion criteria: 
• 
Patients with T2D (drug-naïve or on antidiabetic therapy) and 
documented severe renal insufficiency – chronic kidney 
disease (CKD) stage-4-defined by an eGFR equation (based 
on the 4 variable MDRD) of ≥15 and <30 mL/min/1.73 m2  
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• 
Signed written informed consent to participate in the study in 
accordance with local regulations. 
Major exclusion criteria: 
• 
At the time of Screening age <18 years or < legal age of 
majority, whichever is greater 
• 
Body Mass Index (BMI) ≤20 or >45 kg/m² at Screening 
• 
Use of a selective SGLT2 inhibitor (eg, canagliflozin, 
dapagliflozin, or empagliflozin) within 12 months prior to the 
trial 
• 
Oral antidiabetic agent or insulin use where the dose was not 
stable for 8 weeks before randomization (ie, oral agents 
changed during past 8 weeks or total daily basal insulin dose 
increased or decreased by more than 20% during the past 
4 weeks) 
• 
Use of systemic glucocorticoids (excluding topical, 
intra-articular, or ophthalmic application, nasal spray or 
inhaled forms) for more than 10 consecutive days within 
90 days prior to the Screening Visit 
• 
Patients with severe anemia, severe cardiovascular disease 
(including congestive heart failure New York Heart 
Association IV), respiratory, hepatic, neurological, psychiatric, 
or active malignant tumor or other major systemic disease or 
patients with short life expectancy that, according to the 
Investigator, will preclude their safe participation in this study, 
or will make implementation of the protocol or interpretation of 
the study results difficult 
• 
Known presence of factors that interfere with the Central Lab 
HbA1c measurement (eg, genetic Hb variants) compromising 
the reliability of HbA1c assessment or medical conditions that 
affect interpretation of HbA1c results (eg, Blood transfusion or 
severe blood loss in the last 3 months prior to randomization, 
any condition that shortens erythrocyte survival) 
• 
Patient who has taken other investigational drugs or 
prohibited therapy for this study within 12 weeks or 5 half-lives 
from prior to Screening, whichever is longer. Current 
enrollment in any other clinical study involving an 
investigational study treatment or any other type of medical 
research. 
• 
Type 1 diabetes mellitus 
• 
HbA1c <7% or HbA1c >11% at Screening 
• 
History of diabetic ketoacidosis or nonketotic hyperosmolar 
coma within 3 months prior to the Screening Visit 
• 
History of severe hypoglycemia that resulted in 
unconsciousness, coma or hospitalization within 6 months prior 
to the Screening Visit 
• 
Renal disease that required a transplant at any time or that 
required treatment with immunosuppressive therapy within the 
last 12 months 
• 
CKD5:defined as chronic dialysis or GFR <15  
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• 
Reversible causes of renal failure such as obstruction 
• 
Pregnancy or breastfeeding  
• 
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  
Appendix A), during the study 
• 
Mean of 3 separate blood pressure (BP) measurements 
>180 mmHg (SBP) or >100 mmHg (diastolic blood pressure 
[DBP]) 
• 
Systolic BP <120 mmHg or DBP <60 mmHg if the patient is 
on hypertensive medications 
• 
History of prior gastric surgery including history of gastric 
banding or inflammatory bowel disease within 3 years prior to  
the Screening Visit 
• 
Aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) >3 times the upper limit of the normal 
laboratory range (ULN) 
• 
Total bilirubin: >1.5 times the ULN (except in the case of 
Gilbert’s Syndrome) 
• 
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 
Total expected number of patients: 
276 randomized patients 
Expected number of sites: 
Approximately 110 
STUDY TREATMENTS 
 
Investigational medicinal products 
 
• 
Sotagliflozin 200 mg, given as 2 tablets: 1 sotagliflozin 
200-mg tablet and 1 placebo tablet (identical to sotagliflozin in 
appearance), once daily before the first meal of the day;  
• 
Sotagliflozin 400 mg, given as 2 sotagliflozin 200-mg tablets, 
once daily before the first meal of the day; 
• 
Placebo, given as 2 placebo tablets (identical to sotagliflozin 
in appearance), once daily before the first meal of the day. 
Formulation: 
Tablet 
Route of administration: 
Oral 
Dose regimen: 
Once daily 
Noninvestigational medicinal product 
Rescue therapy 
The thresholds values are defined as follows, depending on study 
period: 
• 
From Baseline Visit (V3, Day 1) to Visit 8 (Week 8) (including 
value at Visit 8): FPG >270 mg/dL (15.0 mmol/L) 
• 
From Visit 8 (Week 8) to Visit 9 (Week 12) (including value at 
Visit 9): FPG >240 mg/dL (13.3 mmol/L) 
• 
From Visit 9 (Week 12) up to the EOT Period Visit 13 (Week 
52) (including value at Visit 13): FPG >200 mg/dL (11.1 
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mmol/L) or HbA1c ≥8.5% (the 8.5% criterion does not apply if 
the HbA1c decrease from Baseline was ≥1.0%). 
Routine fasting (SMBG will be presented as equivalent self-monitoring 
plasma glucose [SMPG]) and central lab alerts on FPG (and HbA1c at 
Week 12 and onwards) are set up to ensure that glycemic parameters 
remain under predefined thresholds values (see hereinafter). 
• 
If one fasting SMBG value exceeds the specific glycemic limit 
on one day, the patient checks it again during the 2 following 
days. If all the values in 3 consecutive days exceed the 
specific limit, the patient should contact the Investigator and a 
central laboratory FPG measurement (and HbA1c at Week 
12 and onwards) is 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 criterion for rescue before rescue therapy is 
initiated. The re-test confirmation should be performed as 
soon as possible, but within 7 days of receipt by unscheduled 
visit. 
In case of a confirmatory FPG and/or HbA1c above the threshold values, 
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 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. 
If any of the above can reasonably explain the insufficient glycemic 
control, Investigator should consider not initiating rescue medication and 
the Investigator 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 adverse event [AE]/concomitant medication parts 
of the electronic case report form [e-CRF] and the medical 
record) 
• 
Stress on the absolute need to be compliant with treatment 
• 
Organize a specific interview with the patient and a Registered 
Dietician or other qualified nutrition professional and to reinforce 
on the absolute need to be compliant to diet and lifestyle 
recommendations, and schedule an FPG/HbA1c assessment at 
the next visit  
If none of the above mentioned reasons can be found, or if appropriate 
action fails to decrease FPG/HbA1c under the threshold values, rescue 
medication may be introduced.  
• 
Open label rescue medication(s) to treat hyperglycemia must 
be in accordance with local standard of care and prescribing 
practice for patients with CKD and will be at the discretion of the 
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Investigator. Except for SGLT2 inhibitors and medications with 
specific contraindications in renal impairment, any approved 
medication(s) including oral antidiabetic drugs or insulin can be 
considered with appropriate dose modification as indicated. 
• 
The patient continues the IMP (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 
• 
Rescue therapy is considered an 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. 
ENDPOINTS 
 
Primary efficacy endpoint: 
Change from Baseline to Week 26 in HbA1c (%) comparing sotagliflozin 
400 mg versus placebo in CKD stage 4 patients. 
Secondary efficacy endpoints: 
To compare sotagliflozin 200 mg versus placebo in change from 
Baseline in HbA1c at Week 26. 
To compare sotagliflozin 400 mg and 200 mg versus placebo, 
respectively, in terms of: 
• 
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. 
• 
Percentage change in the UACR from Baseline to Week 26 for 
patients with a UACR >30 mg/g at baseline 
• 
Proportion of patients with HbA1c <6.5% and <7.0% at 
Week 26 
Other efficacy endpoints: 
To compare sotagliflozin 400 mg and 200 mg versus placebo, 
respectively, in terms of: 
• 
Change from Baseline in SBP at Weeks 26 and 52 for patients 
with Baseline SBP ≥130 mmHg 
• 
Change from Baseline in SBP at Weeks 26 and 52 for all 
patients 
• 
Change from Baseline in HbA1c at Week 52. 
• 
Change from Baseline in FPG at Week 52. 
• 
Change from Baseline in body weight at Week 52. 
• 
Change from Baseline in eGFR 
• 
Change from Baseline to Week 26 in: 
- 
Cystatin C 
- 
UGE 
- 
UGCR 
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- 
Fructosamine 
- 
NT-proBNP. 
• 
Proportion of patients with progression to end stage renal 
disease (ESRD) at Week 4 or any time later during the trial. 
• 
Proportion of patients with >50% decline in eGFR from baseline 
to Week 26 and Week 52 
• 
Proportion of patients with progression from normal to 
microalbuminuria or from microalbuminuria to macroalbuminuria 
from Baseline to Week 26 and Week 52 
• 
Proportion of patients with improvement from microalbuminuria 
to normal or from macroalbuminuria to microalbuminuria from 
Baseline to Week 26 and Week 52 
• 
Change from Baseline in SBP at Week 12 for patients with 
baseline SBP <130 mmHg. 
• 
Change from Baseline in DBP at Week 12 for all patients and 
the subset of patients with baseline DBP ≥80 mmHg. 
• 
Proportion of patients requiring rescue for hyperglycemia during 
the 26-week double-blind Treatment Period 
Safety endpoints: 
• 
AEs, hypoglycemia (all, severe and/or documented 
symptomatic hypoglycemia), events of special interest (EOSIs), 
AE of special interest (AESIs), AEs leading to discontinuation 
from the IMP, serious AEs (SAE), and deaths. 
• 
Acute renal failure. 
• 
Clinical laboratory results, vital signs results, and 
electrocardiogram (ECG) results. 
• 
Markers of intestinal transit and absorption. 
• 
Markers of bone and calcium metabolism. 
Pharmacokinetic endpoints: 
• 
Plasma levels of sotagliflozin and sotagliflozin-3-O-glucuronide 
in the sotagliflozin treatment arms 
ASSESSMENT SCHEDULE 
See Study Flow Chart, Section 1.2. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
The sample size/power calculations were performed based on the 
primary endpoint. Assuming a common standard deviation of 1.2% and 
using a 2-sided test at a 0.05 α-level, 92 patients in each group will 
provide at least 80% power to detect a treatment difference of 0.5% in 
mean HbA1c change from Baseline to Week 26 between sotagliflozin 
400 mg and placebo. 
Analysis population: 
Efficacy analyses will be based on the intention-to-treat (ITT) population, 
defined as all randomized patients irrespective of compliance with the 
study protocol and procedures. Patients will be analyzed according to the 
treatment group to which they are randomized. 
 
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Analysis of the primary efficacy endpoint: 
Analysis of the primary efficacy endpoint (change from Baseline to 
Week 26 in HbA1c) will be performed using the ITT population, using 
HbA1c measurements obtained during the study, including those 
obtained after IMP discontinuation or introduction of rescue therapy. 
The primary efficacy endpoint of change in HbA1c from Baseline to 
Week 26 will be analyzed with missing values imputed by control-based 
multiple imputation method under the missing not at random framework. 
• 
For placebo patients, missing data will be imputed based on the 
placebo group data. 
• 
For patients in the sotagliflozin groups, missing data will be 
imputed as if the patients were on placebo throughout the 
study, where all patients’ measurements including the 
on-treatment measurements will be considered as if the 
measurements were from the placebo group in the imputation 
model. 
Each of the complete datasets will be analyzed by the Analysis of 
Covariance (ANCOVA) model with treatment groups (sotagliflozin 
400 mg, sotagliflozin 200 mg, and placebo), randomization stratum of 
Screening HbA1c (≤8.5% and >8.5%), randomization stratum of 
Screening SBP (<130 mmHg, ≥130 mmHg), country as fixed effects, 
and baseline HbA1c 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 versus 
placebo) and its associated 95% confidence intervals (CI) using 
contrast statements. 
Summary statistics (for screening value, baseline value observed 
values, and observed changes from Baseline) at scheduled visits will be 
provided for each treatment group. The summary will include the 
number of observations, mean, standard deviation (SD), standard error 
(SE), minimum, median, and maximum. Graphical presentations will 
also be used to examine trends over time using mean values (±SE) at 
each of the scheduled visits (using observed cases). 
Baseline definition: 
The baseline value is defined generally as the last available value 
before the first dose of double-blind IMP or the last available value prior 
to randomization for patients who were randomized but never exposed 
to IMP. 
For serum creatinine (or eGFR), the baseline value is defined as the 
mean of creatinine levels (or eGFR) at the Screening, and 
Randomization Visits that prior to the first dose of double-blind IMP or 
prior to randomization for patients who were randomized but never 
exposed to IMP. 
Analysis of secondary efficacy endpoints: 
The secondary endpoints will be analyzed using a similar approach to 
the primary efficacy endpoint, with missing values imputed by the 
control-based multiple imputation method under the missing not at 
random framework. For each of the continuous secondary endpoints, 
each of the complete datasets will be analyzed by the ANCOVA model 
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with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, and 
placebo), randomization stratum of Screening HbA1c (≤8.5% and 
>8.5%), randomization stratum of Screening SBP (<130 mmHg, 
≥130 mmHg), 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 (Week 12 for SBP endpoints) for each treatment group, as 
well as the between-group difference (comparing each sotagliflozin 
group versus placebo) and its associated 95% CI using contrast 
statements. 
The UACR will be log-transformed before the analysis. Change from 
Baseline to Week 26 of UACR in log scale will be analyzed. Results in 
the log scale will be back-transformed to provide the ratio and then the 
percent change of UACR at Week 26 versus Baseline based on the 
geometric means as well as the corresponding 95% CIs. 
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 (≤8.5%, >8.5%), and 
randomization stratum of SBP (<130 mmHg, ≥130 mmHg). For the 
HbAc1 <7% or <6.5% analysis, patients with missing HbA1c data at 
Week 26 will be considered non-responders in the ITT population. 
Summary statistics for the secondary endpoints at scheduled visits will 
be provided for each treatment group. 
Analysis of other efficacy endpoints: 
The analysis of other endpoints will be descriptive with no formal 
testing. Summary statistics at scheduled visits using observed cases 
will be provided by each treatment group. Graphical presentations will 
also be used to illustrate trends over time. 
Analysis of safety data: 
All safety summaries will be descriptive; no statistical significance tests 
will be performed on the safety data. These analysis 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 60 weeks, including a 4-week Screening Period (comprised of a 
2-week Screening Phase, a 2-week, single-blind placebo Run-in 
Phase), a 26-week double-blind Treatment Period, a 26-week 
double-blind Extension Period, and a 4-week post-treatment Follow-up 
Visit. 
STUDY COMMITTEES 
Steering committee:  
 Yes    
 No 
Data monitoring committee: 
 Yes    
 No 
Clinical Endpoint Committee:  
 Yes    
 No  
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
eGFR = estimated glomerular filtration rate; N = number; T2D = type 2 diabetes; R = randomization; SBP = systolic blood pressure; V = visits; Wk = weeks 
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1.2 
STUDY FLOW CHART 
Screening Period 
 
Screening 
Run-in 
Double-Blind Treatment Perioda 
Extension 
Follow-
upa  
Visit 
1 
2 
3  
Random-
ization 
4 
5 
6 
7 
8 
9 
10 
11 
 
12 
13 
14 
Week 
-4 
-2 
0  
Baseline 
1 
2 
3 
4 
8 
12 
18 
26 
39 
52 
56 
Day (window [days]) 
 
(±3) 
1 
7 (±5) 
14 (±5) 
21(±5) 
28 (±5) 
56 (±5) 
84 (±5) 
126 (±5) 
182 (±5) 
273(±5) 
364(±5) 
392(±5) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight, heightb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 complete 
X 
 
 
 
 
 
  
 
 
 
X 
 
X 
 
 abbreviatedd 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
Diet & exercise instruction 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
Instruction on basic genito-
urinary hygiene & hydration 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Interactive response 
technology (IRT) contacte 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense glucose meter  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect glucose meter 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Dispense diary  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect/review diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Instruction on diabetic 
ketoacidosis symptoms and 
glucose testing 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense IMP  
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
IMP accounting & 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Screening Period 
 
Screening 
Run-in 
Double-Blind Treatment Perioda 
Extension 
Follow-
upa  
Visit 
1 
2 
3  
Random-
ization 
4 
5 
6 
7 
8 
9 
10 
11 
 
12 
13 
14 
Week 
-4 
-2 
0  
Baseline 
1 
2 
3 
4 
8 
12 
18 
26 
39 
52 
56 
Day (window [days]) 
 
(±3) 
1 
7 (±5) 
14 (±5) 
21(±5) 
28 (±5) 
56 (±5) 
84 (±5) 
126 (±5) 
182 (±5) 
273(±5) 
364(±5) 
392(±5) 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-monitored blood 
glucosef 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGg 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Laboratory testing h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FPG 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
HbA1c 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Fructosamine 
 
 
X 
 
 
 
X 
X 
X 
 X 
X 
X 
X 
 
Safety laboratory,i 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
X 
Xl 
X 
Cystatin C 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
NT-proBNP 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Fasting lipids 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
Pregnancy test 
(WOCBP)j 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
FSH and/or estradiol 
(menopausal women 
only) j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sotagliflozin Plasma 
concentration k 
 
 
 
 
 
 
X 
 
 
X 
Xl 
X 
Xl 
 
Markers of intestinal 
transit & absorption m 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
Markers of bone & 
calcium metabolism n 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
Urinalysis (dipstick and 
microscopy)o  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Screening Period 
 
Screening 
Run-in 
Double-Blind Treatment Perioda 
Extension 
Follow-
upa  
Visit 
1 
2 
3  
Random-
ization 
4 
5 
6 
7 
8 
9 
10 
11 
 
12 
13 
14 
Week 
-4 
-2 
0  
Baseline 
1 
2 
3 
4 
8 
12 
18 
26 
39 
52 
56 
Day (window [days]) 
 
(±3) 
1 
7 (±5) 
14 (±5) 
21(±5) 
28 (±5) 
56 (±5) 
84 (±5) 
126 (±5) 
182 (±5) 
273(±5) 
364(±5) 
392(±5) 
Collection of home urine 
for albumin,protein, 
creatinine, calcium, 
phosphorus, magnesium, 
glucose and albumine-
creatinine ratiop 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Evaluate for glycemic 
rescue 
 
 
To be assessed and reported throughout the treatment period 
 
Evaluate for 50% increase 
in creatinine s  
 
 
To be assessed and reported throughout the treatment period 
 
Hypoglycemia 
To be assessed and reported throughout the study 
AEs/SAEs/EOSIs/AESIs 
To be assessed and reported throughout the studyt 
a All visits’ dates will be scheduled based on the date of randomization within visit window allowed as per flowchart. If a patient discontinues treatment with investigational medicinal product (IMP) early during the 
Treatment Period, the patient will have a Premature EOT Visit (similar to Visit 13, see Section 10.1.3.2 and a Follow-up Visit 4 weeks after the last dose of IMP (similar to Visit 14, see Section 10.1.4.1). However, 
every effort will be made to have the patients return to the site for all scheduled visits, in particular the Week 26 and Week 52 Visits. 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 for both premature EOT and follow-up will be performed. 
b Height to be measured only at screening. 
c Vital sign measurements (sitting blood pressure [BP], heart rate temperature, and respiratory 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 9.2.1.5 and detailed instructions in Appendix C). 
d The abbreviated physical exam should focus on cardiac and respiratory systems, as well as any areas important for assessment of AEs if necessary. 
e Additional visit (recheck creatinine) from visit 8 every 2 weeks, contact IRT for treatment allocation if applicable. 
f 
Self-monitored blood glucose (SMBG) is to be performed fasting, at least 3 times per week from start of Run-in until end of Treatment Period including on day of each on-site study visit except Visits 4 and 5. 
Patients will also be requested to self-assess blood glucose levels whenever they experience symptoms of hypoglycemia. SMPG ≤70 mg/dL (3.9 mmol/L) will be documented on the hypoglycemia eCRF. The 
SMBG will be presented as equivalent self-monitoring plasma glucose (SMPG). 
g The 12-lead ECG recordings should be obtained prior to IMP administration. The ECG will be evaluated as “normal” or “abnormal”. 
h All laboratory assessments occur prior to dose of double-blind IMP. All visit dates will be scheduled based on the date of randomization with a ±5 days visit window allowed during the treatment period. 
i 
Safety laboratory will include hematology and clinical chemistry, please see the list in Table 2.  Other clinical chemistry tests will include amylase and lipase. 
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j 
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. 
k Plasma concentration samples for sotagliflozin and sotagliflozin-3-O-glucuronide collected on Weeks 4, 18, 26, 39, and 52 may be drawn with the other laboratory assessments but MUST be collected before 
administration of IMP. The time of the last intake of study drug 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, neither at all subsequent visits. 
l 
An additional blood sample will be drawn at Weeks 26 and 52 Visits at 3 hours after administering the dose of IMP for creatinine (for eGFR) and for assessing plasma concentration of sotagliflozin and 
sotagliflozin-3-O-glucuronide. 
m The markers of intestinal transit and absorption include vitamins B6, B12, K, E, and A, serum folate, and ferritin. 
n Markers of bone and calcium metabolism :serum calcium , serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum phosphorus , serum magnesium, serum parathyroid hormone (iPTH), markers of 
bone resorption (serum NTX, serum β-CTX-1), bone formation (serum P1NP and osteocalcin) and serum alkaline phosphatase. 
o Urinalysis includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte esterase. 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 (UTI), 
urine culture should be performed. Positive urine culture determination will be based upon the criteria of the reporting laboratory. Additionally, urine cultures should be performed if at any point the PI suspects the 
presence of a UTI. 
p Patients will collect overnight urine on Weeks 0, 2, 4, 12, 26, and 52.  In the night prior to the visits, the urine before sleep will be discarded and the urine during sleep and the first morning urine (after getting up) 
will be collected. The visits should be rescheduled to allow for urine collection in case a patient missed it. Urinary albumin, total protein, creatinine, calcium (adjusted for creatinine), phosphorus (adjusted for serum 
phosphorus and creatinine), magnesium (adjusted for serum magnesium and urinary creatinine), and glucose will be assessed. 
 
 
 
s The 50% increase will be from baseline value (to Week 8) or from the arithmetic mean of creatinine values from last 2 visits (after Week 8) only at visits having a measurement of creatinine. 
t 
All serious adverse events (SAEs), 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 visit 4 weeks after the last dose of IMP to collect safety and some efficacy information. 
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL NO. 01.......................................................................................1 
1 
FLOW CHARTS.............................................................................................................................13 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................13 
1.2 
STUDY FLOW CHART ..................................................................................................................14 
2 
TABLE OF CONTENTS ................................................................................................................18 
2.1 
LIST OF TABLES...........................................................................................................................24 
2.2 
LIST OF FIGURES.........................................................................................................................24 
3 
LIST OF ABBREVIATIONS ..........................................................................................................25 
4 
INTRODUCTION AND RATIONALE.............................................................................................28 
4.1 
BACKGROUND: SOTAGLIFLOZIN AND DISEASE .....................................................................28 
4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS ................................................................30 
4.3 
RATIONALE FOR SELECTION OF DOSE ...................................................................................31 
4.4 
RATIONALE FOR STUDY DESIGN AND CONTROL GROUPS..................................................31 
4.5 
BENEFIT/RISK OF SOTAGLIFLOZIN...........................................................................................32 
5 
STUDY OBJECTIVES ...................................................................................................................34 
5.1 
PRIMARY.......................................................................................................................................34 
5.2 
SECONDARY ................................................................................................................................34 
5.3 
OTHER...........................................................................................................................................34 
6 
STUDY DESIGN ............................................................................................................................36 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................36 
6.1.1 
Screening period............................................................................................................................36 
6.1.1.1 
Screening phase (Visit 1)...............................................................................................................36 
6.1.1.2 
Run-in phase (Visit 2).....................................................................................................................36 
6.1.2 
Double-blind Treatment Period (Day 1 to Week 26)......................................................................37 
6.1.3 
Double-blind Extension Period.......................................................................................................37 
6.1.4 
Follow-up period.............................................................................................................................38 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................38 
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6.2.1 
Duration of study participation for each patient .............................................................................38 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................38 
6.3 
STUDY COMMITTEES..................................................................................................................38 
6.3.1 
Steering committee ........................................................................................................................38 
6.3.2 
Data monitoring committee ............................................................................................................39 
6.3.3 
Clinical endpoint committee(s).......................................................................................................39 
6.3.4 
Safety adjudication of events requiring ongoing monitoring ..........................................................39 
7 
SELECTION OF PATIENTS..........................................................................................................41 
7.1 
INCLUSION CRITERIA..................................................................................................................41 
7.2 
EXCLUSION CRITERIA ................................................................................................................41 
7.2.1 
Exclusion criteria related to study methodology ............................................................................41 
7.2.2 
Exclusion criteria related to the diabetes or CKD history and treatment .......................................42 
7.2.3 
Exclusion criteria related to the current knowledge of sotagliflozin ...............................................43 
7.2.4 
Additional exclusion criteria during or at the end of the Run-in phase before randomization .......44 
8 
STUDY TREATMENTS .................................................................................................................45 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................45 
8.1.1 
Dose reduction...............................................................................................................................45 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................46 
8.2.1 
Rescue therapy..............................................................................................................................46 
8.3 
BLINDING PROCEDURES............................................................................................................47 
8.3.1 
Methods of blinding........................................................................................................................47 
8.3.1.1 
First step data analysis ..................................................................................................................48 
8.3.2 
Randomization code breaking during the study.............................................................................48 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................49 
8.5 
PACKAGING AND LABELING ......................................................................................................49 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................50 
8.7 
RESPONSIBILITIES ......................................................................................................................50 
8.7.1 
Treatment accountability and compliance......................................................................................50 
8.7.2 
Return and/or destruction of treatments ........................................................................................51 
8.8 
CONCOMITANT MEDICATION.....................................................................................................51 
8.8.1 
Prohibited prior and concomitant medications...............................................................................52 
8.8.2 
Concomitant diabetes therapy .......................................................................................................52 
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8.9 
POSTSTUDY TREATMENT..........................................................................................................53 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................54 
9.1 
EFFICACY ENDPOINT..................................................................................................................54 
9.1.1 
Primary efficacy endpoint...............................................................................................................54 
9.1.2 
Secondary efficacy endpoints........................................................................................................54 
9.1.3 
Other efficacy endpoints ................................................................................................................54 
9.1.4 
Assessment methods of efficacy endpoints...................................................................................55 
9.1.4.1 
Hemoglobin A1c.............................................................................................................................55 
9.1.4.2 
Fasting plasma glucose measurement ..........................................................................................55 
9.1.4.3 
Body weight measurement ............................................................................................................56 
9.1.4.4 
Blood pressure measurements ......................................................................................................56 
9.1.4.5 
Kidney function parameter assessments.......................................................................................56 
9.1.4.6 
Fructosamine, cystatin C, and NT-proBNP measurements...........................................................56 
9.1.4.7 
Use of rescue medication for hyperglycemia.................................................................................56 
9.1.4.8 
Proportion of patients with progression of renal disease...............................................................57 
9.2 
SAFETY ENDPOINTS ...................................................................................................................57 
9.2.1 
Assessment methods of safety endpoints .....................................................................................58 
9.2.1.1 
Adverse events ..............................................................................................................................58 
9.2.1.2 
Hypoglycemia.................................................................................................................................58 
9.2.1.3 
Laboratory safety variables............................................................................................................58 
9.2.1.4 
Urinalysis........................................................................................................................................61 
9.2.1.5 
Vital signs and physical exam........................................................................................................61 
9.2.1.6 
Electrocardiogram variables ..........................................................................................................61 
9.2.1.7 
Self-monitoring of blood glucose....................................................................................................62 
9.3 
OTHER ENDPOINTS.....................................................................................................................63 
9.3.1 
Pharmacokinetics of sotagliflozin...................................................................................................63 
9.3.1.1 
Sampling time ................................................................................................................................63 
9.3.1.2 
Pharmacokinetics handling procedure...........................................................................................63 
9.3.1.3 
Bioanalytical method......................................................................................................................64 
 
64 
 
64 
 
65 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................65 
10 
STUDY PROCEDURES ................................................................................................................67 
10.1 
VISIT SCHEDULE..........................................................................................................................67 
10.1.1 
Screening period............................................................................................................................67 
10.1.1.1 Screening phase ............................................................................................................................67 
10.1.1.2 Run-in phase..................................................................................................................................69 
10.1.2 
Double-blind randomized treatment period (Day 1 to Week 26) ...................................................70 
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10.1.2.1 On-site randomization visit on Day 1 (Baseline; Week 0)..............................................................70 
10.1.2.2 On-site visits at Weeks 1 and 2 (Visits 4 and 5) ............................................................................72 
10.1.2.3 On-site Visits 6 to 10 (Weeks 3 to 18) ...........................................................................................73 
10.1.2.4 On-site Visit 11 (Week 26).............................................................................................................74 
10.1.3 
Double-blind Extension Period (Week 27 to Week 52)..................................................................75 
10.1.3.1 On-site Visit 12 (Week 39).............................................................................................................76 
10.1.3.2 On-site Visit 13 (Week 52 – end of treatment)...............................................................................77 
10.1.4 
Post-treatment follow-up period.....................................................................................................78 
10.1.4.1 On-site follow-up Visit 14 (Week 56 - end of study).......................................................................78 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................79 
10.2.1 
Source data to be found in patient’s file.........................................................................................79 
10.2.2 
Source data verification requirements for screen failures .............................................................80 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................80 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product................................80 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product ...............................81 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................81 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................82 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................82 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................83 
10.4.1 
Definitions of adverse events.........................................................................................................83 
10.4.1.1 Adverse event ................................................................................................................................83 
10.4.1.2 Serious adverse event ...................................................................................................................83 
10.4.1.3 Adverse event of special interest...................................................................................................84 
10.4.1.4 Events of special Interest...............................................................................................................85 
10.4.2 
General guidelines for reporting adverse events ...........................................................................86 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................86 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................87 
10.4.5 
Guidelines for reporting events of special interest.........................................................................87 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................87 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................88 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................88 
10.6.1 
Hypoglycemia.................................................................................................................................88 
10.6.2 
Deterioration of renal function........................................................................................................90 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................91 
11 
STATISTICAL CONSIDERATIONS..............................................................................................92 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................92 
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11.2 
DISPOSITION OF PATIENTS .......................................................................................................92 
11.3 
ANALYSIS POPULATIONS...........................................................................................................93 
11.3.1 
Efficacy population.........................................................................................................................93 
11.3.1.1 Intent-to-treat population................................................................................................................93 
11.3.2 
Safety population ...........................................................................................................................93 
11.4 
STATISTICAL METHODS .............................................................................................................94 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................94 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................94 
11.4.1.2 Compliance ....................................................................................................................................95 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................95 
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................95 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................96 
11.4.2.3 Analyses of other efficacy endpoints .............................................................................................97 
11.4.2.4 Multiplicity considerations ..............................................................................................................97 
11.4.3 
Analyses of safety data..................................................................................................................98 
11.4.3.1 Analysis of adverse events ............................................................................................................99 
11.4.3.2 Analyses of hypoglycemia ...........................................................................................................100 
11.4.3.3 Analyses of adverse events of special interest............................................................................100 
11.4.3.4 Analyses of events of special interest..........................................................................................101 
11.4.3.5 Analyses of laboratory variables..................................................................................................101 
11.4.3.6 Analyses of vital sign variables ....................................................................................................101 
11.4.3.7 Analysis of 12 lead electrocardiogram status ..............................................................................101 
11.4.4 
Analyses of pharmacokinetic variables........................................................................................101 
11.5 
INTERIM ANALYSIS....................................................................................................................102 
12 
ETHICAL AND REGULATORY CONSIDERATIONS.................................................................103 
12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................103 
12.2 
INFORMED CONSENT ...............................................................................................................103 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC).................................................................................................103 
13 
STUDY MONITORING.................................................................................................................105 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).....................................................................105 
13.2 
RESPONSIBILITIES OF THE SPONSOR OR SERVICE PROVIDER .......................................105 
13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................105 
13.4 
USE AND COMPLETION OF CASE REPORT FORM(S) AND ADDITIONAL REQUEST.........106 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................106 
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14 
ADDITIONAL REQUIREMENTS.................................................................................................107 
14.1 
CURRICULUM VITAE..................................................................................................................107 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................107 
14.3 
CONFIDENTIALITY .....................................................................................................................107 
14.4 
PROPERTY RIGHTS...................................................................................................................108 
14.5 
DATA PROTECTION...................................................................................................................108 
14.6 
INSURANCE COMPENSATION..................................................................................................109 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................109 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................110 
14.8.1 
By the Sponsor.............................................................................................................................110 
14.8.2 
By the Investigator .......................................................................................................................110 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................110 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................110 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................112 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................113 
17 
APPENDICES..............................................................................................................................115 
APPENDIX A 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION....................................................................................................116 
APPENDIX B 
RECOMMENDATIONS ON BASIC GENITO-URINARY HYGIENE, MAINTAINING 
HYDRATION AND RECOGNIZING DIABETIC KETOACIDOSIS...............................................119 
APPENDIX C MEASUREMENT OF BLOOD PRESSURE AND PULSE RATE......................................122 
APPENDIX D GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................124 
 
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2.1 
LIST OF TABLES 
Table 1 - Summary of investigational medicinal products during treatment period ......................................45 
Table 2 - Blood safety laboratory ..................................................................................................................60 
Table 3 - Sotagliflozin samples identification ................................................................................................63 
 
2.2 
LIST OF FIGURES 
Figure 1 - Hypoglycemia classification in Study EFC15166..........................................................................89 
 
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3 
LIST OF ABBREVIATIONS 
 
AEs: 
adverse events 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
AUC: 
area under the concentration versus time curve 
BMI: 
body mass index 
BP: 
blood pressure 
CECs: 
Clinical Endpoint Committees 
CFDA: 
Chinese Food and Drug Association 
CI: 
confidence interval 
CKD: 
chronic kidney disease 
CRF: 
case report form 
CRO: 
contract research organization 
CSR: 
clinical study report 
CV: 
cardiovascular 
CYP: 
cytochrome P450 
DBP: 
diastolic blood pressure 
DILI: 
drug-induced liver injury 
DKA: 
diabetic ketoacidosis 
DMC: 
data monitoring committee 
DRF: 
Discrepancy Resolution Form 
DVT: 
deep vein thrombosis 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EMA: 
European Medicines Agency 
EOSI: 
event of special interest 
EOT: 
end of treatment 
ESRD: 
end stage renal disease 
FDA: 
US Food and Drug Administration 
FPG: 
fasting plasma glucose 
FSH: 
follicle-stimulating hormone 
GCP: 
Good Clinical Practices 
GI: 
gastrointestinal 
GLP-1: 
glucagon-like peptide-1 
GU: 
genito-urinary 
HbA1c: 
hemoglobin A1c 
HLGT: 
high-level group term 
HLT: 
high level term 
HR: 
heart rate 
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IB: 
Investigator's Brochure 
ICF: 
informed consent form 
ICH: 
International Conference on Harmonization 
IDF: 
International Diabetes Federation 
IEC: 
independent ethics committee 
IMP: 
investigational medicinal product 
iPTH: 
parathyroid hormone 
IRB: 
institutional review board 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
MACE: 
 major adverse cardiac events  
MDRD: 
modification of diet in renal disease 
MI: 
myocardial infarction 
NIMP: 
noninvestigational medicinal product 
NT-proBNP: 
N-terminal prohormone of brain natriuretic peptide 
NTX: 
N-terminal telopeptide 
OC: 
observed cases 
P1NP: 
type 1 procollagen N terminal 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamics 
P-gp: 
P-glycoprotein 
PI: 
Principal Investigator 
PK: 
pharmacokinetics 
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 
SGLT1: 
sodium-glucose cotransporter type 1 
SGLT2: 
sodium-glucose cotransporter type 2 
SMBG: 
self-monitoring of blood glucose 
SMPG: 
self-monitoring plasma glucose 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
T1D: 
type 1 diabetes 
T2D: 
type 2 diabetes mellitus 
TEAE: 
treatment-emergent adverse events 
UACR: 
urine albumin: creatinine ratio 
UGCR: 
urine glucose: creatinine ratio 
UGE: 
urinary glucose excretion 
ULN: 
upper limit of normal 
UTI: 
urinary tract infection 
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VTE: 
venous thrombotic event 
WOCBP: 
women of childbearing potential 
β-CTX-1: 
beta-C-terminal telopeptide 
 
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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 
SGLT2) being developed for use in type 2 diabetes (T2D); a metabolic disorder characterized by 
hyperglycemia that results from a combination of increased insulin resistance and beta-cell 
dysfunction (1). The microvascular complications of diabetes are well known and can result in 
impaired renal function, retinopathy and neuropathy and macrovascular complications result in 
coronary disease, amputations and stroke. Other comorbidities that are frequently associated with 
diabetes are hypertension, obesity, and cardiovascular (CV) disease. According to the most recent 
International Diabetes Federation (IDF) Atlas, the estimates in 2015 were that 1 in 11 adults have 
diabetes, which means 415 million people and estimated to be 642 million by 2040 (2). 
According to the World Health Organization, there are about 60 million people with diabetes in 
the European Region, or about 10.3% of men and 9.6% of women aged 25 years and over (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. 
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 (4). 
The SGLT1 is expressed predominantly in the gastrointestinal (GI) tract; SGLT1 is responsible 
for the majority of glucose absorption by the small intestine (5). Inhibition of SGLT1 in the GI 
tract delays glucose absorption and lowers peak postprandial glucose levels (6). 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 (7), pharmacologic inhibition of SGLT1 by sotagliflozin has not produced these 
effects in preclinical models or patients with T2DM. 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 (4, 8) and have led to approvals by the US Food and 
Drug Administration (FDA) and the European Medicines Agency (EMA). Studies with 
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sotagliflozin, a 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 (9). These data suggest that sotagliflozin should be of therapeutic benefit to patients with 
T2D. 
Diabetic nephropathy with advancing duration of diabetes and the treatment of T2D in the face of 
advancing renal insufficiency represents a particular challenge to the clinician. Many agents used 
to treat T2DM, including sulfonylurea, metformin, and incretin-based insulin secretagogues, can 
no longer be used or must be dosed with caution in the clinical setting of renal insufficiency. 
The glucose lowering efficacy of selective SGLT2 inhibitors will diminish when renal function 
(glomerular filtration rate) diminishes because SGLT2 is located exclusively in the renal tubule 
and selective SGLT2 inhibitors act solely by blocking reabsorption of glucose that has been 
filtered at the glomerulus (6). For this reason the use of dapagliflozin is restricted to patients with 
estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 and that of empagliflozin and 
canagliflozin is limited to patients with eGFR ≥45 ml/min/1.73 m2 (10, 11, 12). Sotagliflozin, in 
contrast, lowers glucose by blocking absorption of glucose in the small intestine (SGLT1) as well 
as by blocking reabsorption at the kidney (SGLT2) and thus would be expected to maintain 
glucose lowering efficacy as renal function diminishes. In fact this was shown to be the case in an 
early Phase 1 trial (LX4211.1-107 DM. Patients with T2D and either chronic kidney disease 
(CKD stage 3A (eGFR 45 to 59 mL/min/1.73 m2) or CKD stage 3B (eGFR 30 to 
44 mL/min/1.73 m2) were randomized to sotagliflozin 400 mg once daily or placebo for 7 days 
while being closely monitored, partly as inpatients. 
Sotagliflozin significantly reduced postprandial glucose (PPG) levels relative to placebo in the 
total population and in patients with an eGFR <45 mL/min/1.73 m2, with a placebo-adjusted 
decrease in incremental area under the concentration versus time curve (AUC) predose –4 hrs of 
73.5 mg*h/dL (p = 0.009) and 137.2 mg*h/dL (p = 0.001) for the total population and the eGFR 
<45 mL/min/1.73 m2 subgroup, respectively.  
As expected sotagliflozin caused less increase in UGE in the CKD3B subsets than in the total 
population subset (placebo-subtracted increase in UGE was 38.7, 53.5, and 20.4 g/24h for the 
total population, CKD3A subset, and CKD3B subset, respectively [p = 0.007 for all 3]). This 
suggests that something other than inhibition of SGLT2 mediated renal glucose absorption is 
being inhibited by sotagliflozin, eg, SGLT1 effect in the GI. In addition, the patients with CKD4 
have decreased insulin clearance and better glucose control. These results also suggest that dual 
SGLT1 and SGLT2 inhibition with sotagliflozin could prove useful for the treatment of patients 
with T2D and renal impairment (13). 
Sotagliflozin has shown effect in patients with renal impairment and since SGLT1 inhibition does 
not depend on kidney, the purpose of this study is to evaluate the effects of sotagliflozin in 
glucose lowering in patients with severe renal impairment. 
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4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS 
Approximately 840 subjects (698 assigned to sotagliflozin and 229 assigned to placebo) have 
participated in completed clinical studies of sotagliflozin. No significant safety concerns have 
been identified in the sotagliflozin drug program, and sotagliflozin has been well-tolerated in all 
studies to date. Serious AEs (SAEs) and discontinuations due to adverse events (AEs) have been 
infrequent and have been balanced between treatment and comparator groups. Reports of 
treatment-emergent AEs (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, dizziness, and upper respiratory 
tract infection, all of which were reported at a frequency greater than placebo. However, the 
majority were described as mild to moderate, and most resolved spontaneously and without 
discontinuation of the study drug. 
In completed and ongoing clinical trials, no additional safety issues beside those already described 
in the current Investigator’s Brochure (IB) have been observed. In general, no significant 
imbalances of SAE/AEs between sotagliflozin and comparators were observed in completed 
studies. Cumulatively, across the completed studies 8 SAEs were reported in 6 patients (4 T2D 
and 2 T1D), all of which were assessed as unrelated to study drug; those reported in 4 T2D 
patients who received sotagliflozin included pulmonary embolism, deep vein thrombosis (DVT), 
bile duct stone, cholangitis and lower limb fracture, while a myocardial infarction (MI) was 
experienced by a patient receiving placebo. Two SAEs of diabetic ketoacidosis (DKA) were 
reported in 2 T1D patients in the ongoing (blinded) 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. Based on drug-drug interaction studies, the effect of 
sotagliflozin in competing with compounds metabolized with cytochrome P450 (CYP)3A4 are 
minimal. Sotagliflozin was profiled as perpetrator regarding CYP3A4/5 interaction in INT14972, 
in which a weak induction of CYP3A4/5 was observed at a dose of 400 mg as well as a weak 
inhibition of CYP2D6. These effects were more pronounced at a higher dose of 800 mg. It was 
concluded, that for the vast majority of drugs metabolized predominantly by CYP3A4/5 or 
CYP2D6, the clinical effect is negligible. However, caution is suggested for patients treated with 
narrow therapeutic index drugs. 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. 
In trial 202, it has been demonstrated the systolic blood pressure (SBP) in all the patients was 
decreased by 5.4 mmHg compared to the placebo while the decrease in patients with SBP >130 
mmHg was 14 mmHg. 
More information on the safety of sotagliflozin and on the clinical program can be found in the 
IB. 
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4.3 
RATIONALE FOR SELECTION OF DOSE 
Both the 200 mg and 400 mg doses are being developed in the Phase 3 program for sotagliflozin 
for the treatment of T2D. These doses are being tested in several Phase 3 trials including the 
current trial in patients with T2D and CKD4. 
The proposed sotagliflozin 200 mg and 400 mg once daily doses are based on the results of the 
Phase 2b study LX4211.1-202-DM. In this study 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 sotagliflozin 200 mg and 400 mg once daily doses were chosen for further evaluation 
based on their HbA1c lowering effects and the overall safety and tolerability observed at these 
doses. At 12 weeks, the 200 mg and 400 mg once daily doses lowered HbA1c by a mean of 0.52% 
and 0.93%, respectively (p <0.001 for both arms), while placebo lowered HbA1c by a mean of 
0.14%. Sotagliflozin also produced statistically significant reductions in body weight (200 mg and 
400 mg doses) and SBP (400 mg dose). 
The overall incidences of AEs on sotagliflozin 200 mg and 400 mg once daily were similar to 
placebo. A maximum dose of sotagliflozin has not been established in terms of either safety or 
HbA1c reduction. 
From a safety perspective, sotagliflozin was well-tolerated across studies. In healthy subjects 
sotagliflozin was well-tolerated following single doses up to 2000 mg, and in multiple doses up to 
800 mg over 10 days. Furthermore, in a thorough QT study, single doses of sotagliflozin (800 mg 
and 2000 mg) were well-tolerated and did not prolong the QT interval. Additionally, evaluation of 
metabolites in urine and plasma of healthy subjects resulted in no safety concerns following single 
doses of 400 mg sotagliflozin. In patients with T2D, single doses of sotagliflozin 400 mg in 
combination with sitagliptin, and multiple doses up to sotagliflozin 400 mg in combination with 
metformin over 12 weeks were also well-tolerated. 
Based on the pharmacokinetic (PK) extrapolation and approximation the safety margin based on 
400 mg multiple dosing in CKD stage 3 patients (30 ≤eGFR <60 mL/min/1.73 m2) is 3-fold and in 
CKD stage 4 patients (15 ≤eGFR <30 mL/min/1.73 m2) is 1.9-fold. 
4.4 
RATIONALE FOR STUDY DESIGN AND CONTROL GROUPS 
This study is designed to demonstrate the efficacy and safety of sotagliflozin when used as add-on 
therapy to standard care (any combination of oral agents and/or insulin deemed clinically 
appropriate) in patients with T2D and CKD stage 4 who have inadequate glycemic control. 
Sotagliflozin 200 mg daily as well as sotagliflozin 400 mg daily will be compared to placebo in 
this randomized, double-blind, placebo-controlled, 3-arm, parallel-group trial. Safety, tolerability, 
PK and pharmacodynamics (PD) effects of sotagliflozin are supported by Phase 1 and Phase 2 
studies and animal toxicology data in rats up to 26 weeks and dogs up to 39 weeks as well as 
2-year carcinogenicity data in rats. Efficacy and safety in patients with CKD stages 3A and 3B are 
supported by 7 day PD and safety data in patients with T2D and CKD (Trial LX4211.107). 
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In a Phase 1 trial, 31 patients with T2D and eGFR <60 mL/min/1.73 m2 were randomized to 
sotagliflozin or placebo. Despite reduction of more than 50% in UGE, the patients with eGFR 
<45 mL/min/1.73 min2 and patients with eGFR ≥45 mL/min/1.73 m2 had the same level of 
reduction in the PPG (the primary endpoint). 
Randomization will be stratified based on Screening HbA1c (≤8.5% versus >8.5%) and SBP 
Screening (SBP <130 mmHg versus ≥130 mmHg). Since the reduction in the SBP for patients 
with SBP >130 mmHg was significantly higher than all the patients, these patients will be 
monitored for blood pressure (BP) reduction closely. 
A placebo control will be used to allow for an unbiased assessment of treatment effects and safety 
data. Bias will be minimized by randomizing the patients to treatment groups, blinding the 
patients, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating 
endpoints in a blinded fashion. 
A 2-week Run-in phase has been implemented to stabilize HbA1c and minimize response to 
placebo and effects inherent to participation in a controlled clinical trial. 
Sotagliflozin treatment for 26 weeks is likely to be of sufficient duration to observe effects on 
reduction of HbA1c, BP, and body weight, and is therefore selected as the timepoint for 
assessment of the primary endpoint HbA1c. Treatment up to 52 weeks will provide additional 
long-term data on safety and efficacy. 
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 spot urine 
analyses. At 6 times during the trial (Baseline, Weeks 2, 4, 12, 26, and 52) patients will be 
instructed to bring overnight urine collection. Cystatin C, UGE, urine glucose:creatinine ratio 
(UGCR), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are other valid 
markers of renal function and volume status, and will be assessed at appropriate timepoints in this 
study. In addition, although clinical outcomes are not expected to occur at a high enough rate to 
yield statistically significant information in this trial, outcomes such as death will be adjudicated 
by an independent adjudication committee. 
4.5 
BENEFIT/RISK OF SOTAGLIFLOZIN 
Sotagliflozin is currently being investigated as an adjunct to diet and exercise to improve glycemic 
control in adults with T2D. The development program will also provide efficacy and safety data for 
sotagliflozin in combination with other antidiabetic medications. Sotagliflozin has effects on SGLT2 
and SGLT1. Based on the GI contribution of sotagliflozin in reducing the glucose through SGLT1 
inhibition and the improvement of glycemia caused by the increase in half-life of insulin (as a result 
of the decreased renal function), efficacy is expected in advanced CKD patients. In addition the 
clinical outcomes will be evaluated in patients with high CV risk and in patients with renal 
impairment. Results to date from an earlier Phase 1 study also suggest that patients with T2D and 
renal impairment stage 3A and 3B could benefit from dual SGLT1 and SGLT2 inhibition with 
sotagliflozin as detailed in Section 4.3 without any safety concerns. The use of sotagliflozin in the 
treatment of T1D is also being studied in a separate development program. 
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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 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 levels of the intestinal peptides GLP-1 and PYY 
(from inhibition of SGLT1). In addition, the improvements in body weight and BP observed with 
sotagliflozin treatment have the potential to benefit patients with diabetes through their effects on 
common diabetic comorbidities. 
Phase 2 data indicated that sotagliflozin may reduce SBP by 10 to 15 mmHg in patients with SBP 
≥130 mmHg at Baseline, while having no significant effect in patients with SBP <130 mmHg, and 
did not induce hypotension in normotensive patients. Since this could be of benefit to patients 
with T2D, this finding is being followed up as a secondary objective in this trial. 
SGLT2 inhibitors class have been associated with small decreases of eGRF and increased rate of 
genital infections, which are usually mild and well tolerated in clinical trials. Overall, sotagliflozin 
has been well-tolerated in all studies to date, with the majority of events assessed as mild to 
moderate, most of which resolved spontaneously. Serious AEs and discontinuations due to AEs 
have been limited and balanced between treatment and comparator groups.  
Events of special interest (EOSI) are evaluated based on either their potential link to the drug’s 
mechanism of action, events that occur in other SGLT-inhibitor drugs, or regulatory 
interest/guidance for diabetes products, but found not to be in imbalance in clinical trials. In 
addition to the identified and potential risks (genital mycotic infections [male and female], 
metabolic acidosis, DKA, UTIs, volume depletion, severe hypoglycemia) for the sotagliflozin 
program, other EOSI have been defined. These EOSI are: MACEs and other cardiovascular 
events, venous thrombotic events (VTEs), drug-induced liver injuries (DILIs) / ALT increase 
>3 times ULN, diarrhea, pancreatitis, bone fractures, renal events, malignancies of special interest 
(including but not limited to: breast, bladder, renal cell, Leydig cell, pancreatic, prostate and 
thyroid cancer), and AEs leading to amputation. 
However, reports of these events have been infrequent and have responded to standard treatment. 
The improvement in glycemic control, the reductions in weight and BP, and the tolerability and 
safety profile of sotagliflozin to date demonstrate a favorable benefit-risk assessment for 
sotagliflozin. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this study is to demonstrate the superiority of sotagliflozin 400 mg 
versus placebo with respect to HbA1c reduction at Week 26 in patients with T2D who have 
inadequate glycemic control and severe renal impairment. 
5.2 
SECONDARY 
The secondary objectives of this study are: 
• 
To assess the effects of sotagliflozin 200 mg versus placebo based on: Change from 
Baseline in HbA1c at Week 26 
• 
To assess the effects of sotagliflozin 400 mg and 200 mg versus placebo, based on: 
- 
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 
- 
Percentage change in urine albumin:creatinine ratio (UACR) from baseline to Week 26 
(for patients with baseline UACR >30 mg/g) 
- 
The proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
• 
To evaluate the safety of sotagliflozin 400 mg and 200 mg versus placebo over the 
52 weeks of treatment. 
5.3 
OTHER 
Other objectives of this study are to compare sotagliflozin 400 mg and 200 mg versus placebo 
with respect to:  
• 
Change from Baseline in SBP at Weeks 26 and 52 for patients with Baseline SBP 
≥130 mmHg 
• 
Change from Baseline in SBP at Weeks 26 and 52 for all patients 
• 
Change from Baseline in HbA1c at Week 52 
• 
Change from Baseline in FPG at Week 52 
• 
Change from Baseline in body weight at Week 52 
• 
Change from Baseline in eGFR 
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• 
Change from baseline on the following endpoints: 
- 
Cystatin C 
- 
UGE 
- 
UGCR 
- 
Fructosamine 
- 
NT-proBNP 
• 
Progression of kidney disease, based upon changes in eGFR or albuminuria 
• 
Change from Baseline in additional measures of sitting BP 
• 
The proportion of patients requiring rescue for hyperglycemia during 26-week 
double-blind Treatment Period 
• 
To assess plasma levels of sotagliflozin and sotagliflozin-3-O-glucuronide in the 
sotagliflozin treatment arms. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This is a Phase 3, multicenter and multinational, 1:1:1 randomized, double-blind (single-blind 
Run-in Phase), placebo-controlled, parallel-group study that is anticipated to enroll approximately 
276 patients. 
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, 26-week, double-blind Extension 
Period, and a 4-week, post-treatment Follow-up Visit. 
The study design is presented graphically in Section 1.1. 
6.1.1 Screening period 
6.1.1.1 Screening phase (Visit 1) 
The Screening phase will last up to 2 weeks. It must be long enough to collect the data required to 
establish whether the patient satisfies the inclusion/exclusion criteria. 
Patients with T2D (14) who have inadequate glycemic control (HbA1c 7% to 11%) and severe 
renal insufficiency (CKD4; defined by an eGFR) (15) are eligible for enrollment in this study. 
At the Screening Visit after signing of the informed consent form (ICF), eligibility criteria will be 
assessed and Screening assessments will be performed. Women of childbearing potential 
(WOCBP) not willing to use highly effective 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 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) (identical to sotagliflozin 200 mg in appearance) administered once daily during the 
Run-in Period, starting from Visit 2. 
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6.1.2 Double-blind Treatment Period (Day 1 to Week 26) 
Eligible patients will be randomized on Day 1 (Visit 3). In order to qualify for randomization, 
patients must also demonstrate compliance during the single-blind placebo Run-in Phase based 
upon tablet count (≥80%) and, as assessed, at the Investigator’s discretion. 
Randomization will be stratified by: 
• 
HbA1c at Screening (≤8.5% and >8.5%) 
• 
SBP at Screening (<130 mmHg, ≥130 mmHg). 
Following randomization, patients will be treated in a double-blind manner for 26 weeks. A total 
of 276 patients ≥18 years of age (or ≥ legal age of the majority, whichever is greater) are planned 
to be randomly assigned 1:1:1 to the following treatment groups: 
• 
Placebo, given as 2 placebo tablets (identical to sotagliflozin 200 mg in appearance), once 
daily 
• 
Sotagliflozin 200 mg, given as 2 tablets: 1 sotagliflozin 200 mg tablet and 1 placebo tablet 
(identical to sotagliflozin 200 mg in appearance), once daily 
• 
Sotagliflozin 400 mg, given as 2 sotagliflozin 200 mg tablets, once daily. 
Fasting glucose (plasma or serum) and HbA1c results will be masked to study sites and patients 
after randomization until study end. To prevent partial unblinding, UGE and UGCR will be 
masked to study sites and patients, and the central laboratory urine dipstick will not include the 
measurement of urine glucose.  
Quantitative urine glucose, albumin, calcium, and creatinine will be measured separately at 
selected on-site visits by the central laboratory. 
All visits will be on-site visits. 
If a patient discontinues treatment with investigational medicinal product (IMP) early during the 
Treatment Period, the patient will have a premature end of treatment (EOT) Visit and a Follow-up 
Visit, 4 weeks (± 5 days) 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 
Weeks 26 and 52 Visits. 
If a patient does not agree to site visits, he/she will be contacted by telephone to inquire about 
their safety status, particularly at the time of the initially scheduled end of study. 
6.1.3 Double-blind Extension Period 
From Weeks 27 to 52, patients will be in a 26-week double-blind Extension Period. Patients will 
continue to receive the blinded medication (sotagliflozin 400 mg, 200 mg, or placebo) to which 
they were randomized on Day 1. Patients who received rescue medication during the initial 
26-week Treatment Period will continue on the same rescue medication during the double-blind 
Extension Period (unless the Investigator considers a change necessary for safety reasons). 
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If a patient discontinues treatment with IMP early during the Extension Period, the patient will 
have a premature 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 52 Visit. 
If a patient does not agree to site visits, he/she will be contacted by telephone to inquire about 
their safety status, particularly at the time of the initially scheduled end of study. 
6.1.4 Follow-up period 
Following the last dose of the IMP (either as scheduled or prematurely), a post-treatment 
follow-up should be scheduled for all patients 28 days (4 weeks) ±5 days after permanent IMP 
discontinuation.  
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The total duration of the study for each patient will be up to 60 weeks and will include a 
Screening Phase of up to 2 weeks, a 2-week Run-in Phase, a 26-week double-blind Treatment 
Period, a 26-week double-blind Extension Period, and a 4-week Follow-up Period after 
completion of study treatment. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is defined as being the “last patient last visit” planned with the protocol, 
including the follow-up visit. 
The Sponsor can terminate the trial prematurely based on the advice of the Independent data 
monitoring committee (DMC) or other unforeseen developments. 
6.3 
STUDY COMMITTEES 
6.3.1 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, 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. 
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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 a separate SC Charter. 
6.3.2 Data monitoring committee 
A DMC with members who are independent from the Sponsor and the Investigators will meet on 
a regular basis and will be responsible for: 
• 
Review of accumulating clinical study safety data by treatment 
• 
Make a recommendation to the Sponsor regarding the study following each meeting. 
To ensure safety, all randomized patients will be monitored weekly for their laboratories and 
safety for the first 4 weeks. When 10 patients in each group are exposed for 4 weeks there will be 
a formal evaluation by DMC. 
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. To maintain continuous 
blinding and study integrity, the analysis will be conducted by an independent statistician and 
measures will be taken to ensure the validity of the data.  
Details describing the DMC processes and procedures are outlined in a separate DMC Charter. 
6.3.3 Clinical endpoint committee(s) 
The Clinical Endpoint Committees (CECs) is/are comprised of experts in cardiology and 
nephrology (and other appropriate medical specialties such as neurology and endocrinology as 
needed) who are independent of the Sponsor and the contract research organization (CRO). The 
CEC(s) will review and adjudicate all deaths, major adverse cardiac 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). 
6.3.4 Safety adjudication of events requiring ongoing monitoring 
Two independent committees will review safety events that require ongoing monitoring to ensure 
timing protocol amendments in case a safety signal is identified. These events are: 1) potential 
cases of DILI, and 2) cases of amputations. 
The two committees will review the cases in a treatment-blinded manner and will present their 
assessments to the DMC. 
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The members, roles and responsibilities of the two committees will be described in separate 
Charters. 
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7 
SELECTION OF PATIENTS 
Note: A patient 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 with T2D (drug-naïve or on antidiabetic therapy) and documented severe renal 
insufficiency - CKD4 - defined by an eGFR equation (based on the 4 variable modification 
of diet in renal disease [MDRD] equation) of ≥15 and <30 mL/min/1.73 m2. 
I 02. Signed written informed consent to participate in the study in accordance with local 
regulations. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 4 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. At the time of Screening age <18 years or < legal age of majority, whichever is greater. 
E 02. Body Mass Index (BMI) ≤20 or >45 kg/m² at the Screening Visit. 
E 03. Use of systemic glucocorticoids (excluding topical, intra-articular, or ophthalmic 
application, nasal spray or inhaled forms) for more than 10 consecutive days within 
90 days prior to the Screening Visit. 
E 04. Use of weight loss medications within 12 weeks or weight change of 5 kg or more during 
the 12 weeks before Screening. 
E 05. Likelihood of requiring treatment during the study period with drugs not permitted by the 
study protocol (eg, long-term systemic glucocorticoids) and refusing or unable to take 
alternative treatment. 
E 06. Patients who has previously participated in any clinical trial of sotagliflozin/LX4211. 
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E 07. Patients with severe anemia, severe CV disease (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 08. Current diagnosis of chronic hepatitis and/or other clinically active liver disease requiring 
treatment. 
E 09. Known presence of factors that interfere with the Central Lab HbA1c measurement (eg, 
genetic Hb variants) compromising the reliability of HbA1c assessment or medical 
conditions that affect interpretation of HbA1c results (eg, Blood transfusion or severe 
blood loss in the last 3 months prior to randomization, any condition that shortens 
erythrocyte survival). 
E 10. History of drug or alcohol abuse within 6 months prior to the Screening Visit. 
E 11. Patient is an employee of the Sponsor, or is the Investigator or any Sub-Investigator, 
research assistant, pharmacist, study coordinator, other staff or relative thereof directly 
involved in conducting the study. 
E 12. Patient who has taken other investigational drugs or prohibited therapy for this study 
within 12 weeks or 5 half-lives from prior to Screening, whichever is longer. Current 
enrollment in any other clinical study involving an investigational study treatment or any 
other type of medical research. 
7.2.2 Exclusion criteria related to the diabetes or CKD history and treatment 
E 13. Type 1 diabetes mellitus. 
E 14. HbA1c <7% or >11% measured by the central laboratory at Screening. 
E 15. Oral antidiabetic agent or insulin use where the dose was not stable for 8 weeks before 
randomization (ie, oral agents changed during past 8 weeks or total daily basal insulin dose 
increased or decreased by more than 20% during the past 4 weeks). 
E 16. Use of a selective SGLT2 inhibitor (eg, canagliflozin, dapagliflozin, or empagliflozin) 
within 12 months prior to the trial. 
E 17. History of DKA or nonketotic hyperosmolar coma within 12 weeks prior to the Screening 
Visit. 
E 18. History of severe hypoglycemia that resulted in unconsciousness, coma, or hospitalization 
within 6 months prior to the Screening Visit. 
E 19. CKD stage 5: defined as chronic dialysis or eGFR < 15. 
E 20. Reversible causes of renal failure such as obstruction within 6 months of Screening. 
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E 21. Renal disease that required treatment with immunosuppressive therapy within the last 
12 months, or renal transplant or initiation of chronic dialysis within 4 weeks prior to the 
Screening Visit or expected to occur during the study duration. 
E 22. History of hereditary glucose galactose malabsorption or primary renal glucosuria. 
7.2.3 Exclusion criteria related to the current knowledge of sotagliflozin 
E 23. Pregnant (confirmed by serum pregnancy test at Screening) or breastfeeding women. 
E 24. Women of childbearing potential not willing to use highly effective method(s) of birth 
control during the study treatment period and follow-up period, or who are unwilling or 
unable to be tested for pregnancy (see Appendix A) during the study. 
E 25. Mean of 3 separate BP measurements >180 mmHg (SBP) or >100 mmHg (diastolic blood 
pressure [DBP]) with or without hypertensive medications. 
E 26. Systolic BP <120 mmHg or DBP <60 mmHg if the patient is on antihypertensive 
medications. 
E 27. History of hypertensive emergency within 12 weeks prior to screening (16). 
E 28. History of prior gastric surgery including history of gastric banding or inflammatory bowel 
disease within 3 years prior to the Screening Visit. 
E 29. Difficulty swallowing such that the patient cannot take the IMP. 
E 30. Known allergies, hypersensitivity, or intolerance to SGLT2 inhibitor or any inactive 
component of sotagliflozin or placebo (ie, microcrystalline cellulose, croscarmellose 
sodium [disintegrant], talc, silicone dioxide, and magnesium stearate [nonbovine]), unless 
the reaction is deemed irrelevant to the study by the Investigator. 
E 31. Laboratory findings with the central lab tests at Visit 1: 
- 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the 
upper limit of the normal laboratory range (ULN) 
- 
Total bilirubin >1.5 times the ULN (except in case of Gilbert’s syndrome) 
- 
Neutrophils <1500/mm3 (or according to ethnic group) and/or platelets <100 000/mm3 
- 
Amylase and/or lipase >3 times the ULN 
E 32. Any country-related specific regulation that would prevent the patient from entering the 
study (eg, individuals committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities). 
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7.2.4 Additional exclusion criteria during or at the end of the Run-in phase before 
randomization 
E 33. Patients unwilling or unable to perform self-monitoring of blood glucose (SMBG), 
complete the patient diary or comply with study visits and other procedures as required per 
protocol. 
E 34. Patients insufficiently compliant during Run-in phase. Noncompliance will be based on 
tablet count (<80%) or based on the opinion of the Investigator. 
E 35. Informed consent withdrawal before randomization (patient who is not willing to continue 
or fails to return). 
E 36. Any clinically significant abnormality identified on physical examination, laboratory tests, 
electrocardiogram (ECG) or vital signs at the time of screening or any AE during screening 
period which, in the judgment of the Investigator or any Sub-investigator, would preclude 
safe completion of the study or constrains efficacy assessment. 
E 37. Lower extremity complications (such as skin ulcers, infection, osteomyelitis, and 
gangrene) identified during the Screening period, and still requiring treatment at 
Randomization. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
The IMPs are sotagliflozin 400 mg, sotagliflozin 200 mg, and matching placebos. Patients will be 
provided with: 
• 
Run in kit containing 1 wallet of 34 placebo tablets (identical to sotagliflozin 200 mg in 
appearance) for the Run-in phase 
• 
Treatment kit containing 2 wallets of 38 tablets each (identical to sotagliflozin 200 mg in 
appearance) will be dispensed as needed for the duration of the treatment period in a 
double-blind manner. 
Table 1 provides a summary of each IMP (dose and timing). 
Table 1 - Summary of investigational medicinal products during treatment period 
IMP: 
Sotagliflozin (200 mg group) 
Sotagliflozin (400 mg group) 
Placebo group 
Name of the IMPs 
Sotagliflozin (SAR439954) 
Sotagliflozin (SAR439954) 
Placebo 
Pharmaceutical 
form 
Sotagliflozin (SAR439954) will 
be supplied as 200 mg tablets 
Sotagliflozin (SAR439954) will 
be supplied as 200 mg tablets 
Placebo will be supplied as 
tablets (identical to sotagliflozin 
in appearance) 
Dose, timing and 
route of 
administration 
Sotagliflozin 200 mg group:  
One 200 mg tablet, taken orally 
once daily, before first meal of 
the day 
One placebo tablet, taken orally 
once daily, before first meal of 
the day 
Sotagliflozin 400 mg group:  
Two 200 mg tablets, taken orally 
once daily, before first meal of 
the day  
 
Placebo group:  
Two placebo tablets, taken orally 
once daily, before first meal of 
the day  
 
Duration of 
treatment 
52 weeks following randomization 
Storage conditions  
Store between +15°C and +30°C (59°F and 86°F) 
IMP = investigational medicinal product 
8.1.1 Dose reduction 
The dose maintenance will be handled according to the renal function assessed by the creatinine 
measurement throughout the study. If at any visit after randomization there is a rise in creatinine 
level (see details in Section 10.6.2), the Investigator should ensure that no reasonable explanation 
exists for creatinine increase. Sites will be notified by central laboratory alert if a patient has a 
>50% increase from Baseline level or >50% above the mean of creatinine values from the last 
2 visits, where Baseline level is defined as the mean of creatinine values obtained at Screening 
and Randomization. The IMP should be stopped for 2 weeks. If at creatinine recheck the patient 
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has returned to the below threshold then IMP will be restarted at a reduced dose (ie, dose reduced 
via IRT to 200 mg for patients randomized to 400 mg, maintained to 200 mg for patients 
randomized to 200 mg, and to placebo for those randomized to placebo). Since IMP received is 
blinded, patients must return to the site and IRT will be contacted for this IMP re-initiation. Dose 
reduction can only be obtained at on-site visit by IRT. If the creatinine does not return to below 
the threshold, the IMP will be permanently discontinued but the patient will be asked to continue 
attending all study visits. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
Noninvestigational medicinal product (NIMP) treatment is defined as the rescue medication(s) 
that will be used to treat hyperglycemia when a patient’s hyperglycemia reaches the rescue 
threshold (see Section 8.2.1 for details). 
8.2.1 Rescue therapy 
The thresholds values are defined as follows, depending on study period: 
• 
From Baseline Visit (V3, Day 1) to Visit 8 (Week 8) (including value at Visit 8): FPG 
>270 mg/dL (15.0 mmol/L) 
• 
From Visit 8 (Week 8) to Visit 9 (Week 12) (including value at Visit 9): FPG >240 mg/dL 
(13.3 mmol/L) 
• 
From Visit 9 (Week 12) up to the EOT Period Visit 13 (Week 52) (including value at 
Visit 13): FPG >200 mg/dL (11.1 mmol/L) or HbA1c ≥8.5% (the 8.5% criterion does not 
apply if the HbA1c decrease from Baseline was ≥1.0%). 
Routine fasting SMBG (SMBG will be presented as equivalent self-monitoring plasma glucose 
[SMPG]) and central lab alerts on FPG (and HbA1c at Week 12 and onwards) are set up to ensure 
that glycemic parameters remain under predefined thresholds:  
• 
If one fasting SMBG value exceeds the specific glycemic limit on 1 day, the patient 
checks it again during the 2 following days. If all the values in 3 consecutive days exceed 
the specific limit, the patient should contact the Investigator and a central laboratory 
FPG measurement (and HbA1c at Week 12 and onwards) is 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 criterion for rescue before rescue therapy is 
initiated. The re-test confirmation should be performed as soon as possible, but within 
7 days of receipt by unscheduled visit. 
In the event that a confirmatory FPG and/or HbA1c exceed the threshold, the Investigator should 
ensure that no reasonable explanation exists for insufficient glucose control and in particular that: 
• 
The increased FPG has been tested at a fasting status (ie, no food intake for ≥8 hours) 
• 
Investigational product is given at the planned dose 
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• 
There is no intercurrent disease, which may jeopardize glycemic control (eg, infectious 
disease) 
• 
Compliance to treatment is appropriate 
• 
Compliance to diet and lifestyle is appropriate. 
If any of the above can reasonably explain 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 electronic case report form (e-CRF) and the 
medical record) 
• 
Stress on the absolute need to be compliant with treatment 
• 
Organize a specific interview with the patient and a Registered Dietician or other qualified 
nutrition professional and to reinforce on the absolute need to be compliant to diet and 
lifestyle recommendations, and schedule an FPG/HbA1c assessment at the next visit. 
If none of the above mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, rescue medication may be introduced (17). 
• 
Open label rescue medication(s) to treat hyperglycemia must be in accordance with local 
standard of care and prescribing practice for patients with CKD and will be at the 
discretion of the investigator. Except for SGLT2 inhibitors and medications with specific 
contraindications in renal impairment, any approved medication(s) including oral 
antidiabetic drugs or insulin can be considered with appropriate dose modification as 
indicated. 
• 
The patient continues the IMP (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 
• 
Rescue therapy is considered an 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. 
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
To maintain blinding sotagliflozin and their matching placebo tablets (including packaging) will 
be blinded and indistinguishable. 
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During the double-blind Treatment Period, each treatment package will be labeled with a number, 
which is generated by a computer program from the Sanofi. Investigators will not have access to 
the randomization (treatment) code except under circumstances described in Section 8.3.2. 
The randomization and the treatment allocation will be performed centrally by an IRT. The study 
biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the patient 
randomization list from which it allocates treatment arms to the patients. 
Fasting glucose (plasma or serum) and HbA1c will be masked to study sites and patients after 
randomization and until study end. To prevent partial unblinding, UGE and UGCR results will be 
masked to study sites and patients. Additionally, urinalysis by dipstick will not include the 
measurement of urine glucose.  
Quantitative urine glucose, albumin, calcium, phosphorus, magnesium, and creatinine will be 
measured separately at selected on-site visits by the central laboratory. 
The CEC members will perform adjudication in a blinded manner. 
8.3.1.1 First step data analysis 
The sponsor representatives that will be involved in the first step analysis will not be involved in 
the conduct of the study from that point forward, and unblinded patient level results at the first 
step analysis will not be provided to the study sites. 
8.3.2 Randomization code breaking during the study 
In case of an AE, the randomization code should only be broken in circumstances when 
knowledge of the IMP is required for treating the patient.  
Code breaking can be performed at any time by using the proper module of the IRT and/or by 
calling any other phone number provided by the Sponsor for that purpose. Code breaking can be 
performed by a local study Investigator, sponsor physician or healthcare professional with direct 
responsibility for patient care. If the blind is broken, the Investigator should document the date, 
time of day, and reason for code breaking. The identity of the unblinded personnel, how the code 
was broken, and the treatment kit number should also be recorded. The Sponsor should also be 
informed. If the code is broken by the Investigator (or other medical doctor in emergency 
situation); the patient must be withdrawn from IMP administration.  
Randomization code breaking will also be performed during the analysis of the Pharmacokinetic 
plasma concentration samples. Only the Project manager and lead scientist at the Bioanalytical 
laboratory will have access to the randomization code to allow for the sorting of the sotagliflozin 
plasma samples. The Bioanalytical 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. 
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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. Sotagliflozin should be 
stored between +15ºC and +30ºC (59ºF and 86ºF). 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor or Delegate and in accordance with applicable regulatory 
requirements. 
All IMP will be dispensed in accordance with the Investigator’s prescription and it is the 
Investigator’s responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) 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 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 on-treatment 
on-site 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 
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should be counted by site staff. In addition, the dosing information will be recorded on the 
appropriate pages of the e-CRF. 
Rescue therapy (see Section 8.2.1) is to be reported in the e-CRF. This information should include 
specific drug name, dose, route of administration, and frequency. 
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/CRO’s 
medical monitor. 
8.7.2 Return and/or destruction of treatments 
Patients are to return all IMP (unused, in-use or used treatment kits) at each on-site visit or at 
on-site visits after permanent premature treatment discontinuation as described in Section 1.2). 
At Visit 4 (Week 1), Visit 5 (Week 2), and Visit 6 (Week 3), because no IMP re-supply is planned 
during these visits, patients will be sent home after these visits with the in-use treatment kit 
dispensed at randomization. 
Patients are to return all the used, in-use and unused IMP at Visit 13 (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. 
For NIMP not provided by the Sponsor (ie, rescue therapy), tracking and reconciliation is to be 
undertaken by the Investigator (or pharmacist if appropriate) according to the system proposed by 
the CRO. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP. The 
IMP includes placebo and sotagliflozin 400 mg and 200 mg. 
Background antidiabetic medication: Except for SGLT2 inhibitor (eg, canagliflozin, 
dapagliflozin, or empagliflozin), at the study entry patients can be treated with any injectable or 
oral antidiabetic medication(s) in accordance with the local medical care guidance. The type or 
dose of medication(s) should remain unchanged during the study course. The dose modification or 
discontinuation of an existing antidiabetic medication is allowed for safety concerns at the 
Investigator’s medical judgment. 
All concomitant medications should be documented on the Medications pages of the e-CRF. This 
includes all NIMP treatments that are taken by the patients at any time during the clinical study, 
beginning at Visit 1. 
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Additionally, all medications taken in the 3 months prior to Visit 1 and any prior use of SGLT2 
inhibitor should be reported. 
8.8.1 Prohibited prior and concomitant medications 
During the study treatment period, the following medications are prohibited: 
• 
Initiation of any antidiabetic agents, including oral or injectable antihyperglycemic agents 
other than the IMP and NIMP is not allowed before the rescue therapy. The existing 
background medication (NIMP) should not be modified before the rescue. 
Note: short term use (<10 consecutive days) of the prohibited medication eg, short-acting 
insulin for treatment of acute illness or surgery is allowed. 
• 
SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin) are not allowed for 
rescue.  
• 
Systemic use of glucocorticoids for more than 10 consecutive days (topical, intra-articular, 
ophthalmic, nasal spray or inhaled applications are allowed). 
• 
Investigational medicinal products in any other clinical study. 
• 
Modification of antihypertensive medication before Week 12 is not allowed unless for 
safety reasons. 
• 
Initiation of any weight loss drugs (eg, phentermine, orlistat). 
• 
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 following discussion between the 
Investigator and the Sponsor/CRO. However, doses of chronically administered medicines should 
be kept fixed during the trial if at all possible. 
The dose of all antihypertensive agents should be kept constant during the 12 weeks following 
randomization and no antihypertensive agents should be added or withdrawn for the 12 weeks 
following randomization unless it is considered necessary for safety reasons. 
8.8.2 Concomitant diabetes therapy 
Any background antidiabetic therapy (oral or injected including insulin) is permitted with the 
exception of other sodium-glucose cotransporter type 2 (SGLT2) inhibitors 
The rescue medication(s) that will be used to treat hyperglycemia (see Section 8.2.1) when a 
patient’s hyperglycemia reaches the rescue threshold is also defined as NIMPs. Except for SGLT2 
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inhibitors and medications with specific contraindications in renal impairment, any approved 
medication(s) including oral/subcutaneous antidiabetic drugs or insulin can be prescribed to treat 
the hyperglycemia as long as it is used within labeling guidelines for renal impairment. In 
addition, for patients already prescribed insulin the dose may be increased. If a patient requires 
glycemic rescue the IMP received during the randomized, double-blind Treatment Period and 
Extension Period should continue and must remain blinded until the end of the study. Background 
medication may need to be adjusted if hypoglycemia occurs. 
8.9 
POSTSTUDY TREATMENT 
Because sotagliflozin may reduce BP, adjustment of antihypertensive medication may be needed 
during the study in patients with hypertension. Conversely, monitoring for an increase in BP 
should be performed after withdrawal of study medication. If the BP is elevated after withdrawal 
of study treatment, the Investigator should consider adding or adjusting antihypertensive 
medication. Sotagliflozin will not be provided after EOT. Patient’s further treatment, for diabetes 
and other pathologies will be at the Investigator’s discretion based on his/her clinical judgment. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
EFFICACY ENDPOINT 
The methods of assessment of efficacy endpoints are detailed in Section 9.1.4. 
9.1.1 Primary efficacy endpoint 
• Change from Baseline to Week 26 in HbA1c (%); comparing sotagliflozin 400 mg versus 
placebo in CKD stage 4 patients 
9.1.2 Secondary efficacy endpoints 
The continuous secondary efficacy endpoints are: 
• 
Change from Baseline to Week 26 in HbA1c (%) comparing sotagliflozin 200 mg versus 
placebo 
To compare sotagliflozin 400 mg and 200 mg, respectively, versus placebo for: 
• 
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 
• 
Change in the UACR (%) from Baseline to Week 26 for patients with a UACR >30 mg/g 
at baseline 
• 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26. 
9.1.3 Other efficacy endpoints  
To compare of sotagliflozin 400 mg and 200 mg versus placebo, respectively, in terms of: 
• 
Change from Baseline in SBP at Weeks 26 and 52 for patients with Baseline SBP 
≥130 mmHg 
• 
Change from Baseline in SBP at Weeks 26 and 52 for all patients 
• 
Change from Baseline in HbA1c at Week 52 
• 
Change from Baseline in FPG at Week 52 
• 
Change from Baseline in body weight at Week 52 
• 
Change from Baseline in eGFR. 
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• 
Change from Baseline to Week 26 in: 
- 
Cystatin C 
- 
UGE 
- 
UGCR 
- 
Fructosamine 
- 
NT-proBNP 
• 
Proportion of patients with progression to end stage renal disease (ESRD) (dialysis or 
transplant) at Week 4 or any time later during the trial 
• 
Proportion of patients with >50% decline in eGFR from Baseline to Week 26 and 
Week 52 
• 
Proportion of patients with progression from normal to microalbuminuria or from 
microalbuminuria to macroalbuminuria from Baseline to Week 26 and Week 52 
• 
Proportion of patients with improvement from microalbuminuria to normal or from 
macroalbuminuria to microalbuminuria from Baseline to Week 26 and Week 52 
• 
Change from Baseline to Week 12 in SBP for patients with baseline SBP <130 mmHg 
• 
Change from Baseline to Week 12 in DBP for all patients and the subset of patients with 
baseline DBP ≥80 mmHg 
• 
Proportion of patients requiring rescue for hyperglycemia during 26-week double-blind 
period. 
9.1.4 Assessment methods of efficacy endpoints 
9.1.4.1 Hemoglobin A1c 
Hemoglobin A1c will be assessed at Screening (Visit 1), Baseline (Visit 3), and all on-site visits 
during the double-blind Treatment Period with the exception of Week 1 (Visit 4), Week 2 
(Visit 5), Week 3 (Visit 6), and Week 4 (Visit 7). HbA1c is measured by a certified Level I 
“National Glycohemoglobin Standardization Program” central laboratory at time points described 
in the flow chart (Section 1.2). 
9.1.4.2 Fasting plasma glucose measurement 
Plasma glucose is measured in the fasting state at Screening (Visit 1) and all on-site visits during 
the treatment period (with the exception of Visits 4, 5, and 6). For the eligibility and efficacy 
assessments of the study, FPG is measured at a central laboratory to allow estimation of change 
from Baseline to Weeks 26 and 52 in FPG.  
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9.1.4.3 Body weight measurement 
Body weight is measured at all on-site visits. Body weight should be obtained with the patient 
wearing undergarments or very light clothing and no shoes, and with an empty bladder. The same 
scale should be used throughout the study, and calibrated on a regular basis as recommended by 
the manufacturer. Calibration should be documented in source documents.  The use of balance 
scales is recommended; if digital scales are used, testing with standard weights is of particular 
importance. The floor surface on which the scale rests must be hard and should not be carpeted or 
covered with other soft material. The scale should be balanced with both weights at zero and the 
balance bar aligned. The patient should stand in the center of the platform as standing off-center 
may affect measurement. The weights are moved until the beam balances (the arrows are aligned). 
The weight is read and recorded in the e-CRF and Source Data. Self-reported weights are not 
acceptable; patients must not read the scales themselves. 
9.1.4.4 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 9.2.1.5 with details provided in Appendix C. 
9.1.4.5 Kidney function parameter assessments 
Serum creatinine and urine albumin, protein, calcium, creatinine, phosphorus, magnesium, and 
glucose will be assessed at Baseline (Visit 3) and at selected on-site visits (see Section 1.2). A 
central laboratory will analyze samples and estimate change from Baseline in UACR, UGE, 
UGCR, serum creatinine, and eGFR. To prevent partial unblinding, UGE and UGCR results will 
be masked to study sites.  
9.1.4.6 Fructosamine, cystatin C, and NT-proBNP measurements 
Fructosamine is measured in the fasting state at Baseline (Visit 3) and all on-site visits during the 
treatment period with the exception of Week 1 (Visit 4), Week 2 (Visit 5), and Week 3 (Visit 6). 
Cystatin C and NT-proBNP are measured in the fasting state at Baseline (Visit 3) and all on-site 
visits during the treatment period with the exception of Weeks 8 and 18 (Visits 8 and 10). In 
addition, cystatin C is also to be measured at Week 56 (Visit 14). 
For the eligibility and efficacy assessments of the study, fructosamine, cystatin C, and 
NT-proBNP are measured at a central laboratory to allow estimation of change from Baseline to 
Week 26. 
9.1.4.7 Use of rescue medication 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. 
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9.1.4.8 Proportion of patients with progression of renal disease 
Patients will be monitored throughout the Treatment Periods for progression of renal disease 
(>50% decline in eGFR, progression from normal to microalbuminuria, and progression from 
microalbuminuria to macroalbuminuria). 
Patients will be monitored at Week 4, and throughout the remainder of the study for progression 
to ESRD (progression to dialysis either hemodialysis or peritoneal dialysis or transplant).  
9.2 
SAFETY ENDPOINTS 
Assessments for safety include AEs, SMBG, clinical laboratory assessments, physical 
examination, ECG, weight, and vital signs. An independent DMC will meet on a regular basis to 
review accumulating clinical trial safety data. 
Adjudication of all deaths, MACE/other selected CV events, selected renal events, bone fracture, 
and DKA will be performed in a blinded manner by a CEC(s) comprised of experts. Details will 
be provided in the charter of the CEC(s). Further details are available in Section 6.3.3. 
Two expert committees will review all potential cases of DILIs and cases of amputation in a 
treatment-blinded manner to evaluate causality. 
The following safety endpoints will be assessed: 
• 
Incidence of TEAEs, AEs leading to discontinuation from the IMP, AESIs, EOSIs, SAEs 
and deaths 
• 
Hypoglycemia (all, severe and/or documented symptomatic hypoglycemia) 
• 
Acute renal failure (see Appendix D) 
• 
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 
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 
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• The on-treatment period (TEAE period) is defined as the time from the first dose of 
double-blind IMP up to 15 days (1 day for hypoglycemia) after the last dose of 
double-blind IMP, regardless of the introduction of rescue therapy. The 15-day interval is 
chosen based on the half-life of the IMP (approximately 5 times the half-life of 
sotagliflozin) in patients with severe renal dysfunction 
• The post-treatment period is defined as the time starting 16 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 10.7 for details. 
9.2.1.1.1 Adverse events of special interest 
Adverse events of special interest are listed in Section 10.4.1.3; reporting requirements for AESI 
are presented in Section 10.4.4. 
9.2.1.1.2 Events of special interest 
Events of special interest are separate from 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 (all, severe and/or documented symptomatic hypoglycemia) will be assessed from 
the signing of the ICF until 4 weeks after the last dose of IMP. Patients will also complete the 
patient diary, which will be regularly reviewed by Investigators. See Section 10.6.1 for further 
details. 
9.2.1.3 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including hematology clinical chemistry 
amylase, lipase, and 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. 
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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 Visits 4 to 
6 (Weeks 1 to 3). 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. 
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Table 2 - Blood safety laboratory 
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) 
 
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 metabolisma 
Uric acid 
 
Calcium 
Phosphorus 
 
25-hydroxyvitamin D 
Total protein 
 
1,25-dihydroxyvitamin D 
Albumin 
 
Phosphorus 
Magnesium 
 
Parathyroid hormone (PTH) 
Creatine phosphokinase (CPK) 
 
Markers of bone resorption: N-terminal 
telopeptide (NTX), beta-C-terminal telopeptide 
(β-CTX-1) 
Lactic acid dehydrogenase (LDH)  
 
Marker of bone formation: type 1 procollagen 
N-terminal (P1NP), osteocalcin 
 
 
Other chemistry tests 
 
 
Amylase 
 
 
Lipase 
All assessments to be performed by central laboratory. 
All assessment measured in serum. 
a To be collected at Baseline (Visit 3) to Week 4 (Visit 7), and at Visits 11 and 13 
*The recommended equation for estimating eGFR from serum creatinine is the 4 variable Modification of Diet in Renal Disease (MDRD) 
Study equation [18, 19]. The IDMS-traceable version of the MDRD Study equation is used. Either equation below may be used based on 
whether the laboratory reports conventional units or Standardized International (SI) units.:  
 Conventional Units (for use predominantly in the US): http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-conventional -unit.asp  
SI Units (for use predominately outside the US): http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-SI-units.asp. 
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9.2.1.4 Urinalysis 
Urinalysis (urine dipstick with microscopy) by central laboratory will be performed at Run-in 
(Visit 2), Baseline (Visit 3), at all on-site visits during the double-blind Treatment Period, and at 
Week 52. To prevent partial unblinding, 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 UTI, urine culture should be performed. 
Positive urine culture determination will be based upon the criteria of the reporting laboratory. 
Additionally, urine culture should be performed if at any point the Principal Investigator suspects 
the presence of a UTI. 
In addition, urine albumin, calcium, phosphorus, glucose, magnesium, and creatinine will be 
assessed at Baseline (Visit 3) and selected on-site visits during treatment periods.  
If the urine dipstick is positive for blood, the central laboratory will perform reflexive testing to 
include microscopy. Additional testing will be performed according to the judgment of the 
Investigator. Referral to urology/urologic evaluation is recommended for new or unexplained 
cases of confirmed hematuria (urology/urologic evaluation is not required where hematuria is 
considered to be related to diabetic nephropathy). 
9.2.1.5 Vital signs and physical exam 
A complete physical exam (including sitting BP and heart rate [HR], temperature, and respiratory 
rate) will be performed at Visit 1 (Screening), Visit 11 (Week 26), and Visit 13 (Week 52). 
Abbreviated physical exams (including sitting BP and HR) will be performed at all other on-site 
visits, with the exception of Visits 4, 5, 11, and 13 (Weeks 1, 2, 26, and 52, respectively). The 
abbreviated physical exam should focus on cardiac and respiratory systems, as well as any areas 
important for assessment of AEs if necessary. 
Vital signs, including: sitting BP and HR will be assessed at Screening and Run-in (Visits 1 and 
2), and all on-site visits. Three separate seated BPs and HR measurements should be taken with at 
least 1 minute between measurements following a 5-minute rest period and prior to phlebotomy. 
Full details and directions for the measurement of BP are presented in Appendix C. 
9.2.1.6 Electrocardiogram variables 
The ECG assessment of “normal” or “abnormal” will be analyzed. 
A 12-lead ECG record is performed locally at Run-in (Visit 2), Week 26 (Visit 11), and Week 52 
(Visit 13). 
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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. 
9.2.1.7 Self-monitoring of blood glucose 
A meter for self-assessment of blood glucose will be dispensed at the Run-in visit (Visit 2). 
Self-monitoring blood glucose will be presented as equivalent SMPG. In addition to home 
measurements of SMBG, SMBG will be performed at Run-in (Visit 2), Baseline (Visit 3) and all 
subsequent on-site visits with the exception of Weeks 1 and 2 (Visits 4 and 5, respectively). 
Patients will also receive a patient diary at all on-site Visits with the exception of Visits 4, 5, and 
14. The diary will be reviewed at all on-site visits from Visit 2 to Visit 14. 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 the end of treatment, Visit 11. 
Patients will be requested to self-assess blood glucose levels in the fasted state and whenever they 
experience any illnesses (eg, cold, flu), or symptoms of hyperglycemia or hypoglycemia. 
Symptoms of hypoglycemia may include shakiness, dizziness, sweating, hunger, headache, pale 
skin color, sudden moodiness or behavior changes (such as crying for no apparent reason), clumsy 
or jerky movements, seizure, difficulty paying attention or confusion, or tingling sensations 
around the mouth. Patients will be instructed to record the presence or absence of hypoglycemic 
episodes or hypoglycemic symptoms in the patient diary provided. 
Patients will also be instructed to record SMBG values that are ≤70 mg/dL (≤3.9 mmol/L) in the 
patient diary. Patients should be instructed to contact the site if fasting SMBG values over 
3 consecutive days are:  
• 
From Baseline Visit (Visit 3, Day 1) to Visit 8 (Week 8) (including value at Visit 8): FPG 
>270 mg/dL (15.0 mmol/L) 
• 
From Visit 8 (Week 8) to Visit 9 (Week 12) (including value at Visit 9): FPG >240 mg/dL 
(13.3 mmol/L) 
• 
From Visit 9 (Week 12) up to Visit 13 (Week 52): FPG/fasting SMBG >200 mg/dL 
(11.1 mmol/L) or HbA1c ≥8.5% (the 8.5% criterion does not apply if the HbA1c decrease 
from Baseline was ≥1.0%). 
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9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacokinetics of sotagliflozin 
The PK endpoints for sotagliflozin are: 
• 
Plasma concentrations of sotagliflozin and its metabolite sotagliflozin-3-O-glucuronide in 
the sotagliflozin treatment arms at Weeks 4, 18, 26, 39, and 52.  
Pharmacokinetic sotagliflozin data may be subjected to a population PK analysis, which will be 
reported separately to the clinical study report (CSR).  
9.3.1.1 Sampling time 
At Weeks 4, 18, 26, 39, and 52 (Visits 7, 10, 11, 12, and 13, respectively) blood samples for PK 
assessment are to be drawn with the other laboratory assessments prior to IMP administration. An 
additional blood sample will be drawn at Weeks 26 and 52 Visits 3 hours after administering the 
dose of IMP. The time of the last intake of study drug prior to visits were 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; or at subsequent 
visits (see Table 3 for the identification of samples). 
Table 3 - Sotagliflozin samples identification 
Visit 
Week 
Relative to dosing 
Sotagliflozin PK 
Visit 7 
Week 4 
 
Pre-dose 
 
P00 
Visit 10 
Week 18 
Pre-dose 
P01 
Visit 11 
Week 26 
Pre-dose 
P02 
Visit 11 
Week 26 
Post-dose 3 h  
P03 
Visit 12 
Week 39 
Pre-dose 
P04 
Visit 13 
Week 52 
Pre-dose 
P05 
Visit 13 
Week 52 
Post-dose 3 h  
P06 
PK = pharmacokinetic 
9.3.1.2 Pharmacokinetics handling procedure 
Detailed procedures for sample preparation, storage and shipment are described in the specific 
laboratory manual. 
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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). 
Phase 2 data indicated that sotagliflozin may reduce SBP by 10 to 15 mmHg in patients with SBP 
≥130 mmHg at Baseline, while having no significant effect in patients with SBP <130 mmHg, and 
did not induce hypotension in normotensive patients. Since this could be of benefit to patients 
with T2D, this finding is being followed up as a secondary objective in this trial, as well as the 
potential in patients with DBP >80 mmHg. Although effects on BP in Phase 2 data were observed 
with the 400 mg dose at 12 weeks, the effects will be examined at Weeks 12, 26, and 52. 
Because of potential effects on bone and calcium metabolism, specific biomarkers for bone and 
calcium metabolism will be assessed at regular timepoints. In view of the SGLT1 inhibitory 
effects in the GI tract, specific markers of intestinal transit and absorption will also be measured. 
Because of rat toxicology studies of questionable clinical significance showing tubule dilation in 
the kidney, high bone density in the sternum, and hyperplasia of stomach glandular cells, the 
biomarkers for urine, bone, and GI tract will also be measured at early timepoints of 2 and 
4 weeks. 
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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 14 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 Visit 1 through Visit 13 (Week -4 through 
Week 52), unless instructed otherwise by the Investigator. Throughout the study, “fasting” is 
defined as 8 hours without food. Note: If the patient is not fasting at the visits specified above, the 
blood sample will not be collected and a new appointment should be given to the patient for the 
following day if possible, with instruction to be fasted (other procedures can be performed as 
scheduled). All laboratory assessments will occur prior to IMP administration on the day of the 
visit. 
The Run-in visit (Visit 2) can be performed as soon as the results of all screening tests are 
available and the patient is confirmed to be eligible for participation in the study. The visit 
window for on-treatment Visit 4 through Visit 12 is ±5 days. Visits 13 (EOT) should occur at the 
scheduled timepoint ±5 days. For the Follow-up (Visit 14), the visit window should occur within 
±5 days, 4 weeks after last dose of IMP.  
If one visit date is changed, the next visit should occur according to the original schedule, ie, 
calculated from the date of Baseline visit (Visit 3, Week 0). 
For a complete list of procedures scheduled for each study visit please refer to the Study 
Flowchart (Section 1.2), which details the procedures to be performed.  
All data obtained during the trial visits are reviewed by the Investigator and Sub-Investigators 
who are qualified in treatment of T2D and are trained on the study. 
10.1.1 Screening period 
The Screening period is up to 4 weeks and includes 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. 
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• 
The following laboratory testing (by the central laboratory): 
- 
FPG 
- 
HbA1c 
- 
Clinical chemistry (including amylase, lipase, and uric acid) and hematology 
- 
Serum pregnancy testing for WOCBP or serum FSH and estradiol (for women of 
nonreproductive potential if definition of postmenopausal or premenopausal cannot be 
satisfied, see Appendix A) 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are instructed to return to the site in the fasting state for Visit 2 (Week -2). 
10.1.1.2 Run-in phase 
The Run-in phase is 2 weeks and includes Visit 2 (Week -2).  
10.1.1.2.1 On-site Visit 2 (Run-in, Week -2) 
The following procedures/assessments will be performed at Visit 2 (Week -2): 
• 
Measurement of body weight 
• 
Vital signs (SBP, DBP, and HR). After 5 minutes resting, seated SBP, DBP, and HR will 
be assessed 3 times with at least 1 minute between each measurement (see Appendix C for 
details) 
• 
Abbreviated physical examination (the abbreviated physical examination should focus on 
cardiac and respiratory systems, as well as any areas important for assessment of AEs, if 
necessary) 
• 
Diet and exercise instruction 
• 
Instruction on basic GU hygiene and hydration (see Appendix B) 
• 
IRT to be notified (registration of Run-in) 
• 
Blood glucose meter is dispensed, instructions/training are provided, and fasting SMBG 
testing is assessed 
• 
Patient diary is dispensed and instructions/training are provided  
• 
Run-in kit/placebo is dispensed  
• 
Changes in concomitant medication are reported 
• 
12-lead ECG. 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia occurring since Visit 1 (if any) are reported 
• 
The following laboratory testing (by the central laboratory): 
- 
Urinalysis (dipstick and microscopy) 
• 
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 (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: 
sotagliflozin concentration; markers of intestinal transit and absorption; markers of bone and 
calcium metabolism; urine albumin, calcium, glucose, magnesium, protein, phosphorus, 
creatinine, and albumin creatinine ratio. 
The date and time of the last intake of IMP prior to visits where PK samples are taken should be 
recorded by the patient in the patient diary. Patients should be reminded of this at visits preceding 
PK time points to ensure these details are captured. 
In the event of abnormal urinalysis findings suspicious of UTI, urine culture should be performed. 
Positive urine culture determination will be based upon the criteria of the reporting laboratory. 
Additionally, urine culture should be performed if at any point the Principal Investigator suspects 
the presence of a UTI. 
10.1.2.1 On-site randomization visit on Day 1 (Baseline; Week 0) 
The following procedures will be performed at this visit: 
• 
Exclusion criteria are to be reviewed, including assessment of compliance during Run-in 
phase 
• 
Measurement of body weight 
• 
Vital signs. After 5 minutes resting, seated SBP, DBP, and HR will be assessed 3 times 
with at least 1 minute between each measurement (see Appendix C for details) 
• 
Abbreviated physical examination (the abbreviated physical examination should focus on 
cardiac and respiratory systems, as well as any areas important for assessment of AEs, if 
necessary). 
• 
Diet and exercise instruction 
• 
Instruction on DKA symptoms and basic GU hygiene and hydration (see Appendix B) is 
provided 
• 
IMP accounting and compliance for single-blind placebo Run-in treatment  
• 
IRT to be notified and randomization will occur 
• 
Patient diary is collected/reviewed and a new diary is dispensed. Instructions/training are 
provided as needed  
• 
IMP is dispensed 
• 
Concomitant medications are assessed 
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• 
Fasting SMBG is assessed 
• 
The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose  
- 
HbA1c 
- 
Fructosamine 
- 
Clinical chemistry (including amylase, lipase, uric acid) and hematology 
- 
Cystatin C 
- 
NT-proBNP 
- 
Fasting lipids 
- 
Urine pregnancy testing for WOCBP 
- 
Urinalysis (dipstick and microscopy) 
- 
Collection of home urine for albumin, protein, creatinine, calcium, phosphorus, 
magnesium, glucose and albumin:creatinine ratio 
• 
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 calcium, serum 25-hydroxyvitamin 
D, serum 1,25-dihydroxyvitamin D, serum phosphorus, serum magnesium, serum 
parathyroid hormone (iPTH), markers of bone resorption [serum N-terminal 
telopeptide (NTX), serum beta-C-terminal telopeptide (β-CTX-1)], and bone formation 
[serum type 1 procollagen N terminal (P1NP)]), osteocalcin and alkaline phosphatase 
(ALP) 
 
  
 
 
• 
Patients are evaluated for glycemic rescue (see Section 8.2) 
• 
Evaluate for 50% increase in creatinine 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are instructed to return to the site in the fasting state for Visit 4 (Week 1) 
• 
Patients should be reminded to record the time of study drug intake on the day before their 
next visit  
• 
For accountability and compliance purposes, patients are instructed to return to the site 
with all their used, in-use and not used treatment kits(s) dispensed during Visit 2. 
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10.1.2.2 On-site visits at Weeks 1 and 2 (Visits 4 and 5) 
The following procedures will be performed at this visit: 
• 
Measurement of body weight 
• 
Vital signs. After 5 minutes resting, seated SBP, DBP, and HR will be assessed 3 times 
with at least 1 minute between each measurement (see Appendix C for details) 
• 
Diet and exercise instruction 
• 
Patient diary is collected/reviewed and a new diary is dispensed. Instructions/training are 
provided as needed  
• 
IMP accounting and compliance for double-blind IMP 
• 
Concomitant medications are assessed 
• 
The following laboratory testing (by the central laboratory): 
- 
Clinical chemistry (including amylase, lipase, uric acid) and hematology 
- 
Cystatin C 
- 
NT-proBNP 
- 
Urinalysis (dipstick and microscopy) 
- 
Collection of home urine for albumin, protein, creatinine, calcium, phosphorus, 
magnesium, glucose and albumin:creatinine ratio only at Week 2 (Visit 5) 
• 
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 calcium, serum 25-hydroxyvitamin 
D, serum 1,25-dihydroxyvitamin D, serum phosphorus, serum PTH, markers of bone 
resorption [serum NTX, serum β-CTX-1], and bone formation [serum P1NP]), serum 
magnesium, osteocalcin, and ALP 
• 
Patients are evaluated for glycemic rescue (see Section 8.2) 
• 
Evaluate for 50% increase in creatinine 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are instructed to return to the site in the fasting state for following visit 
• 
Patients should be reminded to record the time of study drug intake on the day before their 
next visit  
• 
For accountability and compliance purposes, patients are instructed to return to the site 
with all their used, in-use and not used treatment kits(s) dispensed during Visit 3. 
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10.1.2.3 On-site Visits 6 to 10 (Weeks 3 to 18)  
The following procedures will be performed at this visit: 
• 
Measurement of body weight 
• 
Vital signs. After 5 minutes resting, seated SBP, DBP, and HR will be assessed 3 times 
with at least 1 minute between each measurement (see Appendix C for details) 
• 
Abbreviated physical examination (the abbreviated physical examination should focus on 
cardiac and respiratory systems, as well as any areas important for assessment of AEs, if 
necessary). 
• 
Diet and exercise instruction (only for Visits 6 and 7) 
• 
Instruction on DKA symptoms and basic GU hygiene and hydration (see Appendix B) is 
provided 
• 
IRT to be notified IMP for re-supply 
• 
Patient diary is collected/reviewed and a new diary is dispensed. Instructions/training are 
provided as needed  
• 
IMP is dispensed (except for Visit 6) 
• 
IMP accounting and compliance for double-blind IMP 
• 
Concomitant medications are assessed 
• 
Fasting SMBG is assessed 
• 
The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose (except for Visit 6) 
- 
HbA1c (except for Visits 6 and 7) 
- 
Fructosamine (except for Visit 6) 
- 
Clinical chemistry (including amylase, lipase, uric acid) and hematology 
- 
Cystatin C (except for Visits 8 and 10) 
- 
NT-proBNP (except for Visits 8 and 10) 
- 
Urine pregnancy testing for WOCBP (except for Visit 6) 
- 
Urinalysis (dipstick and microscopy) 
- 
Collection of home urine for albumin, protein, creatinine, calcium, phosphorus, 
magnesium, glucose and albumin:creatinine ratio (except for Visits 6, 8 and 10) 
• 
Additional laboratory testing at this visit: 
- 
PK (plasma concentration samples for sotagliflozin and sotagliflozin-3-O-glucuronide) 
(Visits 7 and 10 only) 
- 
Markers of intestinal transit and absorption (vitamins B6, B12, K, E, and A, serum 
folate, and ferritin) (except for Visits 8, 9, and 10) 
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- 
Markers of bone and calcium metabolism (serum calcium, serum 
25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum magnesium, serum 
phosphorus, serum PTH, markers of bone resorption [serum NTX, serum β-CTX-1], 
and bone formation [serum P1NP]), osteocalcin, and ALP (except for Visits 8, 9, and 
10) 
- 
 
• 
Patients are evaluated for glycemic rescue (see Section 8.2) 
• 
Evaluate for 50% increase in creatinine 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are instructed to return to the site in the fasting state for Visit 11 (Week 26) 
• 
Patients should be reminded to record the time of study drug intake on the day before their 
next visit  
• 
For accountability and compliance purposes, patients are instructed to return to the site 
with all their used, in-use and not used treatment kits(s) dispensed during the previous visit 
10.1.2.4 On-site Visit 11 (Week 26)  
The following procedures will be performed at this visit: 
• 
Measurement of body weight 
• 
Vital signs. After 5 minutes resting, seated SBP, DBP, and HR will be assessed 3 times 
with at least 1 minute between each measurement (see Appendix C for details) 
• 
Complete physical examination  
• 
Diet and exercise instruction  
• 
Instruction on DKA symptoms and basic GU hygiene and hydration (see Appendix B) is 
provided 
• 
IRT to be notified IMP for re-supply 
• 
Patient diary is collected/reviewed and a new diary is dispensed. Instructions/training are 
provided as needed  
• 
IMP is dispensed 
• 
IMP accounting and compliance for double-blind IMP 
• 
Concomitant medications are assessed 
• 
Fasting SMBG is assessed 
• 
12-lead ECG 
• 
The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose  
- 
HbA1c 
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- 
Fructosamine 
- 
Clinical chemistry (including amylase, lipase, uric acid) and hematology 
- 
Cystatin C 
- 
NT-proBNP 
- 
Fasting lipids  
- 
Urine pregnancy testing for WOCBP 
- 
Urinalysis (dipstick and microscopy) 
- 
Collection of home urine for albumin, protein, creatinine, calcium, phosphorus, 
magnesium, glucose and albumin:creatinine ratio 
• 
Additional laboratory testing at this visit: 
- 
Pre-dose PK (plasma concentration sample for sotagliflozin and sotagliflozin-3-O-
glucuronide); an additional blood sample will be collected 3 hours after IMP 
administration for the assessment of creatinine (for eGFR) and for assessing plasma 
concentration of sotagliflozin and sotagliflozin-3-O-glucuronide 
- 
Markers of intestinal transit and absorption (vitamins B6, B12, K, E, and A, serum 
folate, and ferritin)  
- 
Markers of bone and calcium metabolism (serum calcium, serum 25-hydroxyvitamin 
D, serum 1,25-dihydroxyvitamin D, serum magnesium, serum phosphorus, serum 
PTH, markers of bone resorption [serum NTX, serum β-CTX-1], and bone formation 
[serum P1NP]), osteocalcin, and ALP 
 
 
• 
Patients are evaluated for glycemic rescue (see Section 8.2) 
• 
Evaluate for 50% increase in creatinine 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are instructed to return to the site in the fasting state for Visit 12 (Week 39) 
• 
For accountability and compliance purposes, patients are instructed to return to the site 
with all their used, in-use and not used treatment kits(s) dispensed during visit 10 
10.1.3 Double-blind Extension Period (Week 27 to Week 52) 
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: 
sotagliflozin concentration; markers of intestinal transit and absorption; markers of bone and 
calcium metabolism; urine albumin, calcium, glucose, and creatinine. 
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The date and time of the last intake of IMP prior to visits where PK samples are taken should be 
recorded by the patient in the patient diary. Patients should be reminded of this at visits preceding 
PK time points to ensure these details are captured. 
In the event of abnormal urinalysis findings suspicious of UTI, urine culture should be performed. 
Positive urine culture determination will be based upon the criteria of the reporting laboratory. 
Additionally, urine culture should be performed if at any point the Principal Investigator suspects 
the presence of a UTI. 
10.1.3.1 On-site Visit 12 (Week 39)  
The following procedures will be performed at this visit: 
• 
Measurement of body weight 
• 
Vital signs. After 5 minutes resting, seated SBP, DBP, and HR will be assessed 3 times 
with at least 1 minute between each measurement (see Appendix C for details) 
• 
Abbreviated physical examination (the abbreviated physical examination should focus on 
cardiac and respiratory systems, as well as any areas important for assessment of AEs, if 
necessary) 
• 
Instruction on DKA symptoms and basic GU hygiene and hydration (see Appendix B) is 
provided 
• 
Patient diary is collected/reviewed and a new diary is dispensed. Instructions/training are 
provided as needed  
• 
IRT to be notified IMP for re-supply 
• 
IMP is dispensed  
• 
IMP accounting and compliance for double-blind IMP 
• 
Concomitant medications are assessed 
• 
Fasting SMBG is assessed. 
• 
The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose  
- 
HbA1c  
- 
Fructosamine  
- 
Clinical chemistry (including amylase, lipase, uric acid) and hematology 
- 
Cystatin C 
- 
NT-proBNP 
- 
Fasting lipids  
- 
Urine pregnancy testing for WOCBP  
- 
Urinalysis (dipstick and microscopy) 
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• 
Additional laboratory testing at this visit: 
- 
PK (plasma concentration samples for sotagliflozin and sotagliflozin-3-O-glucuronide)  
• 
Patients are evaluated for glycemic rescue (see Section 8.2) 
• 
Evaluate for 50% increase in creatinine 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are instructed to return to the site in the fasting state  
• 
Patients should be reminded to record the time of study drug intake on the day before their 
next visit  
• 
For accountability and compliance purposes, patients are instructed to return to the site 
with all their used, in-use and not used treatment kits(s). 
10.1.3.2 On-site Visit 13 (Week 52 – end of treatment)  
The following procedures will be performed at this visit: 
• 
Measurement of body weight 
• 
Vital signs. After 5 minutes resting, seated SBP, DBP, and HR will be assessed 3 times 
with at least 1 minute between each measurement (see Appendix C for details) 
• 
Complete physical examination  
• 
Diet and exercise instruction  
• 
Instruction on DKA symptoms and basic GU hygiene and hydration (see Appendix B) is 
provided 
• 
IRT to be notified of EOT 
• 
Patient diary is collected/reviewed and a new diary is dispensed. Instructions/training are 
provided as needed  
• 
IMP accounting and compliance for double-blind IMP 
• 
Concomitant medications are assessed 
• 
Fasting SMBG is assessed 
• 
12-lead ECG 
• 
The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose  
- 
HbA1c 
- 
Fructosamine 
- 
Clinical chemistry (including amylase, lipase, uric acid) and hematology 
- 
Cystatin C 
- 
NT-proBNP 
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- 
Fasting lipids  
- 
Urine pregnancy testing for WOCBP 
- 
Urinalysis (dipstick and microscopy) 
- 
Collection of home urine for albumin, protein, creatinine, calcium, phosphorus, 
magnesium, glucose and albumin:creatinine ratio. 
• 
Additional laboratory testing at this visit: 
- 
Pre-dose PK (plasma concentration sample for sotagliflozin and 
sotagliflozin-3-O-glucuronide); an additional blood sample will be collected 3 hours 
after IMP administration for the assessment of creatinine (for eGFR) and for assessing 
plasma concentration of sotagliflozin and sotagliflozin-3-O-glucuronide. 
- 
Markers of intestinal transit and absorption (vitamins B6, B12, K, E, and A, serum 
folate, and ferritin) 
- 
Markers of bone and calcium metabolism (serum calcium, serum 25-hydroxyvitamin 
D, serum 1,25-dihydroxyvitamin D, serum magnesium, serum phosphorus, serum 
iPTH, markers of bone resorption [serum NTX, serum β-CTX-1], and bone formation 
[serum P1NP]), osteocalcin, and ALP 
• 
Patients are evaluated for glycemic rescue (see Section 8.2) 
• 
Evaluate for 50% increase in creatinine 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are instructed to return to the site in the fasting state for Visit 14 (Week 56). 
10.1.4 Post-treatment follow-up period 
The post-treatment follow-up period will include an on-site visit 4 weeks after the last dose of 
IMP. 
10.1.4.1 On-site follow-up Visit 14 (Week 56 - end of study) 
The following procedures will be performed at this visit: 
• 
Measurement of body weight 
• 
Vital signs. After 5 minutes resting, seated SBP, DBP, and HR will be assessed 3 times 
with at least 1 minute between each measurement (see Appendix C for details) 
• 
Abbreviated physical examination (the abbreviated physical examination should focus on 
cardiac and respiratory systems, as well as any areas important for assessment of AEs, if 
necessary)  
• 
IRT to be notified of EOS 
• 
Glucose meter to be collected 
• 
Patient diary is collected/reviewed  
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• 
Concomitant medications are assessed 
• 
Fasting SMBG is assessed 
• 
The following laboratory testing (by the central laboratory): 
- 
Clinical chemistry (including amylase, lipase, uric acid) and hematology 
- 
Cystatin C 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
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 to collect vital 
safety status and endpoint data. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. 
Lower extremity complications (such as skin ulcers, infection, osteomyelitis, and gangrene) 
requiring treatment should lead to temporary discontinuation of IMP. 
If at any visit after randomization up to Week 8 there is a rise in creatinine level (ie, >50% 
increase from baseline level, where baseline level is defined as the mean of creatinine values 
obtained at Screening and Randomization) or if at any visit after Week 8 there is a rise of >50% 
above the mean of creatinine values from last 2 visits, the Investigator should ensure that no 
reasonable explanation exists for creatinine increase.  
The IMP should be stopped for 2 weeks.  
Re-initiation of treatment with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator has considered according to his/her best medical 
judgment that the responsibility of the IMP in the occurrence of the concerned event was unlikely 
to be related to the IMP and that the selection criteria for the study are still met (refer to 
Section 7.1 and Section 7.2). 
If at creatinine recheck the patient has returned to the below threshold then IMP will be restarted 
at a reduced dose (ie, dose reduced via IRT to 200 mg for those randomized to 400 mg; 
maintained at 200 mg for those randomized to 200 mg). Since the IMP received is blinded, 
patients must return to the site and IRT will be contacted for IMP re-initiation.   
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 (see  
Section 9.2.1.7). 
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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 other 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 
Permanent treatment discontinuation defined as any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. Patients should discuss 
stopping study medication with the site before doing so 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 can lead to permanent discontinuation: 
• 
At the patient’s own request (ie, withdrawal of consent for treatment) 
• 
If, in the Investigator’s opinion, continuation with the administration of the study 
treatment would be detrimental to the patient's well-being 
• 
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) 
• 
Deterioration of renal function (defined as increase in serum creatinine >50% from 
baseline) that is not recovered after a temporary IMP discontinuation for 2 weeks 
• 
Patient requires renal replacement therapy (transplant or dialysis) 
• 
Pregnancy (in female patients) 
• 
Specific request of the Sponsor. 
Any abnormal laboratory value will be rechecked immediately to confirm the result before a 
decision is made to permanently discontinue IMP for the concerned patient. 
For patients who prematurely discontinue the IMP, the assessments planned at EOT visit  
(Section 10.1.3.2) will be performed at the premature EOT Visit scheduled preferably prior to 
treatment discontinuation or as soon as possible after the time of discontinuation (at the latest at 
the next scheduled on-site visit). In the case of premature IMP discontinuation, PK samples 
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should not be drawn at the premature EOT visit, neither at all subsequent visits. The 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 later. 
If a patient prematurely discontinues study treatment, a premature EOT visit  
(see Section 10.1.3.2) 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, or at any subsequent visit. For patients 
who discontinue treatment but remain in the study, the remaining study visits should occur as 
scheduled where possible. The IRT should be notified of EOT. 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the e-CRF. 
10.3.5  Procedure and consequence for patient withdrawal from study 
Patients may withdraw from the study before study completion if they decide to do so, at any time 
and irrespective of the reason. Withdrawal of consent for treatment should be distinguished from 
withdrawal of consent for follow-up visits. Patients will be told that they are free to withdraw 
from the study at any time without any adverse effect on their care. However, if they no longer 
wish to take the IMP, they will be encouraged to remain in the study and attend the remaining 
study visits. The value of all their study data collected during their continued involvement will be 
emphasized as important to the public health value of the study. 
If possible, the patients are assessed using the procedure normally planned for the end of study 
visit. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing.  
All confirmed study withdrawals should be recorded by the Investigator in the appropriate screens 
of the e-CRF and in the patient’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator should make the best effort to re-contact the patient (eg, contact patient’s family or 
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private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts (3 phone call attempts followed by a 
certified letter) to contact such patients must be documented in the patient’s records (eg, times and 
dates of attempted telephone contact, receipt for sending a registered letter). 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events 
10.4.1.1 Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with the IMP. 
10.4.1.2 Serious adverse event 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death, or 
• 
Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect, or 
• 
Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
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• 
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 times ULN + total bilirubin >2 times ULN or asymptomatic ALT increase 
>10 times ULN 
• 
Suicide attempt or any event suggestive of suicidality 
• 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
• 
Bullous cutaneous eruptions 
• 
Cancers diagnosed during the study or aggravated during the study  
• 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study. 
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or 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. 
• 
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 
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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 >3 times ULN  
10.4.1.4 Events of special Interest 
An EOSI is a serious or nonserious AE of scientific and medical concern specific to the Sponsor’s 
product or program, for which ongoing monitoring may be appropriate. Such events may require 
further investigation 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: 
• 
MACE (CV death, MI, or stroke)and other specific CV events (eg, heart failure leading to 
hospitalization) 
• 
Severe hypoglycemia (see Section 10.6.1) 
• 
Genital mycotic infections (to include vulvovaginal candidiasis in females and candidal 
balanitis in males) 
• 
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 events leading to amputation. 
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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).  
• 
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 e-mail address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient’s identity is protected and the patient’s 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
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• 
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 case report form [CRF] process) is available and should be 
used when the e-CRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest 
For 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 D.  
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices:  
• 
Neutropenia 
• 
Thrombocytopenia 
• 
Increase in ALT 
• 
Acute renal insufficiency 
• 
Suspicion of rhabdomyolysis 
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10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• 
All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR) to 
the regulatory authorities, independent ethics committee (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 
- 
ALT increase >3 times ULN 
Adverse events that are considered expected will be specified by the reference safety information 
provided in the current IB. 
If required, unblinding of SUSARs will be the responsibility of the Sponsor. 
The Sponsor will report all safety observations made during the conduct of the trial in the CSR. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Hypoglycemia 
During the study, patients are instructed to document 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 American Diabetes Association workgroup on 
hypoglycemia classification (20, 21) and summarized in Figure 1. 
In addition to the threshold of less than or equal to 70 mg/dL (3.9 mmol/L), hypoglycemia 
episodes with a plasma glucose of <54 mg/dL (3.0 mmol/L) will be analyzed separately. 
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Figure 1 - Hypoglycemia classification in Study EFC15166 
 
PG = plasma glucose; SAE = serious adverse event 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, intravenous glucose or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. 
Self-monitored plasma glucose values may not be available, but neurological recovery attributable 
to the restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. 
Note: “Requiring assistance of another person” means that the patient could not help himself or 
herself to treat the hypoglycemia. Assisting a patient out of kindness, when assistance is not 
required, should not be considered a “requires assistance” incident. 
Any hypoglycemic event which leads to unconsciousness, coma, or seizure should also be 
reported as an SAE. 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L 
(≤70 mg/dL).  
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Clinical symptoms that are considered to result from a hypoglycemic episode include, increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL).  
Note: low plasma glucose values without symptoms or signs should not be reported more than 
once within 30 minutes. Repeated low glucose values within a short period could be due to 
malfunction of the device, error testing or following up a low glucose reading. The Investigator 
should try not to document false low SMBG values or redundant low glucose values as 
asymptomatic hypoglycemic events. Further clarification with the patients is needed. 
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms of hypoglycemia are not 
accompanied by a plasma glucose determination, (but that was presumably caused by a plasma 
glucose concentration ≤3.9 mmol/L [≤70 mg/dL]), ie, symptoms treated with oral carbohydrate 
without a test of plasma glucose.  
Relative hypoglycemia 
Relative hypoglycemia, recently termed “pseudo-hypoglycemia” (22), is an event during which 
the patient reports typical symptoms of hypoglycemia, and interprets the symptoms as indicative 
of hypoglycemia, but with a measured plasma glucose concentration >3.9 mmol/L (>70 mg/dL). 
10.6.2 Deterioration of renal function 
Patients will be monitored throughout the double-blind Treatment Period for signs of deterioration 
in renal function (eg, decrease in eGFR or increase in creatinine as defined below) as well as other 
routine clinical and laboratory findings (see Study Flowchart, Section 1.2). If at any visit after 
randomization up to Week 8 there is a rise in creatinine level (ie, >50% increase from baseline 
level, where baseline level is defined as the mean of creatinine values obtained at Screening and 
Randomization) or if at any visit after Week 8 there is a rise of >50% above the mean of 
creatinine values from last 2 visits, the Investigator should ensure that no reasonable explanation 
exists for creatinine increase and in particular the following causes: 
• Medications that increase creatinine 
• Decrease in cardiac output 
• Obstructive uropathy 
• Urinary tract infection 
• Volume depletion 
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If addressing these causes does not reduce the creatinine level below the above stated threshold, 
the IMP will be stopped for 2 weeks. The dose will be handling according to the renal function 
assessed by the creatinine measurement throughout the study and as detailed in Section 10.3.1. 
If the creatinine dose not return to below the threshold, then the IMP will be permanently 
discontinued but the patient will be asked to continue attending all study visits. 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final CSR. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
The sample size/power calculations were performed based on the primary endpoint. Assuming a 
common standard deviation of 1.2% and using a 2-sided test at a 0.05 α-level, 92 patients in each 
group will provide at least 80% power to detect a treatment difference of 0.5% in mean HbA1c 
change from Baseline to Week 26 between sotagliflozin 400 mg and placebo. 
11.2 
DISPOSITION OF PATIENTS 
The total number of patients for each of the following categories will be presented in the CSR: 
• 
Screened patients: patients who have signed the ICF 
• 
Run-in patients 
• 
Randomized patients: patients with a treatment kit number allocated and recorded in IRT 
database, regardless of whether the treatment kit was used or not 
• 
The safety population (ie, randomized and treated patients) 
• 
The intent-to-treat (ITT) population (as defined in Section 11.3.1.1 and analyzed as 
randomized) 
• 
The randomization strata (HbA1c at Screening [≤8.5%, >8.5%] and SBP at Screening 
[<130 mmHg, ≥130 mmHg]). The discrepancy between the strata assigned by IRT and the 
information reported on e-CRF will be listed for all randomized patients 
• 
Patients who have completed the 26-week double-blind Treatment Period 
• 
Patients who discontinued the IMP during the 26-week double-blind Treatment Period, 
and the reasons for treatment discontinuation 
• 
Patients who have completed the 52-week entire treatment period 
• 
Patients who discontinued the IMP during the 52-week entire 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. 
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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 population 
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. 
11.3.2 Safety population  
Safety analyses will be based on the safety population, defined as all randomized patients who 
receive at least 1 dose of double-blind IMP (regardless of the amount of treatment administered). 
Patients will be analyzed for safety analyses according to the treatment actually received. 
In addition: 
• 
Non-randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately 
• 
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized 
• 
When a patient is exposed to both sotagliflozin and placebo, the patient will be analyzed in 
the sotagliflozin group according to the treatment kit taken (400 mg or 200 mg, 
respectively) 
• 
When a patient is exposed to both sotagliflozin 400 mg (treatment kit) and 200 mg 
(treatment kit), the patient will be analyzed in the sotagliflozin 200 mg group 
• 
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 
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11.4 
STATISTICAL METHODS 
Continuous data will be summarized by treatment group using the number of observations 
available (N), mean, standard deviation (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. 
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. 
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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, minimum, and maximum). 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, 20%], and >20% under-planned dosing administrations. 
11.4.2  Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population. Statistical testing will be performed 
for primary endpoint and secondary endpoints at Week 26 (or Week 12 for SBP). All efficacy 
endpoints after Week 26 will only be summarized by descriptive statistics without formal 
statistical testing. 
11.4.2.1 Analysis of primary efficacy endpoint 
The statistical test will be two-sided tests at a nominal 5% significance level. 
Analysis of the primary efficacy endpoint (change from Baseline to Week 26 in HbA1c; see 
Section 9.1.1) will be performed on the ITT population, using HbA1c measurements obtained 
from visits during the study, including those obtained after IMP discontinuation or introduction of 
rescue therapy. 
The primary efficacy endpoint of change 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 framework: 
• 
For placebo patients, missing data will be imputed based on the placebo group data. 
• 
For patients in the sotagliflozin groups, missing data will be imputed as if the patients 
were on placebo group throughout the study, where all patients’ measurements including 
the on-treatment measurements will be considered as if the measurements were from the 
placebo group in the imputation model. 
Each of the complete datasets will be analyzed by an Analysis of Covariance (ANCOVA) model 
with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), randomization 
stratum of Screening HbA1c (≤8.5%, >8.5%), randomization stratum of screening SBP (<130 
mmHg, ≥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 versus placebo) and its associated 95% confidence 
interval (CI) using contrast statements.  
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Summary statistics (for screening value, baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided for each treatment group. The summary will 
include the number of observations, mean, SD, standard error (SE), minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (± SE) and mean changes from Baseline (± SE) at each of the scheduled visits (using OC). 
Assessment of treatment effect by subgroup 
Descriptive analyses will be performed on the primary endpoint to summarize the treatment 
effects across subgroups defined by the following Baseline or Screening factors: 
• 
Race 
• 
Ethnicity (Hispanic, Not Hispanic) 
• 
Age group (<50 years, ≥50 to <65 years, ≥65 years) 
• 
Gender 
• 
Baseline BMI level (<30, ≥30 kg/m2) 
• 
Baseline HbA1c (≤8.5%, >8.5%) 
• 
Baseline SBP (<130 mmHg, ≥130 mmHg) 
• 
Country. 
The treatment effects across the subgroups defined for each of these factors will be estimated for 
the change from baseline to Week 26 in HbA1c in the ITT population, and using a similar 
approach to the analysis for the primary efficacy endpoint. The adjusted estimates of treatment 
mean differences (comparing sotagliflozin 400 mg versus placebo) with SE and 95% CIs will be 
provided as appropriate across the subgroups using contrast statements. 
In the event that the subgroup factor is identical or similar to a randomization strata factor (eg, 
baseline HbA1c category); only the subgroup factor (as a single factor and/or an interaction 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. 
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 framework.  
• 
For placebo patients, missing data will be imputed based on the placebo group data. 
• 
For patients in the sotagliflozin groups, missing data will be imputed as if the patients 
were on placebo group throughout the study, where all patients’ measurements including 
the on-study measurements will be considered as if the measurements were from the 
placebo group in the imputation model. 
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For each of the continuous secondary endpoint, each of the complete datasets will be analyzed by 
the ANCOVA model with treatment groups sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), 
randomization stratum of screening HbA1c (≤8.5%, >8.5%), randomization stratum of screening 
SBP (<130 mmHg, ≥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 versus placebo) and its 
associated 95% CI using contrast statements. 
The categorical secondary endpoint such as HbA1c responders (<6.5% or <7%) at Week 26 will 
be analyzed using a Cochran-Mantel-Haenszel method stratified by randomization stratum of 
Screening HbA1c (≤8.5%, >8.5%) and randomization stratum of screening SBP (<130 mmHg, 
≥130 mmHg). The proportion in each treatment group will be provided, as well as the difference 
of proportions between each sotagliflozin group and placebo with associated 2-sided 95% CI. 
For HbA1c responders at Week 26, all values at Week 26 will be used to determine whether a 
patient is a responder or not, even if they are measured after IMP discontinuation or rescue 
medication use. Patients who have no HbA1c measurement at Week 26 will be treated as 
non-responders. 
The urinary albumin/creatinine ratio will be log-transformed before the analysis. Change from 
baseline to Week 26 of urinary albumin/creatinine ratio in log scale will be analyzed. Results in 
the log scale will be back-transformed to provide the ratio and then the percent change of urinary 
albumin/creatinine ratio at Week 26 versus Baseline based on the geometric means as well as the 
corresponding 95% CIs. 
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 
For the primary efficacy endpoint, no multiplicity adjustment is needed to control Type 1 error. 
Once the comparison of sotagliflozin 400 mg versus placebo is statistically significant at α = 0.05 
(2-sided) for the primary efficacy endpoint (change from Baseline to Week 26 in HbA1c), a 
hierarchical testing procedure will be performed to test the secondary efficacy endpoints in the 
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following prioritized order. The testing will stop as soon as an endpoint is found to be not 
statistically significant at α = 0.05 (2-sided). 
• 
Comparing sotagliflozin 200 mg versus placebo in change from Baseline to Week 26 in 
HbA1c 
• 
Comparing sotagliflozin 400 mg versus placebo 
- 
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 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 
Once the above secondary variables are statistically significant at α = 0.05 (2-sided), Hochberg’s 
step-up procedure (23) will be performed to test the remaining 4 secondary variables: order a 
number of m (m=4 here) tests by p-values (from lowest to highest) P(1) ……, P(m) associated with 
tests H(1) ……, H(m), find the largest k (called R) so that P(k) ≤ α / (m+1-k), conclude H(1) ……, 
H(R) statistically significant. 
• Percentage change in UACR from Baseline to Week 26 for patients with UACR >30 mg/g 
at Baseline, comparing sotagliflozin 400 mg and 200 mg, respectively, versus placebo 
• Proportion of patients with HbA1c <7.0% at Week 26, comparing sotagliflozin 200 mg 
versus placebo 
• Change from Baseline to Week 12 in SBP for all patients comparing sotagliflozin 200 mg 
versus placebo. 
No multiplicity adjustment will be made on efficacy variables other than those mentioned above. 
11.4.3 Analyses of safety data 
All safety summaries will be descriptive; no statistical significance tests will be performed on 
safety data. 
Safety endpoints are presented in Section 9.2. The summary of safety results will be presented by 
treatment group. The safety data will be summarized for the 26-week double-blind Treatment 
Period and the entire treatment period (52 weeks) separately, unless specified otherwise. All 
safety analyses will be performed on the Safety population as defined in Section 11.3.2 using the 
following common rules: 
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The following definitions will be applied to laboratory parameters and vital signs: 
• 
The potentially clinically significant abnormality (PCSA) values for clinical laboratory 
tests and vital signs are defined as abnormal values considered medically important by the 
Sponsor’s Global Pharmacovigilance and Epidemiology department and in effect at the 
time of the final SAP approval. The PCSA criteria for parameters not cited in the protocol 
as safety parameters will not be analyzed 
• 
The PCSA criteria will determine which patients had at least 1 PCSA during the on-
treatment period, taking into account all evaluations performed during the on-treatment 
period, including unscheduled or repeated evaluations. The number of all such patients 
will be the numerator for the on-treatment PCSA percentage 
The “observation periods” defined in Section 9.2.1 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 are AEs that developed or worsened (according to the Investigator’s 
opinion) or became serious during the on-treatment period. 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
The primary focus of AE reporting in the CSR will be on TEAEs. Pre- and post-treatment AEs 
will be described separately. 
All adverse events 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (N) and percentage 
(%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient 
will be counted only once in the tables within a treatment phase. The denominator for 
computation of percentages is the safety population within each treatment group.  
Summaries of all TEAEs in each treatment group will include: 
• 
The overview of AEs, summarizing number (%) of patients with any 
- 
Treatment-emergent AE 
- 
Serious TEAE 
- 
Treatment-emergent AE leading to death 
- 
Treatment-emergent AE leading to permanent treatment discontinuation. 
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• 
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 non-randomized patients or randomized and not treated patients 
• 
Treatment-emergent AE 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 
Treatment-emergent AEs leading to permanent treatment discontinuation will be summarized and 
presented as number and percent of patients in each treatment group. 
11.4.3.2 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 hypoglycemia events reported by the 
patient and confirmed by the Investigator, severe, and/or documented symptomatic hypoglycemia, 
will be summarized by 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. An ALT 
increase >3 times ULN is included in laboratory PCSA summary if any. 
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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 predefined categories (if no PCSA 
criterion is defined) at any evaluation during the on-treatment period will be summarized for each 
clinical laboratory test within each treatment group. The summaries will include patients in the 
safety population who have at least one laboratory test performed during the on-treatment period 
and, when required by the definition of the abnormality, with an available baseline value and 
available laboratory normal ranges. 
Descriptive statistics will be used to summarize the laboratory results and the changes from 
baseline by visit and for the last on-treatment value within each treatment group. Shift tables and 
other tabular and graphical methods may be used to present the results for laboratory tests of 
interest. Listings will be provided with flags indicating the out of laboratory range values as well 
as the PCSA values. 
The liver function tests, namely ALT, AST, ALP, 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. 
11.4.3.7 Analysis of 12 lead electrocardiogram status 
A shift table will be provided to present the ECG on-treatment status according to the baseline 
status within each treatment group. 
11.4.4 Analyses of pharmacokinetic variables 
The PK endpoints are presented in Section 9.3.1.  
Individual plasma concentrations of sotagliflozin and of sotagliflozin-3-O-glucuronide at nominal 
sampling times will be listed.  
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Concentration data will be summarized by visit and, if appropriate, within visit by nominal 
sampling times (pre-dose, 3 hour post-dose), using descriptive statistics by N, geometric mean, 
coefficient of variation, median, minimum and maximum at each visit/nominal sampling time 
point for sotagliflozin-treated patients. 
11.5 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned since analysis of primary and key secondary 
efficacy endpoints will be considered final at the time of first step analyses described below. The 
study analyses will be conducted in 2 steps. 
• First step: Efficacy analyses up to Week 26 and interim safety analyses 
The first step analyses will be conducted when all patients have been randomized and have 
their data at the minimum up to Week 26 collected and validated. The first step analyses will 
include: 
- 
Efficacy analyses up to Week 26, which are considered as the final analyses for 
primary and key secondary efficacy endpoints.  
- 
Interim safety analyses which will be performed on all safety data collected and 
validated at the time of the first step analyses. 
The first step analyses will not be used to change the conduct of the ongoing study in any 
aspect. Since the primary and key secondary efficacy analyses would have been concluded at 
the time of the first step analyses, the significance level for the study remains at 0.05 (see 
Section 11.4.2.4). The first step analyses will be included in the submission dossier to health 
authorities. 
• Second step: Final analyses 
The second step analyses will be conducted at the end of the study. The second step analyses 
will include the final analyses of efficacy endpoints at Week 52 and safety endpoints, which 
will be descriptive only. 
Individuals who are involved in the unblinding of the first step analysis will not be involved in the 
conduct of the study afterwards. 
An independent DMC will monitor and assess the safety of patients from this trial through 
periodic review of the accumulated safety data provided by an independent statistical group. 
Related details are provided in separate documents (DMC charter and DMC SAP).  
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The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, IB with any addenda or labeling documents, summary of 
product characteristics, package insert, Investigator’s curriculum vitae, etc) and the date of the 
review should be clearly stated on the written (IRB/IEC) approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC, before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the IB or labeling information, will 
be sent to the IRB/IEC and to health authorities (competent regulatory authority), as required by 
local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
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 
Sub-Investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-Investigators shall be appointed and listed in a timely manner. The 
Sub-Investigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR OR SERVICE PROVIDER 
The Sponsor and/or service provider of this clinical trial is responsible to regulatory authorities for 
taking all reasonable steps to ensure the proper conduct of the clinical trial as regards ethics, 
clinical trial protocol compliance, and integrity and validity of the data recorded on the e-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 e-CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the e-CRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
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ethics committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the e-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 FORM(S) 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 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 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 and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the CV describing the experience, qualification and training of each 
Investigator and Sub-Investigator will be signed, dated and provided to the Sponsor 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 e-CRFs, the IB, and the results obtained 
during the course of the clinical trial, is confidential, prior to the publication of results. The 
Investigator and any person under his/her authority agree to undertake to keep confidential and 
not to disclose the information to any third party without the prior written approval of the 
Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Sub-Investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-Investigators of the confidential nature of the clinical trial. 
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The data collected in this study will only be used for the purpose(s) of the study and to document 
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, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel are bound by professional secrecy, and 
as such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he/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. 
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14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor 
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• 
The information on the product leads to doubt as to the benefit/risk ratio 
• 
Patient enrollment is unsatisfactory 
• 
The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon 
• 
Noncompliance of the Investigator or Sub-Investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP 
• 
The total number of patients is included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a CSR and to provide a summary of study results to 
the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
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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.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor, and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be re-collected if necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes:  
perspectives on the past, present, and future. Lancet. 2014;383:1068–83. 
2. International Diabetes Federation. IDF Diabetes Atlas, 7th ed. Brussels, Belgium: 
International Diabetes Federation, 2015. Available from URL: http://www.diabetesatlas.org. 
[Accessed November 2016]. 
3. World Health Organization, Regional Office for Europe, Data and Statistics. Available from 
URL: http://www.euro.who.int/en/health-topics/noncommunicable-diseases/diabetes/data-
andstatistics. [Accessed November 2016]. 
4. Bailey CJ. The current drug treatment landscape for diabetes and perspectives for the future. 
Clin Pharmacol Ther. 2015;98(2):170-84. 
5. Hediger HA, Coady MJ, Ikeda TS, Wright EM. Expression cloning and cDNA sequencing of 
the Na+/glucose co-transporter. Nature. 1987;330(6146):379-81. 
6. Mudalier S, Polidori D, Zambrowicz B, Henry RR.  Sodium–glucose cotransporter inhibitors: 
Effects on renal and intestinal glucose transport:  from bench to bedside. Diabetes Care. 
2015;38:2344–53. 
7. Wright EM. I. Glucose galactose malabsorption. Am J Physiol. 1998;275(5 Pt 1):G879-82. 
8. Raskin P. Sodium–glucose cotransporter inhibition:  therapeutic potential for the treatment of 
type 2 diabetes mellitus.  Diabetes Metab Res Rev. 2013;29(5):347–56. 
9. Zambrowicz B, Freiman J, Brown PM, Frazier KS, Turnage A, Bronner J, et al. LX4211, a  
dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a 
randomized, placebo-controlled trial. Clin Pharmacol Ther. 2012;92(2):158-69. 
10. Canagliflozin [prescribing information]. Titusville, NJ, Janssen Pharmaceuticals, Inc.;July 
2016. p 1-15. 
11. Dapagliflozin [prescribing information]. Wilmington, DE, AstraZeneca Pharmaceuticals 
LP;June 2016. p 1-10. 
12. Empagliflozin [prescribing information]. Ridgefield, CT, Boehringer Ingelheim 
Pharmaceuticals, Inc., and Indianapolis, IN, Eli Lilly and Company;July 2016. p 1-25. 
13. Zambrowicz, B. Lapuerta P, Strumph P, Banks P, Wilson A, Ogbaa I, et al.  LX4211 therapy 
reduces postprandial glucose levels in patients with type 2 diabetes mellitus and renal 
impairment despite low urinary glucose excretion. Clin Ther. 2015;37(1):71-82. 
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14. American Diabetes Association. Standards of Medical Care in Diabetes – 2017. Diabetes 
Care. 2017;40(Suppl 1):S1-S135. 
15. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 
Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. 
Kidney inter., Suppl. 2013;3:1-150. 
16. Cremer A, Amraoui F, Lip GY, Morales E, Rubin S, Segura J, et al. From malignant 
hypertension to hypertension-MOD: a modern definition for an old but still dangerous 
emergency. J Hum Hypertens. 2016;30(8):463-466. 
17. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 
2012 update. Am J Kidney Dis. 2012, 60, 5: 850-86 
18. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-70. 
19. Florkowski CM, Chew-Harris JS. Methods of Estimating GFR - Different Equations Including 
CKD-EPI. Clin Biochem Rev. 2011;32(2):75-9. 
20. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on 
Hypoglycemia. Diabetes Care. 2005;28(5):1245-9. 
21. FDA Guidance for Industry:  Diabetes Mellitus - Developing Drugs and Therapeutic Biologics 
for Treatment and Prevention. Lines 1144 – 1215. Available from: 
http://www.fda.gov/downloads/ 
Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071624.pdf. Accessed 
July 12, 2016. 
22. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95. 
23. Hochberg Y. A Sharper Bonferroni Procedure for Multiple Tests of Significance. Biometrika. 
1988;75(4):800–2. 
24. Mancia G, Fagard R, Narkiewicz K,  Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC 
guidelines for the management of arterial hypertension: the Task Force for the Management of 
Arterial Hypertension of the European Society of Hypertension (ESH) and of the European 
Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159–219. 
 
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APPENDICES 
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Appendix A 
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 
2. 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 hormone replacement therapy (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 enrollment. 
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). 
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Female patients: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated 
with inhibition of ovulation 
- 
oral 
- 
intravaginal 
- 
transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation 
- 
oral 
- 
injectable 
Highly Effective Methods That Are User Independent 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If 
not, an additional highly effective method(s) of contraception should be used. Spermatogenesis cycle is 
approximately 90 days.) 
• 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the patient.) 
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 participant's pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which will be forwarded to 
the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date.  
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the Investigator, will be reported to the Sponsor as 
described in Section 10.4.3. While the Investigator is not obligated to actively seek this 
information in former study patients, he or she may learn of an SAE through spontaneous 
reporting.  
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Appendix B 
Recommendations on basic genito-urinary hygiene, maintaining 
hydration and recognizing diabetic ketoacidosis 
Patients with T2D are at risk for developing genito-urinary (GU) infections. The following 
guidelines should be communicated to females and uncircumcised males regarding GU infections. 
Patient communication cards will be printed with the following: 
For females: 
“The following advice may be useful in helping you to keep your bladder and urethra free from 
infection: 
• 
Go to the toilet as soon as you feel the need to urinate, rather than holding it in.  
• 
Wipe from front to back after going to the toilet.  
• 
Practice good hygiene by washing your genitals every day, and before having sex.  
• 
Empty your bladder after having sex.”  
For uncircumcised males: 
“The following advice may be useful in helping you to keep the foreskin free from infection: 
• 
Wash the end of your penis and foreskin with soap and water (do not let soap get in the 
opening).  
• 
After your shower or bath, dry the end of your penis and foreskin properly and replace the 
foreskin.  
• 
Also, when you urinate, slide the foreskin back enough so that urine does not get on the 
foreskin-this helps to keep it clean.” 
Maintaining Hydration: 
Sodium-glucose cotransporter type 2 inhibitors are associated with osmotic diuresis and volume 
depletion, which may lead to dizziness or hypotension, especially in the elderly. Before initiating 
study drug (at Screening, Run-in and Randomization) and during all on-site study visits thereafter, 
assess volume status in patients with renal impairment, the elderly, in patients with low SBP, or if 
receiving diuretics, angiotensin-converting-enzyme inhibitors, or angiotensin receptor blockers. 
All patients will be advised to maintain proper fluid intake and to consider increasing it if they 
sense greater thirst, more urine production, or if they feel dizzy or faint. 
Patient communication cards will be printed with the following for patients with T2D: 
“The following advice may be useful in helping you to maintain proper hydration and prevent 
dehydration: 
• 
Dehydration is when your body loses too much fluid, frequently due to diarrhea or 
increased urination 
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• 
Consider increasing the amount of fluids you drink if: 
- 
You sense greater thirst than usual 
- 
You have a dry mouth or cracked lips 
- 
You have a fever 
- 
You have diarrhea or vomiting  
- 
You urinate more frequently or in larger amounts than usual 
- 
You get up in the middle of the night to urinate (more than usual) 
- 
You feel dizzy or light-headed 
- 
You exercise, or when it is hot outside 
Recognizing Diabetic Ketoacidosis 
Potential GI adverse events occurring with sotagliflozin may mask presenting symptoms of 
diabetic ketoacidosis (DKA). Patient communication cards will be printed with the following: 
If you have any of these symptoms on the list, then contact your study site immediately for 
assistance with managing your diabetes: 
• 
Inability to maintain oral intake 
• 
Generalized weakness 
• 
Abdominal (belly) pain 
• 
Increased weight loss 
• 
Fever 
• 
Frequent urination, including at night 
• 
Fruity-scented breath 
• 
Confusion 
• 
Acute illness 
• 
Consistently elevated blood glucose 
• 
Feeling very thirsty or drinking a lot 
• 
Nausea or vomiting 
• 
Having trouble thinking clearly or feeling tired 
It is possible to have DKA even if your blood glucose is not elevated. Regardless of your blood 
glucose level, if you have any of these symptoms on the list, then contact your study site 
regarding the need to be evaluated for possible DKA, which will include specific blood testing. 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, GI symptoms including nausea, 
vomiting, or abdominal pain or other symptoms or signs that the Investigator believes may be 
consistent with DKA, then the site will determine if an assessment for DKA is appropriate. If 
laboratory testing confirms presence of metabolic acidosis, then the “Possible DKA” e-CRF will 
be completed. 
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Appendix C 
Measurement of blood pressure and pulse rate  
Equipment 
1. Blood pressure measurements will be taken by an automated BP monitor or a manual 
sphygmomanometer 
2. Bladder Length – Should nearly or completely encircle the patient’s arm. For many adults, 
the standard “adult” size bladder is not long enough and the “large” size bladder is 
recommended 
3. Bladder Width – Should be at least 40% of the bladder length 
Patient Factors 
Extraneous variables associated with the measurement of BP should be minimized. These include: 
1. Food intake, caffeine-containing beverages, cigarette smoking, or strenuous exercise 
within 2 hours prior to measuremen 
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. 
Determination of the arm with the highest blood pressure 
At Visit 1 (Week -4), seated BP should be measured in both arms after 5-minute rest period, and 
then again after 1 minute in both arms in seated position. The arm with the highest SBP will be 
determined at this visit, and BP should be measured in this arm throughout the study. 
Measurement Technique (24) 
At visit 1, immediately following arm selection, with the patient in the same position, an 
additional seated BP should be measured in the selected arm (at least 1 minute after last 
measurement). 
At all other on-site visits, following the 5-minute rest period, 3 separate seated BPs should be 
measured in the arm selected at Visit 1, with at least 1 minute between BP measurements and with 
the cuff fully deflated between measurements. 
(electronic 
 
 
 
1.0)
(electronic 
 
 
 
1.0)
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Amended Clinical Trial Protocol No. 01  
13-Dec-2017 
EFC15166 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 123 
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 also be obtained. The mean of the 3 seated pulse rate 
measurements will constitute the pulse rate value for that visit. 
(electronic 
 
 
 
1.0)
(electronic 
 
 
 
1.0)
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SAP_001.pdf: 
 
Official Title: 
 
A Randomized, Double-blind, Placebo-controlled, 3-arm, 
Parallel-group, 52-week Multicenter Study to Evaluate the 
Efficacy and Safety of Sotagliflozin in Patients with Type 2 
Diabetes Mellitus and Severe Renal Impairment who have 
Inadequate Glycemic Control 
NCT Number: NCT03242018  
Document Date: SAP Version 3: 25-November-2019  
 
 
 


COVANCE INC. CONFIDENTIAL 
Page 1 of 97 
Lexicon Pharmaceuticals, Inc. 
Protocol No.: EFC15166 
A Randomized, Double-blind, Placebo-controlled, 3-arm, 
Parallel-group, 52-week Multicenter Study to Evaluate the 
Efficacy and Safety of Sotagliflozin in Patients with Type 2 
Diabetes Mellitus and Severe Renal Impairment who have 
Inadequate Glycemic Control 
Statistical Analysis Plan  
Version: Final 3.0 
DATE OF ISSUE: 21 November 2019 
Author: 
 
 
Lexicon Pharmaceuticals, Inc.  
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Covance Clinical Development Services 
206 Carnegie Center 
Princeton, NJ 08540-6233 




Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
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Page 3 of 97 
 
VERSION HISTORY 
Version Status 
Version Date 
 Final 1.0 
11 October 2018 
 Final 2.0 
20 May 2019 
Final 3.0 
21 November 2019 
 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 4 of 97 
 
Table of contents 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 7 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 9 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 9 
1.2 
OBJECTIVES ................................................................................................................................... 9 
1.2.1 
Primary objectives ............................................................................................................................ 9 
1.2.2 
Secondary objectives ....................................................................................................................... 9 
1.2.3 
Other objectives ............................................................................................................................. 10 
1.3 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 11 
1.4 
STUDY PLAN ................................................................................................................................. 11 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 11 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 12 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 17 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 17 
2.1.1 
Demographic and baseline characteristics .................................................................................... 17 
2.1.2 
Prior or concomitant medications ................................................................................................... 18 
2.1.2.1 
Rescue therapy .............................................................................................................................. 19 
2.1.2.2 
Prohibited prior and concomitant medications ............................................................................... 19 
2.1.3 
Efficacy endpoints .......................................................................................................................... 20 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 20 
2.1.3.2 
Secondary efficacy endpoints ........................................................................................................ 20 
2.1.3.3 
Other efficacy endpoints ................................................................................................................ 21 
2.1.4 
Safety endpoints ............................................................................................................................ 22 
2.1.4.1 
Hypoglycemia ................................................................................................................................. 23 
2.1.4.2 
Adverse events variables ............................................................................................................... 25 
2.1.4.3 
Deaths ............................................................................................................................................ 28 
2.1.4.4 
Laboratory safety variables ............................................................................................................ 29 
2.1.4.5 
Vital signs variables ....................................................................................................................... 30 
2.1.4.6 
Physical examination ..................................................................................................................... 30 
2.1.4.7 
Electrocardiogram variables .......................................................................................................... 30 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 31 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 31 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 33 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 33 
2.3.1 
Efficacy population ......................................................................................................................... 34 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 5 of 97 
 
2.3.1.1 
Intent–to-treat population ............................................................................................................... 34 
2.3.2 
Safety population ........................................................................................................................... 34 
2.3.3 
PK population ................................................................................................................................. 35 
2.4 
STATISTICAL METHODS ............................................................................................................. 35 
2.4.1 
Demographics and baseline characteristics .................................................................................. 35 
2.4.2 
Prior or concomitant medications ................................................................................................... 35 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 36 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 36 
2.4.3.2 
Compliance .................................................................................................................................... 37 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 37 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 38 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 41 
2.4.4.3 
Analyses of other efficacy endpoints ............................................................................................. 42 
2.4.4.4 
Multiplicity issues ........................................................................................................................... 43 
2.4.5 
Analyses of safety data .................................................................................................................. 44 
2.4.5.1 
Analyses of hypoglycemia ............................................................................................................. 45 
2.4.5.2 
Analyses of adverse events ........................................................................................................... 46 
2.4.5.3 
Deaths ............................................................................................................................................ 50 
2.4.5.4 
Analyses of laboratory variables .................................................................................................... 50 
2.4.5.5 
Analyses of vital sign variables ...................................................................................................... 52 
2.4.5.6 
Analyses of electrocardiogram variables ....................................................................................... 52 
2.4.5.7 
Analyses of physical examination variables .................................................................................. 52 
2.4.6 
Analyses of pharmacokinetic variables .......................................................................................... 52 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 53 
2.5.1 
General conventions ...................................................................................................................... 53 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 54 
2.5.3 
Missing data ................................................................................................................................... 54 
2.5.4 
Windows for time points ................................................................................................................. 56 
2.5.5 
Unscheduled visits ......................................................................................................................... 60 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 60 
2.5.7 
Statistical technical issues ............................................................................................................. 60 
3 
INTERIM ANALYSIS ..................................................................................................................... 61 
4 
DATABASE LOCK ........................................................................................................................ 63 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 64 
6 
REFERENCES ............................................................................................................................... 65 
7 
LIST OF APPENDICES ................................................................................................................. 66 
APPENDIX A 
SAMPLE SAS® CODE FOR ANALYSES OF EFFICACY ENDPOINTS ............................. 67 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 6 of 97 
 
APPENDIX B 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 75 
APPENDIX C 
LIST OF PTS FOR SELECT EOSIS (MEDDRA V22.0) ...................................................... 80 
APPENDIX D 
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 91 
APPENDIX E 
STUDY FLOW CHART ........................................................................................................ 94 
 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 7 of 97 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACR: 
albumin: creatinine ratio 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
ATC: 
anatomic category 
BMI: 
body mass index 
BP: 
blood pressure 
CEC: 
Clinical Endpoint Committee 
CI: 
confidence interval 
CKD: 
chronic kidney disease 
CRO: 
contract research organization 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DCCT: 
Diabetes Control and Complications Trial  
DILI: 
drug-induced liver injury  
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EMA: 
European Medicines Agency 
EOSI: 
event of special interest 
EOT: 
end of treatment 
ESRD: 
end stage renal disease 
FPG: 
fasting plasma glucose 
GCR: 
glucose: creatinine ratio 
HbA1c: 
hemoglobin A1c 
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 
KM: 
Kaplan-Meier 
LDH: 
lactic acid dehydrogenase 
LLN: 
lower limit of normal 
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 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 8 of 97 
 
MNAR: 
missing not at random 
NIMP: 
noninvestigational medicinal product 
NTX: 
N-terminal telopeptide 
P1NP: 
type 1 procollagen N-terminal 
PCSA: 
potentially clinically significant abnormality 
PD: 
phamacodynamics 
P-gp: 
P-glycoprotein 
PI: 
Principal Investigator 
PK: 
pharmacokinetic 
PRAC: 
Pharmacovigilance Risk Assessment Committee 
PT: 
preferred term 
PTH: 
parathyroid hormone 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SE: 
standard error 
SGLT: 
sodium-glucose cotransporter 
SGLT2: 
sodium-glucose cotransporter type 2 
SOC: 
system organ class 
T2D: 
type 2 diabetes mellitus 
TEAE: 
treatment-emergent adverse event 
UACR: 
urine albumin: creatinine ratio 
UGCR: 
urine glucose: creatinine ratio 
UGE: 
urinary glucose excretion 
ULN: 
upper limit of normal 
UTI: 
urinary tract infection 
WHO-DD: 
World Health Organization-Drug Dictionary 
β-CTX-1: 
beta-C-terminal telopeptide 
 
 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 9 of 97 
 
1 
OVERVIEW AND INVESTIGATIONAL PLAN 
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a Phase 3, multicenter and multinational, double-blind (single-blind Run-in Phase), 
placebo-controlled, parallel-group study.  Patients were 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, 26-week, double-blind Extension 
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). 
The randomization will be stratified by: 
• Hemoglobin A1c (HbA1c) at the screening (≤8.5% and >8.5%) 
• Mean systolic blood pressure (SBP) at the screening visit (<130 mmHg, ≥130 mmHg). 
It is anticipated to randomize a total of approximately 276 patients.  
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 with respect to hemoglobin A1c (HbA1c) reduction at Week 26 in patients with 
type 2 diabetes (T2D) who have inadequate glycemic control and severe renal impairment. 
1.2.2 Secondary objectives 
• To assess the effects of sotagliflozin 200 mg versus placebo based on: Change from 
Baseline in HbA1c at Week 26 
• To assess the effects of sotagliflozin 400 mg and 200 mg versus placebo, based on: 
- 
Change from Baseline in fasting plasma glucose (FPG) at Week 26 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
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COVANCE INC. CONFIDENTIAL 
Page 10 of 97 
 
- 
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 
- 
Percentage change in urine albumin:creatinine ratio (UACR) from baseline to Week 26 
(for patients with baseline UACR >30 mg/g) 
- 
The proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
• To evaluate the safety of sotagliflozin 400 mg and 200 mg versus placebo over the 
52 weeks of treatment. 
1.2.3 Other objectives 
To compare sotagliflozin 400 mg and 200 mg versus placebo with respect to: 
• Change from Baseline in SBP at Weeks 26 and 52 for patients with Baseline SBP 
≥130 mmHg 
• Change from Baseline in SBP at Weeks 26 and 52 for all patients 
• Change from Baseline in HbA1c at Week 52 
• Change from Baseline in FPG at Week 52 
• Change from Baseline in body weight at Week 52 
• Change from Baseline in estimated glomerular filtration rate (eGFR) 
• Change from baseline on the following endpoints 
- 
Cystatin C 
- 
Urinary glucose excretion (UGE) 
- 
Urine glucose:creatinine ratio (UGCR) 
- 
Fructosamine 
- 
N-terminal prohormone of brain natriuretic peptide (NT-proBNP) 
• Progression of kidney disease, based upon changes in eGFR or albuminuria 
• Change from Baseline in additional measures of sitting blood pressure (BP) 
• The proportion of patients requiring rescue for hyperglycemia during the 26-week 
double-blind treatment period 
• To assess plasma levels of sotagliflozin and sotagliflozin-3-Oglucuronide in the 
sotagliflozin treatment arms 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 11 of 97 
 
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size/power calculations were performed based on the primary endpoint. Assuming a 
common standard deviation of 1.2% and using a 2-sided test at a 0.05 α-level, 92 patients in each 
group will provide 80% power to detect a treatment difference of 0.5% in mean HbA1c change 
from Baseline to Week 26 between sotagliflozin 400 mg and placebo. 
1.4 
STUDY PLAN 
 
The study flowchart can be found in Appendix E. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled). 
The protocol history table below gives the timing, rationale, and key details of major changes to 
the protocol statistical section.  
The first patient was enrolled on 12 September 2017. The study analysis will be conducted in 
2 steps. The first step analysis is planned when all patients have been randomized and have their 
data at the minimum up to Week 26 collected and validated. The second step will be conducted at 
the end of the study. 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
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Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 12 of 97 
 
Table 1 - Protocol amendment statistical changes 
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
1 
13-Dec-2017 
Urgent coronary revascularization 
not adjudicated by CEC to be 
consistent with outcome trials 
Urgent coronary revascularization not 
included in adjudication related analyses. 
1 
13-Dec-2017 
5 half-lives of sotagliflozin prolonged 
to 15 days considering patients with 
severe renal dysfunction 
5 half-lives of IMP updated from 5 days to 
15 days; TEAE period updated accordingly 
1 
13-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. 
 
1 
13-Dec-2017 
The effect in body weight is 
considered more closely associated 
with the planned indication. 
Change in the order of secondary objectives, 
endpoints and multiplicity considerations 
 
 
 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
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.  






Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
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Covance Study ID: 000000155203 
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Page 15 of 97 
 
The first step analysis was conducted and reported for top line results; it was not used to inform a 
standalone Clinical Study Report (CSR) limited to just the 6-month data. A single CSR will be 
written for this study and will include the results coming from the analyses specified at both the 
first and second steps (see Section 3 of this SAP for more details). 
The statistical methods detailed in this section will be performed in addition to those specified in 
other sections of the SAP. The majority of these additional assessments will serve as sensitivity 
analyses and will be used to support/qualify the robustness of results from the originally planned 
analyses. 
The primary and continuous secondary efficacy endpoints for the overall population missing 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.  
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, 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 400 mg and 200 mg 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. 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 16 of 97 
 
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.          
For the overall population each of the completed datasets after the imputation will be analyzed 
using the Analysis of Covariance (ANCOVA) model with treatment groups (sotagliflozin 400 mg, 
200 mg and placebo), randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum 
of SBP (<130 mmHg, ≥130 mmHg), and country as fixed factors, and baseline HbA1c value as a 
covariate. Results from each analysis will be combined using Rubin’s formula, to provide the 
adjusted mean change in HbA1c from Baseline to Week 26 (or Week 12 for SBP) for each 
treatment group, as well as the between-group difference (comparing sotagliflozin 400 mg versus 
placebo and sotagliflozin 200 mg versus placebo) and its associated 95% confidence interval (CI).  
 
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, and the tipping point analyses previously specified in this section. 
Analysis of the primary and secondary endpoints at Week 26 as specified in Section 2.4.4.1and 
2.4.4.2 will be repeated for these same measures at Week 52, even though Section 2.4.4.4 called 
for these analyses to be descriptive only. In addition, the sensitivity analysis methods described in 
this section will be applied to these variables at Week 52. 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
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Covance Study ID: 000000155203 
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Page 17 of 97 
 
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 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 
• 
Age (years) derived as: (Year of informed consent - Year of birth), 
• 
Age categories (<50, ≥50 to <65, ≥65 to < 75, ≥75 years), 
• 
Gender (Male, Female), 
• 
Race (White, Black or African American, Asian, American Indian or Alaska native, 
Native Hawaiian or other pacific islander, Multiple, Unknown), 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown), 
• 
HbA1c (%) at screening visit, 
• 
Randomization strata of HbA1c (≤8.5%, >8.5%) at screening 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. 
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, 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
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Page 18 of 97 
 
• Duration of diabetes categories: (<10, ≥10 years), 
• Age at diagnosis of diabetes (years) derived as: Year of diagnosis of diabetes – Year of 
birth, 
• Prior use of sodium-glucose cotransporter type 2 (SGLT2) (Yes, No), 
- 
Prior antidiabetic medication (no antidiabetic therapy, insulin, non-insulin), 
• Baseline diabetic microvascular complications (Yes, No) [ie, diabetic retinopathy, diabetic 
neuropathy, diabetic nephropathy (duration of diabetic nephropathy for patients with 
diabetic nephropathy), diabetic peripheral neuropathy (sensory or motor), diabetic 
autonomic neuropathy, and diabetic foot infection], 
• Baseline UACR categories (<30 mg/g [Normal], ≥30 to <300 mg/g [Microalbuminuria], 
and ≥300 mg/g [Macroalbuminuria]), 
• eGFR at screening (mL/min/1.73m2), 
• 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 Sanofi at the time of database lock. 
Any technical details related to computation, dates, and imputations for missing dates are 
described in Section 2.5. 
2.1.2 Prior or concomitant medications  
All medications taken in the 3 months before the screening visit (any time for prior SGLT2) until 
the end of the study are to be reported in the electronic case report form (e-CRF). 


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All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi 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 + 
15 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 16th 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 
Open label rescue medication(s) to treat hyperglycemia must be in accordance with local standard 
of care and prescribing practice for patients with CKD and will be at the discretion of the 
Investigator. Except for SGLT2 inhibitors and medications with specific contraindications in renal 
impairment, any approved medication(s) including oral antidiabetic drugs or insulin can be 
considered with appropriate dose modification as indicated. Rescue therapy is considered as 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 and NIMP is not allowed before the rescue therapy. The existing 
background medication (NIMP) should not be modified before the rescue. 
Note: short term use (<10 consecutive days) of the prohibited medication eg, short-acting 
insulin for treatment of acute illness or surgery is allowed. 
• SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin) are not allowed for 
rescue. 
• Systemic use of glucocorticoids for more than 10 consecutive days (topical, intra-articular, 
ophthalmic, nasal spray or inhaled applications are allowed). 
• Investigational medicinal products in any other clinical study. 
• Modification of antihypertensive medication before Week 12 is not allowed unless for 
safety reasons. 
• Initiation of any weight loss drugs (eg, phentermine, orlistat).  


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• Reduction of digoxin dose should be considered because sotagliflozin acts as a weak 
P-glycoprotein (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 pharmacokinetic (PK) or 
pharmacodynamics (PD) of the IMP or confound interpretation of the study endpoints are allowed 
as needed following discussion between the Investigator and the Sponsor/CRO. However, doses 
of chronically administered medicines should be kept fixed during the trial if at all possible. 
The dose of all antihypertensive agents should be kept constant during the 12 weeks following 
randomization and no antihypertensive agents should be added or withdrawn for the 12 weeks 
following randomization unless it is considered necessary for safety reasons. 
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, FPG, UACR, UGE, urine glucose: creatinine ratio (UGCR), Cystatin C, Fructosamine, 
NT-proBNP and eGFR are measured/calculated in a central laboratory (see study flowchart in 
Appendix E). FPG, Cystatin C, Fructosamine, NT-proBNP are measured in the fasting state.  
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) 
Change from Baseline to Week 26 in HbA1c (%) comparing sotagliflozin 400 mg versus placebo 
in CKD stage 4 patients. 
2.1.3.2 Secondary efficacy endpoints 
The secondary efficacy endpoints are: 
• Change from Baseline to Week 26 in HbA1c (%) comparing sotagliflozin 200 mg versus 
placebo 
• Comparison sotagliflozin 400 mg and 200 mg, respectively, versus placebo for: 
- 
Change from Baseline in FPG at Week 26 


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- 
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 
- 
Change in the UACR (%) from Baseline to Week 26 for patients with a UACR 
>30 mg/g at baseline 
- 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26. 
2.1.3.3 Other efficacy endpoints 
• To compare sotagliflozin 400 mg and 200 mg versus placebo, respectively, in terms of: 
- 
Change from Baseline in SBP at Weeks 26 and 52 for patients with Baseline SBP 
≥130 mmHg 
- 
Change from Baseline in SBP at Weeks 26 and 52 for all patients 
- 
Change from Baseline in HbA1c at Week 52 
- 
Change from Baseline in FPG at Week 52 
- 
Change from Baseline in body weight at Week 52 
- 
Change from Baseline in eGFR 
- 
Change from Baseline to Week 26 in: 
- 
Cystatin C 
- 
UGE 
- 
UGCR 
- 
Fructosamine 
- 
NT-proBNP 
- 
Proportion of patients with progression to end stage renal disease (ESRD) (dialysis or 
transplant) at Week 4 or any time later during the trial 
- 
Proportion of patients with >50% decline in eGFR from Baseline to Week 26 and 
Week 52 
- 
Proportion of patients with progression from normal to microalbuminuria or from 
microalbuminuria to macroalbuminuria from Baseline to Week 26 and Week 52 
- 
Proportion of patients with improvement from microalbuminuria to normal or from 
macroalbuminuria to microalbuminuria from Baseline to Week 26 and Week 52 
- 
Change from Baseline to Week 12 in SBP for patients with baseline SBP <130 mmHg 
- 
Change from Baseline to Week 12 in DBP for all patients and the subset of patients 
with baseline DBP ≥80 mmHg 
- 
Proportion of patients requiring rescue for hyperglycemia during 26-week double-
blind period. 


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2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events, hypoglycemia, acute renal 
failure and other safety information, such as clinical laboratory data, vital signs, electrocardiogram 
(ECG), physical examination and marker of intestinal transit and absorption, markers of bone and 
calcium metabolism, etc. 
Observation period  
The observation period will be divided into 4 epochs: 
• The screening epoch is defined as the time from the signed informed consent date up to 
the first administration of the double-blind IMP.   
• The treatment epoch is defined as the time from the first administration of double-blind 
IMP to the last administration of double-blind IMP. This epoch includes the 26-week 
double-blind core treatment period and the 26-week double-blind extension treatment 
period. The 26-week core treatment period is the time from the first administration of 
double-blind IMP to the last administration of double-blind IMP on or before Visit 11 
(Week 26) [or Day 182 if Visit 11 (Week 26) date is missing]. 
• The residual treatment epoch is defined as the time from the last administration of the 
IMP to the last administration of the IMP + 15 days (1 day for hypoglycemia). 
The treatment-emergent adverse event (TEAE) period will include both treatment and residual 
treatment epochs (See the TEAE period for the 26-week core treatment period in Section 2.5.4). 
• 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. 


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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, 
To the question “Countermeasure Administration”, ticked the option “Subject was Not Capable of 
Treating Self and Required Assistance”, and  
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). 


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


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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 Sanofi at 
the time of database lock. 
The occurrence of adverse events (including SAE, AESI and EOSI) will be recorded from the 
time of signed informed consent until the end of the study (see Section 2.1.4) or the 
resolution/stabilization of all SAE, AESI and EOSI. 
AESI include: 
• Pregnancy 
• Symptomatic overdose with IMP/NIMP 
• Alanine aminotransferase (ALT) increase > 3 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 


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• 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 
The Clinical Endpoint Committee (CEC) will, in a blinded manner, review and adjudicate all 
deaths, myocardial infarction, stroke, unstable angina requiring hospitalization, and heart failure 
requiring hospitalization, selected renal events, bone fracture, and DKA. 
Two independent committees will review safety events that require ongoing monitoring to ensure 
timing protocol amendments in case a safety signal is identified. These events are: 1) potential 
cases of drug-induced liver injury (DILI), and 2) cases of amputations. The two committees will 
review the cases in a treatment-blinded manner and will present their assessment to the DMC. 
AESI and EOSI will be identified based on criteria in Table 3. 
Table 3 - Criteria for AESI and EOSI 
AE Grouping 
Criteria 
AESI 
 
Pregnancy 
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?” 


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AE Grouping 
Criteria 
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”. 
   
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 
      (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,  


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AE Grouping 
Criteria 
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 
 
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 Sanofi at the time of database lock for EOSI identified by them. 
AE potentially leading to amputation: not one of EOSI defined in protocol, included and analyzed due to their relevance in regards to lower limb 
complications and amputations as a requirement from health authorities. 
2.1.4.3 Deaths 
The deaths observation period are per the observation periods defined above.  
• Death on-study:  deaths occurring during the on-study observation period 
• Death on-treatment:  deaths occurring during the TEAE period  
• Death poststudy:  deaths occurring after the end of the study  


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2.1.4.4 Laboratory safety variables 
Clinical laboratory data consist 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 taken at designated visits (see study flowchart in 
Appendix E).  The following laboratory parameters will be assessed at a central laboratory: 
• Hematology  
- 
Red blood cells and platelets:  hemoglobin, hematocrit, red blood cell count, platelet 
count,  
- 
White blood cells:  white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
• Clinical chemistry  
- 
Metabolism:  Glucose (serum), creatine phosphokinase (CPK),  
- 
Electrolytes and minerals:  sodium, potassium, chloride, calcium, phosphorus, 
bicarbonate (ie, carbon dioxide), magnesium  
- 
Renal function:  creatinine, blood urea nitrogen (BUN), uric acid 
- 
Liver function:  total protein, Albumin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), Lactic acid dehydrogenase 
(LDH), total bilirubin (TB) 
• Lipid parameters (fasting):  
- 
Total cholesterol (TC) 
- 
High density lipoprotein cholesterol (HDL-C) 
- 
Low density lipoprotein cholesterol (LDL-C) (calculated by Friedwald equation, See 
Section 2.5.1)  
- 
Non-HDL-C (calculated as the difference between TC and HDL-C),  
- 
Triglycerides (TG). 
• Pancreatic enzymes: lipase, amylase. 
• Markers of Intestinal Transit and Absorption  
- 
Vitamins: B6, B12, K, E and A 
- 
Serum folate  
- 
Ferritin  
• Markers of bone and calcium metabolism 
- 
Calcium  
- 
25-hydroxyvitamin D 


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- 
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), osteocalcin 
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 albumin, calcium, phosphorus, glucose, magnesium, and creatinine 
Serum glucose, UGE, calculated UACR and calculated UGCR will be presented as efficacy 
parameters in Section 2.4.4. 
• 
Technical formulas are described in Section 2.5.1. 
2.1.4.5 Vital signs variables 
Vital signs include:  heart rate, 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), Visit 11 (Week 26) and 
Visit 13 (Week 52).  “Normal”, “Abnormal” or “Not done” as determined by the Investigator will 
be reported in the e-CRF by body system. 
2.1.4.7 Electrocardiogram variables 
12-lead ECG record is performed locally at Visit 2 (Run-in), Visit 11 (Week 26), and Visit 13 
(Week 52).  ECG status of “normal” or “abnormal” will be reported in the e-CRF as determined 
by the investigator. 


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2.1.5 Pharmacokinetic variables  
Pharmacokinetic variables include the concentration of sotagliflozin and its 3-O-glucuronide 
metabolite in the sotagliflozin group (see study flowchart in Appendix E for designated visits).  
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 any 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 table: 
• Screened patients 
• Run-in patients: patient who had a run-in record in IRT 
• Screen failure patients (including failures during run-in) and reasons for screen failure  
• Nonrandomized but treated patients 
• Randomized patients  
• Randomized but not treated patients 
• Randomized and treated patients 
• Patients who completed the 26-week double-blind core treatment period (see Section 2.5.4 
as scheduled).  
• Patients who did not complete the 26-week double-blind core treatment period (see 
Section 2.5.4) as scheduled and the reasons for permanent treatment discontinuation 
• Patients who completed the 52-week entire treatment period as scheduled  
• Patients who did not complete the 52-week entire treatment period as scheduled , and the 
reasons for permanent treatment discontinuation  
• Patients who completed the study as scheduled. 
• Patients who did not complete the study as per protocol and the reasons for study 
discontinuation 
• Patients’ end of study status at Week 26 (ongoing, discontinued) and corresponding end of 
26-week core treatment status (ongoing, discontinued)  


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• Patients’ end of study status (completed, not completed) and corresponding end of entire 
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 but not treated as randomized) will be part of efficacy and safety 
analyses (Section 2.3). Patients randomized but not treated will be included in efficacy analysis. 
Safety data of patients treated but not randomized will be reported separately. 
The randomization strata [HbA1c at Screening (≤8.5%, >8.5%) and mean SBP at Screening 
(<130, ≥130 mmHg)] assigned by IRT will be summarized. The percentages will be calculated 
using the number of randomized patients as the denominator. The discrepancy between the strata 
assigned by IRT and the information reported on e-CRF will be listed for all randomized patients. 
Kaplan-Meier (KM) plots of the cumulative incidence of double-blind IMP discontinuation due to 
any reason and due to AE will be provided for the entire 52-week entire treatment period only (see 
Section 2.5.4). A listing of these patients, along with the reason for discontinuation 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 2.3.3 will be summarized in a table by number of patients in the randomized population.  
• Efficacy population: intent-to-treat (ITT) population  
• Safety population 
• Pharmacokinetics population 


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2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, c) a patient is randomized twice, or d) in a dynamic randomization 
scheme the treatment assignment is, in fact, not random, due to a computer program error. 
 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
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. 


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For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
2.3.1 Efficacy population 
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. 
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), analyzed according to the treatment actually received. 
In addition:  
• Nonrandomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately 
• Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized 
• When a patient is exposed to both 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 observation 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 on the randomized population analyzed in the treatment group to 
which they were randomized.  Analyses for the safety population will be included in the 
appendices if the size of the safety population is different (>10%) from the size of that in the 
primary analysis population 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 anatomic 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.  
Antidiabetic medications will be presented separately by pharmacological class, chemical class 
and standardized medication name. 
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, 
mean, SD, median, minimum, and maximum) during the 26-week core treatment period and 
52-week entire treatment period, respectively.  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,  
• 
183 to 364 days,  
• 
>364 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. 


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Number and percentages of patients with dose interruption/reduction due to creatinine increase 
(identified as those who answered Yes to the question “If Actual Total Daily Dose is 0, Was the 
dose interruption due to creatinine increase per protocol?” in e-CRF “Exposure” page) will be 
summarized.  
Number and percentages of patients by final dose at the end of the treatment will also be 
presented by each treatment group. 
2.4.3.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol.  No imputation will be made for patients with 
missing or incomplete data. 
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 to the last 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 also 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 will 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. 
Statistical testing will be performed for primary endpoint and secondary endpoints at Week 26 
(with the exception of Week 12 for SBP). All efficacy endpoints after Week 26 will only be 
summarized by descriptive statistics without formal statistical testing. 
Missing data for efficacy analyses is identified through steps described in Section 2.5.4.  


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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 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. 
1. Missing endpoint data for patients who prematurely discontinue the IMP before the 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 (retrieved dropouts). Considering that the number of 
patients in each treatment group who discontinue the IMP but have the measurement for 
the endpoint is expected to be small, a simple imputation model based on regression will 
be used with baseline measurement included as the predictor. Each treatment group will 
have their own imputation model. 
2. Missing endpoint data for all patients who stay on the IMP until the Week 26 (or Week 12 
for SBP) visit, including those in the sotagliflozin groups, will be imputed separately. The 
wash-out imputation method will be used, where missing endpoint data in the sotagliflozin 
groups, as well as in the placebo group are imputed from a model estimated from patients 
in the placebo group who stay on the IMP until the Week 26 (or Week 12 for SBP) visit 
and have the endpoint data available. The imputation model will include the 
randomization strata and the corresponding baseline value. Missing data will be imputed 
using the regression method. 
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, not sufficient retrieved dropouts 
to support the imputation method described above). This criterion will be assessed for each 
primary or continuous secondary efficacy endpoint separately.  
In the back-up imputation method, missing post-baseline values will be imputed by control-based 
copy reference multiple imputation (MI) method under the missing not at random (MNAR) 
framework. 
To compare sotagliflozin 400 mg and 200 mg, respectively, versus placebo 
• For placebo patients, missing data will be imputed based on the placebo group data, 
• For patients in the sotagliflozin 400 mg and 200 mg groups, 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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Using either imputation method, missing endpoint data will be imputed multiple times to generate 
multiple data sets with complete data (see sample code Part 1a or Part 2a of Appendix A). The 
change from baseline to Week 26 will be derived from observed and imputed HbA1c values at 
Week 26.  Each of the complete datasets after the imputation will be analyzed by an Analysis of 
Covariance (ANCOVA) model with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, 
placebo), randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of SBP (<130, 
≥130 mmHg), and country as fixed factors, and baseline HbA1c value as a covariate (see sample 
code Part 4a of Appendix A). Results from each complete dataset will be combined using Rubin’s 
formula, 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, 
sotagliflozin 200 mg, respectively, versus placebo) and the 95% confidence interval (CI) for the 
between-group difference (see sample code Part 5 in Appendix A). 
Sensitivity analyses 
Tipping point analysis based on the same multiple imputation 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 groups 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 will be provided for each penalty 
level. The steps to perform the tipping point analysis comparing sotagliflozin 400 mg versus 
placebo are as follows: 
1. Missing data will be imputed using the same MI method as applied to the primary analysis 
(see sample code Part 3 in Appendix A), 
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 (see sample code Part 3 in 
Appendix A), 
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 (see sample code Part 
4a in Appendix A), 
4. Results will be combined across complete datasets using Rubin’s rule (see sample code 
Part 5 in Appendix A), 
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 instead of  
sotagliflozin 400 mg group in Step 2). 
The tipping point analysis will be performed on the ITT population. The tipping point analysis 
will be performed only if the corresponding primary or secondary variables (change from 
Baseline to Week 26 in HbA1c) is statistically significant at α = 0.05 (2-sided). 
If the retrieved dropout imputation is applied to the primary analysis, the analysis based on the 
control-based imputation (ie, the backup imputation method) will be presented as a sensitivity 
analysis. 
Assessment of treatment effect by subgroup  
Descriptive analyses will be performed on the primary endpoint to summarize the treatment 
effects across subgroups defined by the following Baseline or Screening factors: 
• Race (White, Black or African American, Asian, Other) (any race groups with fewer than 
5 patients may be combined with “Other” category as appropriate),  
• Ethnicity (Hispanic, Not Hispanic), 
• Age group (<50, ≥50 to <65, ≥65 years) (any category with fewer than 5 patients may be 
combined with another category as appropriate), 
• Gender (Male, Female), 
• Baseline BMI level (<30, ≥30 kg/m²), 
• Baseline HbA1c (≤8.5%, >8.5%), 
• Baseline mean SBP (<130 mmHg, ≥130 mmHg), 
• Duration of diabetes (<10, ≥10 years), 
• Prior antidiabetic medication (insulin, non-insulin), 
• Country. 
The treatment effect (sotagliflozin 400 mg versus placebo) across the subgroups defined for each 
of these factors will be estimated for the change from Baseline to Week 26 in HbA1c in the ITT 
population, and using the same MI method as applied to the primary analysis as applied to the 
analysis for the primary efficacy endpoint. The ANCOVA model will include treatment groups 
(sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), randomization stratum of HbA1c (≤8.5%, 
>8.5%), randomization stratum of SBP (<130, ≥130 mmHg), subgroup factor, treatment-by-
subgroup factor, and country as fixed factors and using baseline HbA1c value as a covariate. The 
adjusted estimates of treatment mean differences (sotagliflozin 400 mg versus placebo) with 
standard error (SE) and 95% CIs will be provided as appropriate across the subgroups (see sample 
code Part 4a in Appendix A). A graphical presentation of the results (ie, forest plot) will also be 
provided. 


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Similarly, the treatment effect across the subgroups will be estimated for the comparison of 
sotagliflozin 200 mg versus placebo as a sensitivity analysis. 
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 
entire 52-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 (≤8.5%, >8.5%), randomization stratum of SBP (<130, ≥130 mmHg), and baseline value 
in the imputation model (see sample code Part 1 or 2b in Appendix A). 
Each continuous secondary endpoints (see 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 & washout imputation 
method or by the control-based copy reference imputation method according to the criterion 
described in Section 2.4.4.1. After the imputation, each of the complete datasets will be analyzed 
by an ANCOVA model. 
The ANCOVA model with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, 
placebo), randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of SBP (<130, 
≥130 mmHg), and country as fixed effects, and baseline secondary endpoint 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 rule 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 
sotagliflozin 400 mg, sotagliflozin 200 mg vs placebo) and the 95% CI for the difference. 
UACR will be log-transformed at patient level before analysis, and geometric means (with and 
without ANCOVA model adjustment), differences between treatments and 95% CIs will be back-
transformed to original scale. Summary statistics of UACR in log scale will then be calculated for 


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each treatment group at each visit and back-transformed to provide the geometric mean and its 
associated percent change of UACR from baseline. 
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 of HbA1c (<6.5%, <7% at Week 26 respectively) will be 
analyzed using a Cochran-Mantel-Haenszel (CMH) method stratified by randomization stratum of 
HbA1c (≤8.5%, >8.5%), and randomization stratum of SBP (<130, ≥130 mmHg). The proportion 
in each treatment group, as well as the difference of proportions between sotagliflozin and placebo 
with associated 2-sided 95% CI will be provided. 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. 
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 will be provided by treatment group during 
the 26-week core (see Section 2.5.4) and the 52-week entire double-blind treatment periods. A 
KM curve for the time to first rescue therapy will be presented during the 26-week core treatment 
period and 52-week entire treatment period (see Section 2.5.4). The list of patients who used 
rescue therapy will also be provided.  
ESRD is defined as: (1) dialysis that persists for a duration of ≥90 days, or positively adjudicated 
as ESRD if dialysis <90 days; (2)  eGFR <15 ml/min/1.73 m2 sustained for at least 30 days or 
positively adjudicated as chronic; or (3) renal transplant. The number (%) of patients with 
progression to ESRD at Week 4 or any time later during the study will be summarized. The same 
analysis will be provided during the period from the first administration of double-blind IMP (or 
the date of randomization if not exposed) to Week 4 (exclusive). A KM plot will be provided for 
time to first occurrence of ESRD up to Week 26 and the end of study respectively (see  
Section 2.5.4).  


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The number (%) of patients with >50% decline in eGFR from baseline at each scheduled visit 
(including Week 26 and Week 52) will be presented. The same analysis will be presented from 
Week 4 at each scheduled visit afterwards (including Week 26 and Week 52). A KM plot will be 
provided for time to first occurrence of >50% decline in eGFR from baseline up to Week 26 and 
the end of study respectively (see Section 2.5.4). 
The number (%) of patients with UACR progression from baseline to Week 26 and Week 52, (ie, 
from normal to microalbuminuria or from microalbuminuria to macroalbuminuria) will be 
provided by treatment group respectively. A KM plot will be provided for time to UACR 
progression up to Week 26 and the end of study respectively (see Section 2.5.4). Similarly, the 
number (%) of patients with UACR improvement from baseline to Week 26 and Week 52 (from 
microalbuminuria to normal or from macroalbuminuria to microalbuminuria) will be provided, as 
well as the KM plot if appropriate. 
2.4.4.4 Multiplicity issues 
To control the family-wise type I error, a hierarchical 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 200 mg versus placebo in change from Baseline to Week 26 in 
HbA1c 
• Comparing sotagliflozin 400 mg versus placebo 
- 
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 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 
Once the above secondary variables are statistically significant at α = 0.05 (2-sided), Hochberg’s 
step-up procedure (1) will be performed to test the remaining 4 secondary variables: order a 
number of m (m=4 here) tests by p-values (from lowest to highest) P(1) ……, P(m) associated with 
tests H(1) ……, H(m), find the largest k (called R) so that P(k) ≤ α / (m+1-k), conclude H(1) ……, 
H(R) statistically significant. 


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• Percentage change in UACR from Baseline to Week 26 for patients with UACR >30 mg/g 
at Baseline, comparing sotagliflozin 400 mg and 200 mg, respectively, versus placebo 
• Proportion of patients with HbA1c <7.0% at Week 26, comparing sotagliflozin 200 mg 
versus placebo 
• Change from Baseline to Week 12 in SBP for all patients comparing sotagliflozin 200 mg 
versus placebo. 
No multiplicity adjustment will be made on other secondary efficacy variables than mentioned 
above. 
In addition, no further multiplicity adjustment (split of alpha) is needed for multiple analyses (ie, 
first step and second step analyses Section 3). The results of the first step analysis will not be used 
to change the conduct of the ongoing study in any aspect and all primary and secondary efficacy 
endpoints will be fully evaluable at the time of the first step analysis. Analyses beyond Week 26 
will be descriptive. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group. The safety data will be 
summarized for the 26-week core treatment period and the 52-week entire treatment period 
separately, unless otherwise specified. 
The “observation period” defined in Section 2.1.4 is applicable in all safety analyses for the 
classification of AEs, determination of treatment-emergent PCSA values and the last on-treatment 
value for the laboratory, vital sign and ECG. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately 
• The baseline value (with the exception of serum creatinine and eGFR) is defined as the 
last available value before the first dose of double-blind IMP.  For serum creatinine and 
eGFR, the baseline value is defined as the average of all values before the first dose of 
double-blind IMP.  
• PCSA values are defined as abnormal values considered medically important by the 
Sponsor according to predefined criteria/thresholds based on literature review and defined 
by the Sponsor for clinical laboratory tests, vital signs, and ECG (Appendix B) 
• PCSA criteria will determine which patients had at least 1 PCSA during the treatment-
emergent adverse event period, taking into account all evaluations performed during the 
treatment-emergent adverse event period, including nonscheduled or repeated evaluations.  


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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 in the treatment-emergent 
adverse event period by treatment group on 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 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 for the 52-week entire treatment period only. 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 for the 52-week 
entire treatment period. If this value is missing, this last on-treatment value will be the 
closest value prior to the last administration of IMP during the 52-week entire treatment 
period. 
• 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 2.5.2). 
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). 
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 duration of treatment-emergent AE period, ie, 
duration of IMP treatment in days +1 (Section 2.1.4). 
• 
The summary of frequency and incidence rate in patient years for severe hypoglycemia or 
documented symptomatic hypoglycemia will be provided as appropriate by gender (Male, 
Female), age group (<50, ≥50 to <65, ≥65 years), race (White, Black or African American, 
Asian, Other) and prior antidiabetic medication (no antidiabetic therapy , insulin, non-
insulin).  


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• 
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 for the 
52-week entire treatment period only (see Section 2.5.4). 
Documented symptomatic hypoglycemia may be 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 e vent 
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.  
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the 26-week 
core treatment period and the 52 week entire treatment period respectively in the safety 
population. 


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• 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 system organ class, 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 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 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 prior 
antidiabetic medication (no antidiabetic therapy, insulin, non-insulin). SOC will be sorted 
by internationally agreed order and the PT by decreasing incidence within each SOC in the 
sotagliflozin 400 mg group, as described above. 
• TEAEs (PTs with 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.  


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• Acute renal failure (narrow search on “Acute renal failure (SMQ)” [20000003]) by PT.  
Analysis of all treatment emergent serious adverse event(s) 
• All treatment-emergent serious adverse events 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 serious 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 serious 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 
• The summaries of AESI will be presented for the 52-week entire treatment period only in 
the safety population. 
• 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 
• The summaries of EOSI will be presented for the 52-week entire treatment period only in 
the safety population.” 
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 (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, 09 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, changes from baseline, 
and/or percent change from baseline [eg, lipid parameters, albumin, total protein, hemoglobin, 
hematocrit]) will be calculated for each applicable visit or study assessment (screening, baseline, 
postbaseline time point, last on-treatment value) by treatment group. Graphical presentations may 
be used to examine trends over time using mean (±SE) and/or mean change from baseline (±SE) 
at scheduled visits (eg, creatinine, eGFR). 
The incidence of PCSAs (list provided in Appendix B) at any time during the treatment-emergent 
adverse event period will be summarized 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 creatinine, ≥50% change from baseline will be provided in addition to the PCSA criteria 
defined, ie, ≥150 μmol/L (Adults), ≥30% change from baseline, ≥50% change from baseline, and 
≥100% change from baseline. For eGFR, ≥50% decrease from baseline will be provided in 


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addition to the PCSA criteria defined, ie, <15 (end stage renal disease), ≥15 - <30 (severe 
decrease in GFR), ≥30 - < 60 (moderate decrease in GFR), ≥60 - <90 (mild decrease in GFR), and 
≥50% decrease from baseline. For parameters for which no PCSA criteria are defined, similar 
tables using the normal range will be provided. 
All measurements collected during the TEAE period, including values from unscheduled visits, 
will be considered for the PCSA summaries. These summaries will include patients in the safety 
population who have at least 1 assessment performed during the TEAE period. When a PCSA 
definition involves a change from baseline value, patients must also have a baseline value to be 
included in the summaries, and when required by the definition of the abnormality, patients must 
also have available laboratory normal ranges. 
A listing of patients with at least 1 post-baseline PCSA (or out of normal range when no PCSA 
criterion is defined) will be provided 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 lower limit of normal (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 (see Section 2.4.3.1) 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. 




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2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
HbA1c 
The formula to convert HbA1c from Diabetes Control and Complications Trial (DCCT) aligned 
value to International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) 
standardized value is, 
IFCC-HbA1c (mmol/mol) = [DCCT-HbA1c (%) - 2.15] x 10.929. 
Renal function formulas  
The estimated GFR (mL/min/1.73 m2) will be calculated using the 4 variable Modification of Diet 
in Renal Disease (MDRD) formula:  
Standard unit: eGFR (mL/min/1.73 m2) = 175 x [Serum Creatinine (µmol/L)/88.4] -1.154 x Age 
(year) -0.203 x 1.212 (if Black) x 0.742 (if female) 
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) 
UACR 
Standard unit: UACR (mg/g) = Urine Albumin (mg/dL) / [Urine Creatinine (mmol/L) x 11.31] x 
1000 
Conventional unit: UACR (mg/g) = Urine Albumin (mg/dL) / Urine Creatinine (mg/dL) x 1000 
UGCR 
Standard unit: UGCR = Urine Glucose (mmol/L) / Urine Creatinine (mmol/L) 
Conventional unit: UGCR = 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. 


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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. 
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 investigational medicinal product end of 
treatment date is missing. 
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the on the e-CRF “Treatment status library” page.  If this date is 
missing, the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 


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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 posttreatment medication. 
Handling of adverse events/hypoglycemia with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information does not indicate that the adverse event started prior to 
treatment or after the treatment-emergent adverse event period, the adverse event will be 
classified as treatment-emergent.  No imputation of adverse event end dates/times will be 
performed.  These data imputations are for categorization purpose only and will not be used in 
listings.  No imputation is planned for date/time of adverse event resolution. 
Handling of adverse events/hypoglycemia when date and time of first investigational medicinal 
product administration is missing 
When the date and time of the first 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 e-CRF “Completion of End of Study/Follow-up”.  
• Completely missing, it will be imputed with the date of last available information on 
e-CRF “Completion of End of Study/Follow-up” page.  
If the date of last available information on e-CRF “Completion of End of Study/Follow-up” page 
is: 
• Partially missing, it will be imputed with a date as late as possible. 
Completely missing, all adverse events occurred on or after the first administration of double-
blind IMP will be considered as treatment emergent adverse events. 
Handling of missing assessment of relationship of adverse events to IMP  
If the assessment of the relationship to IMP is missing, then 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. 


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Handling of missing severity/grades of adverse events 
If the severity/grade is missing for 1 of the treatment-emergent occurrences of an adverse event, 
the maximal severity on the remaining occurrences will be considered.  If the severity is missing 
for all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
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 
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. 


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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 10 
Week 2 (Visit 5) 
14 
11 to 17 
Week 3 (Visit 6) 
21 
18 to 24 
Week 4 (Visit 7) 
28 
25 to 41 
Week 8 (Visit 8) 
56 
42 to 69 
Week 12 (Visit 9) 
84 
70 to 104 
Week 18 (Visit 10) 
126 
105 to 153 
Week 26 (Visit 11) 
182 
154 to 227 
Week 39 (Visit 12) 
Week 52 (Visit 13) 
273 
364 
228 to 318 
≥319   
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 


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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 
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 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. 
26-week double blind core treatment period  
The 26-week double-blind core treatment period is the time from first administration of double-
blind IMP to the last administration of double-blind IMP on or before Visit 11 (Week 26) (or 
Day 182 if Visit 11 (Week 26) date is missing). This is for defining EOT status at Week 26 and 
analyzing selected efficacy parameters (eg, rescued patients) during the core treatment period.  


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TEAE period for the 26-week double blind core treatment period  
The TEAE period for the 26-week double-blind core treatment period is (1) the time from the first 
administration of the double-blind IMP up to 15 days (1 day for hypoglycemia) after the last 
administration of IMP if the patient discontinued treatment on or before Visit 11 (or Day 182 if 
Visit 11 date is missing), or (2) the time from the first administration of the double-blind IMP to 
the administration at Visit 11 (Week 26) (or Day 182 if Visit 11 (Week 26) date is missing) if the 
patient remained treated beyond Visit 11 (Week 26). This is for the purpose of safety analyses 
during the core treatment period. 
26-week core study period  
The 26-week core study period is the time from first administration of double-blind IMP to 
Visit 11 (Week 26) (or Day 182 if Visit 11 (Week 26) date is missing) or the end of TEAE period 
for the 26-week double-blind core treatment period (as defined above) whichever is later. This is 
for defining EOS status at Week 26. 
Time to event analysis  
For time to event analysis/KM plot, time to event (eg, treatment discontinuation, rescue therapy, 
hypoglycemia, ESRD, 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 respective analysis period.  
Patients who did not experience any event during the respective analysis period are considered 
censored observations. The censoring rules are defined below. 
Time to event 
Censorsing date at Week 26 
(1st step analysis) 
Censorsing date at 
EOT/EOS 
(2nd step analysis) 
Treatment discontinuation due to any 
reason 
Not applicable 
EOT 
Treatment discontinuation due to AE 
Not applicable 
EOT 
Time to rescue 
min (EOT, Date of W26 visit) 
EOT 
Time to severe or documented 
hypoglycemia 
See Section 3 
Min (EOT+1, EOS) 
Time to ESRD 
min (EOS, Date of W26/re-allocated W26 eGFR value) 
EOS 
Time to eGFR decrease 
min (EOS, Date of W26/re-allocated W26 eGFR value) 
EOS 
Time to UACR 
progression/improvement 
min (EOS, Date of W26/re-allocated W26 UACR value) 
EOS 
Note: (1) Day 182 will be used if Date of Week 26 visit (or date of W26/re-allocated W26) is not available. 
          (2) 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.  


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2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG but 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 
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 since analysis of primary and secondary 
efficacy endpoints will be considered final at the time of first step analyses described below. The 
study analyses will be conducted in 2 steps. 
• 
First step: Efficacy analyses up to Week 26 and interim safety analyses 
The first step analyses will be conducted when all patients have been randomized and have their 
data at the minimum up to Week 26 collected and validated. For this analysis the common cut-off 
date is 15 days after the date of last patient last Week 26 visit. The first step analyses will include: 
- 
Efficacy analyses up to Week 26, which are considered as the final analyses for 
primary and secondary efficacy endpoints. The analyses beyond 26-week will be 
descriptive. 
- 
Interim safety analyses which will be performed on all safety data collected and 
validated at the time of the first step analyses. 
The first step analyses will not be used to change the conduct of the ongoing study in any aspect. 
Since the primary and secondary efficacy analyses would have been concluded at the time of the 
first step analyses, the significance level for the study remains at 0.05 (see Section 2.4.4.2).The 
first step analyses will be included in the submission dossier to health authorities. 
• 
Second step: Final analyses 
The second step analyses will be conducted at the end of the study. The second step analyses will 
include the final analyses of efficacy endpoints at Week 52 and safety endpoints, which will be 
descriptive only. 
Individuals who are involved in the unblinding of the first step analysis will not be involved in the 
conduct of the study afterwards. 
Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses as applicable. The following additional rules will be applied for analyses performed at 
first step analysis: 
• 
Any assessments within analysis windows up to Week 26 will be taken into account (may 
include few unscheduled data after the cut-off date). 
• 
Patients without end of treatment visit performed at the time of the cut-off date will be 
considered as ongoing and exposed up to the cut-off date. Therefore: 
- 
Patients who did not complete 52-Week entire treatment period nor prematurely 
discontinued the study treatment at cut-off date will be analyzed as “ongoing” in the 
disposition summary; 
- 
Their TEAE period, and on-study observation period will end at the cut-off date; 


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- 
Their treatment duration will be derived by considering date of cut-off as last 
administration date. 
- 
Analyses of percentage of days with under/above-planned dosing and compliance will 
be performed before the last administration reported in the e-CRF up to the last visit 
before cut-off date. 
- 
AEs occurring, worsening or becoming serious after the cut-off date will not be 
included in the analyses. However, any available outcome before database lock, 
regardless of timing in relation to the cut-off date, of an adverse event starting prior to 
the cut-off date will be taken into account. Medications, treatment 
discontinuations/completions, and deaths occurring after the cut-off date will not be 
included in the analyses. 
- 
For time to severe or documented symptomatic hypoglycemia at the 1st step analysis, 
the censoring date is min (EOT+1, EOS, common cut-off date). 
- 
Post-treatment period, post-study period are not applicable for ongoing patients. 
Analyses of post-treatment AEs, post-study deaths, and post-treatment medications 
will be performed for patients who either completed or prematurely discontinued the 
treatment before or at the cut-off date. 
- 
Status at last study contact will be provided for patients who either completed or 
prematurely discontinued the study before or at the cut-off date.  
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 
Two database locks will be done: 
• First database lock (for first step analysis): will include all available data on all 
randomized patients up to the common cut-off date as defined in Section 3. This database 
lock is planned to be done approximately 4 weeks after the common cut-off date. 
• Final database lock (for second step analysis): will include all data, including follow-up, 
for all randomized patients. This database lock is planned to be done approximately 
4 weeks after 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 
 
1. Hochberg Y. A sharper bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75(4):800-2. 
 


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7 
LIST OF APPENDICES 
Appendix A: 
Sample SAS® code for analyses of efficacy endpoints 
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 
Sample SAS® code for analyses of efficacy endpoints 
 
* VARIABLES;  
* ptid - patient identification;  
* treat - treatment; 
* strata1 - stratification factor 1; 
* strata2 - stratification factor 2; 
* value0 - value at baseline;  
* value1  … valuen - value at each post-baseline visit for a total of n visits; valuen at the endpoint visit; 
* change - change from baseline; 
 
********** Part 1: Preferred imputation method: the retrieved dropouts and washout imputation *****;;; 
*************************************************************************************************************************
*; 
/* Part 1a, for parameters with no missing data at baseline */; 
* MI in patients who prematurely discontinued IMP before the endpoint using the endpoint data from its 
own group (retrieved dropouts); 
      proc sort data=ads; 
 
by treat ptid; 
      run;  
 
      proc mi data=ads out=disc_mi  nimpute=2000 seed=97531; 
where discontinue = “Y"; 
 
by treat; 
 
var value0 valuen; 
 
monotone regression (valuen = value0 ); 
      run; 
* MI in patients who stay on the IMP until the endpoint visit using the endpoint data from the placebo group 
(wash-out MI);  
      proc sort data=ads; 
 
by ptid; 
      run;  
 
      proc mi data=ads out=comp_mi  nimpute=2000 seed=75319; 
where discontinue="N" and (treat=1 or (treat ne 1 and valuen =. )); *1 denotes placebo group; 
 
class strata1 strata2; 
 
var strata1 strata2 value0 valuen; 
 
monotone regression (valuen = strata1 strata2  value0 ); 
      run; 
* Repeat dataset with the same number of replications for remaining patients who have complete data at 
the endpoint visit; 
      data comp_trt; 


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set ads (where=(discontinue="N" and  treat ne 1 and valuen ne .)); 
_imputation_=0; 
do i = 1 to 2000; 
_imputation_=_imputation_+1; 
output; 
end; 
      run; 
    * Combine MI from the three subsets of patients; 
      data mi_1; 
 
set disc_mi  comp_mi  comp_trt; 
      run; 
/*Part 1b, for parameters with missing data at baseline */ 
* To impute the missing data at baseline; 
      proc sort data=ads; 
 
by ptid; 
      run;  
 
      proc mi data=ads out=mi_base nimpute=2000 seed=13579; 
             class strata1 strata2; 
             var strata1 strata2 value0; 
             monotone regression; 
     run; 
* MI in patients who prematurely discontinued IMP before the endpoint using the endpoint data from its 
own group (retrieved dropouts); 
      proc sort data=mi_base; 
 
by _imputation_ treat ptid; 
      run;  
 
    proc mi data=mi_base out=disc_mi  nimpute=1 seed=97531; 
where discontinue = “Y"; 
 
by _imputation_ treat ; 
 
var value0 valuen; 
 
monotone regression (valuen = value0 ); 
    run; 
* MI in patients who stay on the IMP until the endpoint visit using the endpoint data from the placebo group 
(wash-out MI);  
      proc sort data=mi_base; 
 
by _imputation_ ptid; 
      run;  
 
    proc mi data= mi_base out=comp_mi  nimpute=1 seed=75319; 


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where discontinue="N" and (treat=1 or (treat ne 1 and valuen =. )); *1 denotes control group; 
by _imputation_; 
 
class strata1 strata2; 
 
var strata1 strata2 value0 valuen; 
 
monotone regression (valuen = strata1 strata2 value0 ); 
    run; 
    * Combine datasets; 
    data mi_1; 
 
set disc_mi  comp_mi  mi_base (where=( discontinue="N" and  treat ne 1 and valuen ^=.)); 
run; 
 
*****************************************************************************************; 
**********Part 2:  Backup imputation method : Control-based copy reference multiple imputations 
**********; 
*****************************************************************************************; 
 
/* Data  preparation */; 
/*For categorical variables with more than 2 levels, dummy binary variables have to be created 
before using SAS procedure to generate monotone missing data since MCMC method does not 
take categorical variables */; 
/*Below using a treatment group of 3 levels as an example*/; 
 
      data ads1; 
             set ads0 (keep=ptid treat); 
      run; 
       
* Output dataset ADS1 contains the original variable TREAT & dummy variables TREAT1, TREAT2; 
      proc transreg data=ads1 design; 
             model class (treat / zero= last);  * proper sorting needed to ensure correct reference group; 
             output out=ads2 (drop=_type_ _name_ intercept); 
              id ptid; 
      run; 
 
      data ads; 
             merge ads0 ads2; 
             by ptid; 
      run; 
 
/*Part 2a, for parameters with no missing data at baseline*/; 
     * Partial imputations to render monotone missing data; 
      proc sort data=ads; 
             by treat1 treat2 strata1 strata2 strata3 ptid;    
      Run; 
 
      proc mi data=ads out=monotone nimpute=2000 seed=97531; 


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by treat1 treat2 strata1 strata2 ; 
var value:; 
             mcmc chain=multiple impute=monotone; 
      run; 
 
 
      * Partial imputations to render monotone missing data; Drop strata if not converge; 
      proc sort data=ads; 
             by treat1 treat2 ptid;    
      Run; 
      proc mi data=ads out=monotone nimpute=2000 seed=97531; 
             by treat1 treat2;                  
             var value:;   
             mcmc chain=multiple impute=monotone; 
      run; 
 
 
* To impute the missing data at post-baseline visits; 
      proc sort data= monotone; 
             by _imputation_ ptid; 
      run; 
 
      proc mi data= monotone out=mi_1 nimpute=1 seed=75319; 
             by _imputation_; 
             class treat strata1 strata2; 
             monotone reg (  / details); 
             mnar model (value: / modelobs=(treat='1')); *1 denotes placebo group; 
             var strata1 strata2 value:; 
     run; 
 
/*Part 2b, for parameters with missing data at baseline */ 
* To impute the missing data at baseline; 
      proc sort data=ads; 
 
by ptid; 
      run;  
 
      proc mi data=ads out=mi_base nimpute=2000 seed=13579; 
            class strata1 strata2;              
             var strata1 strata2 value0; 
             monotone regression; 
     run; 
     * Partial imputation to render monotone missing; 
      proc sort data=ads; 


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             by _imputation_ treat1 treat2 strata1 strata2 ptid;               
      Run; 
 
     proc mi data=ads out=monotone nimpute=1 seed=97531; 
             by _imputation_ treat1 treat2 strata1 strata2 ; 
             var value:; 
             mcmc chain=multiple impute=monotone; 
      run; 
      * Partial imputations to render monotone missing data; see Part 2a for dropping strata if not converge;  
 
     * To impute the missing data at post-baseline visits; 
      proc sort data= monotone; 
             by _imputation_ ptid; 
      run; 
 
      proc mi data=monotone out=mi_1 nimpute=1 seed=57913; 
             by _imputation_; 
             class treat strata1 strata2; 
             monotone reg (  / details); 
             mnar model (value: / modelobs=(treat='1')); *1 denotes placebo group; 
             var strata1 strata2 value:; 
      run; 
 
*****************************************************************************************; 
********** Part 3: Multiple imputation for tipping point analysis *************; 
*****************************************************************************************; 
/* Part 3a, Primary imputation method: for parameters with no missing data at baseline */; 
* MI in patients who prematurely discontinued IMP before the endpoint using the endpoint data from its 
own group (retrieved dropouts); 
    proc sort data=ads; 
 
by treat ptid; 
    run; 
 
    proc mi data=ads out=disc_mi  nimpute=2000 seed=97531; 
 
where discontinue = “Y"; 
 
by treat; 
 
var value0 valuen; 
 
monotone regression (valuen = value0 ); 
             mnar adjust (valuen / shift=0.1 adjustobs=(treat='2')); *2 denotes test drug group of lower dose; 
                      adjust (valuen / shift=0.1 adjustobs=(treat='3')); *2 denotes test drug group of higher dose; 
    run; 


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* MI in patients who stay on the IMP until the endpoint visit using the endpoint data from the placebo group 
(wash-out MI);  
    proc sort data=ads; 
 
by ptid; 
    run; 
 
    proc mi data=ads out=comp_mi  nimpute=2000 seed=75319; 
where discontinue="N" and (treat=1 or (treat ne 1 and valuen =. )); *1 denotes placebo group; 
 
class treat strata1 strata2; 
 
var treat strata1 strata2 value0 valuen; 
 
monotone regression (valuen = strata1 strata2 value0 ); 
             mnar adjust (valuen / shift=0.1 adjustobs=(treat='2')); *2 denotes test drug group of lower dose; 
                      adjust (valuen / shift=0.1 adjustobs=(treat='3')); *3 denotes test drug group of higher dose; 
    run; 
 
/*Part 3b, backup imputation method, for parameters with no missing data at baseline*/; 
     * Partial imputation to render monotone missing data; 
      proc sort data=ads; 
             by treat1 treat2 strata1 strata2 ptid;               
      run; 
 
      proc mi data=ads out=monotone nimpute=2000 seed=97531; 
             by treat1 treat2  strata1 strata2;  
             var value:;   
             mcmc chain=multiple impute=monotone; 
      run; 
* Partial imputations to render monotone missing data; see Part 2a for dropping strata if not converge; 
     * To impute the missing data at post-baseline visits with penalty in test drug group ; 
      proc sort data= monotone; 
             by _imputation_ ptid; 
      run; 
 
      proc mi data= monotone out=mi_1 nimpute=1 seed=75319; 
             by _imputation_; 
             class treat strata1 strata2; 
             monotone reg (  / details); 
             mnar model (value: / modelobs=(treat='1')); *1 denotes placebo group; 
             mnar adjust (valuen / shift=0.1 adjustobs=(treat='2')); *2 denotes test drug group of lower dose; 
                      adjust (valuen / shift=0.1 adjustobs=(treat='3')); *3 denotes test drug group of higher dose; 
             var strata1 strata2 value:; 


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     run; 
 
*****************************************************************************************; 
********** Part 4: ANCOVA **********; 
*****************************************************************************************; 
 
      proc mixed data=mi_2; 
             by _imputation_; 
             class treat strata1 strata2 country; 
             model change= treat strata1 strata2 country value0; 
             lsmeans treat /diff cl;  
lsmestimate  treat "A1 Placebo"   1 0 0 /cl; 
             lsmestimate  treat "A2 200mg drug"    0 1 0  /cl; 
lsmestimate  treat "A3 400mg drug"    0 0 1  /cl; 
             lsmestimate  treat "B1 200mg drug vs Placebo"   -1 1 0 /cl; 
lsmestimate  treat "B2 400mg drug vs Placebo"   -1 0 1/cl; 
             ods output LSMEstimates=LSMEstimates;        
       run; 
 
* Subgroup analyses using gender as an example; 
proc mixed data=mi_2; 
by _imputation_; 
class treat strata1 strata2 country gender; 
model change= strata1 strata2 country value0 treat*gender; 
lsmeans treat*gender /diff cl; 
lsmestimate treat*gender "SA11 Placebo - Female" 1 0 0 0 /cl; 
lsmestimate treat*gender "SA12 Placebo - Male" 0 1 0 0 /cl; 
lsmestimate treat*gender “SA21 Test drug - Female” 0 0 1 0 /cl; 
lsmestimate treat*gender “SA22 Test drug - Male” 0 0 0 1 /cl; 
lsmestimate treat*gender “SB1 Test drug vs Placebo - Female” -1 0 1 0 /cl; 
lsmestimate treat*gender “SB2 Test drug vs Placebo - Male” 0 -1 0 1 /cl; 
ods output Diffs=diffs Lsmestimates = lsmestimates; 
run; 
*****************************************************************************************; 
********** Part 5: Combining results using Rubin’s formula**********; 
*****************************************************************************************; 
      proc sort data= lsmestimates; 
             by label _imputation_; 
      run; 
 
      proc mianalyze data=lsmestimates; 
             by label; 
             modeleffects estimate; 
             stderr stderr; 
             ods output parameterestimates=ancova; 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 74 of 97 
 
      run; 
 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 75 of 97 
 
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. 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 76 of 97 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
CLcr (mL/min) 
(Estimated creatinine 
clearance based on the 
Cokcroft -Gault equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based 
on an MDRD equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 77 of 97 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count 
available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are 
more relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of 
Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 78 of 97 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline ≥20 
mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 
mmHg 
≥110 mmHg and increase from baseline ≥10 
mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 79 of 97 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), 
and Cardiac Safety Research Consortium White 
Paper on PR and QRS (Nada et al. Am Heart J. 
2013; 165(4) : 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and ∆QTc>60 ms are the 2 PCSA 
categories to be identified in individual 
subjects/patients listings. 
 
 
 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 80 of 97 
 
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 
Urinary tract infections 
10048302 
Tubulointerstitial nephritis 
Urinary tract infections 
10048709 
Urosepsis 
Urinary tract infections 
10048837 
Cystitis glandularis 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 81 of 97 
 
EOSI 
Preferred term code 
Preferred term 
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 
Urinary tract infections 
10081163 
Fungal urethritis 
Urinary tract infections 
10081262 
Candida urethritis 
Urinary tract infections 
10082040 
Nephritis bacterial 
Volume depletion 
10005697 
Blood osmolarity increased 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 82 of 97 
 
EOSI 
Preferred term code 
Preferred term 
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 
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 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 83 of 97 
 
EOSI 
Preferred term code 
Preferred term 
Pancreatitis 
10033635 
Pancreatic pseudocyst 
Pancreatitis 
10033636 
Pancreatic pseudocyst drainage 
Pancreatitis 
10033645 
Pancreatitis 
Pancreatitis 
10033647 
Pancreatitis acute 
Pancreatitis 
10033649 
Pancreatitis chronic 
Pancreatitis 
10033650 
Pancreatitis haemorrhagic 
Pancreatitis 
10033654 
Pancreatitis necrotising 
Pancreatitis 
10033657 
Pancreatitis relapsing 
Pancreatitis 
10048984 
Pancreatic abscess 
Pancreatitis 
10052400 
Oedematous pancreatitis 
Pancreatitis 
10056277 
Pancreatorenal syndrome 
Pancreatitis 
10056975 
Pancreatic phlegmon 
Pancreatitis 
10056976 
Hereditary pancreatitis 
Pancreatitis 
10056977 
Alcoholic pancreatitis 
Pancreatitis 
10058096 
Pancreatic necrosis 
Pancreatitis 
10065189 
Pancreatitis helminthic 
Pancreatitis 
10066127 
Ischaemic pancreatitis 
Pancreatitis 
10069002 
Autoimmune pancreatitis 
Pancreatitis 
10074894 
Traumatic pancreatitis 
Pancreatitis 
10076058 
Haemorrhagic necrotic pancreatitis 
Venous thrombotic events 
10003192 
Arteriovenous fistula thrombosis 
Venous thrombotic events 
10003880 
Axillary vein thrombosis 
Venous thrombotic events 
10006537 
Budd-Chiari syndrome 
Venous thrombotic events 
10007830 
Cavernous sinus thrombosis 
Venous thrombotic events 
10008138 
Cerebral venous thrombosis 
Venous thrombotic events 
10014522 
Embolism venous 
Venous thrombotic events 
10019713 
Hepatic vein thrombosis 
Venous thrombotic events 
10023237 
Jugular vein thrombosis 
Venous thrombotic events 
10027402 
Mesenteric vein thrombosis 
Venous thrombotic events 
10034272 
Pelvic venous thrombosis 
Venous thrombotic events 
10034324 
Penile vein thrombosis 
Venous thrombotic events 
10036206 
Portal vein thrombosis 
Venous thrombotic events 
10037377 
Pulmonary embolism 
Venous thrombotic events 
10037421 
Pulmonary microemboli 
Venous thrombotic events 
10037437 
Pulmonary thrombosis 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 84 of 97 
 
EOSI 
Preferred term code 
Preferred term 
Venous thrombotic events 
10037459 
Pulmonary venous thrombosis 
Venous thrombotic events 
10038547 
Renal vein embolism 
Venous thrombotic events 
10038548 
Renal vein thrombosis 
Venous thrombotic events 
10038908 
Retinal vein thrombosis 
Venous thrombotic events 
10041659 
Splenic vein thrombosis 
Venous thrombotic events 
10042567 
Superior sagittal sinus thrombosis 
Venous thrombotic events 
10043570 
Thrombophlebitis 
Venous thrombotic events 
10043581 
Thrombophlebitis migrans 
Venous thrombotic events 
10043595 
Thrombophlebitis superficial 
Venous thrombotic events 
10043605 
Thrombosed varicose vein 
Venous thrombotic events 
10044457 
Transverse sinus thrombosis 
Venous thrombotic events 
10047193 
Vena cava embolism 
Venous thrombotic events 
10047195 
Vena cava thrombosis 
Venous thrombotic events 
10047249 
Venous thrombosis 
Venous thrombotic events 
10048591 
Post thrombotic syndrome 
Venous thrombotic events 
10049446 
Subclavian vein thrombosis 
Venous thrombotic events 
10050216 
Paget-Schroetter syndrome 
Venous thrombotic events 
10050902 
Postoperative thrombosis 
Venous thrombotic events 
10051055 
Deep vein thrombosis 
Venous thrombotic events 
10053182 
Arteriovenous graft thrombosis 
Venous thrombotic events 
10061251 
Intracranial venous sinus thrombosis 
Venous thrombotic events 
10061408 
Venous thrombosis limb 
Venous thrombotic events 
10063363 
Brachiocephalic vein thrombosis 
Venous thrombotic events 
10063909 
Post procedural pulmonary embolism 
Venous thrombotic events 
10066881 
Deep vein thrombosis postoperative 
Venous thrombotic events 
10067270 
Thrombosis corpora cavernosa 
Venous thrombotic events 
10069909 
Metastatic pulmonary embolism 
Venous thrombotic events 
10072059 
Ovarian vein thrombosis 
Venous thrombotic events 
10074349 
Ophthalmic vein thrombosis 
Venous thrombotic events 
10077623 
Portosplenomesenteric venous thrombosis 
Venous thrombotic events 
10077829 
Visceral venous thrombosis 
Venous thrombotic events 
10078810 
Hepatic vein embolism 
Thyroid cancer 
10002240 
Anaplastic thyroid cancer 
Thyroid cancer 
10016935 
Follicular thyroid cancer 
Thyroid cancer 
10027105 
Medullary thyroid cancer 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 85 of 97 
 
EOSI 
Preferred term code 
Preferred term 
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 
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 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 86 of 97 
 
EOSI 
Preferred term code 
Preferred term 
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 
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 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 87 of 97 
 
EOSI 
Preferred term code 
Preferred term 
Bladder cancer 
10005009 
Bladder cancer stage I, without cancer in situ 
Bladder cancer 
10005010 
Bladder cancer stage II 
Bladder cancer 
10005011 
Bladder cancer stage III 
Bladder cancer 
10005012 
Bladder cancer stage IV 
Bladder cancer 
10005056 
Bladder neoplasm 
Bladder cancer 
10005075 
Bladder squamous cell carcinoma recurrent 
Bladder cancer 
10005076 
Bladder squamous cell carcinoma stage 0 
Bladder cancer 
10005077 
Bladder squamous cell carcinoma stage I 
Bladder cancer 
10005078 
Bladder squamous cell carcinoma stage II 
Bladder cancer 
10005079 
Bladder squamous cell carcinoma stage III 
Bladder cancer 
10005080 
Bladder squamous cell carcinoma stage IV 
Bladder cancer 
10005081 
Bladder squamous cell carcinoma stage unspecified 
Bladder cancer 
10005084 
Bladder transitional cell carcinoma 
Bladder cancer 
10051690 
Urinary bladder sarcoma 
Bladder cancer 
10057352 
Metastatic carcinoma of the bladder 
Bladder cancer 
10066749 
Bladder transitional cell carcinoma stage 0 
Bladder cancer 
10066750 
Bladder transitional cell carcinoma recurrent 
Bladder cancer 
10066751 
Bladder transitional cell carcinoma stage I 
Bladder cancer 
10066752 
Bladder transitional cell carcinoma stage IV 
Bladder cancer 
10066753 
Bladder transitional cell carcinoma stage II 
Bladder cancer 
10066754 
Bladder transitional cell carcinoma stage III 
Bladder cancer 
10071664 
Bladder transitional cell carcinoma metastatic 
Bladder cancer 
10078341 
Neuroendocrine carcinoma of the bladder 
Potentially leading to amputation 
10003084 
Areflexia 
Potentially leading to amputation 
10003178 
Arterial thrombosis 
Potentially leading to amputation 
10003210 
Arteriosclerosis 
Potentially leading to amputation 
10003222 
Arteriosclerotic gangrene 
Potentially leading to amputation 
10006784 
Burning sensation 
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 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 88 of 97 
 
EOSI 
Preferred term code 
Preferred term 
Potentially leading to amputation 
10012680 
Diabetic neuropathy 
Potentially leading to amputation 
10017711 
Gangrene 
Potentially leading to amputation 
10020937 
Hypoaesthesia 
Potentially leading to amputation 
10021137 
Hypovolaemia 
Potentially leading to amputation 
10021519 
Impaired healing 
Potentially leading to amputation 
10021784 
Infected skin ulcer 
Potentially leading to amputation 
10022562 
Intermittent claudication 
Potentially leading to amputation 
10024774 
Localised infection 
Potentially leading to amputation 
10028862 
Necrosis ischaemic 
Potentially leading to amputation 
10029331 
Neuropathy peripheral 
Potentially leading to amputation 
10031149 
Osteitis 
Potentially leading to amputation 
10031252 
Osteomyelitis 
Potentially leading to amputation 
10031253 
Osteomyelitis acute 
Potentially leading to amputation 
10031256 
Osteomyelitis chronic 
Potentially leading to amputation 
10031262 
Osteomyelitis salmonella 
Potentially leading to amputation 
10031264 
Osteonecrosis 
Potentially leading to amputation 
10033775 
Paraesthesia 
Potentially leading to amputation 
10034568 
Peripheral coldness 
Potentially leading to amputation 
10034576 
Peripheral ischaemia 
Potentially leading to amputation 
10034620 
Peripheral sensory neuropathy 
Potentially leading to amputation 
10034636 
Peripheral vascular disorder 
Potentially leading to amputation 
10036155 
Poor peripheral circulation 
Potentially leading to amputation 
10036410 
Postoperative wound infection 
Potentially leading to amputation 
10040026 
Sensory disturbance 
Potentially leading to amputation 
10040840 
Skin erosion 
Potentially leading to amputation 
10040872 
Skin infection 
Potentially leading to amputation 
10040943 
Skin ulcer 
Potentially leading to amputation 
10042343 
Subcutaneous abscess 
Potentially leading to amputation 
10043607 
Thrombosis 
Potentially leading to amputation 
10048031 
Wound dehiscence 
Potentially leading to amputation 
10048038 
Wound infection 
Potentially leading to amputation 
10049927 
Dry gangrene 
Potentially leading to amputation 
10050473 
Abscess limb 
Potentially leading to amputation 
10050502 
Neuropathic ulcer 
Potentially leading to amputation 
10051548 
Burn infection 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 89 of 97 
 
EOSI 
Preferred term code 
Preferred term 
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 
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 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 90 of 97 
 
EOSI 
Preferred term code 
Preferred term 
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: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 91 of 97 
 
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 
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)  
Subgroups: 
race, ethnicity, 
age, gender, 
baseline BMI, 
baseline HbA1c, 
baseline SBP, 
duration of 
diabetes  
and country. 
 
Summary statistics for observed values and 
changes from baseline by visit. 
Graphical presentations for mean changes from 
baseline (±SE) and mean values (±SE) by visit. 
By-visit summary and graph excluding 
measurements after rescue therapy. 
 
See Section 1.6 for additional planned analyses. 
 
Secondary endpoints 
 
 
 
 
 
HbA1c (sotagliflozin 200 mg 
vs placebo), 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 
UACR (for patients with 
baseline UACR >30 mg/g, 
all patients): Change from 
Baseline to Week 26 
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,  
No 
No 
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. 
 
See Section 1.6 for additional planned analyses. 
 
Proportion of patients with 
HbA1c <6.5%, <7.0% at 
ITT 
CMH method stratified on 
randomization strata (HbA1c / SBP 
CMH method stratified on 
randomization strata (HbA1c 
No 
By-visit summary and graphs of HbA1c responders 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 92 of 97 
 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Week 26 
at screening)  
/ SBP at screening): 
excluding patients with 
baseline HbA1c values 
<6.5% (for <6.5% 
responders) or <7% (for 
<7% responders) 
respectively 
(<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. 
 
See Section 1.6 for additional planned analyses. 
 
 
Other endpoints 
 
SBP (for patients with 
baseline SBP <130 mmHg), 
DBP (for all patients and 
patients with baseline≥80 
mmHg), UACR, UGE, and 
UGCR, 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 
>50% decline in eGFR; with 
progression to end-stage 
renal disease, with 
progression/improvement of 
UACR categories, 
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: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 93 of 97 
 
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 
 
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: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 94 of 97 
 
Appendix E 
Study Flow Chart 
 
Screening Period 
Double-Blind Treatment Perioda 
Extension 
Follow-
upa  
Screening 
Run-in 
Visit 
1 
2 
3  
Random-
ization 
4 
5 
6 
7 
8 
9 
10 
11 
 
12 
13 
14 
Week 
-4 
-2 
0  
Baseline 
1 
2 
3 
4 
8 
12 
18 
26 
39 
52 
56 
Day (window [days]) 
 
(±3) 
1 
7 (±5) 
14 (±5) 
21 (±5) 
28 (±5) 
56 (±5) 
84 (±5) 
126 (±5) 
182 (±5) 
273 (±5) 
364 (±5) 
392 (±5) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight, heightb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 complete 
X 
 
 
 
 
 
  
 
 
 
X 
 
X 
 
 abbreviatedd 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
Diet & exercise instruction 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
Instruction on basic genito-
urinary hygiene & hydration 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Interactive response 
technology (IRT) contacte 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense glucose meter  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect glucose meter 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Dispense diary  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect/review diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Instruction on diabetic 
ketoacidosis symptoms and 
glucose testing 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense IMP  
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 95 of 97 
 
 
Screening Period 
Double-Blind Treatment Perioda 
Extension 
Follow-
upa  
Screening 
Run-in 
Visit 
1 
2 
3  
Random-
ization 
4 
5 
6 
7 
8 
9 
10 
11 
 
12 
13 
14 
Week 
-4 
-2 
0  
Baseline 
1 
2 
3 
4 
8 
12 
18 
26 
39 
52 
56 
Day (window [days]) 
 
(±3) 
1 
7 (±5) 
14 (±5) 
21 (±5) 
28 (±5) 
56 (±5) 
84 (±5) 
126 (±5) 
182 (±5) 
273 (±5) 
364 (±5) 
392 (±5) 
IMP accounting & 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-monitored blood 
glucosef 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGg 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Laboratory testing h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FPG 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
HbA1c 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Fructosamine 
 
 
X 
 
 
 
X 
X 
X 
 X 
X 
X 
X 
 
Safety laboratory,i 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
X 
Xl 
X 
Cystatin C 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
NT-proBNP 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Fasting lipids 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
Pregnancy test 
(WOCBP)j 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
FSH and/or estradiol 
(menopausal women 
only) j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sotagliflozin Plasma 
concentration k 
 
 
 
 
 
 
X 
 
 
X 
Xl 
X 
Xl 
 
Markers of intestinal 
transit & absorption m 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
Markers of bone & 
calcium metabolism n 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 96 of 97 
 
 
Screening Period 
Double-Blind Treatment Perioda 
Extension 
Follow-
upa  
Screening 
Run-in 
Visit 
1 
2 
3  
Random-
ization 
4 
5 
6 
7 
8 
9 
10 
11 
 
12 
13 
14 
Week 
-4 
-2 
0  
Baseline 
1 
2 
3 
4 
8 
12 
18 
26 
39 
52 
56 
Day (window [days]) 
 
(±3) 
1 
7 (±5) 
14 (±5) 
21 (±5) 
28 (±5) 
56 (±5) 
84 (±5) 
126 (±5) 
182 (±5) 
273 (±5) 
364 (±5) 
392 (±5) 
Urinalysis (dipstick and 
microscopy)o  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collection of home urine 
for albumin, protein, 
creatinine, calcium, 
phosphorus, magnesium, 
glucose and albumine-
creatinine ratiop 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Evaluate for glycemic 
rescue 
 
 
To be assessed and reported throughout the treatment period 
 
Evaluate for 50% increase 
in creatinine s 
 
 
To be assessed and reported throughout the treatment period 
 
Hypoglycemia 
To be assessed and reported throughout the study 
AEs/SAEs/EOSIs/AESIs 
To be assessed and reported throughout the studyt 
a All visits’ dates will be scheduled based on the date of randomization within visit window allowed as per flowchart. If a patient discontinues treatment with investigational medicinal product (IMP) early during the 
Treatment Period, the patient will have a Premature EOT Visit (similar to Visit 13, see Section 10.1.3.2 in protocol and a Follow-up Visit 4 weeks after the last dose of IMP (similar to Visit 14. See Section 10.1.14.1 
in protocol). However, every effort will be made to have the patients return to the site for all scheduled visits, in particular the Week 26 and Week 52 Visits. 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 for both premature EOT after the last dose of IMP. 
b Height to be measured only at screening. 
c Vital sign measurements (sitting blood pressure [BP], heart rate temperature, and respiratory 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 9.2.1.5 in protocol and detailed instructions in Appendix C in protocol). 
d The abbreviated physical exam should focus on cardiac and respiratory systems, as well as any areas important for assessment of AEs if necessary. 
e Additional visit (recheck creatinine) from visit 8 every 2 weeks, contact IRT for treatment allocation if applicable. 
f 
Self-monitored blood glucose (SMBG) is to be performed fasting, at least 3 times per week from start of Run-in until end of Treatment Period including on day of each on-site study visit except Visits 4 and 5. 
Patients will also be requested to self-assess blood glucose levels whenever they experience symptoms of hypoglycemia. SMPG ≤70 mg/dL (3.9 mmol/L) will be documented on the hypoglycemia e-CRF. The 
SMBG will be presented as equivalent self-monitoring plasma glucose (SMPG). 
g The 12-lead ECG recordings should be obtained prior to IMP administration. The ECG will be evaluated as “normal” or “abnormal”. 


Statistical Analysis Plan 
Version: Final 3.0 
Date of Issue: 21 November 2019 
Lexicon Pharmaceuticals Protocol No. EFC15166 
Covance Study ID: 000000155203 
COVANCE INC. CONFIDENTIAL 
Page 97 of 97 
 
h All laboratory assessments occur prior to dose of double-blind IMP. All visit dates will be scheduled based on the date of randomization with a ±5 days visit window allowed during the treatment period. 
i 
Safety laboratory will include hematology and clinical chemistry, please see the list in Table 2 in protocol. Other clinical chemistry tests will include amylase and lipase. 
j 
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) unless there is documented history of menopause (based on documented follicle-stimulating hormone [FSH] and estradiol levels – if results not documented then FSH and estradiol will be tested at 
Screening Visit) or they are surgically sterile. 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. 
k Plasma concentration samples for sotagliflozin and sotagliflozin-3-O-glucuronide collected on Weeks 4, 18, 26, 39, and 52 may be drawn with the other laboratory assessments but MUST be collected before 
administration of IMP. The time of the last intake of study drug 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, neither at all subsequent visits. 
l 
An additional blood sample will be drawn at Weeks 26 and 52 Visits at 3 hours after administering the dose of IMP for creatinine (for eGFR) and for assessing plasma concentration of sotagliflozin and 
sotagliflozin-3-O-glucuronide. 
m The markers of intestinal transit and absorption include vitamins B6, B12, K, E, and A, serum folate, and ferritin. 
n Markers of bone and calcium metabolism :serum calcium , serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum phosphorus , serum magnesium, serum parathyroid hormone (iPTH), markers of 
bone resorption (serum NTX, serum β-CTX-1), bone formation (serum P1NP and osteocalcin) and serum alkaline phosphatase. 
o Urinalysis includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, blood, ketones, bilirubin, urobilinogen, nitrate, and leukocyte esterase. 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 (UTI), 
urine culture should be performed. Positive urine culture determination will be based upon the criteria of the reporting laboratory. Additionally, urine cultures should be performed if at any point the PI suspects the 
presence of a UTI. 
p Patients will collect overnight urine on Weeks 0, 2, 4, 12, 26, and 52. In the night prior to the visits, the urine before sleep will be discarded and the urine during sleep and the first morning urine (after getting up) 
will be collected. The visits should be rescheduled to allow for urine collection in case a patient missed it. Urinary albumin, total protein, creatinine, calcium (adjusted for creatinine), phosphorus (adjusted for serum 
phosphorus and creatinine), magnesium (adjusted for serum magnesium and urinary creatinine), and glucose will be assessed. 
 
 
s The 50% increase will be from baseline value (to Week 8) or from the arithmetic mean of creatinine values from last 2 visits (after Week 8) only at visits having a measurement of creatinine. 
t 
All serious adverse events (SAEs), 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 visit 4 weeks after the last dose of IMP to collect safety and some efficacy information.