Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 571
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 in participants with type 2 diabetes mellitus (T2D) who have inadequate glycemic control on basal insulin alone or with oral antidiabetes drugs (OADs).

Secondary Objectives:

* To assess the effects of sotagliflozin 400 mg versus placebo on fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP), and HbA1c.
* To assess the effects of sotagliflozin 200 mg versus placebo on HbA1c, body weight, FPG, and SBP.
* To evaluate the safety of sotagliflozin 400 and 200 mg versus placebo.

Detailed description:
Up to 60 weeks (Screening phase of up to 2 weeks, a 4-week Lantus titration/single-blind placebo Run-in phase), a 52-week double blind Treatment Period, and a 2-week post-treatment Follow-up Period.

Arms:
arm 1: Following a 4-week run-in period, participants were randomized to matching placebo to sotagliflozin 200 milligrams (mg) administered as 2 tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 52 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study. arm 2: Following a 4-week run-in period, participants were randomized to sotagliflozin 200 mg administered as 1 tablet and matching placebo as 1 tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 52 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study. arm 3: Following a 4-week run-in period, participants were randomized to sotagliflozin 400 mg administered as 2 tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 52 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.

Interventions: intervention 1: Sotagliflozin intervention 2: Insulin glargine (HOE901) intervention 3: Placebo intervention 4: Oral Antidiabetes Drugs (OADs)
Intervention descriptions: intervention 1: Pharmaceutical form: Tablet

Route of administration: Oral intervention 2: Pharmaceutical form: Solution

Route of administration: Subcutaneous intervention 3: Pharmaceutical form: Tablet

Route of administration: Oral intervention 4: OADs (including metformin) as prescribed by the investigator as per local labeling.

Protocol document:
Prot_000.pdf: 
Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-
week Multicenter Study to Evaluate the Efficacy and Safety of 
Sotagliflozin in Patients with Type 2 Diabetes Who Have Inadequate 
Glycemic Control on Basal Insulin Alone or in Addition to Oral 
Antidiabetes Drugs (OADs) 
NCT Number: NCT03285594 
         Document Date: Protocol Version 3: 12-March-2018 


 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
 
 
Page 1 
 
AMENDED CLINICAL TRIAL PROTOCOL NO. 02 
 
COMPOUND: sotagliflozin/SAR439954 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week 
Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin in Patients 
with Type 2 Diabetes Who Have Inadequate Glycemic Control on Basal Insulin 
Alone or in Addition to Oral Antidiabetes Drugs (OADs) 
STUDY NUMBER: EFC14868 
STUDY NAME: SOTA-INS 
VERSION DATE / STATUS: Approval date (06-Mar-2018) / Approved 
Protocol Amendment 03 
Version number: 1 (electronic 1.0) 
Date : 06-Mar-2018 
Amended protocol 01 
Version number: 1 (electronic 1.0) 
Date : 27-Sep-2017 
Protocol Amendment 02 
Version number: 1 (electronic 1.0) 
Date : 27-Sep-2017 
Protocol Amendment 01 (GB) 
Version number: 1 (electronic 1.0) 
Date : 11-Sep-2017 
Clinical Trial Protocol 
Version number: 1 (electronic 3.0) 
Date : 22-May-2017 
EudraCT  
2016-001804-43 
IND Number(s) 
 
Version Number: 
1  
WHO universal trial number: 
U1111-1190-7567 
Date: 
06-Mar-2018  
Total number of pages: 
133 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 2 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 3 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 3 
CLINICAL TRIAL SUMMARY 
 
COMPOUND: sotagliflozin/SAR439954 
STUDY No.: EFC14868  
STUDY NAME: SOTA-INS 
TITLE 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 
52-week Multicenter Study to Evaluate the Efficacy and Safety of 
Sotagliflozin in Patients with Type 2 Diabetes Who Have Inadequate 
Glycemic Control on Basal Insulin Alone or in Addition to Oral 
Antidiabetes Drugs (OADs) 
INVESTIGATOR/TRIAL LOCATION 
Multinational 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVES 
Primary objective: 
To demonstrate the superiority of sotagliflozin 400 mg versus 
placebo with respect to hemoglobin A1c (HbA1c) reduction at 
Week 18 in patients with type 2 diabetes (T2D) who have inadequate 
glycemic control on basal insulin alone or with OADs. 
Secondary objectives: 
• 
To assess the effects of sotagliflozin 400 mg versus placebo 
on: 
- 
Change from Baseline to Week 18 in fasting plasma 
glucose (FPG) 
- 
Change from Baseline to Week 18 in body weight (BW) 
- 
Change from Baseline to Week 12 in systolic blood 
pressure (SBP) for patients with Baseline SBP 
≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all 
patients 
- 
Change form baseline to Week 52 in HbA1c 
- 
Change from baseline to Week 52 in BW 
• 
To assess the effects of sotagliflozin 200 mg versus placebo 
on: 
- 
Change from Baseline to Week 18 in HbA1c 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 12 in SBP for patients 
with Baseline SBP ≥130 mmHg 
- 
Change form baseline to Week 52 in HbA1c 
- 
Change from baseline to Week 52 in BW 
• 
To evaluate the safety of sotagliflozin 400 mg and 200 mg 
versus placebo throughout the 52-week trial 
Other objectives: 
• 
To assess the effects of sotagliflozin 400 mg versus placebo 
on the proportion of patients with HbA1c <7.0% or HbA1c 
<6.5% at Weeks 18, 26, and 52 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 4 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 4 
• 
To assess the effects of sotagliflozin 200 mg versus placebo 
on the proportion of patients with HbA1c <7.0% or HbA1c 
<6.5% at Weeks 18, 26, and 52 
• 
To assess the effects of sotagliflozin 200 mg versus placebo 
on the change from Baseline to Week 12 in SBP for all 
patients 
• 
To assess the effects of sotagliflozin 400 mg and 200 mg 
versus placebo on: 
- 
Change from baseline to Week 26 in HbA1c 
- 
Change from Baseline to Weeks 26 and 52 in SBP in 
all patients and the subset of patients with Baseline 
SBP ≥130 mmHg 
- 
Change from Baseline to Weeks 12, 26, and 52 in SBP 
in patients with Baseline SBP <130 mmHg 
- 
Change from Baseline to Weeks 12, 26, and 52 in 
diastolic blood pressure (DBP) for all patients and the 
subset of patients with Baseline DBP ≥80 mmHg 
- 
Change from Baseline to Week 52 in the total daily 
insulin dose 
- 
Proportion of patients requiring rescue therapy during 
the 52-week double-blind Treatment Period 
- 
Change from Baseline to Week 18 and Week 52  on 
7-point Self-Monitored Blood Glucose (SMBG) profile 
(mean daily value at each time point)  
- 
Change from Baseline on estimated glomerular 
filtration rate (eGFR) 
- 
Change from Baseline in urinary albumin creatinine 
ratio (UACR) 
- 
Patient Qualitative Assessment of Treatment (PQAT) 
during the 52-week Treatment Period 
- 
Patient perception of treatment impact and satisfaction 
using the Treatment Related Impact Measure - 
Diabetes (TRIM-D) during the 52-week Treatment 
Period 
• 
To assess plasma concentrations of sotagliflozin and its 
3-O-glucuronide metabolite. 
Continuous Glucose Monitoring (CGM) substudy: 
In the United States, a substudy employing Continuous Glucose 
Monitoring (CGM) technology will be performed to assess detailed 
glycemic profiles. The details of the CGM substudy procedures, 
endpoints and statistical analyses will be provided in a separate 
substudy protocol document. 
STUDY DESIGN 
This is a Phase 3, multicenter, randomized, double-blind (with 
single-blind Run-in Phase), placebo-controlled, parallel-group study. 
Patients with T2D will be included in this study if at Screening they 
have inadequate glycemic control (as demonstrated by a mean 
HbA1c ≥7.5% or HbA1c ≤10.5%), despite use of basal insulin (at a 
total daily dose that has been stable within ±20% of the dose at 
Screening for 8 weeks, inclusive). Patients may also be using up to 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 5 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 5 
2 OADs which may include metformin at a dose of at least 
1500 mg/day or the maximum tolerated dose (documented). Patients 
who satisfy the entry criteria will be switched to Lantus® (1:1 dose 
conversion from basal insulin being used at Screening). 
The trial will consist of 3 periods: 
• 
An up to 6-week Screening Period comprised of: 
- 
An up to 2-week Screening phase 
- 
A 4-week Lantus titration/single-blind placebo Run-in 
Phase. 
• 
A 52-week double-blind Treatment Period comprised of: 
- 
An initial 18-week fixed-dose phase during which 
Lantus dose is held constant except for safety reasons 
- 
Subsequent 34 weeks during which Lantus can be 
titrated. 
• 
A 2-week, post-treatment Follow-up Period. 
Screening Period 
Up to 2-week Screening phase (see Section 1.2) 
4-week Lantus titration/single-blind placebo Run-in Phase 
If the patient satisfies the entry criteria, their basal insulin will be 
converted to Lantus supplied by the Sponsor (1:1 conversion based 
on units) and a 4-week Lantus optimization phase will commence at 
Week -4 (Visit 2). 
Lantus titration: The target range of fasting SMBG is 80-100 mg/dL 
(4.4-5.6 mmol/L). The titration will be based on SMBG readings 
performed before the first meal of the day for at least 5 days per 
week. The Lantus dose will be adjusted based on the mean of the 
3 most recent fasting SMBG values according to the following 
titration rule: 
• 
≥140 mg/dL (≥7.8 mmol/L): increase Lantus by 4 units, or 
split to 2 x 2 units 
• 
≥120 mg/dL (≥6.7 mmol/L) but <140 mg/dL (<7.8 mmol/L): 
increase Lantus by 2 units 
• 
>100 mg/dL (>5.6 mmol/L) but <120 mg/dL (<6.7 mmol/L): 
increase Lantus by 1 unit 
• 
80-100 mg/dL (4.4-5.6 mmol/L), inclusive: no change in 
dose 
• 
<80 mg/dL (<4.4 mmol/L): decrease Lantus by 2 units. 
Lantus dose adjustment will occur every 3 days (twice a week). The 
dose adjustments will be made in consultation with the study site 
either at site visits, phone visits, or unscheduled phone contacts. In 
case of hypoglycemia, insulin titration may be withheld according to 
the Investigator’s medical judgment. 
During the 4-week Lantus titration/single-blind placebo Run-in 
Phase, patients will also take single-blind placebo, given as two (2) 
placebo tablets (identical to sotagliflozin 200 mg in appearance), 
once daily before the first meal of the day. In order to qualify for 
randomization, patients must demonstrate compliance at the end of 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 6 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 6 
the Run-in Phase, based upon tablet count (≥80%) and the 
Investigator’s discretion. 
Patients will not initiate any new antidiabetic medication. The 
pre-existing OAD should remain stable without any changes. 
Monitoring for serum ketones: At Visit 2, patients will be provided 
meters and test strips for monitoring capillary blood 
beta-hydroxybutyrate (BHB). Patients will be instructed to measure 
their BHB levels by fingerstick if they experience any symptoms 
consistent with ketosis/ketoacidosis throughout the entire study 
period. Patients will be instructed on how to respond (seek help, 
hydrate, ingest carbohydrates, etc) if they present with possible 
ketoacidosis symptoms and the BHB value is abnormal (>0.6 mM/L). 
Randomized Core Treatment Period: Weeks 0 to18 
Randomization: To be randomized, patients must have HbA1c 
value ≥7% based on value obtained at Week -1 (Visit 5). 
Patients will be randomly assigned at a ratio of 2:1:1 respectively to 
one of 3 arms: 
• 
Sotagliflozin 400 mg, given as two (2) 200-mg tablets, once 
daily before the first meal of the day 
• 
Sotagliflozin 200 mg, given as one (1) 200-mg tablet and 
one (1) placebo tablet (identical to sotagliflozin 200 mg in 
appearance), once daily before the first meal of the day 
• 
Placebo, given as two (2) placebo tablets (identical to 
sotagliflozin 200 mg in appearance), once daily before the 
first meal of the day. 
Randomization will be stratified by the following 3 binary factors: 
HbA1c at Week -1 (≤8.5%, >8.5%) and SBP at Week -1 
(<130 mmHg, ≥130 mmHg), sulfonylureas use at Week -1 (yes, no). 
Administration of blinded investigational medicinal product (IMP) 
begins at Randomization (Day 1). 
Lantus dose: The dose of Lantus should be held constant for the 
first 18 weeks unless glycemic rescue criteria are satisfied (see 
below). 
In addition, the doses of the two OADs (if applicable) should be held 
constant throughout the entire 52-week double-blind Treatment 
Period (ie, not changed except for safety reasons), and the dose of 
all antihypertensive medications should be held constant for the first 
12 weeks (until Visit 11) except for safety reasons. 
Hyperglycemic rescue: For the first 18 weeks, the total daily insulin 
should remain stable (< ±10% from randomization dose, or 
<±4 units, whichever is less). Patients requiring glycemic rescue 
may initiate rescue therapy with prandial insulin, or glucagon-like 
peptide-1 (GLP-1) agonists, or another antidiabetic medication 
(except sodium-glucose cotransporter type 2 [SGLT2] inhibitors), 
according to the Investigator’s clinical judgment and in accordance 
with the treatment guidelines. Criteria for hyperglycemic rescue have 
been set for different phases of the study (see STUDY 
TREATMENTS, Rescue Therapy) and are consistent with accepted 
treatment goals for diabetic therapy. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 7 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 7 
The dose of double-blind study treatment (sotagliflozin or placebo) 
will not be adjusted throughout the study. 
Weeks 19 to 52 Treatment Period 
Lantus Titration: Lantus titration resumes after Visit 12 (Week 18). 
During Weeks 19 to 52, SMBG values will be reviewed with site staff 
at site visits as well as extemporaneously if the patient calls site due 
to low or high SMBG readings. The same titration rule as described 
above (for the 4 week pre-Randomization Lantus titration period) will 
be followed. The Lantus dose will be adjusted based on the mean of 
the 3 most recent fasting SMBG values according to the following 
titration rule: 
• 
≥140 mg/dL (≥7.8 mmol/L): increase Lantus by 4 units, or 
split to 2 x 2 units 
• 
≥120 mg/dL (≥6.7 mmol/L) but <140 mg/dL (<7.8 mmol/L): 
increase Lantus by 2 units, or split to 2 x 1 unit 
• 
>100 mg/dL (>5.6 mmol/L) but <120 mg/dL (<6.7 mmol/L): 
increase Lantus by 1 unit 
• 
80-100 mg/dL (4.4-5.6 mmol/L), inclusive: no change in 
dose 
• 
<80 mg/dL (<4.4 mmol/L): decrease Lantus by 2 units. 
The doses of the two OADs (if applicable) should be held constant 
throughout the entire 52-week double-blind Treatment Period (ie, not 
changed except for safety reasons). 
In case of hypoglycemia, insulin titration may be withheld according 
to the Investigator’s medical judgment. 
Hyperglycemic rescue: During Weeks 19 to 52, patients exceeding 
glucose rescue limits may have their Lantus dose up-titrated without 
a maximum limit as a first approach. If up-titration of the Lantus 
regimen, based on the previously described titration rules, has been 
unsuccessful (ie, increase in basal insulin is associated with low 
FPG values despite high HbA1c or elevated post-prandial values), it 
is appropriate to initiate rescue therapy with prandial insulin, or a 
GLP-1 agonist, or another antidiabetic medication (except SGLT2 
inhibitors), according to the Investigator’s clinical judgment and in 
accordance with the treatment guidelines. 
Hyperglycemia rescue criteria: Rescue is defined by the criteria 
described below (see STUDY TREATMENTS, Rescue Therapy). 
2-Week, Post-treatment Follow-up Visit 
Blood pressure (BP) and laboratory values will be assessed, and 
safety information including adverse events (AEs) will be collected. 
The HbA1c and centrally measured FPG will be masked to study 
sites and patients after Randomization and until study end. 
Additionally, urinalysis by dipstick will not include the measurement 
of urine glucose. 
Early Termination 
If a patient discontinues treatment with IMP any time during the 
Treatment Period, the patient will have a Premature End of 
Treatment (EOT) Visit, and a Follow-up Visit 2 weeks after the last 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 8 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 8 
dose of IMP. In addition, every effort will be made to have the 
patients return to the site at the time corresponding to their 
scheduled visits, particularly the visits at Week 18 (Visit 12) and 
Week 52 (Visit 15). If the patient does not agree to site visits, the 
patient will be contacted by respective sites by telephone to inquire 
about safety status. If a patient discontinues (or completes) 
treatment and study at the same time, a single visit for both EOT and 
end of study (EOS) will be performed. 
The study design is presented graphically in Section 1.1. The CGM 
substudy will be detailed in a sub-protocol. 
STUDY POPULATION 
Main selection criteria 
Inclusion criteria: 
• 
Patients with T2D using any types of basal insulin alone or in 
combination with up to 2 OADs 
• 
Patient has given written informed consent to participate in 
the study in accordance with local regulations. 
Major exclusion criteria: 
• 
At the time of Screening age <18 years or <legal age of 
majority, whichever is greater 
• 
Type 1 diabetes mellitus 
• 
OAD dose not stable for 8 weeks before Screening 
• 
Use of basal insulin therapy (eg, insulin glargine, Neutral 
Protamine Hagedorn [NPH], detemir, or degludec) for less 
than 6 months before Screening 
• 
Dose of basal insulin (eg, insulin glargine, NPH, detemir, or 
degludec) not stable for 8 weeks before Screening (ie, total 
daily insulin dose increased or decreased by more than 
20%) 
• 
Use of injectable diabetes drugs other than basal insulin (eg, 
insulin glargine, NPH, detemir, or degludec), ie, prandial or 
rapid-acting insulins, short-acting insulins, GLP-1 receptor 
agonists, or inhaled prandial insulin (Afrezza) within 8 weeks 
of Screening 
• 
Use of a selective SGLT2 inhibitor (eg, canagliflozin, 
dapagliflozin, or empagliflozin) within 3 months prior to the 
trial 
• 
Use of systemic glucocorticoids (excluding topical, 
intra-articular, or ophthalmic application, nasal spray or 
inhaled forms) for more than 10 consecutive days within 
90 days prior to the Screening Visit 
• 
Patients with severe anemia, severe cardiovascular 
(including congestive heart failure New York Heart 
Association IV), respiratory, hepatic, neurological, 
psychiatric, or active malignant tumor or other major 
systemic disease or patients with short life expectancy that, 
according to the Investigator, will preclude their safe 
participation in this study, or will make implementation of the 
protocol or interpretation of the study results difficult 
• 
Known presence of factors that interfere with the Central Lab 
HbA1c measurement (eg, genetic Hb variants) 
compromising the reliability of HbA1c assessment or 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 9 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 9 
medical conditions that affect interpretation of HbA1c results 
(eg, blood transfusion or severe blood loss in the last 3 
months prior to randomization, any condition that shortens 
erythrocyte survival) 
• 
Patient who has taken other investigational drugs or 
prohibited therapy for this study within 12 weeks or 
5 half-lives from prior to Screening, whichever is longer  
• 
Patients unwilling or unable to perform SMBG 
(Section 8.2.1.4), complete the patient diary or comply with 
study visits and other study procedures as required per 
protocol 
• 
HbA1c <7.5% or HbA1c >10.5% measured by the central 
laboratory at Screening 
• 
HbA1c <7% measured by the central laboratory at Visit 5 
(Week -1) 
• 
History of diabetic ketoacidosis or nonketotic hyperosmolar 
coma within 12 weeks prior to the Screening Visit 
• 
Pregnant (confirmed by serum pregnancy test at screening) 
or breastfeeding women 
• 
Women of childbearing potential not willing to use highly 
effective method(s) of birth control during the study 
treatment period and the follow-up period, or who are 
unwilling or unable to be tested for pregnancy (see  
Appendix A), during the study 
• 
Mean of 3 separate BP measurements >180 mmHg (SBP) 
or >100 mmHg (DBP) 
• 
History of gastric surgery including history of gastric banding 
or inflammatory bowel disease within 3 years prior to the 
Screening Visit. Note: Patients who have had bariatric 
surgery or gastric banding more than 3 years prior to the 
Screening Visit must have a stable weight (±10%) for 
6 months prior to the Screening Visit. 
• 
Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 times the upper limit of normal 
(ULN) laboratory range 
• 
Total bilirubin >1.5 times the ULN (except in case of Gilbert’s 
syndrome). 
Total expected number of patients: 
560 randomized patients in the main study. 
STUDY TREATMENTS 
 
Investigational medicinal products 
Sotagliflozin 400 mg 
• 
200 mg tablets 
• 
Oral 
• 
400 mg, given as two (2) 200-mg tablets, once daily before 
the first meal of the day. 
 
Sotagliflozin 200 mg 
• 
200 mg tablets 
• 
Oral 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 10 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 10 
• 
200 mg, given as one (1) 200-mg tablet and one (1) placebo 
tablet (identical to sotagliflozin 200 mg in appearance), once 
daily before the first meal of the day. 
 
Placebo 
• 
Tablets identical in appearance to sotagliflozin 200 mg 
• 
Oral 
• 
Two (2) placebo tablets, once daily before the first meal of 
the day. 
Noninvestigational medicinal product(s) 
Lantus (insulin glargine, 100 U/mL) 
• 
Prefilled pen (3.0 mL solution) 
• 
Subcutaneous injection 
• 
Lantus to be provided by the Sponsor at the beginning of the 
Lantus titration phase. Patients who are receiving any basal 
insulin other than Lantus before screening will switch to 
Lantus. For patients who are using long-acting insulin 
analogs other than Lantus (eg, Levemir, Tresiba, Basaglar), 
the existing basal insulin will be converted to an equivalent 
dose of Lantus on a 1:1 unit basis (ie, the same dose on the 
day before Visit 2). If the patient is using Toujeo® (glargine 
U-300/mL), the initial Lantus dose is 80% of the existing 
Toujeo dose as recommended in the Lantus label. If the 
patient is using NPH twice daily, it’s recommended that the 
converted Lantus dose should be reduced by 20% and given 
once daily. If using NPH once a day, it can be converted to 
Lantus unit-to-unit. 
• 
Metformin (optional) tablets to be administered as per 
Principal Investigator and in accordance with local labeling 
• 
Other OADs (up to 2 in total, including metformin) to be 
administered as per Principal Investigator and in accordance 
with local labeling, with the exception of SGLT2 inhibitors. 
 
Rescue Therapy 
The threshold values for rescue are defined as follows, depending 
on study period: 
• 
From Baseline Visit (Visit 6, Day 1) to Visit 10 (Week 8) 
(including value at Visit 10): FPG >270 mg/dL (15.0 mmol/L) 
• 
From Visit 10 (Week 8) to Visit 11 (Week 12) (including 
value at Visit 11): FPG >240 mg/dL (13.3 mmol/L) 
• 
From Visit 11 (Week 12) up to Visit 12 (Week 18): FPG >200 
mg/dL (11.1 mmol/L) or HbA1c ≥8.5% (the 8.5% criteria 
does not apply if the HbA1c decrease from Baseline was 
≥1.5%) 
• 
From Visit 12 (Week 18) up to the EOT, Visit 15 (Week 52): 
FPG >170 mg/dL (9.4 mmol/L) or HbA1c ≥8.0% (the 8.0% 
criteria does not apply if the HbA1c decrease from Baseline 
was ≥1.5%). 
Routine fasting SMBG and central laboratory alerts on FPG (and 
HbA1c at Week 12 and onwards) are set up to ensure that glycemic 
parameter results remain within predefined thresholds.  
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 11 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 11 
If a central laboratory FPG and/or HbA1c is above the threshold, the 
Investigator will receive an alert from the central laboratory. Upon 
receipt of a central laboratory rescue alert, a central laboratory 
re-test must be completed and confirmed.  
Likewise, patients are instructed to contact the sites for a 
confirmatory FPG test via central lab in case of consecutive 3 days 
high readings in fasting SMBG. Hyperglycemia must be confirmed as 
exceeding the criterion for rescue before rescue therapy is initiated. 
The central Lab FPG confirmation should be performed as soon as 
possible preferably within 7 days by unscheduled visit. 
The recommended approach to rescue if rescue thresholds have 
been reached despite up-titration of the Lantus dose includes 
initiating a prandial dose of short-acting insulin, or GLP-1 agonist, or 
another antidiabetic medication (except SGLT2 inhibitors) according 
to the Investigator’s clinical judgment and in accordance with the 
treatment guidelines. 
If a patient requires rescue, the IMP received at Randomization 
should continue and must remain blinded until EOS. 
ENDPOINTS 
 
Primary endpoint (Sotagliflozin 400 mg dose): 
Change from Baseline to Week 18 in HbA1c. 
Secondary endpoints (Sotagliflozin 400 mg dose): 
• 
Change from Baseline to Week 18 in FPG 
• 
Change from Baseline to Week 18 in BW. 
• 
Change from Baseline to Week 12 in SBP for patients with 
Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 12 in SBP for all patients 
• 
Change from Baseline to Week 52 in HbA1c 
• 
Change from Baseline to Week 52 in BW 
Secondary endpoints (Sotagliflozin 200 mg dose): 
• 
Change from Baseline to Week 18 in HbA1c 
• 
Change from Baseline to Week 18 in BW. 
• 
Change from Baseline to Week 18 in FPG 
• 
Change from Baseline to Week 12 in SBP for patients with 
Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 52 in HbA1c 
• 
Change from Baseline to Week 52 in BW 
Other efficacy endpoints (Sotagliflozin 400 mg and 200 mg): 
• 
Proportion of patients with HbA1c <7.0% or HbA1c <6.5% at 
Weeks 18, 26, and 52 
• 
Change from Baseline to Week 26 in HbA1c 
• 
Change from Baseline to Week 12 in SBP for all patients in 
the sotagliflozin 200 mg arm, and from Baseline to 
Weeks 26 and 52 in SBP for all patients and the subset of 
patients with Baseline SBP ≥130 mmHg in the sotagliflozin 
400 mg and 200 mg arms 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 12 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 12 
• 
Change from Baseline to Weeks 12, 26, and 52 in SBP in 
patients with Baseline SBP <130 mmHg 
• 
Change from Baseline to Weeks 12, 26, and 52 in DBP for 
all patients and for the subset of patients with Baseline DBP 
≥80 mmHg 
• 
Change from Baseline to Week 52 in total daily insulin dose 
• 
Proportion of patients requiring rescue therapy during the 
52-week double-blind Treatment Period 
• 
Change from Baseline to Weeks 18 and 52 in 7-point SMBG 
profile (mean daily value and at each time point) 
• 
Change from Baseline in eGFR 
• 
Change from Baseline in UACR during the 52-week 
Treatment Period 
• 
PQAT at Weeks 18 and 52 
• 
Change in TRIM-D from Baseline to Week 52 for total score 
and 5 domain scores. 
Safety endpoints: 
• 
AEs, hypoglycemia (all, severe and/or documented 
symptomatic hypoglycemia), events of special interest 
(EOSI), adverse events of special interest (AESI), AEs 
leading to discontinuation from the IMP, serious adverse 
events (SAEs), and deaths 
• 
Markers of calcium metabolism 
• 
Safety laboratory results, vital signs results, and 12-lead 
electrocardiogram (ECG) results. 
Pharmacokinetic endpoints: 
Plasma concentrations of sotagliflozin and its 3-O-glucuronide 
metabolite. 
CGM substudy endpoints: 
The list of endpoints will be outlined in a separate substudy protocol. 
ASSESSMENT SCHEDULE 
See Section 1.2 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
The sample size/power calculations were performed based on the 
primary endpoint. Assuming a common standard deviation (SD) of 
1.2% and using a 2-sided test at a 0.05 α-level, 280 patients in the 
sotagliflozin 400 mg arm and 140 patients in the placebo arm will 
provide at least 95% power to detect a treatment difference of 0.5% 
in mean HbA1c change from Baseline to Week 18 between 
sotagliflozin 400 mg and placebo. 
A sample size of 140 patients in the sotagliflozin 200 mg arm and 
140 patients in the placebo arm will provide 80% power to detect a 
treatment difference of 0.4% in mean HbA1c change from Baseline 
to Week 18 between sotagliflozin 200 mg and placebo (SD 1.2%; 5% 
significance level 2-sided). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 13 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 13 
The total sample size will be 560 patients to be randomized 
(280 patients in the sotagliflozin 400 mg arm; 140 patients in the 
sotagliflozin 200 mg arm; 140 patients in the placebo arm). 
Analysis population: 
Efficacy analyses will be based on the intention to treat (ITT) 
population, defined as all randomized patients irrespective of 
compliance with the study protocol and procedures. Patients will be 
analyzed according to the treatment group to which they are 
randomized. 
Analysis of the primary efficacy endpoint: 
Analysis of the primary efficacy endpoint (change from Baseline to 
Week 18 in HbA1c) will be performed using the ITT population, using 
HbA1c measurements obtained during the study, including those 
obtained after IMP discontinuation or introduction of rescue therapy. 
The primary efficacy endpoint of change in HbA1c from Baseline to 
Week 18 will be analyzed with missing values imputed by 
control-based multiple imputation method under the missing not at 
random framework. 
• 
For placebo patients, missing data will be imputed based on 
the placebo group data 
• 
For patients in the sotagliflozin groups, missing data will be 
imputed as if the patients were on placebo group throughout 
the study, where all patients’ measurements including the 
on-treatment measurements will be considered as if the 
measurements were from the placebo group in the 
imputation model. 
Each of the complete datasets will be analyzed by the analysis of 
covariance (ANCOVA) model with treatment groups (sotagliflozin 
400 mg, sotagliflozin 200 mg, placebo), randomization strata of 
Week -1 HbA1c (≤8.5%, >8.5%), randomization strata of Week -1 
SBP (<130 mmHg, ≥130 mmHg), randomization strata of 
sulfonylureas use at Week -1 (yes, no), and country as fixed effects, 
and Baseline HbA1c value as a covariate. Results from each 
complete dataset will be combined to provide the adjusted mean 
change in HbA1c from Baseline to Week 18 for the sotagliflozin 
400 mg arm and placebo arm, as well as the between-group 
difference (comparing sotagliflozin 400 mg arm versus placebo) and 
the 95% confidence interval (CI) using contrast statements. 
Summary statistics (for Screening value, Baseline value, observed 
values, and observed changes from Baseline) at scheduled visits will 
be provided for each treatment group. The summary will include the 
number of observations, mean, SD, standard error (SE), minimum, 
median, and maximum. Graphical presentations will also be used to 
examine trends over time using mean values (±SE) and mean 
changes from Baseline (±SE) at each of the scheduled visits (using 
observed cases [OC]). 
Baseline definition: 
The Baseline value is defined generally as the last available value 
before the first dose of double-blind IMP or the last available value 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 14 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 14 
prior to Randomization for patients who were randomized but never 
exposed to IMP. 
Analysis of secondary efficacy endpoints: 
The secondary endpoints will be analyzed using a similar approach 
to the primary efficacy endpoint, with missing values imputed by the 
control-based multiple imputation method under the missing not at 
random framework. For each of the continuous secondary endpoints, 
each of the complete datasets will be analyzed by the ANCOVA 
model with treatment groups (sotagliflozin 400 mg, sotagliflozin 
200 mg, placebo), randomization strata of Week -1 HbA1c (≤8.5%, 
>8.5%), randomization strata of Week -1 SBP (<130 mmHg, 
≥130 mmHg), randomization strata of sulfonylureas use at Week -1 
(yes, no), and country as fixed effects, and Baseline secondary 
endpoint value as a covariate. Results from each complete dataset 
will be combined to provide the adjusted mean change from Baseline 
to Week 18 (Week 12 for SBP endpoints) for each treatment group, 
as well as the between-group difference (comparing each 
sotagliflozin group versus placebo) and the 95% CI using contrast 
statements. For HbA1c endpoint, results from each complete dataset 
will be combined to provide the adjusted mean change from Baseline 
to Week 18 for sotagliflozin 200 mg arm and placebo arm, as well as 
the between-group difference (comparing the sotagliflozin 200 mg 
arm versus placebo arm) and the 95% CI using contrast statements. 
The categorical secondary efficacy variables of HbA1c <6.5% or 
<7% at Week 18 will be analyzed using a Cochran-Mantel-Haenszel 
method stratified by randomization strata of Week -1 HbA1c (≤8.5%, 
>8.5%), randomization strata of Week -1 SBP (<130 mmHg, 
≥130 mmHg), and randomization strata of sulfonylureas use at 
Week -1 (yes, no). For the HbA1c <7% or <6.5% analysis, patients 
with missing HbA1c data at Week 18 will be considered 
non-responders in the ITT population. 
Summary statistics for the secondary endpoints at scheduled visits 
will be provided for each treatment group. 
Analysis of other efficacy endpoints: 
Except for patient reported outcome (PRO) endpoints, the analysis 
of other endpoints will be descriptive with no formal testing. 
Summary statistics at scheduled visits using OC will be provided by 
each treatment group. Graphical presentations will also be used to 
illustrate trends over time. 
For TRIM-D scores (total and domain scores), descriptive statistics 
will be presented by treatment group per visit. The change from 
Baseline to endpoint will be analyzed using a similar approach as the 
primary efficacy endpoint with missing values imputed by 
control-based multiple imputation method under the missing not at 
random framework. 
Analysis of Safety Data: 
All safety summaries will be descriptive; no statistical significance 
tests will be performed on safety data. These analyses will be based 
on the safety population, which is defined as all randomized patients 
who receive at least 1 dose of double-blind IMP, regardless of the 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 15 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 15 
amount of treatment administered. Patients will be analyzed for 
safety analyses according to the treatment actually received. The 
safety analyses will be provided for the 18-week randomized 
Treatment Period and for the entire 52-week double-blind Treatment 
Period. 
DURATION OF STUDY PERIOD (per 
patient) 
Up to 60 weeks, including an up to 6-week Screening Period 
(comprised of an up to 2-week Screening phase and a 4-week, 
Lantus titration/single-blind placebo Run-in Phase), a 52-week 
double-blind Treatment Period, and a 2-week post-treatment 
Follow-up Visit. 
STUDY COMMITTEES 
Steering committee: 
 Yes 
 No 
Data monitoring committee: 
 Yes 
 No 
Adjudication committee: 
 Yes 
 No 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 16 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 16 
1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
Abbreviations: CGM = continuous glucose monitoring; HbA1c = hemoglobin A1c; MMTT = mixed-meal tolerance test; R = Randomization; T2D = type 2 diabetes. 
(electronic 
 
 
2.0)
(electronic 
 
 
1.0)
Page 17 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 17 
1.2 
STUDY FLOW CHART 
Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
 
Screen-
ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight, heightd 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signse 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examination: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Abbreviatedf 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
Concomitant Medication 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Diet & exercise instruction 
 
X 
 
 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Instruction on basic GU 
hygiene & hydration 
 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Interactive response 
technology (IRT) contact 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
(electronic 
 
 
2.0)
(electronic 
 
 
1.0)
Page 18 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 18 
Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
 
Screen-
ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense glucose meter, 
Beta-hydroxybutyrate (BHB) 
meter 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense glucose test strips 
and BHB strips 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Measurement of capillary 
BHB at the site 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
Dispense diary 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Collect/review diary 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Instruction on diabetic 
ketoacidosis symptoms, 
glucose testing 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Dispense IMP and Lantus 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
IMP and Lantus accounting & 
compliance 
 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Review results of SMBG and 
recommend Lantus dose 
adjustments as necessaryg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record results of a 7-point 
SMBGh 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
12-lead ECGi 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
(electronic 
 
 
2.0)
(electronic 
 
 
1.0)
Page 19 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 19 
Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
 
Screen-
ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
Laboratory Assessmentsj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FPGk 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
BHB 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
HbA1c 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Clinical Chemistry l 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
Fasting lipids 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Pregnancy test (WOCBP)m 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
FSH and/or estradiol as 
neededm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma concentrationn 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Markers of calcium 
metabolismo 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Urinalysis w/microscopyp 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Collection of home 
overnight urine for albumin, 
protein, creatinine, calcium, 
phosphorus, magnesium, 
glucose, and albumin-
creatinine ratioq 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
(electronic 
 
 
2.0)
(electronic 
 
 
1.0)
Page 20 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 20 
Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
 
Screen-
ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
PRO: PQATt 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
PRO: TRIM-Dt 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
Evaluate for glycemic rescue 
 
 
 
 
 
To be assessed and reported throughout the Treatment Period 
 
Hypoglycemia 
To be assessed and reported throughout the study 
AEs/SAEs/AESI/EOSIu 
To be assessed and reported throughout the study 
a If a patient discontinues treatment with IMP early during the Treatment Period, the patient will have a Premature EOT Visit, and a Follow-up Visit 2 weeks after the last dose of IMP. However, every effort will be 
made to have the patients return to the site for all scheduled visits, in particular the visits at Week 18 (Visit 12) and Week 52 (Visit 15). If the patient does not agree to a site visits, the patient will be contacted by 
telephone to inquire about safety status. If a patient discontinues (or completes) treatment and study at the same time, a single visit for both EOT and EOS will be performed. 
b To ensure effective Lantus dose titration during the Run-in Phase, patients will be instructed to call the Investigator to discuss the necessary adjustments in Lantus dose if they have 2 or more SMBG 
measurements above 100 mg/dL or below 80 mg/dL. 
c Two weeks after the last dose of IMP. 
d Height to be measured only at Screening. 
e Vital sign measurements (sitting blood pressure [BP], heart rate): 3 separate seated BP and heart rate measurements should be taken with at least 1 minute between readings, following a 5-minute rest period and 
prior to phlebotomy (if applicable). 
f 
The abbreviated physical exam should focus on cardiac and respiratory systems, as well as any areas important for assessment of AEs if necessary. 
g Fasting (pre-breakfast/pre-injection if available) SMBG: during the 4-week Run-in Lantus titration period, fasting SMBG should be performed daily. Thereafter, the number of fasting SMBG checks can be reduced 
according to the Investigator’s judgment, however at least 3 fasting (pre-breakfast) SMBG measurements per week should be done from Weeks 0 to 18 and 3 measurements during the week prior to study visits 
from Weeks 19 to 52 (Section 8.2.1.4). Patients will review SMBG values with site staff either at site visits, phone visits or extemporaneously if patient feels high or low SMBG values may necessitate a dose 
adjustment. See Table 2 for permitted adjustments. Patients should be advised to check SMBG whenever they experience any symptoms of hypoglycemia, if possible, before taking the treatment. Note: Units in 
table represent plasma glucose values as glucometers used for SMBG display results already adjusted to plasma concentration and no conversion is required. 
h 7-point SMBG profile (before [pre-injection after randomization] and 2 hours after breakfast, lunch and dinner, and bedtime): at least ONE day during the weeks prior to Weeks 0 (Visit 6), 18 (Visit 12), and 52 
(Visit 15). 
i 
The 12-lead ECG recordings should be obtained after at least 10 minutes in a supine position and prior to IMP administration. The ECG will be evaluated as “normal” or “abnormal”. 
(electronic 
 
 
2.0)
(electronic 
 
 
1.0)
Page 21 of 365




Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 22 
2 
TABLE OF CONTENTS 
 
AMENDED CLINICAL TRIAL PROTOCOL NO. 02.......................................................................................1 
1 
FLOW CHARTS.............................................................................................................................16 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................16 
1.2 
STUDY FLOW CHART ..................................................................................................................17 
2 
TABLE OF CONTENTS ................................................................................................................22 
2.1 
LIST OF TABLES...........................................................................................................................28 
2.2 
LIST OF FIGURES.........................................................................................................................28 
3 
LIST OF ABBREVIATIONS ..........................................................................................................29 
4 
INTRODUCTION AND RATIONALE.............................................................................................31 
4.1 
BACKGROUND: SOTAGLIFLOZIN AND DISEASE .....................................................................31 
4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS ................................................................32 
4.3 
RATIONALE FOR SELECTION OF DOSE ...................................................................................33 
4.4 
RATIONALE FOR STUDY DESIGN AND CONTROL GROUPS..................................................34 
4.5 
BENEFIT/RISK OF SOTAGLIFLOZIN...........................................................................................35 
5 
STUDY OBJECTIVES ...................................................................................................................37 
5.1 
PRIMARY.......................................................................................................................................37 
5.2 
SECONDARY ................................................................................................................................37 
5.3 
OTHER...........................................................................................................................................37 
6 
STUDY DESIGN ............................................................................................................................39 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................39 
6.1.1 
Screening period............................................................................................................................39 
6.1.1.1 
Screening phase (Visit 1)...............................................................................................................39 
6.1.1.2 
Run-in phase (Visits 2 to 5)............................................................................................................40 
6.1.2 
Double-blind Treatment Period (Day 1 to Week 52)......................................................................40 
6.1.3 
Follow-up period.............................................................................................................................41 
 
41 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 23 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 23 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................41 
6.2.1 
Duration of study participation for each patient .............................................................................41 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................41 
6.3 
STUDY COMMITTEES..................................................................................................................41 
6.3.1 
Steering committee ........................................................................................................................41 
6.3.2 
Data monitoring committee ............................................................................................................42 
6.3.3 
Clinical endpoint committee(s).......................................................................................................42 
6.3.4 
Safety adjudication of events requiring ongoing monitoring ..........................................................42 
7 
SELECTION OF PATIENTS..........................................................................................................43 
7.1 
INCLUSION CRITERIA..................................................................................................................43 
7.2 
EXCLUSION CRITERIA ................................................................................................................43 
7.2.1 
Exclusion criteria related to study methodology ............................................................................43 
7.2.2 
Exclusion criteria related to the diabetes history and treatment....................................................44 
7.2.3 
Exclusion criteria related to the current knowledge of sotagliflozin ...............................................45 
7.2.4 
Additional exclusion criteria during or at the end of the Run-in Phase before Randomization .....46 
8 
STUDY TREATMENTS .................................................................................................................47 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................47 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT .......................................................................47 
8.2.1 
Lantus (insulin glargine 100 U/mL) ................................................................................................48 
8.2.1.1 
Dosage schedule ...........................................................................................................................48 
8.2.1.2 
Starting dose..................................................................................................................................48 
8.2.1.3 
Dose titration and modification.......................................................................................................49 
8.2.1.4 
Self-monitoring of blood glucose (SMBG) .....................................................................................51 
8.2.2 
Metformin .......................................................................................................................................52 
8.2.3 
Other oral antidiabetes drugs.........................................................................................................52 
8.2.4 
Rescue therapy..............................................................................................................................53 
8.3 
BLINDING PROCEDURES............................................................................................................55 
8.3.1 
Methods of blinding........................................................................................................................55 
8.3.2 
Randomization code breaking during the study.............................................................................55 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................56 
8.5 
PACKAGING AND LABELING ......................................................................................................56 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................57 
8.7 
RESPONSIBILITIES ......................................................................................................................57 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 24 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 24 
8.7.1 
Treatment accountability and compliance......................................................................................58 
8.7.2 
Return and/or destruction of treatments ........................................................................................58 
8.8 
CONCOMITANT MEDICATION.....................................................................................................59 
8.8.1 
Prohibited prior and concomitant medications...............................................................................59 
8.8.2 
Concomitant diabetes therapy .......................................................................................................60 
8.9 
POST-STUDY TREATMENT.........................................................................................................60 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................61 
9.1 
EFFICACY ENDPOINTS ...............................................................................................................61 
9.1.1 
Primary efficacy endpoint (sotagliflozin 400 mg dose) ..................................................................61 
9.1.2 
Secondary efficacy endpoints........................................................................................................61 
9.1.3 
Other efficacy endpoints (sotagliflozin 400 mg and 200 mg doses)..............................................61 
9.1.4 
Assessment methods of efficacy endpoints...................................................................................62 
9.1.4.1 
Hemoglobin A1c.............................................................................................................................62 
9.1.4.2 
Fasting plasma glucose measurement ..........................................................................................62 
9.1.4.3 
Blood pressure measurements ......................................................................................................62 
9.1.4.4 
Body weight measurement ............................................................................................................63 
9.1.4.5 
Kidney function parameter measurement......................................................................................63 
9.1.4.6 
7-point SMBG profiles....................................................................................................................63 
9.1.4.7 
Proportion of patients starting rescue therapy...............................................................................63 
9.1.4.8 
Insulin dose....................................................................................................................................64 
9.2 
SAFETY ENDPOINTS ...................................................................................................................64 
9.2.1 
Assessment methods of safety endpoints .....................................................................................65 
9.2.1.1 
Adverse events ..............................................................................................................................65 
9.2.1.2 
Hypoglycemia.................................................................................................................................65 
9.2.1.3 
Laboratory safety variables............................................................................................................65 
9.2.1.4 
Urinalysis........................................................................................................................................67 
9.2.1.5 
Vital signs.......................................................................................................................................67 
9.2.1.6 
Electrocardiogram variables ..........................................................................................................67 
9.2.1.7 
Diabetic ketoacidosis .....................................................................................................................68 
9.3 
OTHER ENDPOINTS.....................................................................................................................68 
9.3.1 
Pharmacokinetics...........................................................................................................................68 
9.3.1.1 
Sampling time ................................................................................................................................68 
9.3.1.2 
Pharmacokinetic handling procedure.............................................................................................69 
9.3.1.3 
Bioanalytical method......................................................................................................................69 
 
69 
 
69 
9.3.3 
Patient reported outcomes assessments.......................................................................................70 
9.3.3.1 
Patient’s qualitative assessment of treatment ...............................................................................70 
9.3.3.2 
Treatment related impact measure for diabetes (TRIM-D)............................................................71 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 25 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 25 
 
71 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................72 
10 
STUDY PROCEDURES ................................................................................................................74 
10.1 
VISIT SCHEDULE..........................................................................................................................74 
10.1.1 
Screening Period............................................................................................................................74 
10.1.1.1 Screening phase (Visit 1)...............................................................................................................74 
10.1.1.2 Run-in phase (Visits 2 to 5)............................................................................................................76 
10.1.2 
Double-blind Treatment Period (Day 1 to Week 52)......................................................................77 
10.1.2.1 On-site Visits 6, 8, 10, 11, 12, 13, and 14 (Weeks 0, 4, 8, 12, 18, 26, and 39).............................78 
10.1.2.2 Telephone Visits 7 and 9 (Weeks 2 and 6)....................................................................................80 
10.1.2.3 On-site Visit 15 (Week 52) - end of treatment ...............................................................................80 
10.1.3 
Post-treatment follow-up period.....................................................................................................81 
10.1.3.1 On-site Follow-up Visit 16 (Week 54) ............................................................................................81 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................82 
10.2.1 
Source data to be found in patient’s file.........................................................................................82 
10.2.2 
Source data verification requirements for screen failures .............................................................82 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................82 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product................................83 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................83 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................83 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................84 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................84 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................85 
10.4.1 
Definitions of adverse events.........................................................................................................85 
10.4.1.1 Adverse event ................................................................................................................................85 
10.4.1.2 Serious adverse event ...................................................................................................................85 
10.4.1.3 Adverse event of special interest...................................................................................................86 
10.4.1.4 Events of special interest ...............................................................................................................87 
10.4.2 
General guidelines for reporting adverse events ...........................................................................88 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................88 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................89 
10.4.5 
Guidelines for reporting events of special interest.........................................................................89 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................89 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................90 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................90 
10.6.1 
Hypoglycemia.................................................................................................................................90 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 26 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 26 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................92 
11 
STATISTICAL CONSIDERATIONS..............................................................................................93 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................93 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................93 
11.3 
ANALYSIS POPULATIONS...........................................................................................................94 
11.3.1 
Efficacy populations .......................................................................................................................94 
11.3.2 
Intent-to-treat population................................................................................................................94 
11.3.3 
Safety population ...........................................................................................................................94 
11.4 
STATISTICAL METHODS .............................................................................................................95 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................95 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................95 
11.4.1.2 Compliance ....................................................................................................................................96 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................96 
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................96 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................98 
11.4.2.3 Analysis of other efficacy endpoints...............................................................................................98 
11.4.2.4 Multiplicity considerations ..............................................................................................................99 
11.4.3 
Analyses of safety data................................................................................................................100 
11.4.3.1 Analysis of adverse events ..........................................................................................................100 
11.4.3.2 Analysis of hypoglycemia.............................................................................................................101 
11.4.3.3 Analysis of adverse events of special interest .............................................................................102 
11.4.3.4 Analysis of events of special interest...........................................................................................102 
11.4.3.5 Analysis of laboratory variables ...................................................................................................102 
11.4.3.6 Analyses of vital sign variables ....................................................................................................102 
11.4.3.7 Analyses of 12-lead electrocardiogram status.............................................................................103 
11.4.3.8 Analyses of pharmacokinetic variables........................................................................................103 
11.5 
INTERIM ANALYSIS....................................................................................................................103 
12 
ETHICAL AND REGULATORY CONSIDERATIONS.................................................................104 
12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................104 
12.2 
INFORMED CONSENT ...............................................................................................................104 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE .................................................................................................................104 
13 
STUDY MONITORING.................................................................................................................106 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS .......................................................................106 
13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................106 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 27 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 27 
13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................106 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST ...........107 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................107 
14 
ADDITIONAL REQUIREMENTS.................................................................................................108 
14.1 
CURRICULUM VITAE..................................................................................................................108 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................108 
14.3 
CONFIDENTIALITY .....................................................................................................................108 
14.4 
PROPERTY RIGHTS...................................................................................................................109 
14.5 
INSURANCE COMPENSATION..................................................................................................109 
14.6 
DATA PROTECTION...................................................................................................................109 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................110 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................111 
14.8.1 
By the Sponsor.............................................................................................................................111 
14.8.2 
By the Investigator .......................................................................................................................111 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................111 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................111 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................113 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................114 
17 
APPENDICES..............................................................................................................................116 
APPENDIX A 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION....................................................................................................117 
APPENDIX B 
TREATMENT RELATED IMPACT MEASURE - DIABETES (TRIM-D) ............................120 
APPENDIX C RECOMMENDATIONS ON BASIC GENITOURINARY HYGIENE, MAINTAINING 
HYDRATION, AND RECOGNIZING DIABETIC KETOACIDOSIS..............................................122 
APPENDIX D MEASUREMENT OF BLOOD PRESSURE AND HEART RATE .....................................125 
APPENDIX E 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................127 
APPENDIX F PATIENT QUALITATIVE ASSESSMENT OF TREATMENT (PQAT) ...............................132 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 28 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 28 
2.1 
LIST OF TABLES 
Table 1 – Summary of investigational medicinal products............................................................................47 
Table 2 – Lantus titration regimen.................................................................................................................50 
Table 3 – Instruction for SMBG performed during the study.........................................................................51 
Table 4 – Blood safety parameters ...............................................................................................................66 
Table 5 – Samples identification ...................................................................................................................69 
 
2.2 
LIST OF FIGURES 
Figure 1 - Hypoglycemia classification in Study EFC14868..........................................................................91 
 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 29 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 29 
3 
LIST OF ABBREVIATIONS 
 
AE: 
adverse event 
AESI: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
BHB: 
beta-hydroxybutyrate 
BMI: 
body mass index 
BP: 
blood pressure 
BW: 
body weight 
CEC: 
Clinical Endpoint Commitee 
CGM: 
continuous glucose monitoring 
CI: 
confidence interval 
CRF: 
case report form 
CRO: 
contract research organization 
CSR: 
clinical study report  
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DILI: 
drug-induced liver injury 
DKA: 
diabetic ketoacidosis 
DMC: 
Data Monitoring Committee 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOS: 
end of study 
EOSI: 
events of special interest 
EOT: 
end of treatment 
FDA: 
Food and Drug Administration 
FPG: 
fasting plasma glucose 
FSH: 
follicle-stimulating hormone 
GCP: 
good clinical practice 
GI: 
gastrointestinal 
GLP-1: 
glucagon-like peptide-1 
GU: 
genitourinary 
HbA1c: 
hemoglobin A1C 
HLGT: 
high-level group term 
HLT: 
high level term 
HRT: 
hormone replacement therapy 
IB: 
Investigator's Brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
ID: 
identification 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 30 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 30 
IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ITT: 
intention-to-treat 
MACE: 
major adverse cardiac event 
MDRD: 
Modification of Diet in Renal Disease 
MI: 
myocardial infarction 
N: 
number (of observations) 
NIMP: 
noninvestigational medicinal product 
NPH: 
Neutral Protamine Hagedorn 
OAD: 
oral antidiabetes drug 
OC: 
observed cases 
PCSA: 
potentially clinically significant abnormality  
P-gp: 
P-glycoprotein 
PK: 
pharmacokinetic 
PQAT: 
Patient Qualitative Assessment of Treatment 
PRO: 
patient reported outcome 
PT: 
preferred term 
PYY: 
peptide YY 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SC: 
Steering Committee 
SD: 
standard deviation 
SE: 
standard error 
SGLT: 
sodium-glucose cotransporter 
SGLT1: 
sodium-glucose cotransporter type 1 
SGLT2: 
sodium-glucose cotransporter type 2 
SMBG: 
self-monitored blood glucose 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
T1D: 
type 1 diabetes 
T2D: 
type 2 diabetes 
TEAE: 
treatment-emergent adverse event 
TRIM-D: 
Treatment Related Impact Measure - Diabetes 
UACR: 
urinary albumin creatinine ratio 
ULN: 
upper limit of normal 
US: 
United States 
UTI: 
urinary tract infection 
VTE: 
venous thrombotic event 
WOCBP: 
women of childbearing potential 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 31 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 31 
4 
INTRODUCTION AND RATIONALE 
4.1 
BACKGROUND: SOTAGLIFLOZIN AND DISEASE 
Sotagliflozin is a dual inhibitor of the sodium-glucose cotransporters (SGLT) type 1 and 2 
(SGLT1 and SGLT2). Sotagliflozin is being developed for use in type 2 diabetes (T2D), a 
metabolic disorder characterized by hyperglycemia that results from a combination of increased 
insulin resistance and beta cell dysfunction (1). The microvascular complications of diabetes are 
well known and can result in impaired renal function, retinopathy, and neuropathy, while results 
of macrovascular complications are coronary artery disease, peripheral arterial disease, and stroke 
(2). Other comorbidities that are frequently associated with diabetes are hypertension, obesity, and 
cardiovascular (CV) disease. According to the most recent International Diabetes Federation 
Diabetes Atlas, it was estimated in 2015 that 1 in 11 adults have diabetes, equivalent to 
415 million people, which is estimated to rise to 642 million adults by 2040 (3). 
According to the World Health Organization, there are about 60 million people with diabetes in 
the European Region, or about 10.3% of men and 9.6% of women aged 25 years and over (4). 
While these numbers include both people with T2D and type 1 diabetes (T1D), over 90% of 
adults with diabetes have T2D. Diabetes is among the leading causes of death by disease and is a 
leading cause of heart disease, stroke, blindness, kidney disease, and amputation (3, 4). Despite 
the fact that the population of people with diabetes is growing, none of the current therapies is 
curative and the results of treatment are variable. 
Although lifestyle changes, including diet, exercise, and education, are valuable components of 
diabetes treatment, the vast majority of people with T2D must receive pharmacological therapy to 
control the disease. In the United States (US) and Europe, metformin is the standard first-line 
therapy in the absence of any contraindications or tolerability issues, as per guidance from the 
American Diabetes Association (5). 
Despite the numerous treatment options available, monotherapy fails in many patients as beta cell 
function continues to deteriorate leading to progressively increasing hyperglycemia. Aggressive 
glycemic control with the currently available agents often leads to side effects, most notably 
weight gain and an increased frequency of hypoglycemia. These concerns emphasize the need to 
develop new agents that effectively and safely lower glucose in diabetic patients (6). 
In patients with diabetes, it is desirable to maintain blood glucose in the normal range without 
exhausting the ability of the pancreatic beta-cells to produce insulin. Glucose is transported across 
the cell membrane by 2 different types of glucose transporters: glucose-facilitated transporters and 
SGLT proteins (7). In the kidney, after blood is filtered by the glomerulus, glucose passes into the 
urine, but 99% is reabsorbed, primarily via SGLT2, which is responsible for 90% of glucose 
reabsorption, while 10% is reabsorbed by SGLT1. When functional SGLT2 is lacking in humans, 
a significant amount of glucose remains in the urine and is removed from the body (8). This way 
of reducing blood glucose is an insulin-independent mechanism and therefore hyperglycemia may 
be reduced while the pancreas is spared from an increased demand for insulin production that is 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 32 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 32 
caused by hyperglycemia. Since obesity is a significant comorbidity in T2D, and insulin 
resistance is increased in obesity, the caloric loss from glucose in the urine may represent an 
additional benefit resulting in decreased weight, which should result in decreased insulin 
resistance (8). 
SGLT1 is expressed predominantly in the gastrointestinal (GI) tract and is responsible for the 
majority of glucose absorption by the small intestine (9). Inhibition of SGLT1 in the GI tract 
delays glucose absorption and lowers peak postprandial glucose levels (8). Additionally, there is 
accumulating evidence that SGLT1 inhibition stimulates secretion of glucagon-like peptide-1 
(GLP-1) and peptide YY (PYY), gut hormones involved in pancreatic beta cell function and 
appetite control, respectively. Reduced glucose absorption in the proximal intestine leads to more 
glucose being delivered distally, which allows L cells in both the ileum and the colon to sense 
glucose and its byproducts and, as a result, they secrete GLP-1 and PYY. Although a complete 
lack of functional SGLT1 may be associated with symptoms of glucose and galactose 
malabsorption (10), pharmacologic inhibition of SGLT1 by sotagliflozin has not produced these 
effects in preclinical models or patients with T2D. Selective inhibitors of the SGLT1 transporter 
are in early stages of development. 
Extensive clinical studies conducted for selective SGLT2 inhibitors have established this class as 
effective agents for the treatment of T2D (6, 11) and have led to approvals by the US Food and 
Drug Administration (FDA) and the European Medicines Agency. Studies with sotagliflozin, a 
dual inhibitor of SGLT1 and SGLT2, have shown that this agent produces significant glucosuria 
in preclinical animal models, healthy human volunteers, and patients with T2D. Single- and 
multiple-dose administration of sotagliflozin to healthy human patients has resulted in 
dose-dependent increases in glucosuria. Multiple-dose (28-day) administration in diabetic patients 
produced improvements in several metabolic parameters, including urinary glucose excretion, 
fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), GLP-1, and PYY (12). These data 
suggest that sotagliflozin should be of therapeutic benefit to patients with T2D. 
4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS 
Approximately 840 subjects (698 assigned to sotagliflozin and 229 assigned to placebo) have 
participated in completed clinical studies of sotagliflozin. No significant safety concerns have 
been identified in the sotagliflozin drug program, and sotagliflozin has been well-tolerated in all 
studies to date. Serious adverse events (SAEs) and discontinuations due to adverse events (AEs) 
have been infrequent and have been balanced between treatment and comparator groups. Reports 
of treatment-emergent adverse events (TEAEs) across all sotagliflozin studies for which data are 
available were generally balanced between treatment and comparator groups. The most frequently 
reported TEAEs (≥2.0%) were headache, nausea, diarrhea, constipation, dizziness, and upper 
respiratory tract infection, all of which were reported at a frequency greater than placebo. 
However, the majority were described as mild to moderate, and most resolved spontaneously and 
without discontinuation of the study drug. 
In completed and ongoing clinical trials, no additional safety issues beside those already described 
in the current Investigator’s Brochure (IB) have been observed. In general, no significant 
imbalances of SAEs/AEs between sotagliflozin and comparators were observed in completed 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 33 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 33 
studies. Cumulatively, across the completed studies, 8 SAEs were reported in 6 patients 
(4 patients with T2D and 2 with T1D), all of which were assessed as unrelated to study drug; 
those reported in 4 patients with T2D who received sotagliflozin included pulmonary embolism, 
deep vein thrombosis, bile duct stone, cholangitis and lower limb fracture, while a patient 
receiving placebo had a myocardial infarction (MI). Two SAEs of diabetic ketoacidosis (DKA) 
were reported in 2 patients with T1D in the ongoing (blinded) Phase 2 T1D study (LX4211.1-203-
TIDM) using insulin pumps; in each case basal insulin was within 7% of Baseline, and both SAEs 
were assessed as due to failure of insulin delivery via insulin pump. Both cases were associated 
with high blood glucose readings >300 mg/dL, a finding expected in DKA and notable in that this 
value did not appear to be masked by sotagliflozin treatment. 
A drug interaction study with digoxin, a sensitive P-glycoprotein (P-gp) substrate, indicated that 
sotagliflozin acts as a weak P-gp inhibitor. Thus, sotagliflozin increases systemic exposure of 
digoxin and could also increase the exposure of other P-gp substrates. Patients taking sotagliflozin 
with concomitant digoxin should have digoxin concentrations monitored and doses reduced as 
needed. In addition, other P-gp substrates may be affected and the labels of P-gp substrate drugs 
should be consulted with regards to monitoring and dose adjustments. 
Safety, tolerability, pharmacokinetic (PK) and pharmacodynamic effects of sotagliflozin are 
supported by Phase 1 and Phase 2 studies and animal toxicology data in rats up to 26 weeks and 
dogs up to 39 weeks as well as 2-year carcinogenicity data in rats. 
More information on the safety of sotagliflozin and on the clinical program can be found in the 
IB. 
4.3 
RATIONALE FOR SELECTION OF DOSE 
Both the 200 mg and 400 mg doses are being developed in the Phase 3 program for sotagliflozin 
for the treatment of T2D. These doses are being tested in several Phase 3 trials, including the 
current trial in patients with T2D and inadequate glycemic control. 
The proposed sotagliflozin 200 mg and 400 mg once daily doses are based on the results of the 
Phase 2b study LX4211.1-202-DM. In this study sotagliflozin doses of 75 mg once daily, 200 mg 
once daily, 200 mg twice daily, and 400 mg once daily were tested over a 12-week, double-blind 
period. The sotagliflozin 200 mg and 400 mg once daily doses were chosen for further evaluation 
based on their HbA1c lowering effects and the overall safety and tolerability observed at these 
doses. At 12 weeks, the 200 mg and 400 mg once daily doses lowered HbA1c by a mean of 0.52% 
and 0.93%, respectively (p <0.001 for both arms), while placebo lowered HbA1c by a mean of 
0.14%. Sotagliflozin also produced statistically significant reductions in body weight (BW) 
(200 mg and 400 mg doses) and systolic blood pressure (SBP) (400 mg dose). 
The overall incidences of AEs on sotagliflozin 200 mg and 400 mg once daily doses were similar 
to placebo. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 34 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 34 
From a safety perspective, sotagliflozin was well-tolerated across studies. In healthy subjects, 
sotagliflozin was well-tolerated following single doses up to 2000 mg, and in multiple doses up to 
800 mg over 10 days. Furthermore, in a thorough QT study, single doses of sotagliflozin (800 mg 
and 2000 mg) were well-tolerated and did not prolong the QT interval. Additionally, evaluation of 
metabolites in urine and plasma of healthy subjects resulted in no safety concerns following single 
doses of 400 mg sotagliflozin. In patients with T2D, single doses of 400 mg in combination with 
sitagliptin, and multiple doses up to 400 mg in combination with metformin over 12 weeks were 
also well-tolerated. 
4.4 
RATIONALE FOR STUDY DESIGN AND CONTROL GROUPS 
This study is designed to assess the efficacy and safety of sotagliflozin (compared to placebo) 
when used as add-on therapy to basal insulin (Lantus), alone or in combination with oral 
antidiabetes drugs (OADs). Patients will be switched from their current basal insulin to Lantus 
(1:1 dose conversion, or 20% reduction if on treatment with Toujeo or Neutral Protamine 
Hagedorn [NPH] twice daily) and will have a 4-week dose titration period to improve their basal 
insulin dose prior to Randomization, utilizing a standard titration algorithm. During this period, 
compliance with the algorithm will be reviewed by an internal group blinded to the treatment 
assignment and investigators will be contacted as needed to encourage adherence to titration 
algorithm. During this Lantus titration period, the dose of concomitant OADs should stay 
unchanged, except if decreases are needed due to hypoglycemia. 
The primary endpoint is HbA1c reduction from Baseline to Week 18 because it is expected that 
sotagliflozin can provide significant additional glycemic efficacy even in an advanced T2D 
population with presumed beta cell failure. During the first 18 weeks no adjustment of Lantus is 
permitted (except for safety reasons or if rescue criteria are met) to enable the assessment of the 
effect of randomized treatment drug on top of a stable background therapy of insulin ±OADs. 
After Week 18, titration of Lantus may resume following the same titration algorithm utilized 
during the Run-in period. This will enable the assessment of the effect of the randomized study 
drug in a context of total dose of insulin being simultaneously adjusted and more typical of a 
real-world setting. Prandial insulin or GLP-1 agonists will be the recommended rescue therapy for 
patients on a stable regimen of oral antihyperglycemic agents who cannot adequately achieve 
glycemic control by up-titrating their Lantus dose, as per international diabetes treatment 
guidelines (13, 14). However, the investigator will be allowed to choose from any antidiabetic 
agent (with the exception of the SGLT2 inhibitors class) according to their clinical judgment and 
in line with the local standard of care. The protocol stipulates that patients be provided rescue 
therapy according to increasingly stringent hyperglycemia criteria (based on FPG and/or HbA1c) 
as aligned with regulatory guidance (15). 
Randomization will be stratified based on HbA1c at Week -1 (≤8.5%, >8.5%), SBP at Week -1 
(<130 mmHg, ≥130 mmHg), and use of sulfonylureas at Week -1 (yes, no), to achieve balanced 
randomization for assessment of the primary and main secondary study endpoints. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 35 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 35 
A placebo control will be used to allow for an unbiased assessment of treatment effects and safety 
data. Bias will be minimized by randomizing the patients to treatment groups, blinding the 
patients, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating 
endpoints in a blinded fashion. 
Two Patient Reported Outcomes (PROs) will be assessed in this trial. The Patient Qualitative 
Assessment of Treatment (PQAT) will be assessed at Week 18 and at the final on-treatment visit 
(Week 52). This instrument includes a 7-point Likert Scale for the patient to evaluate his/her 
subjective response to the treatment (-3 to +3 including 0 for a neutral response) and 2 free-text 
response questions to describe key advantages and disadvantages. The Treatment Related Impact 
Measure – Diabetes (TRIM-D) includes questions related to satisfaction with weight and 
hypoglycemia; it will be assessed at Screening, at Baseline (after the Lantus titration phase), and 
at several visits during the Treatment Period. 
A continuous glucose monitoring (CGM) substudy is planned to include a subset of patients. This 
study will allow assessing the impact of sotagliflozin on additional parameters of glucose control 
and variability over 24 hours which cannot be inferred by the HbA1c as an aggregate measure of 
overall glycemic control. The details of the CGM substudy are specified in the separate substudy 
protocol. 
4.5 
BENEFIT/RISK OF SOTAGLIFLOZIN 
Sotagliflozin is currently being investigated as an adjunct to diet and exercise to improve 
glycemic control in adults with T2D. The development program will also provide efficacy and 
safety data for sotagliflozin in combination with other antidiabetes medications. In addition, the 
program will evaluate clinical outcomes in patients with high CV risk and in patients with renal 
impairment. The use of sotagliflozin in the treatment of T1D is also being studied in a separate 
development program. 
Sotagliflozin may benefit a wide variety of diabetic patients based on multiple potential beneficial 
effects of dual SGLT1/SGLT2 inhibition, and its insulin-independent mechanism of action. 
Improvements in HbA1c, FPG, and postprandial glucose were observed with sotagliflozin in 
multiple studies. As anticipated from the mechanism of action, treatment with sotagliflozin 
resulted in increased urinary glucose excretion (from inhibition of SGLT2) as well as increased 
levels of the intestinal peptides GLP-1 and PYY (from inhibition of SGLT1). In addition, the 
improvements in BW and blood pressure (BP) observed with sotagliflozin treatment have the 
potential to benefit patients with diabetes through their effects on common diabetic comorbidities. 
Phase 2 data indicated that sotagliflozin may reduce SBP by 10 to 15 mmHg in patients with SBP 
≥130 mmHg at Baseline, while having no significant effect in patients with SBP <130 mmHg, and 
did not induce hypotension in normotensive patients. Since this could be of benefit to patients 
with T2D, this finding is being followed up as a secondary objective in this trial. 
Additionally, the insulin-independent glucose lowering mechanism can result in an insulin sparing 
effect and consequently reduce the insulin requirements of patients managed with basal insulin. 
This outcome can result in a clinical benefit in patients on insulin therapy by lowering the risk of 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 36 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 36 
hypoglycemia and weight gain associated with higher insulin doses. Also, the reduction in glucose 
levels can also delay the need for initiation of rescue treatment, which can include prandial insulin 
and GLP-1 receptor agonists. 
SGLT2 inhibitors class have been associated with small decreases of glomerular filtration rate and 
increased rate of genital infections, which are usually mild and well tolerated in clinical trials. 
Overall, sotagliflozin has been well-tolerated in all studies to date, with the majority of events 
assessed as mild to moderate; most of which resolved spontaneously. Serious AEs and 
discontinuations due to AEs have been limited and balanced between treatment and comparator 
groups. 
Events of special interest (EOSI) are evaluated based on either their potential link to the drug’s 
mechanism of action, events that occur in other SGLT-inhibitor drugs, or regulatory 
interest/guidance for diabetes products, but found not to be in imbalance in clinical trials. In 
addition to the identified and potential risks (genital mycotic infections [male and female], 
metabolic acidosis, DKA, urinary tract infections [UTIs], volume depletion, severe hypoglycemia) 
for the sotagliflozin program, other EOSI have been defined. These EOSI are: major adverse 
cardiac events (MACEs) and other CV events, venous thrombotic events (VTEs), drug-induced 
liver injuries (DILIs)/alanine aminotransferase (ALT) increase >3 times the upper limit of normal 
(ULN), diarrhea, pancreatitis, bone fractures, renal events, malignancies of special interest 
(including but not limited to: breast, bladder, renal cell, Leydig cell, pancreatic, prostate and 
thyroid cancer), and AEs leading to amputation. 
However, reports of these events have been infrequent and have responded to standard treatment. 
The improvement in glycemic control, the reductions in weight and BP, and the tolerability and 
safety profile of sotagliflozin to date demonstrate a favorable benefit-risk assessment for 
sotagliflozin. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 37 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 37 
5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To demonstrate the superiority of sotagliflozin 400 mg versus placebo with respect to HbA1c 
reduction at Week 18 in patients with T2D who have inadequate glycemic control on basal insulin 
alone or with OADs. 
5.2 
SECONDARY 
• 
To assess the effects of sotagliflozin 400 mg versus placebo on: 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all patients 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
• 
To assess the effects of sotagliflozin 200 mg versus placebo on: 
- 
Change from Baseline to Week 18 in HbA1c 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 18 in FPG. 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
• 
To evaluate the safety of sotagliflozin 400 mg and 200 mg versus placebo throughout the 
52-week trial. 
5.3 
OTHER 
• 
To assess the effects of sotagliflozin 400 mg versus placebo on the proportion of patients 
with HbA1c <7.0% or HbA1c <6.5% at Weeks 18, 26, and 52 
• 
To assess the effects of sotagliflozin 200 mg versus placebo on the proportion of patients 
with HbA1c <7.0% or HbA1c <6.5% at Weeks 18, 26, and 52 
• 
To assess the effects of sotagliflozin 200 mg versus placebo on the change from Baseline 
to Week 12 in SBP for all patients 
• 
To assess the effects of sotagliflozin 400 mg and 200 mg versus placebo on: 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 38 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 38 
- 
Change from baseline to Week 26 in HbA1c 
- 
Change from Baseline to Weeks 26 and 52 in SBP in all patients and the subset of 
patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Weeks 12, 26, and 52 in SBP in patients with Baseline SBP 
<130 mmHg 
- 
Change from Baseline to Weeks 12, 26, and 52 in diastolic blood pressure (DBP) for 
all patients and the subset of patients with Baseline DBP ≥80 mmHg 
- 
Change from Baseline to Week 52 in the total daily insulin dose 
- 
Proportion of patients requiring rescue therapy during the 52-week double-blind 
Treatment Period 
- 
Change from Baseline to Weeks 18 and 52 on 7-point Self-Monitored Blood Glucose 
(SMBG) profile (mean daily value at each time point)  
- 
Change from Baseline on estimated glomerular filtration rate (eGFR) 
- 
Change from Baseline in urinary albumin creatinine ratio (UACR) 
- 
Patient Qualitative Assessment of Treatment (PQAT) during the 52-week Treatment 
Period 
- 
Patient perception of treatment impact and satisfaction using the TRIM-D during the 
52-week Treatment Period. 
• 
To assess plasma concentrations of sotagliflozin and its 3-O-glucuronide metabolite. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 39 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 39 
6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This study is a Phase 3, multicenter, randomized, double-blind (with single-blind Run-in Phase), 
placebo-controlled, parallel-group study that is anticipated to enroll approximately 560 patients. 
The study will consist of 3 periods: 1) an up to 6-week Screening Period comprised of a Screening 
phase of up to 2 weeks and a 4-week Lantus titration/single-blind placebo titration Run-in Phase; 
2) a 52-week double-blind Treatment Period; and 3) a 2-week, post-treatment Follow-up Period. 
The study design is presented graphically in Section 1.1. 
In the United States, a substudy employing CGM technology will be performed to assess detailed 
glycemic profiles. The details of the CGM substudy procedures, endpoints and statistical analyses 
will be provided in a separate substudy protocol. 
6.1.1 Screening period 
6.1.1.1 Screening phase (Visit 1) 
The Screening phase will last up to 2 weeks. The period must be long enough to collect the data 
required to establish whether the patient satisfies the inclusion/exclusion criteria. 
Patients with T2D (16) will be included in this study if at Screening they have inadequate 
glycemic control (as demonstrated by a mean HbA1c ≥7.5% or HbA1c ≤10.5%), despite use of 
basal insulin (at a total daily dose that has been stable within ±20% of the dose at Screening for 
8 weeks inclusive). Patients may also be using up to any 2 OADs which may include metformin at 
a dose of at least 1500 mg/day or the maximum tolerated dose (documented). 
At the Screening Visit after signing of the informed consent form (ICF), eligibility criteria will be 
assessed, and Screening assessments will be performed. Women of childbearing potential 
(WOCBP) not willing to use highly effective contraceptive method(s), and/or who are 
unwilling or unable to be tested for pregnancy during the study will be excluded; guidance on 
highly effective contraceptive methods and collection of pregnancy information is provided in 
Appendix A. If another contraceptive method is used (such as a barrier method), it should be used 
in combination with one of the highly effective methods described in Appendix A (such as an oral 
contraceptive). 
The interactive response technology (IRT; either Interactive Voice Response System or 
Interactive Web Response System) will be contacted at Visit 1 for notification of Screening and 
for patient number allocation. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 40 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 40 
6.1.1.2 Run-in phase (Visits 2 to 5) 
The Lantus titration/single-blind placebo Run-in Phase will last 4 weeks. If the patient satisfies 
the entry criteria during the Screening phase, the basal insulin that the patient is currently taking 
will be replaced by Lantus (Section 8.2.1) provided by the Sponsor. A 4-week Lantus 
optimization phase will commence. 
During the 4-week Lantus titration/single-blind placebo Run-in Phase, patients will also take 
single-blind placebo (2 tablets, identical to sotagliflozin 200 mg in appearance) once daily before 
the first meal of the day, starting from Visit 2. 
6.1.2 Double-blind Treatment Period (Day 1 to Week 52) 
Eligible patients will be randomized on Day 1 (Visit 6). In order to qualify for randomization, 
patients must have an HbA1c value ≥7.0% at Week -1 (Visit 5) and must demonstrate compliance 
at the end of the single-blind placebo Run-in Phase based upon tablet count (≥80%), and as 
assessed at the Investigator’s discretion. 
Randomization will be stratified by: 
• 
HbA1c at Week -1 (≤8.5%, >8.5%) 
• 
SBP at Week -1 (<130 mmHg, ≥130 mmHg) 
• 
Sulfonylureas use at Week -1 (yes, no). 
Following randomization, patients will be treated in a double-blind manner for 52 weeks. A total 
of 560 patients ≥18 years of age (or ≥legal age of majority if greater) will be randomly assigned 
2:1:1 to the following 3 treatment groups: 
• 
Sotagliflozin 400 mg, given as two (2) 200-mg tablets, once daily before the first meal of 
the day (N = 280 patients) 
• 
Sotagliflozin 200 mg, given as one (1) 200-mg tablet and one (1) placebo tablet (identical 
to sotagliflozin 200 mg in appearance), once daily before the first meal of the day 
(N = 140 patients) 
• 
Placebo, given as two (2) placebo tablets (identical to sotagliflozin 200 mg in appearance), 
once daily before the first meal of the day (N = 140 patients). 
The doses of the OADs (if applicable) should be held constant throughout the entire 52-week 
double-blind Treatment Period (ie, not changed except for safety reasons), and the dose of all 
antihypertensive medications should be held constant for the first 12 weeks (until Visit 11) except 
for safety reasons. 
The dose of Lantus should be held constant for the first 18 weeks unless glycemic rescue criteria 
are satisfied (Section 8.2.1.4). Insulin titration resumes after Visit 12. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 41 of 365




Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 42 
Detailed activities and responsibilities for the SC are provided in the SC Charter. 
6.3.2 Data monitoring committee 
A DMC with members who are independent from the Sponsor and the Investigators will meet on 
a regular basis, and will be responsible for: 
• 
Review of accumulating clinical trial safety data by treatment 
• 
Making a recommendation to the Sponsor regarding the study following each meeting. 
Safety data to be reviewed will include events and outcomes described below for adjudication, as 
well as any additional safety data considered relevant. Details describing the DMC processes and 
procedures are outlined in a separate DMC Charter. To maintain continuous blinding and study 
integrity, the analysis will be conducted by an independent statistician, and measures will be taken 
to ensure the validity of the data. 
6.3.3 Clinical endpoint committee(s) 
The Clinical Endpoint Committees (CECs) is/are comprised of experts in cardiology and 
nephrology (and other appropriate medical specialties such as neurology and endocrinology as 
needed) who are independent of the Sponsor and the contract research organization (CRO). The 
CEC(s) will review and adjudicate all deaths, MACE/selected CV events (MI, stroke, unstable 
angina leading to hospitalization, and heart failure leading to hospitalization), selected renal 
events, bone fracture, and DKA. 
The details regarding the CEC processes and procedures will be outlined in the CEC Charter(s). 
6.3.4 Safety adjudication of events requiring ongoing monitoring 
Two independent committees will review safety events that require ongoing monitoring to ensure 
timing protocol amendments in case a safety signal is identified. These events are: 1) potential 
cases of DILI, and 2) cases of amputations.  
The 2 committees will review the cases in a treatment-blinded manner and will present their 
assessment to the DMC. 
The members, roles and responsibilities of the two committees will be described in a separate 
Charter. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 43 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 43 
7 
SELECTION OF PATIENTS 
Note: A patient should not be randomized more than once. In cases where original screen failure 
was due to reasons expected to change at rescreening and based upon the Investigator’s clinical 
judgment, the patient can be rescreened once prior to entering Run-in for this study. 
7.1 
INCLUSION CRITERIA 
I 01. Patients with T2D using any types of basal insulin alone or in combination with up to 
2 OADs 
I 02. Patient has given written informed consent to participate in the study in accordance with 
local regulations. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 4 subsections: 
7.2.1 Exclusion criteria related to study methodology 
E 01. At the time of Screening age <18 years or <legal age of majority, whichever is greater. 
E 02. Body Mass Index (BMI) ≤20 or >45 kg/m2 at the Screening Visit. 
E 03. Use of systemic glucocorticoids (excluding topical, intra-articular, or ophthalmic 
application, nasal spray or inhaled forms) for more than 10 consecutive days within 
90 days prior to the Screening Visit. 
E 04. Use of weight loss medications within 12 weeks or weight change of 5 kg or more during 
the 12 weeks before Screening. 
E 05. Likelihood of requiring treatment during the study period with drugs not permitted by the 
study protocol (eg, long-term systemic glucocorticoids) and refusing or unable to take 
alternative treatment. 
E 06. Patients who have previously been randomized in any clinical trial of 
sotagliflozin/LX4211. 
E 07. Patients with severe anemia, severe CV (including congestive heart failure New York 
Heart Association IV), respiratory, hepatic, neurological, psychiatric, or active malignant 
tumor or other major systemic disease or patients with short life expectancy that, 
according to the Investigator, will preclude their safe participation in this study, or will 
make implementation of the protocol or interpretation of the study results difficult. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 44 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 44 
E 08. Current diagnosis of chronic hepatitis, and/or other clinically active liver disease requiring 
treatment. 
E 09. Known presence of factors that interfere with the Central Lab HbA1c measurement (eg, 
genetic Hb variants) compromising the reliability of HbA1c assessment or medical 
conditions that affect interpretation of HbA1c results (eg, blood transfusion or severe 
blood loss in the last 3 months prior to randomization, any condition that shortens 
erythrocyte survival). 
E 10. History of drug or alcohol abuse within 6 months prior to Screening. 
E 11. Patient is an employee of the Sponsor, or is the Investigator or any Sub-investigator, 
research assistant, pharmacist, study coordinator, other staff or relative thereof directly 
involved in conducting the study. 
E 12. Patient who has taken other investigational drugs or prohibited therapy for this study 
within 12 weeks or 5 half-lives from prior to Screening, whichever is longer.  
7.2.2 Exclusion criteria related to the diabetes history and treatment 
E 13. Type 1 diabetes mellitus. 
E 14. HbA1c <7.5% or HbA1c >10.5% measured by the central laboratory at Screening. 
E 15. Use of a selective SGLT2 inhibitor (eg, canagliflozin, dapagliflozin, or empagliflozin) 
within 3 months prior to the trial. 
E 16. History of DKA or nonketotic hyperosmolar coma within 12 weeks prior to the Screening 
Visit. 
E 17. History of severe hypoglycemia resulting in unconsciousness, seizure or hospitalization 
within 6 months prior to the Screening Visit. 
E 18. For patients using metformin or other OADs, contraindication to metformin or the other 
OADs as per local labeling. 
E 19. Use of injectable diabetes drugs other than basal insulin (eg, insulin glargine, NPH, 
detemir, or degludec), ie, prandial or rapid-acting insulins, short-acting insulins, GLP-1 
receptor agonists, or inhaled prandial insulin (Afrezza) within 8 weeks of Screening. 
E 20. OAD dose not stable for 8 weeks before Screening. 
E 21. Use of basal insulin therapy (eg, insulin glargine, NPH, detemir, or degludec) for less than 
6 months before Screening. 
E 22. Dose of basal insulin (eg, insulin glargine, NPH, detemir, or degludec) not stable for 
8 weeks before Screening (ie, total daily insulin dose increased or decreased by more than 
20%). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 45 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 45 
E 23. Known unstable proliferative diabetic retinopathy or any other rapidly progressive 
diabetic retinopathy or macular edema that is likely to require laser, surgical treatment 
during study period. 
7.2.3 Exclusion criteria related to the current knowledge of sotagliflozin 
E 24. Pregnant (confirmed by serum pregnancy test at Screening) or breastfeeding women. 
E 25. Women of childbearing potential not willing to use highly effective method(s) of birth 
control during the study treatment period and follow-up period, or who are unwilling or 
unable to be tested for pregnancy (see Appendix A), during the study. 
E 26. Mean of 3 separate BP measurements >180 mmHg (SBP) or >100 mmHg (DBP). 
E 27. History of hypertensive emergency within 12 weeks prior to Screening. 
E 28. History of gastric surgery including history of gastric banding or inflammatory bowel 
disease within 3 years prior to the Screening Visit. Note: Patients who have had bariatric 
surgery or gastric banding more than 3 years prior to the Screening Visit must have a 
stable weight (±10%) for 6 months prior to the Screening Visit. 
E 29. Difficulty swallowing such that the patient cannot take the IMP. 
E 30. Known allergies, hypersensitivity, or intolerance to SGLT2 inhibitor or any inactive 
component of sotagliflozin or placebo (ie, microcrystalline cellulose, croscarmellose 
sodium [disintegrant], talc, silicone dioxide, and magnesium stearate [nonbovine]), unless 
the reaction is deemed irrelevant to the study by the Investigator. 
E 31. Renal disease as defined by eGFR of <30 mL/min/1.73m2 at Screening by the 4 variable 
Modification of Diet in Renal Disease (MDRD) equation. 
E 32. Laboratory findings with the central lab tests at Visit 1 
• 
ALT or aspartate aminotransferase (AST) >3 times the ULN laboratory range 
• 
Total bilirubin >1.5 times the ULN (except in case of Gilbert’s syndrome) 
• 
Neutrophils <1500/mm3 (or according to ethnic group) and/or platelets <100 000/mm3 
• 
Amylase and/or lipase >3 times the ULN. 
E 33. Any country-related specific regulation that would prevent the patient from entering the 
study (eg, individuals committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 46 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 46 
7.2.4 Additional exclusion criteria during or at the end of the Run-in Phase before 
Randomization 
E 34. Patients unwilling or unable to perform SMBG (failure to perform at least 3 fasting 
SMBG per week during Run-in), complete the patient diary, or comply with study visits 
and other study procedures as required per protocol. 
E 35. HbA1c <7% measured by the central laboratory at Visit 5 (Week -1). 
E 36. Informed consent withdrawal before randomization (patient who is not willing to continue 
or fails to return). 
E 37. Any clinically significant abnormality identified on physical examination, laboratory 
tests, electrocardiogram (ECG) or vital signs at the time of screening or any AE during 
screening period which, in the judgment of the Investigator or any Sub-investigator, 
would preclude safe completion of the study or constrains efficacy assessment. 
E 38. Patient insufficiently compliant during Run-in Phase based upon tablet count (<80%) or 
in the opinion of the Investigator. 
E 39. Lower extremity complications (such as skin ulcers, infection, osteomyelitis and 
gangrene) identified during the Screening period, and still requiring treatment at 
Randomization. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 47 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 47 
8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The IMPs are sotagliflozin 400 mg, sotagliflozin 200 mg, and matching placebo. Patients will be 
provided with kits containing wallets of sotagliflozin or sotagliflozin-matching placebo (supplied 
as tablets identical to sotagliflozin 200 mg in appearance). 
Each patient will be supplied with the appropriate number of kit according to the dispensing 
scheme indicated in the study flowchart (see Section 1.2).  
A summary of the IMP (dose and timing) is provided in Table 1. 
Table 1 – Summary of investigational medicinal products 
IMP: 
Sotagliflozin 200 mg 
Sotagliflozin 400 mg 
Placebo group 
Name of IMP 
Sotagliflozin (SAR439954) 
Sotagliflozin (SAR439954) 
Placebo 
Pharmaceutical 
form 
Sotagliflozin (SAR439954) will 
be supplied as 200-mg tablets 
Sotagliflozin (SAR439954) will 
be supplied as 200-mg tablets 
Placebo will be supplied as 
tablets (identical to sotagliflozin 
200 mg in appearance) 
Dose, timing, and 
route of 
administration 
Sotagliflozin 200 mg group: 
One 200-mg tablet, taken orally 
once daily, before the first meal 
of the day 
One placebo tablet, taken orally 
once daily, before the first meal 
of the day 
Sotagliflozin 400 mg group: 
Two 200-mg tablets, taken orally 
once daily, before the first meal 
of the day 
Placebo group: 
Two placebo tablets, taken orally 
once daily, before the first meal 
of the day 
Duration of 
treatment 
52-week double-blind Treatment 
Period following randomization 
52-week double-blind Treatment 
Period following randomization 
4 weeks Run-in and 52 weeks 
following randomization 
Storage conditions 
Store between +15°C and +30°C (59°F and 86°F) 
IMP = Investigational medicinal product 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT 
Noninvestigational medicinal product (NIMP) treatment is defined as the rescue medication that 
will be used to treat hyperglycemia when a patient’s hyperglycemia reaches the rescue threshold 
and the mandatory background therapy (Lantus [see Section 8.2.1]), and/or the patients’ existing 
OADs (metformin [see Section 8.2.2]; other OADs [see Section 8.2.3]). The recommended rescue 
medication is the initiation of prandial injection of short-acting insulin or GLP-1 agonists, or 
another antidiabetic agent (except SGLT2 inhibitors) as per the Investigator’s discretion and in 
line with local treatment guidelines (see Section 8.2.4). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 48 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 48 
8.2.1 Lantus (insulin glargine 100 U/mL) 
All patients will use the study provided basal insulin, Lantus (insulin glargine 100 U/mL), starting 
from Visit 2 (beginning of the single-blind Run-in Phase) and continuing throughout the entire 
Run-in Phase and double-blind Treatment Period. Lantus will be supplied as a sterile, 
non-pyrogenic, clear, colorless solution in the marketed Lantus SoloStar prefilled (disposable) pen 
(insulin glargine 100 U/mL solution for subcutaneous injection) specifically labeled for use in this 
study. The disposable self-injector prefilled pens will be provided to each patient entering in the 
single-blind Run-in Phase at Visit 2. 
Each Lantus SoloStar contains 300 units of insulin glargine (3.0 mL of 100 U/mL insulin glargine 
solution) in total. This pen allows dose setting in the range of 1 to 80 units with a minimum 
increment of 1 unit. Dosing and dose adjustments should be performed according to details 
provided in Section 8.2.1.1, Section 8.2.1.2, Section 6.1.1.2 and Section 6.1.2. Each patient will 
be supplied with the appropriate number of pens according to the dispensing scheme indicated in 
the study flow chart (see Section 1.2). (Patients will be provided with kit containing 5 prefilled 
pens.) 
Pen-device related issues (malfunctions) should be reported to the Sponsor by the means of a 
procedure on Product Technical Complaint forms, which are described in a separate manual. 
8.2.1.1 Dosage schedule 
Lantus will be administered once a day. Patients should keep their existing basal insulin 
administration time (eg, morning or evening dosing) for Lantus dosing time. If a dose greater than 
80 units is required, it may be given as two or more consecutive subcutaneous injections at the 
same dosing time with daily dose split in equal or close to equal doses. Patients who are receiving 
NPH (or any other basal insulin) twice daily prior to Screening should administer Lantus once a 
day either in the morning or evening, following the Investigator’s advice since the beginning of 
Run-In. However, once the NIMP Lantus starts, the patients should not change the injection time 
during the study course. Lantus should be given at the same time daily within a ±1 hour window, 
which should be maintained for the duration of the study. 
Lantus should be administered by deep subcutaneous injection, alternating between the left and 
right anterolateral and left and right posterolateral abdominal wall or thighs or upper arms. Within 
a given area, location should be changed (rotated) at each time to prevent injection site skin 
reactions. 
8.2.1.2 Starting dose 
From Visit 2 (start of the single-blind Run-in period) all patients will receive Lantus as basal 
insulin. Patients who are already receiving Lantus prior to the study will start Run-in (Visit 2) at 
their pre-study dose level. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 49 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 49 
Patients who are receiving any basal insulin other than Lantus before Screening will switch to 
Lantus once a day. For patients who are using long-acting insulin analogs other than Lantus (eg, 
Levemir, Tresiba, Basaglar) the existing basal insulin will be converted to an equivalent dose of 
Lantus on a 1:1 unit basis (ie, the same dose on the day before Visit 2). If the patient is using 
Toujeo (glargine U-300/mL), the initial Lantus dose is 80% of the existing Toujeo dose as 
recommended in the Lantus label. If the patient is using NPH twice daily, it’s recommended that 
the converted Lantus dose should be reduced by 20% and given once daily. (If using NPH once a 
day, it can be converted to Lantus unit-to-unit.) 
8.2.1.3 Dose titration and modification 
Lantus will be titrated during the 4-week single-blind Run-in Phase and if necessary after 
18 weeks of the core Treatment Period to reach and maintain the target fasting glucose. 
The target range for fasting (pre-breakfast/pre-injection if available) blood glucose is 
80-100 mg/dL (4.4 to 5.6 mmol/L) avoiding hypoglycemia. 
During Run-in (Week -4 to Week -1): after initiating the study provided basal insulin, Lantus, 
the insulin dose will be up-titrated every 3 days (twice per week) until the patient reaches the 
target fasting blood glucose according to the recommended regimen (Table 2). The dose 
adjustments will be made in consultation with the study site either at site visits, phone visits, or 
unscheduled phone contacts. At the end of Run-in, patients with HbA1c ≥7.0% measured at 
Visit 5 (Week -1) are eligible to be randomized to receive the IMP treatment (sotagliflozin 
200 mg, sotagliflozin 400 mg or placebo) on top of Lantus.  
During the randomized core Treatment Period (Weeks 0 to 18): no insulin titration should be 
implemented.  
For patients with HbA1c <7.5% measured at Week-1, a 10% reduction in the Lantus dose at the 
randomization may be considered by the Investigator as needed, to reduce a potential risk of 
hypoglycemia. 
Lantus daily dose will remain stable (< ±10% from the dose at randomization, or < ±4 units, 
whichever is less) unless it is deemed necessary by the investigator to reduce or increase the dose 
for safety reasons (ie, severe hypoglycemia or AE/SAE) or the patient has met the hyperglycemic 
threshold for rescue therapy. In such a case, rescue assessment will apply and be implemented 
(Section 8.2.4). Increase and optimization in Lantus dose will be the first step of rescue therapy 
prior to initiation of prandial insulin or GLP-1 receptor agonists. 
After the core Treatment Period (Weeks 19 to 52): if the target fasting SMBG level is not 
achieved at the end of Week 18, insulin dose should be continuously up-titrated to maintain the 
fasting SMBG in the target range until the EOT. Titration will be done on a weekly basis, or as 
frequently as deemed necessary by the Investigator. 
Lantus dose adjustment is based on fasting SMBG values using study glucose meter that displays 
results already converted to plasma glucose concentration. Regular self-monitoring of plasma 
glucose is very important in order to achieve the blood glucose targets. It is recommended to 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 50 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 50 
perform daily fasting/pre-breakfast SMBG to support Lantus titration process during the 4-week 
Run-in period and less frequent afterward during the Treatment Period (Section 8.2.1.4 and 
Table 3). 
The recommended Lantus titration regimen is outlined in Table 2, based on the mean of the 
3 most recent fasting pre-breakfast SMBG values, as measured by the patients. 
Table 2 – Lantus titration regimen 
Mean of 3 most recent fasting SMBG valuesa 
Lantus dose adjustments (IU/day) 
≥140 mg/dL (≥7.8 mmol/L) 
Increase Lantus by 4 units, or split to 2 x 2 units 
≥120 mg/dL and <140 mg/dL (≥6.7 mmol/L and <7.8 mmol/L) 
Increase Lantus by 2 units 
>100 mg/dL and <120 mg/dL (>5.6 mmol/L and <6.7 mmol/L) 
Increase Lantus by 1 unit 
80 mg/dL and 100 mg/dL (4.4 and 5.6 mmol/L), inclusive 
No change in dose 
<80 mg/dL (<4.4 mmol/L) 
Decrease Lantus by 2 units 
a The glucometers, used for SMBG, display results already calibrated to plasma glucose concentrations, thus no conversion is required. 
SMBG = self-monitored blood glucose 
In addition: 
1. Lantus dose titration may be withheld for a week or reduced in a patient who experiences 
two or more episodes of symptomatic hypoglycemia (with symptoms of hypoglycemia and 
an SMBG reading ≤70 mg/dL [≤3.9 mmol/L]) or one episode of severe hypoglycemia 
(patient required assistance from others to treat the hypoglycemic event; see  
Section 10.6.1). 
2. In both Run-in phase or post-Week 18 Treatment Phase, Investigators are allowed to 
modulate or stop titration or temporarily reduce dosage if they believe further titration 
would be hazardous to the patient (eg, due to age, comorbid conditions, individual patient 
considerations, other than hypoglycemia). In such a case the reason for the exceptions 
should be recorded in the source document. 
Good clinical judgment is to be exercised while titrating the insulin dose. For example, when 
implementing the weekly Lantus titration dose, a dose increase could be split into two incremental 
increases over the course of the week, rather than implementing the entire dose increase at one 
time, if it was concluded by the investigator or medically qualified designee to be in the best 
interest of the patient to do so. 
Patients will be familiarized with the titration schedule so that they would be able to monitor the 
titration with the assistance of the investigator or medically qualified designee. All dose 
adjustments must be discussed between the patient and appropriate site personnel. 
Patients who experienced mild to moderate hypoglycemia as a result of a missed meal, unusual 
exercise, or alcohol use will be counseled on the correction of those behaviors and may not need 
to have their insulin dose decreased. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 51 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 51 
8.2.1.4 Self-monitoring of blood glucose (SMBG) 
Self-monitoring of blood glucose measured by patients will be used for investigators to guide 
Lantus dose modification and monitor for hypoglycemia or hyperglycemia. 
A meter for self-assessment of blood glucose will be dispensed at the Week -4 Run-in visit 
(Visit 2). Patients will be trained on how to accurately measure plasma glucose values with the 
blood glucose meter. The study provided glucose meter will be used over the course of the study 
period. The investigator or site study staff will explain the need to measure glucose at the times 
requested for profiles and how to correctly record the values and times in the diary. Training is 
repeated as often as necessary at the study visits and the site study staff reviews the patient’s diary 
at each on-site visit. 
Patients will also receive a patient diary at all on-site visits with the exception of Visit 5 and 
Follow-up (Visit 16). The diary will be reviewed at all on-site visits from Visit 2 to Visit 16. 
The performance of SMBG is outlined in Table 3 and is also specified in Section 1.2. 
Table 3 – Instruction for SMBG performed during the study 
Frequency 
SMBG 
Definition 
Recommended 
Mandatory 
Weeks/Visits 
Fasting SMBG 
Overnight fasting pre-breakfast 
and before Lantus injection or 
any OAD intake 
Daily until achieving 
fasting SMBG target 
Daily SMBG 
Week -4 to Week -1 
 
 
5 days per week 
5 days per week 
until achieving 
fasting SMBG target 
3 days per week 
3 days during the week 
prior to study visit 
Week 0 to Week 18 
Week 19 to Week 52 
7-points 
Before and 2 hours after 
breakfast, lunch and dinner, 
and bedtime 
As needed 
1 day during the weeks 
prior to Weeks 0, 18, 
and 52 
Visit 6, 12, and 15 
OAD = oral antidiabetes drugs; SMBG = self-monitored blood glucose. 
Fasting SMBG readings will be used to guide the Lantus dose modification to reach and maintain 
the glucose targets. The investigators should review the SMBG records at each study visit 
including the phone visits so that they can provide instruction to the patients for appropriate 
insulin dose adjustment. 
Fasting SMBG 
Fasting SMBG should be tested in the morning before breakfast and before Lantus injection (for 
morning regimen) and taking any antidiabetic oral medications (if applicable). Patients should be 
instructed to check the fasting SMBG without food intake (except for water) for at least 8 hours 
(overnight) if possible. Patients should also be advised that a SMBG value should be excluded for 
insulin dose titration if the data were measured after taking food. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 52 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 52 
SMBG during hypoglycemic event 
Patients will also be requested to self-assess blood glucose levels whenever they experience any 
illnesses (eg, cold, flu), or hypoglycemia. Symptoms of hypoglycemia may include shakiness, 
dizziness, sweating, hunger, headache, pale skin color, sudden moodiness or behavior changes 
(such as crying for no apparent reason), clumsy or jerky movements, seizure, difficulty paying 
attention or confusion, or tingling sensations around the mouth. Patients should be instructed to 
measure blood glucose prior to carbohydrate intake/administration of glucose whenever 
symptomatic hypoglycemia is suspected, unless safety considerations necessitate immediate 
carbohydrate/glucose rescue prior to confirmation with the SMBG. 
Patients will be instructed to record the presence or absence of hypoglycemic episodes or 
hypoglycemic symptoms in the patient diary provided. 
All hypoglycemia episodes will be documented on the “hypoglycemia specific form” in the 
electronic case report form (eCRF). This includes all symptomatic hypoglycemia events and 
asymptomatic hypoglycemia. 
Hypoglycemia events fulfilling the criteria of a SAE will be documented on the SAE form in the 
eCRF. 
SMBG for monitoring hyperglycemia 
Patients should be instructed to contact the site if the fasting SMBG values over 3 consecutive 
days are: 
• 
From Baseline Visit (Visit 6, Day 1) to Visit 10 (Week 8): fasting SMBG >270 mg/dL 
(15.0 mmol/L) 
• 
From Visit 10 (Week 8) to Visit 11 (Week 12): fasting SMBG >240 mg/dL (13.3 mmol/L) 
• 
From Visit 11 (Week 12) up to Visit 12 (Week 18): fasting SMBG >200 mg/dL 
(11.1 mmol/L) 
• 
From Visit 12 (Week 18) up to the EOT Period Visit 15 (Week 52): fasting SMBG 
>170 mg/dL (9.4 mmol/L) 
8.2.2 Metformin 
Patients may use metformin at a dose of ≥1500 mg/day or maximum tolerated dose (as 
documented). Use of metformin is not required but the dose should be stable throughout the study; 
a dose decrease is allowed only for safety reasons. 
Metformin tablets are administered as per Investigator and in accordance with local labeling. 
8.2.3 Other oral antidiabetes drugs 
Patients may use up to 2 OADs (including metformin). Other OADs are administered as per 
Investigator and administered in accordance with local labeling. Doses of OADs should be kept 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 53 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 53 
constant during the trial, but decrease for safety reasons during the insulin titration period is 
allowed. 
8.2.4 Rescue therapy 
If a patient needs to receive rescue antidiabetes medication, assessment of HbA1c should be 
performed before the introduction of the rescue medication. 
The threshold values for FPG and HbA1c are defined as follows, depending on study period: 
• 
From Baseline Visit (Visit 6, Day 1) to Visit 10 (Week 8) (including value at Visit 10): 
FPG >270 mg/dL (15.0 mmol/L) 
• 
From Visit 10 (Week 8) to Visit 11 (Week 12) (including value at Visit 11): FPG 
>240 mg/dL (13.3 mmol/L) 
• 
From Visit 11 (Week 12) up to Visit 12 (Week 18): FPG >200 mg/dL (11.1 mmol/L) or 
HbA1c ≥8.5% (the 8.5% criteria does not apply if the HbA1c decrease from Baseline was 
≥1.5%) 
• 
From Visit 12 (Week 18) up to the EOT Period Visit 15 (Week 52): FPG >170 mg/dL 
(9.4 mmol/L) or HbA1c ≥8.0% (the 8.0% criteria does not apply if the HbA1c decrease 
from Baseline was ≥1.5%). 
Routine fasting SMBG and central laboratory alerts on FPG (and HbA1c at Week 12 and 
onwards) are set up to ensure that glycemic parameter results remain within predefined thresholds. 
• 
If one fasting SMBG value exceeds the specific glycemic limit on one day, the patient will 
check again during the two following days. If all the values in 3 consecutive days exceed 
the specific limit, the patient should contact the Investigator and a central laboratory FPG 
measurement (and HbA1c at Week 12 and onwards) will be performed as soon as 
possible, preferably within 7 days, to confirm the hyperglycemia. 
• 
Likewise, upon receipt of a central laboratory rescue alert, a central laboratory re-test 
must be completed and confirmed as exceeding the criterion for rescue before rescue 
therapy is initiated. The re-test confirmation should be performed as soon as possible, but 
within 7 days of receipt, by unscheduled visit. 
In the event that a confirmatory FPG and/or HbA1c exceed the threshold, the Investigator should 
ensure that no reasonable explanation exists for insufficient glucose control and in particular that: 
• 
The increased FPG has been tested at a fasting status (ie, no food intake for ≥8 hours) 
• 
IMP is given at the maximum planned dose and the basal insulin is titrated according to 
the titration algorithm 
• 
Lantus is appropriately titrated, according to the titration algorithm, during the Run-in 
Phase and from Week 18 to EOT 
• 
There is no intercurrent disease, which may jeopardize glycemic control (eg, infectious 
disease) 
• 
Compliance to treatment is appropriate 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 54 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 54 
• 
Compliance to diet and lifestyle is appropriate. During these phases, increase in Lantus 
dose is the first choice prior to initiating prandial insulin or a GLP-1 receptor agonist. 
If any of the above can reasonably explain insufficient glycemic control, the Investigator should 
consider not initiating rescue medication and should undertake appropriate action, ie: 
• 
Assess plasma glucose in fasting condition (ie, after at least 8-hour fast) 
• 
Initiate an evaluation and treatment of intercurrent disease (to be reported in 
AE/concomitant medication parts of the eCRF and the medical record) 
• 
Stress the absolute need to be compliant with treatment. Increase in Lantus dose is the first 
choice prior to initiating prandial insulin 
• 
Organize a specific interview with the patient and a Registered Dietician or other qualified 
nutrition professional and to reinforce on the absolute need to be compliant to diet and 
lifestyle recommendations, and schedule an FPG/ HbA1c assessment at the next visit (in 
case the next visit is a phone call, it should be replaced by an on-site visit). 
If none of the above mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, rescue medication may be introduced. However, patients 
exceeding glucose rescue limits should have their Lantus dose up-titrated without a maximum 
limit as a first approach. If up-titration of the Lantus regimen has been unsuccessful (ie, increase 
in basal insulin is associated with low FPG values despite high HbA1c or elevated post-prandial 
values), it is appropriate to initiate rescue therapy. 
The recommended approach to rescue, if rescue thresholds have reached despite up-titration of the 
Lantus dose, is to initiate a prandial insulin, or a GLP-1 agonist or another antidiabetic agent 
(except SGLT2 inhibitors) as per the Investigator’s discretion and in line with local treatment 
guidelines. The prandial insulin can be any injectable short-acting insulin including fast-acting 
insulin analogs (such as, Humalog, Novolog, Apidra, and Fiasp) or regular insulin (eg, Humulin) 
or inhaled insulin (Afrezza). 
If a patient requires glycemic rescue, the IMP received during the randomized, double-blind 
Treatment Period should continue and must remain blinded until the EOS. The dose of the 
existing OAD may be adjusted after rescue therapy. 
Rescue therapy is considered an NIMP. Rescue therapy is to be reported in the eCRF. This 
information should include specific drug name, dose, route of administration, and frequency. 
If not covered by health insurance, the cost of rescue therapy will be reimbursed by the Sponsor 
where permitted by local regulations. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 55 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 55 
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
To maintain blinding, sotagliflozin and the matching placebo tablets and packaging will be 
blinded and indistinguishable. 
During the double-blind Treatment Period, each treatment package will be labeled with a number, 
which is generated by a computer program from Sanofi. Investigators will not have access to the 
randomization (treatment) code except under circumstances described in Section 8.3.2. 
The randomization and the treatment allocation will be performed centrally by an IRT. The study 
biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the patient 
randomization list from which it allocates treatment arms to the patients. 
Fasting glucose (plasma or serum) and HbA1c will be masked to study sites and patients after 
randomization and until study end. Additionally, the central laboratory urinalysis by dipstick will 
not include the measurement of urine glucose. 
The CEC members will perform adjudication in a blinded manner. 
8.3.2 Randomization code breaking during the study 
In case of an AE, the code should only be broken in circumstances when knowledge of the IMP is 
required for treating the patient. 
Code breaking can be performed at any time by using the proper module of the IRT and/or by 
calling any other phone number provided by the Sponsor for that purpose. Code breaking can be 
performed by a local study Investigator, sponsor physician or healthcare professional with direct 
responsibility for patient care. If the blind is broken, the Investigator should document the date, 
time of day, and reason for code breaking. The identity of the unblinded personnel, how the code 
was broken, and the treatment kit number should also be recorded. The Sponsor should also be 
informed. If the code is broken by the Investigator (or other medical doctor in emergency 
situation), the patient must be withdrawn from IMP administration. 
Refer to Section 10.5 for suspected unexpected serious adverse reaction (SUSAR) unblinding by 
the Sponsor. 
Randomization code breaking will also be performed during the analysis of the Pharmacokinetic 
plasma concentration samples.  Only the Project manager and lead scientist at the Bioanalytical 
laboratory will have access to the randomization code to allow for the sorting of the sotagliflozin 
plasma samples. The Bioanalytical lab and responsible personnel will follow the standard 
procedures (SOP) to ensure the protection of the blind within the Sponsor’s clinical team. The 
randomization code or the individual analytical results will not be disclosed to any clinical team 
personnel prior to the database lock. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 56 of 365




Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 57 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP and 
Lantus in a secure and safe place in accordance with local regulations, labeling specifications, 
policies, and procedures. 
Control of IMP and Lantus storage conditions, especially control of temperature (eg, refrigerated 
storage) and information on in-use stability and instructions for handling the Sanofi compound 
should be managed according to the rules provided by the Sponsor. 
The expiry date and storage conditions are written on the IMP and Lantus labels. 
The treatment kit containing sotagliflozin 400 mg, sotagliflozin 200 mg, or placebo should be 
stored between +15°C and +30°C (59°F and 86°F). 
For the Lantus, prior to the first use, the disposable pens are to be stored between +2°C and +8°C, 
protected from light, and must not be frozen. In-Use Lantus disposable pens are to be stored 
below +25°C (not refrigerated) protected from light. Each pen should not be used for more than 
28 days after the first use. 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP and Lantus supplied by sponsor will be responsible for ensuring that the IMP and Lantus 
used in the clinical trial is securely maintained as specified by the Sponsor and in accordance with 
applicable regulatory requirements. 
All IMPs and Lantus will be dispensed in accordance with the Investigator’s prescription and it is 
the Investigator’s responsibility to ensure that an accurate record of IMP and Lantus issued and 
returned is maintained. 
Any quality issue noticed with the receipt or use of an IMP and Lantus (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) should be promptly notified 
to the Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP and Lantus may be subject to initiation of a recall 
procedure by the Sponsor. In this case, the Investigator will be responsible for promptly 
addressing any request made by the Sponsor or Delegate, in order to recall the IMP and Lantus 
and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP and Lantus to a third party (except for 
direct-to-patient shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP and Lantus to be used other than as directed by this clinical trial protocol, or dispose of 
IMP in any other manner. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 58 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 58 
8.7.1 Treatment accountability and compliance 
Accounting and compliance for IMPs and Lantus will be performed at Visit 5 and all subsequent 
on-treatment visits (excluding telephone visits). 
The Investigator will check the compliance to the study treatments based on the patient diary and 
will then complete the appropriate site treatment and patient treatment log forms. Returned IMP 
and Lantus NIMP (unused, in-use, or used wallets and pens) should be counted by site staff. In 
addition, the dosing information will be recorded on the appropriate pages of the eCRF. 
An internal group will review compliance with the fasting SMBG algorithm for Lantus titration in 
a blinded manner during the study. Mean fasting SMBG and insulin doses over time will be used 
to identify the out of the target values (within the range of 4.4 to 5.6 mmol/L [80-100 mg/dL]) via 
a pre-set program. The identified issues will be sent to the Investigators for their actions on the 
refinement of the titration schedule as needed. 
For other NIMPs (metformin, and other OADs), name, start and end date of treatment, total daily 
dose, etc, will be documented in the source documents. Compliance to NIMPs will be checked by 
interviewing the patient and reviewing diary at each on-treatment visit and be documented in the 
source documents and in the eCRF. 
If compliance is inadequate as determined by the Principal Investigator, patients will be trained 
again and mentored. If sub-optimal compliance continues after training and mentoring, patients 
may be discontinued at the discretion of the Investigator after discussion with the Sponsor’s 
medical monitor. 
8.7.2 Return and/or destruction of treatments 
Patients are to return all IMP and Lantus NIMP (unused, in-use, or used wallets and pens) at each 
on-site visit (or final assessment on-treatment visit, in the case of permanent premature 
discontinuation), as described in Section 1.2). IMP accounting is not required at telephone visits. 
Patients are to return all IMP and Lantus NIMP (unused, in-use, or used wallets and pens) at 
Visit 15 (or final assessment on-treatment visit, in the case of permanent premature 
discontinuation). 
All used wallets and pens, partially-used, or unused IMPs, and basal Lantus NIMP will be 
retrieved by the sponsor or delegate. A detailed site and patient treatment log of the returned IMP 
and basal Lantus NIMP will be established with the Investigator and countersigned by the 
Investigator and the monitoring team. 
For NIMP not provided by the Sponsor (ie, metformin or other OAD), tracking and reconciliation 
is to be undertaken by the Investigator (or pharmacist if appropriate) according to the system 
proposed by the CRO. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 59 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 59 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
The IMP includes placebo and sotagliflozin 400 mg and 200 mg. 
All concomitant medications should be documented on the Medications page of the eCRF. This 
includes all NIMP treatments that are taken by the patients at any time during the clinical study, 
beginning at Visit 1. 
Additionally, all medications in the 3 months prior to Visit 1 and prior use of SGLT1/SGLT2 
inhibitor should be reported. 
8.8.1 Prohibited prior and concomitant medications 
During the study Treatment Period, the following medications are prohibited: 
• 
Initiation of any antidiabetic agents, including oral, inhaled, or injectable 
antihyperglycemic agents other than the IMP and NIMP is not allowed before the rescue 
therapy. The existing background medication (NIMP) should not be modified before the 
rescue. 
• 
SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin) are not allowed for 
rescue. 
• 
Systemic use of glucocorticoids for more than 10 consecutive days (topical, intra-articular, 
ophthalmic, nasal spray, or inhaled applications are allowed). 
• 
IMPs in any other clinical study. 
• 
Modification of any antihypertensive medication before Week 12 is not allowed unless for 
safety reasons. 
• 
Initiation of any weight loss drugs (eg, phentermine, orlistat). 
Patients taking sotagliflozin with concomitant digoxin should have digoxin concentrations 
monitored and doses reduced as needed. In addition, other P-gp substrates may be affected and the 
labels of P-gp substrate drugs should be consulted with regards to monitoring and dose 
adjustments. 
Note: short-term use (<10 consecutive days) of the prohibited medication, eg, short-acting insulin 
for treatment of acute illness or surgery is allowed. 
Other medications which are unlikely to interfere with the PK or pharmacodynamics of the IMP 
or confound interpretation of the study endpoints are allowed as needed and following discussion 
between the Investigator and the Sponsor/CRO. However, doses of chronically administered 
medicines should be kept fixed during the trial if at all possible. 
The dose of all antihypertensive agents should be kept constant during the 12 weeks following 
randomization and no antihypertensive agents should be added or withdrawn for the 12 weeks 
following randomization unless it is considered necessary for safety reasons. During the Run-in 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 60 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 60 
Phase, adjustments to antihypertensive therapy can be made as needed. After randomization, 
antihypertensive regimen should be kept constant during the following 12 weeks. 
8.8.2 Concomitant diabetes therapy 
Noninvestigational medicinal product (see Section 8.2) treatment is defined as the rescue 
medication that will be used to treat hyperglycemia when a patient’s hyperglycemia reaches the 
rescue threshold, plus the protocol-specified background therapy (Lantus), and/or up to 2 OADs 
(metformin and/or other OADs). The recommended approach to rescue, if rescue thresholds have 
been reached despite up-titration of the Lantus dose, is to initiate a prandial insulin, or a GLP-1 
agonist or another antidiabetic agent (except SGLT2 inhibitors) as per the Investigator’s discretion 
and in line with local treatment guidelines. 
8.9 
POST-STUDY TREATMENT 
As sotagliflozin may reduce BP, decrease of antihypertensive medication may be needed during 
the study in patients with hypertension. Conversely, monitoring for an increase in BP should be 
performed after withdrawal of study medication. If the BP is elevated after withdrawal of study 
treatment, the Investigator should consider adding or adjusting antihypertensive medication. 
Sotagliflozin will not be provided after EOT. Patient’s further treatment, for diabetes and other 
pathologies will be at the Investigator’s discretion based on his/her clinical judgment. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 61 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 61 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
EFFICACY ENDPOINTS 
The methods of assessment of efficacy endpoints are detailed in Section 9.1.4. 
9.1.1 Primary efficacy endpoint (sotagliflozin 400 mg dose) 
• 
Change from Baseline to Week 18 in HbA1c. 
9.1.2 Secondary efficacy endpoints 
Continuous secondary efficacy endpoints for the sotagliflozin 400 mg dose: 
• 
Change from Baseline to Week 18 in FPG 
• 
Change from Baseline to Week 18 in BW 
• 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 12 in SBP for all patients 
• 
Change from Baseline to Week 52 in HbA1c 
• 
Change from Baseline to Week 52 in BW 
Continuous secondary efficacy endpoints for the sotagliflozin 200 mg dose: 
• 
Change from Baseline to Week 18 in HbA1c 
• 
Change from Baseline to Week 18 in BW 
• 
Change from Baseline to Week 18 in FPG 
• 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 52 in HbA1c 
• 
Change from Baseline to Week 52 in BW 
9.1.3 Other efficacy endpoints (sotagliflozin 400 mg and 200 mg doses) 
• 
The proportion of patients with HbA1c <7.0% or HbA1c <6.5% at Weeks 18, 26, and 52 
• 
Change from baseline to Week 26 in HbA1c 
• 
Change from Baseline to Week 12 in SBP for all patients in the sotagliflozin 200 mg arm, 
and from Baseline to Weeks 26 and 52 in SBP for all patients and the subset of patients 
with Baseline SBP ≥130 mmHg in the sotagliflozin 400 mg and 200 mg arms 
• 
Change from Baseline to Weeks 12, 26, and 52 in SBP in patients with Baseline SBP 
<130 mmHg 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 62 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 62 
• 
Change from Baseline to Weeks 12, 26, and 52 in DBP for all patients and for the subset 
of patients with Baseline DBP ≥80 mmHg 
• 
Change from Baseline to Week 52 in total daily insulin dose 
• 
Proportion of patients requiring rescue therapy during the 52-week double-blind Treatment 
Period 
• 
Change from Baseline to Weeks 18 and 52 in 7-point SMBG profile (mean daily value and 
at each time point) 
• 
Change from Baseline in eGFR 
• 
Change from Baseline in UACR during the 52-week Treatment Period 
• 
PQAT at Weeks 18 and 52 
• 
Change in TRIM-D from Baseline to Week 52 for total score and 5 domain scores. There 
will be a particular focus on the Diabetes Management domain score, to evaluate patient 
satisfaction of ability of treatment to control diabetes and its effects. 
9.1.4 Assessment methods of efficacy endpoints 
9.1.4.1 Hemoglobin A1c 
Hemoglobin A1c will be assessed at Screening (Visit 1), Week -1 (Visit 5), and all on-site visits 
during the double-blind Treatment Period. 
For the eligibility and efficacy assessments of the study, HbA1c is measured by a certified level I 
“National Glycohemoglobin Standardization Program” central laboratory to allow estimation of 
the change from Baseline to Week 18 in HbA1c and the proportion of patients with HbA1c 
<6.5%, <7.0% at Week 18. 
If a patient needs to receive rescue antidiabetes medication, assessment of HbA1c should be 
performed before the introduction of the rescue medication. 
9.1.4.2 Fasting plasma glucose measurement 
Plasma glucose is measured in the fasting state at Screening (Visit 1) and all on-site visits during 
the Treatment Period. Fasting plasma glucose will be performed in fasting state, ie, without any 
food intake (except for water) for at least 8 hours. For the eligibility and efficacy assessments of 
the study, FPG is measured at a central laboratory to allow estimation of change from Baseline to 
Week 18 in FPG. 
9.1.4.3 Blood pressure measurements 
Systolic BP and DBP will be assessed at all on-site visits. Blood pressure measurements taken as 
described in Section 9.2.1.5 with details provided in Appendix D. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 63 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 63 
9.1.4.4 Body weight measurement 
Body weight is measured at all on-site visits to allow the estimation of change from Baseline to 
Week 52 in BW. Change from Baseline to Week 18 in BW will also be assessed (secondary 
endpoint). 
Body weight should be obtained with the patient wearing undergarments or very light clothing 
and no shoes, and with an empty bladder. The same scale should be used throughout the study, 
and calibrated on a regular basis as recommended by the manufacturer. Calibration should be 
documented in source documents. The use of balance scales is recommended; if digital scales are 
used, testing with standard weights is of particular importance. The floor surface on which the 
scale rests must be hard and should not be carpeted or covered with other soft material. The scale 
should be balanced with both weights at zero and the balance bar aligned. The patient should 
stand in the center of the platform as standing off-center may affect measurement. The weights are 
moved until the beam balances (the arrows are aligned). The weight is read and recorded in the 
eCRF and source data. Self-reported weights are not acceptable; patients must not read the scales 
themselves. 
9.1.4.5 Kidney function parameter measurement 
Serum creatinine will be assessed at Screening (Visit 1), Week -1 (Visit 5), Baseline (Visit 6), and 
all subsequent on-site visits. Urinary albumin, total protein, creatinine, calcium (adjusted for 
creatinine), phosphorus (adjusted for serum phosphorus and creatinine), magnesium (adjusted for 
serum magnesium and urinary creatinine) and glucose will be assessed from overnight urine 
samples taken at Weeks 0, 12, 26, and 52. A central laboratory will analyze samples and estimate 
change from Baseline in serum UACR. 
9.1.4.6 7-point SMBG profiles 
Before (pre-injection after randomization) and 2 hours after breakfast; before and 2 hours after 
lunch; before and 2 hours after dinner and at bedtime: at least one day in the week before the 
Baseline visit (Visit 6), and before Visit 12 (Week 18) and Visit 15 (Week 52). 
Note: Patients should be reminded at the preceding visit to perform at least one day 7-point 
SMBG in the week prior to above study visits. If found missing performance (or any missing 
point), the visit should be postponed to allow the patient for repeating the performance. 
9.1.4.7 Proportion of patients starting rescue therapy 
The use of rescue medication for hyperglycemia will be assessed and reported throughout the 
Treatment Period. Routine alerts on FPG and/or HbA1c will be sent to the Investigator from the 
central laboratory to ensure that glycemic parameter results remain within predefined thresholds. 
For details and further actions should FPG values fall above thresholds, refer to Section 8.2.4. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 64 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 64 
9.1.4.8 Insulin dose 
Patients will record their Lantus daily dose in the diary since Visit 2 at the beginning of Run-in 
and throughout the Treatment Period. In case of rescue therapy with prandial insulin, the meal-
time insulin will also be recorded in the patient’s diary. The insulin doses will be reviewed and 
verified by the investigator and site study staff, and then be documented onto the eCRF. 
The total daily insulin dose (Lantus and prandial, if applicable) will be analyzed by treatment 
groups. 
9.2 
SAFETY ENDPOINTS 
Assessments for safety include AEs, SMBG, clinical laboratory assessments, physical 
examination, 12-lead ECG, weight, and vital signs. An independent DMC will meet on a regular 
basis to review accumulating clinical trial safety data. 
Adjudication of all deaths, MACE/other selected CV events, selected renal events, bone fracture, 
and DKA will be performed in a blinded manner by a CEC(s) comprised of experts. Details will 
be provided in the charter of the CEC(s). Further details are available in Section 6.3.3. 
Two expert committees will review all potential cases of DILIs and cases of amputation in a 
treatment-blinded manner. 
The following safety endpoints will be assessed throughout the 52-week double-blind Treatment 
Period: 
• 
Adverse events, AEs leading to discontinuation from the IMP, adverse events of special 
interest (AESI), EOSI, SAEs, and deaths 
• 
Hypoglycemia (all, severe and/or documented symptomatic) 
• 
Markers of calcium metabolism 
• 
Safety laboratory results (including amylase, lipase, and fasting lipids; see  
Section 9.2.1.3), vital signs results, and 12-lead ECG results. 
Observation period of safety endpoints 
The observation period of safety data will be divided into 3 segments: 
• 
The pre-Treatment Period is defined as the time between the date of informed consent and 
the first dose of double-blind IMP. 
• 
The on-Treatment Period (TEAE period) is defined as the time from the first dose of 
double-blind IMP up to 10 days (1 day for hypoglycemia) after the last dose of double-
blind IMP, regardless of the introduction of rescue therapy. The 10-day interval is chosen 
based on the half-life of the IMP (approximately 5 times the half-life of sotagliflozin) in 
patients with moderate renal dysfunction. 
• 
The post-Treatment Period is defined as the time starting 11 days after the last dose of 
double-blind IMP (after the on-Treatment Period). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 65 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 65 
The Baseline value for safety endpoints in the safety population is the last available value (or the 
average of all values for creatinine or eGFR) prior to the first administration of the double-blind 
IMP. 
9.2.1 Assessment methods of safety endpoints 
9.2.1.1 Adverse events 
Adverse events including SAEs, AESI, and EOSI will be assessed. Refer to Section 10.4 to 
Section 10.7 for details. 
9.2.1.1.1 Adverse events of special interest 
Adverse events of special interest are listed in Section 10.4.1.3; reporting requirements for AESI 
are presented in Section 10.4.4. 
9.2.1.1.2 Events of special interest 
Events of special interest are separate from AESI. For a list of events defined as EOSI and their 
reporting requirements see Section 10.4.1.4 and Section 10.4.5, respectively. 
9.2.1.2 Hypoglycemia 
Hypoglycemia (all, severe and/or documented symptomatic hypoglycemia) will be assessed 
starting with signing of the ICF and continue until 2 weeks after the last dose of IMP (Note: for 
patients who discontinue treatment >2 weeks before Week 52, safety data will be collected until 
scheduled study end). Patients will also complete the patient diary, which will be regularly viewed 
by Investigators. See Section 10.6.1 for further details. 
9.2.1.3 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry, 
amylase, lipase, and fasting lipids) and urinalysis, according to the schedule presented in  
Section 1.2. Clinical laboratory values will be analyzed after conversion into standard 
international units. International units will be used in all listings and tables. Table 4 lists the 
hematology, clinical chemistry, and other blood safety parameters to be assessed by the central 
laboratory. 
In addition, for WOCBP a serum pregnancy test is performed at Screening and urine pregnancy 
tests are taken at all on-site visits during the double-blind Treatment Period. Any positive urine 
test results must be confirmed by a serum pregnancy test. The Investigator may perform 
additional tests at their discretion or as required by local regulations. 
For women of nonreproductive potential (Appendix A), follicle-stimulating hormone (FSH) 
and/or estradiol levels should be tested if the definition of postmenopausal or premenopausal 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 66 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 66 
cannot be satisfied, eg, no medical document of hysterectomy or cessation of menses <12 months 
without an alternative medical cause. 
Table 4 – Blood safety parameters 
Clinical chemistry 
Hematology 
Other blood parameters 
Sodium 
Complete blood count (CBC) 
Lipid profile 
Potassium 
Differential 
Total cholesterol (TC) 
Calcium  
Chloride 
Platelet count 
High-density lipoprotein cholesterol (HDL-C) 
Carbon dioxide (bicarbonate) 
Hemoglobin 
Low-density lipoprotein cholesterol (LDL-C) will be 
calculated by Friedwald equation 
Blood urea nitrogen (BUN) 
Hematocrit 
Non-HDLC will be calculated as the difference 
between TC and HDLC 
Creatinine (eGFR will be 
calculateda) 
 
Triglycerides (TG) 
Glucose (serum) 
 
 
Alanine aminotransferase (ALT) 
 
Markers of calcium metabolismb 
Aspartate aminotransferase (AST) 
 
25-hydroxyvitamin D 
Total bilirubin (TB) 
 
1,25-dihydroxyvitamin D 
Alkaline phosphatase (ALP) 
 
Parathyroid hormone (PTH) 
Uric acid 
 
 
Phosphorus 
 
 
Total protein 
 
 
Albumin 
 
 
Magnesium 
 
 
Creatine phosphokinase (CPK) 
 
 
Lactic acid dehydrogenase (LDH)  
 
 
Amylase 
 
 
Lipase 
 
 
Beta-hydroxybutyrate (BHB)c 
 
 
All assessments to be performed by central laboratory. All assessments measured in serum. 
a The recommended equation for estimating eGFR from serum creatinine is the 4 variable MDRD study equation (17, 18). The isotope 
dilution mass spectrometry (IDMS)-traceable version of the MDRD Study equation is used. Either equation below may be used based on 
whether the laboratory reports conventional units or Standardized International (SI) units. 
Conventional Units (for use predominantly in the US): http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-conventional -unit.asp  
SI Units (for use predominately outside the US): http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-SI-units.asp. 
b To be collected at Baseline (Visit 6) and Week 26 (Visit 13). 
c Serum BHB to be assessed (central lab determination) at Baseline (Visit 6), Week 4 (Visit 8), Week 8 (Visit 10), Week 18 (Visit 12), 
Week 26 (Visit 13), Week 39 (Visit 14), and Week 52 (Visit 15). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 67 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 67 
9.2.1.4 Urinalysis 
Urinalysis (urine dipstick with microscopy) will be performed by central laboratory at Screening 
(Visit 1), Baseline (Visit 6), and Week 26 (Visit 13). To prevent partial unblinding the central 
laboratory urinalysis by dipstick will not include the measurement of urine glucose. Central 
urinalysis includes: 
• 
Urine dipstick includes: specific gravity, pH, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, and leukocyte esterase 
• 
Urine microscopy includes, but is not limited to: detection of formed cellular elements, 
casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. 
In the event of abnormal urinalysis findings suspicious of UTI, urine culture should be performed. 
Positive urine culture determination will be based upon the criteria of the reporting laboratory. 
Additionally, urine culture should be performed if at any point the Principal Investigator suspects 
the presence of a UTI. 
If the urine dipstick is positive for blood, the central laboratory will perform reflexive testing to 
include microscopy. Additional testing will be performed according to the judgment of the 
Investigator. Referral to urology/urologic evaluation is recommended for new or unexplained 
cases of confirmed hematuria (urology/urologic evaluation is not required where hematuria is 
considered to be related to diabetic nephropathy). 
9.2.1.5 Vital signs 
A complete physical exam (including sitting BP and heart rate, temperature and respiratory rate) 
will be performed at Visit 1 (Screening) and Week 26 (Visit 13). Abbreviated physical exams 
(including sitting BP and heart rate) will be performed at all other on-site visits. The abbreviated 
physical exam should focus on cardiac and respiratory systems, as well as any areas important for 
assessment of AEs if necessary. 
Three separate seated BPs and heart rate measurements should be taken with at least 1 minute 
between measurements following a 5-minute rest period, and prior to phlebotomy. Full details and 
directions for the measurement of BP are presented in Appendix D. 
9.2.1.6 Electrocardiogram variables 
The ECG assessment of “normal” or “abnormal” will be analyzed. 
A 12-lead ECG record is performed locally at Screening (Visit 1), Baseline (Visit 6), and 
Week 26 (Visit 13). 
The 12-lead ECG should be performed after at least 10 minutes in a supine position and prior to 
the morning IMP administration. The Investigator should review the ECG and the document the 
interpretation, and sign and date it on the ECG print out and on the eCRF. Each ECG trace is 
analyzed in comparison with the Screening recorded trace. All original traces are kept as source 
data. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 68 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 68 
Note: any new ECG abnormality should be rechecked for confirmation and reported as 
appropriate for that finding. 
9.2.1.7 Diabetic ketoacidosis 
During the Run-in Phase patients will be provided meters and test strips for monitoring capillary 
blood beta-hydroxybutyrate (BHB). Patients will be instructed to measure their BHB levels by 
fingerstick if they experience any symptoms consistent with ketosis/ketoacidosis throughout the 
Lantus titration phase/Run-in Phase and randomized Treatment Period. Patients will be instructed 
on how to respond (seek help, hydrate, ingest carbohydrates, etc) if they present with possible 
ketoacidosis symptoms and the BHB value is abnormal (>0.6 mM/L) (see Appendix C). 
Patients will be provided with instructions on how to recognize the symptoms of DKA and 
perform the BHB measurement at home in these situations, and will be instructed to contact the 
site (or seek emergency medical services if after business hours) if these symptoms develop. 
Patients should have a full clinical evaluation with laboratory testing for possible DKA by the 
Investigator or emergency medical services physician. If such an evaluation and laboratory testing 
confirm the presence of metabolic acidosis, then appropriate treatment should be implemented 
and the “Possible DKA” eCRF should be completed. 
In addition, serum BHB will be assessed at the study site via a central lab determination at 
Baseline (Visit 6), Week 4 (Visit 8), Week 8 (Visit 10), Week 18 (Visit 12), Week 26 (Visit 13), 
Week 39 (Visit 14), and Week 52 (Visit 15) and a capillary BHB measurement will also be done 
at the study site at these same visits. An alert will be sent to the investigator if the serum BHB 
measured by central lab value is ≥1.5 mM/L. Upon receiving the alert, investigator/designees 
should call the patient to assess if the patient experiences a suspected DKA, insulin dosing 
compliance, and any action to take, eg, seek urgent care or unscheduled site visit for further 
evaluation. 
9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacokinetics 
The PK endpoint for sotagliflozin is: 
• 
Plasma concentrations of sotagliflozin and its 3-O-glucuronide metabolite. 
Pharmacokinetic sotagliflozin data may be subjected to a population PK analysis, which will be 
reported separately to the clinical study report (CSR). 
9.3.1.1 Sampling time 
At Weeks 4, 18, 26, and 52 (Visits 8, 12, 13, and 15, respectively) blood samples for PK 
assessment are to be drawn with the other laboratory assessments, prior to administration of IMP. 
Pharmacokinetic samples must be collected before administration of IMP. The date and time of 
the last intake of study drug prior to visits when PK samples are taken should be recorded by the 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 69 of 365








Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 72 
9.5 
APPROPRIATENESS OF MEASUREMENTS 
The addition of sotagliflozin to background therapy consisting of Lantus with or without up to 
2 OADs (which may include metformin) is expected to lower HbA1c over 18 weeks of treatment 
(primary efficacy analysis). Sotagliflozin treatment for 18 weeks is likely to be of sufficient 
duration to observe effects on reduction of HbA1c, FPG, BP, and BW, and is therefore selected as 
the time point for assessment of the primary endpoint HbA1c. Treatment up to 52 weeks will 
provide additional long-term data on safety and efficacy. 
The concentration of HbA1c reflects the glycemic history of the previous 120 days and is thus an 
index of mean glycemia, documenting glycemic control over the past 2 to 3 months. Hemoglobin 
A1c has also been shown to correlate with the development of long-term complications of 
diabetes, and reduction of HbA1c is considered an appropriate primary endpoint for assessing the 
effect of a treatment on glycemic control. The duration of study treatment (18 weeks for the 
primary HbA1c endpoint) is considered to be sufficient for achieving stable conditions with IMP 
and for enabling an adequate assessment of time-dependent changes in HbA1c. 
The problem of weight gain in T2D is widely recognized. More than 80% of individuals with T2D 
are overweight, many at the time of diagnosis. Consequently, iatrogenic weight gain is not only 
unwelcome, but represents an important clinical issue that can become a barrier to the successful 
management of glycemic control. Therefore, in this study, assessing change in BW from Baseline 
to Week 18 is a secondary endpoint. 
Potential therapeutic effect of sotagliflozin on BP reduction will be assessed in all trial patients 
and in patients with a mean SBP ≥130 mmHg at Baseline. To avoid confounding factors, 
modification of antihypertensive medications is not allowed during the first 12 weeks of 
Treatment Period (Section 8.8.1). The beneficial effect of sotagliflozin to patients with 
inadequately controlled hypertension could be best assessed by the key secondary endpoint, “the 
change in the SBP from Baseline to Week 12 for patients with Baseline SBP ≥ 130 mmHg”. In 
addition, the effect of sotagliflozin on BP will be evaluated in all patients, including normotensive 
individuals. 
Improvement in FPG has been observed with sotagliflozin in multiple studies. Therefore 
assessment of FPG is relevant in this study. This parameter is also considered by regulatory 
agencies to be supportive of the efficacy of an antidiabetes agent. 
The other efficacy and safety assessments in this study are standard, well established 
measurements for a Phase 3 study evaluating the treatment of T2D in adult patients. Safety 
laboratory parameters include BHB (beta-hydroxybutyrate), which is considered as a sensitive 
indicator for DKA diagnosis and monitoring (20). The values measured during study course will 
be analyzed between the treatment groups. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 73 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 73 
The length of the study is considered appropriate for detection of efficacy endpoints given the 
power estimates (see Section 11). 
Phase 2 data indicated that sotagliflozin may reduce SBP by 10 to 15 mmHg in patients with SBP 
≥130 mmHg at Baseline, while having no significant effect in patients with SBP <130 mmHg, and 
did not induce hypotension in normotensive patients. Since this could be of benefit to patients 
with T2D, this finding is being followed up as a secondary objective in this trial, as well as the 
potential in patients with DBP ≥80 mmHg. Although effects on BP in Phase 2 data were observed 
with the 400 mg dose at 12 weeks, the effects will be examined at Weeks 12, 26, and 52. 
Because of potential effects on calcium metabolism, specific biomarkers for calcium metabolism 
will be assessed at regular time points. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 74 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 74 
10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The visit schedule and procedures/assessments are listed in the Study Flow Chart (Section 1.2). 
The aim of this section is to provide details on how some of the procedures/assessments should be 
performed. 
This is an out-patient study and consists of 12 on-site visits and 4 telephone visits, although 
optional on-site and/or telephone visits can be scheduled at any time for any reason during the 
study whenever considered necessary by the Investigator. 
The patients need to be fasting for on-site visits Visit 1 through Visit 15 (Week -6 through 
Week 52), unless otherwise instructed by the Investigator. Throughout the study, “fasting” is 
defined as at least 8 hours without any food intake (except for water). Note: if the patient is not 
fasting at the visits specified above, the blood sample will not be collected and a new appointment 
should be given to the patient for the following day if possible, with instruction to be fasted (other 
procedures can be performed as scheduled). The first Run-in Visit (Visit 2) can be performed as 
soon as the results of all Screening tests are available and the patient is confirmed to be eligible 
for participation in the study. The visit window for Visit 5 is ±2 days, and Visits 7 through 13 
should occur within ±3 days. Visits 14 and 15 should occur at the scheduled time point ±7 days. 
Visit 15 (EOT) should occur from Day 357 to Day 371. For the Follow-up Visit (Visit 16), the 
visit should occur within a window of ±3 days, 2 weeks after the last dose of IMP. If one date is 
changed, the next visit should occur according to the original schedule, ie, calculated from the 
date of Baseline Visit (Visit 6, Day 1). 
For a complete list of procedures scheduled for each study visit, please refer to the Study Flow 
Chart (Section 1.2), which details the procedures to be performed. 
All data obtained during the trial visits are reviewed by the Investigator and/or Sub-investigators 
who are qualified in the treatment of T2D and are trained on the study. 
10.1.1 Screening Period 
The Screening Period is up to 6 weeks in duration and includes the Screening phase and the 
Run-in phase. 
10.1.1.1 Screening phase (Visit 1) 
The Screening phase will be up to 2 weeks in duration and includes Visit 1 (Week -6) only. It 
must be long enough to collect the data to establish whether the patient satisfies the 
inclusion/exclusion criteria. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 75 of 365




Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 76 
• 
The following laboratory testing (by the central laboratory): 
- 
HbA1c 
- 
Safety laboratory, including amylase and lipase 
- 
Hematology 
- 
Serum pregnancy testing for WOCBP or serum FSH and estradiol (for women of 
nonreproductive potential if definition of postmenopausal or premenopausal cannot be 
satisfied; see Appendix A) 
- 
Urinalysis (dipstick and microscopy) 
• 
PRO: TRIM-D 
• 
Patients are instructed to return to the site in the fasting state for Visit 2 (Week -4). 
10.1.1.2 Run-in phase (Visits 2 to 5) 
The Run-in phase is 4 weeks in duration and includes Visits 2 to 5 (Weeks -4 to -1, inclusive). 
10.1.1.2.1 On-site Visit 2 (Run-in, Week -4) 
The following procedures/assessments will be performed at Visit 2 (Week -4): 
• 
Assessment of exclusion criteria 
• 
Measurement of BW 
• 
Abbreviated physical examination including vital signs (SBP, DBP, and heart rate). After 
5 minutes resting, seated SBP, DBP, and heart rate will be assessed 3 times with at least 
1 minute between each measurement (see Appendix D for details). 
• 
Diet and exercise instruction 
• 
Blood glucose and BHB meters are dispensed and instructions/training is provided 
• 
Glucose test strips and BHB strips are dispensed 
• 
IRT to be notified (registration of Run-in, allocation of single-blind placebo Run-in kit and 
Lantus kit) 
• 
Instruction on DKA symptoms and glucose testing is provided 
• 
Patient diary is collected and reviewed and a new one dispensed. Instructions/training are 
provided as needed. 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia occurring since Visit 1 (if any) are reported 
• 
Run-in kit/placebo (IMP) and Lantus are dispensed 
• 
Treatment with study provided Lantus is started either on evening of Visit 2 (if evening 
dose) or the following morning (if morning dose) 
• 
Changes in concomitant medication are reported 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 77 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 77 
• 
Patients are instructed to return to the site for Visit 5. 
10.1.1.2.2 Telephone Visits 3 and 4 (Run-in Weeks -3 and -2) 
The following will be performed at this visit: 
• 
Assessment of exclusion criteria 
• 
Fasting SMBG is reviewed from diary and Lantus dose adjustments are made as necessary 
(Section 8.2) 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are instructed to return to the site for Visit 5. 
10.1.1.2.3 On-site Visit 5 (Run-in, Week -1) 
The following procedures/assessments will be performed at Visit 5 (Week -1): 
• 
Assessment of exclusion criteria 
• 
Measurement of BW 
• 
Abbreviated physical examination including vital signs (SBP, DBP, and heart rate). After 
5 minutes resting, seated SBP, DBP, and heart rate will be assessed 3 times with at least 
1 minute between each measurement (see Appendix D for details). 
• 
Diet and exercise instruction 
• 
Instruction on DKA symptoms, glucose testing, and basic genitourinary (GU) hygiene and 
hydration (see Appendix C) is provided 
• 
Patient diary is collected/reviewed. Instructions/training are provided as needed. 
• 
IMP and Lantus accountability and compliance 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Changes in concomitant medication are reported 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary  
(Section 8.2) 
• 
Patients are instructed to return to the site in the fasting state for Visit 6 (Randomization) 
• 
The following laboratory testing (by the central laboratory): 
- 
HbA1c 
- 
Clinical chemistry, including amylase and lipase. 
10.1.2 Double-blind Treatment Period (Day 1 to Week 52) 
Upon successful completion of the Run-in phase, patients will be randomly allocated to 
sotagliflozin 400 mg, sotagliflozin 200 mg, or placebo for the double-blind Treatment Period. All 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 78 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 78 
randomized patients will be followed at regular on-site visits for the duration of the Treatment 
Period. Visit 7 (Week 2) and Visit 9 (Week 6) are telephone visits.  
Patients will be instructed that their Lantus dose should remain unchanged (< ±10% of the 
randomization dose, or < ±4 units, whichever is less) until after Week 18 unless for safety reasons 
(eg, hypoglycemia, during treatment of an SAE) or meet the rescue criteria. After Week 18, 
Lantus dose may be adjusted if deemed necessary by the Investigator. 
In addition to routine laboratory testing, the following will be performed at specified time points: 
plasma concentration, serum and capillary BHB, hematology, fasting lipids, urinalysis, complete 
physical examination, diet and exercise instruction, 
, PQAT, and TRIM-D. 
The date and time of the last intake of IMP prior to visits where PK samples are taken should be 
recorded by the patient in the patient diary. Patients should be reminded of this at visits preceding 
PK time points to ensure these details are captured. 
In the event of abnormal urinalysis findings suspicious of UTI, urine culture should be performed. 
Positive urine culture determination will be based upon the criteria of the reporting laboratory. 
Additionally, urine culture should be performed if at any point the Principal Investigator suspects 
the presence of a UTI. 
10.1.2.1 On-site Visits 6, 8, 10, 11, 12, 13, and 14 (Weeks 0, 4, 8, 12, 18, 26, and 39) 
The following procedures will be performed at these visits: 
• 
Exclusion criteria are to be reviewed, including assessment of compliance during the 
Run-in phase (Visit 6 only) 
• 
Randomization (Visit 6 only) 
• 
Measurement of BW (all visits) 
• 
Abbreviated physical examination including vital signs (SBP and DBP, and heart rate). 
After 5 minutes resting, seated SBP, DBP, and heart rate will be assessed 3 times with at 
least 1 minute between each measurement (see Appendix D for details) (all visits except 
Visit 13, where a complete physical examination will be performed). 
• 
Concomitant medications are assessed (all visits) 
• 
Glucose test strips and BHB strips are dispensed (all visits) 
• 
Measurement of capillary BHB (all visits, except Visit 11) 
• 
Diet and exercise instruction (Visits 6 and 13 only) 
• 
Instruction on DKA symptoms, glucose testing, and basic GU hygiene and hydration (see 
Appendix C) is provided (all visits) 
• 
IRT to be notified, IMP and Lantus for resupply (all visits) 
• 
Patient diary is collected/ reviewed and new diary dispensed. Instructions/training are 
provided as needed (all visits). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 79 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 79 
• 
IMP and Lantus are dispensed (all visits) 
• 
IMP and Lantus accountability and compliance (all visits) 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary (all visits) 
• 
Record results of 7-point SMBG (Visits 6 and 12 only) 
• 
Patients are evaluated for glycemic rescue (see Section 9.1.4.7) (all visits) 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
The following laboratory testing (by the central laboratory): 
- 
FPG (all visits) 
- 
BHB (all visits except Visit 11) 
- 
HbA1c (all visits) 
- 
Clinical chemistry, including amylase and lipase (all visits) 
- 
Hematology (Visits 6, 11, 13, and 14 only) 
- 
Fasting lipids (Visits 6, and 12 only) 
- 
Urine pregnancy testing for WOCBP (all visits) 
- 
Pre-dose plasma concentration samples are collected and sent to the appropriate 
laboratory (Visits 8, 12, and 13 only) 
- 
Markers of calcium metabolism (Visits 6 and 13 only) 
- 
Urinalysis (dipstick and microscopy) (Visits 6 and 13 only) 
- 
Overnight urine collection for albumin, protein, creatinine, calcium, phosphorus, 
magnesium, glucose, and albumin-creatinine ratio (Visits 6, 11, and 13 only) 
 
 
 
 
• 
PRO: PQAT (Visit 12 only) 
• 
PRO: TRIM-D (Visits 6, 12, 13, and 14 only) 
• 
12-lead ECG (Visits 6 and 13 only) 
• 
Patients are instructed to return to the site in the fasting state for their next visit (all visits 
except Visits 6 and 8, which precede telephone visits). They should be reminded to record 
in the diary the date and time of IMP intake on the day before their next visit (reminder at 
Visits 7, 11, and 12 only). 
• 
For accountability and compliance purposes, patients are instructed to return to the site 
with their unused, in-use, and used wallets and pens at the next on-site visit (all visits). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 80 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 80 
10.1.2.2 Telephone Visits 7 and 9 (Weeks 2 and 6) 
The following will be performed at this visit: 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are evaluated for glycemic rescue (see Section 9.1.4.7) 
• 
Patients are instructed to return to the site in the fasting state for Visits 8 and 10. 
10.1.2.3 On-site Visit 15 (Week 52) - end of treatment 
The following procedures will be performed at this visit: 
• 
Measurement of BW 
• 
Abbreviated physical examination including vital signs (SBP and DBP, and heart rate). 
After 5 minutes resting, seated SBP, DBP, and heart rate will be assessed 3 times with at 
least 1 minute between each measurement (see Appendix D for details). 
• 
Concomitant medications are assessed 
• 
Glucose test strips and BHB strips are dispensed 
• 
Diet and exercise instruction 
• 
Instruction on DKA symptoms, glucose testing, and basic GU hygiene and hydration (see 
Appendix C) is provided 
• 
IRT to be notified 
• 
Patient diary is collected and reviewed and new diary dispensed. Instructions/training are 
provided as needed 
• 
IMP and Lantus accountability and compliance 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary 
• 
Record results of 7-point SMBG 
• 
Measurement of capillary BHB at the site using the meter 
• 
Patients are evaluated for glycemic rescue (see Section 9.1.4.7) 
• 
The following laboratory testing (by the central laboratory): 
- 
FPG 
- 
BHB 
- 
HbA1c 
- 
Clinical chemistry, including amylase and lipase 
- 
Hematology 
- 
Fasting lipids 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 81 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 81 
- 
Urine pregnancy testing for WOCBP 
- 
Plasma concentration of sotagliflozin and its 3 O-glucuronide metabolite 
- 
Overnight urine collection for albumin, protein, creatinine, calcium, phosphorus, 
magnesium, glucose, and albumin-creatinine ratio 
 
 
• 
PRO: PQAT 
• 
PRO: TRIM-D 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Patients are instructed to return to the site in the fasting state for their next visit (Visit 16) 
• 
For accountability and compliance purposes, patients are instructed to return to the site 
with their unused, in-use, and used wallets and pens at the next visit. 
10.1.3 Post-treatment follow-up period 
The post-treatment Follow-up Period (EOS) will include an on-site visit 14 days (2 weeks) 
±3 days after the last dose of IMP. 
10.1.3.1 On-site Follow-up Visit 16 (Week 54) 
The following will be performed at this visit: 
• 
Measurement of BW 
• 
IRT notified for EOS 
• 
Patient diary is collected and reviewed 
• 
Concomitant medications are assessed 
• 
AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• 
Abbreviated physical examination including vital signs (SBP, DBP, and heart rate). After 
5 minutes resting, seated SBP, DBP and heart rate will be assessed 3 times with at least 
1 minute between each measurement (see Appendix D for details). 
• 
Fasting SMBG is assessed and Lantus dose adjustments are made as necessary. 
• 
The following laboratory testing (by the central laboratory): 
- 
Clinical chemistry, including amylase and lipase. 
• 
The patient is instructed to schedule future follow-up with their own personal physician. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 82 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 82 
10.2 
DEFINITION OF SOURCE DATA 
10.2.1 Source data to be found in patient’s file 
Evaluations recorded in the eCRF must be supported by appropriately signed source 
documentation related but not limited to the following: 
• 
Agreement and signature of ICF with the study identification 
• 
Study identification (name) 
• 
Patient number, confirmation of randomization, treatment batch number, dates, and doses 
of study medication administration 
• 
Medical, surgical, diabetes history, including information on: 
- 
Demography, inclusion, and exclusion criteria 
- 
Last participation in a clinical trial 
- 
Contraception method for WOCBP 
- 
Previous and concomitant medication. 
• 
Dates and times of visits and assessments including examination results 
• 
Vital signs, height, BW, laboratory reports, Investigation results (eg, ECG traces, imaging 
reports) 
• 
Adverse events and follow-up: 
- 
In case of an SAE, the site should file in the source documents at least copies of the 
hospitalization reports and any relevant examination reports documenting the 
follow-up of the SAE. 
• 
Date of premature treatment discontinuation (if any) and reason 
• 
Date of premature study discontinuation (if any) and reason 
• 
Nursing notes 
• 
Dietician’s notes 
• 
Physician’s notes. 
10.2.2 Source data verification requirements for screen failures 
For screen failure patients, the following source data must be verified: patient’s ID details, the 
informed consent signed by the patient, the study identification (name), dates of study visits, and 
the main reasons for screen failure. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporary; permanent IMP discontinuation should be a 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 83 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 83 
last resort. Any IMP discontinuation should be fully documented in the eCRF. In any case, the 
patient should remain in the study and followed for the remainder of the study to collect vital 
safety status and endpoint data. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Low extremity complications (such as skin ulcers, infection, osteomyelitis and gangrene) 
requiring treatment should lead to temporary discontinuation of IMP.  Re-initiation of treatment 
with the IMP will be done under close and appropriate clinical and/or laboratory monitoring once 
the Investigator will have considered according to his/her best medical judgment, that the 
occurrence of the concerned event was unlikely to be related to the IMP. 
It is in the interest of the patient to monitor their blood glucose during the temporary 
discontinuation period, therefore regular determination of SMBG is to be performed and 
documented (see Section 8.2.1.4). 
For all temporary treatment discontinuations, the duration should be recorded by the Investigator 
in the appropriate pages of the eCRF when considered as confirmed. 
Temporary treatment discontinuation, as decided by the Investigator, corresponds to more than 
1 dose not administered to the patient. 
Use of any other antihyperglycemic medication during the time of temporary treatment 
discontinuation (ie, insulin during a hospitalization) is recorded as concomitant medication with 
the name and doses recorded in the eCRF. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is defined as any treatment discontinuation associated with 
the definitive decision from the Investigator or the patient not to re-expose the patient to the IMP 
at any time. 
10.3.3 List of criteria for permanent treatment discontinuation 
Patients may withdraw from treatment with the IMP at any time for any reason or this may be the 
Investigator’s decision. Patients should discuss stopping study medication with the site before 
doing so in order that questions can be addressed, glycemic therapy adjusted, and a follow-up 
assessment arranged. All efforts should be made to document the reasons for treatment 
discontinuation and this should be documented in the eCRF. 
The following reasons lead to permanent discontinuation: 
• 
At the patient’s own request (ie, withdrawal of consent for treatment) 
• 
If, in the Investigator’s opinion, continuation with the administration of the study 
treatment would be detrimental to the patient’s well-being 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 84 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 84 
• 
Intercurrent condition that requires permanent discontinuation of the study treatment as 
long as the abnormality persists and if the causal relationship of the concerned event and 
the IMP is possible (according to the Investigator’s best medical judgment) 
• 
Pregnancy (in female patients) 
• 
Specific request of the Sponsor. 
Any abnormal laboratory value will be immediately rechecked to confirm the result before a 
decision is made to permanently discontinue IMP for the concerned patient. 
For patients who prematurely discontinue the IMP, the assessments planned at the EOT Visit (see 
Section 10.1.2.3) will be performed at the Premature EOT Visit scheduled preferably prior to 
treatment discontinuation or as soon as possible after the time of discontinuation (at the latest at 
the next scheduled on-site visit). In the case of premature IMP discontinuation, PK samples 
should not be drawn at the Premature EOT Visit, or at any subsequent visit. The reason(s) for IMP 
discontinuation will be clearly specified. This EOT assessment may occur at a regularly scheduled 
or unscheduled visit. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Every effort should be made to maintain patients in the study. Patients should be followed-up 
according to the study procedures specified in this protocol up to the scheduled date of study 
completion, or up to recovery or stabilization of any AE to be followed up as specified in this 
protocol, whichever comes last. 
If a patient decides to discontinue study treatment early, a Premature EOT Visit (see  
Section 10.1.2.3) should be scheduled prior to treatment discontinuation, if possible. If not 
possible, the Premature EOT Visit should be scheduled as soon as possible after treatment 
discontinuation. In the case of premature IMP discontinuation, PK samples should not be drawn at 
the Premature EOT Visit, or at any subsequent visits. For patients that discontinue treatment but 
remain in the study, remaining study visits should occur as scheduled where possible. The IRT 
should be notified of EOT. 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the eCRF. 
10.3.5 Procedure and consequence for patient withdrawal from study 
Patients may withdraw from the study before study completion if they decide to do so, at any time 
and irrespective of the reason. Withdrawal of consent for treatment should be distinguished from 
withdrawal of consent for follow-up visits. Patients will be told that they are free to withdraw 
from the study at any time without any adverse effect on their care. However, if they no longer 
wish to take the IMP, they will be encouraged to remain in the study and attend the remaining 
study visits. The value of all their study data collected during their continued involvement will be 
emphasized as important to the public health value of the study. 
If possible, the patients are assessed using the procedure normally planned for the EOT Visit. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 85 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 85 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing. 
All confirmed study withdrawals should be recorded by the Investigator in the appropriate screens 
of the eCRF and in the patient’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator should make the best effort to re-contact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts (3 phone call attempts followed by a 
certified letter) to contact such patients must be documented in the patient’s records (eg, times and 
dates of attempted telephone contact, receipt for sending a registered letter). 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused. 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events 
10.4.1.1 Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death, or 
• 
Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect, or 
• 
Is a medically important event. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 86 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 86 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention (ie, specific measures or corrective treatment) to prevent one of 
the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
• 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
• 
Development of drug dependence or drug abuse 
• 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase >10 × ULN 
• 
Suicide attempt or any event suggestive of suicidality 
• 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
• 
Bullous cutaneous eruptions 
• 
Cancers diagnosed during the study or aggravated during the study 
• 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study. 
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid notification by the 
Investigator to the Sponsor may be appropriate. Such events may require further investigation in 
order to characterize and understand them. Adverse events of special interest may be added, 
modified, or removed during a study by protocol amendment. 
The AESI for this study are: 
• 
Pregnancy of a female patient entered in a study as well as pregnancy occurring in a 
female partner of a male patient entered in a study with IMP/NIMP: 
- 
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.4.1.2) 
- 
In the event of pregnancy in a female participant, IMP should be discontinued 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (see Appendix A). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 87 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 87 
• 
Symptomatic overdose with IMP/ NIMP 
- 
A symptomatic overdose (accidental or intentional) with the IMP/NIMP is an event 
suspected by the Investigator or spontaneously notified by the patient and resulting in 
clinical symptoms and/or signs accompanied by administration of more than twice the 
intended daily dose within a 24-hour period. It will be recorded in the eCRF as an 
AESI with immediate notification “Symptomatic OVERDOSE (accidental or 
intentional)” in all cases and will be qualified as an SAE only if it fulfills the SAE 
criteria 
- 
(Please note that an asymptomatic overdose with the IMP/NIMP, accidental or 
intentional, defined administration of more than twice the intended daily dose within a 
24-hour period, without clinical symptoms and/or signs, either suspected by the 
Investigator or spontaneously notified by the patient, not based on accountability 
assessment. It will be recorded as an AE “Asymptomatic OVERDOSE, accidental or 
intentional”). 
• ALT increase >3 × ULN (refer to related flow chart, Appendix E). 
10.4.1.4 Events of special interest 
An EOSI is a serious or non-serious AE of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring may be appropriate. Such events 
may require further investigation in order to characterize and understand them. These events 
should be reported on the specific eCRF page and will only qualify for expedited reporting when 
serious (fulfilling SAE criteria). 
The EOSI for this study are: 
• 
MACE (CV death, MI, or stroke) and other specific CV events (eg, heart failure leading to 
hospitalization) 
• 
Severe hypoglycemia (see Section 9.2.1.2) 
• 
Genital mycotic infections (to include vulvovaginal candidiasis in females and candidal 
balanitis in males) 
• 
UTIs 
• 
Clinically relevant volume depletion and events related/possibly related to volume 
depletion 
• 
Diarrhea 
• 
Pancreatitis 
• 
Bone fractures 
• 
Venous thrombotic events to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism) 
• 
DKA 
• 
Renal events to include 50% decline in eGFR, end stage kidney disease, renal death 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 88 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 88 
• 
Malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, 
prostate, and thyroid carcinoma) 
• 
Adverse events leading to an amputation. 
10.4.2 General guidelines for reporting adverse events 
• 
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the ICF until the end of the study as defined by the protocol for that patient, 
are to be recorded on the corresponding page(s) or screen(s) of the eCRF. 
• 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s). 
• 
In this study, the use of concomitant medications including antidiabetes medications may 
make it difficult to assess the causal relationship, particularly for hypoglycemia. The 
Global Safety Officer, with input from other appropriate study team members, will 
determine the causal relationship when it is not clearly provided by the Investigator. 
• 
The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
• 
When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
• 
Laboratory, vital signs, or ECG abnormalities are to be recorded as AEs if they are 
medically relevant based on the investigator’s’ medical judgment, eg: 
- 
Symptomatic, and/or 
- 
Requiring either corrective treatment or consultation, and/or 
- 
Leading to IMP discontinuation or modification of dosing, and/or 
- 
Fulfilling a seriousness criterion, and/or 
- 
Defined as an AESI or EOSI. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to the Monitoring team and 
Pharmacovigilance after approval of the Investigator within the eCRF 
• 
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 89 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 89 
team whose name, fax number, and e-mail address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient’s identity is protected and the patient’s 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
• 
All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification. 
• 
A back-up plan (using a paper case report form [CRF] process) is available and should be 
used when the eCRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest 
For AESI, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the eCRF. 
10.4.5 Guidelines for reporting events of special interest 
If an EOSI fulfills the criteria of an SAE, reporting should be performed according to the 
instructions for reporting of SAEs (see Section 10.4.3). Otherwise, reporting should follow the 
instructions for an AE (see Section 10.4.2). 
10.4.6 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix E. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices. 
• 
Neutropenia 
• 
Thrombocytopenia 
• 
Increase in ALT 
• 
Acute renal insufficiency 
• 
Suspicion of rhabdomyolysis. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 90 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 90 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• 
All SAEs that are both unexpected and at least reasonably related to the IMP (SUSARs), 
to the regulatory authorities, and Independent Ethics Committee (IECs)/Institutional 
Review Board (IRBs) as appropriate and to the Investigators 
• 
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations 
• 
The following AESI to those regulatory authorities who require such reporting: 
- 
Pregnancy 
- 
Symptomatic overdose 
- 
ALT increase >3 × ULN. 
Adverse events that are considered expected will be specified by the reference safety information 
provided in the current IB. 
If required, unblinding of SUSARs will be the responsibility of the Sponsor. 
The Sponsor will report all safety observations made during the conduct of the trial in the CSR. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Hypoglycemia 
During the study, patients are instructed to document the presence or absence of hypoglycemic 
episodes or hypoglycemic symptoms in their study diary. The hypoglycemia will be reported in 
the specific eCRF page with onset date and time, symptoms and/or signs, the SMBG value if 
available, and the treatment. If the event fulfills SAE criteria, hypoglycemia will also be reported 
as an SAE. 
Hypoglycemia is categorized according to the American Diabetes Association workgroup on 
hypoglycemia classification (21) and summarized in Figure 1. 
In addition to the threshold of ≤3.9 mmol/L (≤70 mg/dL), hypoglycemia episodes with a plasma 
glucose of <3.0 mmol/L (<54 mg/dL) will be analyzed separately. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 91 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 91 
Figure 1 - Hypoglycemia classification in Study EFC14868 
 
PG = plasma glucose; SAE = serious adverse event 
 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate (sugar), glucagon, intravenous glucose, or other resuscitative actions. These 
episodes may be associated with sufficient neuroglycopenia to induce seizure, unconsciousness, 
or coma. Self-monitored plasma glucose values may not be available, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient evidence that 
the event was induced by a low plasma glucose concentration. 
Note: “Requiring assistance of another person” means that the patient could not help himself or 
herself to treat the hypoglycemia. Assisting a patient out of kindness, when assistance is not 
required, should not be considered a “requires assistance” incident. 
Any hypoglycemic event which leads to unconsciousness, coma, or seizure should also be 
reported as an SAE. 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L 
(≤70 mg/dL). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 92 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 92 
Clinical symptoms that are considered to result from a hypoglycemic episode include increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL). 
Note: low plasma glucose values without symptoms or signs should not be reported more than 
once within 30 minutes. Repeated low glucose values within a short period could be due to 
malfunction of the device, error testing or following up a low glucose reading. The Investigator 
should try not to document false low SMBG values or redundant low glucose values as 
asymptomatic hypoglycemic events. Further clarification with the patients is needed. 
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms of hypoglycemia are not 
accompanied by a plasma glucose determination, (but that was presumably caused by a plasma 
glucose concentration ≤3.9 mmol/L [≤70 mg/dL]), ie, symptoms treated with oral carbohydrate 
without a test of plasma glucose. 
Relative hypoglycemia 
Relative hypoglycemia recently termed “pseudo-hypoglycemia” (21) is an event during which the 
patient reports typical symptoms of hypoglycemia, and interprets the symptoms as indicative of 
hypoglycemia, but with a measured plasma glucose concentration >3.9 mmol/L (>70 mg/dL). 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final CSR. 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 93 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 93 
11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
The sample size/power calculations were performed based on the primary endpoint. Assuming a 
common standard deviation (SD) of 1.2% and using a 2-sided test at a 0.05 α-level, 280 patients 
in the sotagliflozin 400 mg arm and 140 patients in the placebo arm will provide at least 95% 
power to detect a treatment difference of 0.5% in mean HbA1c change from Baseline to Week 18 
between sotagliflozin 400 mg and placebo. 
A sample size of 140 patients in the sotagliflozin 200 mg arm and 140 patients in the placebo arm 
will provide 80% power to detect a treatment difference of 0.4% in mean HbA1c change from 
Baseline to Week 18 between sotagliflozin 200 mg and placebo (SD 1.2%; 5% significance level 
2-sided). 
The total sample size will be 560 patients to be randomized (280 patients in the sotagliflozin 
400 mg arm; 140 patients in the sotagliflozin 200 mg arm; 140 patients in the placebo arm). 
11.2 
DISPOSITION OF PATIENTS 
The total number of patients for each of the following categories will be presented in the CSR: 
• 
Screened patients: patients who have signed the ICF 
• 
Run-in patients 
• 
Randomized patients: patients with a treatment kit number allocated and recorded in IRT 
database, regardless of whether the treatment kit was used or not 
• 
The safety population (ie, randomized and treated patients). 
• 
The intention to treat (ITT) population (as defined in Section 11.3.2 and analyzed as 
randomized) 
• 
The randomization strata (HbA1c at Week -1 [≤8.5%, >8.5%], SBP at Week -1 
[<130 mmHg, ≥130 mmHg], and sulfonylureas use at Week -1 [yes, no]). The discrepancy 
between the strata assigned by IRT and the information reported on eCRF will be listed for 
all randomized patients. 
• 
Patients who have completed the 18-week randomized core Treatment Period 
• 
Patients who discontinued the IMP during the 18-week randomized core Treatment Period, 
and the reasons for treatment discontinuation 
• 
Patients who have completed the entire 52-week double-blind Treatment Period 
• 
Patients who discontinued the IMP during the entire 52-week double-blind Treatment 
Period, and the reasons for treatment discontinuation 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 94 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 94 
• 
Patients who have completed the study 
• 
Patients who discontinued the study, and the reasons for study discontinuation. 
For all categories of patients except screened, percentages will be calculated using the number of 
randomized patients as denominator for each treatment group. 
A list of patients prematurely discontinued from the treatment, along with reasons for 
discontinuation, will be provided. Similarly, a list of patients prematurely discontinued from the 
study, along with reasons for discontinuation, will be provided. 
Patients treated but not randomized, patients randomized but not treated and patients randomized 
but not treated as randomized will be identified and described in separate listings. The safety 
experience of patients treated and not randomized will be reported separately, and these patients 
will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
Efficacy analyses will be based on the treatment group allocated by the IRT according to the 
schedule at Randomization Visit (as randomized), irrespective of the treatment group actually 
received. 
11.3.2 Intent-to-treat population 
Efficacy analyses will be based on the ITT population, defined as all randomized patients 
irrespective of compliance with the study protocol and procedures. Patients will be analyzed for 
efficacy analyses according to the treatment group to which they are randomized. 
11.3.3 Safety population 
Safety analyses will be based on the safety population, defined as all randomized patients who 
receive at least 1 dose of double-blind IMP (regardless of the amount of treatment administered). 
Patients will be analyzed for safety analyses according to the treatment actually received. 
In addition: 
• 
Non-randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately. 
• 
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
• 
When a patient is exposed to both sotagliflozin and placebo, the patient will be analyzed in 
the sotagliflozin group (depending on the treatment kit taken [400 mg or 200 mg]). 
• 
When a patient is exposed to both sotagliflozin 400 mg (treatment kit) and 200 mg 
(treatment kit), the patient will be analyzed in the sotagliflozin 200 mg group. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 95 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 95 
• 
Randomized patients will be excluded from the safety population only if there is 
documented evidence (ie, all study dates recorded as no medication taken) that patients 
have not taken the study medication. 
11.4 
STATISTICAL METHODS 
Continuous data will be summarized by treatment group using the number of observations 
available (N), mean, SD, minimum, median, and maximum. Categorical data will be summarized 
by treatment group using count and percentage. 
In general, descriptive statistics of quantitative efficacy and safety parameters (result and change 
from Baseline) by scheduled visits will be provided on observed cases (OC), ie, inclusion of only 
patients having non-missing assessments at a specific visit. 
The Baseline value is defined generally as the last available value before the first dose of 
double-blind IMP or the last available value prior to Randomization for patients who were 
randomized but never exposed to IMP. 
For serum creatinine and eGFR, the Baseline value is defined as average of all values before the 
first dose of double-blind IMP for those patients randomized and exposed or before randomization 
for those patients who were randomized but never exposed to IMP. 
Analysis of demographics and Baseline characteristics, prior and concomitant medications will be 
provided in detail in the SAP. 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received in the Safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
The extent of study treatment exposure will be assessed by the duration of treatment exposure 
during the study. 
The duration of treatment exposure will be the total number of days of administration of the 
double-blind IMP, regardless of unplanned intermittent discontinuations. The duration of IMP 
exposure will be calculated as: 
(Date of the last double-blind IMP taken – Date of the first double-blind IMP taken) + 1 
The number (%) of patients randomized and exposed to double-blind IMP will be presented by 
specific time periods for each treatment group. The time periods of interest will be defined in the 
SAP. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 96 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 96 
Descriptive statistics of duration of treatment exposure (number, mean, SD, minimum, median, 
and maximum) and cumulative exposure in patient year will also be presented by treatment group 
in the Safety population. 
11.4.1.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, mean, SD, median, min, and max). The percentage of patients with compliance 
<80% will be summarized. In addition, the number and percentage of patients with at least 
1 above-planned dosing administration will be given, as well as the number and percentage of 
patients with 0, 0 to 20%, and >20% under-planned dosing administrations. 
11.4.2 Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population. 
Statistical testing will be performed for primary endpoint at Week 18, and at Week 12 (for SBP) 
and Week 18 and Week 52 (for HbA1c and BW) for secondary endpoints. All other efficacy 
variables will only be summarized by descriptive statistics without formal statistical testing. 
11.4.2.1 Analysis of primary efficacy endpoint 
The statistical test will be two-sided tests at a nominal 5% significance level. 
Analysis of the primary efficacy endpoint (change from Baseline to Week 18 in HbA1c) will be 
performed using the ITT population, using HbA1c measurements obtained from visits during the 
study, including those obtained after IMP discontinuation or introduction of rescue therapy. 
The primary efficacy endpoint of change in HbA1c from Baseline to Week 18 will be analyzed 
with missing values imputed by control-based multiple imputation method under the missing not 
at random framework. 
• For placebo patients, missing data will be imputed based on the placebo group data 
• For patients in the sotagliflozin groups, missing data will be imputed as if the patients 
were on placebo group throughout the study, where all patients’ measurements including 
the on-treatment measurements will be considered as if the measurements were from the 
placebo group in the imputation model. 
Each of the complete datasets will be analyzed by the analysis of covariance (ANCOVA) model 
with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), randomization strata 
of Week -1 HbA1c (≤8.5%, >8.5%), randomization strata of Week -1 SBP (<130 mmHg, 
≥130 mmHg), randomization strata of sulfonylureas use at Week -1 (yes, no), and country as fixed 
effects, and Baseline HbA1c value as a covariate. Results from each complete dataset will be 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 97 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 97 
combined to provide the adjusted mean change in HbA1c from Baseline to Week 18 for the 
sotagliflozin 400 mg arm and placebo arm, as well as the between-group difference (comparing 
sotagliflozin 400 mg arm versus placebo) and the 95% confidence interval (CI) using contrast 
statements. 
Summary statistics (for Screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided for each treatment group. The summary will 
include the number of observations, mean, SD, standard error (SE), minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from Baseline (±SE) at each of the scheduled visits (using OC). 
Assessment of treatment effect by subgroup 
Descriptive analyses will be performed on the primary endpoint to summarize the treatment 
effects across subgroups defined by the following Baseline or Screening factors: 
• 
Race 
• 
Ethnicity (Hispanic, Not Hispanic) 
• 
Age group (<50 years, ≥50 to <65 years, ≥65 years) 
• 
Gender 
• 
Baseline BMI level (<30, ≥30 kg/m2) 
• 
Baseline HbA1c (≤8.5%, >8.5%) 
• 
Baseline SBP (<130 mmHg, ≥130 mmHg) 
• 
Country 
• 
Use of sulfonylureas at Week -1 (yes, no). 
The treatment effects across the subgroups defined for each of these factors will be estimated for 
the change from Baseline to Week 18 in HbA1c in the ITT population, and using a similar 
approach to the analysis for the primary efficacy endpoint. The adjusted estimates of treatment 
mean differences (sotagliflozin 400 mg versus placebo) with SE and 95% CIs will be provided as 
appropriate across the subgroups. 
In the event that the subgroup factor is identical or similar to a randomization strata factor (eg, 
Baseline HbA1c category, Baseline SBP category, or sulfonylurea use), only the subgroup factor 
will be included in the model in order to avoid the issue of co-linearity in the analysis. 
Baseline definition 
The Baseline value is defined generally as the last available value before the first dose of 
double-blind IMP or the last available value prior to Randomization for patients who were 
randomized but never exposed to IMP. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 98 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 98 
11.4.2.2 Analyses of secondary efficacy endpoints 
The secondary endpoints (Section 9.1.2) will be analyzed using a similar approach to the primary 
efficacy endpoint, with missing values imputed by the control-based multiple imputation method 
under the missing not at random framework. 
• 
For placebo patients, missing data will be imputed based on the placebo group data 
• 
For patients in the sotagliflozin groups, missing data will be imputed as if the patients 
were on placebo group throughout the study, where all patients’ measurements including 
the on-treatment measurements will be considered as if the measurements were from the 
placebo group in the imputation model. 
For each of the continuous secondary endpoints, each of the complete datasets will be analyzed by 
the ANCOVA model with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), 
randomization strata of Week -1 HbA1c (≤8.5%, >8.5%), randomization strata of Week -1 SBP 
(<130 mmHg, ≥130 mmHg), randomization strata of sulfonylureas use at Week -1 (yes, no), and 
country as fixed effects, and Baseline secondary endpoint value as a covariate. Results from each 
complete dataset will be combined to provide the adjusted mean change from Baseline to 
Week 18 (Week 12 for SBP endpoints) for each treatment group, as well as the between-group 
difference (comparing each sotagliflozin group versus placebo) and the 95% CI using contrast 
statements. For HbA1c endpoint, results from each complete dataset will be combined to provide 
the adjusted mean change from Baseline to Week 18 for sotagliflozin 200 mg arm and placebo 
arm, as well as the between group difference (comparing the sotagliflozin 200 mg arm versus 
placebo arm) and the 95% CI using contrast statements. 
Summary statistics for the secondary endpoints at scheduled visits will be provided for each 
treatment group. The summary will include the number of observations, mean, SD, SE, minimum, 
median, and maximum. Graphical presentations will also be used to examine trends over time 
using mean values (± SE) and mean changes from Baseline (± SE) at each of the scheduled visits 
(using OC). 
11.4.2.3 Analysis of other efficacy endpoints 
Except for PRO endpoints, the analysis of other endpoints (see Section 9.1.3) will be descriptive 
with no formal testing. Summary statistics at scheduled visits using OC will be provided by each 
treatment group. Graphical presentations will also be used to illustrate trends over time. 
The analysis of the TRIM-D PRO scores will be conducted on the ITT population. 
For TRIM-D scores (total and domain scores), descriptive statistics will be presented by treatment 
group per visit. The change in TRIM-D scores from Baseline to endpoint will be analyzed using a 
similar approach to the primary efficacy endpoint, with missing values imputed by control-based 
multiple imputation method under the missing not at random framework. 
Each of the complete datasets will be analyzed by the ANCOVA model with treatment groups 
(sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), randomization strata of Week -1 HbA1c 
(≤8.5%, >8.5%), randomization strata of Week -1 SBP (<130 mmHg, ≥130 mmHg), and 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 99 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 99 
randomization strata of sulfonylureas use at Week -1 (yes, no), and country as fixed effects, and 
TRIM-D scores at Baseline as a covariate. Results from each complete dataset will be combined 
to provide the adjusted mean change from Baseline to Week 52 for each treatment group, as well 
as the between-group difference (comparing sotagliflozin group versus placebo) and the 95% CI 
using contrast statements. 
The number (%) of patients achieving HbA1c response (<6.5%, <7% at Week 18 and Week 52, 
respectively) will be descriptive summarized at each scheduled visit. 
Sensitivity analysis may be performed as appropriate. 
11.4.2.4 Multiplicity considerations 
To control for the family wise type I error, a fixed-sequence testing procedure will be applied to 
the primary and key secondary endpoints to the following order: 
Once the main study primary variable (change from Baseline to Week 18 in HbA1c comparing 
sotagliflozin 400 mg versus placebo) is statistically significant at α = 0.05 (2-sided), a hierarchical 
testing procedure will be performed to test the following main study secondary efficacy variables 
by the following prioritized order. The testing will stop as soon as an endpoint is found to be not 
statistically significant at α = 0.05 (2-sided). 
• 
Comparing sotagliflozin 400 mg versus placebo: 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all patients 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
• 
Comparing sotagliflozin 200 mg versus placebo: 
- 
Change from Baseline to Week 18 in HbA1c 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
No multiplicity adjustment will be made on other secondary efficacy variables than mentioned 
above. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 100 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 100 
11.4.3 Analyses of safety data 
The summary of safety results will be presented by treatment group. All safety summaries will be 
descriptive; no statistical significance tests will be performed on safety data.  
Safety endpoints are presented in Section 9.2. These analyses will be based on the safety 
population as defined in Section 11.3.3. Patients will be analyzed for safety analyses according to 
the treatment actually received. The safety analyses will be provided for the 18-week randomized 
core Treatment Period and for the entire 52-week double-blind Treatment Period, unless specified 
otherwise. 
The following definitions will be applied to laboratory parameters and vital signs: 
• The potentially clinically significant abnormality (PCSA) values for clinical laboratory 
tests and vital signs are defined as abnormal values considered medically important by the 
Sponsor’s Global Pharmacovigilance and Epidemiology department and in effect at the 
time of the final SAP approval. The PCSA criteria for parameters not cited in the protocol 
as safety parameters will not be analyzed. 
• The PCSA criteria will determine which patients had at least 1 PCSA during the 
on-treatment period, taking into account all evaluations performed during the on-treatment 
period, including unscheduled or repeated evaluations. The number of all such patients 
will be the numerator for the on-treatment PCSA percentage. 
The “observation periods” defined in Section 9.2 are applicable for classification of AEs, 
determination of on-treatment PCSA values and the last on-treatment value for the laboratory, 
vital sign and ECG parameters. 
11.4.3.1 Analysis of adverse events 
Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-Treatment Period. 
Treatment-emergent AEs are AEs that developed or worsened (according to the Investigator’s 
opinion) or became serious during the on-Treatment Period. 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-Treatment Period. 
The primary focus of AE reporting in the CSR will be on TEAEs. Pre- and post-treatment AEs 
will be described separately. 
All adverse events 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the N and percentage (%) of 
patients experiencing an AE. Multiple occurrences of the same event in the same patient will be 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 101 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 101 
counted only once in the tables within a treatment phase. The denominator for computation of 
percentages is the safety population within each treatment group. 
Summaries of all TEAEs in each treatment group will include: 
• 
The overview of AEs, summarizing number (%) of patients with any 
- 
TEAE 
- 
Serious TEAE 
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation. 
• 
The N and percentage (%) of patients with at least one TEAE by primary SOC, HLGT, 
HLT, and PT 
• 
Summary of TEAEs by maximal severity (severe, moderate, mild), presented by primary 
SOC and PT 
• 
Summary of TEAEs possibly related to IMP, presented by primary SOC, HLGT, HLT, 
and PT. 
A detailed listing of TEAE summaries will be provided in the SAP. 
Death and serious adverse events 
Death and treatment-emergent SAEs will be summarized and presented as number and percent of 
patients in each treatment group. 
The following deaths summaries will be generated: 
• Number (%) of patients who died by study period (on-study, on-treatment, post-study) 
summarized on the safety population by treatment received 
• Death in non-randomized patients or randomized and not treated patients 
• TEAE leading to death (death as an outcome on the AE eCRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT, and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT. 
Adverse events leading to permanent treatment discontinuation 
Treatment-emergent AEs leading to permanent treatment discontinuation will be summarized and 
presented as number and percent of patients in each treatment group. 
11.4.3.2 Analysis of hypoglycemia 
The number (%) of patients and rate in patient years (2 types: the number of patients with events 
or the number of events per 100 patient-years) of all, severe and/or documented symptomatic 
hypoglycemia, will be summarized by treatment group respectively. In addition, documented 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 102 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 102 
hypoglycemia will also be analyzed by using a threshold of plasma glucose of <54 mg/dL 
(3.0 mmol/L).  
Their pattern of occurrence over time will also be assessed, as appropriate. 
11.4.3.3 Analysis of adverse events of special interest 
Pregnancy and overdose will be included in overall AE summaries if any are reported. Alanine 
aminotransferase increase >3 × ULN is included in laboratory PCSA summary, if any. 
11.4.3.4 Analysis of events of special interest 
The number (%) of patients with each EOSI event will be summarized by treatment group. All 
events reported by the Investigators on the AE forms for special interest will be listed along with 
the adjudication outcome (if applicable). 
11.4.3.5 Analysis of laboratory variables 
The number and percentage of patients with PCSA or by the predefined categories (if no PCSA 
criterion is defined) at any evaluation during the on-Treatment Period will be summarized for 
each clinical laboratory test within each treatment group. The summaries will include patients in 
the safety population who have at least one laboratory test performed during the on-Treatment 
Period and, when required by the definition of the abnormality, with an available Baseline value 
and available laboratory normal ranges. 
Descriptive statistics will be used to summarize the laboratory results and the changes from 
Baseline by visit and for the last on-treatment value within each treatment group. Shift tables and 
other tabular and graphical methods may be used to present the results for laboratory tests of 
interest. Listings will be provided with flags indicating the out of laboratory range values as well 
as the PCSA values. 
The liver function tests, namely ALT, AST, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
post-Baseline visit by Baseline status will be displayed by treatment group for each parameter. 
11.4.3.6 Analyses of vital sign variables 
The number and percentage of patients with PCSA at any evaluation during the on-Treatment 
Period will be summarized for each vital sign parameter within each treatment group. The 
summaries will include patients in the safety population who have at least one parameter to be 
analyzed during the on-Treatment Period. Descriptive statistics will be used to summarize the 
results and the changes from Baseline by visit and for the last on-treatment value within each 
treatment group. Tabular and graphical methods may be used to present the results for parameters 
of interest. Listings will be provided with flags indicating the PCSA values. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 103 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 103 
11.4.3.7 Analyses of 12-lead electrocardiogram status 
A shift table will be provided to present the ECG on-treatment status according to the Baseline 
status within each treatment group. 
11.4.3.8 Analyses of pharmacokinetic variables 
The PK endpoint is presented in Section 9.3.1. Individual plasma concentrations of sotagliflozin 
and of its 3-O-glucuronide at nominal sampling times will be listed. 
Concentration data will be summarized by visit and, if appropriate, within visit by nominal 
sampling times (pre-dose), using descriptive statistics by N, geometric mean, coefficient of 
variation, median, minimum, and maximum at each visit/nominal sampling time point for 
sotagliflozin-treated patients. 
11.5 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned for this study. The study will not be terminated 
early for excellent efficacy. 
An independent DMC will monitor and assess the safety of patients from this trial through 
periodic review of the accumulated safety data provided by an independent statistical group. 
Related details are provided in separate documents (DMC charter and DMC SAP). 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 104 of 365




Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 105 
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. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 106 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 106 
13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the eCRF, Discrepancy Resolution Form or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient’s data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Sub-investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The 
Sub-investigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor and/or service provider of this clinical trial is responsible to regulatory authorities for 
taking all reasonable steps to ensure the proper conduct of the clinical trial as regards ethics, 
clinical trial protocol compliance, and integrity and validity of the data recorded on the eCRFs. 
Thus, the main duty of the monitoring team is to help the Investigator and the Sponsor maintain a 
high level of ethical, scientific, technical, and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters, or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator, and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE and EOSI documentation, IMP allocation, 
patient compliance with the IMP regimen, IMP accountability, concomitant therapy use, and 
quality of data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the pre-identified source data directly recorded in the eCRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 107 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 107 
ethics committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the eCRFs (eg, patient's medical file, appointment 
books, original laboratory records, etc). These personnel, bound by professional secrecy, must 
maintain the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All eCRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification. 
Data will be available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor/service provider may generate additional 
requests (Discrepancy Resolution Form) to which the Investigator is obliged to respond by 
confirming or modifying the data questioned. The requests with their responses will be managed 
through the eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor/service provider and Investigator study files. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 108 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 108 
14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification, and training of 
each Investigator and Sub-investigator will be signed, dated, and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation and take measures to prevent 
accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee. 
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to the clinical trial 
protocol, personal data in relation to the patients, the eCRFs, the IB, and the results obtained 
during the course of the clinical trial, is confidential, prior to the publication of results. The 
Investigator and any person under his/her authority agree to undertake to keep confidential and 
not to disclose the information to any third party without the prior written approval of the 
Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Sub-investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-investigators of the confidential nature of the clinical trial. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 109 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 109 
The Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party’s account. 
14.4 
PROPERTY RIGHTS 
All information, documents, and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Sub-investigator not to 
mention any information or the product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents, and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market, or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Sub-Investigators shall provide all assistance 
required by the Sponsor, at the Sponsor’s expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document. 
14.6 
DATA PROTECTION 
• 
The patient’s personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations 
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party 
• 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Patient race and ethnicity (race: American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, not reported, unknown; ethnicity: 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 110 of 365




Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 111 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor 
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following: 
• 
The information on the product leads to doubt as to the benefit/risk ratio 
• 
Patient enrollment is unsatisfactory 
• 
The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon 
• 
Noncompliance of the Investigator or Sub-investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP 
• 
The total number of patients is included earlier than expected. 
In any case, the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial. 
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a CSR and to provide a summary of study results to 
the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 112 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 112 
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. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 113 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 113 
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. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 114 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 114 
16 
BIBLIOGRAPHIC REFERENCES 
1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: 
perspectives on the past, present, and future. Lancet. 2014;383(9922):1068-83. 
2. Fowler MJ. Microvascular and Macrovascular Complications of Diabetes. Clinical Diabetes. 
2008;26(2):77-82. 
3. International Diabetes Federation. IDF Diabetes Atlas, 7th ed. Brussels, Belgium: 
International Diabetes Federation, 2015.  http://www.diabetesatlas.org. Accessed: 19 Mar 
2017. 
4. World Health Organization, Regional Office for Europe, Data and Statistics. 
http://euro.who.int/en/health-topics/noncommunicable-diseases/diabetes/data-and-statistics. 
Accessed: 17 Mar 2017. 
5. American Diabetes Association. Standards of Medical Care in Diabetes - 2013. Diabetes Care. 
2013;36(Supplement 1):S11-S66. 
6. Bailey CJ. The Current Drug Treatment Landscape for Diabetes and Perspectives for the 
Future. Clin Pharmacol Ther. 2015;98(2):170-84. 
7. Castaneda-Sceppa C, Castaneda F. Sodium-dependent glucose transporter protein as a 
potential therapeutic target for improving glycemic control in diabetes. Nutr Rev. 
2011;69(12):720-9. 
8. Mudaliar S. Sodium-Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal 
Glucose Transport: From Bench to Bedside. Diabetes Care. 2015;38(12):2344-53. 
9. Hediger HA, Coady MJ, Ikeda TS, Wright EM. Expression cloning and cDNA sequencing of 
the Na+/glucose cotransporter. Nature. 1987;330(6146):379-81. 
10. Wright EM. I. Glucose galactose malabsorption. Am J Physiol. 1998;275(5 Pt 1):G879-82. 
11. Raskin P. Sodium-glucose cotransporter inhibition: therapeutic potential for treatment of type 
2 diabetes mellitus. Diabetes Metab Res Rev. 2013;29(5):347-56. 
12. Zambrowicz B, Freiman J, Brown PM, Frazier KS, Turnage A, Bronner J, et al. LX4211, a 
dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a 
randomized, placebo-controlled trial. Clin Pharmacol Ther. 2012;92(2):158-69. 
13. American Diabetes Association. Pharmacologic approaches to glycemic treatment. Sec. 8. In 
Standards of Medical Care in Diabetes - 2017. Diabetes Care. 2017;40(Suppl. 1):S64–S74. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 115 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 115 
14. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update 
to a position statement of the American Diabetes Association and the European Association 
for the Study of Diabetes. Diabetes Care. 2015;38(1):140-9. 
15. U.S. Department of Health and Human Services. Food and Drug Administration. Center for 
Drug Evaluation and Research (CDER). Guidance for Industry. Diabetes Mellitus: Developing 
Drugs and Therapeutic Biologics for Treatment and Prevention. February 2008. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM071624.pdf. Accessed: 11 Apr 2017. 
16. American Diabetes Association. Standards of Medical Care in Diabetes – 2017. Diabetes 
Care. 2017;40(Suppl 1):S1-S135. 
17. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-70. 
18. Florkowski CM, Chew-Harris JS. Methods of Estimating GFR - Different Equations Including 
CKD-EPI. Clin Biochem Rev. 2011;32(2):75-9 
19. Brod M, Hammer M, Christensen T, Lessard S, Bushnell DM. Understanding and assessing 
the impact of treatment in diabetes: the Treatment-Related Impact Measures for Diabetes and 
Devices (TRIM-Diabetes and TRIM-Diabetes Device). Health Qual Life Outcomes. 
2009;7:83. 
20. Brooke J, Stiell M, Ojo O. Evaluation of the Accuracy of Capillary Hydroxybutyrate 
Measurement Compared with Other Measurements in the Diagnosis of Diabetic Ketoacidosis: 
A Systematic Review. Int J Environ Res Public Health. 2016;13(9). pii:E837. 
21. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and The Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95. 
 
 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 116 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 116 
17 
APPENDICES 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 117 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 117 
Appendix A 
Guidance on contraceptive methods and collection of pregnancy 
information 
DEFINITIONS 
Non-reproductive potential 
• Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy. 
• Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm 
a postmenopausal state in women not using hormonal contraception or hormone 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Women of reproductive potential (WOCBP) must use a highly effective method of contraception 
during the treatment period and the post-treatment follow up period (14 ± 3 days). If another 
contraceptive method is used (such as a barrier method), it should be used in combination with 
one of the highly effective methods (such as an oral contraceptive).  
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 118 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 118 
 
Female patients: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 
- 
Oral 
- 
Intravaginal 
- 
Transdermal. 
• Progestogen-only hormone contraception associated with inhibition of ovulation 
− Oral 
− Injectable. 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method(s) of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.) 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the patient.) 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for patients participating in clinical studies. 
 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 119 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 119 
COLLECTION OF PREGNANCY INFORMATION 
Male patients with partners of reproductive potential who become pregnant 
• The Investigator will attempt to collect pregnancy information on any female partner of a 
male study patient who becomes pregnant while participating in this study. This applies 
only to patients who receive study treatment 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy 
• Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor 
• Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure. 
Female patients who become pregnant 
• The Investigator will collect pregnancy information on any female patient, who becomes 
pregnant while participating in this study 
• Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant’s pregnancy 
• Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which will be forwarded to 
the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date 
• Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE 
• A spontaneous abortion is always considered to be an SAE and will be reported as such 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the study treatment by the Investigator, will be reported to the Sponsor as described in  
Section 10.4.3. While the Investigator is not obligated to actively seek this information in former 
study patients, he/she may learn of an SAE through spontaneous reporting. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 120 of 365






Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 122 
Appendix C 
Recommendations on basic genitourinary hygiene, maintaining 
hydration, and recognizing diabetic ketoacidosis 
Patients with T2D are at risk for developing genitourinary (GU) infections. The following 
guidelines should be communicated to females and uncircumcised males regarding GU infections. 
Patient communication cards will be printed with the following: 
For females: 
“The following advice may be useful in helping you to keep your bladder and urethra free from 
infection: 
• 
Go to the toilet as soon as you feel the need to urinate, rather than holding it in 
• 
Wipe from front to back after going to the toilet 
• 
Practice good hygiene by washing your genitals every day, and before having sex 
• 
Empty your bladder after having sex.” 
For uncircumcised males: 
“The following advice may be useful in helping you to keep the foreskin free from infection: 
• 
Wash the end of your penis and foreskin with soap and water (do not let soap get in the 
opening) 
• 
After your shower or bath, dry the end of your penis and foreskin properly and replace the 
foreskin 
• 
Also, when you urinate, slide the foreskin back enough so that urine does not get on the 
foreskin-this helps to keep it clean.” 
Maintaining hydration: 
Sodium-glucose cotransporter type 2 inhibitors are associated with osmotic diuresis and volume 
depletion, which may lead to dizziness or hypotension, especially in the elderly. Before initiating 
study drug (at Screening, Run-in and Randomization) and during all on-site study visits thereafter, 
assess volume status in patients with renal impairment, the elderly, in patients with low SBP, or if 
receiving diuretics, angiotensin-converting-enzyme inhibitors, or angiotensin receptor blockers. 
All patients will be advised to maintain proper fluid intake and to consider increasing it if they 
sense greater thirst, more urine production, or if they feel dizzy or faint. 
Patient communication cards will be printed with the following for patients with T2D: 
“The following advice may be useful in helping you to maintain proper hydration and prevent 
dehydration: 
• 
Dehydration is when your body loses too much fluid, frequently due to diarrhea or 
increased urination 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 123 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 123 
• 
Consider increasing the amount of fluids you drink if: 
- 
You sense greater thirst than usual 
- 
You have a dry mouth or cracked lips 
- 
You have a fever 
- 
You have diarrhea or vomiting 
- 
You urinate more frequently or in larger amounts than usual 
- 
You get up in the middle of the night to urinate (more than usual) 
- 
You feel dizzy or light-headed 
- 
You exercise, or when it is hot outside.” 
Recognizing diabetic ketoacidosis 
Potential GI AEs occurring with sotagliflozin may mask presenting symptoms of DKA. Patients 
will be provided with the BHB meter and instructions for use at the start of the Run-in Phase at 
Visit 2 (Week -4). Patients will be instructed to measure their BHB levels by fingerstick if they 
experience any symptoms consistent with ketosis/ketoacidosis throughout the entire study period. 
Patients will be instructed on how to respond (seek help, hydrate, ingest carbohydrates, etc) if they 
present with potential ketoacidosis symptoms and the BHB value is abnormal (>0.6 mM/L). 
Patient communication cards will be printed with the following: 
“If you have any of these symptoms on the list, measure your glucose and BHB by fingerstick, 
and then contact your study site immediately for assistance with managing your diabetes: 
• 
Inability to maintain oral intake 
• 
Generalized weakness 
• 
Abdominal (belly) pain 
• 
Increased weight loss 
• 
Fever 
• 
Frequent urination, including at night 
• 
Fruity-scented breath 
• 
Confusion 
• 
Acute illness 
• 
Consistently elevated blood glucose 
• 
Feeling very thirsty or drinking a lot 
• 
Nausea or vomiting 
• 
Having trouble thinking clearly or feeling tired. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 124 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 124 
It is possible to have DKA even if your blood glucose is not elevated. Regardless of your blood 
glucose level, if you have any of these symptoms on the list, then contact your study site 
regarding the need to be evaluated for possible DKA, which will include specific blood testing. If 
your study site is closed and your study doctor is not available, go to the nearest emergency room 
for evaluation. 
If your blood BHB reading is >0.6 mM/L and you have symptoms of ketoacidosis, seek help, 
hydrate, ingest carbohydrates, etc, as described above. 
If you are scheduled for a procedure or surgery that requires you to not take any food or liquids, 
please contact your study doctor for instructions on continuing study drug. In such cases your 
study doctor may advise you NOT to take your study drug from the day prior to the procedure or 
surgery until after the procedure or surgery is complete, and you are taking food and liquids as 
you normally do.” 
Whenever AE data is collected or the patient reports DKA or intercurrent illness (including 
infections), generalized weakness, increased weight loss, GI symptoms including nausea, 
vomiting, or abdominal pain or other symptoms or signs that the Investigator believes may be 
consistent with DKA, then the site will determine if an assessment for DKA is appropriate. If 
laboratory testing confirms presence of metabolic acidosis, then the “Possible DKA” eCRF will 
be completed. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 125 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 125 
Appendix D 
Measurement of blood pressure and heart rate 
Equipment 
1. Blood pressure measurements will be taken by an automated BP monitor or a manual 
sphygmomanometer. Same equipment should be used throughout the study and should be 
calibrated as per manufacturer recommendation. 
2. Bladder Length – Should nearly or completely encircle the patient’s arm. For many adults, 
the standard “adult” size bladder is not long enough and the “large” size bladder is 
recommended. 
3. Bladder Width – Should be at least 40% of the bladder length. 
Patient factors 
Extraneous variables associated with the measurement of BP should be minimized. These include: 
1. Food intake, caffeine-containing beverages, cigarette smoking, or strenuous exercise 
within 2 hours prior to measurement. 
2. Full urinary bladder. 
3. The patient should not be allowed to talk while BP is being measured. 
4. The patient should be placed in the examination room and the cuff should be placed on the 
patient’s nondominant arm. The proper sized cuff should fit snugly with the lower edge 
2 to 3 cm above the antecubital fossa. 
5. The patient should be allowed to sit quietly in a comfortably warm place (temperature 
around 25°C or 77°F) for 5 minutes with the arm supported at heart level, preferably with 
the cuff in place and with no restrictive clothing on the arm. The patient should be 
encouraged not to tense his/her muscles. 
Determination of the reference arm 
At Visit 1 (Week -6), seated BP should be measured in both arms after 5-minute rest period, and 
then again after 1 minute in both arms in seated position. The arm with the highest SBP will be 
determined at this visit, and BP should be measured always in this same arm throughout the study. 
Measurement technique 
At Visit 1, immediately following arm selection, with the patient in the same position, an 
additional seated BP should be measured in the selected arm (at least 1 minute after last 
measurement). 
At all other on-site visits, following the 5-minute rest period, 3 separate seated BPs should be 
measured in the selected arm with at least 1 minute between BP measurements and with the cuff 
fully deflated between measurements. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 126 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 126 
All 3 BPs will be recorded in the patient’s eCRF. The mean of the 3 seated BPs will constitute the 
BP value for that visit. 
Three seated heart rate measurements will be obtained. The mean of the 3 seated heart rate 
measurements will constitute the pulse rate value for that visit. 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 127 of 365












Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 132 
Appendix F 
Patient Qualitative Assessment of Treatment (PQAT) 
Week 18 Assessment 
The following questions ask for your opinion on the drug you received during this clinical study. 
There are no right or wrong answers; we would like to better understand your own experience of the drug. 
 
1. 
During this trial, so far, what were the main benefits you experienced with the drug you 
received? 
 
 
 
 
 
 
2. 
During this trial, so far, what were the main disadvantages you experienced with the drug you 
received? 
 
 
 
 
 
 
3. 
After this trial, would you be willing to continue using the drug you received during this trial? 
Yes   
No  
Please explain why? 
 
 
 
 
 
4. 
Based on your own experience in this trial so far, please select a response on the scale 
below 
The 
disadvantages of 
the drug I 
received 
significantly 
outweigh the 
benefits 
 
 
There were 
equal benefits 
and 
disadvantages 
of the drug I 
received 
 
 
The benefits of 
the drug I 
received 
significantly 
outweigh the 
disadvantages 
 
- 3 
 
- 2 
 
- 1 
 
0 
 
1 
 
2 
 
3 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 133 of 365


Amended Clinical Trial Protocol No. 02  
06-Mar-2018 
EFC14868 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 133 
Week 52 Assessment 
The following questions ask for your opinion on the drug you received during this clinical study. 
There are no right or wrong answers; we would like to better understand your own experience of the drug. 
 
1. 
In the past 6 months, what were the main benefits you experienced with the drug you 
received? 
 
 
 
 
 
 
2. 
In the past 6 months, what were the main disadvantages you experienced with the drug you 
received?  
 
 
 
 
 
 
3. 
After this trial, would you be willing to continue using the drug you received during this trial?  
Yes   
No  
Please explain why? 
 
 
 
 
 
4. 
Based on your own experience in the past 6 months, please select a response on the scale 
below 
The 
disadvantages of 
the drug I 
received 
significantly 
outweigh the 
benefits 
 
 
There were 
equal benefits 
and 
disadvantages 
of the drug I 
received 
 
 
The benefits of 
the drug I 
received 
significantly 
outweigh the 
disadvantages 
 
- 3 
 
- 2 
 
- 1 
 
0 
 
1 
 
2 
 
3 
 
(electronic 
 
 
 
2.0)
(electronic 
 
 
 
1.0)
Page 134 of 365



SAP_001.pdf: 
 
Official Title: 
 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 
52-week Multicenter Study to Evaluate the Efficacy and Safety of 
Sotagliflozin in Patients with Type 2 Diabetes Who Have 
Inadequate Glycemic Control on Basal Insulin 
Alone or in Addition to Oral Antidiabetes Drugs (OADs) 
NCT Number: NCT03285594 
Document Date: SAP Version 2: 05-December-2019 
 
 
 


Lexicon Pharmaceuticals, Inc. 
Protocol No.: EFC14868 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week 
Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin in Patients 
with Type 2 Diabetes Who Have Inadequate Glycemic Control on Basal Insulin 
Alone or in Addition to Oral Antidiabetes Drugs (OADs)  
Covance Study ID: 000000155200 
Statistical Analysis Plan  
Version: Final 2.0 
DATE OF ISSUE: 04 December 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 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 3 of 105 
VERSION HISTORY 
Version Status 
Version Date 
Final 1.0 
27 July 2018 
Final 2.0 
04 December 2019 
 


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 4 of 105 
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 ................................................................................................................................. 10 
1.2.1 
Primary objectives .......................................................................................................................... 10 
1.2.2 
Secondary objectives ..................................................................................................................... 10 
1.2.3 
Other objectives ............................................................................................................................. 10 
1.2.4 
Objectives of CGM sub-study ........................................................................................................ 11 
1.2.4.1 
Primary sub-study objective ........................................................................................................... 11 
1.2.4.2 
Secondary sub-study objectives ..................................................................................................... 11 
1.2.4.3 
Other sub-study objectives ............................................................................................................. 12 
1.3 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 12 
1.4 
STUDY PLAN ................................................................................................................................. 14 
1.4.1 
Main study ...................................................................................................................................... 14 
1.4.2 
CGM sub-study .............................................................................................................................. 15 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 16 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN...................... 16 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ..................................................................... 19 
2.1 
ANALYSIS ENDPOINTS ................................................................................................................ 19 
2.1.1 
Demographic and baseline characteristics .................................................................................... 19 
2.1.2 
Prior or concomitant medications ................................................................................................... 21 
2.1.2.1 
Rescue therapy .............................................................................................................................. 21 
2.1.2.2 
Prohibited prior and concomitant medications ............................................................................... 22 
2.1.3 
Efficacy endpoints .......................................................................................................................... 23 
2.1.3.1 
Primary efficacy endpoint(s) ........................................................................................................... 23 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 23 
2.1.3.3 
Other efficacy endpoints (sotagliflozin 400 mg and 200 mg doses) .............................................. 24 
2.1.3.4 
CGM sub-study endpoint(s) ........................................................................................................... 24 
2.1.4 
Safety endpoints ............................................................................................................................. 25 
2.1.4.1 
Hypoglycemia ................................................................................................................................. 26 
2.1.4.2 
Adverse events variables ............................................................................................................... 28 
2.1.5 
Bone fractures ................................................................................................................................ 30 
2.1.5.1 
Deaths ............................................................................................................................................ 32 
2.1.5.2 
Laboratory safety variables ............................................................................................................ 32 


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 5 of 105 
2.1.5.3 
Vital signs variables ........................................................................................................................ 34 
2.1.5.4 
Physical examination ...................................................................................................................... 34 
2.1.5.5 
Electrocardiogram variables ........................................................................................................... 34 
2.1.6 
Pharmacokinetic variables ............................................................................................................. 34 
2.1.7 
Patient-reported outcome variables ............................................................................................... 34 
2.1.7.1 
Patient’s qualitative assessment of treatment (PQAT) .................................................................. 34 
2.1.7.2 
Treatment related impact measure for diabetes (TRIM-D) ............................................................ 35 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 35 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 38 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 39 
2.3.1 
Efficacy populations ....................................................................................................................... 39 
2.3.1.1 
Intent-to treat population ................................................................................................................ 39 
2.3.1.2 
CGM sub-study population ............................................................................................................. 39 
2.3.2 
Safety population ............................................................................................................................ 39 
2.3.3 
PK population ................................................................................................................................. 40 
2.4 
STATISTICAL METHODS ............................................................................................................. 40 
2.4.1 
Demographics and baseline characteristics .................................................................................. 40 
2.4.2 
Prior or concomitant medications ................................................................................................... 41 
2.4.3 
Extent of investigational medicinal product exposure and compliance .......................................... 41 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 41 
2.4.3.2 
Compliance .................................................................................................................................... 42 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 43 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ......................................................................................... 43 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 47 
2.4.4.3 
Analyses of other efficacy endpoints .............................................................................................. 48 
2.4.4.4 
Multiplicity issues ............................................................................................................................ 49 
2.4.4.5 
Analyses of CGM sub-study efficacy variables .............................................................................. 50 
2.4.5 
Analyses of safety data .................................................................................................................. 56 
2.4.5.1 
Analyses of hypoglycemia .............................................................................................................. 57 
2.4.5.2 
Analyses of adverse events ........................................................................................................... 58 
2.4.5.3 
Deaths ............................................................................................................................................ 62 
2.4.5.4 
Analyses of laboratory variables .................................................................................................... 62 
2.4.5.5 
Analyses of vital sign variables ...................................................................................................... 64 
2.4.5.6 
Analyses of electrocardiogram variables ....................................................................................... 64 
2.4.5.7 
Analyses of physical examination variables ................................................................................... 64 
2.4.6 
Analyses of pharmacokinetic variables .......................................................................................... 64 
2.4.7 
Analyses of patient reported outcomes .......................................................................................... 65 
2.4.7.1 
Scoring methods ............................................................................................................................ 65 
2.4.7.2 
Analysis methods ........................................................................................................................... 65 


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 6 of 105 
2.5 
DATA HANDLING CONVENTIONS............................................................................................... 66 
2.5.1 
General conventions ...................................................................................................................... 66 
2.5.2 
Data handling conventions for secondary efficacy variables.......................................................... 67 
2.5.3 
Missing data ................................................................................................................................... 67 
2.5.4 
Windows for time points ................................................................................................................. 70 
2.5.5 
Unscheduled visits ......................................................................................................................... 72 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 72 
2.5.7 
Statistical technical issues ............................................................................................................. 72 
3 
INTERIM ANALYSIS ..................................................................................................................... 73 
4 
DATABASE LOCK ........................................................................................................................ 74 
5 
SOFTWARE DOCUMENTATION .................................................................................................. 75 
6 
REFERENCES ............................................................................................................................... 76 
7 
LIST OF APPENDICES ................................................................................................................. 77 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ....................... 78 
APPENDIX B 
LIST OF PTS FOR SELECT EOSIS (MEDDRA V22.0) ...................................................... 84 
APPENDIX C 
SUMMARY OF STATISTICAL ANALYSES ......................................................................... 93 
APPENDIX D 
STUDY FLOW CHART ........................................................................................................ 99 


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 7 of 105 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AESI: 
adverse events of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
BUN: 
blood urea nitrogen 
CGM: 
continuous glucose monitoring 
CI: 
confidence interval 
CPK: 
creatine phosphokinase 
CV: 
coefficient of variability 
DBP: 
diastolic blood pressure, diastolic blood pressure 
DCCT: 
Diabetes Control and Complications Trial  
DILI: 
drug-induced liver injury  
DMC: 
Data Monitoring Committee 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate, estimated glomerular filtration rate 
EOSI: 
events of special interest 
FPG: 
fasting plasma glucose 
HbA1c: 
hemoglobin A1c 
HDL-C: 
high density lipoprotein cholesterol 
HLGT: 
high level group term 
HLT: 
high level term 
HR: 
heart rate 
IFCC: 
International Federation of Clinical Chemistry and Laboratory Medicine  
IMP: 
investigational medicinal product 
IQR: 
interquartile range 
ITT: 
intent-to-treat 
KM: 
Kaplan-Meier 
LDH: 
Lactic acid dehydrogenase 
LDL-C: 
low density lipoprotein cholesterol 
LLT: 
lower level term 
MAGE: 
Mean Amplitude of Glycemic Excursion 
MAR: 
Missing at random 
MDRD: 
Modification of Diet in Renal Disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MI: 
multiple imputation, multiple imputation 
MNAR: 
missing not at random, missing not at random 


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 8 of 105 
NIMP: 
noninvestigational medicinal product 
OAD: 
oral antidiabetes drug 
PCSA: 
Potentially Clinically Significant Abnormality 
PQAT: 
Patient Qualitative Assessment of Treatment 
PT: 
preferred term 
PTH: 
Parathyroid hormone 
SAE: 
serious adverse events 
SBP: 
systolic blood pressure 
SD: 
standard deviation 
SE: 
standard error 
SMBG: 
self-monitored blood glucose, self-monitored blood glucose 
SOC: 
system organ class 
TC: 
total cholesterol 
TEAE: 
treatment-emergent adverse event 
TG: 
triglycerides 
TRIM-D: 
Treatment Related Impact Measure - Diabetes 
UACR: 
urinary albumin creatinine ratio, urinary albumin creatinine ratio 
ULN: 
upper limit of normal 
WHO-DD: 
World Health Organization-Drug Dictionary, World Health Organization-Drug 
Dictionary 


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 9 of 105 
1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a Phase 3, multicenter, randomized, double-blind (with single-blind Run-in Phase), 
placebo-controlled, parallel-group stratified study. Patients are to be randomly assigned 2: 1: 1 to 
the following 3 treatment groups 
• Sotagliflozin 400 mg 
• Sotagliflozin 200 mg 
• Placebo 
All patients will have Screening Period comprised of a Screening Phase of up to 2 weeks and a 4-
week Lantus titration/single-blind placebo titration Run-in Phase prior to randomization. 
Following randomization, patients will have a 52-week double-blind Treatment Period, and a 2-
week post-treatment Follow-up period (patients who prematurely discontinue the study treatment 
are expected to continue in the study). 
At the end of screening period, eligible patients are centrally randomized (using permuted block 
randomization schedule) via interactive response technology (IRT) in a 2:1:1 ratio to Sotagliflozin 
400 mg group, Sotagliflozin 200 mg group and Placebo group. The randomization will be 
stratified by hemoglobin A1c (HbA1c) (≤8.5%, >8.5%) and systolic blood pressure (SBP) (<130 
mmHg, ≥130 mmHg) and sulfonylureas use (Yes, No) at Week -1. 
It is anticipated to randomize a total of approximately 560 patients (Sotagliflozin 400 mg: 280; 
Sotagliflozin 200 mg: 140; Placebo: 140). 
Continuous Glucose Monitoring sub-study (CGM sub-study) 
Approximately 132 eligible patients participating at a number of pre-selected sites in the United 
States will also be involved in the CGM sub-study with approximately 66 patients in the 
sotagliflozin 400 mg arm, 33 patients in the sotagliflozin 200 mg arm and 33 patients in the 
placebo arm. Two CGM assessment periods are planned: Baseline CGM during Week -1 for 7 
consecutive days and post-randomization CGM during Week 18 and 19 for 14 consecutive days. 
Both patients and investigators will be masked to glucose values. 


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 10 of 105 
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 HbA1c reduction at Week 18 in patients with type 2 diabetes 
mellitus (T2D) inadequate glycemic control on basal insulin alone or with OADs.  
1.2.2 Secondary objectives 
• 
To assess the effects of sotagliflozin 400 mg versus placebo on: 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all patients 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
• 
To assess the effects of sotagliflozin 200 mg versus placebo on: 
- 
Change from Baseline to Week 18 in HbA1c 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 18 in FPG. 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
• 
To evaluate the safety of sotagliflozin 400 mg and 200 mg versus placebo throughout the 
52-week trial. 
1.2.3 Other objectives 
• 
To assess the effects of sotagliflozin 400 mg versus placebo on the proportion of patients 
with HbA1c < 7% or HbA1c < 6.5% at Weeks 18, 26, and 52 
• 
To assess the effects of sotagliflozin 200 mg versus placebo on the proportion of patients 
with HbA1c < 7% or HbA1c < 6.5% at Weeks 18, 26, and 52 
• 
To assess the effects of sotagliflozin 200 mg versus placebo on the change from Baseline 
to Week 12 in SBP for all patients 
• 
To assess the effects of sotagliflozin 400 mg and 200 mg versus placebo on: 
- 
Change from baseline to Week 26 in HbA1c 


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 11 of 105 
- 
Change from Baseline to Weeks 26 and 52 in SBP in all patients and the subset of 
patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Weeks 12, 26, and 52 in SBP in patients with Baseline SBP 
<130 mmHg 
- 
Change from Baseline to Weeks 12, 26, and 52 in diastolic blood pressure (DBP) for 
all patients and the subset of patients with Baseline DBP ≥80 mmHg 
- 
Change from Baseline to Week 52 in the total daily insulin dose 
- 
Proportion of patients requiring rescue therapy during the 52-week double-blind 
Treatment Period 
- 
Change from Baseline to Week 18 and Week 52 in 7-point Self-Monitored Blood 
Glucose (SMBG) profile (mean daily value at each time point)  
- 
Change from Baseline on estimated glomerular filtration rate (eGFR) 
- 
Change from Baseline in urinary albumin creatinine ratio (UACR) 
- 
Patient Qualitative Assessment of Treatment (PQAT) during the 52-week Treatment 
Period 
- 
Patient perception of treatment impact and satisfaction using the TRIM-D during the 
52-week Treatment Period. 
• 
To assess plasma concentrations of sotagliflozin and its 3-O-glucuronide metabolite. 
1.2.4 Objectives of CGM sub-study 
1.2.4.1 Primary sub-study objective 
To compare the effect of sotagliflozin 400 mg versus placebo on the percentage of time within the 
glucose range of 70 to 180 mg/dL (3.9 to 10.0 mmol/L) over 24 hours, as assessed with CGM 
1.2.4.2 Secondary sub-study objectives 
• 
To compare the effect of sotagliflozin 200 mg versus placebo on the percentage of time 
spent within the glucose range of 70 to 180 mg/dL (3.9 to 10.0 mmol/L) over 24 hours, as 
assessed with CGM 
• 
To compare the effect of sotagliflozin (200 and 400 mg) versus placebo over 24 hours, as 
assessed by CGM, on the following:  
- 
Mean 24 hour glucose concentration 
- 
Percentage of time spent within the glucose range of  70 to 140 mg/dL (3.9 to 
7.8 mmol/L) 
- 
Coefficient of variability (CV) of glucose concentrations 
- 
AUC of glucose concentrations for 2 hours after a standardized mixed meal 


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 12 of 105 
- 
2 hour postprandial plasma glucose (PPG) following a standardized mixed meal. 
1.2.4.3 Other sub-study objectives 
To compare the effects of sotagliflozin (200 and 400 mg) versus placebo on the following: 
• 
Percentage of time over 24 hours with glucose levels >140 mg/dL (>7.8 mmol/L), >180 
mg/dL (>10.0 mmol/L), >250 mg/dL (>13.8 mmol/L), <70 mg/dL (<3.9 mmol/L), and <54 
mg/dL (<3.0 mmol/L) 
• 
Percentage of time over 24 hours spent within the target range of 70 to 180 mg/dL (3.9 to 
10.0 mmol/L) during the diurnal period (6:00 AM to 11:59 PM) and nocturnal period 
(0:00 AM to 5:59 AM) 
• 
AUC of glucose concentrations over 24 hours  >140 mg/dL (>7.8 mmol/L), >180 mg/dL 
(>10.0 mmol/L), >250 mg/dL (>13.8 mmol/L), <70 mg/dL (<3.9 mmol/L), and <54 mg/dL 
(<3.0 mmol/L) 
• 
Various measures of glucose variability including Mean Amplitude of Glycemic Excursion 
(MAGE), standard deviation (SD) of glucose levels within and between days, and 
interquartile range (IQR)  
• 
Proportion of patients (%) with at least one hypoglycemic episode defined as CGM values 
<70 mg/dL (<3.9 mmol/L) for ≥15 minutes. 
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size/power calculations were performed based on the primary endpoint, change in 
HbA1c from baseline to Week 18 between sotagliflozin 400 mg and placebo. Assuming a 
common standard deviation (SD) of 1.2% and using a 2-sided test at a 0.05 α-level, 280 patients in 
the sotagliflozin 400 mg arm and 140 patients in the placebo arm will provide at least 95% power 
to detect a treatment difference of 0.5% in mean HbA1c change from Baseline to Week 18 
between sotagliflozin 400 mg and placebo. 
A sample size of 140 patients in the sotagliflozin 200 mg arm and 140 patients in the placebo arm 
will provide 80% power to detect a treatment difference of 0.4% in mean HbA1c change from 
Baseline to Week 18 between sotagliflozin 200 mg and placebo (SD 1.2%; 5% significance level 
2-sided). 
The total sample size will be 560 patients to be randomized (280 patients in the sotagliflozin 400 
mg arm; 140 patients in the sotagliflozin 200 mg arm; 140 patients in the placebo arm). 
The sample size/power calculations for the CGM sub-study are based on the primary variable, 
change from Baseline to Week 19 in the percentage of time within the target range of 70 to 180 
mg/dL over 24 hours for sotagliflozin 400 mg as compared to placebo. Assuming a common 
standard deviation of 18%, a common missing rate of 15% and using a 2-sided test at a 
0.05 α-level, 66 patients in the sotagliflozin 400 mg arm and 33 patients in the placebo arm will 


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 13 of 105 
provide at least 80% power to detect a difference of 12% of time within the target range of 70 to 
180 mg/dL over 24 hours between sotagliflozin 400 mg and placebo 
The total sample size for the CGM sub-study will be 132 patients (approximately 66 patients in 
sotagliflozin 400 mg arm, 33 patients in the sotagliflozin 200 mg arm, and 33 patients in the 
placebo arm).


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
Covance Study ID:000000155200 
 
 
 
Page 14 of 105 
1.4 
STUDY PLAN 
1.4.1 Main study 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version: Final 2.0 
 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868 
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 15 of 105 
1.4.2 CGM sub-study  
 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 16 of 105 
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 Nov 2, 2017. There are no planned interim analyses 
Table 1 - Protocol amendment statistical changes 
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
1 
27-Sep-2017 
Addition of other endpoints following 
the addition of study objectives 
Change in HbA1c from baseline to Week 26 
and 52 are added as other endpoints and 
other objectives  
1 
27-Sep-2017 
Urgent coronary revascularization 
not adjudicated by CEC to be 
consistent with outcome trials  
Urgent coronary revascularization not 
included in adjudication related analyses. 
1 
27-Sep-2017 
5 half-lives of sotagliflozin prolonged 
to 10 days considering patients with 
moderate renal dysfunction  
5 half-lives of IMP updated from 5 days to 10 
days; TEAE period updated accordingly 
1 
27-Sep-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. 
3 
06-Mar-2018 
Addition of secondary objectives to 
evaluate the long-term efficacy on 
HbA1c and body weight for 52 
weeks 
Change in HbA1c and body weight from 
baseline to Week 52 are added as secondary 
objectives/endpoints. The order of secondary 
objectives/endpoints/multiplicity adjustment 
updated 
 
 
 
 
 
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 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 18 of 105 
SAP version  
number 
Date approved 
Rationale 
Description of statistical 
changes 
2 
This version 
Lexicon process 
Appendix A removed 
2 
This version 
Assess robustness on the ITT-based 
analyses 
Identify possible need to conduct 
sensitivity analyses for PK anomalies 
2 
This version 
Numbering update 
Section 2.1.4 Subsections numbering 
corrected; 2.1.5 and 2.1.6 re-numbered 
accordingly 
2 
This version 
Consistency with other studies within 
the project 
UGE and UGCR added to Section 
2.4.4.3  
2 
This version 
 Lexicon medical group request 
Clarification on the analysis of the 2-hour 
PPG endpoint following a standardized 
mixed meal to be performed based on 
Time 0 adjusted values added to Section 
2.4.4.5 
*Change made in Protocol Amendment 1 dated 27-Sep-2017. 
**Change made in Protocol Amendment 2 dated 06-Mar-2018. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 19 of 105 
2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value (with the exception of serum creatinine and eGFR) is defined as the last 
available value before the first dose of double-blind investigational medicinal product (IMP) or 
the last available value prior to randomization for patients who were randomized but never 
exposed to IMP. 
For serum creatinine and eGFR, the baseline value is defined as the average of all values before 
the first dose of double-blind IMP for those randomized and exposed or before randomization for 
those who were randomized but never exposed to IMP. 
All baseline safety and efficacy parameters are presented along with the summary statistics in the 
safety and efficacy sections (Section 2.4.5 and Section 2.4.4). 
Demographic characteristics 
Demographic characteristics to be summarized are: 
• 
Age (years) derived as: (Year of informed consent - Year of birth), 
• 
Age categories (<50, ≥50 to <65, ≥65 to < 75, ≥75 years), 
• 
Gender (Male, Female), 
• 
Race (White, Black or African American, Asian, American Indian or Alaska native, Native 
Hawaiian or other pacific islander, Multiple, Unknown), 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown), 
• 
HbA1c (%) at Screening, 
• 
HbA1c (%) at Visit 5 (Week -1), 
• 
Randomization strata of HbA1c (≤8.5%, >8.5%) at Visit 5 (Week -1) (data from IRT), 
• 
SBP at Screening, 
• 
SBP at Visit 5 (Week -1), 
• 
Randomization strata of SBP (<130 mmHg, ≥130 mmHg) at Visit 5 (Week -1) (data from 
IRT), 
• 
Randomization strata of sulfonylureas use  (yes, no) at Visit 5 (Week -1) (data from IRT), 
• 
Baseline body mass index (BMI) (kg/m2) derived as: (Weight in kg)/(Height in meters)2, 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 20 of 105 
• 
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, 
• 
Duration of diabetes categories: (<10, ≥10 years) 
• 
Age at diagnosis of diabetes (years) derived as: Year of diagnosis of diabetes – Year of 
birth, 
• 
Duration of basal insulin treatment (years) derived as: (Date of informed consent – Date of 
first dose of basal insulin + 1)/365.25 
• 
Prior basal insulin use at screening by type/regimen: insulin glargine 100 U/mL, insulin 
glargine 300 U/mL, insulin detemir, insulin degludec, NPH, and other, 
• 
Daily dose of basal insulin (U) and daily dose of basal insulin adjusted by body weight 
(U/Kg) at screening, 
• 
Daily dose of Lantus (U) and daily dose of Lantus adjusted by body weight (U/Kg) at 
baseline, 
• 
Antidiabetic medication use at screening (Basal insulin only, Basal insulin and OAD(s)), 
• 
Baseline diabetic microvascular complications (Yes, No) [ie, diabetic retinopathy, diabetic 
neuropathy, diabetic nephropathy, diabetic peripheral neuropathy (sensory or motor), 
diabetic autonomic neuropathy, and diabetic foot infection], 
• 
Baseline urinary albumin creatinine ratio (UACR) categories (<30 mg/g [Normal], ≥30 to 
<300 mg/g [Microalbuminuria], and ≥300 mg/g [Macroalbuminuria]), 
• 
eGFR at screening (mL/min/1.73m2), 
• 
eGFR categories at screening (<15 mL/min/1.73m2 [End stage renal disease], ≥15 to <30 
mL/min/1.73m2 [Severe decrease in GFR], ≥30 to <60 mL/min/1.73m2 [Moderate 
decrease in GFR], ≥60 to <90 mL/min/1.73m2 [Mild decrease in GFR], and ≥90 
mL/min/1.73m2 [Normal]). 
• 
Prior antihypertensive medication identified by therapeutic class as agents acting on the 
renin-angiotensin system, beta blocking agents, diuretics (a sub-category: loop diuretics 
identified by pharmacological class as high-ceiling diuretics), calcium channel blockers, 
and antihypertensives according to World Health Organization-Drug Dictionary (WHO-
DD). 
Medical or surgical history  
Medical history and medical findings include: 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 21 of 105 
• 
Physical examination, 
• 
Medical or surgical history, 
• 
Medical history cardiovascular  
• 
Surgical history amputation 
• 
Alcohol habits, 
• 
Tobacco smoking habits. 
Medical and surgical history will be coded to a “lower level term (LLT)”, “preferred term (PT)”, 
“high level term (HLT)”, “high level group term (HLGT)”, and associated primary “system organ 
class (SOC)” using the version of Medical Dictionary for Regulatory Activities (MedDRA) 
currently in effect at Covance at the time of database lock. 
Any technical details related to computation, dates, and imputations for missing dates are 
described in Section 2.5. 
2.1.2 Prior or concomitant medications  
All medications taken within 3 months before the screening visit (any time for prior 
SGLT1/SGLT2) and until the end of the study are to be reported in the electronic case report form 
(eCRF). 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Covance at the time of database lock. 
• 
Prior medications are those the patient used prior to first administration of double-blind 
IMP. Prior medications can be discontinued before first administration or can be ongoing 
during treatment phase.   
• 
Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, from the 1st administration of double-blind IMP to the date of last administration + 
10 days.  A given medication can be classified both as a prior medication and as a 
concomitant medication.   
• 
Posttreatment medications are those the patient took in the period running from the 11th 
day after the last administration of double-blind IMP up to the end of the study. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.2.1 Rescue therapy 
The recommended approach to rescue, if rescue thresholds have been reached despite up-titration 
of the Lantus dose, is to initiate a prandial insulin, or a GLP-1 agonist or another antidiabetic 
agent (except SGLT2 inhibitors) as per the Investigator’s discretion and in line with local 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 22 of 105 
treatment guidelines. The prandial insulin can be any injectable short-acting insulin including 
rapid-acting insulin analogs (Humalog, Novolog and Apidra) or regular insulin (eg, Humulin). 
Rescue therapy is considered a noninvestigational medicinal product (NIMP). 
2.1.2.2 Prohibited prior and concomitant medications 
During the study Treatment Period, the following medications are prohibited: 
• 
Initiation of any antidiabetes agents, including oral, inhaled, or injectable 
antihyperglycemic agents other than the IMP and NIMP is not allowed before the rescue 
therapy. The existing background medication (NIMP) should not be modified before the 
rescue. 
• 
SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin) are not allowed for 
rescue. 
• 
Systemic use of glucocorticoids for more than 10 consecutive days (topical, intra-articular, 
ophthalmic, nasal spray, or inhaled applications are allowed). 
• 
IMPs in any other clinical study. 
• 
Modification of any antihypertensive medication before Week 12 is not allowed unless for 
safety reasons. 
• 
Initiation of any weight loss drugs (eg, phentermine, orlistat). 
Patients taking sotagliflozin with concomitant digoxin should have digoxin concentrations 
monitored and doses reduced as needed. In addition, other P-gp substrates may be affected and the 
labels of P-gp substrate drugs should be consulted with regards to monitoring and dose 
adjustments. 
Note: short-term use (<10 consecutive days) of the prohibited medication, eg, short-acting insulin 
for treatment of acute illness or surgery is allowed. 
Other medications which are unlikely to interfere with the PK or pharmacodynamics of the IMP or 
confound interpretation of the study endpoints are allowed as needed and following discussion 
between the Investigator and the Sponsor/CRO. However, doses of chronically administered 
medicines should be kept fixed during the trial if at all possible. 
The dose of all antihypertensive agents should be kept constant during the 12 weeks following 
randomization and no antihypertensive agents should be added or withdrawn for the 12 weeks 
following randomization unless it is considered necessary for safety reasons. During the Run-in 
Phase, adjustments to antihypertensive therapy can be made as needed. After randomization, 
antihypertensive regimen should be kept constant during the following 12 weeks. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 23 of 105 
2.1.3 Efficacy endpoints 
All efficacy measurements collected during the study will be considered for analyses, including 
those obtained after IMP discontinuation or introduction of rescue therapy (see Section 2.5.4). 
HbA1c, 2-hour PPG, FPG, UACR, and eGFR are measured/calculated in a central laboratory (see 
study flowchart in Appendix D). Body weight, SBP and DBP (see Section 2.1.5.3) 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 or with the answer to the 
question “Is intended daily dose give per protocol or rescue therapy” ticked “rescue therapy” in e-
CRF “Exposure-Treatment Period (Lantus)” page. 
Efficacy variables will be summarized in both standard international units and conventional units 
when applicable. 
2.1.3.1 Primary efficacy endpoint(s) 
Comparison of sotagliflozin 400 mg versus placebo in change from baseline to Week 18 in HbA1c 
(%). 
2.1.3.2 Secondary efficacy endpoint(s) 
• 
Continuous secondary efficacy endpoints for the sotagliflozin 400 mg dose: 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 18 in BW. 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all patients 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
• 
Continuous secondary efficacy endpoints for the sotagliflozin 200 mg dose: 
- 
Change from Baseline to Week 18 in HbA1c 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 24 of 105 
2.1.3.3 Other efficacy endpoints (sotagliflozin 400 mg and 200 mg doses) 
• 
Proportion of patients with HbA1c <7.0% or HbA1c <6.5% at Week 18, 26 and Week 52. 
• 
Change from Baseline to Week 26 in HbA1c 
• 
Change from Baseline to Week 12 in SBP for all patients in the sotagliflozin 200 mg arm, 
and from Baseline to Weeks 26 and 52 in SBP for all patients and the subset of patients 
with Baseline SBP ≥130 mmHg in the sotagliflozin 400 mg and 200 mg arms 
• 
Change from Baseline to Weeks 12, 26, and 52 in SBP in patients with Baseline SBP <130 
mmHg 
• 
Change from Baseline to Weeks 12, 26, and 52 in DBP for all patients and for the subset 
of patients with Baseline DBP ≥80 mmHg 
• 
Change from Baseline to Week 52 in total daily insulin dose 
• 
Proportion of patients requiring rescue therapy during the 52-week double-blind Treatment 
Period 
• 
Change from Baseline to Week 18 and Week 52 in 7-point SMBG profile (mean daily 
value and at each time point) 
• 
Change from Baseline in eGFR 
• 
Change from Baseline in UACR during the 52-week Treatment Period 
• 
PQAT at Weeks 18 and 52 
• 
Change in TRIM-D from Baseline to Week 52 for total score and 5 domain scores. There 
will be a particular focus on the Diabetes Management domain score, to evaluate patient 
satisfaction of ability of treatment to control diabetes and its effects. 
2.1.3.4 CGM sub-study endpoint(s) 
Primary sub-study endpoint 
The primary endpoint in this CGM sub-study is the change from Baseline to Week 19 in 
percentage of time spent within the target glucose range of 70 to 180 mg/dL (3.9 to 10.0 mmol/L) 
over 24 hours (sotagliflozin 400 mg and placebo arms). 
Secondary sub-study endpoints 
The secondary endpoints in this CGM sub-study are as follows: 
• 
Change from Baseline to Week 19 in percentage of time spent within the target glucose 
range of 70 to 180 mg/dL (3.9 to 10.0 mmol/L) over 24 hours (sotagliflozin 200 mg and 
placebo arms) 
• 
Change from Baseline to Week 19 in mean 24-hour glucose concentrations 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 25 of 105 
• 
Change from Baseline to Week 19 in the percentage of time spent within the glucose range 
of 70 to 140 mg/dL (3.9 to 7.8 mmol/L) over 24-hours 
• 
Change from Baseline to Week 19 in the CV of glucose concentrations over 24 hours by 
CGM 
• 
Change from Baseline to Week 18 in the AUC of plasma glucose concentration 2 hours 
after a standardized mixed meal. 
• 
Change from Baseline to Week 18 in 2-hour PPG following a standardized mixed meal. 
Other sub-study endpoints 
Other endpoints in this CGM sub-study are as follows: 
• 
Change from Baseline to Week 19 in the percentage of time over 24 hours spent with 
glucose levels >140 mg/dL (>7.8 mmol/L), >180 mg/dL (>10.0 mmol/L), >250 mg/dL (> 
13.8 mmol/L), <70 mg/dL (<3.9 mmol/L), and <54 mg/dL (<3.0 mmol/L) 
• 
Change from Baseline to Week 19 in percentage of time over 24 hours spent inside the 
target glucose range of 70 to 180 mg/dL (3.9 to 10 mmol/L) during the diurnal period (6:00 
to 11:59 pm) and during the nocturnal period (0:00 am to 5:59 am) 
• 
Change from Baseline to Week 19 in the AUC of glucose concentrations over 24 hours 
>140 mg/dL (>7.8 mmol/L), >180 mg/dL (>10.0 mmol/L), >250 mg/dL (> 13.8 mmol/L), 
<70 mg/dL (<3.9 mmol/L), and <54 mg/dL (<3.0 mmol/L)  
• 
Change from Baseline to Week 19 in measures of glucose variability including Mean 
Amplitude of Glycemic Excursion (MAGE), standard deviation (SD) of glucose levels 
within and between days, and interquartile range (IQR) 
• 
Number of patients with ≥1 episode of hypoglycemia, defined as CGM values <70 mg/dL 
(<3.9 mmol/L) for ≥15 minutes. 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events, hypoglycemia, and other safety 
information, such as clinical laboratory data, vital signs, electrocardiogram (ECG), and physical 
examination, etc.  
Observation period  
The observation period will be divided into 4 epochs: 
• 
The screening epoch is defined as the time from the signed informed consent date up to 
the first administration of the double-blind IMP.  
• 
The treatment epoch is defined as the time from the first administration of the double-
blind IMP to the last administration of the double-blind IMP.  


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 26 of 105 
• 
The residual treatment epoch is defined as the time from the last administration of the 
double-blind IMP up to 10 days (1 day for hypoglycemia) after the last administration of 
the double-blind IMP. 
The treatment-emergent adverse event (TEAE) period will include both treatment and residual 
treatment epochs (see the TEAE period of the 18-week randomized core treatment period for 
analyses in hypoglycemia in Section 2.4.5.1). 
• 
The posttreatment epoch is defined as the period of time starting the day after the end of 
the treatment-emergent adverse event period up to the last protocol-planned visit or the 
resolution/stabilization of all serious adverse events (SAE), adverse events of special 
interest (AESI) and events of special interest (EOSI), whichever is later. 
The on-study observation period is defined as the time from start of double-blind treatment until 
the end of the study (defined as the last scheduled visit for those who completed the study and the 
date collected on e-CRF page “Completion of End of Study/Follow-up” for those who did not 
complete the study). 
The post-study observation period is defined as the time from the day after the end of the study 
until the resolution/stabilization of all SAE, AESI and EOSI if applicable. 
2.1.4.1 Hypoglycemia 
Hypoglycemia will be identified as events recorded on the dedicated e-CRF “Hypoglycemic event 
information” page, and will be categorized as follows (see study protocol for further details): 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, intravenous glucose or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. 
Self-monitored plasma glucose values may not be available, but neurological recovery attributable 
to the restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. 
Severe hypoglycemia is identified in e-CRF “Hypoglycemic event” 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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 27 of 105 
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” page as 
those documented as, 
• To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and  
• To the question “Were Symptoms Present”, ticked “Yes”, and  
• With a plasma glucose value before countermeasure ≤3.9 mmol/L (≤70 mg/dL).  
Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL). 
Asymptomatic hypoglycemia is identified in e-CRF “Hypoglycemic event” page as those 
documented as, 
• To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and 
• To the question “Were Symptoms Present”, ticked “No”, and  
• 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” page as those 
documented as, 
• To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and 
• To the question “Were Symptoms Present”, ticked “Yes”, and 
• With no plasma glucose value before countermeasure, and  


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 28 of 105 
• 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” page as those documented 
as, 
• To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance” 
• To the question “Were Symptoms Present”, ticked “Yes”, and  
• With a plasma glucose value before countermeasure >3.9 mmol/L (>70 mg/dL).  
In addition of the threshold of >3.9 mmol/L (≤70 mg/dL), hypoglycemia episodes with a plasma 
glucose of <3.0 mmol/L (<54 mg/dL) will be analyzed separately.  
Any hypoglycemic event fulfilling the criteria of a SAE or leading to unconsciousness, coma, or 
seizure will also be recorded as a SAE (see Section 2.1.4.2). 
2.1.4.2 Adverse events variables 
Adverse event observation period  
• 
Pretreatment adverse events are adverse events that developed or worsened or became 
serious from the signed informed consent date up to first administration of double-blind 
IMP 
• 
Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the treatment-emergent adverse event period 
• 
Posttreatment adverse events are adverse events that developed or worsened or became 
serious during the posttreatment period. 
 
All adverse events (including SAE, AESI and EOSI will be coded to a lower-level term (LLT), 
preferred term (PT), high-level term (HLT), high-level group term (HLGT), and associated 
primary system organ class (SOC) using the version of MedDRA currently in effect at Covance at 
the time of database lock. 
The occurrence of adverse events (including SAE, AESI and EOSI) will be recorded from the time 
of signed informed consent until the end of the study (see Section 2.1.4) or the 
resolution/stabilization of all SAE, AESI and EOSI. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 29 of 105 
AESI include: 
• 
Pregnancy 
• 
Symptomatic overdose with IMP/NIMP 
• 
Alanine aminotransferase (ALT) increase > 3 times upper limit of normal (ULN) 
EOSI include:  
• 
MACE (CV death, myocardial infarction, or stroke) and other specific cardiovascular 
events (eg, heart failure requiring hospitalization)   
• 
Severe hypoglycemia 
• 
Genital mycotic infections (to include vulvovaginal candidiasis in females and candida 
balanitis in males) 
• 
Urinary tract infection 
• 
Clinically relevant volume depletion and events related/possibly related to volume 
depletion 
• 
Diarrhea 
• 
Pancreatitis 
• 
Bone fractures 
• 
Venous thrombotic events, to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism) 
• 
Diabetic ketoacidosis 
• 
Renal events, to include 50% decline in eGFR, end stage kidney disease, renal death 
• 
Malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, 
prostate, and thyroid carcinoma) 
• 
Adverse event leading to an amputation 
A Clinical Endpoint Committee(s) (CEC) will in a blinded manner review and adjudicate all 
deaths, myocardial infarction, stroke, unstable angina requiring hospitalization, and heart failure 
requiring hospitalization, selected renal events, bone fracture, and diabetic ketoacidosis. 
Two independent committees will review safety events that require ongoing monitoring to ensure 
timing protocol amendments in case a safety signal is identified. These events are: 1) potential 
cases of drug-induced liver injury (DILI), and 2) cases of amputations. The two committees will 
review the cases in a treatment-blinded manner and will present their assessment to the DMC. 
 
AESI and EOSI will be identified based on criteria in Table 3.  


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 30 of 105 
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?”  
Bone fractures 
Positively adjudicated by CEC: Yes to the question “Did the Fracture 
occur?” 
Diabetic ketoacidosis 
Positively adjudicated by CEC: Yes to the question “Does this event 
meet the criteria to be a DKA event?” 
EOSI Renal events where select events adjudicated 
Sustained ≥50% decrease 
in eGFR 
(1) For ≥50% decrease in eGFR from baseline, 
      (1a) confirmed ≥50% decrease in GFR for ≥30 days with no 
reversible cause as recorded in eCRF “eGFR decrease”, OR  
      (1b) positively adjudicated by CEC: Yes to the question “Does the 
subject meet the criteria of CKD progression” for ≥50% decrease in 
eGFR. 
Sustained eGFR <15 
mL/min/1.73 m2 
(2) For eGFR <15 mL/min/1.73 m2, 
      (2a) confirmed eGFR <15 mL/min/1.73 m2 for ≥30 days with no 
reversible cause as recorded in eCRF form “eGFR decrease”, OR 
       (2b) positively adjudicated by CEC: Yes to the question “Does the 
subject meet the criteria of CKD progression”. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 31 of 105 
AE Grouping 
Criteria 
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 B  
Urinary tract infections 
PTs in Appendix B  
Clinically relevant volume 
depletion and events 
related/possibly related to 
volume depletion 
PTs in Appendix B  
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 B  
Venous thrombotic events 
PTs in Appendix B  


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 32 of 105 
AE Grouping 
Criteria 
Malignancies of special 
interest 
Breast cancer: Narrow search on “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 B  
Renal cell cancer: PTs in Appendix B  
Pancreatic cancer: PTs in Appendix B  
Bladder cancer: PTs in Appendix B 
EOSI AE leading to an amputation 
AE 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 B 
*  Search terms will be updated using the MedDRA version currently in effect at Covance at the time of database lock for EOSI identified by 
them. 
* AE potentially leading to amputation: not belong to the EOSI list defined in protocol, the item is 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 periods are per the observation periods defined below.  
• 
Death on-study:  deaths occurring during the on-study observation period 
• 
Death on-treatment:  deaths occurring during the TEAE period  
• 
Death post-study:  deaths occurring after the end of the study  
2.1.4.4 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, 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 D).  The following laboratory data will be measured at a central laboratory:  
• 
Hematology  


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 33 of 105 
- 
Red blood cells and platelets:  hemoglobin, hematocrit, red blood cell, platelets count  
- 
White blood cells:  white blood cell, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils 
• 
Clinical chemistry  
- 
Metabolism:  glucose (serum), creatine phosphokinase (CPK) 
- 
Electrolytes and minerals:  sodium, potassium, chloride, bicarbonate (ie, carbon 
dioxide), calcium, phosphorus, magnesium  
- 
Renal function:  blood urea nitrogen (BUN), creatinine, uric acid         
- 
Liver function:  total protein, albumin, ALT, aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), total bilirubin, Lactic acid dehydrogenase (LDH)       
• 
Lipid parameters (fasting): total cholesterol (TC), high density lipoprotein cholesterol 
(HDL-C), low density lipoprotein cholesterol (LDL-C) (calculated by Friedwald equation, 
See Section 2.5.1), Non-HDL-C (calculated as the difference between TC and HDL-C), 
triglycerides (TG). 
• 
Pancreatic enzymes: lipase, amylase. 
• 
Beta-hydroxybutyrate (BHB) 
• 
Markers of bone and calcium metabolism  
- 
25-hydroxyvitamin D,  
- 
1,25-dihydroxyvitamin D,  
- 
Parathyroid hormone (PTH),  
 
Urine samples will be collected at designated visits (see study flowchart in Appendix D). 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 
Serum glucose and Calculated UACR will be presented as efficacy parameters in Section 2.4.4. 
For calculated eGFR, PCSA summaries will be presented in the safety section while descriptive 
summaries in the efficacy section. 
Technical formulas are described in Section 2.5.1. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 34 of 105 
2.1.4.5 Vital signs variables 
Vital signs include:  heart rate (HR), systolic and diastolic blood pressure, temperature, and 
respiratory rate (see study flowchart in Appendix D for designated visits).  They will be performed 
after the patient has been seated for at least 5 minutes. Blood pressure and HR will be assessed 3 
times with at least 1 minute between each measurement following the 5-minute rest period. The 
mean of the 3 measurements will be analyzed for each vital sign variable (HR, SBP, and DBP). 
2.1.4.6 Physical examination 
A complete physical exam will be performed at Visit 1 (Screening) and Visit 13(Week 26). 
“Normal”, “Abnormal” or “Not done” as determined by the Investigator will be reported in the e-
CRF by body system. 
2.1.4.7 Electrocardiogram variables 
12-lead ECGs will be performed at Visit 1 (Screening), Visit 6 (Randomization) and Visit 13 
(Week 26). ECG status of “normal” or “abnormal” will be reported in the e-CRF as determined by 
the investigator. 
2.1.5 Pharmacokinetic variables  
Pharmacokinetic variables include the plasma concentration of sotagliflozin and its 3-O-
glucuronide metabolite in the sotagliflozin group. 
2.1.6 Patient-reported outcome variables  
The schedule of PQAT and TRIM-D are specified in the study flowchart in Appendix D. The 
questionnaires can be found in the study protocol.   
2.1.6.1 Patient’s qualitative assessment of treatment (PQAT) 
The PQAT aims to understand patient perspective on benefit/risk of the IMP during the Treatment 
Period. This instrument includes a 7-point Likert Scale for the patient to evaluate his/her 
subjective response to the treatment (-3 to +3 including 0 for a neutral response) and 3 free-text 
response questions to describe key advantages and disadvantages of treatment experienced and 
willingness to pursue it or not. 
All patients’ answers will be analyzed qualitatively and quantitatively, as relevant, using 
appropriate qualitative data analysis software. The analysis method for this exploratory analysis 
will be provided in a separate SAP and the analyses results will be documented in a separate 
report. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 35 of 105 
If a patient discontinues treatment with IMP during the Treatment Period, the patient will be asked 
to complete this qualitative assessment of treatment at time of discontinuation. 
2.1.6.2 Treatment related impact measure for diabetes (TRIM-D) 
The general treatment-related impact on patients’ health related quality of life (HRQoL) will be 
assessed using the TRIM-D questionnaire. The TRIM-D questionnaire is a 28-item measure 
comprising of 5 domains: Treatment Burden, Daily Life, Diabetes Management, Compliance, and 
Psychological Health (1). Table 4 below presents further technical details on this questionnaire. 
Items are answered on a 5-point Likert scale ranging from (1) Not at all satisfied/convenient, or 
Never/Almost never, or Never/Almost never interferes to (5) Extremely satisfied/convenient, or 
Almost always/Always, or Almost always/Always interferes. Scales are converted into a score 
valued from 0 to 100 so that a higher score indicates a better health state (less negative impact). 
Score for each domain (called “domain score”) and total score are computed. See Section 2.4.7 for 
more details on the scoring method. 
The TRIM-D variables include TRIM-D scores (total and domain scores) and the change in 
TRIM-D scores from baseline to endpoint. 
Table 4 - TRIM-D domains and clusters  
Domains 
Number of 
Items 
Cluster of Items 
Item 
Reversion 
Direction of Domains 
Treatment Burden 
6 
1a, 2a, 2b, 2c, 2d, 2e 
No 
Higher score = better health state (less 
negative impact) 
Daily Life 
5 
3a, 3b, 5a, 5b, 5c 
Yes, for all items 
Diabetes 
Management 
5 
4a, 4b, 4c, 4d, 4e 
No 
Compliance 
4 
6a, 6b, 6c, 6e 
Yes, for all items 
Psychological 
Health 
8 
6d, 7a, 7b, 7c, 7d, 7e, 
7f, 7g 
Yes, for all items 
 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as all patients who 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. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 36 of 105 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary tables: 
• 
Screened patients 
• 
Run-in patients: patients who had a run-in record in IRT, 
• 
Screen failure patients (including failures during run-in) and reasons for screen failure 
• 
Nonrandomized but treated patients 
• 
Randomized patients 
• 
Randomized but not treated patients 
• 
Randomized and treated patients 
• 
Patients who have completed the 18-week randomized core treatment period (see Section 
2.5.4) as per protocol 
• 
Patients who discontinued the IMP during the 18-week randomized core treatment period 
(see Section 2.5.4) and the reasons for treatment discontinuation 
• 
Patients who have completed the entire 52-week double-blind Treatment Period 
• 
Patients who discontinued the IMP during the entire 52-week double-blind Treatment 
Period and the reasons for treatment discontinuation 
• 
Patients who have completed the study as scheduled 
• 
Patients who discontinued the study, and the reasons for study discontinuation 
• 
Patients’ end of study status (completed, not completed) and corresponding end of 
treatment status (completed, not completed) 
• 
Status at last study contact  
For screened, run in, screen failure, and nonrandomized but treated patients, percentages will be 
calculated using the number of screened patients as the denominator. All other categories of 
patients will be presented by treatment group and the percentages will be calculated using the 
number of randomized patients within each treatment group as the denominator.  Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages by treatment 
group.  Patients prematurely discontinued from treatment and/or study, along with reasons for 
discontinuation, will also be listed.  
A summary of the distribution of patients by country and center will also be provided (overall 
number of patients screened, run-in, randomized, and treated, as well as number of patients 
randomized, discontinued from study treatment, and discontinued from study for each treatment 
group). 
Patients treated but not randomized, patients randomized but not treated and patients randomized 
but not treated as randomized will be identified and described in separate listings. The patients of 
the third category (randomized and not treated as randomized) will be part of efficacy and safety 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 37 of 105 
analyses (see Section 2.3). Patients randomized but not treated will be included in efficacy 
analysis. Safety data of patients treated but not randomized will be reported separately. 
The randomization strata [HbA1c at Week -1 (≤8.5%, >8.5%), SBP (<130, ≥130 mmHg) at Week 
-1 and sulfonylurea use at Week -1 (yes, no)] assigned by IRT will be summarized. The 
percentages will be calculated using the number of randomized patients as the denominator. The 
discrepancy between the strata assigned by IRT and the information reported on e-CRF will be 
listed for all randomized patients. 
Kaplan-Meier (KM) plots of the cumulative incidence of double-blind IMP discontinuations due 
to any reason and due to AEs will be provided for the entire 52-week double-blind treatment 
period separately (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.  
For CGM sub-study, the number of patients in each of the following categories will be 
summarized.  
• 
Screened CGM sub-study population: patients who consented to CGM sub-study  
• 
Patients who did not meet all eligibility criteria for inclusion into the CGM sub-study 
• 
Randomized CGM sub-study population: patients who were randomized and met all 
eligibility criteria for inclusion into the CGM sub-study as reported in e-CRF. 
• 
Patients who completed CGM sub-study   
• 
Patients who discontinued CGM sub-study and the reason for discontinuation 
For patients not meeting all eligibility criteria for inclusion into the CGM sub-study, percentages 
will be calculated using the number of patients consented to sub-study as the denominator. All 
other categories of patients will be presented by treatment group and the percentages will be 
calculated using the number of patients randomized and met all eligibility criteria for inclusion 
into the CGM sub-study within each treatment group as the denominator.  Reasons for CGM sub-
study discontinuation will be supplied in tables giving numbers and percentages by treatment 
group. Patients prematurely discontinued the CGM sub-study, along with reasons for 
discontinuation, will also be listed.  
All important deviations including randomization and drug-dispensing irregularities will be 
summarized in tables giving numbers and percentages of deviations by randomized treatment 
group. 
Additionally, the analysis populations for safety, efficacy, and pharmacokinetics defined in 
Section 2.3 will be summarized in a table by number of patients in the randomized population.  
• 
Efficacy population: intent-to-treat (ITT) population 
• 
Efficacy population for sub-study: CGM sub-study population  


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 38 of 105 
• 
Safety population 
• 
PK population 
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
• 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 
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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 39 of 105 
2.3 
ANALYSIS POPULATIONS 
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population.   
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and these 
patients will not be in the safety population. 
2.3.1 Efficacy populations 
Efficacy analyses will be based on the treatment group allocated by the IRT according to the 
randomization schedule at Randomization Visit (as randomized), irrespective of the treatment 
actually received. 
2.3.1.1 Intent-to treat population  
Efficacy analyses will be based on the ITT population, defined as all randomized patients 
irrespective of compliance with the study protocol and procedures. Patients will be analyzed for 
efficacy according to the treatment group to which they are randomized. 
2.3.1.2 CGM sub-study population 
The CGM sub-study population will include all patients from the ITT population (see Section 
2.3.1.1), who met all eligibility criteria for inclusion into the CGM sub-study. 
2.3.2 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. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 40 of 105 
• 
When a patient is exposed to both sotagliflozin and placebo, the patient will be analyzed in 
the appropriate sotagliflozin group (depending on the treatment kit taken [400 mg or 
200 mg]). 
• 
When a patient is exposed to both sotagliflozin 400 mg (treatment kit) and 200 mg 
(treatment kit), the patient will be analyzed in the sotagliflozin 200 mg group. 
• 
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. If a patient is dispensed double-blind IMP and is lost 
to follow-up without any documented evidence, the patient will be considered exposed 
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 available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group.  Categorical and 
ordinal data will be summarized using the number 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. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 41 of 105 
2.4.2 Prior or concomitant medications  
The prior, concomitant and posttreatment medications will be presented in the randomized 
population for each treatment group (and overall for the summary of prior medications), using 
counts and percentages. No statistical test for the between-group difference will be performed. 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomical therapeutic chemical (ATC) class (anatomic category) 
and the first 3 digits of the ATC class (therapeutic category).  A given medication may be 
classified in more than 1 ATC class. All ATC codes corresponding to a medication will be 
summarized, and a patient will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. Therefore, a patient may be counted several times for the same 
medication.  
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 medication 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).   


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 42 of 105 
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number of 
patients exposed, mean, SD, median, minimum, and maximum).  In addition, duration of 
treatment exposure will also be summarized categorically by numbers and percentages for each of 
the following categories and cumulatively according to these categories:  
• 
1 to 28 days,  
• 
29 to 56 days,  
• 
57 to 84 days,  
• 
85 to 126 days,  
• 
127 to 182 days,  
• 
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. 
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 date to the last date of double-blind 
IMP administration).  
Above-planned dosing percentage for a patient will be defined as the number of days that the 
patient took a higher dose than planned divided by the total number of days that the patient was 
planned to take during the treatment epoch.  
Under-planned dosing percentage for a patient will be defined as the number of days that the 
patient took a lower dose than planned divided by the total number of days that the patient was 
planned to take during the treatment epoch.  
Treatment compliance, above-planned, and under-planned dosing percentages will be summarized 
descriptively as quantitative variables (number, mean, SD, median, minimum, and maximum). 
The percentage of patients whose compliance is <80% will be summarized. In addition, numbers 
and percentages of patients with at least 1 day above-planned dose administration will be 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 43 of 105 
provided, as well as numbers and percentages of patients with (0, 20%], and >20% of days under-
planned dose administrations. 
Cases of overdose (see study protocol for further details) will constitute AEs/SAEs and be 
analyzed as such. More generally, dosing irregularities will be listed in Section 2.2.1. 
2.4.4 Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population using the efficacy assessments 
collected during the study, including those obtained after IMP discontinuation or introduction of 
rescue therapy, unless otherwise specified. 
Missing data for efficacy analyses is identified through steps described in Section 2.5.4. 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
The statistical tests will be two-sided tests at a nominal 5% significance level. 
Primary analysis 
The primary efficacy endpoint of change in HbA1c from baseline to Week 18 will be analyzed by 
an Analysis of Covariance (ANCOVA) model using HbA1c values measured at baseline and 
Week 18 (observed or imputed). The missing data at endpoint will be imputed by multiple 
imputation (MI) methods as detailed below. To be concise, the following texts related to 
imputation are generalized to accommodate primary as well as continuous secondary efficacy 
endpoints. 
Missing endpoint data at Week 18 (or Week 12 for SBP or Week 52 for HbA1c and BW) 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 18 (or 
Week 12 for SBP or Week 52 for HbA1c and BW) visit but have the measurement for the 
endpoint (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 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. This will serve as the primary model of 
imputation for missing data should sampling criteria be satisfied (see below).  
An alternative (back-up) imputation method will be used if the number of patients who 
prematurely discontinue the IMP before the Week 18 (or Week 12 for SBP or Week 52 for HbA1c 
and BW) 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. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 44 of 105 
In the back-up imputation method, missing post-baseline endpoint values at Week 18 (or Week 12 
for SBP or Week 52 for HbA1c and BW) will be imputed by washout multiple imputation (MI) 
method under the missing not at random (MNAR) framework.  
Missing endpoint data at Week 18 (or Week 12 for SBP or Week 52 for HbA1c and BW) in the 
sotagliflozin group(s), as well as in the placebo group 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 groups with missing data at Week 18 (or 
Week 12 for SBP or Week 52 for HbA1c and BW), 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 18 (or Week 12 for SBP or 
Week 52 for HbA1c and BW). 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 18 (or Week 12 for SBP or Week 52 for HbA1c and BW) endpoint 
values will be subsequently imputed from the multiple copies of the original dataset where each 
copy will have a monotone missing pattern. 
The imputation models for the washout MI method will include the randomization strata and the 
corresponding baseline value. Missing data will be imputed using the regression method. In cases 
of non-convergence during the imputations, especially for the MCMC application in the placebo 
non-monotone datasets, graphical measures (eg, trace and autocorrelation plots) will be used to 
identify the offending variable and once detected, that variable(s) will be dropped from the model 
and the imputations will be re-run. These re-run models will use the same seed number and 
number of imputations as used in the original models. 
Using either imputation method, missing endpoint data will be imputed multiple times to generate 
multiple data sets with complete data. The change from baseline to Week 18 will be derived from 
observed and imputed HbA1c value at Week 18. Each of the complete datasets after the 
imputation will be analyzed by the ANCOVA model with treatment groups (sotagliflozin 400 mg, 
sotagliflozin 200 mg, placebo), randomization strata of Week -1 HbA1c (≤8.5%, >8.5%), 
randomization strata of Week -1 SBP (<130 mmHg, ≥130 mmHg), randomization strata of 
sulfonylureas use at Week -1 (yes, no), and country as fixed effects, and baseline HbA1c value as 
a covariate. Results from each complete dataset will be combined using Rubin’s rule to provide 
the adjusted mean change in HbA1c from Baseline to Week 18 for each treatment group, as well 
as the between-group difference (comparing sotagliflozin 400 mg, 200 mg vs placebo) and the 
95% confidence interval (CI). 
 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 45 of 105 
Sensitivity analyses 
Tipping point analysis based on the same MI method as applied to the primary analysis will be 
performed to examine the robustness of the results from the primary analysis. Patients who were 
randomized to sotagliflozin groups and had no HbA1c data at Week 18 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 (see below). The tipping point is the penalty level, at 
which the magnitude of efficacy reduction in patients without HbA1c data at Week 18 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, 
2. The imputed HbA1c value at Week 18 in the sotagliflozin group will be penalized by 
adding a penalty δ (eg, δ = 0.1%) in each complete dataset, 
3. Change from baseline at Week 18 in HbA1c will be analyzed using the same 
ANCOVA model as specified in the primary analysis in each complete dataset, 
4. Results will be combined across complete datasets using Rubin’s rule, 
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. 
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). 
The tipping point analysis will be performed only if the corresponding primary or secondary 
endpoint (change from baseline to Week 18 in HbA1c comparing sotagliflozin 400 mg vs placebo, 
or comparing sotagliflozin 200 mg vs placebo) is statistically significant at α = 0.05 (2-sided).  
In addition, if the retrieved dropout imputation is applied to the primary analysis, the analysis 
based on the washout (ie, the backup imputation method) will be presented as a sensitivity 
analysis. 
To investigate the impact of randomization stratification error of HbA1c at Week -1 (≤8.5%, 
>8.5%), the following sensitivity analyses will be performed for the primary or secondary 
endpoint (change from baseline to Week 18 in HbA1c comparing sotagliflozin 400 mg vs placebo 
or comparing sotagliflozin 200 mg vs placebo): 
• 
The same model as described in the primary analysis will be performed by excluding those 
patients with randomization stratification error regarding HbA1c at Week -1 (≤8.5%, 
>8.5%).  


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 46 of 105 
• 
The same model with the same MI method as described in the primary analysis will also be 
performed by replacing randomization strata of HbA1c (≤8.5%, >8.5%) at Week -1 from 
IRT with the actual strata calculated based on HbA1c value (≤8.5%, >8.5%) at Week -1 
from central lab in both imputation model and analysis model. 
 
Patients in this study have undergone sampling for plasma levels of sotagliflozin and its main 
active metabolite in order to perform population PK analysis. Patients may be identified who have 
no detectable levels of active study drug or metabolite in their samples (ie, Below Lower Limit of 
Quantification or BLLOQ). When sample analysis has been completed and the study has been 
unblinded, explanations for some of these patients may be found: known non-compliance or 
sampling occurring after treatment had been discontinued. In other cases, drug intake history 
relative to the randomization assignment may not be fully explained. The ITT-based analyses 
specified in this document provides for a conservative assessment of the efficacy data should 
patients have been subjected to these unexplained non-compliance findings or PK ‘anomalies’. To 
provide a broader perspective on the impact of these apparent errors in compliance, additional 
sensitivity analyses of the primary efficacy endpoint and continuous efficacy endpoints may be 
conducted. The need to perform such analyses, their specifics, and results will be provided in the 
Clinical Study Report (CSR), if applicable. The analysis methods applied to the patient 
subpopulations defined by the occurrence of the PK anomalies (eg., exclusion of patients with PK 
anomalies from the ITT dataset) will include the ANCOVA model using the retrieved dropout 
and/or washout MI methods previously specified in this section. 
 
Assessment of treatment effect by subgroup  
Descriptive analyses will be performed on the primary endpoint to summarize the treatment 
effects across subgroups defined by the following Baseline or Screening factors: 
• 
Race (White, Black or African American, Asian, Other) (any race groups with fewer than 5 
patients may be combined with “Other” category as appropriate),  
• 
Ethnicity (Hispanic, Not Hispanic), 
• 
Age group (<50, ≥50 to <65, ≥65 years) (any category with fewer than 5 patients may be 
combined with another category as appropriate), 
• 
Gender (Male, Female), 
• 
Baseline BMI level (<30, ≥30 kg/m²), 
• 
Baseline HbA1c (≤8.5%, >8.5%), 
• 
Baseline SBP (<130 mmHg, ≥130 mmHg), 
• 
Sulfonylurea use at Week -1 (yes, no), 
• 
Baseline eGFR (≥30 to <60 mL/min/1.73m2 [Moderate decrease in GFR], ≥60 to <90 
mL/min/1.73m2 [Mild decrease in GFR], and ≥90 mL/min/1.73m2 [Normal]) 
• 
Duration of diabetes (<10, ≥10 years) 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 47 of 105 
• 
Country. 
 
The treatment effects (sotagliflozin 400 mg versus placebo and sotagliflozin 200 mg versus 
placebo) across the subgroups defined for each of these factors will be estimated for the change 
from Baseline to Week 18 in HbA1c in the ITT population, and using the same MI method as 
applied to the primary analysis. The ANCOVA model will include treatment groups (sotagliflozin 
400 mg, sotagliflozin 200 mg, placebo), randomization strata of Week -1 HbA1c (≤8.5%, >8.5%), 
randomization strata of Week -1 SBP (<130 mmHg, ≥130 mmHg), randomization strata of 
sulfonylureas use at Week -1 (yes, no), 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. A graphical presentation of the 
results (ie, forest plot) will also be provided. 
In the case that the subgroup factor is identical or similar to a randomization strata factor (eg, 
baseline HbA1c or baseline SBP category or Sulfonylurea use at Week -1), 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 52-
week entire 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 strata of 
Week -1 HbA1c (≤8.5%, >8.5%), randomization strata of Week -1 SBP (<130 mmHg, 
≥130 mmHg), randomization strata of sulfonylureas use at Week -1 (yes, no), and baseline value 
in the imputation model. 
Each continuous secondary efficacy endpoint (Section 2.1.3) will be analyzed using a similar 
ANCOVA model including the measurements at baseline and endpoint (observed or imputed). 
The missing data at endpoint will be imputed by the retrieved dropouts if there are at least 5 
patients in each study treatment group who discontinued but have the endpoint data. Otherwise, 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 48 of 105 
the washout imputation method will be used. After the imputation, each of the complete datasets 
will be analyzed by an ANCOVA model.  
The ANCOVA model will include treatment groups (sotagliflozin 400 mg, 200 mg, and placebo), 
randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of SBP (<130 mmHg, 
≥130 mmHg), randomization strata of sulfonylureas use at Week -1 (yes, no), and country as fixed 
effects, and the corresponding baseline of 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. Results from each complete dataset will be combined using Rubin’s formula 
to provide the adjusted mean change from Baseline to Week 18 (or Week 12 for SBP, week 52 for 
HbA1c and BW) for each treatment group, as well as the between-group differences and the 95% 
CIs for the differences.  
For all continuous secondary endpoints, summary statistics at scheduled visits will be provided for 
each treatment group. The summary will include the number of observations, mean, SD, SE, 
minimum, median, and maximum. Graphical presentations will also be used to examine trends 
over time using mean values (±SE) and mean changes from baseline (±SE) at each of the 
scheduled visits. In addition, SBP will be summarized descriptively at each visit for those patients 
with baseline SBP ≥140 mmHg.  
The categorical secondary and other efficacy variables of HbA1c <6.5%, <7% at Week 18 will be 
analyzed respectively using a Cochran-Mantel-Haenszel (CMH) method stratified by 
randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of SBP (<130 mmHg, 
≥130 mmHg), and randomization strata of sulfonylureas use at Week -1 (yes, no). The proportion 
in each treatment group will be provided, as well as the difference of proportions between 
sotagliflozin (400 mg, 200 mg) and placebo with associated 2-sided 95% CI. For HbA1c 
responders at Week 18 (<6.5%, <7% respectively), all values at Week 18 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 18 
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 
Except for PRO endpoints, the analysis of other endpoints (see Section 2.1.3) will be descriptive 
with no formal testing. Summary statistics at scheduled visits will be provided by each treatment 
group. Graphical presentations will also be used to illustrate trends over time. For the daily Lantus 
dose (U) and daily Lantus dose adjusted by body weight (Lantus dose/body weight in U/Kg), 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 49 of 105 
summary statistics (for screening value, run-in value, baseline value, and observed values) at 
scheduled visits (using OC) will also be provided for each treatment group.  
The change from baseline values will be summarized for UGE and UGCR. These 2 variables have 
been added for analyses. 
For the daily Lantus dose and total daily insulin dose, the baseline value is defined as the available 
value on the last day prior to 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. 
The number (%) of patients achieving HbA1c response (<6.5%, <7% at Week 18, Week 26 and 
Week 52, respectively) will be descriptive summarized at each scheduled visit. 
The number (%) of patients who used rescue therapy and a KM curve for the time to first rescue 
therapy will be provided by treatment group during the entire 52-week treatment period (see 
Section 2.5.4). A list of patients who used rescue therapy will also be provided.  
UACR will be log-transformed at patient level. Summary statistics of UACR in log scale will then 
be calculated for each treatment group at each visit and back-transformed to provide the geometric 
mean and its associated percent change of UACR from baseline. 
Shift tables will be provided for UACR at Week 26 and Week 52 using the pre-defined categories. 
That is, the number (%) of patients with progression from one category at baseline to another 
category at Week 26 and Week 52 will be provided by treatment group. The pre-defined 
categories are, for UACR, <30 mg/g creatinine [Normal], ≥30 to <300 mg/g creatinine 
[Microalbuminuria], and ≥300 mg/g creatinine [Macroalbuminuria].  
The analysis of TRIM-D scores is in Section 2.4.7. 
2.4.4.4 Multiplicity issues 
To control for the family wise type I error, a fixed-sequence procedure will be applied to the 
primary and key secondary endpoints to the following order: 
Once the main study primary variable (change from Baseline to Week 18 in HbA1c comparing 
sotagliflozin 400 mg versus placebo) is statistically significant at α = 0.05 (2-sided), the following 
secondary efficacy variables will be tested in the following prioritized order. The testing will stop 
as soon as an endpoint is found to be not statistically significant at α = 0.05 (2-sided). 
• 
Comparing sotagliflozin 400 mg versus placebo: 
- 
Change from Baseline to Week 18 in FPG 
- 
Change from Baseline to Week 18 in BW. 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 12 in SBP for all patients 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 50 of 105 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
• 
Comparing sotagliflozin 200 mg versus placebo: 
- 
Change from Baseline to Week 18 in HbA1c 
- 
Change from Baseline to Week 18 in BW 
- 
Change from Baseline to Week 18 in FPG. 
- 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline to Week 52 in HbA1c 
- 
Change from Baseline to Week 52 in BW 
If any hypothesis is found to be not statistically significant, the testing procedure will be stopped 
and the following hypotheses will not be tested. 
No multiplicity adjustment will be made on other secondary efficacy variables than mentioned 
above. 
2.4.4.5 Analyses of CGM sub-study efficacy variables 
The analysis of CGM endpoints will be performed on the CGM sub-study population using CGM 
measurements obtained during the study, including those obtained after IMP discontinuation or 
introduction of rescue therapy. 
All CGM derived variables will be subject to the following criteria. 
• 
CGM data are masked to both the patients and investigators. 
• 
A complete 24-hour CGM profile includes 288 data points given that CGM reading is 
recorded every 5 minutes. 
• 
The start and end time of a 24-hour CGM profile is defined as midnight, i.e. each CGM 
profile begins at midnight (0.00) and ends at midnight (23:59). Partial CGM data points 
prior to the first midnight and after the last midnight from the visit will not be used in the 
CGM parameter calculation as the partial CGM profile may introduce additional 
variabilities to the data. 
• 
Useable CGM data for a day/a 24-hour CGM profile are defined as at least 80% time of 
records (230 data points) without a gap (missing data) lasting for ≥ 2 hours per 24 hours. 
• 
Qualified CGM data for calculating baseline value should have at least 4 days (not 
necessarily consecutive) of useable 24-hour CGM data from 7-day CGM profiles. 
Qualified CGM data for calculating the post randomization value at Week 19 should have 
at least 4 days (not necessarily consecutive) of useable 24-hour CGM data from 14-day 
CGM profiles.  


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 51 of 105 
• 
In case that there are more than 288 data points or more than one data point per 5 minutes, 
usually due to recalibration or switching CGM devices, averaging the data points every 5 
minutes will be performed so that there is only one data point per 5 minutes. 
• 
For all CGM parameters except the standard deviation of glucose levels between days, 
AUC of glucose concentrations for 2 hours after a standardized mixed meal and 2-hour 
PPG, a CGM parameter will be first calculated based on each 24-hour CGM profile from 
the visit, the final values of the CGM parameters for the visit will be based on the average 
of parameter values taken on each CGM profile from each CGM visit. 
• 
The percentage of time glucose within or outside a specific range will be calculated as time 
of CGM glucose within/outside the range divided by total time with valid data. 
Analysis of CGM sub-study primary endpoint 
The CGM primary endpoint of change in percentage of time glucose levels within the target range 
of 70 to 180 mg/dL (3.9 to 10.0 mmol/L) over 24 hours from baseline to Week 19 will be 
analyzed by an ANCOVA model using the values measured at baseline and Week 19 (observed or 
imputed). The missing CGM values at endpoint will be imputed by multiple imputation (MI) 
methods as described below.  
Note that the comparison of change in percentage of time glucose levels within the target range of 
70 to 180 mg/dL (3.9 to 10.0 mmol/L) over 24 hours from baseline to Week 19 between 
sotagliflozin 200 mg and placebo is a CGM sub-study secondary endpoint, however the analysis is 
identical to that of CGM primary endpoint and is detailed here for concision. 
Missing endpoint data at Week 19 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 19 visit but have the measurement for the endpoint 
(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 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. This will serve as the primary model of 
imputation for missing data should sampling criteria be satisfied (see below).  
An alternative (back-up) imputation method will be used if the number of patients who 
prematurely discontinue the IMP before the Week 19 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 CGM sub-study 
primary or continuous secondary endpoint. 
In the back-up imputation method, missing post-baseline endpoint values at Week 19 will be 
imputed by washout multiple imputation (MI) method under the missing not at random (MNAR) 
framework.  


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 52 of 105 
Missing endpoint data at Week 19 in the sotagliflozin group(s), as well as in the placebo group 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 groups with missing data at Week 19, 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 19. 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 19 endpoint values will 
be subsequently imputed from the multiple copies of the original dataset where each copy will 
have a monotone missing pattern. 
The imputation models for the washout MI method will include the randomization strata and the 
corresponding baseline value. Missing data will be imputed using the regression method. In cases 
of non-convergence during the imputations, especially for the MCMC application in the placebo 
non-monotone datasets, graphical measures (eg, trace and autocorrelation plots) will be used to 
identify the offending variable and once detected, that variable(s) will be dropped from the model 
and the imputations will be re-run. These re-run models will use the same seed number and 
number of imputations as used in the original models. 
Using either imputation method, missing endpoint data will be imputed multiple times to generate 
multiple data sets with complete data. Each of the complete datasets after the imputation will be 
analyzed by the ANCOVA model with treatment arms (sotagliflozin 400 mg, sotagliflozin 200 
mg, and placebo), randomization strata of Week -1 HbA1c (≤8.5%, >8.5%), randomization strata 
of Week -1 systolic blood pressure (<130 mmHg, ≥130 mmHg), randomization strata of 
sulfonylureas use at Week -1 (yes, no), Lantus injection time (morning, evening) and country, as 
fixed effects, and Baseline CGM percentage value as a covariate. Results from each complete 
dataset will be combined to provide the adjusted mean change of percentage of time inside the 
target range (≥70 to ≤ 180 mg/dL) from Baseline to Week 19 for each treatment group, as well as 
the between group difference (comparing the sotagliflozin 400 mg, 200 mg versus placebo), and 
the 95% confidence interval (CI). 
For the purpose of categorizing Lantus injection time (morning, evening), the available Lantus 
injection time on the last day prior to 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 will 
be used.  The injection time during the period of 0:00 to 11:59 will be in morning category and in 
evening category if the injection time is during the period of 12:00 to 23:59.  If the patient is using 
Lantus more than once daily, the category will be based on the injection time of the largest dose. If 
the doses are equal, the injection time of the latest dose will be used. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 53 of 105 
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. 
Analyses of CGM sub-study secondary endpoints 
Continuous CGM secondary endpoints will be analyzed using a similar approach as the CGM sub-
study primary endpoint, with missing post-randomization CGM values (ie, final values of the 
CGM parameter) imputed by the retrieved dropouts imputation method or by the washout 
imputation method according to the criterion described in Section 2.4.4.5.  
For each of the continuous CGM sub-study secondary endpoints, each of the complete datasets 
will be analyzed by the ANCOVA model with treatment groups (sotagliflozin 400 mg, 
sotagliflozin 200 mg, placebo), randomization strata of Week -1 HbA1c (≤8.5%, >8.5%), 
randomization strata of Week -1 SBP (<130 mmHg, ≥130 mmHg), randomization strata of 
sulfonylureas use at Week -1 (yes, no), Lantus injection time (morning, evening) 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 19 (Week 
18 for MMTT related endpoints) for each treatment group, as well as the between group difference 
(comparing each sotagliflozin group versus placebo), and the 95% CI using contrast statement. 
For all continuous CGM sub-study 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). 
Mean 24-hour glucose concentration is calculated by sum of glucose values divided by total 
number of glucose measurements for the 24 hourly intervals and then averaged for the period 
before each visit. 
The CV over 24-hour is calculated as the ratio of the standard deviation of the glucose values to 
mean of the glucose values over 24-hour profile. For each patient and visit, the CV from all CGM 
profiles will be averaged as the final values of the CV for the visit. It will be log-transformed 
before the analysis.  Change from Baseline to Week 19 of CV in log scale will be analyzed.  
Results in the log scale will be back-transformed. 
AUC of glucose concentrations for 2 hours after a standardized mixed meal will be calculated 
using the linear trapezoidal method. CGM data will be limited to CGM readings taken from the 
start of the standardized meal through 2 hours after the start of the standardized meal, inclusive. 
The analysis of the 2-hour PPG endpoint following a standardized mixed meal will be based on a 
Time 0 adjusted value (ie, the 2-hour PPG value minus the Time 0 value, FPG sample) at both the 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 54 of 105 
Baseline and Week 18 time points. These Time 0 adjusted values will be used to derive the Week 
18 minus Baseline scores, which will serve as the measure of interest for comparative purposes. 
Analyses of CGM sub-study other endpoints 
The analysis of other sub-study endpoints (see Section 2.1.3 ) will be descriptive with no formal 
testing.  Summary statistics at scheduled visits using observed cases will be provided by each 
treatment group. 
The details for calculation AUCs outside of target ranges, MAGE and SD of glucose levels within 
and between days (24-hour CGM profile) are provided below. 
Inter-quartile range (IQR) is determined by calculating the difference between the 75th and 25th 
percentile values for the 24 hourly intervals over each 24-hour CGM profile and then averaged for 
the period of each visit. 
A hypoglycemic episode is defined as a set of any number of consecutive CGM glucoses, all of 
which are <70 mg/dL (< 3.9 mmol/L) for at least 15 minutes. No provisions are made for gaps in 
measurements. 
Calculation of CGM sub-study parameters  
1) Mean Amplitude of Glycemic Excursion (MAGE) 
It is defined as mean glucose value by summing absolute rises and falls (local minima and 
maxima) of more than 1 SD (within a 24-hour CGM profile). It includes only peak-to-
nadir or nadir-to-peak excursions. 
∑
=
n
MAGE j
λ  if 
SD
>
λ
, where λ  is the glucose 
increase or decrease (peak-to-nadir or nadir-to-peak excursions for the jth 24-hour CGM 
profile). n  is the number of peak-to-nadir or nadir-to-peak excursions for the jth 24-hour 
CGM profile. 
2) Standard deviation of glucose levels (SD) of glucose levels within and between days and 
coefficient of variation 
(
)
1
2
,
−
−
= ∑
j
j
ij
j
within
h
x
x
SD
, where 
ijx  is individual CGM data points within the jth 24-hour 
CGM profile, 
jx  is the mean glucose reading from all CGM data points for the jth 24-hour 
CGM profile. 
jh  is number of CGM data points within the jth 24-hour CGM profile. For 
each patient and visit, the 
j
within
SD
, from all CGM profiles will be averaged as the final 
values of the within SD for the visit. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 55 of 105 
(
)
1
2
−
−
= ∑
m
x
x
SD
j
between
 where x  is the mean glucose reading from all evaluable CGM 
data points from all evaluable CGM profiles from the same visit for the patient. 
jx  is the 
mean glucose reading from all CGM data points within the jth 24-hour CGM profile. m  is 
the number of evaluable 24-hour CGM profiles,  
m
x
SD
CV
j
j
within
∑
=
,
 
where 
jx  is the mean glucose reading from all CGM data points within the jth CGM 24-
hour profile. 
3) Calculations of glucose AUC outside target ranges (daily average over the period prior 
to a visit) 
Calculations of glucose AUC of hyperglycemia (hypoglycemia) are described as follows. 
Let it  represent the time of each CGM glucose measurement and 
ix
∆
 equals the absolute 
value of change from target at each time point. 
The glucose AUC outside target range at each time point will be determined using the 
following formulas: 
• 
(
)(
) 2
/
1
1
−
−
∆
+
∆
−
=
i
i
i
i
i
x
x
t
t
AUC
 if the both measurements are above (below) the 
target range  
• 
(
)
(
)
(
) 2
/
/
1
2
1
−
−
∆
+
∆
∆
−
=
i
i
i
i
i
i
x
x
x
t
t
AUC
 if the first measurement is below (above) the 
target range and the second measurement is above (below) the target range 
• 
(
)
(
)
(
) 2
/
/
1
2
1
1
−
−
−
∆
+
∆
∆
−
=
i
i
i
i
i
i
x
x
x
t
t
AUC
 if the first measurement is above (below) 
the target range and the second measurement is below (above) the target range 
• 
0
=
i
AUC
 if both measurements are below (above) the target range 
The CGM glucose AUC for the full 24 hours will be calculated as the sum of the
i
AUC  values 
using the available CGM data within the 24-hour CGM profile. The daily average will be 
calculated from this sum. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 56 of 105 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group. The safety data except 
hypoglycemia will be summarized for the entire 52-week double-blind treatment period. The 
hypoglycemia will be summarized for the 18-week randomized core treatment period and the 
entire 52-week double-blind treatment period (see Section 2.4.5.1).  
The “observation period” defined in Section 2.1.4 is applicable in all safety analyses for the 
classification of AEs, determination of treatment-emergent Potentially Clinically Significant 
Abnormality (PCSA) values and the last on-treatment value for the laboratory, vital sign and ECG. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• 
Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately 
• 
The baseline value (with the exception of serum creatinine and eGFR) is defined as the last 
available value before the first dose of double-blind IMP. For serum creatinine and eGFR, 
the baseline value is defined as the average of all values before the first dose of double-
blind IMP.  
• 
PCSA values are defined as abnormal values considered medically important by the 
Sponsor according to predefined criteria/thresholds based on literature review and defined 
by the Sponsor for clinical laboratory tests, vital signs, and ECG [Appendix A]. 
• 
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.  
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 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 entire 52-week double-blind 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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 57 of 105 
IMP. If this value is missing, this last on-treatment value will be the closet value prior to 
the last dose administration of IMP during the entire 52-week 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% confidence intervals may be 
provided, if relevant 
• 
Selected safety analyses will be summarized by age, gender, racial subgroups, and any 
pertinent subgroups (see details in Section 2.4.5.1 and Section 2.4.5.2). 
2.4.5.1 Analyses of hypoglycemia 
Analyses of hypoglycemia will be performed on the TEAE period as defined in Section 2.1.4. For 
the purpose of hypoglycemia analyses during the 18-week randomized core treatment period, the 
TEAE period for 18-week randomized core treatment period is (1) the time from the first 
administration of the double-blind IMP up to 1 day after the last administration of IMP if the 
patient discontinued treatment on or before Visit 12 (or Day 126 if Visit 18 date is missing), or (2) 
the time from the first administration of the double-blind IMP to the administration at Visit 
12/Week 18 (or Day 126 if Visit 12/Week 18 date is missing) if the patient remained treated 
beyond Visit 12/Week 18. Hypoglycemia will be classified as severe hypoglycemia, documented 
symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia or 
relative hypoglycemia (see Section 2.1.4.1).  
The number (%) of patients with any hypoglycemia, severe hypoglycemia and documented 
symptomatic hypoglycemia will be summarized respectively by treatment group during the TEAE 
period, as well as the incidence rate in patient years. Two types of incidence rates will be 
presented: the number of patients with at least 1 event per 100 patient-years (calculated as the 
number of patients with at least 1 event / total exposure in 100 patient-years), and the number of 
events per 100 patient-years (calculated as the total number of events / total exposure in 100 
patient-years). Note: here exposure (in days) is the duration of TEAE period, ie, duration of IMP 
treatment in days +1 (see Section 2.1.4). 
The summary of frequency and incidence rate in patient years for severe hypoglycemia or 
documented symptomatic hypoglycemia will be provided as appropriate by gender (Male, 
Female), age group (<50, ≥50 to <65, ≥65 years), race (White, Black or African American, Asian, 
Other), sulfonylurea use at Week -1 (yes, no). 
The number (%) of patients with at least 1 severe hypoglycemia or documented symptomatic 
hypoglycemia during the TEAE period,  as well as the corresponding number of events, will be 
summarized as necessary by hour of the day for each treatment group, using the following hour 
intervals: ≥23:00 to <06:00, ≥06:00 to <10:00, ≥10:00 to <14:00, ≥14:00 to <18:00, ≥18:00 to 
<23:00. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 58 of 105 
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 entire 52-week double-
blind treatment period only (see Section 2.5.4). 
Documented symptomatic hypoglycemia maybe presented by ≤70 mg/dL (3.9 mmol/L) and <54 
mg/dL (3.0 mmol/L) respectively, as appropriate. 
A listing of patients for all events reported on the dedicated e-CRF “Hypoglycemic event 
information” page will be provided with each category flagged (ie, severe hypoglycemia, 
documented symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic 
hypoglycemia and relative hypoglycemia). 
2.4.5.2 Analyses of adverse events 
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.  
Pretreatment and posttreatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, treatment-
emergent, or posttreatment.  The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pretreatment or posttreatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will be presented by SOC, HLGT, HLT, and PT, sorted by the 
internationally agreed order for SOCs and alphabetic order for HLGT, HLT and PT within a SOC, 
the number (n) and percentage (%) of patients experiencing an adverse event.  Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a 
treatment phase.  The denominator for computation of percentages is the safety population within 
each treatment group. 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pretreatment, treatment-emergent, and posttreatment).  For that purpose, the 
table of all treatment-emergent adverse events presented by primary SOC and PT (sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs in the 
sotagliflozin 400 mg group) will define the presentation order for all other similar tables unless 
otherwise specified. In case of equal frequency regarding PTs, alphabetical order will be used. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 59 of 105 
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
• 
Overview of treatment-emergent adverse events, summarizing number (%) of patients with 
any 
- 
TEAE 
- 
Serious TEAE 
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
• 
All treatment-emergent adverse events by primary SOC, showing number (%) of patients 
with at least 1 treatment-emergent adverse event, sorted by internationally agreed order of 
primary system organ class  
• 
All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the SOC 
internationally agreed order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order 
• 
Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing 
incidence of PT in the sotagliflozin 400 mg group 
• 
All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC in the sotagliflozin 
400 mg group.  This sorting order will be applied to all other similar tables, unless 
otherwise specified 
• 
All treatment-emergent adverse events regardless of relationship and related to IMP by 
primary SOC, HLGT, HLT and PT, showing the number (%) of patients with at least 1 
treatment-emergent adverse event, sorted by the internationally agreed SOC order.  The 
other levels (HLGT, HLT, PT) will be presented in alphabetical order 
• 
All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (ie, mild, moderate, or severe), sorted by the sorting order defined above 
• 
Common TEAEs (PTs with an incidence ≥2% in any treatment group) by primary SOC, 
HLGT, HLT, and PT, sorted by internationally agreed order of SOCs. The other levels 
(HLGT, HLT, PT) will be presented in alphabetic order.  
• 
Common TEAEs (PTs with an incidence ≥2% in any treatment group) will be provided as 
appropriate by primary SOC, and PT and by demographic factors including gender (Male, 
Female), age group (<50, ≥50 to <65, ≥65 years of age), race (White, Black or African 
American, Asian, other), sulfonylurea use at Week -1 (yes, no), baseline SBP category 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 60 of 105 
(<130 mmHg, ≥130 mmHg), and baseline eGFR category (≥30 to <60 mL/min/1.73m2 
[Moderate decrease in GFR], ≥60 to <90 mL/min/1.73m2 [Mild decrease in GFR], and ≥90 
mL/min/1.73m2 [Normal]). SOC will be sorted by internationally agreed order and the PT 
by decreasing incidence within each SOC in the sotagliflozin 400 mg group, as described 
above.  
• 
TEAEs (PTs with an incidence ≥5% in any treatment group) by primary SOC, HLGT, 
HLT, and PT, sorted by internationally agreed order of SOCs. The other levels (HLGT, 
HLT, PT) will be presented in alphabetic order.  
Analysis of all treatment emergent serious adverse event(s) 
• 
All treatment-emergent 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 
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 
Cardiovascular 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. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 61 of 105 
Renal events 
For the EOSI renal events where selected events are adjudicated, the number (%) of patients with 
any renal events identified in Table 3 in Section 2.1.4.2 will be summarized by treatment group.  
The following renal events will be listed along with the adjudication outcome if applicable, 
including events,  
i. 
recorded in e-CRF “GFR decrease”,  
ii. 
recorded in e-CRF “Renal Event – Dialysis”,  
iii. 
identified as “Renal transplant” in e-CRF “Other procedure”,  
Renal death will be part of all deaths specified above. 
Other EOSIs  
For EOSIs that are not adjudicated, the number (%) of patients with at least one event will be 
summarized by treatment group and by PT (as identified in Table 3 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 
during the study (ie, regardless of on- or post-treatment). Amputation is a procedure recorded in 
eCRF “Other Procedures related to Amputation”. Patients who had a procedure related to 
amputation will be listed.  
The number (%) of patients with an “AE leading to an amputation” will be summarized by 
treatment group and by PT.  The “AE leading to an amputation” is determined by the AE identifier 
recorded in eCRF “Other Procedures related to Amputation” when “AE correction” is chosen as 
the reason for the amputation procedure.  
In addition, the number (%) of patients with an “AE potentially leading to an amputation” will be 
summarized by treatment group and by PT (as identified in Table 3 in Section 2.1.4.2). 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 commonly precedes 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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 62 of 105 
• 
All posttreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 posttreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC in the sotagliflozin 400 mg 
group 
Listings 
Supportive AE listings will be provided for all AEs, SAEs, 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 at least 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 2.1.5.2. 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all laboratory variables (central laboratory values and changes from baseline) 
will be calculated for each visit or study assessment (screening, run-in, baseline, postbaseline time 
point, last on-treatment value) by treatment group.   
The incidence of PCSAs (list provided in Appendix A) 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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 63 of 105 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
All measurements collected during the TEAE period, including values from unscheduled visits, 
will be considered for the PCSA summaries. These summaries will include patients in the safety 
population who have at least 1 assessment performed during the TEAE period. When a PCSA 
definition involves a change from baseline value, patients must also have a baseline value to be 
included in the summaries, and when required by the definition of the abnormality, patients must 
also have available laboratory normal ranges. 
A listing of patients with at least 1 post-baseline PCSA (or out of normal range when no PCSA 
criterion is defined) will be provided which will display the entire patients’ profile across time for 
all parameters belonging to the corresponding biological function. Individual data listings will 
include the following flags when applicable: 
• 
Baseline values will be flagged “B”. 
• 
Normal laboratory ranges, available for most laboratory parameters, will be identified as 
ULN and LLN. Baseline, last on-treatment value, and individual data will be flagged “L” if 
the value is below the LLN and will be flagged “H” if it is above the ULN. 
• 
Laboratory PCSA criteria will be used for the corresponding laboratory parameters. Values 
reaching a PCSA limit will be flagged (+, ++, -, or -- depending upon the direction and 
level of the abnormality). Flags for WBC and differential counts will be determined using 
data expressed in international units. 
For parameters whose PCSA criteria are multiples of the ULN, the parameter’s value will also be 
expressed as a multiple of the ULN in the individual data provided. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity.  The proportion of patients with PCSA values at any 
postbaseline visit by baseline status will be displayed by treatment group for each parameter.  The 
proportion of patients with PCSA values at any postbaseline visit will also be displayed by 
duration of exposure for each treatment group (only if a tabulation summary is necessary).  
Listing of possible Hy’s law cases identified by treatment group (eg, patients with any elevated 
ALT>3 x ULN, and associated with an increase in bilirubin ≥2 x ULN) with ALT, AST, alkaline 
phosphatase, total bilirubin, and the following complementary parameters (if available):  
conjugated bilirubin and prothrombin time/international normalized ratio, creatine phosphokinase, 
serum creatinine, complete blood count, anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA, 
anti-CMV IgM and anti-HEV IgM antibodies, auto-antibodies: anti-nuclear, anti-DNA, anti-
smooth muscle, Epstein-Barr virus, herpes viruses, and anti-LKM. 




Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 65 of 105 
2.4.7 Analyses of patient reported outcomes 
2.4.7.1 Scoring methods 
TRIM-D is scored [1] in the following steps: 
Step 1:  Reverse the scale of the 17 items that need to be reverse coded (see Table 4). 
Step 2:  Sum the raw score across items in each domain for domain scores and the raw score of all 
items for total score. 
Note: A domain score is calculated if at least half of the items in a multi-item domain are 
answered (or half plus 1 in the case of domains with an odd number of items). Total score is 
calculated if 14 or more items are answered. 
Step 3:  Transform the raw score to a score ranging from 0 (worst) to 100 (best) using the 
following: 
Domain score = [(raw score – lowest possible raw score) / possible raw score range] * 100 
Lowest possible raw score and possible raw score range are provided in Table 5. 
Table 5 - TRIM-D range of scores 
Domains 
Cluster of Items 
Lowest / Highest possible raw 
scores 
Possible raw score 
range 
Treatment Burden 
1a, 2a, 2b, 2c, 2d, 2e 
6/30 
24 
Daily Life 
3a, 3b, 5a, 5b, 5c 
5/25 
20 
Diabetes 
Management 
4a, 4b, 4c, 4d, 4e 
5/25 
20 
Compliance 
6a, 6b, 6c, 6e 
4/20 
16 
Psychological 
Health 
6d, 7a, 7b, 7c, 7d, 7e, 
7f, 7g 
8/40 
32 
Total 
All items 
28 / 140 
112 
 
2.4.7.2 Analysis methods 
The analysis of the TRIM-D PRO scores will be conducted on the ITT population. 
For TRIM-D scores (total and domain scores), descriptive statistics (mean, median, SD, minimum 
and maximum) for absolute values and for changes from baseline will be presented by treatment 
group at baseline, Week 18, Week 26, Week 39 and Week 52.  


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 66 of 105 
The change in TRIM-D scores from Baseline to endpoint will be analyzed using a similar 
approach to the primary efficacy endpoint, with missing post-baseline values imputed by the 
retrieved dropouts imputation method or by the washout 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 the ANCOVA model with 
treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), randomization strata of 
Week -1 HbA1c (≤8.5%, >8.5%), randomization strata of Week -1 SBP (<130 mmHg, ≥130 
mmHg), and randomization strata of sulfonylureas use at Week -1 (yes, no), and country as fixed 
effects, and TRIM-D scores at Baseline as a covariate. Results from each complete dataset will be 
combined to provide the adjusted mean change from Baseline to Week 52 for each treatment 
group, as well as the between group difference (comparing each sotagliflozin group versus 
placebo) and the 95% CI using contrast statements. 
Cumulative distribution functions of scores change from baseline to endpoint will be displayed by 
treatment groups for TRIM-D scores (total and domain scores). 
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) 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 67 of 105 
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 
Calculation of LDL-C 
When TG is lower than or equal to 4.52 mmol/L (400 mg/dL), LDL-C is calculated using the 
Friedewald equation as: 
• 
in standard unit (mmol/L), TC – HDL-C – TG/2.17; 
• 
in conventional unit (mg/dL), TC – HDL-C – TG/5. 
2.5.2 Data handling conventions for secondary efficacy variables 
Scheduled measurements (see Section 2.5.4) of continuous efficacy variables collected during the 
study will be used in the analyses including those obtained after IMP discontinuation or 
introduction of rescue therapy. Continuous secondary efficacy endpoints will be analyzed with 
missing values imputed by the retrieved dropouts imputation method or by the washout 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 6 (eg. only the treatment kit number is reported in the e-CRF “Exposure 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 68 of 105 
- treatment period” module without any dose information), the date of first administration will be 
imputed using the date of randomization. When a patient is randomized but not exposed, “Not 
taken” should be ticked in the e-CRF “First dose IMP” module.  
Handling of computation of treatment duration if IMP end of treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of double-blind IMP is equal 
to the date of last administration reported on the e-CRF “Treatment status library” page.  If this 
date is missing, the exposure duration should be left as missing.  
The last dose administration should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Handling of adverse events/hypoglycemia with missing or partial date/time of onset 
Missing or partial adverse event/hypoglycemia onset dates and times will be imputed so that if the 
partial adverse event/hypoglycemia onset date/time information does not indicate that the adverse 
event/hypoglycemia started prior to treatment or after the treatment-emergent adverse event 
period, the adverse event/hypoglycemia will be classified as treatment-emergent.  No imputation 
of adverse event end dates/times will be performed.  These data imputations are for categorization 
purpose only and will not be used in listings.  No imputation is planned for date/time of adverse 
event resolution. 
Handling of adverse events/hypoglycemia when date and time of first IMP administration is 
missing 
When the date and time of the first double-blind IMP administration is missing, the day of 
randomization should be considered as the start date of TEAE period (see Section 2.1.4).  The 
exposure duration should be kept as missing. 
Handling of adverse events/hypoglycemia when IMP end of treatment date is missing 
For the purpose of defining TEAE period, the date of the last administration of double-blind IMP 
is equal to the date of the last administration reported on the eCRF “Treatment Status Library” 
page.  
If the date of last administration reported on the eCRF “Treatment Status Library” page is  
• 
Partially missing, it will be imputed with a date as late as possible before or on the date of 
last available information on eCRF “Completion of End of Study/Follow-up”.  


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 69 of 105 
• 
Completely missing, it will be imputed with the date of last available information on eCRF 
“Completion of End of Study/Follow-up” page.  
If the date of last available information on eCRF “Completion of End of Study/Follow-up” page is  
• 
Partially missing, it will be imputed with a date as late as possible. 
• 
Completely missing, all adverse events occurred on or after the first administration of 
double-blind IMP will be considered as treatment emergent adverse events.  
Handling of missing assessment of relationship of adverse events to IMP  
If the assessment of the relationship to IMP is missing, the relationship to IMP has to be assumed 
and the adverse event considered as such in the frequency tables of possibly related adverse 
events, but no imputation should be done at the data level. 
Handling of missing severity/grades of adverse events 
If the severity/grade is missing for 1 of the treatment-emergent occurrences of an adverse event, 
the maximal severity on the remaining occurrences will be considered.  If the severity is missing 
for all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
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. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 70 of 105 
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 2.1.5.2 and vital signs in Section 2.1.5.3). 
Step 1 A scheduled measurement will be used if it is available; otherwise, an unscheduled 
measurement (including the end of treatment/study visit for those prematurely discontinued) will 
be used if it happens to be on the same date as the date of the scheduled visit. 
Step 2 After Step 1, if there are still no measurement for a given parameter at a scheduled visit, the 
analysis window below (Table 6) will be applied to re-allocate a post-baseline unscheduled 
measurement to a scheduled measurement. 
Table 6 - Analyses window definition 
Scheduled visit post baseline 
Targeted study day 
Analysis window in study days 
Week 4 (Visit 8) 
28 
2 to 41 
Week 8 (Visit 10) 
56 
42 to 69 
Week 12 (Visit 11) 
84 
70 to 104 
Week 18 (Visit 12) 
126 
105 to 153 
Week 26 (Visit 13) 
182 
154 to 227 
Week 39 (Visit 14) 
273 
228 to 318 
Week 52 (Visit 15) 
364 
≥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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 71 of 105 
The reference day for the calculation of extent of exposure, time to onset, and relative days will be 
the day of the first administration of double-blind IMP or the day of randomization if not exposed 
to double-blind IMP, denoted as Day 1. 
Baseline definition for efficacy/safety data 
For the safety analyses, the baseline for a given parameter is defined as the last available 
measurement (or the average of all measurements for creatinine and eGFR), including 
unscheduled assessments, assessed prior to the first administration of double-blind IMP. For the 
efficacy analyses, the baseline for a given parameter is defined as the last available measurement 
(or the average of all measurements for creatinine and eGFR), including unscheduled assessments, 
assessed prior to the first administration of double-blind IMP or the last available value (or the 
average of all measurements for creatinine and eGFR) before randomization if not treated with 
double-blind IMP. 
Summary statistics by visit for continuous efficacy endpoints 
Summary statistics (number, mean, SD, SE, minimum, median, maximum) of continuous efficacy 
endpoints (observed data and change from baseline) will be provided at scheduled visits as per 
protocol. Summaries showing data by visit will be presented according to the visit number (or re-
allocated visit number, see Section 2.5.4) and labeled with the targeted approximate day/week.  
Last on-treatment value for laboratory variables and vital signs 
The last on-treatment value is the final measurement assessed during the treatment epoch, 
regardless of the introduction of rescue therapy, including measurements at unscheduled visits. 
Please see details in Section 2.1.4 and Section 2.4.5 
Display of safety data by visit (laboratory variables and vital signs)  
Descriptive statistics (number, mean, SD, minimum, median, maximum) of quantitative 
laboratory variables and vital signs (observed data and change from baseline) during the TEAE 
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, local results will only be used 
in the PCSA summary if they are accompanied by a local laboratory normal range. 
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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 72 of 105 
scheduled visit, the value closest to the date of the visit will be used for the scheduled visit. When 
the values for the same scheduled visit are equidistant, the last value should be used for the 
scheduled visit. Similar rules will be applicable to a patient who has more than 1 set of 
measurements for the same vital sign parameter (ie, SBP, DBP, or HR) on the same date. 
Time to event analysis  
For time to event analysis/KM plot, time to event (eg, treatment discontinuation, rescue therapy, 
hypoglycemia, etc) is defined as the number of days from the date of the first administration of 
double-blind IMP (or the date of randomization if not exposed) to the start date of the first 
occurrence of the event during entire 52-week double-blind treatment period.  
Patients who did not experience any event during the entire 52-week double-blind treatment 
period are considered censored observations. For treatment discontinuation and time to rescue, 
censoring date is the date of EOT. For time to severe or documented hypoglycemia, censoring date 
is date of EOT+1 or date of EOS, whichever is the earliest. Date of EOS will be used if date of 
EOT is not available. Last contact date will be used if date of EOS is not available.  
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline, the last on-treatment value, PCSAs, and the shift summaries for safety or 
efficacy. They will be included in the by-visit summaries if they are re-allocated to scheduled 
visits (see Section 2.5.4). 
2.5.6 Pooling of centers for statistical analyses 
Center will not be included in the statistical models for efficacy analyses. However, all centers 
within a country will be pooled, and country will be included as a fixed effect in a parametric 
statistical model (eg, ANCOVA, etc) for primary and secondary efficacy endpoints. Countries 
with fewer than 5 randomized patients will be grouped, if patients from grouped countries are still 
fewer than 5, they will then be further grouped with the country  with the country with the lowest 
number of patients that is 5 or more. 
2.5.7 Statistical technical issues 
None 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 73 of 105 
3 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned for this study. The study will not be terminated 
early for excellent efficacy. 
An independent Data Monitoring Committee (DMC) will be used to monitor and assess the safety 
of patients from this trial through periodic review of the accumulated safety data provided by an 
independent statistical group. Related details are provided in separate documents (DMC charter 
and DMC SAP). 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 74 of 105 
4 
DATABASE LOCK 
The database is planned to be locked approximately 4 weeks after the last patient last visit. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 75 of 105 
5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS® version 9.2 or higher. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 76 of 105 
6 
REFERENCES 
 
1. 
Savre I, Mapi Research Trust. TRIM-D Treatment Related Impact Measure-Diabetes. 
Information booklet. 1st ed. Hojbjerre L, Novo Nordisk. France. Mapi Research Trust; c2013. 41 
p. 
 
 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 77 of 105 
7 
LIST OF APPENDICES 
 
 
  
Appendix A 
Potentially clinically significant abnormalities criteria 
Appendix B 
List of PTs for select EOSIs (MedDRA v22.0) 
Appendix C 
Summary of statistical analyses  
Appendix D 
Study flow chart 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 78 of 105 
Appendix A 
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 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 79 of 105 
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 
 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 80 of 105 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
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 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 81 of 105 
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 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 82 of 105 
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 
 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 83 of 105 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
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 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 84 of 105 
Appendix B 
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 
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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 85 of 105 
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 
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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 86 of 105 
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 
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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 87 of 105 
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 
Venous thrombotic events 
10037459 
Pulmonary venous thrombosis 
Venous thrombotic events 
10038547 
Renal vein embolism 
Venous thrombotic events 
10038548 
Renal vein thrombosis 
Venous thrombotic events 
10038908 
Retinal vein thrombosis 
Venous thrombotic events 
10041659 
Splenic vein thrombosis 
Venous thrombotic events 
10042567 
Superior sagittal sinus thrombosis 
Venous thrombotic events 
10043570 
Thrombophlebitis 
Venous thrombotic events 
10043581 
Thrombophlebitis migrans 
Venous thrombotic events 
10043595 
Thrombophlebitis superficial 
Venous thrombotic events 
10043605 
Thrombosed varicose vein 
Venous thrombotic events 
10044457 
Transverse sinus thrombosis 
Venous thrombotic events 
10047193 
Vena cava embolism 
Venous thrombotic events 
10047195 
Vena cava thrombosis 
Venous thrombotic events 
10047249 
Venous thrombosis 
Venous thrombotic events 
10048591 
Post thrombotic syndrome 
Venous thrombotic events 
10049446 
Subclavian vein thrombosis 
Venous thrombotic events 
10050216 
Paget-Schroetter syndrome 
Venous thrombotic events 
10050902 
Postoperative thrombosis 
Venous thrombotic events 
10051055 
Deep vein thrombosis 
Venous thrombotic events 
10053182 
Arteriovenous graft thrombosis 
Venous thrombotic events 
10061251 
Intracranial venous sinus thrombosis 
Venous thrombotic events 
10061408 
Venous thrombosis limb 
Venous thrombotic events 
10063363 
Brachiocephalic vein thrombosis 
Venous thrombotic events 
10063909 
Post procedural pulmonary embolism 
Venous thrombotic events 
10066881 
Deep vein thrombosis postoperative 
Venous thrombotic events 
10067270 
Thrombosis corpora cavernosa 
Venous thrombotic events 
10069909 
Metastatic pulmonary embolism 
Venous thrombotic events 
10072059 
Ovarian vein thrombosis 
Venous thrombotic events 
10074349 
Ophthalmic vein thrombosis 
Venous thrombotic events 
10077623 
Portosplenomesenteric venous thrombosis 
Venous thrombotic events 
10077829 
Visceral venous thrombosis 
Venous thrombotic events 
10078810 
Hepatic vein embolism 
Thyroid cancer 
10002240 
Anaplastic thyroid cancer 
Thyroid cancer 
10016935 
Follicular thyroid cancer 
Thyroid cancer 
10027105 
Medullary thyroid cancer 
Thyroid cancer 
10033701 
Papillary thyroid cancer 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 88 of 105 
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 
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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 89 of 105 
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 
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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 90 of 105 
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 
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 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 91 of 105 
Potentially leading to amputation 
10050473 
Abscess limb 
Potentially leading to amputation 
10050502 
Neuropathic ulcer 
Potentially leading to amputation 
10051548 
Burn infection 
Potentially leading to amputation 
10052428 
Wound 
Potentially leading to amputation 
10052949 
Arterial therapeutic procedure 
Potentially leading to amputation 
10053692 
Wound complication 
Potentially leading to amputation 
10053716 
Wound necrosis 
Potentially leading to amputation 
10054044 
Diabetic microangiopathy 
Potentially leading to amputation 
10056340 
Diabetic ulcer 
Potentially leading to amputation 
10056418 
Arterial bypass operation 
Potentially leading to amputation 
10056673 
Peripheral sensorimotor neuropathy 
Potentially leading to amputation 
10057518 
Peripheral artery angioplasty 
Potentially leading to amputation 
10057525 
Peripheral artery occlusion 
Potentially leading to amputation 
10058041 
Wound sepsis 
Potentially leading to amputation 
10058042 
Wound abscess 
Potentially leading to amputation 
10059245 
Angiopathy 
Potentially leading to amputation 
10059385 
Extremity necrosis 
Potentially leading to amputation 
10059442 
Wound infection staphylococcal 
Potentially leading to amputation 
10059444 
Wound infection pseudomonas 
Potentially leading to amputation 
10060734 
Diabetic foot 
Potentially leading to amputation 
10060803 
Diabetic foot infection 
Potentially leading to amputation 
10060963 
Arterial disorder 
Potentially leading to amputation 
10060965 
Arterial stenosis 
Potentially leading to amputation 
10061627 
Amputation 
Potentially leading to amputation 
10061655 
Arterial graft 
Potentially leading to amputation 
10061657 
Arterial stent insertion 
Potentially leading to amputation 
10061666 
Autonomic neuropathy 
Potentially leading to amputation 
10061815 
Diabetic vascular disorder 
Potentially leading to amputation 
10062198 
Microangiopathy 
Potentially leading to amputation 
10062255 
Soft tissue infection 
Potentially leading to amputation 
10062585 
Peripheral arterial occlusive disease 
Potentially leading to amputation 
10062599 
Arterial occlusive disease 
Potentially leading to amputation 
10062610 
Ischaemic limb pain 
Potentially leading to amputation 
10062932 
Wound treatment 
Potentially leading to amputation 
10064250 
Staphylococcal osteomyelitis 
Potentially leading to amputation 
10064601 
Iliac artery occlusion 
Potentially leading to amputation 
10065237 
Osteomyelitis bacterial 
Potentially leading to amputation 
10065239 
Osteomyelitis fungal 
Potentially leading to amputation 
10065240 
Wound infection bacterial 
Potentially leading to amputation 
10065242 
Wound infection fungal 
Potentially leading to amputation 
10068653 
Bone abscess 
Potentially leading to amputation 
10069379 
Peripheral arterial reocclusion 
Potentially leading to amputation 
10072170 
Skin wound 
Potentially leading to amputation 
10072557 
Peripheral artery restenosis 
Potentially leading to amputation 
10072560 
Peripheral endarterectomy 
Potentially leading to amputation 
10072561 
Peripheral artery bypass 
Potentially leading to amputation 
10072562 
Peripheral artery stent insertion 
Potentially leading to amputation 
10072563 
Peripheral artery stenosis 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 92 of 105 
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 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 93 of 105 
Appendix C 
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 18, 
(sotagliflozin 400 mg vs 
placebo)  
 
ITT 
ANCOVA (with missing values 
imputed by the retrieved dropouts 
imputation method or by washout 
MI method under MNAR 
framework): treatment, 
randomization stratum (HbA1c / 
SBP/SU use at Week -1), and 
country as fixed effects, and 
baseline HbA1c value as a 
covariate 
Tipping point analysis; 
ANCOVA (with missing 
values imputed by the 
retrieved dropouts 
imputation method or by 
washout MI method under 
MNAR framework)  
ANCOVA (with missing 
values imputed by the 
retrieved dropouts 
imputation method or by 
washout MI method under 
MNAR framework): 
excluding patients with 
randomization stratification 
error of HbA1c; use HbA1c 
(≤8.5%, >8.5%) factor 
instead of randomization 
stratum of HbA1c. 
Subgroups: 
race, ethnicity, 
age, gender, 
baseline BMI, 
baseline HbA1c, 
baseline SBP, 
SU use at Week 
-1, baseline 
eGFR, duration 
of diabetes and 
country. 
 
Summary statistics for observed values and 
changes from baseline by visit. 
Graphical presentations for mean changes from 
baseline (±SE) and mean values (±SE) by visit. 
By-visit summary and graph for patients who 
completed the 18-week randomized core treatment 
period. 
 
Secondary endpoints 
 
 
 
 
 
HbA1c, FPG, body weight: 
Change from Baseline to 
Week 18; HbA1c and body 
weight: change from 
ITT 
ANCOVA (with missing values 
imputed by the retrieved dropouts 
imputation method or by washout 
MI Method under MNAR 
Tipping point analysis on 
HbA1c 
Subgroups on 
HbA1c: race, 
ethnicity, age, 
gender, baseline 
Summary statistics for observed values and 
changes from baseline by visit. 
Graphical presentations for mean changes from 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 94 of 105 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
baseline to Week 52 
SBP (for patients with 
baseline SBP ≥130 mmHg, 
all patients): Change from 
Baseline to Week 12 
framework): treatment, 
randomization stratum (HbA1c / 
SBP/SU use at Week -1), and 
country as fixed effects, and 
baseline endpoint value as a 
covariate. 
BMI, baseline 
HbA1c, baseline 
SBP, baseline 
eGFR  and 
country. 
baseline (±SE) and mean values (±SE) by visit. 
 
 
 
 
 
 
Other endpoints 
 
Proportion of patients with 
HbA1c <6.5%, <7.0% at 
Week 18 
ITT 
 
 
No 
By-visit summary and graphs of HbA1c responders 
(<6.5%, <7%). 
 
SBP (for patients with 
baseline SBP <130 mmHg, 
≥130 mmHg), DBP (for 
patients with baseline DBP 
≥ 80 mmHg, all patients), 
total insulin dose, 7-point 
SMBG, UACR, eGFR, UGE, 
UGCR: 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 
requiring rescue for 
hyperglycemia 
 
Summary statistics 
No 
No 
KM plot; List of patients rescued 
TRIM-D (total score and 5 
domain scores): change 
from baseline 
 
ANCOVA (with missing values imputed 
by the retrieved dropouts imputation 
method or by washout MI Method under 
MNAR framework): treatment, 
randomization stratum (HbA1c / 
No 
No 
Summary statistics for observed values and 
changes from baseline by visit. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 95 of 105 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
SBP/SU use at Week -1), and country 
as fixed effects, and baseline TRIM-D 
value as a covariate. 
 
 
 
 
 
 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 96 of 105 
SAFETY ANALYSES 
Endpoint 
Analysis 
Population 
Primary 
analysis 
Supportive 
Analysis 
Subgroup 
analysis 
Other 
analyses 
Hypoglycemia 
Safety 
Follow safety guidelines 
Number (%) of patients with any 
hypoglycemia, severe 
hypoglycemia, documented 
symptomatic hypoglycemia during 
TEAE period of 18-week 
randomized core treatment period 
and entire 52-week double-blind 
treatment period, and incidence 
rates in 100 patient-years. 
 
Severe hypoglycemia or 
documented symptomatic 
hypoglycemia by subgroups: 
race, age, gender, SU use at 
Week -1 
KM plot time to first event of severe hypoglycemia 
or documented symptomatic hypoglycemia  
Summary of frequency/events of documented 
symptomatic hypoglycemia by hour during the 
TEAE period 
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, 
SU use at Week -1, baseline 
SBP, baseline eGFR  
 
Clinical laboratory 
data 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
Vital signs 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
ECG, Physical 
examination 
Safety 
Follow safety guidelines 
Frequency 
summary 
No 
No 
 
 
 
 
 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 97 of 105 
CGM SUB-STUDY ANALYSIS 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
CGM sub-study primary endpoint 
Percentage of time within 
the target glucose range of 
70 to 180 mg/dL over 24 
hours: Change from 
baseline to Week 19, 
(sotagliflozin 400 mg vs 
placebo)  
 
CGM  
ANCOVA (with missing values 
imputed by the retrieved dropouts 
imputation method or by washout 
MI method under MNAR 
framework): treatment, 
randomization stratum (HbA1c / 
SBP/SU use at Week -1), and 
country as fixed effects, and 
baseline CGM percentage 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. 
CGM sub-study 
secondary endpoints 
 
 
 
 
 
Mean 24-hour glucose 
concentration, percentage 
of time within the glucose 
range of 70 to 140 mg/dL, 
CV of glucose 
concentrations over 24 
hours: change from 
baseline to Week 19; 
AUC of plasma glucose 
concentrations 2 hours after 
a standardized mixed meal, 
2-hour PPG: change from 
baseline to Week 18 
 
CGM  
ANCOVA (with missing values 
imputed by retrieved dropouts  
imputation method or by washout 
MI Method under MNAR 
framework): treatment, 
randomization stratum (HbA1c / 
SBP/SU use at Week -1), and 
country as fixed effects, and 
baseline endpoint 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. 
CGM sub-study other endpoints 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 98 of 105 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
 
Percentage of time over 24 
hours with glucose levels 
>140 mg/dL, >180 mg/dL, 
>250 mg/dL, <70 mg/dL, 
<54 mg/dL, 70-180 mg/dL 
(diurnal, nocturnal period); 
AUC of glucose 
concentrations over 24 
hours >140 mg/dL, >180 
mg/dL, >250 mg/dL, <70 
mg/dL, <54 mg/dL; MAGE, 
SD of glucose levels within 
and between days: change 
from baseline  
CGM  
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. 
Percentage of patients with 
≥ 1 episode of 
hypoglycemia with CGM 
values < 70 mg/dL for ≥ 10 
minutes. 
CGM  
Summary statistics 
No 
No 
No 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 99 of 105 
Appendix D 
Study flow chart 
MAIN STUDY FLOW CHART 
 
Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
Screen
- ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight, heightd 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signse 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examination: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Abbreviatedf 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
Concomitant Medication 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 100 of 105 
 
Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
Screen
- ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
Diet & exercise instruction 
 
X 
 
 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Instruction on basic GU 
hygiene & hydration 
 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Interactive response 
technology (IRT) contact 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense glucose meter, 
Beta-hydroxybutyrate (BHB) 
meter 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense glucose test strips 
and BHB strips 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Measurement of capillary 
BHB at the site 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
Dispense diary 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Collect/review diary 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Instruction on diabetic 
ketoacidosis symptoms, 
glucose testing 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Dispense IMP and Lantus 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
IMP and Lantus accounting & 
compliance 
 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 101 of 105 
 
Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
Screen
- ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
Review results of SMBG and 
recommend Lantus dose 
adjustments as necessaryg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record results of a 7-point 
SMBGh 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
12-lead ECGi 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Laboratory Assessmentsj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FPGk 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
BHB 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
HbA1c 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Clinical Chemistryl 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
Fasting lipids 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Pregnancy test (WOCBP)m 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
FSH and/or estradiol as 
neededm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma concentrationn 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Markers of calcium 
metabolismo 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 102 of 105 
 
Screening Period 
Double-Blind Treatment Perioda 
FU 
Period 
Screen
- ing 
Run-in 
(Lantus titration, single-blind placebo 
Run-in) 
No titration of Lantus (except for safety) 
Lantus titration permitted 
VISIT 
1 
2 
3b 
4b 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16c 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
Urinalysis w/microscopyp 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Collection of home 
overnight urine for albumin, 
protein, creatinine, calcium, 
phosphorus, magnesium, 
glucose, and albumin-
creatinine ratioq 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
PRO: PQATt 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
PRO: TRIM-Dt 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
Evaluate for glycemic rescue 
 
 
 
 
 
To be assessed and reported throughout the Treatment Period 
 
Hypoglycemia 
To be assessed and reported throughout the study 
AEs/SAEs/AESI/EOSIu 
To be assessed and reported throughout the study 
a If a patient discontinues treatment with IMP early during the Treatment Period, the patient will have a Premature EOT Visit, and a Follow-up Visit 2 weeks after the last dose of IMP. However, every effort will be 
made to have the patients return to the site for all scheduled visits, in particular the visits at Week 18 (Visit 12) and Week 52 (Visit 15). If the patient does not agree to a site visits, the patient will be contacted by 
telephone to inquire about safety status. If a patient discontinues (or completes) treatment and study at the same time, a single visit for both EOT and EOS will be performed. 
b To ensure effective Lantus dose titration during the Run-in Phase, patients will be instructed to call the Investigator to discuss the necessary adjustments in Lantus dose if they have 2 or more SMBG 
measurements above 100 mg/dL or below 80 mg/dL. 
c Two weeks after the last dose of IMP. 
d Height to be measured only at Screening. 




Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 104 of 105 
CGM SUB-STUDY FLOW CHART 
 
 
Screening period 
Double Blind Treatment Period  
FU 
period 
Scr 
Run-in 
Lantus titration, single-blind placebo  
No titration of Lantus (except for safety) 
Lantus titration permitted  
VISIT 
1 
2 
3  
4  
5 
6 
7 
8 
9 
10 
11 
12Aa 
12b  
13 
14 
15 
16 
Week 
-6 
-4 
-3 
-2 
-1 
0 
2 
4 
6 
8 
12 
17 
18 
26 
39 
52 
54 
Day (window [days]) 
-42 
-28  
(±3) 
-21  
(±2) 
-14  
(±2) 
-7  
(±2) 
1  
(-) 
14  
(±3) 
28  
(±3) 
42 
(±3) 
56  
(±3) 
84  
(±3) 
119 
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
378 
(±3) 
CGM sub-study 
procedures 
 
 
 
 
Baseline CGM 
 
 
 
 
 
Post-
randomization  
CGM 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility  
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
CGM Training/Review 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Dispense CGM supplies 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
CGM sensor insertion 
 
 
 
 
X 
Xc 
 
 
 
 
 
X 
X 
 
 
 
 
CGM start  
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Mixed-Meal Tolerance 
Testd (MMTT) 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Collect CGM supplies 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Upload CGM data to PC 
and review the quality 
report  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
a Patients in the CGM sub-study will return to the study site for an additional visit (Visit 12A) at the end of Week 17 for insertion of CGM sensors for the post-randomization CGM assessment which will be conducted 
over Weeks 18 and 19.  If a patient discontinued the IMP before Visit 12A, the post-randomization CGM and the MMTT will not be performed. 
b For patients in the CGM sub-study, at Visit 12 the CGM sensors will be replaced for continuing the next 7-day CGM.  For patients in the CGM sub-study, during Week 19 the total Lantus dose should remain stable 
(dose change less than ±10%, or less than ±4 Units, whichever is less).  At the end of Week 19 patients will remove the CGM sensor at home and return the device and supplies (including sensor, transmitter, and 
receiver) to the study site in person or via mail using the provided packaging.  Following removal of the CGM sensor, Lantus titration may resume as needed. 


Statistical Analysis Plan 
Version: Final 2.0 
Date of Issue: 04 December 2019 
Lexicon Pharmaceuticals Protocol No. EFC14868  
Covance Study ID:000000155200 
COVANCE INC. CONFIDENTIAL 
Page 105 of 105 
c Repeat 7-day CGM assessment conducted ONLY for patients who fail to provide adequately usable CGM data during the previous 7 days.  In such a case, randomization will be postponed for 7 days and MMTT 
will be repeated.   
d Mixed meal tolerance test is to be performed while CGM sensor is in place and functioning.