Clinical trial NCT03386344
Conditions: Type 2 Diabetes Mellitus
Sponsor: Lexicon Pharmaceuticals
Start date: 2018-02-19; Completion date: 2020-05-30
Enrollment: 376 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to demonstrate the superiority of Sotagliflozin 400 milligrams (mg) versus placebo with respect to hemoglobin A1c (Hb1Ac) reduction in participants with type 2 diabetes (T2D) who have inadequate glycemic control on diet and exercise only or with a stable antidiabetes regimen.

Detailed description:
Study duration per participant is approximately 110 weeks (Screening period of up to 2 weeks, 2 week single-blind run-in period), a 26-week double-blind core treatment period, a 78-week double-blind extension period, and a 2- week post treatment follow up period.

Dual-energy X-ray absorptiometry (DXA) scans will be performed to assess Bone Mineral Density and Fat vs. Lean body mass at baseline and Weeks 26, 52, and 104.

Arms: arm 1: Following a 2 week run-in period, participants were randomized to matching placebo to sotagliflozin administered as 2 tablets, once daily, before the first meal of the day, for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 106 weeks. arm 2: Following a 2 week run-in period, participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day, for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 104 weeks. arm 3: Following a 2 week run-in period, participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day, for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 104 weeks.
Interventions: intervention 1: Sotagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Tablet; Route of administration: Oral intervention 2: Pharmaceutical form: Tablet; Route of administration: Oral

Protocol documents:
Prot_000.pdf: 
Official Title: A 26-week Randomized, Double-blind, Placebo-controlled, Parallel-
group, Multicenter, Phase 3 Study with a 78-week Extension Period to 
Evaluate the Efficacy and Bone Safety of Sotagliflozin in Patients 55 
years or Older with Type 2 Diabetes Mellitus and Inadequate Glycemic 
Control 
NCT Number: NCT03386344 
Document Date: Protocol Version 1: 14-November-2017 


 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
 
 
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CLINICAL TRIAL PROTOCOL 
 
COMPOUND: sotagliflozin/SAR439954 
A 26-week Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Multicenter, Phase 3 Study with a 78-week Extension Period to Evaluate the 
Efficacy and Bone Safety of Sotagliflozin in Patients 55 years or Older with Type 2 
Diabetes Mellitus and Inadequate Glycemic Control 
STUDY NUMBER: EFC15294 
STUDY NAME: SOTA-BONE 
EudraCT: 
2017-002041-30 
IND Number(s): 
 
Version Number: 
1 
WHO universal trial number: 
U1111-1195-6371 
Date: 
10-Nov-2017 
Total number of pages: 
120 
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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
COMPOUND: sotagliflozin/SAR439954 
STUDY No.: EFC15294  
STUDY NAME: SOTA-BONE 
TITLE 
A 26-week Randomized, Double-blind, Placebo-controlled, 
Parallel-group, Multicenter, Phase 3 study with a 78-week Extension 
Period to Evaluate the Efficacy and Bone Safety of Sotagliflozin in 
Patients 55 years or older with Type 2 Diabetes Mellitus and 
Inadequate Glycemic Control. 
INVESTIGATOR/TRIAL LOCATION 
Multinational 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVE(S) 
 
Primary objective: 
The primary objective of this study is to demonstrate the superiority 
of sotagliflozin 400 mg versus placebo with respect to hemoglobin 
A1c (HbA1c) reduction at Week 26 in patients with Type 2 diabetes 
(T2D) who have inadequate glycemic control on diet and exercise 
only or with a stable antidiabetes regimen. 
Secondary objective(s): 
The secondary objectives of this study are: 
• To compare the effects of sotagliflozin 400 mg and 200 mg 
versus placebo with respect to the percent change from 
Baseline to Week 26 in bone mineral density (BMD) (lumbar 
spine, total hip, and femoral neck) measured by dual-energy 
X-ray absorptiometry (DXA) (key secondary safety objective). 
• To demonstrate the superiority of sotagliflozin 400 mg versus 
placebo on: 
- 
Change from Baseline to Week 26 in body weight (BW). 
- 
Change from Baseline to Week 26 in fasting plasma 
glucose (FPG). 
- 
Change from Baseline to Week 12 in systolic blood 
pressure (SBP) for all patients. 
- 
Proportion of patients with HbA1c <7.0% at Week 26. 
• To demonstrate the superiority of sotagliflozin 200 mg versus 
placebo with respect to: 
- 
HbA1c reduction from Baseline to Week 26. 
- 
Change from Baseline to Week 26 in BW. 
- 
Change from Baseline to Week 26 in FPG. 
- 
Change from Baseline to Week 12 in SBP for all patients. 
- 
Proportion of patients with HbA1c <7.0% at Week 26. 
• To evaluate the safety of sotagliflozin 200 mg and 400 mg 
compared with placebo over the 104 weeks of treatment. 
Other objectives: 
Other objectives of this study are: 
• To compare the effects of sotagliflozin 200 mg and 400 mg 
versus placebo with respect to: 
- 
Change from Baseline to Weeks 52 and 104 in HbA1c. 
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- 
Change from Baseline to Weeks 52 and 104 in FPG. 
- 
Change from Baseline to Weeks 52 and 104 in BW. 
- 
Proportion of patients with HbA1c <7.0% at Weeks 52 and 
104. 
- 
Proportion of patients starting rescue therapy during the 
104 weeks of treatment. 
- 
Change from Baseline to Weeks 26 and 104 in SBP for all 
patients. 
- 
Change from Baseline to Weeks 12, 26, and 104 in SBP 
for the subset of patients with baseline SBP ≥130 mmHg 
and SBP <130 mmHg, respectively. 
- 
Change from Baseline to Weeks 12, 26, and 104 in 
diastolic blood pressure (DBP) for all patients and the 
subsets of patients with Baseline DBP ≥80 mmHg and 
<80 mmHg, respectively. 
- 
Changes from Baseline to Weeks 26, 52, and 104 in total 
body fat mass and total lean mass measured by DXA. 
- 
Changes from Baseline to Weeks 26, 52, and 104 in 
serum estradiol (only for women). 
- 
Changes from Baseline to Weeks 26, 52, and 104 in 
urinary albumin to creatinine ratio (UACR). 
- 
Changes from Baseline to Weeks 26, 52, and 104 on 
estimated glomerular filtration rate (eGFR). 
STUDY DESIGN 
This is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study that is anticipated to enroll 
approximately 360 patients. 
Patients with T2D who are 55 years of age or older currently 
managed with diet and exercise only or with a stable antidiabetes 
regimen in monotherapy or combination therapy (including oral 
antidiabetes medications, insulin, or glucagon-like peptide-1 [GLP-1] 
agonists) for more than 12 weeks are eligible for enrollment in the 
study. 
The study will consist of 4 periods: 
• A Screening Period of up to 4 weeks comprised of: 
- 
A Screening Phase of up to 2 weeks. 
- 
A 2-week single-blind placebo Run-in Phase. 
• A 26-week Randomized Double-blind Core Treatment Period. 
• A 78-week Randomized Double-blind Extension Period. 
• A 2-week, post-treatment Follow-up Period. 
To qualify for randomization, patients must demonstrate compliance 
based upon tablet count (≥80%) during the Run-in Phase. 
Randomization will be stratified by: 
• HbA1c at Screening (≤8.5%, >8.5%). 
• Sex (male, female). 
Patients will be randomized at a 1:1:1 ratio to the following 
3 treatment groups: 
• Sotagliflozin 400 mg as two (2) 200 mg tablets, taken orally 
once daily (N=120). 
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• Sotagliflozin 200 mg as one (1) 200 mg tablet and one (1) 
placebo tablet (identical to sotagliflozin 200 mg in 
appearance), taken orally once daily (N=120). 
• Placebo as two (2) placebo tablets, taken orally once daily 
(N=120). 
To avoid partial unblinding, HbA1c and FPG will be masked to study 
sites and patients after randomization. Additionally, urinalysis by 
dipstick will not include the measurement of urine glucose. 
Early termination 
If a patient discontinues treatment with the investigational medicinal 
product (IMP) at any time during the Randomized Double-blind Core 
Treatment Period or during the Randomized Double-blind Extension 
Period, the patient will have a Premature End of Treatment (EOT) 
visit, and a Follow-up Visit, 2 weeks after the last dose of IMP. In 
addition, every effort will be made to have the patients return to the 
site at the time corresponding to their scheduled visits, particularly 
the Week 26 Visit and Week 104 Visit to perform the respective 
study assessments and collect safety data, emphasizing the 
measurement of HbA1c and BMD. If the patient does not agree to 
site visits, the patient will be contacted by respective sites by 
telephone to inquire about safety status. 
The study design is presented graphically in Section 1.1. 
STUDY POPULATION 
Main selection criteria 
Inclusion criteria: 
• Patient with T2D managed with diet and exercise only or with a 
stable antidiabetes regimen (in monotherapy or combination 
therapy that can include oral antidiabetes medications, insulin, 
or GLP-1 agonists). 
• Patient has given written informed consent to participate in the 
study in accordance with local regulations. 
Major Exclusion criteria: 
• Age <55 years at the Screening Visit. 
• Women who have been postmenopausal (or undergone 
bilateral oophorectomy) for less than 5 years. 
• Type 1 diabetes mellitus. 
• Body mass index ≤20 or >45 kg/m2 at Screening or BW that 
exceeds the weight limits of the DXA scanner. 
• HbA1c <7.0% or HbA1c >11.0% via central laboratory test at 
the Screening Visit. 
• Not on stable prior antidiabetes treatment in the last 12 weeks 
prior to the Screening Visit (for prior insulin treatment: change 
of total daily dose of basal insulin by more than 20% within 
8 weeks prior to the Screening Visit). 
• Use of a selective sodium-glucose cotransporter 
Type 2 (SGLT2) inhibitor or thiazolidinedione within 24 months 
prior to Screening. 
• Anatomical changes or conditions that interfere with accurate 
measurement of BMD by DXA. 
 
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• BMD T-score <-2.0 at any site (ie, lumbar spine, total hip, or 
femoral neck) measured by DXA during the Screening Period 
(determination of eligibility based on this test can be made until 
the time of randomization). 
• Hypercalcemia based on total serum calcium level 
>10.5 mg/dL (2.63 mmol/L) at Screening by central laboratory. 
• Serum 25-hydroxyvitamin D levels ≤20 ng/mL (≤50 nmol/L) at 
the Screening Visit by central laboratory (determination of 
eligibility based on this test can be made until the time of 
randomization). 
• History of fracture within 12 months prior to the Screening Visit 
(except for fractures of the hand/fingers, foot/toes, facial 
bones, and skull). 
• Treatment with medications known to affect bone mass or 
modify the risk of fractures within 36 months prior to the 
Screening Visit (eg, bisphosphonates, selective 
estrogen-receptor modulators, calcitonin, teriparatide, 
denosumab, strontium ranelate, growth hormone, aromatase 
inhibitors, androgen deprivation therapy, carbamazepine, 
phenytoin, phenobarbital). Use of hormonal replacement that 
includes systemic or transdermal estrogen and testosterone is 
excluded unless is stable for at least 24 months prior to 
Screening. 
• 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 Screening. 
• Use of weight loss medication within 12 weeks or weight 
change of 5 kg or more during the 12 weeks prior to 
Screening. 
• History of gastric surgery including history of gastric banding or 
surgery for inflammatory bowel disease within 3 years prior to 
Screening. 
• History of diabetic ketoacidosis or nonketotic hyperosmolar 
coma within 12 weeks prior to Screening. 
• History of severe hypoglycemia resulting in unconsciousness, 
seizure, or hospitalization within 6 months prior to Screening. 
• Lower extremity complications (such as skin ulcers, infection, 
osteomyelitis and gangrene) identified during the Screening 
Period, and still requiring treatment at Randomization. 
• Mean of 3 separate measurements SBP >180 mmHg or 
DBP >100 mmHg at the Screening Visit. 
• History of hypertensive emergency within 12 weeks prior to 
Screening. 
• Patients with severe anemia, severe cardiovascular disease 
(including congestive heart failure New York Heart Association 
IV), respiratory, hepatic, neurological, psychiatric, or active 
malignant tumor or other major systemic disease or patients 
with short life expectancy that, according to the Investigator, 
will preclude their safe participation in this study or will make 
implementation of the protocol or interpretation of the study 
results difficult. 
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• Aspartate aminotransferase and/or alanine aminotransferase 
>3 times the upper limit of the normal laboratory range (ULN). 
• Total bilirubin >1.5 times the ULN (except in case of Gilbert's 
syndrome). 
• Alkaline phosphatase >1.5 times the ULN. 
• Renal disease as defined by eGFR <30 mL/min/1.73m² at the 
Screening Visit by the 4 variable Modification of Diet in Renal 
Disease equation. 
• Patient is unwilling or unable to perform self-monitoring of 
blood glucose (SMBG), complete the patient diary, or comply 
with study visits and other study procedures as required per 
protocol. 
• Patient who has taken other investigational drugs or prohibited 
therapy for this study within 12 weeks or 5 half-lives from 
Screening or randomization, whichever is longer. 
Total expected number of patients 
360 
STUDY TREATMENTS 
 
Investigational medicinal product(s) 
During the single-blind Run-in period all patients will receive two (2) 
placebo tablets (identical to sotagliflozin 200 mg in appearance). 
During the Randomized Double-blind Core Treatment Period and 
Double-blind Extension Period, the patients will receive treatment 
with the IMP, as follows: 
• Sotagliflozin 400 mg given as two (2) 200-mg tablets, or, 
• Sotagliflozin 200 mg given as one (1) 200-mg sotagliflozin 
tablet and one (1) sotagliflozin-matching placebo tablet, or, 
• Placebo, given as two (2) sotagliflozin-matching placebo tablets. 
Formulation 
Tablet 
Routes of administration 
Oral 
Dose regimen 
Once daily before the first meal of the day 
Noninvestigational medicinal product(s) 
Dose of background antidiabetes medication (if any) should be 
stable throughout the study, unless a change is required for safety 
reasons or if hyperglycemia rescue criteria are satisfied. For patients 
on insulin therapy, the total daily dose of basal insulin should remain 
within 20% of the randomization dose, unless changes are needed 
for safety reasons or hyperglycemia rescue criteria are met. 
Rescue Therapy 
The threshold values for rescue are defined as follows, depending 
on study period: 
• From Baseline visit (Visit 3, Day 1) to Visit 5 (Week 6), 
inclusive: FPG >270 mg/dL (15.0 mmol/L). 
• From Visit 5 (Week 6) to Visit 6 (Week 12), inclusive: FPG 
>240 mg/dL (13.3 mmol/L). 
• From Visit 6 (Week 12) up to Visit 8 (Week 26), inclusive: FPG 
>200 mg/dL (11.1 mmol/L) or HbA1c ≥8.5% (the 8.5% criteria 
does not apply if the HbA1c decrease from Baseline was 
≥1.0%). 
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• From Visit 8 (Week 26) up to Visit 10 (Week 52), inclusive: 
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 ≥1.0%). 
• From Visit 10 (Week 52) up to the EOT Visit 13 (Week 104): 
FPG >160 mg/dL (8.9 mmol/L) or HbA1c ≥7.5%. 
The HbA1c and FPG results will be masked to study sites and 
patients after randomization and until study end. Routine fasting 
SMBG and central laboratory alerts on FPG and/or HbA1c are set up 
to ensure that glycemic parameter results remain within predefined 
thresholds. If a central laboratory FPG and/or HbA1c is above the 
threshold, the Investigator will receive an alert from the central 
laboratory. Upon receipt of a central laboratory rescue alert, a central 
laboratory re-test must be completed and confirmed as soon as 
possible, preferably within 7 days, by unscheduled visit. 
Likewise, patients will be 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 laboratory re-test confirmation should be performed as 
soon as possible, preferably within 7 days, by unscheduled visit. 
Open-label rescue treatment may be added at the Principal 
Investigator’s discretion (with exception of treatment with SGLT2 
inhibitors or thiazolidinediones). 
If a patient requires rescue, the IMP received at Randomization 
should continue and must remain blinded until the end of the study. 
ENDPOINT(S) 
 
Primary endpoint: 
• Change from Baseline to Week 26 in HbA1c (sotagliflozin 
400 mg). 
Secondary endpoint(s): 
Key secondary safety endpoint: 
• Percent change from Baseline to Week 26 in BMD (lumbar 
spine, total hip, and femoral neck). 
Secondary efficacy endpoints: 
• Change from Baseline to Week 26 in HbA1c (sotagliflozin 
200 mg only). 
• Change from Baseline to Week 26 in BW. 
• Change from Baseline to Week 26 in FPG. 
• Change from Baseline to Week 12 in SBP for all patients. 
• Proportion of patients with HbA1c <7.0% at Week 26. 
Other efficacy endpoint(s): 
• Change from Baseline to Weeks 52 and 104 in HbA1c. 
• Change from Baseline to Weeks 52 and 104 in FPG. 
• Change from Baseline to Weeks 52 and 104 in BW. 
• Proportion of patients with HbA1c <7.0% at Weeks 52 and 
104. 
• Proportion of patients starting rescue therapy during the 
104 weeks of treatment. 
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• Change from Baseline to Weeks 26 and 104 in SBP for all 
patients. 
• Change from Baseline to Weeks 12, 26, and 104 in SBP for 
the subset of patients with baseline SBP ≥130 mmHg and 
SBP<130 mmHg, respectively. 
• Change from Baseline to Weeks 12, 26, and 104 in DBP for all 
patients and the subsets of patients with Baseline DBP 
≥80 mmHg and <80 mmHg, respectively. 
• Change from Baseline to Weeks 26, 52, and 104 in total body 
fat mass and total lean mass measured by DXA. 
• Change from Baseline to Weeks 26, 52, and 104 in serum 
estradiol (only for women). 
• Change from Baseline to Weeks 26, 52, and 104 in UACR. 
• Change from Baseline to Weeks 26, 52, and 104 in eGFR. 
Other safety endpoints: 
• Percent change from Baseline to Week 52 and 104 in BMD 
(lumbar spine, total hip, and femoral neck). 
• Proportion of patients with adjudicated bone fractures over 
104 weeks. 
• Proportion of patients with ≥3% decline in BMD at Week 104. 
• Changes from Baseline to Week 26, 52, and 104 in bone 
turnover markers (serum bone resorption markers: N-terminal 
telopeptide of Type 1 collagen (NTX) and beta C-terminal 
telopeptide of Type 1 collagen (β-CTX-1); serum bone 
formation markers: Type 1 procollagen N-terminal propeptide 
[P1NP] and osteocalcin). 
• Changes from Baseline to Week 26, 52, and 104 in markers of 
calcium metabolism (serum: calcium, phosphorus, 
magnesium, parathyroid hormone [iPTH], 25-hydroxyvitamin D 
and 1,25-dihydroxyvitamin D; urinary: calcium, phosphorus 
and magnesium). 
• Clinical laboratory results, vital signs results, and 12-lead 
electrocardiogram (ECG). 
• Adverse events (AEs), hypoglycemia (all, severe and/or 
documented symptomatic hypoglycemia), events of special 
interest (EOSI), adverse events of special interest (AESI), AEs 
leading to discontinuation from the IMP, serious adverse 
events (SAEs), and deaths. 
ASSESSMENT SCHEDULE 
See Study Flow Chart in Section 1.2 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
The sample size/power calculations were performed based on the 
primary variable of change from Baseline to Week 26 in HbA1c. 
Assuming a common standard deviation (SD) of 1.2% and using a 
2-sided test at a 0.05 α-level, 360 patients (120 patients per arm) will 
have 97% power to detect a treatment difference of -0.6% in mean 
HbA1c change from Baseline to Week 26 between sotagliflozin 
400 mg and placebo. 
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This sample size will also allow to exclude a decline in BMD from 
Baseline of >2% with a 95% power, assuming a missing rate of 30% 
and an SD of 3.5%. 
Analysis population: 
Efficacy analyses will be based on the Intention-to-Treat (ITT) 
population, defined as all randomized patients irrespective of 
compliance with the study protocol and procedures. Patients will be 
analyzed for efficacy analyses according to the treatment group to 
which they are randomized. 
The safety analysis will be conducted on the safety population, 
defined as all randomized patients who did actually receive at least 
one dose of study treatment during the Treatment Period (regardless 
of the amount of treatment administered). Patients will be analyzed 
according to the treatment actually received. 
The analyses will be conducted in 2 steps: 
• First step: Efficacy analyses up to Week 26, and interim 
safety analysis. 
The first step analyses will be conducted when all randomized 
patients have at least all their data up to Week 26 (Visit 8) collected 
and validated. The first step analyses will consist of efficacy 
analyses up to Week 26 and analysis for key secondary safety 
endpoint of BMD at Week 26, which are considered as the final 
analyses for the primary and secondary endpoints. The other safety 
analysis will be performed on all safety data collected and validated 
at the time of the first step analysis. The results of the first step 
analyses will not be used to change the conduct of the ongoing study 
in any aspect. Since primary efficacy, secondary efficacy, and key 
safety analyses will have been concluded in all patients at the time of 
this first step analyses, the significance level for the study remains at 
0.05. The first step analyses plan will be used for the submission 
dossier to health authorities. 
• Second step: Final analyses 
The second step analyses will be conducted at the end of the study 
and will include the efficacy endpoints analysis at Week 52 and 
Week 104, which will be descriptive only. The second step analysis 
will also include safety analysis for the entire Week 104 Treatment 
Period. 
Analysis of the primary efficacy endpoint: 
Analysis of the primary efficacy endpoint (change from Baseline to 
Week 26 in HbA1c) will be performed on the ITT population, using 
HbA1c measurements obtained during the study, including those 
obtained after IMP discontinuation or introduction of rescue therapy 
(de facto estimand). The primary efficacy endpoint of change in 
HbA1c from Baseline to Week 26 will be analyzed with missing 
values imputed by control-based copy reference multiple imputation 
method under the missing not at random framework for the active 
treatment group: 
• For placebo patients, missing data will be imputed based on 
the placebo group data. 
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• For patients in the sotagliflozin groups, missing data will be 
imputed as if the patients were on placebo throughout the 
study, where all patients’ measurements including the 
on-treatment measurements will be considered as if the 
measurements were from the placebo group in the imputation 
model. 
Each of the complete datasets will be analyzed by the Analysis of 
Covariance (ANCOVA) model with treatment groups (sotagliflozin 
400 mg, sotagliflozin 200 mg, placebo), randomization stratum of 
HbA1c (≤8.5%, >8.5%) at Screening, randomization stratum sex 
(male, female) and country as fixed effects, and Baseline HbA1c 
value as a covariate. 
Results from each complete dataset will be combined to provide the 
adjusted least squares (LS) mean change in HbA1c from Baseline to 
Week 26 for each treatment group, as well as the between-group 
difference (comparing sotagliflozin 400 mg versus placebo) and the 
95% confidence intervals (CIs) for the difference. 
Summary statistics (for Screening value, Baseline value, observed 
values, and observed changes from Baseline) at scheduled visits will 
be provided for each treatment group. The summary will include the 
number of observations, mean, SD, standard error (SE), minimum, 
median, and maximum. Graphical presentations will also be used to 
examine trends over time using mean values (±SE) and mean 
changes from Baseline (±SE) at each of the scheduled visits (using 
observed cases [OC]). 
Analysis of secondary endpoints: 
The secondary efficacy endpoints will be analyzed using a similar 
approach to the primary efficacy endpoint, with missing values 
imputed by control-based multiple imputation method under the 
missing not at random framework. 
For each of the continuous secondary endpoints, each of the 
complete datasets will be analyzed by the ANCOVA model. 
The model will include treatment groups (sotagliflozin 400 mg, 
sotagliflozin 200 mg, placebo), randomization strata of HbA1c 
(≤8.5%, >8.5%) at Screening, sex (male, female) 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 LS mean change from Baseline to Week 26 (respectively 
Week 12 for SBP) for each treatment group, as well as the 
between-group difference (comparing each sotagliflozin group 
versus placebo group) and the 95% CI for the difference. 
The categorical secondary efficacy variables of HbA1c <7.0% at 
Week 26 will be analyzed using a Cochran-Mantel-Haenszel method 
stratified by randomization strata of HbA1c (≤8.5%, >8.5%) at 
Screening and sex (male, female). 
Analysis of the key secondary safety endpoint of percent change 
from Baseline to Week 26 in BMD will be performed on the safety 
population, using an ANCOVA model. 
To compare sotagliflozin 400 mg and 200 mg versus placebo, the 
model will include treatment groups (sotagliflozin 400 mg, 
sotagliflozin 200 mg, placebo), randomization strata of HbA1c 
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Page 12 
(≤8.5%, >8.5%), sex (male, female) and country as fixed effects, and 
Baseline BMD value as a covariate, providing the adjusted LS mean 
percent change from Baseline to Week 26 for each treatment group, 
as well as the between-group difference (comparing each 
sotagliflozin group vs placebo group) and the 95% CI for the 
difference. 
The last-observation-carried-forward (LOCF) approach will be 
applied for the missing data imputation of the key safety endpoint of 
percent change in BMD from Baseline to Week 26. As the 
Week 26 Visit is the first post-Baseline scheduled visit for BMD 
measurement, if a patient withdraws early from the study before 
Week 26, the BMD measurement collected at the withdrawal visit will 
be used carrying forward to Week 26 in analysis. 
Multiplicity considerations 
To control the family-wise Type I error, a fixed sequence testing 
approach will be used to test primary and secondary endpoints. Only 
if the difference in mean change from Baseline to Week 26 in 
HbA1c of sotagliflozin 400 mg versus placebo is statistically 
significant at α=0.05 (2-sided), a hierarchical testing procedure will 
be performed to test the secondary endpoints in the following 
prioritized order: 
Superiority of sotagliflozin 400 mg versus placebo with respect to: 
• Change from Baseline to Week 26 in BW. 
• Change from Baseline to Week 26 in FPG. 
• Change from Baseline to Week 12 in SBP for all patients. 
Superiority of sotagliflozin 200 mg versus placebo with respect to: 
• Change from Baseline to Week 26 in HbA1c. 
• Change from Baseline to Week 26 in BW. 
• Change from Baseline to Week 26 in FPG. 
• Change from Baseline to Week 12 in SBP for all patients. 
Superiority tests will be tested at 2-sided 5% significant level. If any 
of the endpoints is found to be not statistically significant, the testing 
procedure will be stopped and the following endpoints will not be 
tested. Multiplicity adjustment will not be performed on other 
secondary endpoints not mentioned above. 
Analysis of other efficacy endpoints: 
The analysis of other efficacy endpoints will be descriptive with no 
formal testing. Summary statistics at scheduled visits using OC will 
be provided by each treatment group. Graphical presentations will 
also be used to illustrate trends over time. 
Analysis of other safety endpoints: 
The percent change from Baseline to Week 52 (or Week 104) in 
BMD will be analyzed using a mixed-effect model with repeated 
measures (MMRM). The MMRM model will include treatment groups 
(sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), randomization 
strata of HbA1c (≤8.5%, >8.5%), sex (male, female), visit, 
treatment-by-visit interaction and country as fixed effects, and 
Baseline BMD value-by-visit interaction as covariate, providing the 
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adjusted LS mean percent change from Baseline to Week 52 (or 
Week 104) for each treatment group, as well as the between-group 
difference (comparing each sotagliflozin group vs placebo group) 
and the 95% CI for the difference. 
No statistical significance tests will be performed on safety 
endpoints. These analyses will be based on the Safety Population.  
DURATION OF STUDY PERIOD (per 
patient)  
Up to 110 weeks, including a 4-week Screening Period (comprised 
of a Screening Phase of up to 2 weeks and a 2-week single-blind 
placebo Run-in Phase), a 26-week Randomized Double-blind Core 
Treatment Period, a 78-week Randomized Double-blind Extension 
Period, and a 2-week post-treatment Follow-up Period. 
STUDY COMMITTEES 
Steering Committee: 
 Yes 
 No 
Data monitoring committee: 
 Yes 
 No 
Clinical Endpoint Committees: 
 Yes 
 No 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
 
Abbreviations: HbA1c = hemoglobin A1c; N = number; R = randomization; T2D = Type 2 Diabetes; V = visit; W = week. 
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1.2 
STUDY FLOW CHART 
Screening Period 
Double-blind Treatment Perioda 
 
Screening 
Run-in 
Randomized Double-blind Core Treatment Period 
Randomized Double-blind Extension Period 
Follow-
up 
Periodb 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Week 
-4 
-2 
0 
3 
6 
12 
18 
26 
39 
52 
68 
86 
104 
106 
Day (window [days]) 
-28 
-14  
(±3) 
1  
 
21 
(±3) 
42  
(±3) 
84  
(±3) 
126  
(±3) 
182  
(±3) 
273  
(±7) 
364  
(±7) 
476  
(±7) 
602  
(±7) 
728 
(±3) 
742 
(±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight, heightc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Abbreviatede 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SMBGf 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diet & exercise instruction 
 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
Instruction on basic GU 
hygiene & hydration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IRT contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
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Screening Period 
Double-blind Treatment Perioda 
 
Screening 
Run-in 
Randomized Double-blind Core Treatment Period 
Randomized Double-blind Extension Period 
Follow-
up 
Periodb 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Week 
-4 
-2 
0 
3 
6 
12 
18 
26 
39 
52 
68 
86 
104 
106 
Day (window [days]) 
-28 
-14  
(±3) 
1  
 
21 
(±3) 
42  
(±3) 
84  
(±3) 
126  
(±3) 
182  
(±3) 
273  
(±7) 
364  
(±7) 
476  
(±7) 
602  
(±7) 
728 
(±3) 
742 
(±3) 
Dispense glucose meter 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect/review diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense single-blind placebo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense double-blind IMP 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IMP accounting & compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGg 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Laboratory assessmentsh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 25 hydroxyvitamin D 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FPG i 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
HbA1c 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Safety laboratory 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Hematology 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Fasting lipids 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
FSH and estradiol for 
documentation of 
menopausal statusj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estradiol (only for women) 
 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
Bone turnover markersk 
 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
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Page 17 
Screening Period 
Double-blind Treatment Perioda 
 
Screening 
Run-in 
Randomized Double-blind Core Treatment Period 
Randomized Double-blind Extension Period 
Follow-
up 
Periodb 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Week 
-4 
-2 
0 
3 
6 
12 
18 
26 
39 
52 
68 
86 
104 
106 
Day (window [days]) 
-28 
-14  
(±3) 
1  
 
21 
(±3) 
42  
(±3) 
84  
(±3) 
126  
(±3) 
182  
(±3) 
273  
(±7) 
364  
(±7) 
476  
(±7) 
602  
(±7) 
728 
(±3) 
742 
(±3) 
Markers of calcium 
metabolisml 
 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
Collection of home 24-hour 
urine for albumin, creatinine, 
albumin-creatinine ratio, 
calcium, magnesium, and 
phosphorusm 
 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
Urinalysis w/microscopyn 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
DXA scan o 
 
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 
AE/SAE/AESI/EOSI 
recordingp 
To be assessed and reported throughout the study 
Abbreviations: AE = adverse event, AESI = adverse event of special interest, BMD = bone mineral density, BP = blood pressure, DXA = dual-energy X-ray absorptiometry, ECG = electrocardiogram, EOSI = event 
of special interest, EOT = End of Treatment, FPG = fasting plasma glucose, FSH = follicle-stimulating hormone, GU = genito-urinary, HbA1c = hemoglobin A1C, HR = heart rate, IMP = investigational medicinal 
product, iPTH = parathyroid hormone, IRT = Interactive Response Technology, NIMP = noninvestigational medicinal product, NTX = N-terminal telopeptide of Type 1 collagen, P1NP = Type 1 procollagen N-
terminal propeptide, SAE = serious adverse event, SMBG = self-monitoring of blood glucose, β-CTX-1 = beta C-terminal telopeptide of Type 1 collagen. 
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 26 (Visit 8) and Week 104 (Visit 13). If the patient does not agree to a site visit, they will be contacted by 
telephone to inquire about safety status. 
b The Follow-up Visit will take place 2 weeks ± 3 days after the last dose of IMP. All attempts will be made to contact the patient to inquire about safety status. 
c Height to be measured only at Screening, Week 52, Week 104, and at the Premature EOT Visit. 
d Vital sign measurements (sitting BP and HR): 3 separate seated BP and HR measurements should be taken with at least 1 minute between readings, following a 5-minute rest period and prior to phlebotomy 
(see Appendix C). 
e The abbreviated physical exam should focus on cardiac and respiratory systems, as well as any areas important for assessment of AEs if necessary. 
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f 
Patients will be instructed to measure their fasting glucose levels via SMBG and discuss results with site personnel at clinic visits or phone contacts. The frequency of the fasting SMBG measurements will be 
determined by the Investigator according to the clinical need and background diabetes treatment, but it is recommended to be done at least once a week. Patients will also be instructed to self-assess blood 
glucose levels whenever they experience any illnesses (eg, cold, flu), or symptoms of hyperglycemia or hypoglycemia. Note that the SMBG measurements obtained with glucose meters are displayed as plasma 
glucose concentration. The SMBGs ≤70 mg/dL will be reported on the hypoglycemia specific electronic case report form page. 
g The 12-lead ECG recordings should be obtained prior to IMP administration. The ECG will be evaluated as “normal” or “abnormal”. 
h All laboratory assessments occur prior to dose of double-blind IMP and NIMP. 
i 
The FPG is performed in fasting status, ie, without any food intake (except for water) for at least 8 hours. 
j 
The FSH and serum estradiol is performed in all women at Screening to confirm menopausal status as needed. 
k Markers of bone turnover include: markers of bone resorption (serum NTX, serum β-CTX-1) and bone formation (serum P1NP and osteocalcin). 
l 
Markers of calcium metabolism include: serum and urinary calcium (adjusted for creatinine), serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum and urinary phosphorus (adjusted for serum 
phosphorus, and creatinine), serum and urinary magnesium (adjusted for serum magnesium and creatinine), serum iPTH. 
m 24-hour urine samples for calcium, phosphorus, and magnesium will be collected at Weeks 0, 26, 52, and 104. Patients will be instructed to initiate the 24-hour urine collection on the day before the visits. In 
exceptional situations, the 24-hour urine collection can be done up to 2 days maximum prior to or after the visit, and the specimen should be sent to the study site as soon as possible. 
n Urinalysis will be done at central laboratory and includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte 
esterase. Microscopy includes detection of formed cellular elements, casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. In the event of abnormal urinalysis findings, urine cultures should 
be performed (microbial testing). Additionally, urine cultures should be performed if at any point the Principal Investigator suspects the presence of a urinary tract infection. 
o Baseline DXA scans for BMD assessment will be performed during Run-in and centrally reviewed for eligibility assessment. All BMD assessments will be performed locally with a central review. Post-Baseline DXA 
scans will be performed within 2 weeks prior to the on-site visits at Weeks 26, 52, and 104, or no later than 7 days after the visit. Body composition by DXA will be performed at the same visits when the BMD is 
measured. 
p All SAEs, AEs, AESI, and EOSI will be collected starting from signing informed consent and continue until the end of the study. All AEs that occur during treatment should be followed until study completion (or until 
patients leave the study) or until the event has resolved, the condition has stabilized or the patient is lost to follow-up. All patients will have a Follow-up Visit 2 weeks after the last dose of IMP to collect safety 
information. 
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2 
TABLE OF CONTENTS 
 
CLINICAL TRIAL PROTOCOL.......................................................................................................................1 
1 
FLOW CHARTS.............................................................................................................................14 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................14 
1.2 
STUDY FLOW CHART ..................................................................................................................15 
2 
TABLE OF CONTENTS ................................................................................................................19 
2.1 
LIST OF TABLES...........................................................................................................................25 
2.2 
LIST OF FIGURES.........................................................................................................................25 
3 
LIST OF ABBREVIATIONS ..........................................................................................................26 
4 
INTRODUCTION AND RATIONALE.............................................................................................28 
4.1 
BACKGROUND: SOTAGLIFLOZIN AND DISEASE .....................................................................28 
4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS ................................................................29 
4.3 
RATIONALE FOR SELECTION OF DOSE ...................................................................................30 
4.4 
RATIONALE FOR THE STUDY AND OBJECTIVES ....................................................................31 
4.5 
RATIONALE FOR THE STUDY DESIGN AND CONTROL GROUP ............................................32 
4.6 
BENEFIT/RISK OF SOTAGLIFLOZIN...........................................................................................33 
5 
STUDY OBJECTIVES ...................................................................................................................35 
5.1 
PRIMARY.......................................................................................................................................35 
5.2 
SECONDARY ................................................................................................................................35 
5.3 
OTHER...........................................................................................................................................35 
6 
STUDY DESIGN ............................................................................................................................37 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................37 
6.1.1 
Screening period............................................................................................................................37 
6.1.1.1 
Screening Phase............................................................................................................................37 
6.1.1.2 
Single-blind Run-in-Phase .............................................................................................................38 
6.1.2 
Randomized Double-blind Core Treatment Period (Week 0 to Week 26).....................................38 
6.1.3 
Double-blind, Randomized Extension Period (Week 27 to Week 104) .........................................39 
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6.1.4 
Follow-up period.............................................................................................................................39 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................39 
6.2.1 
Duration of study participation for each patient .............................................................................39 
6.2.2 
Early termination ............................................................................................................................39 
6.2.3 
Determination of end of clinical trial (all patients) ..........................................................................39 
6.3 
INTERIM ANALYSIS......................................................................................................................40 
6.4 
STUDY COMMITTEES..................................................................................................................40 
6.4.1 
Steering Committee .......................................................................................................................40 
6.4.2 
Data Monitoring Committee ...........................................................................................................40 
6.4.3 
Clinical Endpoint Committee..........................................................................................................40 
6.4.4 
Other independent safety assessments.........................................................................................41 
7 
SELECTION OF PATIENTS..........................................................................................................42 
7.1 
INCLUSION CRITERIA..................................................................................................................42 
7.2 
EXCLUSION CRITERIA ................................................................................................................42 
7.2.1 
Exclusion criteria related to study methodology ............................................................................42 
7.2.2 
Exclusion criteria related to the diabetes history and treatment ....................................................43 
7.2.3 
Exclusion criteria related to bone health assessments..................................................................43 
7.2.4 
Exclusion criteria related to the current knowledge of sotagliflozin ...............................................45 
7.2.5 
Additional exclusion criteria during or at the end of the Run-in Phase before randomization.......45 
8 
STUDY TREATMENTS .................................................................................................................47 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................47 
8.1.1 
Formulations ..................................................................................................................................47 
8.1.2 
Starting dose and dose adjustment ...............................................................................................47 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................48 
8.2.1 
Background antidiabetes medications ...........................................................................................48 
8.2.2 
Rescue therapy..............................................................................................................................48 
8.3 
BLINDING PROCEDURES............................................................................................................50 
8.3.1 
Methods of blinding........................................................................................................................50 
8.3.2 
Randomization code breaking during the study.............................................................................50 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................50 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING .............................51 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................52 
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8.7 
RESPONSIBILITIES ......................................................................................................................52 
8.7.1 
Treatment accountability and compliance......................................................................................52 
8.7.2 
Return and/or destruction of treatments ........................................................................................53 
8.8 
CONCOMITANT MEDICATION.....................................................................................................53 
8.8.1 
Prohibited prior and concomitant medications...............................................................................53 
8.9 
POSTSTUDY TREATMENT..........................................................................................................54 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................55 
9.1 
EFFICACY ENDPOINT..................................................................................................................55 
9.1.1 
Primary endpoint............................................................................................................................55 
9.1.2 
Secondary endpoints .....................................................................................................................55 
9.1.2.1 
Key secondary safety endpoint......................................................................................................55 
9.1.2.2 
Secondary efficacy endpoints ........................................................................................................55 
9.1.3 
Other efficacy endpoints ................................................................................................................55 
9.1.4 
Assessment methods of efficacy endpoints...................................................................................56 
9.1.4.1 
Hemoglobin A1c.............................................................................................................................56 
9.1.4.2 
Blood pressure...............................................................................................................................56 
9.1.4.3 
Fasting plasma glucose .................................................................................................................56 
9.1.4.4 
Body weight....................................................................................................................................56 
9.1.4.5 
Kidney function and calcium metabolism parameters ...................................................................57 
9.1.4.6 
Body composition measurements..................................................................................................57 
9.1.4.7 
Use of rescue medications for hyperglycemia ...............................................................................57 
9.2 
SAFETY ENDPOINTS ...................................................................................................................57 
9.2.1 
Assessment methods of safety endpoints .....................................................................................59 
9.2.1.1 
Bone mineral density......................................................................................................................59 
9.2.1.2 
Adverse events ..............................................................................................................................59 
9.2.1.3 
Hypoglycemia.................................................................................................................................59 
9.2.1.4 
Laboratory safety variables............................................................................................................60 
9.2.1.5 
Urinalysis........................................................................................................................................61 
9.2.1.6 
Vital signs and physical examination .............................................................................................62 
9.2.1.7 
Electrocardiogram variables ..........................................................................................................62 
9.2.1.8 
Self-monitored blood glucose ........................................................................................................62 
9.3 
OTHER ENDPOINTS.....................................................................................................................63 
.....................................................................................................63 
........................................................................................................63 
9.4 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................64 
10 
STUDY PROCEDURES ................................................................................................................66 
10.1 
VISIT SCHEDULE..........................................................................................................................66 
10.1.1 
Screening Period............................................................................................................................66 
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10.1.1.1 Screening Phase............................................................................................................................67 
10.1.1.2 Run-in Phase .................................................................................................................................68 
10.1.2 
Randomized Double-blind Core Treatment Period (Day 1 to Week 26)........................................69 
10.1.2.1 Randomization (Baseline Day 1/Visit 3/Week 0) ...........................................................................69 
10.1.2.2 On-site visits from Visit 4 to Visit 7 (Week 3 to Week 18)..............................................................70 
10.1.2.3 On-site Visit 8 (Week 26) - End of Randomized Double-blind Core Treatment Period.................71 
10.1.3 
Double-blind, Randomized Extension Period (Week 27 to Week 104) .........................................72 
10.1.3.1 On-site visits from Visit 9 to Visit 12 (Week 27 to Week 86) .........................................................72 
10.1.3.2 On-site Visit 13 (Week 104) - End of treatment (EOT) ..................................................................74 
10.1.4 
Post-treatment follow-up period.....................................................................................................74 
10.1.4.1 Follow-up Visit (Week 106/Visit 14) ...............................................................................................75 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................75 
10.2.1 
Source data verification requirements for screen failures..............................................................76 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................76 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................76 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................77 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................77 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................78 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................78 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................79 
10.4.1 
Definitions of adverse events.........................................................................................................79 
10.4.1.1 Adverse event ................................................................................................................................79 
10.4.1.2 Serious adverse event ...................................................................................................................79 
10.4.1.3 Adverse event of special interest...................................................................................................80 
10.4.1.4 Events of special Interest...............................................................................................................81 
10.4.2 
General guidelines for reporting adverse events ...........................................................................81 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................82 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................83 
10.4.5 
Guidelines for reporting events of special interest.........................................................................83 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................83 
10.4.7 
Guidelines for reporting product complaints (IMP/NIMP) ..............................................................83 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................83 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................84 
10.6.1 
Hypoglycemia.................................................................................................................................84 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................86 
11 
STATISTICAL CONSIDERATIONS..............................................................................................87 
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11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................87 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................87 
11.3 
ANALYSIS POPULATIONS...........................................................................................................88 
11.3.1 
Efficacy population.........................................................................................................................88 
11.3.1.1 Intent-to-treat population................................................................................................................88 
11.3.2 
Safety population ...........................................................................................................................88 
11.4 
STATISTICAL METHODS .............................................................................................................89 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................89 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................89 
11.4.1.2 Compliance ....................................................................................................................................90 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................90 
11.4.2.1 Analysis of primary efficacy endpoints...........................................................................................90 
11.4.2.2 Analysis of secondary efficacy endpoints ......................................................................................92 
11.4.2.3 Analysis of other efficacy endpoints...............................................................................................92 
11.4.2.4 Multiplicity considerations ..............................................................................................................92 
11.4.3 
Analysis of safety endpoints ..........................................................................................................93 
11.4.3.1 Analysis of the key and other safety endpoints for BMD ...............................................................93 
11.4.3.2 Analysis of adverse events ............................................................................................................94 
11.4.3.3 Analyses of hypoglycemia .............................................................................................................96 
11.4.3.4 Analyses of events of special interest............................................................................................96 
11.4.3.5 Analyses of laboratory variables....................................................................................................96 
11.4.3.6 Analyses of vital sign variables ......................................................................................................97 
11.4.3.7 Analysis of 12-lead electrocardiogram status ................................................................................97 
11.4.3.8 Analyses of body composition measurements ..............................................................................97 
.........................................................................................................................97 
11.5 
INTERIM ANALYSIS......................................................................................................................97 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................99 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................99 
12.2 
INFORMED CONSENT .................................................................................................................99 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC).................................................................................................100 
13 
STUDY MONITORING.................................................................................................................101 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR..........................................................................101 
13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................101 
13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................101 
13.4 
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS (eCRFS) AND 
ADDITIONAL REQUEST .............................................................................................................102 
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13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................102 
14 
ADDITIONAL REQUIREMENTS.................................................................................................103 
14.1 
CURRICULUM VITAE..................................................................................................................103 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................103 
14.3 
CONFIDENTIALITY .....................................................................................................................103 
14.4 
PROPERTY RIGHTS...................................................................................................................104 
14.5 
DATA PROTECTION...................................................................................................................104 
14.6 
INSURANCE COMPENSATION..................................................................................................105 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................105 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................105 
14.8.1 
By the Sponsor.............................................................................................................................105 
14.8.2 
By the Investigator .......................................................................................................................106 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................106 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................106 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................107 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................108 
17 
APPENDICES..............................................................................................................................111 
APPENDIX A 
COLLECTION OF PREGNANCY INFORMATION............................................................112 
APPENDIX B 
RECOMMENDATIONS ON BASIC GENITO-URINARY HYGIENE, MAINTAINING 
HYDRATION AND RECOGNIZING DIABETIC KETOACIDOSIS...............................................113 
APPENDIX C MEASUREMENT OF BLOOD PRESSURE AND PULSE RATE......................................116 
APPENDIX D GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................117 
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2.1 
LIST OF TABLES 
Table 1 - Summary of investigational medicinal products.............................................................................47 
Table 2 - Blood safety parameters ................................................................................................................60 
 
2.2 
LIST OF FIGURES 
Figure 1 - Hypoglycemia classification in Study EFC15294..........................................................................85 
 
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3 
LIST OF ABBREVIATIONS 
 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance  
AST: 
aspartate aminotransferase 
BMD: 
bone mineral density 
BMI: 
body mass index 
BP: 
blood pressure 
BW: 
body weight 
CEC: 
Clinical Endpoint Committee 
CI: 
confidence interval 
CRO: 
contract research organization 
CSR: 
clinical study report 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DILI: 
drug-induced liver injury 
DKA: 
diabetic ketoacidosis 
DMC: 
Data Monitoring Committee 
DNA: 
deoxyribonucleic acid  
DXA: 
dual-energy X-ray absorptiometry 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
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  
GLP-1: 
glucagon-like peptide-1 
GU: 
genito-urinary 
HbA1c: 
hemoglobin A1c 
HLGT: 
high level group term  
HLT: 
high level term  
HR: 
heart rate  
IB: 
investigator's brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
ID: 
identification 
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IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
iPTH: 
parathyroid hormone 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ITT: 
Intention-to-Treat 
LS: 
least squares  
MACE: 
major adverse cardiovascular event 
MDRD: 
modification of diet in renal disease 
MI: 
myocardial infarction 
MMRM: 
mixed-effect model with repeated measures 
NIMP: 
noninvestigational medicinal product 
NTX: 
N-terminal telopeptide of type 1 collagen 
OC: 
observed cases 
P1NP: 
type 1 procollagen N-terminal propeptide 
PCSA: 
potentially clinically significant abnormality 
P-gp: 
P-glycoprotein 
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  
SERM: 
selective estrogen receptor modulator 
SGLT1: 
sodium-glucose cotransporter type 1 
SGLT2: 
sodium-glucose cotransporter type 2 
SMBG: 
self-monitored/monitoring of 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 
UACR: 
urinary albumin to creatinine ratio 
ULN: 
upper limit of the normal laboratory range 
US: 
United States 
UTI: 
urinary tract infection 
β-CTX-1: 
beta C-terminal telopeptide of type 1 collagen 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
BACKGROUND: SOTAGLIFLOZIN AND DISEASE 
Sotagliflozin is being developed as a therapy to improve glycemic control 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 macrovascular complications result in coronary artery disease, peripheral arterial disease, 
and stroke (2). 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). 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 (5). 
While these numbers include both people with T2D and Type 1 diabetes (T1D), over 90% of 
adults with diabetes have T2D. 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 diabetes education, are important 
components of diabetes treatment, the vast majority of people with T2D need to receive 
pharmacological therapy to control the disease. Despite the numerous treatment options 
available (3), a large proportion of patients fail to achieve the glycemic control targets as beta cell 
function continues to deteriorate leading to progressively increasing hyperglycemia. Concerns 
with side effects of currently available agents, most notably hypoglycemia and weight gain, also 
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 and avoiding hypoglycemia. 
Sotagliflozin is being investigated as a novel antidiabetic agent that can improve glycemic control 
by an insulin-independent mechanism of dual inhibition of sodium-glucose cotransporters 
Type 1 and 2 (SGLT1 and SGLT2). 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 excreted from the body, rather than being 
reabsorbed (8). This mechanism of reducing blood glucose is insulin-independent, sparing the 
pancreas from an increased demand for insulin production, and therefore hyperglycemia is 
controlled with little or no risk of hypoglycemia. 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). 
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The SGLT1 is expressed predominantly in the gastrointestinal tract and is responsible for the 
majority of glucose absorption by the small intestine (9). Inhibition of SGLT1 in the 
gastrointestinal 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. 
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 United States 
(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 
As of December 2016, approximately 840 subjects (including 698 subjects assigned to 
sotagliflozin and 229 assigned to placebo) have participated in 19 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. 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 
leading to discontinuation from the study. Genital mycotic infections have occurred with more 
frequency in subjects taking sotagliflozin than with placebo, although the majority of the events 
were mild and all events resolved with usual standard of care therapy. 
In completed and ongoing clinical trials, no additional safety issues beside those already described 
in the current Investigator’s Brochure (IB) were observed. In general, no significant imbalances of 
serious adverse events (SAEs)/adverse events (AEs) between sotagliflozin and comparators were 
observed in completed studies. Cumulatively, during the clinical trial program, 8 SAEs were 
reported by 6 patients (4 patients with T2D and 2 with T1D), all of which were assessed as 
unrelated to study drug; those reported by 4 patients with T2D who received sotagliflozin 
included pulmonary embolism, deep vein thrombosis, bile duct stone, cholangitis, and lower limb 
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fracture, while a myocardial infarction (MI) was experienced by a patient receiving placebo. 
Two SAEs of diabetic ketoacidosis (DKA) were reported in 2 patients with T1D receiving 
sotagliflozin 400 mg once daily in the Phase 2 T1D study LX4211.1-203-T1DM (13); both SAEs 
were assessed as due to failure of insulin delivery via insulin pump. 
Study LX4211.1-114-NRM, a drug interaction study with digoxin, a sensitive P-glycoprotein 
(P-gp) substrate, indicated that sotagliflozin acts as a weak P-gp inhibitor (14). Thus, sotagliflozin 
increases systemic exposure of digoxin and could also increase the exposure of other P-gp 
substrates. The efficacy of sotagliflozin has been shown in other studies in T2D patients. 
Study LX4211.1-202-DM was a Phase 2, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study evaluating the safety, and efficacy of sotagliflozin in 
combination with metformin in patients with T2D who had inadequate glycemic control on 
metformin monotherapy (N = 299) (12). All 4 dosing regimens of sotagliflozin (75 mg once daily, 
200 mg once daily, 400 mg once daily, and 200 mg twice daily given as oral tablets) reduced 
mean HbA1c from Baseline to Week 12 to a statistically and clinically significant degree 
compared to placebo (p = 0.025, p = 0.018, p < 0.001, and p < 0.001), respectively. The arithmetic 
mean change from Baseline in HbA1c was greatest for the 400 mg once daily group (-0.92%), 
followed by the 200 mg twice daily group (-0.80%). The least squares (LS) mean difference from 
placebo was also greatest for the 400 mg once daily group (-0.79%; p < 0.001), followed by the 
200 mg twice daily group (-0.61%; p < 0.001). The LS mean differences from placebo were 
similar for the 200 mg once daily group (-0.34%) and the 75 mg once daily group (-0.33%). 
Significant reductions were seen also in body weight (BW) (mean loss of 2 kg or more) with the 
top three dosing regimens and a dose-dependent reduction in systolic blood pressure 
(SBP; -5.7 mmHg with the 400 mg once daily dose), while diastolic blood pressure (DBP) was 
unchanged (12). 
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 sotagliflozin 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 T2D patients with impaired renal function, and the special population of the current trial 
represented by T2D patients aged more than 55 years 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 (15). 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 effect 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 0.92%, respectively (p <0.001 for both arms), while placebo lowered 
HbA1c by a mean of 0.09%. Sotagliflozin also produced statistically significant reductions 
in BW (with 200-mg and 400-mg doses) and SBP (with 400-mg dose). 
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From a safety perspective, sotagliflozin was well tolerated across studies. The overall incidence of 
AEs on sotagliflozin 200-mg and 400-mg once daily doses was similar to placebo. Evaluation of 
safety during long-term treatment with sotagliflozin 400 mg and 200 mg in this study will allow to 
further characterize the bone safety profile of both doses and assess the effect of each dose on 
bone and calcium metabolism. 
4.4 
RATIONALE FOR THE STUDY AND OBJECTIVES 
The primary objective is to assess the efficacy and safety of sotagliflozin compared to placebo in a 
population of T2D patients 55 years or older in inadequate control on a stable antidiabetes 
regimen. This study will enable to evaluate the glucose lowering efficacy of sotagliflozin in the 
context of a broad range of background antidiabetes therapies and in an aging population with 
potentially longer duration of diabetes. Additionally, this study will assess the effects of 
sotagliflozin in reducing SBP, which is another important health issue for people with diabetes 
and in particular this age group. 
This study is also being specifically designed to evaluate the effects of sotagliflozin on bone 
health with a key secondary safety objective of evaluating the changes in bone mineral density 
(BMD) with sotagliflozin treatment. Evaluation of bone safety is relevant due to findings of 
hyperostosis and decreases in bone turnover observed in animal studies with other compounds in 
the class (16, 17). These effects have been hypothesized to be associated with SGLT1 inhibition 
leading to an off-target increase in intestinal calcium absorption and changes in calcium 
homeostasis and vitamin D metabolism (16, 17). Small and inconsistent changes in bone 
biomarkers and no imbalance in fracture rate were reported in clinical trials with dapagliflozin and 
empagliflozin (18, 19). Changes in bone markers (increase in beta C-terminal telopeptide of 
Type 1 collagen [β-CTX-1]) after 1 year and a small decrease in BMD after 2 years 
(placebo subtracted changes of -0.9% and -1.2% with canagliflozin 100 and 300 mg, respectively) 
were reported with canagliflozin treatment (20), although the clinical significance is unknown. 
These clinical findings were inconsistent with the preclinical data and could be explained at least 
in part by the weight loss occurred with canagliflozin treatment (20). An increased risk of 
fractures following treatment with other SGLT2 inhibitors was observed in patients with high risk 
of cardiovascular (CV) disease participating in the canagliflozin CV outcomes trial (21, 22) and in 
a 2-year study with dapagliflozin in patients with renal impairment (23), but in both cases, the 
findings were not seen in the pooled data from Phase 3 studies. It is possible that these subgroups 
present higher susceptibility to hemodynamic events or falls, which could be associated with 
fractures (23, 24). Of note, upon the US FDA review of clinical data at the time of New Drug 
Application submission, the agency concluded that there was no indication of a clinically 
significant effect of dapagliflozin on bone loss or fracture. Canagliflozin remains the only SGLT2 
inhibitor that carries a label warning related to the increased risk of bone fractures in patients with 
T2D. 
Preclinical studies with sotagliflozin in rats showed increase in trabecular bone and small 
reversible decreases in calciotropic hormone and bone markers (Type 1 procollagen N-terminal 
propeptide [P1NP], osteocalcin, 1,25-dihydroxyvitamin D), which were not considered 
biologically significant. No clinically significant changes in calcium and bone biomarkers have 
been observed in clinical studies with sotagliflozin. However, as changes in bone markers and 
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BMD were reported in clinical studies with canagliflozin (17), this study is also planned to further 
assess the effects of sotagliflozin on bone mass, markers of calcium metabolism and bone 
turnover over 104 weeks of treatment in this aging group of patients at higher risk for osteoporosis 
and fractures. To assess the risk of fractures with sotagliflozin treatment, the number of fractures 
will be evaluated and independently adjudicated in this study and in the totality of sotagliflozin 
Phase 3 studies, including in patients with various degrees of renal impairment. 
This study will also include an evaluation of body composition by dual-energy X-ray 
absorptiometry (DXA) to assess the changes in total body fat mass and lean mass with 
sotagliflozin treatment. Clinically meaningful weight loss is observed with SGLT2 inhibitors (25) 
and a significant weight reduction is expected as a result of the dual SGLT1 and SGLT2 inhibition 
with sotagliflozin (26). Body composition study will enable to assess the differential changes in 
lean mass as compared to fat mass as part of the total weight reduction observed with sotagliflozin 
in this population. Reduction of BMD is reported following weight loss interventions and 
mechanical as well hormonal factors have been implicated (27, 28, 29). Adipose tissue is a source 
of multiple adipokines, inflammatory agents, and estrogen, all of them with different impact on 
bone mass. Decline in estradiol levels, which is observed in association with weight loss in 
women treated with canagliflozin in a 2-year study (20). Decrease in estradiol levels affects bone 
turnover and can represent an additional negative effect on bone mass. For this reason, changes in 
estradiol levels in women will also be evaluated during the study, which can be of additional 
interest for the understanding of any changes in bone density with sotagliflozin treatment. 
Selected markers of bone formation and resorption and other biochemical parameters of relevance 
to bone metabolism will also be evaluated in this trial. 
4.5 
RATIONALE FOR THE STUDY DESIGN AND CONTROL GROUP 
A parallel-group, randomized, controlled design was selected because trial participants are 
exposed to a single treatment and assignment to that treatment is based solely on chance. This 
design is free of the limitations of competing designs such as crossover in which there may be a 
carryover effect from one treatment to the following treatment, which can confound interpretation 
of efficacy and safety, especially in regards to some longer term effects, such as bone mass. 
Randomization will be stratified by HbA1c at Screening (≤8.5%, >8.5%) and sex (male, female) 
to enable a balanced treatment assignment considering factors that can impact the primary and key 
secondary safety study endpoint. A placebo control will be used to allow for an unbiased 
assessment of treatment effects and safety data. Bias will be minimized by randomizing the 
patients to treatment groups, blinding the patients, the Investigators, and the Sponsor to the 
treatment allocations, and by adjudicating endpoints in a blinded fashion. A 2-week Run-in Phase 
has been implemented to stabilize HbA1c and minimize response to placebo and effects inherent 
to participation in a controlled clinical trial. 
Sotagliflozin treatment for 26 weeks is considered to be of sufficient duration to observe effects 
on reduction of HbA1c, blood pressure (BP), and BW, and is, therefore, selected as the time point 
for assessment of the primary endpoint HbA1c. The double-blind controlled extension up to 
104 weeks will provide additional long-term data on efficacy and safety, including long-term 
assessment of bone safety with sotagliflozin treatment. 
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4.6 
BENEFIT/RISK OF SOTAGLIFLOZIN 
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 PPG 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 incretin levels 
(from inhibition of SGLT1). In addition, the improvements in BW, BP, and triglycerides observed 
with sotagliflozin treatment have the potential to benefit patients with diabetes through their 
effects on common diabetic comorbidities.  
Overall, sotagliflozin has been well tolerated in all studies to date, with the majority of events 
assessed as mild to moderate; most of which resolved spontaneously. No imbalance was observed 
in the events of hypoglycemia in the sotagliflozin clinical program, and there have been no events 
of severe hypoglycemia or SAEs related to hypoglycemia in completed clinical trials. Serious 
adverse events and discontinuations due to AEs have been infrequent and balanced between 
treatment and comparator groups. 
Based on evaluation of the cumulative safety data for the sotagliflozin clinical program, genital 
infections are monitored closely as an important identified risk. However, reports of these events 
have been infrequent and have responded to standard treatment. Diabetes ketoacidosis has been 
reported with treatment with other SGLT2 inhibitors and for this reason is identified as a potential 
risk. As of December 2016, two SAEs of DKA were reported in 2 patients with T1D and 
receiving sotagliflozin. Both SAEs were considered by the investigator to be due to insulin pump 
failure and unrelated to study treatment. Other potential risks are defined based on either their 
potential link to sotagliflozin mechanism of action, or because occurred during treatment with 
other SGLT2 inhibitor drugs. These potential risks have not been found to be in imbalance in 
sotagliflozin clinical trials, but will be also monitored in the study as events of special interest 
(EOSI), including urinary tract infections (UTI), diarrhea, pancreatitis, CV and renal events, 
drug-induced liver injuries (DILI), malignancies, volume depletion, and amputation. Evaluation of 
bone fractures will be of special relevance in this study as it includes a population of patients at 
increased risk for fractures. 
Risks specific to this study are associated with the placebo-controlled design and long treatment 
duration. There is potential risk of insufficient glucose control, especially in the placebo arm 
during this 2-year study. Investigators will monitor regularly the glucose control at regular study 
visits by reviewing patients’ fasting self-monitored blood glucose (SMBG) in conjunction with 
central laboratory alerts for FPG and HbA1c programed based on progressively stricter 
hyperglycemic thresholds. In case patients develop uncontrolled hyperglycemia during the study, 
Investigators will provide open-label antidiabetes rescue treatment and continue monitoring the 
patients as part of the study. Additionally, investigators can also provide rescue treatment at any 
time if medically indicated. 
Patients may experience some discomfort associated with study procedures, such as blood draws, 
electrocardiogram (ECG), and fingersticks for SMBG. The Investigators will monitor for any 
possible occurrence of side effects related to these procedures. 
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During the study, the patients will perform DXA scans at four different occasions for monitoring 
of bone mass and changes in body composition. This diagnostic procedure is painless and carries 
very low risk of side effects. There is a small increase in radiation exposure with each DXA scan 
and the radiation exposure for the entire study is estimated to be around 56 µSv. This amount is 
equivalent to 9 days of average exposure to background radiation (30, 31). The procedures will be 
performed at qualified centers following standard procedures to ensure patient safety. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this study is to demonstrate the superiority of sotagliflozin 400 mg 
versus placebo with respect to HbA1c reduction at Week 26 in patients with T2D who have 
inadequate glycemic control on diet and exercise only or with a stable antidiabetes regimen. 
5.2 
SECONDARY 
The secondary objectives of this study are: 
• To compare the effects of sotagliflozin 400 mg and 200 mg versus placebo with respect to 
the percent change from Baseline to Week 26 in BMD (lumbar spine, total hip, and 
femoral neck) measured by DXA (key secondary safety objective). 
• To demonstrate the superiority of sotagliflozin 400 mg versus placebo on: 
- 
Change from Baseline to Week 26 in BW. 
- 
Change from Baseline to Week 26 in FPG. 
- 
Change from Baseline to Week 12 in SBP for all patients. 
- 
Proportion of patients with HbA1c <7.0% at Week 26. 
• To demonstrate the superiority of sotagliflozin 200 mg versus placebo with respect to: 
- 
HbA1c reduction from Baseline to Week 26. 
- 
Change from Baseline to Week 26 in BW. 
- 
Change from Baseline to Week 26 in FPG. 
- 
Change from Baseline to Week 12 in SBP for all patients. 
- 
Proportion of patients with HbA1c <7.0% at Week 26. 
• To evaluate the safety of sotagliflozin 200 mg and 400 mg compared with placebo over 
the 104 weeks of treatment. 
5.3 
OTHER 
Other objectives of this study are: 
• To compare the effects of sotagliflozin 200 mg and 400 mg versus placebo with respect to: 
- 
Change from Baseline to Weeks 52 and 104 in HbA1c. 
- 
Change from Baseline to Weeks 52 and 104 in FPG. 
- 
Change from Baseline to Weeks 52 and 104 in BW. 
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- 
Proportion of patients with HbA1c <7.0% at Weeks 52 and 104. 
- 
Proportion of patients starting rescue therapy during the 104 weeks of treatment. 
- 
Change from Baseline to Weeks 26 and 104 in SBP for all patients. 
- 
Change from Baseline to Weeks 12, 26, and 104 in SBP for the subsets of patients with 
Baseline SBP ≥130 mmHg and <130 mmHg, respectively. 
- 
Change from Baseline to Weeks 12, 26, and 104 in DBP for all patients and the subsets 
of patients with Baseline DBP ≥80 mmHg and <80 mmHg, respectively. 
- 
Changes from Baseline to Weeks 26, 52, and 104 in total body fat mass and total lean 
mass measured by DXA. 
- 
Changes from Baseline to Weeks 26, 52, and 104 in serum estradiol (only for women). 
- 
Changes from Baseline to Weeks 26, 52, and 104 in urinary albumin to creatinine ratio 
(UACR). 
- 
Changes from Baseline to Weeks 26, 52, and 104 on estimated glomerular filtration 
rate (eGFR). 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This is a Phase 3, multicenter, 1:1:1 randomized, double-blind (single-blind Run-in Phase), 
placebo-controlled, parallel-group study that is anticipated to enroll approximately 360 patients. 
The trial will consist of 4 periods: 
• A Screening Period of up to 4 weeks comprised of: 
- 
A Screening Phase of up to 2 weeks. 
- 
A 2-week Single-blind placebo Run-in Phase. 
• A 26-week Randomized Double-blind Core Treatment Period. 
• A 78- week Randomized Double-blind Extension Period. 
• A 2-week, post-treatment Follow-up Period. 
To qualify for randomization, patients must demonstrate compliance based upon tablet count 
(≥80%) during the Run-in Phase. 
The study design is presented graphically in Section 1.1. 
6.1.1 Screening period 
6.1.1.1 Screening Phase 
The Screening Phase will last up to 2 weeks. It must be long enough to collect the data required to 
establish whether the patient satisfies the inclusion/exclusion criteria. 
Patients with T2D, who are 55 years of age or older, currently managed with diet and exercise 
only or with a stable antidiabetes regimen in monotherapy or combination therapy (including oral 
antidiabetes medications, insulin, or GLP-1 agonists) for more than 12 weeks prior to Screening 
are eligible for enrollment in this study. 
At the Screening Visit (Visit 1), after signing the informed consent form (ICF), eligibility criteria 
will be assessed and Screening assessments will be performed. 
The Interactive Response Technology (IRT) (either Interactive Voice Response System or 
Interactive Web Response System) will be contacted at Visit 1 for notification of Screening and 
for patient number allocation. 
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6.1.1.2 Single-blind Run-in-Phase 
Patients who satisfy the entry criteria during the Screening phase will continue in the study and 
enter the Run-in Phase. The single-blind placebo Run-in Phase will last 2 weeks. During this 
phase, patients will be treated in a single-blind manner with placebo, given as 2 placebo tablets 
(identical to sotagliflozin 200 mg in appearance), taken orally once daily before the first meal of 
the day starting from Visit 2, to assess patients’ compliance to the study medication. 
During the Run-in Phase, patients will receive a glucose meter and study diary and will be trained 
to perform blood glucose measurements and complete the study diary correctly. During this 
period, patients will also have an assessment of BMD and body composition by DXA. 
In exceptional circumstances, the Run-in Phase may be extended up to a maximum of 
14 additional days, if necessary to obtain appropriate BMD measurements prior to randomization. 
6.1.2 Randomized Double-blind Core Treatment Period (Week 0 to Week 26) 
Eligible patients will be randomized on Day 1 (Visit 3). To qualify for randomization, patients 
must demonstrate compliance with the single-blind treatment at the end of the Run-in phase, 
based upon tablet count (≥80%) and, as assessed, at the Investigator’s discretion. Additionally, 
only patients with BMD T-score ≥-2.0 measured by DXA during the Run-in Phase will be 
allowed to be randomized. 
Randomization will be stratified by: 
• HbA1c at Screening (≤8.5%, >8.5%). 
• Sex (male, female). 
Approximately 360 patients will be randomized at a 1:1:1 ratio to the following 3 treatment 
groups: 
• Sotagliflozin 400 mg arm (estimated N = 120): sotagliflozin 400 mg given as two (2) 
200-mg tablets, taken orally once daily. 
• Sotagliflozin 200 mg arm (estimated N = 120): sotagliflozin 200 mg given as one (1) 
200-mg tablet and one (1) placebo tablet (identical to sotagliflozin 200 mg in appearance), 
taken orally once daily). 
• Placebo arm (estimated N = 120): placebo given as two (2) placebo tablets, taken orally 
once daily. 
Following randomization, patients will be treated in a double-blind manner for 104 weeks. 
The first 26 weeks after the randomization correspond to the Randomized Double-blind Core 
Treatment Period. The doses of the background antidiabetic treatments (if applicable) should be 
held constant throughout the entire 104 weeks of Double-blind treatment (ie, not changed except 
for safety reasons or in case patient meets glycemic rescue criteria). The dose of all 
antihypertensive medications should also be held constant for the first 12 weeks (until Visit 6) 
except for safety reasons. 
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The HbA1c and FPG results will be masked to study sites and patients after randomization and 
until study end. Additionally, the central laboratory urinalysis by dipstick will not include 
measurement of urine glucose. 
6.1.3 Double-blind, Randomized Extension Period (Week 27 to Week 104) 
Patients who remain in the study after Week 26 will continue double-blind treatment from 
Week 27 to Week 104 in a 78-week Double-blind Extension Period. Patients will continue to 
receive the blinded medication (sotagliflozin 400 mg, sotagliflozin 200 mg or placebo) to which 
they were randomized on Day 1. Patients who received rescue medication during the 26-week 
Randomized Double-blind Core Treatment Period will continue on the same rescue medication 
during the Double-blind Extension Period (unless the Investigator considers a change necessary 
for safety reasons). The criteria for initiation of rescue therapy will be indicated in Section 8.2.2. 
6.1.4 Follow-up period 
Following the last dose of the investigational medicinal product (IMP) and after the End of 
Treatment (EOT) visit (either as scheduled or prematurely), a post-treatment Follow-up Visit 
should be scheduled for all patients 14 days ±3 days after permanent IMP discontinuation to 
collect safety information. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The total duration of the study for each patient will be up to 110 weeks and will include a 4-week 
Screening Period (comprised of a Screening Phase of up to 2 weeks and a 2-week single-blind 
placebo Run-in Phase), a 26-week Randomized Double-blind Core Treatment Period, a 78-week 
Randomized Double-blind Extension Period, and a 2-week post-treatment Follow-up Period. 
6.2.2 Early termination 
If a patient discontinues treatment with the IMP at any time during the Randomized Double-blind 
Core Treatment Period or during the Randomized Double-blind Extension Treatment Period, the 
patient will have a Premature EOT visit, and a Follow-up Visit, 2 weeks after the last dose of 
IMP. In addition, every effort will be made to have the patients return to the site at the time 
corresponding to their scheduled visits, particularly the Week 26 Visit and Week 104 visit to 
perform the respective study assessments, emphasizing the measurement of HbA1c and BMD. 
If the patient does not agree to site visits, he or she will be contacted by respective sites by 
telephone to inquire about safety status. 
6.2.3 Determination of end of clinical trial (all patients) 
The end of the study is defined as being the “last patient last visit” planned with the protocol, 
including the Follow-up Visit. 
The Sponsor can terminate the trial prematurely based on the advice of the independent Data 
Monitoring Committee (DMC), or other unforeseen developments (see Section 6.4.2). 
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6.3 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned. See Section 11.5 for more details. 
6.4 
STUDY COMMITTEES 
6.4.1 Steering Committee 
The Steering Committee (SC) is composed of experts in diabetes and scientists with clinical and 
methodological expertise and will serve in an advisory capacity to the Sponsor on the study. 
This committee, led by a Chair, will be responsible for producing and conducting a scientifically 
sound study and for ensuring accurate reporting of the study. In that capacity, the SC must address 
and resolve scientific issues encountered during the study. The members will remain blinded until 
completion of the study. 
Among its responsibilities, the SC will receive blinded study status reports from the Sponsor, and 
will review the recommendations from the DMC throughout the study. The SC members will 
participate in face-to-face meetings at regular intervals throughout the study and in regularly 
scheduled teleconferences. 
Details of the activities and responsibilities of the SC are provided in a separate SC Charter. 
6.4.2 Data Monitoring Committee 
An independent DMC will meet on a regular basis to review accumulating clinical study safety 
data. The DMC will be responsible for: 
• Review of accumulating clinical study safety data by treatment. 
• Making recommendation to the Sponsor regarding the study following each meeting. 
Safety data to be reviewed will be unblinded and include events and outcomes described in 
Section 6.4.3 for adjudication, as well as any additional safety data considered relevant. 
To maintain continuous blinding and study integrity, the analysis will be conducted by an 
independent statistician, and measures will be taken to ensure the validity of the data. 
Details of the DMC processes and procedures are outlined in a separate DMC Charter. 
6.4.3 Clinical Endpoint Committee 
An independent Clinical Endpoint Committee (CEC) will be 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 will review and adjudicate all events of death, major adverse cardiovascular events 
(MACE) and selected CV events (MI, stroke, unstable angina leading to hospitalization, and heart 
failure leading to hospitalization), selected renal events, and DKA in a treatment-blinded manner. 
The CEC will also independently adjudicate the events of bone fractures in a blinded manner. 
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The details regarding the CEC processes and procedures will be outlined in the CEC Charter(s). 
6.4.4 Other independent safety assessments 
An expert review committee will also review all potential cases of DILI in a treatment-blinded 
manner to evaluate causality. 
Expert review of cases of amputation will also take place in a treatment blinded manner. 
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7 
SELECTION OF PATIENTS 
Note: A patient must not be randomized more than once. In cases where original screen failure 
was due to reasons expected to change at rescreening and based upon the Investigator’s clinical 
judgment, the patient can be rescreened once prior to entering Run-in for this study. 
7.1 
INCLUSION CRITERIA 
I 01. Patient with T2D currently managed with diet and exercise only or with a stable 
antidiabetes regimen in monotherapy or combination therapy (including oral antidiabetes 
medications, insulin, or GLP-1 agonists) for more than 12 weeks. 
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 inclusion criteria in Section 7.1 will be screened for the following 
exclusion criteria. 
7.2.1 Exclusion criteria related to study methodology 
E 01. Age <55 years at Screening. 
E 02. Body mass index (BMI) ≤20 or >45 kg/m² at Screening or BW that exceeds the weight 
limits of the DXA scanner. 
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 Screening. 
E 04. Use of weight loss medications within 12 weeks or weight change of 5 kg or more during 
the 12 weeks prior to 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. Patient who has previously been randomized in any clinical trial of sotagliflozin/LX4211. 
E 07. Patients with severe anemia, severe CV disease (including congestive heart failure New 
York Heart Association IV), respiratory, hepatic, neurological, psychiatric, or active 
malignant tumor or other major systemic disease or patients with short life expectancy that, 
according to the Investigator, will preclude their safe participation in this study or will 
make implementation of the protocol or interpretation of the study results difficult. 
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E 08. Current diagnosis of chronic hepatitis and/or other clinically active liver disease. 
E 09. Known presence of factors that interfere with the central laboratory HbA1c measurement 
(eg, genetic Hb variants) compromising the reliability of HbA1c assessment or medical 
conditions that affect interpretation of HbA1c results (eg. blood transfusion or severe blood 
loss in the last 3 months prior to randomization, 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 screening or randomization, whichever is longer. 
7.2.2 Exclusion criteria related to the diabetes history and treatment 
E 13. Type 1 diabetes. 
E 14. Hemoglobin A1c <7.0% or >11.0% measured by the central laboratory at Screening 
(Visit 1). 
E 15. Not on stable prior antidiabetes treatment in the last 12 weeks prior to the Screening Visit 
(for prior insulin treatment: change of total daily dose of basal insulin by more than 20% 
within 8 weeks prior to the Screening Visit). 
E 16. Use of a selective SGLT2 inhibitor (eg, canagliflozin, dapagliflozin, or empagliflozin) or 
thiazolidinedione (eg, pioglitazone, rosiglitazone) within 24 months prior to Screening. 
E 17. History of DKA or nonketotic hyperosmolar coma within 12 weeks prior to Screening. 
E 18. History of severe hypoglycemia resulting in unconsciousness, seizure, or hospitalization 
within 6 months prior to Screening. 
7.2.3 Exclusion criteria related to bone health assessments 
E 19. Women who have been postmenopausal (or had undergone bilateral oophorectomy) for 
less than 5 years. Estradiol and follicle-stimulating hormone (FSH) will be measured at 
Screening to confirm the menopausal status. 
Note: A postmenopausal state is defined as no menses for >12 months without an alternative 
medical cause. The FSH level in the postmenopausal range (>40 IU/L) may be used to confirm a 
postmenopausal state in women not using hormonal replacement therapy. For hysterectomized 
women, determination of menopausal status will be based on history of vasomotor symptoms, or 
FSH >40 IU/L and estradiol levels on postmenopausal range (<20 pg/mL). 
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E 20. BMD T-score <-2.0 at any site (ie, lumbar spine, total hip, or femoral neck), measured by 
DXA during the Screening Period (determination of eligibility based on this test can be 
made until the time of randomization). 
E 21. Serum 25-hydroxyvitamin D levels ≤20 ng/mL (≤50 nmol/L) at the Screening Visit by 
central laboratory (determination of eligibility based on this test can be made until the time 
of randomization). 
E 22. Hypercalcemia based on total serum calcium level >10.5 mg/dL (2.63 mmol/L) at the 
Screening Visit by central laboratory. 
E 23. Alkaline phosphatase levels >1.5 times the upper limit of the normal laboratory range 
(ULN) at the Screening Visit by central laboratory. 
E 24. Conditions that can interfere with accurate measurement of BMD at the hip, femoral neck, 
and lumbar spine, including: 
- 
Rheumatoid arthritis affecting the hip and lumbar vertebrae. 
- 
Degenerative spine changes. 
- 
Severe scoliosis. 
- 
Anatomical changes that affect accurate BMD measurements. 
- 
Spinal fusion or metal implants; or, 
- 
Bilateral hip replacement or other surgery resulting in metal implants in both hips. 
E 25. Bone disorders that may confound assessment of BMD or bone metabolism 
(eg, Paget disease, osteomalacia, osteopetrosis, and osteogenesis imperfecta). 
E 26. Endocrine disorders that affect BMD and bone turnover (eg, hyperparathyroidism, 
uncontrolled hyperthyroidism, endogenous hypercortisolism). 
E 27. Malabsorption diseases (eg, celiac disease, cystic fibrosis, or Crohn’s disease). 
E 28. History of fracture within 12 months prior to the Screening Visit (except for fractures of 
the hand/fingers, foot/toes, facial bones, and skull). 
E 29. Treatment with medications known to affect bone mass or modify the risk of fractures 
within 36 months prior to Screening, including: 
- 
Bisphosphonates, selective estrogen-receptor modulators, calcitonin, teriparatide, 
denosumab, strontium ranelate, growth hormone. 
- 
Hormonal replacement that includes systemic or transdermal estrogen or testosterone 
(except if treatment is stable for at least 24 months prior to the Screening Visit). 
- 
Androgen deprivation therapy. 
- 
Aromatase inhibitors. 
- 
Anticonvulsants (eg. carbamazepine, phenytoin, and phenobarbital). 
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7.2.4 Exclusion criteria related to the current knowledge of sotagliflozin 
E 30. Mean of 3 separate BP measurements >180 mmHg (SBP) or >100 mmHg (DBP) at the 
Screening Visit. 
E 31. History of hypertensive emergency within 12 weeks prior to Screening. 
E 32. History of gastric surgery including history of gastric banding or surgery for inflammatory 
bowel disease within 3 years prior to Screening. 
E 33. Difficulty swallowing such that the patient cannot take the IMP. 
E 34. Known allergies, hypersensitivity, or intolerance to SGLT2 inhibitors or any inactive 
component of sotagliflozin or placebo (ie, microcrystalline cellulose, croscarmellose 
sodium [disintegrant], talc, silicon dioxide, and magnesium stearate [nonbovine]), unless 
the reaction is deemed irrelevant to the study by the Investigator. 
E 35. Renal disease as defined by eGFR <30 mL/min/1.73m2 at the Screening Visit by the 
4 variable Modification of Diet in Renal Disease (MDRD) equation. 
E 36. Laboratory findings with the central laboratory tests at Visit 1: 
- 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the 
ULN. 
- 
Total bilirubin >1.5 times the ULN (except in case of Gilbert’s syndrome). 
- 
Neutrophils <1500/mm3 (or according to ethnic group) and/or platelets <100 000/mm3. 
- 
Amylase and/or lipase >3 times the ULN. 
E 37. Any country-related specific regulation that would prevent the patient from entering the 
study (eg, individuals committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities). 
7.2.5 Additional exclusion criteria during or at the end of the Run-in Phase before 
randomization 
E 38. Patients unwilling or unable to perform SMBG and complete the patient diary, or comply 
with study visits and other study procedures as required per protocol. 
E 39. Patient withdraws informed consent before randomization (patient who is not willing to 
continue) or fails to return. 
E 40. Any clinically significant abnormality identified on physical examination, laboratory tests, 
ECG or vital signs at the time of screening or any AE during Screening Period which, in 
the judgment of the Investigator or any Sub-investigator, would preclude safe completion 
of the study or constrains efficacy assessment. 
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E 41. Patient insufficiently compliant during run-in phase based on tablet count (<80%) or in the 
opinion of the Investigator. 
E 42. Lower extremity complications (such as skin ulcers, infection, osteomyelitis and gangrene) 
identified during the Screening period, and still requiring treatment at Randomization. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
8.1.1 Formulations 
The IMPs are sotagliflozin (400 mg and 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). Treatment kits will be provided to the sites 
containing the appropriate number of IMP for the given Treatment Period, including visit 
windows. Each patient will be supplied with the appropriate number of kits, on a schedule 
according to the dispensing scheme indicated in the study flow chart (see Section 1.2). 
Table 1 provides a summary of each IMP. 
Table 1 - Summary of investigational medicinal products 
Treatment group: 
Sotagliflozin 400 mg  
Sotagliflozin 200 mg 
Placebo 
(sotagliflozin-matching) 
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 and 
sotagliflozin-matching 
placebo tablets.  
Placebo will be supplied as 
sotagliflozin-matching 
placebo tablets. 
Dose, timing, and route of 
administration 
Two 200-mg sotagliflozin 
tablets taken orally once 
daily, before first meal of the 
day. 
One 200-mg sotagliflozin 
tablet and one 
sotagliflozin-matching 
placebo tablet taken orally 
once daily, before first meal 
of the day. 
Two sotagliflozin-matching 
placebo tablets taken orally 
once daily, before first meal 
of the day. 
Duration of treatment 
104 weeks following 
randomization. 
104 weeks following 
randomization 
106 weeks: 2 weeks during 
single-blind Run-in 
phase + 104 weeks following 
randomization. 
Storage conditions 
Store between +15°C and +30°C (59°F and 86°F) 
IMP = Investigational medicinal product 
8.1.2 Starting dose and dose adjustment 
All patients will receive treatment at a fixed dose of sotagliflozin (200 mg or 400 mg), or 
matching placebo as assigned at randomization throughout the 104-week study treatment period. 
No dose reductions are planned. 
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8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
8.2.1 Background antidiabetes medications 
Patients may be enrolled with or without a background therapy consisting of a stable antidiabetes 
regimen in monotherapy or combination therapy (including oral antidiabetes medications, insulin, 
or GLP-1 agonists) for more than 12 weeks. 
Dose of background antidiabetes medication (if any) should be stable throughout the study, unless 
a change is required for safety reasons or if protocol defined hyperglycemia rescue criteria is 
satisfied. For patients on insulin therapy, the total daily dose of basal insulin should remain within 
20% of the randomization dose, unless changes are needed for safety reasons or hyperglycemia 
rescue criteria are met. 
8.2.2 Rescue therapy 
The threshold values for rescue are defined as follows, depending on the study period: 
• From Baseline visit (Visit 3, Day 1) to Visit 5 (Week 6), inclusive: FPG >270 mg/dL 
(15.0 mmol/L). 
• From Visit 5 (Week 6) to Visit 6 (Week 12), inclusive: FPG >240 mg/dL (13.3 mmol/L). 
• From Visit 6 (Week 12) up to Visit 8 (Week 26), inclusive: FPG >200 mg/dL 
(11.1 mmol/L) or HbA1c ≥8.5%.  
Note: The 8.5% criterion does not apply if the HbA1c decrease from Baseline was ≥1.0%. 
• From Visit 8 (Week 26) up to Visit 10 (Week 52), inclusive: FPG >170 mg/dL 
(9.4 mmol/L) or HbA1c ≥8.0%.  
Note: The 8.0% criterion does not apply if the HbA1c decrease from Baseline was ≥1.0%. 
• From Visit 10 (Week 52) up to the EOT Visit 13 (Week 104): FPG >160 mg/dL 
(8.9 mmol/L) or HbA1c ≥7.5%. 
Routine fasting SMBG and central laboratory alerts on FPG (and HbA1c after Week 12 and 
onwards) are set up to ensure that glycemic parameter results remain within predefined thresholds. 
• If one fasting SMBG value exceeds the specific glycemic limit on 1 day, the patient will 
check it again during the 2 following days. If all the values in the 3 consecutive days 
exceed the specific limit, the patients should contact the Investigator and a central 
laboratory FPG measurement (and HbA1c after Week 12 and onwards) will be performed 
as soon as possible, preferably within 7 days to confirm the hyperglycemia. 
• Upon receipt of a central laboratory rescue alert, a central laboratory re-test must be 
completed and confirmed as exceeding the criteria 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. 
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In the event that a confirmatory FPG and/or HbA1c exceed the threshold values, the Investigator 
should ensure that no reasonable explanation exists for insufficient glucose control and in 
particular that: 
• The increased FPG has been tested at a fasting status (ie, no food intake for ≥8 hours). 
• IMP is given at the planned dose or matching placebo. 
• There is no intercurrent disease, which may jeopardize glycemic control (eg, infectious 
disease). 
• Compliance to treatment is appropriate. 
• Compliance to diet and lifestyle is appropriate. 
If any of the above can reasonably explain insufficient glycemic control, the Investigator should 
consider not initiating rescue medication and should undertake appropriate action, ie: 
• Assess plasma glucose in fasting condition (ie, after at least 8 hours fast). 
• Initiate an evaluation and treatment of intercurrent disease (to be reported in 
AE/concomitant medication parts of the electronic case report form (eCRF) and the 
medical record). 
• Stress the absolute need to be compliant with treatment. 
• Organize a specific interview with the patient and a Registered Dietician or other qualified 
nutrition professional and to reinforce on the absolute need to be compliant to diet and 
lifestyle recommendations, and schedule a FPG/HbA1c assessment at the next visit. 
If none of the above mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, open-label rescue medication may be introduced. 
• Rescue medication can be added up to the Investigator’s decision except for SGLT2 
inhibitors and thiazolidinediones. 
• The patient continues the study treatment (blinded) and stays in the study to collect 
efficacy and safety information. The planned visits and assessments should occur until the 
last scheduled visit. 
• Rescue therapy is considered a (NIMP). Rescue therapy is to be reported in the eCRF. 
This information should include specific drug name, dose, route of administration, and 
frequency. 
• The Investigators can provide rescue at any time if there is a medical rationale. 
If not covered by health insurance, the cost of rescue therapy will be reimbursed where permitted 
by local regulations. 
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8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
To maintain blinding, sotagliflozin and the sotagliflozin-matching placebo tablets, and their 
packaging, will be blinded. 
During the double-blind Treatment Periods, 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 will generate the 
patient randomization list from which is allocates treatment groups to the patients. 
To prevent partial unblinding, results of laboratory assessments of 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 randomization code must 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 must 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. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
The randomized treatment kit number list is generated centrally by Sanofi. The IMPs are 
packaged in accordance with this list. 
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8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures. 
Control of IMP storage conditions, especially control of temperature and instructions for handling 
the Sanofi compound, should be managed according to the rules provided by the Sponsor. 
The expiry date and storage conditions are written on the IMP labels. The IMP should be stored 
between +15°C and +30°C (59°F and 86°F). 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 10.4.7). 
A potential defect in the quality of an IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for 
direct-to-patient shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP to be used other than as directed by this clinical trial protocol, or dispose of the IMP in 
any other manner. 
8.7.1 Treatment accountability and compliance 
Accounting and compliance for IMPs will be performed at Visit 3 (Treatment Day 1) and all 
subsequent visits, except for the follow-up visit (Visit 14). 
The Investigator will check the compliance to the IMP dose schedule based on the patient diary 
and will complete the appropriate site treatment and patient treatment log forms. Returned IMP 
should be counted by site staff. In addition, the dosing information will be recorded on the 
appropriate pages of the eCRF. 
For NIMP, the name, start and end date of treatment, total daily dose, etc, will be documented in 
the source documents. Compliance to background therapy medication will be checked by 
interviewing the patient and reviewing the patient diary at each visit, and documented in the 
source documents and eCRF. 
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Rescue therapy (see Section 8.2.2) is to be reported in the eCRF. This information should include 
specific drug name, dose, route of administration, and frequency. 
If compliance is inadequate as determined by the Investigator, patients will be trained again and 
mentored. If suboptimal compliance continues after training and mentoring, patients may be 
discontinued at the discretion of the Investigator after discussion with the Sponsor’s/CRO’s 
medical monitor. 
8.7.2 Return and/or destruction of treatments 
Patients are to return all IMP (unused, in-use, or empty wallet[s]) at each on-site visit (or at final 
assessment visit in case of permanent premature discontinuation), as described in Section 1.2. 
All used, partially-used, or unused IMPs will be retrieved by the Sponsor, CRO, or Delegate. 
A detailed site log and patient treatment log of the returned IMP will be established with the 
Investigator (or the pharmacist) and countersigned by the Investigator and the monitoring team. 
For NIMP not provided by the Sponsor (ie, rescue therapy), tracking and reconciliation is to be 
undertaken by the Investigator (or pharmacist if appropriate) according to the system proposed by 
the CRO. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to the IMP. 
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 trial, 
beginning at Visit 1. 
Additionally, all medications taken in the 3 months prior to Visit 1, and prior use of SGLT2 
inhibitors should be reported. 
8.8.1 Prohibited prior and concomitant medications 
During the study, the following medications are prohibited: 
• Initiation of any antidiabetes agents, including oral or injectable antihyperglycemic agents 
other than the IMP is not allowed before the rescue therapy. The existing background 
medication (NIMP) should not be modified before the rescue. 
Note: Short term use (<10 consecutive days) of short-acting insulin for treatment of acute illness 
or surgery is allowed. 
• SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin) and 
thiazolidinediones (eg. pioglitazone, rosiglitazone) are not allowed for rescue. 
• Systemic use of glucocorticoids for more than 10 consecutive days within 90 days prior to 
the Screening Visit (Note: topical, intra-articular, ophthalmic, nasal spray, or inhaled 
applications are allowed). 
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• Use of investigational medication in any other clinical study. 
• Initiation of any weight loss drugs (eg, phentermine, orlistat, lorcaserin, 
phentermine/topiramate, naltrexone/bupropion, liraglutide). 
• Initiation of medication known to affect bone mass or modify the risk of fractures: 
- 
Bisphosphonates, selective estrogen receptor modulators (SERMs), calcitonin, 
teriparatide, denosumab, strontium ranelate, growth hormone. 
- 
Androgen deprivation therapy. 
- 
Aromatase inhibitors. 
- 
Anticonvulsants (eg. carbamazepine, phenytoin and phenobarbital). 
- 
Hormone replacement therapy (systemic or transdermal) that includes estrogens or 
androgens. 
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 
Sponsor recommends that the labels of P-gp substrate drugs should be consulted with regards to 
monitoring and dose adjustments. Other medications which are unlikely to interfere with the 
pharmacokinetics or pharmacodynamics of the IMP or confound interpretation of the study 
endpoints are allowed as needed following discussion between the Investigator and the 
Sponsor/CRO. 
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. 
It is recommended that patients receiving calcium or vitamin D at the time of screening, or 
initiating supplementation during the study, should maintain as stable a dose as possible 
throughout the study. Patients receiving replacement therapy with estrogen or testosterone for 
more than 24 months at the time of screening should also be advised to maintain stable dose for 
the duration of the study, unless if required for safety reasons. Any changes to ongoing 
medications or initiation of new medications should be discussed with the Investigator and 
documented in the patient records and the respective eCRF page. 
8.9 
POSTSTUDY TREATMENT 
Because sotagliflozin may reduce BP, adjustment of antihypertensive medication may be needed 
during the study in patients with hypertension. Conversely, monitoring for an increase in BP 
should be performed after withdrawal of study medication. If the BP is elevated after withdrawal 
of study treatment, the Investigator should consider adding or adjusting antihypertensive 
medication. 
Sotagliflozin will not be provided after EOT. Patient’s further treatment for diabetes and other 
pathologies will be at the Investigator’s discretion based on his/her clinical judgment and in 
accordance with local standard of care and prescribing practices. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
EFFICACY ENDPOINT 
9.1.1 Primary endpoint 
The primary efficacy endpoint is the change from Baseline to Week 26 in HbA1c comparing 
sotagliflozin 400 mg versus placebo. 
The methods of assessment of efficacy endpoints are detailed in Section 9.1.4. 
9.1.2 Secondary endpoints 
9.1.2.1 Key secondary safety endpoint 
The key secondary safety endpoint is the percent change from Baseline to Week 26 in BMD 
(lumbar spine, total hip, and femoral neck). 
The methods of assessment of safety endpoints are detailed in Section 9.2.1. 
9.1.2.2 Secondary efficacy endpoints 
• Change from Baseline to Week 26 in HbA1c (sotagliflozin 200 mg only). 
• Change from Baseline to Week 26 in BW. 
• Change from Baseline to Week 26 in FPG. 
• Change from Baseline to Week 12 in SBP for all patients. 
• Proportion of patients with HbA1c <7.0% at Week 26. 
9.1.3 Other efficacy endpoints 
• Change from Baseline to Weeks 52 and 104 in HbA1c. 
• Change from Baseline to Weeks 52 and 104 in FPG. 
• Change from Baseline to Weeks 52 and 104 in BW. 
• Proportion of patients with HbA1c <7.0 % at Weeks 52 and 104. 
• Proportion of patients starting rescue therapy during the 104 weeks of treatment. 
• Change from Baseline to Weeks 26 and 104 in SBP for all patients. 
• Change from Baseline to Weeks 12, 26, and 104 in SBP for the subsets of patients with 
Baseline SBP <130 mmHg and ≥130 mmHg, respectively. 
• Change from Baseline to Weeks 12, 26, and 104 in DBP for all patients and the subsets of 
patients with Baseline DBP ≥80 mmHg and <80 mmHg, respectively. 
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• Change from Baseline to Weeks 26, 52, and 104 in total body fat mass and total lean mass 
measured by DXA. 
• Change from Baseline to Weeks 26, 52, and 104 in serum estradiol (only for women). 
• Change from Baseline to Weeks 26, 52, and 104 in UACR. 
• Change from Baseline to Weeks 26, 52, and 104 in eGFR. 
9.1.4 Assessment methods of efficacy endpoints 
9.1.4.1 Hemoglobin A1c 
Hemoglobin A1c will be assessed at Screening (Visit 1), Baseline (Visit 3), Week 12 (Visit 6), 
and Week 26 (Visit 8), Week 52 (Visit 10), Week 86 (Visit 12), and Week 104 (Visit 13) and 
measured by a certified Level I “National Glycohemoglobin Standardization Program” Central 
Laboratory. 
If a patient needs to receive rescue antidiabetic medication, assessment of HbA1c should be 
performed before the introduction of the rescue therapy. 
9.1.4.2 Blood pressure 
Systolic BP and DBP will be assessed at all on-site visits. Blood pressure measurements will be 
taken as described in Section 9.2.1.6 with full details and directions for the measurement of BP 
and heart rate (HR) in Appendix C. 
9.1.4.3 Fasting plasma glucose 
Fasting plasma glucose will be assessed at Baseline (Visit 3), Week 3 (Visit 4), Week 6 (Visit 5), 
Week 12 (Visit 6), Week 26 (Visit 8), Week 52 (Visit 10), Week 86 (Visit 12), and Week 104 
(Visit 13). Fasting is defined as no food intake for ≥8 hours. The FPG assessment is performed on 
the morning of the visit. For the efficacy assessments of the study, FPG is measured at a central 
laboratory. 
9.1.4.4 Body weight 
Body weight is measured at every study visit. Body weight should be obtained with the patient 
wearing undergarments or very light clothing and no shoes, and with an empty bladder. The same 
scale should be used throughout the study, and calibrated on a regular basis as recommended by 
the manufacturer. Calibration should be documented in source documents. The use of balance 
scales is recommended; if digital scales are used, testing with standard weights is of particular 
importance. The floor surface on which the scale rests must be hard and should not be carpeted or 
covered with other soft material. The scale should be balanced with both weights at zero and the 
balance bar aligned. The patient should stand in the center of the platform, as standing off-center 
may affect measurement. The weights are moved until the beam balances (the arrows are aligned). 
The weight is read and recorded in the eCRF and source data. Self-reported weights are not 
acceptable; patients must not read the scales themselves. 
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9.1.4.5 Kidney function and calcium metabolism parameters 
Serum creatinine, 24-hour home-collected urine albumin, calcium (adjusted for creatinine), 
creatinine, phosphorus (adjusted for serum phosphorus and creatinine), magnesium (adjusted for 
serum magnesium and creatinine) will be assessed at Baseline (Visit 3), Week 26 (Visit 8), 
Week 52 (Visit 10), and Week 104 (Visit 13) (see Section 1.2). Serum creatinine will also be 
measured at Screening (Visit 1). Patients will be instructed to initiate the 24-hour urine collection 
on the day before the planned visits. In exceptional situations, the 24-hour urine collection can be 
done up to 2 days maximum prior or after the visit, and the specimen should be sent to the study 
site as soon as possible. Patients will be instructed to keep the 24-hour urine specimens at home in 
a cool place at room temperature, or refrigerated at 2oC to 4oC before they are sent to the site. 
The patient will be advised to refrain from heavy exercise or sex during the day of the collection. 
Specific details about specimen collection, storage, packaging, and shipping will be provided in 
the laboratory operational manual. A central laboratory will analyze samples and calculate the 
eGFR and UACR to allow assessment of change from baseline in eGFR and UACR. Details of 
urine collection and analysis are provided in Section 9.1.4.5. 
9.1.4.6  Body composition measurements 
Body composition assessments, ie, change in total body fat mass and total lean mass, will be 
assessed in all patients using DXA. Baseline DXA scans for body composition assessments will 
be performed during Run-in (between Week -2 [Visit 2] and Baseline [Visit 3]). To assess change 
from Baseline in body composition, post-Baseline DXA scans will be performed within 2 weeks 
prior to the on-site visits at Week 26 (Visit 8), Week 52 (Visit 10), and Week 104 (Visit 13). 
In exceptional situations, if justified based on Investigator’s assessment, the DXA scan can be 
performed up to a maximum of 7 days after the scheduled visit. All scans will be archived onto 
digital media at the site and forwarded to the central image review facility within 24 hours of 
acquiring the scan. The site is also required to maintain a copy of the data. All DXA scans will be 
retained as source data. Details of DXA measurement and data analyses are included in a separate 
protocol for DXA imaging provided by the central image review facility. 
9.1.4.7 Use of rescue medications for hyperglycemia 
The use of rescue medications for hyperglycemia will be assessed and reported throughout the 
104 weeks of double-blind treatment. Routine alerts on FPG and/or HbA1c will be sent to the 
Investigator from the central laboratory to ensure that glycemic parameter results remain within 
predefined thresholds. For details and further actions should FPG values fall above thresholds, 
refer to Section 8.2.2. 
9.2 
SAFETY ENDPOINTS 
Assessments for safety include AEs, SMBG, clinical laboratory assessments, physical 
examination, ECG, weight, and vital signs. An independent DMC will meet on a regular basis to 
review accumulating clinical trial safety data by treatment. 
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Adjudication of all deaths, MACE and other selected CV events, selected renal events, bone 
fracture, and DKA will be performed in a blinded manner by a CEC. Further details are available 
in Section 6.4.3 and in the CEC Charter. 
An expert committee will review all potential cases of DILIs in a treatment-blinded manner to 
evaluate causality. 
The following safety endpoints will be assessed throughout the 104 weeks of double-blind 
treatment: 
• Adverse events, hypoglycemia (all, severe, and/or documented symptomatic 
hypoglycemia), EOSI, adverse events of special interest (AESI), AEs leading to 
discontinuation of IMP, SAEs, and deaths. 
• Percent change from Baseline to Weeks 26, 52 and 104 in BMD (lumbar spine, total hip, 
and femoral neck). 
• Proportion of patients with adjudicated bone fractures over 104 weeks. 
• Proportion of patients with ≥3% decline in BMD at Week 104. 
• Changes from Baseline in bone turnover markers to Week 26, 52, and 104 (serum bone 
resorption markers: N-terminal telopeptide of Type 1 collagen [NTX] and β-CTX-1; 
serum bone formation markers: P1NP and osteocalcin). 
• Changes from Baseline in markers of calcium metabolism to Week 26, 52, and 104 
(serum: calcium, phosphorus, magnesium, parathyroid hormone [iPTH], 
25-hydroxyvitamin D and 1,25-dihydroxyvitamin D; urinary: calcium, phosphorus and 
magnesium). 
Clinical laboratory results (see Section 9.2.1.4), vital signs results, and 12-lead ECG. 
Observation period of safety endpoints 
The observation period of safety data will be divided into 3 segments: 
• The pretreatment period is defined as the time between the date of the informed consent 
and the first dose of double-blind IMP. 
• The treatment-emergent 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 treatment-emergent period). 
The Baseline value for safety endpoints in the safety population is the last available value prior to 
the first administration of the double-blind IMP. 
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9.2.1 Assessment methods of safety endpoints 
9.2.1.1 Bone mineral density 
Change in BMD at lumbar spine, total hip, and femoral neck will be assessed in all patients using 
DXA. Baseline DXA scans for BMD assessment will be performed during Run-in 
(between Week -2 [Visit 2] and Baseline [Visit 3]) and centrally reviewed to confirm eligibility. 
To assess percent change from Baseline in BMD, post-Baseline DXA scans will be performed 
within 2 weeks prior to the on-site visits at Week 26 (Visit 8), Week 52 (Visit 10), and Week 104 
(Visit 13). In exceptional situations, if justified based on Investigator’s assessment, the DXA scan 
can be performed up to a maximum of 7 days after the scheduled visit. All BMD assessments will 
be performed locally with central review. The DXA scanners will be calibrated and monitored 
using phantoms provided by the central image review facility. Detailed guidance on acceptable 
DXA scanners and scanning procedures will be provided by the central review facility to the 
DXA operating sites. Sites will forward scans to the central image review facility on an ongoing 
basis for quality control, data validation, and imaging review. All scans will be archived onto 
digital media at the site and forwarded to the central image review facility within 24 hours of 
acquiring the scan. The site is also required to maintain a copy of the data. All DXA scans will be 
retained as source data. Details of DXA measurement and data analyses will be included in a 
separate protocol for DXA imaging provided by the central image review facility. 
9.2.1.2 Adverse events 
Adverse events including SAE, AESI, and EOSI will be assessed. Refer to Section 10.4 to 
Section 10.7 for details. 
9.2.1.2.1 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. 
9.2.1.2.2 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 10.4.1.3 and Section 10.4.4, respectively. 
9.2.1.3 Hypoglycemia 
Hypoglycemia events (all, severe and/or documented symptomatic hypoglycemia) will be 
assessed starting with signing of the ICF until 2 weeks after the last dose of IMP (Note: for 
patients who discontinue treatment before Week 104, safety data will be collected until scheduled 
study end). Patients will also complete the patient diary, which will be regularly reviewed by 
Investigators. See Section 10.6.1 for further details. 
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9.2.1.4 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including clinical chemistry, hematology 
amylase lipase, fasting lipid profile, and additional evaluations) and urinalysis, according to the 
schedule presented in Section 1.2. Clinical laboratory values will be evaluated after conversion 
into standard international units. International units will be used in all listings and tables. Table 2 
lists the blood analysis parameters to be assessed by the central laboratory. Urinalysis parameters 
are presented in Section 9.2.1.5. 
Serum FSH and estradiol will be measured in women at Screening (Visit 1, Week -4) to confirm 
menopausal status as needed. A postmenopausal state is defined as no menses for >12 months 
without an alternative medical cause. An FSH level in the postmenopausal range (>40 IU/L) may 
be used to confirm a postmenopausal state in women not using hormonal replacement therapy. 
For hysterectomized women, determination of menopausal status will be based on history of 
vasomotor symptoms, or FSH >40 IU/L and estradiol levels on postmenopausal range 
(<20 pg/mL). 
Table 2 - Blood safety parameters 
Clinical chemistry 
Hematology 
Other parameters 
Sodium 
Complete blood count (CBC) 
Fasting lipid profile 
Potassium 
Differential white blood count 
(WBC) 
Total cholesterol (TC) 
Chloride 
Platelet count 
High-density lipoprotein cholesterol (HDL-C) 
Carbon dioxide (bicarbonate) 
Hemoglobin 
Low-density lipoprotein cholesterol (LDL-C)b 
Blood urea nitrogen (BUN) 
Hematocrit 
Non–HDL-Cc 
Creatinine (for eGFR calculationa) 
Erythrocyte count 
Triglycerides (TG) 
Glucose (serum) 
 
 
Alanine aminotransferase (ALT) 
 
Other tests 
Aspartate aminotransferase (AST) 
 
Amylase 
Total bilirubin (TB) 
 
Lipase 
Alkaline phosphatase (ALP) 
 
 
Uric acid 
 
Markers of bone and calcium metabolism  
Phosphorusd 
 
25-hydroxyvitamin D  
Calciumd 
 
1,25-dihydroxyvitamin D 
Magnesiumd 
 
Parathyroid hormone (iPTH) 
Total protein 
 
Markers of bone resorption: NTX, β-CTX-1 
Albumin 
 
Marker of bone formation: P1NP, osteocalcin 
Creatine phosphokinase (CPK) 
 
 
Lactic acid dehydrogenase (LDH) 
 
 
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Clinical chemistry 
Hematology 
Other parameters 
Abbreviations: ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, 
CBC = complete blood count, CPK = creatine phosphokinase, eGFR = estimated glomerular filtration rate, HDL-C = high-density lipoprotein 
cholesterol, IDMS = isotope dilution mass spectrometry, iPTH = parathyroid hormone, LDH = lactic acid dehydrogenase, 
LDL-C = low-density lipoprotein cholesterol, MDRD = Modification of Diet in Renal Disease, NTX = N-terminal telopeptide of Type 1 collagen, 
P1NP = Type 1 procollagen N-terminal propeptide, SI = Standardized International, TB = total blood, TC = total cholesterol, TG = triglycerides, 
US = United States, WBC = white blood count, β-CTX-1 = beta C-terminal telopeptide of Type 1 collagen. 
All assessments to be performed by central laboratory. All assessments measured in serum. 
a The eGFR will be calculated. The recommended equation for estimating eGFR from serum creatinine is the 4-variable MDRD (32) Study 
equation. The IDMS-traceable version of the MDRD Study equation will be used. Either equation below may be used based on whether the 
laboratory reports conventional units or 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 LDL-C will be calculated by Friedwald equation. 
c Non–HDL-C will be calculated as the difference between TC and HDL-C. 
d Serum calcium, phosphorus, and magnesium are also part of the panel of markers of bone and calcium metabolism. 
9.2.1.5 Urinalysis 
Urinalysis (urine dipstick with microscopy) will be performed by central laboratory at Screening 
(Visit 1), Baseline (Visit 3), Week 26 (Visit 8), and Week 52 (Visit 10) and Week 104 (Visit 13). 
The central laboratory 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. 
To prevent partial unblinding, the central laboratory urinalysis dipstick will not include the 
measurement of urine glucose. 
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 cultures should be performed if at any point the Investigator suspects the 
presence of a UTI. 
In addition, urine albumin, calcium, phosphorus, magnesium, and creatinine will be assessed by 
24-hour urine collection at Baseline (Visit 3), Week 26 (Visit 8), Week 52 (Visit 10), and 
Week 104 (Visit 13). See Section 9.1.4.5 for information on 24-hour urine collection. 
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). 
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9.2.1.6 Vital signs and physical examination 
Vital signs, including sitting BP and HR, will be assessed at all study visits for safety and efficacy 
endpoints. Full details and directions for the measurement of BP and HR are presented in 
Appendix C. Physical examinations will be performed at every study visit. 
A complete physical examination will be performed at Screening (Visit 1), Week 26 (Visit 8), and 
Week 104 (Visit 13). An abbreviated physical examination will be performed at all the other 
visits, including the Follow-up Visit/Week 106 (Visit 14). The abbreviated physical examination 
should focus on cardiac and respiratory systems, as well as any areas important for assessment of 
AEs, if necessary. The complete physical examination will also include recording of BW and vital 
signs. Body weight measurements are discussed in Section 9.1.4.4. Height will be measured only 
at Screening Visit, Week 52, Week 104, and Premature EOT Visit. 
9.2.1.7 Electrocardiogram variables 
Twelve-lead ECG recording will be performed locally at the Run-in Visit (Visit 2), and at 
Week 26 (Visit 8), and Visit 13 (Week 104). 
The 12-lead ECG should be performed after the patient has spent at least 10 minutes in supine 
position and prior to IMP administration. The Investigator should review the ECG trace and 
document the interpretation, sign and date the ECG print out, and report the interpretation in the 
eCRF. Each subsequent ECG trace will be analyzed in comparison to the Run-in Phase (Visit 2) 
Screening ECG trace. All original ECG traces are retained as source data. 
The ECG results will be evaluated as “normal” or “abnormal”. 
Note: Any new ECG abnormality should be re-reviewed for confirmation and reported as 
appropriate for that finding. 
9.2.1.8 Self-monitored blood glucose 
A meter for the self-assessment of blood glucose will be dispensed at the Run-in Visit (Visit 2). 
Patients will receive a patient diary at each visit except for Screening Visit (Visit 1) and 
Follow-up Visit (Visit 14, Week 106). The patient will enter SMBG levels into this diary. The 
diary will be collected and reviewed at all visits starting from the Baseline Visit (Visit 3). 
Patients will be requested to self-assess blood glucose levels in the fasted state and whenever they 
experience any illnesses (eg, cold, flu), or symptoms of hyperglycemia or hypoglycemia. 
Symptoms of hypoglycemia may include shakiness, dizziness, sweating, hunger, headache, pale 
skin color, sudden moodiness or behavior changes (such as crying for no apparent reason), clumsy 
or jerky movements, seizure, difficulty paying attention or confusion, or tingling sensations 
around the mouth. Patients will be instructed to record the presence or absence of hypoglycemic 
episodes or hypoglycemic symptoms in the patient diary provided. 
Patients will also be instructed to record SMBG values that are ≤70 mg/dL (≤3.9 mmol/L) in the 
patient diary. 
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9.4 
APPROPRIATENESS OF MEASUREMENTS 
Sotagliflozin therapy in patients with T2D who have inadequate glycemic control with a stable 
antidiabetic therapy is expected to lower HbA1c over 26 weeks of treatment (primary efficacy 
analysis). Sotagliflozin treatment for 26 weeks is likely to be of sufficient duration to observe 
effects on reduction of HbA1c, and is, therefore, selected as the time point for assessment of the 
primary endpoint HbA1c. The length of the study is considered appropriate for detection of the 
primary endpoint given the power estimates. The double-blind controlled extension up to 
104 weeks will provide additional long-term data on efficacy and safety, including long-term 
assessment of bone safety with sotagliflozin treatment. 
The concentration of HbA1c reflects the glycemic history of the previous 120 days and is thus an 
index of mean glycemia, documenting glycemic control over the past 2 to 3 months. 
Hemoglobin A1c has also been shown to correlate with the development of long-term 
complications of diabetes, and reduction of HbA1c is known to reduce the risk of long-term 
microvascular complications. Therefore, HbA1c is considered an appropriate primary endpoint for 
assessing the effect of a treatment on glycemic control. The duration of study treatment (26 weeks 
for the primary HbA1c endpoint) is considered to be sufficient for achieving stable conditions 
with IMP and for enabling an adequate assessment of time-dependent changes in HbA1c. 
Improvements in FPG have been observed with sotagliflozin in multiple studies. Therefore 
assessment of FPG is relevant in this study. This parameter is also considered by regulatory 
agencies to be supportive of efficacy of an antidiabetic agent. 
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. Treatment with sotagliflozin is expected to result in weight loss 
based on the mechanism of action. Therefore, in this study, assessing change in BW from 
Baseline to Week 26 is a secondary endpoint. 
Potential therapeutic effect of sotagliflozin on BP reduction will be assessed in all trial patients. 
To avoid confounding factors, modification of antihypertensive medications is not allowed during 
the first 12 weeks of the Treatment Period. The beneficial effect of sotagliflozin to patients with 
inadequately controlled hypertension (patients with Baseline SBP ≥130 mmHg or Baseline 
DBP ≥80 mmHg) will be assessed, but also the impact of sotagliflozin in the BP of normotensive 
patients (patients with Baseline SBP <130 mmHg or Baseline DBP <80 mmHg) will also be 
assessed. Given the mechanism of action of sotagliflozin on renal tubular absorption of glucose 
and sodium, it is appropriate to assess the impact on calcium metabolism. For this reason, specific 
biomarkers for calcium metabolism and bone turnover will be assessed at several time points. 
Decreases in bone mass measured by BMD have been reported with canagliflozin treatment and 
assessment of BMD changes will be a key safety endpoint for this study. The assessment of 
impact of treatment on bone mass will be performed by evaluation of BMD T-scores initially after 
26 weeks of treatment to enable early detection of a bone safety signal and followed out yearly 
after the beginning of treatment. This duration of follow-up is appropriate to detect longitudinal 
trends in changes in bone mass in this population that is vulnerable to development of age-related 
bone loss. 
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Alterations in calcium homeostasis have been noted in nonclinical studies with selective 
SGLT2 inhibitors. Changes in calcium and bone biomarkers were evaluated in diabetic patients in 
Study LX4211.202, and no clinically significant changes on these parameters were observed. 
However, as changes in bone biomarkers have been observed in clinical studies of other selective 
SGLT2 inhibitors, the Sponsor will continue to evaluate bone biomarkers and events of fractures 
in the sotagliflozin clinical program. 
It is recognized that weight loss is associated with reduction in bone mass and also reduction of 
estradiol levels in postmenopausal women. This study will include assessment of body 
composition to allow evaluation of differential changes in total body fat mass versus lean mass 
during the treatment. The change in levels of estradiol in women will be also assessed as adipose 
tissue is a major source of estradiol in postmenopausal women and decrease in these levels can be 
implicated in changes in bone turnover. 
The other efficacy and safety assessments in this study are standard and well-established 
measurements for a Phase 3 study evaluating the treatment of T2D in adult patients. 
Safety analyses focusing on the TEAE include occurrences with SAE, AESI, EOSI, AE leading to 
IMP discontinuation, and hypoglycemic events. Other standard safety parameters such as vital 
signs, ECG and laboratory measurements will also be evaluated. The other efficacy and safety 
assessments in this study are standard, well-established measurements for a Phase 3 study 
evaluating the treatment of T2D in adult participants. 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The visit schedule and procedures/assessments are listed in the Study Flow Chart (Section 1.2). 
The aim of this section is to provide details on how some of the procedures/assessments should be 
performed. 
This is an out-patient study and consists of 14 on-site visits. Additional on-site visits or telephone 
contacts can be scheduled at any time during the study whenever considered necessary by the 
Investigator. 
The patients need to arrive at the study site in a fasting state for Visit 1, Visit 3, Visit 4, Visit 5, 
Visit 6, Visit 8, Visit 10, Visit 12, Visit 13, and Visit 14 unless instructed otherwise by the 
investigator. Throughout the study, “fasting” is defined as at least 8 hours without food (no food 
or liquid intake, other than 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. All laboratory assessments will occur prior to IMP and NIMP administration on the 
day of the visit. 
The Run-in Visit (Visit 2) can be performed up to 2 weeks (± 3) days after the Screening Visit and 
once the results of all Screening tests are available and the patient is confirmed to be eligible for 
participation in the study. The visit windows for the Double-blind Treatment Period visits will be 
as follows: Visit 3 through Visit 8 should occur at the schedule ±3 days; Visit 9 through Visit 12 
should occur at the schedule ±7 days. Visit 13 should occur at the schedule ±3 days and 
Follow-up Visit (Visit 14) should occur within 2 weeks after last dose of IMP ±3 days. 
If one visit date is changed, the next visit should occur according to the original schedule, ie, 
calculated from the date of Baseline visit (Visit 3, Week 0). 
For a complete list of procedures scheduled for each study visit please refer to the Study Flow 
Chart (Section 1.2), which details the procedures to be performed. 
All data obtained during the study visits are reviewed by the Investigator and Sub-investigators 
who are qualified in treatment of T2D and are trained on the study. 
10.1.1 Screening Period 
The Screening Period is up to 4 weeks and includes a Screening phase and a Run-in phase. 
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- 
HbA1c. 
- 
Serum FSH and estradiol (for documentation of menopausal status). 
- 
Clinical chemistry (including amylase, lipase) and hematology. 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported. 
• Urinalysis (dipstick and microscopy). 
• Patients will be instructed to return to the site in the fasting state for Visit 3 (Week 0). 
10.1.1.2 Run-in Phase 
The Run-in Phase is 2 weeks in duration and includes Visit 2 (Week -2). As an exception, if 
justified according to the Investigator’s assessment, the Run-in period can be extended up to a 
maximum of 14 additional days to complete all the eligibility assessments prior to the 
randomization. 
10.1.1.2.1 Run-in Visit, Visit 2 (Week -2) 
The following procedures/assessments will be performed at Visit 2 (Week -2): 
• Exclusion criteria are to be reviewed. 
• Changes in concomitant medication are reviewed. 
• Measurement of BW. 
• Abbreviated physical examination. 
- 
The abbreviated physical examination should focus on cardiac and respiratory systems, 
(as well as any areas important for assessment of AEs, if necessary), and vital signs 
(SBP and DBP, and HR) (see Appendix C for details). 
- 
Diet and exercise instruction will be provided. 
• Blood glucose meter is dispensed and instructions/training are provided. 
• Patient diary is dispensed and instructions/training are provided. 
• Instruction on glucose testing, basic genito-urinary (GU) hygiene and hydration, and 
recognizing DKA symptoms (see Appendix B) is provided. 
• The IRT is notified for registration of Run-in Visit and allocation of single-blind Run-in 
kit. 
• Run-in kit/placebo is dispensed. 
• 12-lead ECG is conducted. 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported. 
• Patients are instructed to return to the site in the fasting state with used, partially used, or 
not used single-blind Run-in kit for Visit 3 (Randomization). 
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• Patients will be referred to DXA scan facility to perform DXA scan prior to Visit 3 
(Randomization). 
• Patients are provided with a urine container and instructed on how to collect 24-hour urine 
at home to be brought to the site at Visit 3 (Randomization). 
10.1.2 Randomized Double-blind Core Treatment Period (Day 1 to Week 26) 
Upon successful completion of the Run-in Phase, patients will be randomly allocated to either 
sotagliflozin 400 mg, sotagliflozin 200 mg, or sotagliflozin-matching placebo for the entire 
duration of the 104 weeks of Double-blind treatment. The first 26 weeks after the randomization 
correspond to the Core Treatment Period. All randomized patients will be followed at regular 
on-site visits for the duration of the treatment period. 
In addition to routine laboratory testing, the following will be performed at specified time points: 
; collection of home 24-hour urine for assessment of albumin, creatinine, 
calcium (adjusted for creatinine), phosphorus (adjusted for serum phosphorus and creatinine), 
magnesium (adjusted for serum magnesium and urinary creatinine). 
In the event of abnormal urinalysis findings suspicious of UTI, urine culture should be performed. 
Positive urine culture determination will be based upon the criteria of the reporting laboratory. 
Additionally, urine culture should be performed if at any point the Investigator suspects the 
presence of a UTI. 
10.1.2.1 Randomization (Baseline Day 1/Visit 3/Week 0) 
The following procedures will be performed at this visit: 
• Exclusion criteria are to be reviewed, including review of DXA results for eligibility, and 
assessment of compliance with single-blind IMP treatment during Run-in Phase. 
• Concomitant medications are reviewed. 
• Measurement of BW. 
• Abbreviated physical examination and vital signs (see Appendix C). 
• IRT to be notified and randomization to occur. 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported. 
• Diet and exercise instruction. 
• Patient diary collected and reviewed and a new one is dispensed. Instructions/training are 
provided as needed. 
• Instructions on glucose testing, basic GU hygiene, hydration, and DKA symptoms are 
provided. 
• SMBG records will be reviewed. 
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• The following laboratory testing (by the central laboratory): 
- 
FPG. 
- 
HbA1c. 
- 
Clinical chemistry (including amylase, lipase) and fasting lipids. 
- 
Hematology. 
- 
Serum estradiol (only for women). 
- 
Bone turnover markers. 
- 
Markers of calcium metabolism. 
- 
Urinalysis (dipstick and microscopy). 
- 
Albumin, creatinine, calcium, phosphorus, and magnesium concentration in 24-hour 
urine. 
• Collection of samples for additional laboratory testing: 
- 
 
• IRT will be notified IMP for resupply. 
• Double-blind IMP is dispensed. 
• Patients are instructed to return to the site in the fasting state for their next visit. 
• For accountability and compliance purposes, patients are instructed to return to the site at 
the next visit bringing their used, partially used, or not used medication kit(s). 
10.1.2.2 On-site visits from Visit 4 to Visit 7 (Week 3 to Week 18) 
The following procedures will be performed at study visits from Week 3 to Week 18: 
• Concomitant medications will be assessed. 
• Measurement of BW. 
• Abbreviated physical examination and vital signs (see Appendix C). 
• IMP accountability and compliance with double-blind IMP treatment. 
• IRT will be notified for IMP resupply. 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) occurring since the previous visit will 
be reported. 
• Patient diary will be collected and reviewed and a new one will be dispensed. 
Instructions/training will be provided as needed. 
• SMBG records will be reviewed. 
• Patients will be evaluated for glycemic rescue. 
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• Instructions on glucose testing, basic GU hygiene, hydration, and recognizing DKA 
symptoms will be provided (see Appendix B). 
• 12-lead ECG. 
• Central laboratory testing: 
- 
FPG. 
- 
HbA1c. 
- 
Clinical chemistry. 
- 
Hematology. 
- 
Fasting lipids. 
- 
Serum estradiol (only for women). 
- 
Bone turnover markers. 
- 
Markers of calcium metabolism. 
- 
Urinalysis (dipstick and microscopy). 
- 
Albumin, creatinine, calcium, phosphorus, and magnesium concentration in 
24-hour urine. 
• 
 
• Double-blind IMP is dispensed. 
• Confirm with the central review facility that the DXA procedures for Visit 8 (Week 26) 
were performed successfully. In case the DXA scan needs to repeated, or has not been 
done yet, instruct the patients to perform the DXA scan within the next 7 days. 
• For accountability and compliance purposes, patients are instructed to return to the site at 
the next visit bringing their used, partially used, or not used medication kit(s). 
10.1.3 Double-blind, Randomized Extension Period (Week 27 to Week 104) 
10.1.3.1 On-site visits from Visit 9 to Visit 12 (Week 27 to Week 86) 
The following procedures will be performed at each Visit, except as specified: 
• Concomitant medications will be assessed. 
• Measurement of BW. 
• Measurement of height only at Visit 10 (Week 52). 
• Abbreviated physical examination and vital signs (see Appendix C). 
• IMP accountability and compliance with double-blind IMP treatment. 
• IRT will be notified for IMP resupply. 
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• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) occurring since the previous visit will 
be reported. 
• Diet and exercise instruction will be provided, except at Visit 9 (Week 39). 
• Patient diary will be collected and reviewed and a new one will be dispensed. 
Instructions/training will be provided as needed. 
• SMBG records will be reviewed. 
• Patients will be evaluated for glycemic rescue. 
• Instructions on glucose testing, basic GU hygiene, hydration, and recognizing 
DKA symptoms will be provided. 
• Central laboratory testing: 
- 
FPG: Visit 10 (Week 52) and Visit 12 (Week 86). 
- 
HbA1c: Visit 10 (Week 52) and Visit 12 (Week 86). 
- 
Clinical chemistry, including amylase and lipase: Visit 10 (Week 52) and Visit 12 
(Week 86). 
- 
Hematology: Visit 10 (Week 52) and Visit 12 (Week 86). 
- 
Serum estradiol (only for women): Visit 10 (Week 52). 
- 
Bone turnover markers: Visit 10 (Week 52). 
- 
Markers of calcium metabolism: Visit 10 (Week 52). 
- 
Urinalysis (dipstick and microscopy): Visit 10 (Week 52) and Visit 12 (Week 86). 
- 
Albumin, creatinine, calcium, phosphorus, and magnesium concentration in 24-hour 
urine will be done at Visit 10 (Week 52). 
• Double-blind IMP is dispensed. 
• At Visit 10 (Week 52) confirm with the central review facility that the DXA procedures 
for Visit 8 were performed successfully. In case the DXA scan needs to repeated, or has 
not been done yet, instruct the patients to perform the DXA scan within the next 7 days. 
• Patients are instructed to return to the site in the fasting state for the next visit, except for 
Visit 9 (Wek 39) and Visit 11 (Week 68) when fasting is not required. 
• For accountability and compliance purposes, patients are instructed to return to the site at 
the next visit bringing their used, partially used, or not used medication kit(s). 
• At Visit 9 (Week 39) and at Visit 12 (Week 86), patients will be referred to DXA scan 
facility to perform DXA scan within 2 weeks prior to the next visit. 
• At Visit 9 (Week 39) and at Visit 12 (Week 86) patients will be provided with a urine 
container and instructed on how to collect 24-hour urine at home to be brought to the site 
at the next visit. 
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10.1.3.2 On-site Visit 13 (Week 104) - End of treatment (EOT) 
The following procedures will be performed at this Visit: 
• Concomitant medications will be reviewed. 
• Measurement of BW and height. 
• Complete physical examination will be done and vital signs (see Appendix C). 
• IMP accountability and compliance with double-blind IMP treatment. 
• IRT will be notified for end of treatment. 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) occurring since the previous visit will 
be reported. 
• Patient diary will be collected and reviewed and a new one will be dispensed. 
• SMBG records will be reviewed. 
• 12-lead ECG. 
• Central laboratory testing: 
- 
FPG. 
- 
HbA1c. 
- 
Clinical chemistry, including amylase, lipase, and fasting lipids. 
- 
Hematology. 
- 
Serum estradiol (only for women). 
- 
Bone turnover markers. 
- 
Markers of calcium metabolism. 
- 
Urinalysis (dipstick and microscopy). 
- 
Albumin, creatinine, calcium, phosphorus, and magnesium concentration in 24-hour 
urine. 
• Confirm with the central review facility that the DXA procedures for Visit 13 (Week 104) 
were performed successfully. In case the DXA scan needs to repeated, or has not been 
done yet, instruct the patients to perform the DXA scan within the next 7 days. 
• Patients are instructed to return to the site in 2 weeks for the follow-up visit. 
• Patients are instructed to return to the site in the fasting state for the next visit. 
10.1.4 Post-treatment follow-up period 
The post-treatment Follow-up Period will include an on-site visit, 2 weeks ±3 days after the last 
dose of IMP. 
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10.1.4.1 Follow-up Visit (Week 106/Visit 14) 
The following procedures will be performed at this visit: 
• Concomitant medications will be reviewed. 
• Measurement of BW. 
• Abbreviated physical examination including vital signs (see Appendix C). 
• IRT to be notified of End of Study. 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) since the previous visit will be reported. 
• Collect glucose meter. 
• Patient diary is collected and reviewed. 
• The patient is instructed to schedule future follow-up with their health care provider. 
• SMBG records will be reviewed. 
• Central laboratory testing. 
- 
Hematology. 
- 
Clinical chemistry (including amylase and lipase). 
10.2 
DEFINITION OF SOURCE DATA 
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. 
- 
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 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. 
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• 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. 
• Patient’s diary. 
10.2.1 Source data verification requirements for screen failures 
For screen failure patients, the following source data must be verified: patient’s identification 
details, the informed consent signed by the patient, the study identification (name), dates of study 
visits, and the main reasons for screen failure. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation must be fully documented in the eCRF. In any case, the 
patient should remain in the study as long as possible 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(s) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Lower extremity complications (such as skin ulcers, infection, osteomyelitis and gangrene) 
requiring treatment should lead to temporary discontinuation of IMP. Reinitiation of treatment 
with the IMP will be done under close and appropriate clinical and/or laboratory monitoring once 
the Investigator, according to his/her best medical judgment, has determined that the 
responsibility of the IMP(s) in the occurrence of the concerned event was unlikely to be related to 
the IMP. 
Since the IMP received is blinded, patients must return to the site and IRT will be contacted for 
IMP reinitiation. 
It is in the interest of the patient to monitor their blood glucose during the temporary 
discontinuation period, therefore regular determination of SMBG is to be performed and 
documented (see Section 9.2.1.8). 
For all temporary treatment discontinuations, duration must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
Temporary treatment discontinuation decided by the Investigator corresponds to more than 1 dose 
not administered to the patient. 
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Use of any other antihyperglycemic medication during the time of temporary treatment 
discontinuation (ie, insulin during a hospitalization) will be recorded as concomitant medication 
with the name and dose recorded in the eCRF. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator not to re-expose the patient to the IMP at any time during 
the study, or from the patient not to be re-exposed to the IMP whatever the reason. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. Patients should discuss 
stopping study medication with the site before doing so, to allow for questions to be addressed, 
glycemic therapy to be adjusted, and a follow-up assessment to be arranged. All efforts should be 
made to document the reason(s) 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. 
• Intercurrent condition that requires permanent discontinuation of the study treatment as 
long as the abnormality persists and if the casual relationship of the concerned event and 
the IMP is possible (according to the Investigator’s best medical judgment). 
• BMD decrease of >7% from Baseline. 
• Specific request of the Sponsor. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked to confirm the 
result before making a decision of permanent discontinuation of the IMP for the concerned 
patient. 
For patients who prematurely discontinue the IMP, the assessments planned at EOT visit  
(Section 1.2) will be performed at the Premature EOT Visit scheduled preferably prior to 
treatment discontinuation or as soon as possible after the time of discontinuation (at the latest at 
the next scheduled on-site visit), and a Follow-up Visit 2 weeks (±3 days) after the last dose of 
IMP. In addition, every effort will be made to have the patient return to the site at the time 
corresponding to their scheduled visits, particularly the Week 26 Visit and Week 104 Visit. If the 
patient does not agree to site visits, he or she will be contacted by telephone to inquire about 
safety status and collect AE data. The reason(s) for IMP discontinuation will be clearly specified. 
This Premature EOT assessment may occur at a regularly scheduled or at an unscheduled visit. 
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10.3.4 Handling of patients after permanent treatment discontinuation 
Every effort should be made to maintain patients in the study. Patients will 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 10.1.3.2) should be scheduled prior to treatment discontinuation, if possible. If not 
possible, the Premature EOT Visit should be scheduled as soon as possible after the permanent 
treatment discontinuation and the patients will be assessed using the procedure normally planned 
for the last dosing day with the IMP. For patients that discontinue treatment but remain in the 
study, remaining study visits should occur as scheduled, as possible. The IRT should be notified 
of the EOT. 
All cases of permanent treatment discontinuation must 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 Week 104 
(EOT) visit. 
The Investigators should discuss with them key visits to attend. 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. 
Patients who withdraw from the study treatment should be explicitly asked about the contribution 
of possible AEs to their decision, and any AE information elicited must 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 study withdrawals must 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. 
In addition, a patient may withdraw his/her consent to stop participating in the study. Withdrawal 
of consent for treatment should be distinguished from withdrawal of consent for follow-up visits 
and from withdrawal of consent for nonpatient contact follow-up, eg, medical record checks. 
The site should document any case of withdrawal of consent. 
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For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator must 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 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect, or 
• Is a medically important event. 
• Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
• Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm. 
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- 
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. 
• Alanine aminotransferase >3 times the ULN + total bilirubin >2 times the ULN or 
asymptomatic ALT increase >10 times the ULN. 
• Suicide attempt or any event suggestive of suicidality. 
• Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
• Bullous cutaneous eruptions. 
• Cancers diagnosed during the study or aggravated during the study. 
• Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study. 
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation to 
characterize and understand them. Adverse events of special interest may be added, modified, or 
removed during a study by protocol amendment. 
The AESIs for this study are: 
• Pregnancy of a female partner of a male patient entered in a study with IMP/NIMP: 
- 
Pregnancy occurring 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). 
- 
Follow-up of the pregnancy in female partner of a male patient is mandatory until the 
outcome has been determined (see Appendix A). 
• Symptomatic overdose with IMP/NIMP: 
- 
A symptomatic overdose (accidental or intentional) with the IMP/NIMP is an event 
suspected by the Investigator or spontaneously notified by the patient and resulting in 
clinical symptoms and/or signs accompanied by administration of more than twice the 
intended daily dose within a 24-hour period. It will be recorded in the eCRF as an 
AESI with immediate notification “Symptomatic OVERDOSE (accidental or 
intentional)” in all cases and will be qualified as an SAE only if it fulfills the SAE 
criteria. 
Note: An asymptomatic overdose with the IMP/NIMP, accidental or intentional, is defined as 
administration of more than twice the intended daily dose within a 24-hour period, without 
clinical symptoms and/or signs, either suspected by the Investigator or spontaneously notified by 
the patient, not based on accountability assessment. It will be recorded as AE “Asymptomatic 
OVERDOSE, accidental or intentional”. 
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• ALT increase >3 times the ULN (refer to related flowchart [Appendix D]). 
10.4.1.4 Events of special Interest 
An EOSI is a serious or nonserious AE of scientific and medical concern specific to the Sponsor’s 
product or program, for which ongoing monitoring may be appropriate. Such events may require 
further investigation to characterize and understand them. These events should be reported on the 
specific eCRF page (where applicable) and will only qualify for expedited reporting when serious 
(fulfilling SAE criteria). 
The EOSIs for this study are: 
• MACE (CV death, MI, or stroke) and other specific CV events (eg, hospitalization for 
heart failure). 
• Severe hypoglycemia (see Section 10.6.1). 
• Genital mycotic infections (to include vulvovaginal candidiasis in females and candida 
balanitis in males). 
• UTIs. 
• Clinically relevant volume depletion and events related/possibly related to volume 
depletion. 
• Diarrhea. 
• Pancreatitis. 
• Bone fractures. 
• Venous thrombotic events to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism). 
• DKA. 
• Renal events to include 50% decline in eGFR, end stage kidney disease, renal death. 
• Malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, 
prostate, and thyroid carcinoma). 
• TEAEs leading to 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). 
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• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
• 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. 
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 after 
approval of the Investigator within the eCRF or after a standard delay. 
• SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and e-mail address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
• All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification. 
• A back-up plan (using a paper CRF process) 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. 
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10.4.4 Guidelines for reporting adverse events of special interest 
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the 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. 
10.4.6 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix D. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices. 
• Neutropenia. 
• Thrombocytopenia. 
• ALT increase. 
• Acute renal insufficiency. 
• Suspicion of rhabdomyolysis. 
10.4.7 Guidelines for reporting product complaints (IMP/NIMP) 
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels, or documents like pictures or photocopies) related 
to product identification and to the potential deficiencies may need to be gathered. The 
Investigator will assess whether or not the quality issue has to be reported together with an AE or 
SAE. 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, independent ethics committees (IECs)/institutional review 
boards (IRBs) as appropriate and to the Investigators. 
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• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
• The following AESIs to those regulatory authorities who require such reporting: 
- 
Pregnancy in a male participant’s female partner. 
- 
Symptomatic overdose. 
- 
ALT increase >3 times the 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 will be instructed to document any hypoglycemic episodes 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 (33, 34) and summarized in Figure 1. 
In addition to the threshold of ≤70 mg/dL (≤3.9 mmol/L), hypoglycemia episodes with a plasma 
glucose of <54 mg/dL (<3.0 mmol/L) will be analyzed separately. 
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Figure 1 - Hypoglycemia classification in Study EFC15294 
 
PG = plasma glucose; SAE = serious adverse event 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, intravenous glucose or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. 
Self-monitored plasma glucose values may not be available, but neurological recovery attributable 
to the restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. 
Note: “Requiring assistance of another person” means that the patient could not help himself or 
herself to treat the hypoglycemia. Assisting a patient out of kindness, when assistance is not 
required, should not be considered a “requires assistance” incident. 
Any hypoglycemic event which leads to unconsciousness, coma, or seizure should also be 
reported as an SAE. 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of ≤70 mg/dL 
(≤3.9 mmol/L). 
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Clinical symptoms that are considered to result from a hypoglycemic episode include increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). 
Note: Low plasma glucose values without symptoms or signs should not be reported more than 
once within 30 minutes. Repeated low glucose values within a short period could be due to 
malfunction of the device, error testing, or following up a low glucose reading. The Investigator 
should try not to document false low SMBG values or redundant low glucose values as 
asymptomatic hypoglycemic events. Further clarification with the patients is needed. 
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms of hypoglycemia are not 
accompanied by a plasma glucose determination, (but that was presumably caused by a plasma 
glucose concentration ≤70 mg/dL [≤3.9 mmol/L]), ie, symptoms treated with oral carbohydrate 
without a test of plasma glucose. 
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 >70 mg/dL (>3.9 mmol/L). 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final CSR. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
The sample size/power calculations were performed based on the primary variable of change from 
Baseline to Week 26 in HbA1c (%). 
Assuming a common standard deviation (SD) of 1.2% and using a 2-sided test at a 0.05 α-level, 
360 patients (120 patients per arm) will have 97% power to detect a treatment difference of -0.6% 
in mean HbA1c change from Baseline to Week 26 between sotagliflozin 400 mg and placebo. 
This sample size will also allow to exclude a decline in BMD from Baseline of >2% with a 95% 
power, assuming a missing rate of 30% and an SD of 3.5%. 
The total sample size will be approximately 360 patients to be randomized (120 in sotagliflozin 
200 mg group, 120 in sotagliflozin 400 group, and 120 in placebo group). 
Calculations were made using East 6.4 software. 
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 at randomization 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 11.3.1.1. 
• The randomization strata (HbA1c at Screening [≤8.5%, >8.5%]) and sex (female, male). 
Any discrepancy between the strata assigned by IRT and the information reported on 
eCRF will be listed for all randomized patients. 
• Patients who have completed the 26-week Double-blind Core Treatment Period. 
• Patients who discontinued the IMP during the 26-week Double-blind Core Treatment 
Period, and the reasons for treatment discontinuation. 
• Patients who have completed the 104-week Double-blind Treatment Period. 
• Patients who discontinued the IMP during the 104-week entire double-blind treatment 
period, and the reasons for treatment discontinuation. 
• Patients who have completed the study. 
• Patients who discontinued the study, and the reasons for study discontinuation. 
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For all categories of patients except screened, percentages will be calculated using the number of 
randomized patients as denominator for each treatment group. 
A listing of patients prematurely discontinued from the treatment, along with reasons for 
discontinuation, will be provided. Similarly, a listing of patients prematurely discontinued from 
the study, along with reasons for discontinuation, will be provided. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population. The safety experience of patients treated and not randomized 
will be reported separately, and these patients will not be included in the safety population. 
Patients randomized but not treated and patients randomized but not treated as randomized will be 
identified and described in separate listings. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy population 
Efficacy analyses will be based on the treatment group allocated by the IRT according to the 
randomization schedule at randomization visit (as randomized), irrespective of the treatment 
actually received. 
11.3.1.1 Intent-to-treat population 
Efficacy analyses will be based on the ITT population, defined as all randomized patients, 
irrespective of compliance with the study protocol and procedures. Patients will be analyzed for 
efficacy analyses according to the treatment group to which they are randomized. 
11.3.2 Safety population 
The safety analysis will be conducted on the safety population, defined as all randomized patients 
who did actually receive at least one dose of study treatment during the treatment period 
(regardless of the amount of treatment administered). Patients will be analyzed according to the 
treatment actually received. 
In addition: 
• Nonrandomized but treated patients will not be part of the safety population, 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. 
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• 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 and sotagliflozin 200 mg, the 
patient will be analyzed in the sotagliflozin 200 mg group. 
• Randomized patients will be excluded from the safety population only if there is 
documented evidence (ie, all study dates recorded as no medication taken) that patients 
have not taken the study medication. 
11.4 
STATISTICAL METHODS 
Continuous data will be summarized by treatment group using the number of observations 
available (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 nonmissing assessments at a specific visit. 
The Baseline value is defined generally as the last available value before the first dose of 
double-blind IMP or the last available value prior to randomization for patients who were 
randomized but never exposed to IMP. 
For serum creatinine and eGFR, the Baseline value is defined as average of all values before the 
first dose of double-blind IMP for those randomized and exposed or before randomization for 
patients who were randomized but never exposed to IMP. 
Analysis of demographics and Baseline characteristics and prior and concomitant medications 
will be provided in detail in the Statistical Analysis Plan (SAP). 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
The extent of study treatment exposure will be assessed by the duration of treatment exposure 
during the study. 
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 
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The number (%) of patients randomized and exposed to double-blind IMP will be presented by 
specific time periods for each treatment group. The time periods of interest will be defined in the 
SAP. 
Descriptive statistics of duration of treatment exposure (number, mean, SD, minimum, median, 
and maximum) and cumulative exposure in patient year will also be presented by treatment group 
in the safety population. 
11.4.1.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Treatment compliance, above-planned, and under-planned dosing percentages will be summarized 
descriptively (N, mean, SD, median, minimum, and maximum). The percentage of patients with 
compliance <80% will be summarized. In addition, the number and percentage of patients with at 
least 1 above-planned dosing administration will be given, as well as the number and percentage 
of patients with 0, >0 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 and secondary endpoints at Week 26 (or Week 12 for SBP). 
The superiority tests will be tested at two-sided 5% significance level. 
All efficacy endpoints, other than primary and secondary efficacy endpoints, will only be 
summarized by descriptive statistics without formal statistical testing. 
11.4.2.1 Analysis of primary efficacy endpoints 
• Analysis of the primary efficacy endpoint (change from Baseline to Week 26 in HbA1c) 
will be performed on the ITT population, using HbA1c measurements obtained during the 
study, including those obtained after IMP discontinuation or introduction of rescue therapy 
(de facto estimand). The primary efficacy endpoint of change in HbA1c from Baseline to 
Week 26 will be analyzed with missing values imputed by control-based copy reference 
multiple imputation method under the missing not at random framework for the active 
treatment group. The imputation model parameters will be first derived under missing at 
random. Then the mean of the placebo group will be used in the imputation model for 
imputing values for missing data for patients in the placebo group and also the active 
treatment groups. 
• For placebo patients, missing data will be imputed based on the placebo group data. 
• For patients in the sotagliflozin groups, missing data will be imputed as if the patients 
were on placebo throughout the study, where all patients’ measurements including the 
on-treatment measurements will be considered as if the measurements were from the 
placebo group in the imputation model. 
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Each of the complete datasets will be analyzed by the Analysis of Covariance (ANCOVA) model 
with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), randomization 
stratum of HbA1c (≤8.5%, >8.5%) at Screening, randomization stratum of sex (male, female) and 
country as fixed effects, and Baseline HbA1c value as a covariate. 
Results from each complete dataset will be combined using Rubin’s formula to provide the 
adjusted LS mean change in HbA1c from Baseline to Week 26 for each treatment group, as well 
as the between-group difference (comparing sotagliflozin 400 mg vs placebo), with the 
corresponding standard error (SE) and the 95% confidence intervals (CI) for the difference. 
Summary statistics (for Screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided for each treatment group. The summary will 
include the number of observations, mean, SD, 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 (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander). 
• Ethnicity (Hispanic, Not Hispanic). 
• Age group (<65 years, ≥65 years). 
• Sex (male, female). 
• Baseline BMI level (<30, ≥30 kg/m2). 
• Baseline HbA1c (≤8.5%, >8.5%). 
• Baseline SBP (<130 mmHg, ≥130 mmHg). 
• Country. 
The treatment effects across the subgroups defined for each of these factors will be estimated for 
the change from Baseline to Week 26 in HbA1c in the ITT population, and using a similar 
approach to the analysis for the primary efficacy endpoint. The adjusted estimates of treatment 
mean differences (comparing sotagliflozin 400 mg versus placebo) with SE and 95% CIs will be 
provided as appropriate across the subgroups using contrast statements. 
In the event that the subgroup factor is identical or similar to a randomization strata factor 
(eg, Baseline HbA1c category or sex), only the subgroup factor (as a single factor and/or an 
interaction term) will be included in the model to avoid the issue of collinearity in the analysis. 
The corresponding strata factor will not be included in the model. 
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11.4.2.2 Analysis of secondary efficacy endpoints 
The continuous secondary efficacy endpoints (see Section 9.1.2) will be analyzed using a similar 
approach to the primary efficacy endpoint, with missing values imputed by control-based multiple 
imputation method under the missing not at random framework. 
For 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 HbA1c (≤8.5%, >8.5%) at screening and sex (male, female), 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 LS mean change 
from Baseline to Week 26 (respectively, Week 12 for SBP) for each treatment group, as well as 
the between-group difference (comparing each sotagliflozin group vs placebo group) with the 
corresponding (SE) and the 95% CI. 
The categorical secondary endpoint such as HbA1c responders (<7.0%) at Week 26 will be 
analyzed using a Cochran-Mantel-Haenszel method stratified by randomization stratum of 
Screening HbA1c (≤8.5%, >8.5%) and randomization stratum of sex (male, female). 
The proportion in each treatment group will be provided, as well as the difference of 
proportions between each sotagliflozin group and placebo with associated 2-sided 95% CI. 
For HbA1c responders at Week 26, all values at Week 26 will be used to determine whether a 
patient is a responder or not, even if they are measured after IMP discontinuation or rescue 
medication use. Patients who have no HbA1c measurement at Week 26 will be treated as 
nonresponders. 
For all secondary endpoints, summary statistics at scheduled visits will be provided for each 
treatment group. The summary will include the number of observations, mean, SD, SE, minimum, 
median, and maximum. Graphical presentations will also be used to examine trends over time 
using mean values (± SE) and mean changes from Baseline (± SE) at each of the scheduled visits 
(using OC). 
11.4.2.3 Analysis of other efficacy endpoints 
The analysis of other efficacy 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 
11.4.2.4 Multiplicity considerations 
To control the family-wise Type I error, a fixed sequence testing approach will be used to test 
primary and secondary endpoints. Only if the difference in mean change from Baseline to 
Week 26 in HbA1c of sotagliflozin 400 mg versus placebo is statistically significant at α = 0.05 
(2-sided), a hierarchical testing procedure will be performed to test the secondary endpoints in the 
following prioritized order: 
• Superiority of sotagliflozin 400 mg versus placebo with respect to: 
- 
Change from Baseline to Week 26 in BW. 
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- 
Change from Baseline to Week 26 in FPG. 
- 
Change from Baseline to Week 12 in SBP for all patients. 
• Superiority of sotagliflozin 200 mg versus placebo with respect to: 
- 
Change from Baseline to Week 26 in HbA1c. 
- 
Change from Baseline to Week 26 in BW. 
- 
Change from Baseline to Week 26 in FPG. 
- 
Change from Baseline to Week 12 in SBP for all patients. 
Superiority tests will be tested at 2-sided 5% significant level. If any of the endpoints is found to 
be not statistically significant, the testing procedure will be stopped and the following endpoints 
will not be tested. Multiplicity adjustment will not be performed on other secondary endpoints not 
mentioned above. 
11.4.3 Analysis of safety endpoints 
No formal statistical tests will be performed on safety endpoints analysis. 
Safety endpoints are presented in Section 9.2. These analyses will be based on the Safety 
Population as defined in Section 11.3.2. Patients will be analyzed for safety analyses according to 
the treatment actually received. All safety analyses will be performed on the safety population 
using the following common rules: 
The following definitions will be applied to laboratory parameters and vital signs: 
• Potentially clinically significant abnormality (PCSA) values for clinical laboratory tests 
and vital signs will be defined as abnormal values considered medically important by the 
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 TEAE 
Period, taking into account all evaluations performed during the TEAE Period, including 
unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the treatment-emergent PCSA percentage. 
The “observation periods” defined in Section 9.2 are applicable for classification of AEs and 
determination of PCSA values on the TEAE period. 
11.4.3.1 Analysis of the key and other safety endpoints for BMD 
Analysis of percent change from Baseline in BMD to Week 26, Week 52, and Week 104 will be 
performed on the safety population, using BMD measurements obtained during the study, 
including those obtained after IMP discontinuation or introduction of rescue therapy. No 
statistical significance tests will be performed. 
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Analysis of the key secondary safety endpoint of percent change from Baseline to Week 26 in 
BMD will be performed using an ANCOVA model. To compare sotagliflozin 400 mg and 200 mg 
versus placebo, the model will include treatment groups (sotagliflozin 400 mg, sotagliflozin 
200 mg, placebo), randomization strata of HbA1c (≤8.5%, >8.5%), sex (male, female), and 
country as fixed effects, and Baseline BMD value as a covariate, providing the adjusted LS mean 
percent change from Baseline to Week 26 for each treatment group, as well as the between-group 
difference (comparing each sotagliflozin group vs placebo group) and the 95% CI for the 
difference. 
The last-observation-carried-forward (LOCF) approach will be applied for the missing data 
imputation of the key safety endpoint of percent change in BMD from Baseline to Week 26. 
As the Week 26 Visit is the first post-Baseline scheduled visit for BMD measurement, if a patient 
withdraws early from the study before Week 26, the BMD measurement collected at the 
withdrawal visit will be used carrying forward to Week 26 in analysis. 
The percent change from Baseline to Week 52 (or Week 104) in BMD will be analyzed using a 
mixed-effect model with repeated measures (MMRM). The MMRM model will include treatment 
groups (sotagliflozin 400 mg, sotagliflozin 200 mg, placebo), randomization strata of HbA1c 
(≤8.5%, >8.5%), sex (male, female), visit, treatment-by-visit interaction, and country as fixed 
effects, and Baseline BMD value-by-visit interaction as covariate, providing the adjusted LS mean 
percent change from Baseline to Week 52 (or Week 104) for each treatment group, as well as the 
between-group difference (comparing each sotagliflozin group vs placebo group) and the 95% CI 
for the difference. 
Descriptive analyses will be performed on safety endpoints of BMD change to summarize the 
treatment effects across subgroups defined by the following Baseline or Screening factors: 
• Age group (<65 years, ≥65 years). 
• Duration of T2D (<10 years, ≥10 years). 
• Sex (male, female). 
• Baseline BMI level (<25; 25 to <35; ≥35 kg/m2). 
• Baseline eGFR (<45; 45 to <60; ≥60 mL/min/1.73 m2). 
Summary statistics (observed values, observed percent change 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), mean changes from baseline (±SE), and mean 
percent change from baseline at each of the scheduled visits (using OC). 
Sensitivity analyses might be performed to assess the impact of missing data if needed. 
11.4.3.2 Analysis of adverse events 
Pretreatment AEs are AEs that developed or worsened or became serious during the 
pretreatment period. 
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Treatment-emergent AEs are AEs that developed or worsened (according to the Investigator’s 
opinion) or became serious during the TEAE period. 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
The primary focus of AE reporting in the CSR will be on TEAEs. Pre- and post-treatment AEs 
will be described separately. 
All adverse events 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high level group term (HLGT), high level term (HLT), and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (N), and percentage 
(%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient 
will be counted only once in the tables within a treatment Phase. The denominator for 
computation of percentages is the safety population within each treatment group. 
Summaries of all TEAEs in each treatment group will include: 
• The overview of AEs, summarizing number (%) of patients with any: 
- 
TEAE. 
- 
Serious TEAE. 
- 
TEAE leading to death. 
- 
TEAE leading to permanent treatment discontinuation. 
• The number (n) and percentage (%) of patients with at least one TEAE by primary SOC, 
HLGT, HLT, and PT. 
• Summary of TEAEs by maximal severity (severe, moderate, mild), presented by primary 
SOC and PT. 
• Summary of TEAEs possibly related to IMP, presented by primary SOC, HLGT, HLT, 
and PT. 
A detailed listing of TEAE summaries will be provided in the SAP. 
Death and serious adverse events 
Death and treatment-emergent SAEs will be summarized and presented as number and percent of 
patients in each treatment group. 
The following deaths summaries will be generated: 
• Number (n) and percentage (%) of patients who died by study period (on-study, TEAE 
period, poststudy) summarized on the safety population by treatment received. 
• Death in nonrandomized patients or randomized and not treated patients. 
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• TEAE leading to death (death as an outcome on the AE eCRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT, and PT showing number (n) and percentage 
(%) of patients sorted by internationally agreed order of SOC and alphabetic order of 
HLGT, HLT, and PT. 
Adverse events leading to permanent treatment discontinuation 
Treatment-emergent AEs leading to permanent treatment discontinuation will be summarized and 
presented as number (n) and percentage (%) of patients in each treatment group. 
11.4.3.3 Analyses of hypoglycemia 
The number (n) and percentage (%) of patients and rate in patient-years (2 types: the number of 
patients with events or the total number of events per 100 patient-years) of all hypoglycemia, 
severe hypoglycemia, and/or documented symptomatic hypoglycemia will be summarized by 
treatment group respectively. In addition, documented hypoglycemia will also be analyzed by 
using a threshold of plasma glucose of <54 mg/dL (<3.0 mmol/L). Their pattern of occurrence 
over time will also be assessed, as appropriate. 
11.4.3.4 Analyses of events of special interest 
The number (n) and percentage (%) of patients with each EOSI event will be summarized by 
treatment group. All events reported by the Investigators on the AE forms for AESI/EOSI will be 
listed along with the adjudication outcome (if applicable). 
11.4.3.5 Analyses of laboratory variables 
The number (n) and percentage (%) of patients with PCSA or by the predefined categories (if no 
PCSA criterion is defined) at any evaluation during the TEAE 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 TEAE 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 on-treatment and for the last on-treatment value within each treatment group. 
Shift tables and other tabular and graphical methods may be used to present the results for 
laboratory tests of interest. Listings will be provided with flags indicating out of laboratory range 
values and PCSA values. 
The liver function tests, namely ALT, AST, alkaline phosphatase (ALP), and total bilirubin, are 
used to assess possible DILI 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. 
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11.4.3.6 Analyses of vital sign variables 
The number (n) and percentage (%) of patients with PCSA at any evaluation during the TEAE 
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 TEAE period. Descriptive statistics will be used to summarize the results and 
the changes from Baseline by visit on-treatment and for the last on-treatment value within each 
treatment group. Tabular and graphical methods may be used to present the results for parameters 
of interest. Listings will be provided with flags indicating the PCSA values. 
11.4.3.7 Analysis of 12-lead electrocardiogram status 
A shift table will be provided to present the ECG on-treatment status according to the Baseline 
status, by treatment group. 
11.4.3.8 Analyses of body composition measurements 
Change from Baseline in total body fat mass and total lean mass measured by DXA will be 
analyzed on the safety population using descriptive 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), mean changes from baseline (±SE) and mean percent change 
from baseline at each of the scheduled visits (using OC). 
 
 
11.5 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned since analysis of primary and key secondary 
endpoints will be considered final at the time of first step analyses described below. The study 
analyses will be conducted in 2 steps: 
• First step: Efficacy analyses up to Week 26, and interim safety analyses. 
The first step analyses will be conducted when all patients have been randomized and have all 
their data, at the minimum up to Week 26 (Visit 8), collected and validated. The first step analyses 
will include: 
• Efficacy analyses up to Week 26, which are considered as the final analyses for primary 
and secondary endpoints. 
• Safety analysis of the key secondary safety endpoint of BMD at Week 26. 
• Interim safety analyses which will be performed on all safety data collected and validated 
at the time of the first step analyses. 
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The first step analyses will not be used to change the conduct of the ongoing study in any aspect. 
Since the primary efficacy and secondary analyses would have been concluded at the time of the 
first step analyses, the significance level for the study remains at 0.05 (see Section 11.4.2.4). The 
first step analyses will be included in the submission dossier to health authorities. 
• Second step: Final analyses. 
The second step analyses will be conducted at the end of the study. The second step analyses will 
include the final analyses of efficacy endpoints at Week 52 and Week 104 and safety endpoints, 
which will be descriptive only. 
Individuals who are involved in the unblinding of the first step analysis will not be involved in the 
conduct of the study afterwards. 
An independent DMC will monitor and assess the safety of patients from this trial through 
periodic review of the accumulated safety data provided by an independent statistical group. 
Related details are provided in separate documents (DMC charter and DMC SAP). 
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12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, IB with any addenda or labeling documents, summary of 
product characteristics, package insert, Investigator’s curriculum vitae), 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(s). 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial. 
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). 
The Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the eCRF, Discrepancy Resolution Form or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data, particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The investigator may appoint such other individuals as he/she may deem appropriate as 
sub-investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The 
sub-Investigators will be supervised by and work under the responsibility of the Investigator. 
The Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor 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 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 preidentified source data directly recorded in the eCRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
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ethics committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the eCRFs (eg, patient's medical file, appointment 
books, original laboratory records, etc). These personnel, bound by professional secrecy, must 
maintain the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS (eCRFS) AND 
ADDITIONAL REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All eCRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification. 
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor 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 trial master file. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-investigator will be signed, dated, and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial; however, applicable regulatory requirements should be taken 
into account in the event that a longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee. 
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the IB, and the results obtained during 
the course of the clinical trial, is confidential, prior to the publication of results. The Investigator 
and any person under his/her authority agree to undertake to keep confidential and not to disclose 
the information to any third party without the prior written approval of the Sponsor; however, the 
submission of this clinical trial protocol and other necessary documentation to the ethics 
committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same obligation of 
confidentiality. 
The Sub-investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-investigators of the confidential nature of the clinical trial. 
The Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document. 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he or she will 
inform the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor 
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including, but not limited to, the following: 
• The information on the product leads to doubt as to the benefit/risk ratio. 
• 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. 
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• 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, with the understanding that the Sponsor 
will not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights. 
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be re-collected if necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of Type 2 diabetes: 
perspectives on the past, present, and future. Lancet. 2014;383(9922):1068-83. 
2. Fowler MJ. Microvascular and Macrovascular Complications of Diabetes. Clinical Diabetes. 
2008;26(2):77-822. 
3. American Diabetes Association. Standards of Medical Care in Diabetes - 2013. Diabetes Care. 
2013;36(Supplement 1):S11-66. 
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. International Diabetes Federation. IDF Diabetes Atlas, 7th ed. Brussels, Belgium: 
International Diabetes Federation, 2015.  http://www.diabetesatlas.org. Accessed: 19 Mar 
2017. 
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 co transporter. 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.Sands AT, Zambrowicz BP, Rosenstock J, Lapuerta P, Bode BW, Garg SK, et al. Sotagliflozin, 
a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in Type 1 diabetes.  Diabetes 
Care. 2015;38(7):1181-8. 
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14. Lexicon Pharmaceuticals, Inc. Clinical Study Report: a phase 1, randomized, double blind, 
placebo controlled, ascending single and multiple dose study to determine the safety and 
tolerability of orally administered LX4211 in healthy human subjects (LX4211.1114-NRM). 
15. Rosenstock J, Cefalu WT, Lapuerta P, Zambrowicz B, Ogbaa I, Banks P, Sands A. Greater 
dose-ranging effects on A1C levels than on glucosuria with LX4211, a dual inhibitor of 
SGLT1 and SGLT2, in patients with type 2 diabetes on metformin monotherapy. Diabetes 
Care. 2015;38(3):431-8. 
16. Bristol-Myers Squibb Company, Astra Zeneca AB. FDA Advisory Committee Background 
Document: Dapagliflozin. Available from 
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/E
ndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM262996.pdf. 
17. Janssen Pharmaceuticals Inc. Endocrinologic and Metabolic Drugs Advisory Committee: 
Canagliflozin as an Adjunctive Treatment to Diet and Exercise Alone or Co-administered with 
Other Antihyperglycemic Agents to Improve Glycemic Control in Adults with Type 2 
Diabetes Mellitus. Available from: http: 
https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endo
crinologicandmetabolicdrugsadvisorycommittee/ucm334551.pdf. 
18. FDA, Center for Drug Evaluation and Research. Chong WH. Cross discipline team leader 
review. Jardiance (empagliflozin) - NDA 204629. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204629Orig1s000MedR.pdf. 
19. FDA, Center for Drug Evaluation and Research. Pucino F. Clinical review. Farxiga 
(dapagliflozin) – NDA 202293. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000MedR.pdf. 
20. Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, Sullivan D, and Rosenthal N. 
Evaluation of Bone Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes 
Treated With Canagliflozin. J Clin Endocrinol Metab. 2016;101:44-51. 
21. Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G, and Meininger G. Effects 
of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus J Clin Endocrinol 
Metab. 2016;101:157-66. 
22. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, 
Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and 
Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Jun 12. doi: 
10.1056/NEJMoa1611925. [Epub ahead of print] 
23. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and 
moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but 
does not improve glycemic control. Kidney Intl. 2014; 85:962-71. 
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10-Nov-2017 
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24. Alba M, Xie J, Fung A, and Desai M. The effects of canagliflozin, a sodium glucose co-
transporter 2 inhibitor, on mineral metabolism and bone in patients with Type 2 diabetes 
mellitus. Current Medical Research and Opinion. 2016;32(8):1375-85. 
25. Scheen AJ, Paquot N. Metabolic effects of SGLT2 inhibitors beyond increased glucosuria: A 
review of the clinical evidence. Diabetes & Metabolism. 2014;40:S4-S11. 
26. Cariou B, Charbonnel B. Sotagliflozin as a potential treatment for type 2 diabetes mellitus. 
Expert Opinion on Investigational Drugs. 2015;24(12):1647-56. 
27. Soltani S, Hunter GR, Kazemi A, Shab-Bidar S. The effects of weight loss approaches on 
bone mineral density in adults: a systematic review and meta-analysis of randomized 
controlled trials. Osteoporosis International. 2016;27(9):2655-71. 
28. Tirosh A, de Souza RJ, Sex Differences in the Effects of Weight Loss Diets on Bone Mineral 
Density and Body Composition: POUNDS LOST Trial. J Clin Endocrinol Metab. 
2015;100:2463-71. 
29.Zibellini J, Seimon RV, Lee CM, Gibson AA, Hsu MS, Shapses SA, Nguyen TV, Sainsbury A. 
Does Diet-Induced Weight Loss Lead to Bone Loss in Overweight or Obese Adults? A 
Systematic Review and Meta-Analysis of Clinical Trials. J Bone Miner Res. 
2015;30(12):2168-78. 
30. International Atomic Energy Agency. Radiation in everyday life.  Available from: 
https://www.iaea.org/Publications/Factsheets/English/radlif. Accessed: 24 July 2017. 
31. United Nations Scientific Committee on the Effects of Atomic Radiation. UNSCEAR 2008 
Report to the General Assembly. Volume I: Sources and effects of ionizing radiation. 
Available from: http://www.unscear.org/docs/publications/2008/UNSCEAR_2008_Annex-A-
CORR.pdf. Accessed: 24 July 2017. 
32. 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. 
33. International Hypoglycemia Study Group. Glucose Concentrations of Less Than 3.0 mmol/L 
(54 mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of the American 
Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 
2017;40(1):155-157. 
34. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and The Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95. 
 
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17 
APPENDICES 
 
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Appendix A 
Collection of pregnancy information 
 
COLLECTION OF PREGNANCY INFORMATION 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study treatment. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for procedure. 
 
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Appendix B 
Recommendations on basic genito-urinary hygiene, maintaining 
hydration and recognizing diabetic ketoacidosis 
Patients with Type 2 diabetes are at risk for developing genito-urinary (GU) infections. 
The following guidelines should be communicated to females and uncircumcised males regarding 
genito-urinary 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. All patients will 
be advised to maintain proper fluid intake and to consider increasing it if they sense greater thirst, 
more urine production, or if they feel dizzy or faint. 
Patient communication cards will be printed with the following for patients with Type 2 diabetes: 
“The following advice may be useful in helping you to maintain proper hydration and prevent 
dehydration: 
• Dehydration is when your body loses too much fluid, frequently due to diarrhea or 
increased urination. 
• Consider increasing the amount of fluids you drink if. 
• You sense greater thirst than usual. 
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• You have a dry mouth or cracked lips. 
• You have a fever. 
• You have diarrhea or vomiting. 
• You urinate more frequently or in larger amounts than usual. 
• You get up in the middle of the night to urinate (more than usual). 
• You feel dizzy or light-headed. 
• You exercise, or when it is hot outside”. 
Recognizing diabetic ketoacidosis 
Potential gastrointestinal adverse events occurring with sotagliflozin may mask presenting 
symptoms of diabetic ketoacidosis (DKA). Patient communication cards will be printed with the 
following: 
“If you have any of these symptoms on the list, then contact your study site immediately for 
assistance with managing your diabetes: 
• Inability to maintain oral intake. 
• Generalized weakness. 
• Abdominal (belly) pain. 
• Increased weight loss. 
• Fever. 
• Frequent urination, including at night. 
• Fruity-scented breath. 
• Confusion. 
• Acute illness. 
• Consistently elevated blood glucose. 
• Feeling very thirsty or drinking a lot. 
• Nausea or vomiting. 
• Having trouble thinking clearly or feeling tired”. 
It is possible to have DKA even if your blood glucose is not elevated. Regardless of your blood 
glucose level, if you have any of these symptoms on the list, then contact your study site 
regarding the need to be evaluated for possible DKA, which will include specific blood testing. If 
your study site is closed and your study doctor is not available, go to the nearest emergency room 
for evaluation. 
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If you are scheduled for a procedure or surgery that requires you to not take any food or liquids, 
please contact your study doctor for instructions on continuing study drug. In such cases your 
study doctor may advise you NOT to take your study drug from the day prior to the procedure or 
surgery until after the procedure or surgery is complete, and you are taking food and liquids as 
you normally do.” 
Whenever adverse event data are collected or the patient reports DKA or intercurrent illness 
(including infections), generalized weakness, increased weight loss, gastrointestinal symptoms 
including nausea, vomiting, or abdominal pain or other symptoms or signs that the Investigator 
believes may be consistent with DKA, then the site will determine if an assessment for DKA is 
appropriate. If laboratory testing confirms presence of metabolic acidosis, then the “Possible 
DKA” electronic case report form will be completed. 
 
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Appendix C 
Measurement of blood pressure and pulse rate 
Equipment 
1. Blood pressure measurements will be taken by an automated blood pressure (BP) monitor 
or a manual sphygmomanometer. 
2. Bladder Length – Should nearly or completely encircle the patient’s arm. For many adults, 
the standard “adult” size bladder is not long enough and the “large” size bladder is 
recommended. 
3. Bladder Width – Should be at least 40% of the bladder length. 
Patient factors 
Extraneous variables associated with the measurement of BP should be minimized. These include: 
1. Food intake, caffeine-containing beverages, cigarette smoking, or strenuous exercise 
within 2 hours prior to measurement. 
2. Full urinary bladder. 
3. The patient should not be allowed to talk while BP is being measured. 
4. The patient should be placed in the examination room and the cuff should be placed on the 
patient’s arm. The proper sized cuff should fit snugly with the lower edge 2 to 3 cm above 
the antecubital fossa. 
5. The patient should be allowed to sit quietly in a comfortably warm place (temperature 
around 25°C or 77°F) for 5 minutes with the arm supported at heart level, preferably with 
the cuff in place and with no restrictive clothing on the arm. The patient should be 
encouraged not to tense his or her muscles. 
Determination of the reference arm 
At Visit 1 (Week -4), seated BP should be measured in both arms after a 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 the BP should always be measured in this same arm throughout the 
study period. 
Measurement technique 
Following the 5-minute rest period, 3 separate seated BPs should be measured with at least 
1 minute between BP measurements and with the cuff fully deflated between measurements. 
All 3 BPs will be recorded in the patient’s electronic case report form. The mean of the 3 seated 
BPs will constitute the BP value for that visit. 
Three seated pulse rate measurements will be obtained. The mean of the 3 seated pulse rate 
measurements will constitute the pulse rate value for that visit. 
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SAP_001.pdf: 
Official Title: A 26-week Randomized, Double-blind, Placebo-controlled, Parallel-
group, Multicenter, Phase 3 Study with a 78-week Extension Period to 
Evaluate the Efficacy and Bone Safety of Sotagliflozin in Patients 55 
years or Older with Type 2 Diabetes Mellitus and Inadequate Glycemic 
Control 
NCT Number: NCT03386344 
Document Date: SAP Version 3: 31-January-2020 


COVANCE INC. CONFIDENTIAL 
 
 
Page 1 of 90 
 
Lexicon Pharmaceuticals, Inc. 
Protocol No.: EFC15294 
A 26-week Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Multicenter, Phase 3 Study with a 78-week Extension Period to Evaluate the 
Efficacy and Bone Safety of Sotagliflozin in Patients 55 years or Older with Type 2 
Diabetes Mellitus and Inadequate Glycemic Control 
Covance Study ID: 000000155848 
Statistical Analysis Plan  
Version: 3 
DATE OF ISSUE: 30 January 2020 
Author: 
 
 
Lexicon Pharmaceuticals, Inc.  
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Covance Clinical Development Services 
206 Carnegie Center 
Princeton, NJ 08540-6233 
 
 




 
Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
 
VERSION HISTORY 
Version Status 
Version Date 
 Final 1.0 
26 June 2018 
 Final 2.0 
11 October 2018 
 Final 3.0 
30 January 2020 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 4 of 90 
 
 
TABLE OF CONTENTS 
APPROVALS .................................................................................................................................................. 2 
VERSION HISTORY ....................................................................................................................................... 3 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 7 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 9 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 9 
1.2 
OBJECTIVES ................................................................................................................................... 9 
1.2.1 
Primary objectives ............................................................................................................................ 9 
1.2.2 
Secondary objectives ..................................................................................................................... 10 
1.2.3 
Other objectives ............................................................................................................................. 10 
1.3 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 11 
1.4 
STUDY PLAN ................................................................................................................................. 12 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 12 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 12 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 14 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 14 
2.1.1 
Demographic and baseline characteristics .................................................................................... 14 
2.1.2 
Prior or concomitant medications ................................................................................................... 16 
2.1.2.1 
Rescue therapy .............................................................................................................................. 17 
2.1.2.2 
Prohibited prior and concomitant medications ............................................................................... 17 
2.1.3 
Efficacy endpoints .......................................................................................................................... 18 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 18 
2.1.3.2 
Secondary efficacy/safety endpoint(s) ........................................................................................... 18 
2.1.3.3 
Other efficacy endpoint(s) .............................................................................................................. 19 
2.1.4 
Safety endpoints ............................................................................................................................ 19 
2.1.4.1 
Hypoglycemia ................................................................................................................................. 21 
2.1.4.2 
Adverse events variables ............................................................................................................... 23 
2.1.4.3 
Deaths ............................................................................................................................................ 26 
2.1.4.4 
Laboratory safety variables ............................................................................................................ 27 
2.1.4.5 
Vital signs variables ....................................................................................................................... 28 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 5 of 90 
 
 
2.1.4.6 
Physical examination ..................................................................................................................... 28 
2.1.4.7 
Electrocardiogram variables .......................................................................................................... 28 
2.1.4.8 
Bone Mineral Density ..................................................................................................................... 29 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 29 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 31 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 31 
2.3.1 
Efficacy populations ....................................................................................................................... 32 
2.3.1.1 
Intent–to-treat population ............................................................................................................... 32 
2.3.2 
Safety population ........................................................................................................................... 32 
2.4 
STATISTICAL METHODS ............................................................................................................. 33 
2.4.1 
Demographics and baseline characteristics .................................................................................. 33 
2.4.2 
Prior or concomitant medications ................................................................................................... 33 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 34 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 34 
2.4.3.2 
Compliance .................................................................................................................................... 35 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 35 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 36 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 39 
2.4.4.3 
Analyses of other efficacy endpoints ............................................................................................. 40 
2.4.4.4 
Multiplicity issues ........................................................................................................................... 41 
2.4.5 
Analyses of safety data .................................................................................................................. 41 
2.4.5.1 
Analyses of the Bone Mineral Density ........................................................................................... 42 
2.4.5.2 
Analyses of hypoglycemia ............................................................................................................. 45 
2.4.5.3 
Analyses of adverse events ........................................................................................................... 45 
2.4.5.4 
Deaths ............................................................................................................................................ 50 
2.4.5.5 
Analyses of laboratory variables .................................................................................................... 50 
2.4.5.6 
Analyses of vital sign variables ...................................................................................................... 51 
2.4.5.7 
Analyses of electrocardiogram variables ....................................................................................... 52 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 52 
2.5.1 
General conventions ...................................................................................................................... 52 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 53 
2.5.3 
Missing data ................................................................................................................................... 53 
2.5.4 
Windows for time points ................................................................................................................. 56 
2.5.5 
Unscheduled visits ......................................................................................................................... 59 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 59 
2.5.7 
Statistical technical issues ............................................................................................................. 59 
3 
INTERIM ANALYSIS ..................................................................................................................... 60 
4 
DATABASE LOCK ........................................................................................................................ 62 


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5 
SOFTWARE DOCUMENTATION ................................................................................................. 63 
6 
REFERENCES ............................................................................................................................... 64 
7 
LIST OF APPENDICES ................................................................................................................. 65 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 66 
APPENDIX B 
LIST OF PTS FOR SELECT EOSIS (MEDDRA V22.0) ...................................................... 72 
APPENDIX C 
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 83 
APPENDIX D 
STUDY FLOW CHART ........................................................................................................ 87 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE: 
adverse event 
AESI: 
adverse events of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
ATC: 
anatomic class 
BMD: 
bone mineral density 
BMI: 
body mass index 
BUN: 
blood urea nitrogen 
BW: 
body weight 
CEC: 
clinical endpoint committee 
CI: 
confidence interval 
CK: 
creatinine phosphokinase 
CMH: 
Cochran-Mantel-Haenszel 
CSR: 
clinical study report 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DCCT: 
diabetes control and complications trial 
DILI: 
drug-induced liver injury 
DKA: 
diabetic ketoacidosis 
DMC: 
data monitoring committee 
DXA: 
dual-energy X-ray absorptiometry 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration 
EOSI: 
events of special interest 
EOT: 
end of treatment 
FPG: 
fasting plasma glucose 
GLP-1: 
glucagon-like peptide-1 
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 
iPTH: 
parathyroide hormone 
ITT: 
intent-to-treat 
KM: 
Kaplan-Meier 
LDH: 
lactic acid dehydrogenase 


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LDL-C: 
low density lipoprotein cholesterol 
LLT: 
lower level term 
LOCF: 
last-observation-carried-forward 
MACE: 
major adverse cardiovascular events 
MDRD: 
modification of diet in renal disease 
MedDRA: 
medical dictionary for regulatory activities 
MI: 
multiple imputation 
MMRM: 
mixed-effect model with repeated measures 
MNAR: 
missing not at random 
NIMP: 
non-investigational medicinal product 
NTX: 
N-terminal telopeptide 
OC: 
observed case 
P1NP: 
type 1 procollagen N-terminal 
PCSA: 
potentially clinically significant abnomality 
PD: 
pharmacodynamics 
PK: 
pharmacokinetics 
PT: 
preferred term 
PTH: 
parathyroid hormone 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SD: 
standard deviation 
SE: 
standard error 
SERMs: 
selective estrogen receptor modulators 
SGLT2: 
sodium-glucose cotransporter-type2 
SOC: 
system organ class 
T2D: 
type 2 diabetes mellitus 
TB: 
total bilirubin 
TC: 
total cholesterol 
TEAE: 
treatment emergent adverse event 
TG: 
triglycerides 
UACR: 
urinary albumin to creatinine ratio 
ULN: 
upper limit of normal 
WHO-DD: 
World Health Organization-Drug Dictionary 
β-CTX-1: 
beta-C-terminal telopeptide 
  


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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a Phase 3, multicenter, randomized, double-blind (single-blind Run-in Phase), 
placebo-controlled, parallel-group stratified study. 
All patients will have a Screening Period comprised of an up to 2-week Screening Phase and a 
2-week, single-blind placebo Run-in Phase prior to randomization. Following randomization, 
patients will have a 104-week double-blind Treatment Period (26-week double-blind core 
treatment period followed by a 78-week double-blind extension 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 to continue performing their respective study assessments, 
especially HbA1c and BMD, until the time of the last visit planned in the protocol. 
Patients will be centrally randomized (using permuted block randomization schedule) via an 
Interactive Response Technology (IRT) in a 1:1:1 ratio to 1 of the 3 treatment groups: 
 Sotagliflozin 400 mg.  
 Sotagliflozin 200 mg. 
 Placebo. 
The randomization will be stratified by hemoglobin A1c (HbA1c) at the screening visit 
(≤8.5%, >8.5%) and sex (Male, Female).  
It is anticipated to randomize a total of approximately 360 patients (120 per treatment group). 
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 26 in patients with Type 2 diabetes 
mellitus (T2D) who have inadequate glycemic control on diet and exercise only or with a stable 
antidiabetes regimen. 


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1.2.2 Secondary objectives 
The secondary objectives of this study are: 
 To compare the effects of sotagliflozin 400 mg and 200 mg versus placebo with respect to 
the percent change from Baseline to Week 26 in Bone Mineral Density (BMD) (lumbar 
spine, total hip, and femoral neck) measured by dual-energy X-ray absorptiometry (DXA) 
(key secondary safety objective). 
 To demonstrate the superiority of sotagliflozin 400 mg versus placebo on:  
- 
Change from Baseline to Week 26 in body weight (BW), 
- 
Change from Baseline to Week 26 in fasting plasma glucose (FPG), 
- 
Change from Baseline to Week 12 in systolic blood pressure (SBP) for all patients, 
- 
Proportion of patients with HbA1c <7.0% at Week 26. 
 To demonstrate the superiority of sotagliflozin 200 mg versus placebo with respect to: 
- 
HbA1c reduction from Baseline to Week 26, 
- 
Change from Baseline to Week 26 in BW, 
- 
Change from Baseline to Week 26 in FPG, 
- 
Change from Baseline to Week 12 in SBP for all patients, 
- 
Proportion of patients with HbA1c <7.0% at Week 26. 
 To evaluate the safety of sotagliflozin 200 mg and 400 mg compared with placebo over 
the 104 weeks of treatment. 
1.2.3 Other objectives 
Other objectives of this study are to compare the effects of sotagliflozin 200 mg and 400 mg 
versus placebo with respect to: 
 Change from Baseline to Weeks 52 and 104 in HbA1c. 
 Change from Baseline to Weeks 52 and 104 in FPG. 
 Change from Baseline to Weeks 52 and 104 in BW. 
 Proportion of patients with HbA1c <7.0% at Weeks 52 and 104. 
 Proportion of patients starting rescue therapy for hyperglycemia during the 104 weeks of 
treatment. 
 Change from Baseline to Weeks 26 and 104 in SBP for all patients. 
 Change from Baseline to Weeks 12, 26, and 104 in SBP for the subsets of patients with 
Baseline SBP ≥130 mmHg and <130 mmHg, respectively. 


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 Change from Baseline to Weeks 12, 26, and 104 in diastolic blood pressure (DBP) for all 
patients and the subsets of patients with Baseline DBP ≥80 mmHg and <80 mmHg, 
respectively. 
 Changes from Baseline to Weeks 26, 52, and 104 in total body fat mass and total lean 
mass measured by DXA. 
 Changes from Baseline to Weeks 26, 52, and 104 in serum estradiol (only for women). 
 Changes from Baseline to Weeks 26, 52, and 104 in urinary albumin to creatinine ratio 
(UACR). 
 Changes from Baseline to Weeks 26, 52, and 104 on estimated glomerular filtration rate 
(eGFR). 
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size/power calculations were performed based on the primary variable of change from 
Baseline to Week 26 in HbA1c (%). 
Assuming a common standard deviation (SD) of 1.2% and using a 2-sided test at a 0.05 α-level, 
360 patients (120 patients per arm) will have 97% power to detect a treatment difference of 
-0.6% in mean HbA1c change from Baseline to Week 26 between sotagliflozin 400 mg and 
placebo. 
This sample size will also allow to exclude a decline in BMD from Baseline of >2% with a 
95% power, assuming a missing rate of 30% and an SD of 3.5%. 
The total sample size will be approximately 360 patients to be randomized (120 in sotagliflozin 
200 mg group, 120 in sotagliflozin 400 group, and 120 in placebo group). 
Calculations were made using East 6.4 software. 


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1.4 
STUDY PLAN 
 
 
The study flowchart can be found in Appendix D. 
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 statistical section of the protocol was not changed in an amendment. 
The first patient was enrolled on 14-Mar-2018. 
There are no planned interim analyses. 
The study analysis will be conducted in 2 steps. The first step analysis is planned when all patients 
have been randomized and have their data at the minimum up to Week 26 collected and validated. 
The second step will be conducted at the end of the study. 
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.   


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Table 1 - Statistical analysis plan statistical changes 
SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
 
 
 
 
1 
29-Jun-2018 
Clarification on EOSI renal events  
Details specified on renal events to be 
consistent with outcome studies in 
Section 2.1.4.2. 
 
1 
 29-Jun-2018 
 
  
 
 
1 
29-Jun-2018 
 
 
 
 
2 
11-Oct-2018 
Update to be consistent with protocol 
In multiplicity issues, remove “Proportion of 
patients with HbA1c <7.0% at Week 26” for 
both sotagliflozin 400 mg and 200 mg groups. 
3 
This version 
 
 
 
 
 
3 
This version 
Wording change to be consistency 
with CEC charter 
 “Heart failure leading to hospitalization” 
changed to “Heart failure requiring 
hospitalization” 
3 
This version 
MedDRA dictionary updated 
MedDRA version updated to V22.0; list of PTs 
for selected EOSI updated 
3 
This version 
 
 
 
 
 
 
 
3 
This version 
 
 
3 
This version 
 
 
 
3 
This version 
 
 
 
3 
This version 
 
 
 
 
 
 
 
 


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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value (with the exception of serum creatinine and eGFR) is defined as the last 
available value before the first dose of double-blind investigational medicinal product (IMP) or 
the last available value prior to randomization for patients who were randomized but never 
exposed to IMP. 
For serum creatinine and eGFR, the baseline value is defined as average of all values before the 
first dose of double-blind IMP for patients randomized and exposed or before randomization for 
patients 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 (≥55 to <65, ≥65 to < 75, ≥75 years). 
 Gender (Male, Female). 
 Race (White, Black or African American, Asian, American Indian or Alaska native, 
Native Hawaiian or other pacific islander, Multiple, Unknown). 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown). 
 HbA1c (%) at screening visit. 
 Randomization strata of HbA1c (≤8.5%, >8.5%) at screening visit (data from IRT). 
 Randomization strata of Gender (Male, Female) (data from IRT). 
 Mean SBP at screening visit. 
 Mean SBP categories (<130 mmHg, ≥130 mmHg). 
 Baseline body mass index (BMI) (kg/m2) derived as: (Weight in kg)/(Height in meters)2. 
 Baseline BMI categories (<30, ≥30 kg/m2). 
 Baseline BMD T-score (lumbar spine, total hip, or femoral neck). 
 Mean serum 25-hydroxyvitamin D at screening visit. 
 Country. 


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Disease characteristics at screening or Baseline 
Disease history includes: 
 Duration of diabetes (years) derived as: (Date of informed consent – Date of diagnosis of 
diabetes + 1)/365.25. 
 Duration of diabetes categories: (<10, ≥10 years). 
 Age at diagnosis of diabetes (years) derived as: Year of diagnosis of diabetes – Year of 
Birth. 
 Prior antidiabetic medication (in monotherapy or combination):  
      -    No antidiabetic therapy, 
- 
Insulin (alone or with OADs),  
- 
SU and/or glinide (alone or with other OADs),  
- 
Metformin (alone or with OADs other than SU and glinide),  
- 
OADs other than SU, glinide and metformin, 
- 
GLP-1 receptor agonist. 
 Prior antidiabetic medication: 
      -    No antidiabetic therapy, 
- 
Insulin (alone or with other antihyperglycemic agents),  
- 
SU and/or glinide (alone or with other non-insulin antihyperglycemic agents),  
- 
Other (non-insulin antihyperglycemic agents except SU and glinide). 
 Baseline diabetic microvascular complications (Yes, No) (ie, diabetic retinopathy, diabetic 
neuropathy and diabetic nephropathy, diabetic peripheral neuropathy (sensory or motor), 
diabetic autonomic neuropathy, and diabetic foot infection). 
 Baseline UACR categories (<30 mg/g [Normal], ≥30 to <300 mg/g [Microalbuminuria], 
and ≥300 mg/g [Macroalbuminuria]). 
 eGFR at screening (mL/min/1.73m2). 
 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). 


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Medical or surgical history 
Medical history and medical findings include: 
 Physical examination. 
 Medical or surgical history. 
 Medical history cardiovascular. 
 Surgical history amputation. 
 Alcohol habits. 
 Tobacco smoking habits. 
Medical and surgical history will be coded to a “lower level term (LLT)”, “preferred term (PT)”, 
“high level term (HLT)”, “high level group term (HLGT)”, and associated primary “system organ 
class (SOC)” using the version of Medical Dictionary for Regulatory Activities (MedDRA) 
currently in effect at Covance at the time of database lock. 
Any technical details related to computation, dates and imputation for missing dates are described 
in Section 2.5.  
2.1.2 Prior or concomitant medications 
All medications taken within 3 months before the screening visit (any time for prior SGLT2) and 
until the end of the study are to be reported in the electronic case report form (e-CRF) pages. 
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 investigational medicinal product 
(IMP) intake.  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 first administration of double-blind IMP to the date of last administration of 
double-blind IMP + 10 days. A given medication can be classified both as a prior 
medication and as a concomitant medication.   
 Posttreatment medications are those the patient took in the period running from the 
11th day after the last administration of double-blind IMP up to the end of the study. 
Background therapy consisting of a stable antidiabetes regimen in monotherapy or combination 
therapy (including oral antidiabetes medications, insulin, or GLP-1 agonists) for more than 
12 weeks are considered as noninvestigational medicinal products (NIMP). 
Any technical details related to computation, dates imputation for missing dates are described in 
Section 2.5. 


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2.1.2.1 Rescue therapy 
Except for SGLT2 inhibitors and thiazolidinediones, any approved medication(s) including oral 
antidiabetic drugs or insulin can be prescribed to treat the hyperglycemia at the discretion of the 
investigator. Rescue therapy is considered a noninvestigational medicinal product (NIMP). 
2.1.2.2 Prohibited prior and concomitant medications 
During the study, the following medications are prohibited: 
 Initiation of any antidiabetes agents, including oral or injectable antihyperglycemic agents 
other than the IMP and NIMP is not allowed before the rescue therapy. The existing 
background medication (NIMP) should not be modified before the rescue. 
Note: short term use (<10 consecutive days) of the prohibited medication, eg, short-acting insulin 
for treatment of acute illness or surgery is allowed. 
 SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin) and 
thiazolidinediones (eg. pioglitazone, rosiglitazone) are not allowed for rescue. 
 Systemic use of glucocorticoids for more than 10 consecutive days within 90 days prior to 
the Screening Visit (Note: topical, intra-articular, ophthalmic, nasal spray, or inhaled 
applications are allowed). 
 Investigational medication products in any other clinical study 
 Modification of antihypertensive medication before Week 12 is not allowed unless for 
safety reasons. 
 Initiation of any weight loss drugs (eg, phentermine, orlistat, lorcaserin, 
phentermine/topiramate, naltrexone/bupropion, liraglutide). 
 Initiation of medication known to affect bone mass or modify the risk of fractures: 
- 
Bisphosphonates, selective estrogen receptor modulators (SERMs), calcitonin, 
teriparatide, denosumab, strontium ranelate, growth hormone, 
- 
Androgen deprivation therapy, 
- 
Aromatase inhibitors, 
- 
Anticonvulsants (eg. carbamazepine, phenytoin and phenobarbital), 
- 
Hormone replacement therapy (systemic or transdermal) that includes estrogens or 
androgens. 
Reduction of digoxin dose should be considered because sotagliflozin acts as a weak P-gp 
inhibitor and increases systemic exposure to digoxin. 
Other medications which are unlikely to interfere with the pharmacokinetics (PK) or 
pharmacodynamics (PD) of the IMP or confound interpretation of the study endpoints are allowed 
as needed following discussion between the Investigator and the Sponsor/CRO. 


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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. 
It is recommended that patients receiving calcium or vitamin D at the time of screening, or 
initiating supplementation during the study, should maintain as stable a dose as possible 
throughout the study. Patients receiving replacement therapy with estrogen or testosterone for 
more than 24 months at the time of screening should also be advised to maintain stable dose for 
the duration of the study, unless if required for safety reasons. 
2.1.3 Efficacy endpoints 
All efficacy measurements collected during the study will be considered for analyses, including 
those obtained after IMP discontinuation or introduction of rescue therapy (see Section 2.5.4). 
HbA1c, FPG, UACR, eGFR and serum estradiol are measured/calculated in a central laboratory 
(see study flowchart in Appendix D). Body weight, SBP and DBP (see Section 2.1.4.5) are 
measured at on-site visits by the investigator. Patients requiring rescue are identified as those with 
the reason for treatment ticked “rescue therapy” in e-CRF “Medication” page. 
Efficacy variables will be summarized in both standard international units and conventional units 
when applicable. 
2.1.3.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is the change from Baseline to Week 26 in HbA1c (%) comparing 
sotagliflozin 400 mg versus placebo. 
2.1.3.2 Secondary efficacy/safety endpoint(s) 
2.1.3.2.1 Key Secondary safety endpoint(s) 
The key secondary safety endpoint is the percent change from Baseline to Week 26 in BMD 
(lumbar spine, total hip, and femoral neck). 
Analysis of key secondary safety endpoints are detailed in Section 2.4.5.1 . 
2.1.3.2.2 Secondary efficacy endpoint(s) 
The main secondary efficacy endpoints are: 
 Change from Baseline to Week 26 in HbA1c (sotagliflozin 200 mg only). 
 Change from Baseline to Week 26 in BW. 
 Change from Baseline to Week 26 in FPG. 
 Change from Baseline to Week 12 in SBP for all patients. 
 Proportion of patients with HbA1c <7.0% at Week 26. 


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2.1.3.3 Other efficacy endpoint(s) 
The other secondary efficacy endpoints are: 
 Change from Baseline to Weeks 52 and 104 in HbA1c. 
 Change from Baseline to Weeks 52 and 104 in FPG. 
 Change from Baseline to Weeks 52 and 104 in BW. 
 Proportion of patients with HbA1c <7.0 % at Weeks 52 and 104. 
 Proportion of patients starting rescue therapy during the 104 weeks of treatment. 
 Change from Baseline to Weeks 26 and 104 in SBP for all patients. 
 Change from Baseline to Weeks 12, 26, and 104 in SBP for the subsets of patients with 
Baseline SBP <130 mmHg and ≥130 mmHg, respectively. 
 Change from Baseline to Weeks 12, 26, and 104 in DBP for all patients and the subsets of 
patients with Baseline DBP ≥80 mmHg and <80 mmHg, respectively. 
 Change from Baseline to Weeks 26, 52, and 104 in total body fat mass and total lean mass 
measured by DXA. 
 Change from Baseline to Weeks 26, 52, and 104 in serum estradiol (only for women). 
 Change from Baseline to Weeks 26, 52, and 104 in UACR. 
 Change from Baseline to Weeks 26, 52, and 104 in eGFR. 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events, hypoglycemia, adjudicated bone 
fractures, and other safety information, such as BMD data measured by DXA, clinical laboratory 
data (including bone turnover markers and markers of calcium metabolism), vital signs, 
electrocardiogram (ECG), and physical examination, etc. 
The following safety endpoints will be assessed throughout the 104 weeks of double-blind 
treatment: 
 Adverse events, hypoglycemia (all, severe, and/or documented symptomatic 
hypoglycemia), EOSI, adverse events of special interest (AESI), AEs leading to 
discontinuation of IMP, SAEs, and deaths. 
 Percent change from Baseline to Weeks 26, 52 and 104 in BMD (lumbar spine, total hip, 
and femoral neck).  
 Proportion of patients with adjudicated bone fractures over 104 weeks. 
 Proportion of patients with ≥3% decline in BMD at Week 104.  
 Changes from Baseline in bone turnover markers to Week 26, 52, and 104 (serum bone 
resorption markers: N-terminal telopeptide of Type 1 collagen [NTX] and β-CTX-1; 
serum bone formation markers: P1NP and osteocalcin). 


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 Changes from Baseline in markers of calcium metabolism to Week 26, 52, 
and 104 (serum: calcium, phosphorus, magnesium, parathyroid hormone [iPTH], 
25- hydroxyvitamin D and 1,25-dihydroxyvitamin D; urinary: calcium, phosphorus and 
magnesium). 
 Clinical laboratory results, vital signs results, and 12-lead ECG. 
Observation period  
The observation period starts from the time when the patient gives informed consent and 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-bind 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-bind IMP. This epoch includes 
the 26-week double-blind core treatment period and the 78-week double-blind extension 
treatment period. The 26-week double-blind core treatment period is the time from the first 
administration of double-blind IMP to the last administration of double-blind IMP on or 
before Visit 8/Week 26 (or Day 182 if Visit 8/Week 26 date is missing). 
 The residual treatment epoch is defined as the time from the last administration of the 
double-bind IMP up to 10 days (1 day for hypoglycemia) after the last administration of 
the double-bind IMP. 
The treatment-emergent adverse event (TEAE) period will include both treatment and 
residual treatment epochs. (See the TEAE period for the 26-week core treatment period in 
Section 2.5.4). 
 The posttreatment epoch is defined as the period of time starting the day after the end of 
the treatment-emergent adverse event period up to the last protocol-planned visit or the 
resolution/stabilization of all serious adverse events (SAE), adverse events of special 
interest (AESI) and events of special interest (EOSI), whichever is later. 
The on-study observation period is defined as the time from start of double-blind treatment until 
the end of the study (defined as the last scheduled visit for those who completed the study and the 
date collected on e-CRF page “Completion of End of Study/Follow-up” for those who did not 
complete the study). 
The post-study observation period is defined as the time from the day after the end of the study 
until the resolution/stabilization of all SAE, AESI and EOSI if applicable. 


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Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
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2.1.4.1 Hypoglycemia 
Hypoglycemia will be identified as events recorded on the dedicated e-CRF “Hypoglycemic event 
information” page, and will be categorized as follows (see study protocol for further details): 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, intravenous glucose or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. 
Self-monitored plasma glucose values may not be available, but neurological recovery attributable 
to the restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. 
Severe hypoglycemia is identified in e-CRF “Hypoglycemic event” page as those documented as, 
1. To the question “Countermeasure Administration”, ticked the option “Subject was Not 
Capable of Treating Self and Required Assistance”, and  
2. To the question “Were Symptoms Present”, ticked “Yes”. 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L 
(≤70 mg/dL). 
Clinical symptoms that are considered to result from a hypoglycemic episode are eg, increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
Documented symptomatic hypoglycemia is identified in e-CRF “Hypoglycemic event” page as 
those documented as, 
1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and  
2. To the question “Were Symptoms Present”, ticked “Yes”, and  
3. With a plasma glucose value before countermeasure ≤3.9 mmol/L (≤70 mg/dL).  
Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL). 


Statistical Analysis Plan 
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Date of Issue: 30 January 2020 
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Asymptomatic hypoglycemia is identified in e-CRF “Hypoglycemic event” page as those 
documented as, 
1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and 
2. To the question “Were Symptoms Present”, ticked “No”, and  
3. With a plasma glucose value before countermeasure ≤3.9 mmol/L (≤70 mg/dL).  
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms of hypoglycemia are not 
accompanied by a plasma glucose determination, (but that was presumably caused by a plasma 
glucose concentration ≤3.9 mmol/L [≤70 mg/dL]), ie, symptoms treated with oral carbohydrate 
without a test of plasma glucose. 
Probable symptomatic hypoglycemia is identified in e-CRF “Hypoglycemic event” page as those 
documented as, 
1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, and 
2. To the question “Were Symptoms Present”, ticked “Yes”, and 
3. With no plasma glucose value before countermeasure, and  
4. To the question “Did this countermeasure lead a significant improvement or prompt 
recovery?”, ticked “Yes”. 
Relative hypoglycemia 
Relative hypoglycemia, recently termed “pseudo-hypoglycemia” is an event during which the 
patient reports typical symptoms of hypoglycemia, and interprets the symptoms as indicative of 
hypoglycemia, but with a measured plasma glucose concentration >3.9 mmol/L (>70 mg/dL). 
Relative hypoglycemia is identified in e-CRF “Hypoglycemic event” page as those documented 
as, 
1. To the question “Countermeasure Administration”, NOT ticked the option “Subject was 
Not Capable of Treating Self and Required Assistance”, 
2. To the question “Were Symptoms Present”, ticked “Yes”, and  
3. With a plasma glucose value before countermeasure >3.9 mmol/L (>70 mg/dL).  
In addition of the threshold of ≤3.9 mmol/L (≤70 mg/dL), hypoglycemia episodes with a plasma 
glucose of <3.0 mmol/L (<54 mg/dL) will be analyzed separately.  
Any hypoglycemic event fulfilling the criteria of a SAE or leading to unconsciousness, coma, or 
seizure will also be recorded as a SAE (see Section 2.1.4.2). 


Statistical Analysis Plan 
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Date of Issue: 30 January 2020 
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2.1.4.2 Adverse events variables 
Adverse event observation period  
 Pretreatment adverse events are adverse events that developed or worsened or became 
serious from the signed informed consent date up to first administration of double-blind 
IMP. 
 Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the TEAE 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 Medical Dictionary for Regulatory 
Activities (MedDRA) currently in effect at Covance at the time of database lock. 
The occurrence of adverse events (including SAE, AESI and EOSI) will be recorded from the 
time of signed informed consent until the end of the study (see Section 2.1.4) or the 
resolution/stabilization of all SAE, AESI and EOSI. 
AESI include: 
 Pregnancy. 
 Symptomatic overdose with IMP/NIMP. 
 Alanine aminotransferase (ALT) increase >3 times upper limit of normal (ULN). 
EOSI include:  
 Major adverse cardiovascular events (MACE [cardiovascular death, myocardial infarction, 
or stroke]) and other specific cardiovascular (CV) events (eg, heart failure requiring 
hospitalization).   
 Severe hypoglycemia. 
 Genital mycotic infections (to include vulvovaginal candidiasis in females and candida 
balanitis in males). 
 Urinary tract infection. 
 Clinically relevant volume depletion and events related/possibly related to volume 
depletion. 
 Diarrhea. 
 Pancreatitis. 
 Bone fractures. 


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 Venous thrombotic events, to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism). 
 Diabetic ketoacidosis (DKA). 
 Renal events, to include 50% decline in eGFR, end stage kidney disease, renal death. 
 Malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, 
prostate, and thyroid cancer). 
 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 DKA. 
Two independent committees will review safety events that require ongoing monitoring in a 
blinded manner. 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 2.  
Table 2 – 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?” 


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AE Grouping 
Criteria 
EOSI Renal events where select events adjudicated 
Sustained ≥50% decrease in 
eGFR 
(1) For ≥50% decrease in eGFR from Baseline, 
      (1a) confirmed ≥50% decrease in GFR for ≥30 days with no reversible cause as 
recorded in eCRF “eGFR decrease”, OR  
      (1b) positively adjudicated by CEC: Yes to the question “Does the subject meet the 
criteria of CKD progression” for ≥50% decrease in eGFR. 
Sustained eGFR 
<15 mL/min/1.73 m2 
(2) For eGFR <15 mL/min/1.73 m2, 
       (2a) confirmed eGFR <15 mL/min/1.73 m2 for ≥30 days with no reversible cause as 
recorded in eCRF “eGFR decrease”, OR 
       (2b) positively adjudicated by CEC: Yes to the question “Does the subject meet the 
criteria of CKD progression”. 
Chronic dialysis 
(3) For dialysis,  
      (3a) dialysis lasted for ≥90 days (eg, 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 


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AE Grouping 
Criteria 
Malignancies of special interest Breast cancer: Narrow search on “Breast neoplasms, malignant and unspecified (SMQ)” 
[20000149] 
Prostate cancer: Narrow search on “Prostate neoplasms, malignant and unspecified (SMQ)” 
[20000152] 
Leydig-cell cancer: PTs of Leydig cell tumour of the testis (10024407) and Ovarian 
Sertoli-Leydig cell tumour (10073270) based on MedDRA v22.0 
Thyroid cancer: PTs in Appendix 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 one of EOSI defined in protocol, included and analyzed due to their relevance in regards to lower 
limb complications and amputations as an requirement from health authorities. 
2.1.4.3 Deaths 
The death observation periods are per the observation periods defined below.  
 Death on-study:  deaths occurring during the on-study observation period. 
 Death on TEAE period:  deaths occurring during the TEAE period. 
 Death post-treatment: deaths occurring after the treatment-emergent adverse event period 
until the end of the on-study period. 


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2.1.4.4 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, 
amylase, lipase, lipide profile and urinalysis.  Clinical laboratory values after conversion will be 
analyzed into standard international units and conventional units when applicable. 
Blood samples for clinical laboratories will be collected at designated visits (see study flowchart 
in Appendix D). The following laboratory data will be measured at a central laboratory:  
 Hematology: 
- 
Red blood cells and platelets:  hemoglobin, hematocrit, red blood cell, platelets 
count,  
- 
White blood cells:  white blood cell, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils. 
 Clinical chemistry:  
- 
Metabolism:  glucose (serum), creatine phosphokinase (CK),        
- 
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, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TB), 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. 
 Markers of bone and calcium metabolism:  
- 
Calcium,  
- 
Phosphorus,  
- 
Magnesium 
- 
25-hydroxyvitamin D,  
- 
1,25-dihydroxyvitamin D,  
- 
Parathyroid hormone (PTH),  
- 
Markers of bone resorption: N-terminal telopeptide (NTX), beta-C-terminal 
telopeptide (β-CTX-1),  
- 
Marker of bone formation: Type 1 procollagen N-terminal (P1NP), osteocalcin. 


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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. 
 Urine albumin, calcium, phosphorus, magnesium and creatinine (24-hour urine collection). 
Serum glucose, calculated UACR and serum estradiol (for women) will be presented as efficacy 
parameters in Section 2.4.4. For creatinine and calculated eGFR, Potentially Clinically Significant 
Abnormality (PCSA) summaries will be presented in the safety section while descriptive 
summaries in the efficacy section. 
Technical formulas are described in Section 2.5.1. 
2.1.4.5 Vital signs variables 
Vital signs include:  heart rate (HR), systolic and diastolic blood pressure, temperature, and 
respiratory rate (see study flowchart in Appendix 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) Visit 8 (Week 26) and 
Visit 13 (Week 104). “Normal”, “Abnormal” or “Not done” as determined by the Investigator will 
be reported in the e-CRF by body system. 
2.1.4.7 Electrocardiogram variables 
12-lead ECGs will be performed at Visit 2 (Run-in), Visit 8 (Week 26) and Visit 13 (Week 104). 
ECG status of “normal” or “abnormal” will be reported in the e-CRF as determined by the 
investigator. 


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2.1.4.8 Bone Mineral Density 
Bone mineral density at lumbar spine, total hip, and femoral neck will be assessed in all patients 
using DXA. Baseline DXA scans for BMD assessment will be performed during run-in (between 
week -2 [Visit 2] and Baseline [Visit 3]) and centrally reviewed to confirm eligibility. To assess 
percent change from Baseline in BMD, post-Baseline DXA scans will be performed within 
2 weeks prior to the on-site visits at week 26 (Visit 8), week 52 (Visit 10), and week 104 
(Visit 13). In exceptional situations, if justified based on Investigator’s assessment, the DXA scan 
can be performed up to a maximum of 7 days after the scheduled visit. All BMD assessments will 
be performed locally with central review. 
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. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table: 
 Screened patients. 
 Run in patients: patients who has a run-in kit allocated and recorded in IRT database. 
 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 complete the 26-week double-blind core treatment period (see Section 2.5.4) 
as scheduled. 
 Patients who did not complete the 26-week double-blind core treatment period as 
scheduled and the reasons for permanent treatment discontinuation. 
 Patients who complete the 104-week double-blind entire treatment period as scheduled. 
 Patients who did not complete the 104-week double-blind entire treatment period as 
scheduled and the reasons for permanent treatment discontinuation. 
 Patients who complete the study as scheduled. 


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 Patients who did not complete the study as scheduled and the reasons for study 
discontinuation. 
 Patients’ end of study status at Week 26 (ongoing, discontinued) and corresponding end of 
26-week core treatment status (ongoing, discontinued). 
 Patients' end of study status (completed, not completed) and corresponding end of entire 
treatment status (completed, not completed). 
 Status at last study contact. 
For screened, run in, screen failure, and nonrandomized but treated patients, percentages will be 
calculated using the number of screened patients as the denominator. All other categories of 
patients will be presented by treatment group and the percentages will be calculated using the 
number of randomized patients within each treatment group as the denominator. Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages by treatment 
group. Patients prematurely discontinued from treatment and/or study, along with reasons for 
discontinuation, will also be listed. 
A summary of the distribution of patients by country and center will also be provided (overall 
number of patients screened, run-in, randomized, , as well as number of patients randomized and 
treated, discontinued from study treatment, and discontinued from study for each treatment for 
overall patients and by 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 patient 
randomized but not treated as randomized will be part of efficacy and safety analyses 
(see Section 2.3). Patients randomized but not treated will be included in efficacy analysis. 
Safety data of patients treated but not randomized will be reported separately. 
The randomization strata [HbA1c at Screening (≤8.5%, >8.5%) and sex (Male, Female) 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 respectively will be provided for the 104-week double-blind entire 
treatment period only (see Section 2.5.4). A listing of these patients, along with the reason for 
discontinuation treatment, study completion status and the reason for discontinuation study, will 
be provided.  
All important deviations including randomization and drug dispensing irregularities will be 
summarized in tables giving numbers and percentages of deviations by randomized treatment 
group. 
Additionally, the analysis populations for safety and efficacy defined in Section 2.3 will be 
summarized in a table by number of patients on the randomized population.  
 Efficacy population: intent-to-treat (ITT) population. 


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 Safety population. 
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, c) a patient is randomized twice, or d) in a dynamic randomization 
scheme the treatment assignment is, in fact, not random, due to a computer program error.  
 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
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 appendix. 
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
Randomization and drug allocation irregularities 
Kit dispensation without IRT transaction 
Erroneous kit dispensation 
Kit not available 
Randomization by error 
Patient randomized twice 
Stratification error 
Patient switched to another site 
2.3 
ANALYSIS POPULATIONS 
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population.   
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 


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For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
2.3.1 Efficacy 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. 
2.3.2 Safety population 
Safety analyses will be based on the safety population, defined as all randomized patients who 
actually receive at least one dose of double-blind IMP (regardless of the amount of treatment 
administered). Patients will be analyzed according to the treatment actually received.  
In addition:  
 Nonrandomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately. 
 Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized. 
 When a patient is exposed to both sotagliflozin and placebo, the patient will be analyzed in 
the appropriate sotagliflozin group (depending on the treatment kits taken [400 mg or 
200 mg]). 
 When a patient is exposed to both sotagliflozin 400 mg (treatment kits) and 200 mg 
(treatment kits), the patient will be analyzed in the sotagliflozin 200 mg group. 
 Randomized patients will be excluded from the safety population only if there is 
documented evidence (ie, all study dates recorded as no medication taken) that patients 
have not taken the study treatment. If a patient is dispensed double-blind IMP and is lost to 
follow-up without any documented evidence, the patient will be considered exposed. 


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2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
Continuous data will be summarized using the number of observation available (N), mean, 
standard deviation (SD), median, minimum, and maximum for each treatment group.  Categorical 
and ordinal data will be summarized using the count and percentage of patients in each treatment 
group. 
Parameters will be summarized on the randomized population analyzed in the treatment group to 
which they were randomized.  Analyses for the safety population will be included in the 
appendices if the size of the safety population is different (>10%) from the size of that in the 
primary analysis population for any treatment group. 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall 
treatment groups using descriptive statistics.  
Medical/surgical history will be classified into primary system organ class (SOCs) and HLTs 
using MedDRA and will be summarized by treatment groups. Events will be sorted by SOC 
internationally agreed order and decreasing frequency of HLT based on incidence in the overall 
treatment group. 
P-values on the treatment difference for the demographic and baseline characteristic data will not 
be calculated.  
In general, no specific description of the safety parameters will be provided at Baseline.  
If relevant, the baseline values will be described along with each safety analysis. 
In general, no specific description of the efficacy parameters will be provided at Baseline.  
If relevant, the baseline values will be described along with each efficacy analysis. 
2.4.2 Prior or concomitant medications 
The prior, concomitant and posttreatment medications will be presented in the randomized 
population for each treatment group (and overall for the summary of prior medications), using 
counts and percentages. No statistical test for the between-group difference will be performed. 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic therapeutic category (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 patients will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. Therefore patients may be counted several times for the same 
medication.  


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Prior medications will be presented by anatomic and therapeutic categories and sorted by 
decreasing frequency of ATC based on the overall incidence across treatment groups.  In case of 
equal frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be 
used. 
Concomitant and posttreatment medications will be presented by anatomic and therapeutic 
categories and sorted by decreasing frequency of ATC based on the incidence in the sotagliflozin 
400 mg group. In case of equal frequency regarding ATCs (anatomic or therapeutic categories), 
alphabetical order will be used.  
Antidiabetic medications will be presented separately by pharmacological class, chemical class 
and standardized medication name. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure. 
Duration of IMP exposure is defined as last dose date of double-blind IMP – first dose date of 
double-blind IMP + 1 day, regardless of unplanned intermittent discontinuations 
(see Section 2.5.3  for calculation in case of missing or incomplete data).   
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number of 
patients exposed, mean, SD, median, minimum, and maximum) during the 26-week core 
treatment period and 104-week entire treatment period, respectively.  In addition, duration of 
treatment exposure will also be summarized categorically by numbers and percentages for each of 
the following categories and cumulatively according to these categories:  
 1 to 28 days. 
 29 to 56 days. 
 57 to 84 days. 
 85 to 126 days. 
 127 to 182 days. 
 183 to 364 days. 
 365 to 551 days. 
 552 to 728 days. 
 >728 days. 
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient years. 


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Number and percentage of patients by final dose at the end of the treatment will also be presented 
by each treatment group. 
2.4.3.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol.  No imputation will be made for patients with 
missing or incomplete data.  
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 double-blind 
IMP during the treatment epoch defined in Section 2.1.4 (ie, from the first date to the last date of 
double-blind IMP administration).  
Above-planned dosing percentage for a patient will be defined as the number of days that the 
patient took a higher dose than planned divided by the total number of days that the patient was 
planned to take double-blind IMP 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 double-blind IMP during the treatment epoch.  
Treatment compliance, above-planned, and under-planned dosing percentages will be summarized 
descriptively as quantitative variables (number, mean, SD, median, minimum, and maximum).  
The percentage of patients whose compliance is <80% will be summarized.  In addition, numbers 
and percentages of patients with at least 1 day above-planned dose will also be provided, as well 
as numbers and percentages of patients with 0, (0, 20%], and >20% of days under-planned dose 
administrations. 
Cases of overdose (see study protocol for further details) will constitute AEs/SAEs and will be 
listed 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 (de facto estimand), unless otherwise specified.  
Statistical testing will be performed for primary endpoint and secondary endpoints at Week 26 
(or Week 12 for SBP).  The superiority tests will be two-sided tests at nominal 5% significance 
level. All efficacy endpoints, other than primary and main secondary efficacy endpoints, will only 
be summarized by descriptive statistics without formal statistical testing. 
Missing data for efficacy analyses is identified through steps described in Section 2.5.4. 


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2.4.4.1 Analysis of primary efficacy endpoint(s) 
Primary analysis 
The primary efficacy endpoint of change in HbA1c from Baseline to Week 26 will be analyzed by 
an Analysis of Covariance (ANCOVA) model using HbA1c values measured at Baseline and 
Week 26 (observed or imputed). The missing data at endpoint will be imputed by multiple 
imputation (MI) methods as detailed below. To be concise, the following texts related to 
imputation are generalized to accommodate primary as well as continuous secondary efficacy 
endpoints. 
Missing endpoint data at Week 26 (or Week 12 for SBP) visit will be imputed using a model built 
separately in each treatment group and estimated from the patients in the same treatment group 
who prematurely discontinue the IMP before the Week 26 (or Week 12 for SBP) visit but have the 
measurement for the endpoint (ie, retrieved dropouts). The imputation model will include the 
randomization strata and the corresponding baseline value. In cases of non-convergence during 
the imputations, the offending stratum will be identified and then will be dropped from the model. 
Considering that the number of retrieved dropout patients in each treatment group is expected to 
be small, a simple imputation model based on regression will be used with baseline measurement 
included as the predictor. This will serve as the primary method of imputation for missing data 
should sampling criteria be satisfied (see below). 
An alternative (back-up) imputation method will be used if the number of patients who 
prematurely discontinue the IMP before the Week 26 (or Week 12 for SBP) visit but have the 
measurement for the endpoint is < 5 in any treatment groups (ie, an insufficient number of 
retrieved dropouts to support the imputation method described above). This criterion will be 
assessed for each primary or continuous secondary efficacy endpoint. 
In the back-up imputation method, missing post-Baseline endpoint values at Week 26 (or Week 
12 for SBP) will be imputed by the washout Multiple Imputation (MI) method under the missing 
not at random (MNAR) framework.  
Missing endpoint data at the Week 26 (or Week 12 for SBP) in all treatment groups (sotagliflozin 
400 mg, sotagliflozin 200 mg and placebo) are imputed from a model estimated from patients in 
the placebo group who have the endpoint data available.  
For patients in the sotagliflozin groups with missing data at Week 26 (or Week 12 for SBP), their 
missing values will be imputed using observed baseline and the observed primary endpoint data 
from placebo completers; no intermittent values from either placebo or the active treatment 
groups will be used.  
For placebo patients, missing data will be imputed based on the placebo group data. Intermittent 
observed values will be used while imputing missing values at Week 26 (or Week 12 for SBP). In 
cases that a non-monotone missing data pattern occurs at the intermediate visits, these data points 
will be first imputed in the placebo group using the Markov Chain Monte Carlo (MCMC) option 
in PROC MI to achieve a monotone missing pattern for all placebo patients.  The Week 26 (or 
Week 12 for SBP) endpoint values will be subsequently imputed from the multiple copies of the 
original dataset where each copy will have a monotone missing pattern. 


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The imputation models for the washout MI method will include the randomization strata and the 
corresponding baseline value. Missing data will be imputed using the regression method.  In cases 
of non-convergence during the imputations, especially for the MCMC application in the placebo 
non-monotone datasets, graphical measures (eg, trace and autocorrelation plots) will be used to 
identify the offending variable and once detected, that variable(s) will be dropped from the model 
and the imputations will be re-run. These re-run models will use the same seed number and 
number of imputations as used in the original models.          
Using either imputation method, missing endpoint data will be imputed 2000 times to generate 
multiple data sets with complete data. Other details of the imputation procedures such as the seed 
number and sort ordering are specified in the SAS programs. The HbA1c change from Baseline to 
Week 26 will be derived from observed and imputed HbA1c values at Week 26.  
Each of the completed datasets after the imputation will be analyzed using the Analysis of 
Covariance (ANCOVA) model with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, 
placebo), randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of sex (male, 
female), and country as fixed factors, and baseline value of the efficacy endpoint as a covariate.  
Results from each analysis will be combined using Rubin’s formula, to provide the adjusted mean 
change in HbA1c from Baseline to Week 26 (or Week 12 for SBP) for each treatment group, as 
well as the between-group difference (comparing sotagliflozin 400 mg or sotagliflozin 200mg, 
respectively, versus placebo) and its associated 95% confidence interval (CI). 
Sensitivity analyses 
Tipping point analysis based on the same MI method as applied to primary analysis will be 
performed to examine the robustness of the results from the primary analysis. Patients who were 
randomized to sotagliflozin 400 mg group and had no HbA1c data at Week 26 will be given a 
penalty. The penalty will be gradually increased to evaluate at which level the conclusion of the 
analyses in terms of statistical significance is changed. The tipping point is the penalty level, at 
which the magnitude of efficacy reduction in patients without HbA1c data at Week 26 creates a 
shift in the treatment effect of sotagliflozin 400 mg from being statistically significantly better 
than placebo to a non-statistically significant effect. LS mean difference between sotagliflozin  
400 mg and placebo and its associated p-value 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 same MI method as applied for primary analysis, 
2. The imputed HbA1c value at Week 26 in the sotagliflozin 400 mg group will be penalized  
by adding a penalty δ (eg, δ = 0.1%) in each complete dataset, 
3. Change from Baseline at Week 26 in HbA1c will be analyzed using the same ANCOVA 
model as specified in the primary analysis in each complete dataset, 
4. Results will be combined across complete datasets using Rubin’s 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. 


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The above tipping point analysis will be replicated to examine the robustness of the treatment 
effect of sotagliflozin 200 mg (ie, adding penalty to the sotagliflozin 200 mg group instead of  
sotagliflozin 400 mg group in Step 2).  
The tipping point analysis will be performed on the ITT population. The tipping point analyses 
will be performed only if the corresponding primary or secondary endpoints (change from 
Baseline to Week 26 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 to the tipping point analyses, if the retrieved dropout imputation is applied to the 
primary analysis, the analysis based on the washout imputation method (ie, the backup imputation 
method) will be presented as a sensitivity analysis. 
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 ( <65, ≥65 years), 
 Gender (Male, Female). 
 Baseline BMI level (<30, ≥30 kg/m²). 
 Baseline HbA1c (≤8.5%, >8.5%). 
 Baseline mean SBP (<130 mmHg, ≥130 mmHg). 
 Baseline eGFR (≥30 to <60 mL/min/1.73m2 [Moderate decrease in GFR], ≥60 to 
<90 mL/min/1.73m2 [Mild decrease in GFR], and ≥90 mL/min/1.73m2 [Normal]). 
 Duration of diabetes (<10, ≥10 years). 
 Prior antidiabetic medication [No antidiabetic therapy, Insulin (alone or with other 
antihyperglycemic agents), SU and/or glinide (alone or with other non-insulin 
antihyperglycemic agents), other (non-insulin antihyperglycemic agents except SU, and 
glinide)]. 
 Country. 
The treatment effects (sotagliflozin 400 mg and sotagliflozin 200mg, respectively, versus placebo) 
across the subgroups defined for each of these factors will be estimated for the change from 
Baseline to Week 26 in HbA1c in the ITT population, and using the same MI method as applied 
to the primary analysis.  
The ANCOVA model will include treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, 
placebo), randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of sex 


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(male, female), 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 and sotagliflozin 200 mg versus placebo) with SE and 95% 
CIs will be provided as appropriate across the subgroups. A forest plot of the results will also be 
presented. 
In the case that the subgroup factor is identical or similar to a randomization strata factor 
(eg, baseline HbA1c category or sex), only the subgroup factor (as a single factor and/or an 
interaction term) will be included in the model in order to avoid the issue of collinearity in the 
analysis. The corresponding strata factor will not be included in the model. 
Summary statistics at scheduled visits 
Summary statistics (for screening value, baseline value, observed post-Baseline value and its 
changes from Baseline) at scheduled visits will be provided for each treatment group. The 
summary will include the number of observations, mean, SD, SE, minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from Baseline (±SE) at each of the scheduled visits. 
Similar presentations will be provided excluding measurements after rescue therapy during the 
entire 104-week double-blind treatment period. 
2.4.4.2 Analyses of secondary efficacy endpoints 
For continuous secondary efficacy endpoints (see Section 2.1.3) with missing data at Baseline, 
missing data will be imputed using MI under the assumption of missing at random (MAR). 
Missing data at Baseline will be imputed using regression method that includes randomization 
stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of sex (male, female) and baseline 
value in the imputation model. 
Each continuous secondary efficacy endpoint (Section 2.1.3) will be analyzed using a similar 
ANCOVA model including the measurements at Baseline and endpoint (observed or imputed). 
The missing data at endpoint will be imputed by the retrieved dropouts if there are at least 5 
patients in each study treatment group who discontinued but have the endpoint. Otherwise, the 
washout imputation method will be used. After the imputation, each of the complete datasets will 
be analyzed by an ANCOVA model with treatment groups (sotagliflozin 400 mg, sotagliflozin 
200 mg, placebo), randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of 
sex (male, female), and country as fixed effects, and baseline secondary endpoint value as a 
covariate.   
Results from each complete dataset will be combined using Rubin’s rule to provide the adjusted 
mean change from Baseline to week 26 (or week 12 for SBP) for each treatment group, as well as 
the between treatment group difference (comparing each sotagliflozin group to placebo group)  
and the 95% CI for the between-group difference. 
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, 


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minimum, median, and maximum. Graphical presentations will also be used to examine trends 
over time using mean (±SE) and mean change from Baseline (±SE) at each of the scheduled visits. 
In addition, SBP will be summarized descriptively at each visit for those with baseline 
SBP ≥140 mmHg. 
Categorical endpoint of HbA1c <7% at week 26 will be analyzed using a 
Cochran-Mantel-Haenszel (CMH) method stratified by randomization stratum of HbA1c (≤8.5%, 
>8.5%), and randomization stratum of sex (male, female). Proportion of HbA1c responders in 
each treatment group will be provided with the difference between each sotagliflozin group and 
placebo group and their associated 2-sided 95% CI. To determine whether a patient is HbA1c 
responder or not, all measurements at week 26 will be used regardless of discontinuation of IMP 
or initiation of rescue medication. Patients with no HbA1c measurement at week 26 will be 
treated as non-responders. Summary tables and graphs will be provided by treatment group at 
scheduled visit.  
For between-group comparison for HbA1c <7% responder analysis, a sensitivity analysis will be 
performed by excluding patients with baseline HbA1c <7% using the same CMH test mentioned 
above. Similarly, by-visit summary based on above subset of patients may be provided. 
2.4.4.3 Analyses of other efficacy endpoints 
The analysis of other endpoints (see Section 2.1.3) will be descriptive with no formal testing. 
Summary statistics at scheduled visits based on observed value will be provided by each treatment 
group. Graphical presentations will also be used to illustrate trends over time.  
The number (%) of patients who used rescue therapy will be summarized by treatment group 
during the 26-week core (see Section 2.5.4) and the 104-week entire double-blind treatment 
periods. A KM curve for the time to first rescue therapy will be presented during the 26-week core 
treatment period and 104-week entire double-blind treatment period (see Section 2.5.4). The 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 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 104 respectively 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 104 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]. 


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2.4.4.4 Multiplicity issues 
To control the family-wise type I error, a hierarchical testing procedure will be applied. 
Once the primary variable (change from Baseline to Week 26 in HbA1c) is statistically significant 
at α = 0.05 (2-sided), the following secondary efficacy variables will be tested in the following 
prioritized order. The testing will stop as soon as an endpoint is found not to be statistically 
significant at α=0.05 (2-sided). 
 Comparing sotagliflozin 400 mg versus placebo: 
- 
Change from Baseline to Week 26 in body weight, 
- 
Change from Baseline to Week 26 in FPG, 
- 
Change from Baseline to Week 12 in SBP for all patients. 
 Comparing sotagliflozin 200 mg versus placebo: 
- 
Change from Baseline to Week 26 in HbA1c, 
- 
Change from Baseline to Week 26 in body weight, 
- 
Change from Baseline to Week 26 in FPG, 
- 
Change from Baseline to Week 12 in SBP for all patients. 
No multiplicity adjustment will be made on efficacy variables other than those mentioned above. 
In addition, no further multiplicity adjustment (split of alpha) is needed for multiple analyses 
(ie, first step and second step analyses see Section 3). The results of the first step analysis will not 
be used to change the conduct of the ongoing study in any aspect and all primary and secondary 
efficacy endpoints will be fully evaluable at the time of the first step analysis. Analyses beyond 
Week 26 will be descriptive. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group. The safety data will be 
summarized for the 26-week core treatment period and the 104-week entire treatment period 
separately, unless otherwise specified.  
The observation period defined in Section 2.1.4 is applicable in all safety analyses for 
classification of AEs, determination of treatment-emergent Potentially Clinically Significant 
Abnormality (PCSA) values and the last on-treatment value for laboratory, vital sign, BMD 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. 


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 The baseline value (with the exception of serum creatinine and eGFR) is defined as last 
available value before the first dose of double-blind IMP. For 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 one PCSA during the TEAE 
period, taking into account all evaluations performed during the TEAE period, including 
nonscheduled or repeated evaluations, central laboratory/reading or local measurements 
(see Section 2.5.4). The number of all such patients will be the numerator for the 
on-treatment 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 TEAE period by treatment 
group on the safety population. 
 For laboratory parameters cited in the protocol as efficacy endpoints (eg, HbA1c, plasma 
glucose, etc.), PCSA summaries will not be provided. These parameters will be 
summarized in efficacy Section 2.4.4. 
 For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from Baseline values by 
visit and treatment group for the 104-week entire treatment period. Summaries will 
include the last on-treatment value. The last on-treatment value is commonly defined as 
the value collected at the same day/time of the last administration of IMP for the 104-week 
entire treatment period. If this value is missing, the last on-treatment value will be the 
closest value prior to the last administration of IMP during the 104-week entire treatment 
period.   
 The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned. Relative risks versus placebo and their 95% 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 2.4.5.3 and Section 2.4.5.4). 
2.4.5.1 Analyses of the Bone Mineral Density 
Analysis of percent change from Baseline in BMD (lumbar spine, total hip, femoral neck) to 
Week 26, Week 52, and Week 104 will be performed on the safety population, using BMD 
measurements obtained during the study, regardless of IMP discontinuation and/or introduction of 
rescue therapy. No statistical significance tests will be performed. 
All planned analyses will be performed at each location (lumbar spine, total hip, and femoral 
neck) separately. 


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Analysis of the key secondary safety endpoints of percent change from Baseline to Week 26, 
Week 52, and Week 104 respectively in BMD will be performed by an ANCOVA model using 
BMD values measured at Baseline and the corresponding time point  (observed or imputed). The 
missing data at endpoint will be imputed by multiple imputation (MI) methods as detailed below.  
Missing endpoint data at Week 26, Week 52, or Week 104 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 endpoint (Week 26, Week 52, or Week 104) but 
have the measurement for the endpoint (retrieved dropouts). The imputation model will include 
the randomization strata and the baseline value. In cases of non-convergence during the 
imputations, the offending stratum will be identified and then will be dropped from the model. 
Considering that the number of retrieved dropout patients in each treatment group is expected to 
be small, a simple imputation model based on regression will be used with baseline measurement 
included as the predictor. This will serve as the primary method of imputation for missing data 
should sampling criteria be satisfied (ie, ≥5 retrieved dropouts in each treatment group). 
In addition, a sensitivity analysis using a pattern-based multiple imputation method will be 
performed. The imputation method will be implemented in 3 steps:  
1. For missing data at Baseline, a monotone missingness method implemented in PROC MI 
with monotone regression option will be used to impute the missing data at Baseline. The 
imputation model will include the randomization strata and BMD measurements at 
Baseline. 
2. In cases that a non-monotone missing data pattern occurs at the intermediate visits, these 
data points will be imputed using the Markov Chain Monte Carlo (MCMC) option in 
PROC MI to partially impute missing data at the intermediate visits in order to achieve a 
monotone missing pattern for all patients. The imputation model will include treatment, 
BMD measurements at Baseline, Week 26, Week 52, and Week 104.  
3. Using the partially and monotone data sets from the MCMC of step 2, the rest of the 
missing data will be imputed using a sequential imputation approach. Given that the data 
sets have monotone missing data pattern, the approach will be to consider imputation on a 
visit (timepoint) by visit (timepoint) basis and conditioning on all visits (timepoints) data. 
The process will be to repeat, sequentially, in the order specified in the regression model, 
the imputation of missing values at each visit (timepoint). The imputation model will 
include treatment, measurements at Baseline, Week 26, Week 52, and Week 104 in the 
VAR statement.  
A top line analysis to evaluate the efficacy will be conducted when all patients have either 
completed Week 26 or discontinued prior to Week 26.  
The imputation model at Week 26 for the topline analysis will include treatment and measurement 
at Baseline, after missing baseline data imputation as described in step 1above. 
The imputation method will generate multiple complete data sets. The change from Baseline to 
Week 26, Week 52, and Week 104 will be derived from observed and imputed BMD values.  


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The derived change from Baseline to each timepoint in each of the complete datasets will be 
analyzed by the ANCOVA model with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 
mg, placebo), randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of sex 
(male, female), country as fixed effects, and baseline BMD value as a covariate. 
Results from each complete data set will be combined using Rubin’s rule to provide the adjusted 
mean change in BMD from Baseline to each timepoint (Week 26, Week 52, and Week 104) for 
each treatment group, as well as the between-group difference (comparing sotagliflozin 400 mg or 
sotagliflozin 200mg vs placebo) and the 95% confidence interval (CI). 
This sensitivity analysis will serve as the primary analysis at any timepoint if the number of 
patients who prematurely discontinue the IMP before the post-Baseline visit (Week 26, Week 52, 
or Week 104) with the visit data is not sufficient to perform a retrieved dropout analysis. 
Descriptive analyses will be performed on the key safety endpoints to summarize the treatment 
effects across subgroups defined by the following baseline or screening factors: 
 Age group (<65 years, ≥65 years). 
 Duration of T2D (<10 years, ≥10 years). 
 Sex (male, female). 
 Baseline BMI level (<25; 25 to <35; ≥35 kg/m²). 
 Baseline eGFR (<45; 45 to <60; ≥60 mL/min/1.73 m²). 
The treatment effects (sotagliflozin 400 mg and sotagliflozin 200 mg versus placebo respectively) 
across the subgroups defined for each of these factors will be estimated for the percent change 
from Baseline to Week 26, Week 52, and Week 104 in BMD in the safety population, and using 
the same MI method as applied to each of the key safety endpoints, respectively.  
The ANCOVA model will include treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, 
placebo), randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of sex 
(male, female), subgroup factor, treatment-by-subgroup factor, and country as fixed effects, and 
baseline BMD value as covariate. 
The adjusted estimates of treatment mean differences with SE and 95% CIs will be provided as 
appropriate across the subgroups (comparing each sotagliflozin group vs placebo group) with SE 
and 95% CIs will be provided as appropriate across the subgroups. A forest plot of the results will 
also be presented. 
In the case that the subgroup factor is the sex only the subgroup factor (as a single factor and/or an 
interaction term) will be included in the model in order to avoid the issue of collinearity in the 
analysis. The corresponding strata factor will not be included in the model. 
Summary statistics (including number, mean, median, Q1, Q3, standard deviation, standard error, 
minimum and maximum) of BMD (lumbar spine, total hip, femoral neck) (baseline value, 
observed post-Baseline values, observed changes from Baseline and observed percent change 
from Baseline) will be provided at Week 26, Week 52 and Week 104 by treatment group. 
Graphical presentations will be used to examine trends over time using mean (±SE), mean change 


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from Baseline (±SE), and mean percent change from Baseline (±SE), at each of the scheduled 
visits (using OC).  
The number (%) of patients with a percent change from Baseline in BMD ≥3% at Week 104 will 
be also summarized. The number (%) of patients will be summarized by visit for each T-score 
category: normal (T-score ≥-1.0); low bone density (T-score >-2.5 and <-1); osteoporosis 
(T-score ≤-2.5). 
2.4.5.2 Analyses of hypoglycemia 
Analyses of hypoglycemia will be performed on the TEAE period as defined in Section 2.1.4. 
Hypoglycemia will be classified as severe hypoglycemia, documented symptomatic 
hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia or relative 
hypoglycemia (See Section 2.1.4.1). 
The number (%) of patients with 1) any hypoglycemia, 2) 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 event(s) per 100 patient-years (calculated as the number of 
patients with at least 1 event/ total exposure in 100 patient-years) and the total number of events 
per 100 patient-years (calculated as the total number of events / total exposure in 
100 patient-years). Note: Note: here exposure in days is duration of treatment-emergent AE 
period, ie, duration of IMP treatment in days +1 (Section 2.1.4). 
The summary of frequency and incidence rate in patient-years for severe hypoglycemia or 
documented symptomatic hypoglycemia will be provided as appropriate by gender, age group 
(≥55 to <65, ≥65 years), race (White, Black or African American, Asian, Other). 
A KM curve will be provided by treatment group for the time to first severe hypoglycemia or 
documented symptomatic hypoglycemia during the TEAE period for the 104-week entire 
treatment period only (see Section 2.4.5).  
Documented symptomatic hypoglycemia may be 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). 
2.4.5.3 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.  


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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 present the number (n) and percentage (%) of patients 
experiencing an adverse event by SOC, HLGT, HLT, and PT, sorted by the internationally agreed 
order for SOCs and alphabetical order for HLGT, HLT and PT within the SOC. Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a 
treatment phase.  The denominator for computation of percentages is the safety population within 
each treatment group. 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pretreatment, treatment-emergent, and posttreatment).  For that purpose, the 
table of all treatment-emergent adverse events presented by primary SOC and PT (sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs in the 
sotagliflozin 400 mg group) will define the presentation order for all other similar tables unless 
otherwise specified. In case of equal frequency regarding PTs, alphabetical order will be used. 
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the 26-week 
core treatment period and the 104-week entire treatment period respectively, 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 SOC.  
 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 


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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 similar other 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 incidence ≥2% in any treatment group) by primary SOC, 
HLGT, HLT and PT, sorted by the internationally agreed SOC order. The other levels 
(HLGT, HLT, PT) will be presented in alphabetical order. 
 Common TEAEs (PTs with incidence ≥2% in any treatment group) will be provided as 
appropriate by primary SOC and PT and by demographic factors including gender, age 
group (≥55 to <65, ≥65 years), race (White, Black or African American, Asian, other), 
baseline SBP category (<130, ≥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]), prior antidiabetic medication  
[Insulin (alone or with other antihyperglycemic agents), SU and/or glinide (alone or with 
other non-insulin antihyperglycemic agents), Other (non-insulin antihyperglycemic agents 
except SU, and glinide)]. SOC will be sorted by the 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 


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internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
Analysis of adverse events of special interest 
The summaries of AESI will be presented for the 104-week entire treatment period only in the 
safety population. 
Pregnancy and overdose will be included in overall AE summaries if any are reported. ALT 
increase >3 x ULN is included in laboratory PCSA summary if any. 
In addition, the number (%) of patients with an AESI will be summarized by PT and by treatment 
group. Corresponding listings will be provided as appropriately. 
Analysis of events of special interest  
The summaries of EOSI will be presented for the 104-week entire treatment period only in the 
safety population.” 
CV events, bone fracture and DKA  
For EOSIs that are adjudicated (ie, deaths, myocardial infarction, stroke, and unstable angina 
requiring hospitalization, heart failure requiringhospitalization, bone fracture, and diabetic 
ketoacidosis), the number (%) of patients with an EOSI positively adjudicated by CEC will be 
summarized by treatment group. All EOSIs sent for adjudication and/or reported by the 
Investigators in the specific AE forms will be listed along with the adjudication outcome. 
Renal events 
For the EOSI renal events where selected events are adjudicated, the number (%) of patients with 
any renal events identified in Table 3 in Section 2.1.4.2 will be summarized by treatment group.  
The following renal events will be listed along with the adjudication outcome if applicable, 
including events,  
i. Recorded in eCRF “GFR decrease”. 
ii. Recorded in eCRF “Renal Event – Dialysis”. 
iii. Identified as “Renal transplant” in eCRF “Other procedure”, where adjudication is not 
required. 
Renal death will be part of all deaths specified above. 
Other EOSIs 


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For EOSIs that are not adjudicated, the number (%) of patients with at least one event will be 
summarized by treatment group and by PT (as identified in Table 3 in Section 2.1.4.2). 
Severe hypoglycemia will be included in the summary of hypoglycemia (See Section 2.4.5.1). 
AE leading to an amputation is described in the section below. 
Analysis of Amputation: 
The number (%) of patients with amputation will be summarized by treatment group and by PT 
and LLT during the study (ie, regardless of on- or post-treatment). Amputation is a procedure 
recorded in eCRF form “Other Procedures related to Amputation”. Patients who had a procedure 
related to amputation will be listed. 
The number (%) of patients with an “AE leading to an amputation” will be summarized by 
treatment group and by PT.  The “AE leading to an amputation” is determined by the AE 
identifier recorded in 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 2  in Section 2.1.4.2; these PTs 
in Table 2 were requested by the European Medicines Agency/ Pharmacovigilance Risk 
Assessment Committee[EMA/PRAC] Assessment Report 9 February 2017). The associated list 
will be provided as well, with patients who had an amputation procedure flagged. “AE potentially 
leading to amputation” represents the condition that commonly precedes amputation procedure, 
but not in all cases an amputation has occurred (as per the EMA/PRAC request). 
Analysis of pretreatment and posttreatment adverse events  
 All pretreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 pretreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC in sotagliflozin 
400 mg group. 
 All posttreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 posttreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC in sotagliflozin 
400 mg group. 
Listings 
Supportive AE listings will be provided for all AEs, SAEs, and deaths, AEs leading to treatment 
discontinuation and/or death, and EOSI as appropriate. Listing of all AEs, SAEs and AEs leading 
to treatment discontinuation and/or death, sorted by treatment, patient identification, and onset 
date will include the following information: treatment, patient identification, country, age, gender 
race, BMI, primary SOC, PT, reported term, onset date, study day (relative day to the start date of 
double-blind treatment), AE duration, duration of exposure, intensity, corrective treatment, action 
taken with IMP, date of treatment discontinuation (if relevant), relationship to IMP or NIMP, 


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outcome, date of death (if any), seriousness, seriousness criteria, and AE status (‘E’ for TEAE; 
and ‘P’ for on-study post-treatment AE). 
2.4.5.4 Deaths 
The following summaries of deaths will be generated for the safety population. 
 Number (%) of patients who died by study period (on-study, during TEAE period, 
poststudy). 
 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.  
2.4.5.5 Analyses of laboratory variables  
Laboratory parameters will be grouped and summarized by biological function as described in 
Section 2.1.4.4. 
The summary statistics (including number, mean(standard deviation), median, Q1, Q3, minimum 
and maximum) of all laboratory variables (central laboratory values and changes from Baseline, 
and/or percent change from Baseline [eg, lipid parameters])) will be calculated for each planned 
visit or study assessment (screening, Baseline, post-Baseline time point, last on-treatment) 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. 
In that case only the worsening of the worst case are presented. 
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. The summary tables will include patients in the 
safety population that have at least one assessment performed during the TEAE period. When 
PCSA criteria are based on change from Baseline, patients must have non-missing baseline to be 
included in the summary. And when required by the definition of the abnormality, patients must 
also have available laboratory normal ranges. 


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A listing of patients with at least one post-Baseline measurement PCSA or out of normal range 
(when no PCSA is defined) will be provided and will display the patients’ entire profile over time 
for parameters belonging to the corresponding biological function. Individual data listings will 
include 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 based on multiples of ULN, the parameter’s value will 
also be expressed as multiples of ULN in the individual data presented. 
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 
post-Baseline visit by baseline status will be displayed by treatment group for each parameter.  
The proportion of patients with PCSA values at any post-Baseline 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 and total bilirubin and the following complementary parameters if available:  
conjugated bilirubin and prothrombin time/international normalized ratio ,creatine phosphokinase, 
serum creatinine, complete blood count, anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA 
, anti-CMV IgM and anti-HEV IgM antibodies, auto-antibodies: anti-nuclear, anti-DNA, 
anti-smooth muscle, Epstein-Barr virus, herpes viruses, and anti-LKM.. 
2.4.5.6 Analyses of vital sign variables 
The summary statistics (including number, mean (standard deviation), median, Q1, Q3,  minimum 
and maximum) of all vital signs variables (central laboratory values and changes from Baseline) 
will be calculated for each planned visit or study assessment (Baseline, each post-Baseline time 
point, last on-treatment) by treatment group.   
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group for SBP, DBP and HR. All measurements collected during the TEAE period, including 
unscheduled ones, will be considered for the PCSA summaries. The summaries will include 
patients in the safety population who have at least one assessment performed during the TEAE 
period. When a PCSA definition is based on change from Baseline, patients must have a baseline 
to be included in the summaries. 


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A listing of patients with at least one post-Baseline PCSA will be provided and will display the 
patient’s profile over time of all vital sign parameters. Individual data listings will include the 
following flags:  
 Baseline values will be flagged “B”. 
 Parameter values reaching a PCSA limit will be flagged (‘+’ or ‘-’ depending on the 
direction). 
2.4.5.7 Analyses of electrocardiogram variables 
Shift tables will be provided to present ECG status according to baseline status (Normal/Missing, 
Abnormal) for each treatment group during the TEAE period. Supportive listings of patients with 
abnormal ECG status at any post-Baseline visit will be provided. 
2.4.5.8 Analyses of physical examination variables 
Shift tables will be provided to present physical examination findings by body system according 
to baseline status (Normal/Missing, Abnormal) for each treatment group during the TEAE period. 
Supportive listings of patients with abnormal findings at any post-Baseline visit will be provided. 
2.5 
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) = 
.  
Renal function formulas  
The estimated GFR (mL/min/1.73m2) will be calculated using the 4 variable Modification of Diet 
in Renal Disease (MDRD) formula:  
Standard unit: eGFR (mL/min/1.73m2)= 
 


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Conventional unit: eGFR(mL/min/1.73m2) =  
 
Urine ACR 
Standard unit: UACR (mg/g) =  
 
Conventional unit: UACR (mg/g) =  
 
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 (Section 2.5.4) of continuous variables collected during the study will 
be used in the analysis 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 or by 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 


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completed in the e-CRF “First dose IMP” module. 
For patients who are randomized and dispensed a double-blind treatment kit but who are lost to 
follow-up just after Visit 3 (eg. only the treatment kit number is reported in the e-CRF “Exposure 
- treatment period” module without any dose information), the date of first administration will be 
imputed using the date of randomization. When a patient is randomized but not exposed, 
“Not taken” should be ticked in the e-CRF “First dose IMP” module. 
Handling of computation of treatment duration if IMP end of treatment date is missing 
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the end-of-treatment case report form page.  If this date is 
missing, the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and posttreatment medication. 
Handling of adverse events/hypoglycemia with missing or partial date/time of onset 
Missing or partial adverse event/hypoglycemia onset dates and times will be imputed so that if the 
partial adverse event onset date/time information does not indicate that the adverse 
event/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 when date and time of first IMP administration is missing 
When the date and time of the first IMP administration is missing, all adverse events that occurred 
on or after the day of randomization should be considered as treatment-emergent adverse events.  
The exposure duration should be kept as missing. 
Handling of adverse events/hypoglycemia when IMP end of treatment date is missing 
For the purpose of defining TEAE period, the date of the last administration of double-blind IMP 
is equal to the date of the last administration reported on the e-CRF “Treatment Status Library” 
page.  
If the date of last administration reported on the e-CRF “Treatment Status Library” page is: 


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 Partially missing, it will be imputed with a date as late as possible before or on the date of 
last available information on e-CRF “Completion of End of Study/Follow-up”.  
 Completely missing, it will be imputed with the date of last available information on 
e-CRF “Completion of End of Study/Follow-up” page.  
If the date of last available information on e-CRF “Completion of End of Study/Follow-up” page 
is: 
 Partially missing, it will be imputed with a date as late as possible. 
 Completely missing, all adverse events occurred on or after the first administration of 
double-blind IMP will be considered as treatment emergent adverse events. 
Handling of missing assessment of relationship of adverse events to IMP  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of missing severity of adverse events 
If the severity 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. 


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Handling of missing data for continuous efficacy endpoints 
Please See Section 2.4.4.1 and Section 2.4.4.2. 
Handling of missing data for categorical secondary efficacy endpoints 
Please See Section 2.4.4.2. 
Handling of missing data for key secondary safety endpoints 
Please See Section 2.4.5.1 
2.5.4 Windows for time points 
The following will decide how scheduled and/or unscheduled visits will be used in the analyses 
on efficacy variables and the by-visit summaries for safety variables (clinical laboratory data in 
Section 2.1.4.4 and vital signs in Section 2.1.4.5). 
Step 1: A scheduled measurement will be used if available; otherwise, an unscheduled 
measurement (including the end of treatment/study visit for those prematurely discontinued) will 
be used if it were on the same date as a scheduled visit; 
Step 2: After step 1, if there are still no measurement for a given parameter at a scheduled visit, 
analysis window below (Table 3) will be applied to re-allocate a post-Baseline unscheduled 
measurement to the scheduled visit. 
Table 3 – Analyses window definition 
Scheduled visit post Baseline 
Targeted study day 
Analysis window in study days 
Week 3 (Visit 4) 
21 
2 to 31 
Week 6 (Visit 5) 
42 
32 to 62 
Week 12 (Visit 6) 
84 
63 to 104 
Week 18 (Visit 7) 
126 
105 to 153 
Week 26 (Visit 8) 
182 
154 to 227  
Week 39 (Visit 9) 
273 
228 to 318 
Week 52 (Visit 10) 
364 
319 to 419 
Week 68 (Visit 11) 
476 
420 to 538 
Week 86 (Visit 12) 
602 
539 to 664 
Week 104 (Visit 13) 
728 
≥665 
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 


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measurement will be used. Re-allocated scheduled visits (ie, visit numbers) should be sequential if 
ordered by the date of measurement. 
After Step 2, if there are still no measurement for a given parameter at a scheduled visit, data is 
considered missing for efficacy analyses, where multiple imputation would be applied as 
appropriately as described in Section 2.4.4.  
Reference day 
The reference day for the calculation of extent of exposure, time to onset, and relative days will be 
the day of the first administration of double-blind IMP or the day of randomization if not exposed 
to double-blind IMP, denoted as Day 1. 
Baseline definition for efficacy/safety data 
For the safety analyses, the baseline for a given parameter is defined as the last available 
measurement (or the average of all measurements for creatinine and eGFR), including 
unscheduled assessments, assessed prior to the first administration of double-blind IMP. For the 
efficacy analyses, the baseline for a given parameter is defined as the last available measurement 
(or the average of all measurements for 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 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. 
See Section 2.1.4 and Section 2.5.4 for details. 
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 


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baseline for both safety and efficacy analyses. In the safety analyses, for parameters with PCSA 
defined based on normal range, local results will only be used in the PCSA summary if they are 
accompanied by a local laboratory normal range. For parameters with PCSA not defined based on 
normal range, local results will be used in the PCSA summary as appropriate. 
When a patient has more than one 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 one measurement on different dates for the 
same scheduled visit, the value closest to the date of the visit will be used for the scheduled visit. 
When the values for the same scheduled visit are equidistant, the last value should be used for the 
scheduled visit. Similar rules will be applicable to a patient who has more than one set of 
measurements for the same vital sign parameter (ie, SBP, DBP, or HR) on the same date. 
26-week double blind core treatment period  
The 26-week double-blind core treatment period is the time from first administration of 
double-blind IMP to the last administration of double-blind IMP on or before Visit 8/Week 26 
(or Day 182 if Visit 8/Week 26 date is missing). This is for defining EOT status at Week 26 and 
analyzing selected efficacy parameters (eg, rescued patients) and safety during 26-week core 
treatment period.  
TEAE period for the 26-week double blind core treatment period  
The TEAE period for the 26-week double-blind core treatment period is (1) the time from the first 
administration of the double-blind IMP up to 10 days (1 day for hypoglycemia) after the last 
administration of IMP if the patient discontinued treatment on or before Visit 8 (or Day 182 if 
Visit 8 date is missing), or (2) the time from the first administration of the double-blind IMP to 
the administration at Visit 8/Week 26 (or Day 182 if Visit 8/Week 26 date is missing) if the 
patient remained treated beyond Visit 8/Week 26. This is for the purpose of safety analyses during 
the 26-week core treatment period. 
26-week core study period 
The 26-week core study period is the time from first administration of double-blind IMP to 
Visit 8/Week 26 (or Day 182 if Visit 8/Week 26 date is missing) or the end of TEAE period for 
the 26-week double-blind core treatment period (as defined above) whichever is later. This is for 
defining EOS status at Week 26. 
Time to event analysis  
For time to event analysis/KM plot, time to event (eg, treatment discontinuation, rescue therapy, 
hypoglycemia, etc) is defined as the number of days from the date of the first administration of 
double-blind IMP (or the date of randomization if not exposed) to the start date of the first 
occurrence of the event during the respective analysis period.  
Patients who did not experience any event during the respective analysis period are considered 
censored observations. The censoring rules are defined below: 


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Time to event 
Censoring date at Week 26 
(1st step analysis) 
Censoring date at 
EOT/EOS 
(2nd step analysis) 
Treatment discontinuation due to any 
reason 
Not applicable 
EOT 
Treatment discontinuation due to AE 
Not applicable 
EOT 
Time to rescue 
min (EOT, Date of W26 visit) 
EOT 
Time to severe or documented 
hypoglycemia 
min (EOT+1, EOS, Date of W26 visit). 
See Section 3 
Min (EOT+1, EOS) 
Note: (1) Day 182 will be used if Date of Week 26 visit (or date of W26/re-allocated W26) is not available. 
          (2) Date of EOS will be used if date of EOT is not available; Last contact date will be used if date of EOS is not available.  
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will not be included in 
the by-visit summaries, but will be used for computation of baseline, the last on-treatment value, 
PCSAs and the shift summaries for safety or efficacy. 
They will be included in the by-visit summaries if they are re-allocated to scheduled visits 
(see Section 2.5.4) 
2.5.6 Pooling of centers for statistical analyses 
Center will not be included in the statistical models for efficacy analyses. However, all centers 
within a country will be pooled, and country will be included as a fixed effect in a parametric 
statistical model (eg, ANCOVA etc) for primary and secondary efficacy endpoints. Countries with 
fewer than 5 randomized patients will be grouped, if patients from grouped countries are still 
fewer than5, they will be further grouped with the country with the lowest number of patients that 
is 5 or more. 
2.5.7 Statistical technical issues 
None. 


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3 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned, however analysis of primary and secondary 
endpoints at Week 26 will be considered final at the time of first step analyses described below. 
The study analyses will be conducted in 2 steps: 
 First step: Efficacy analyses up to Week 26, and interim safety analyses. 
The first step analyses will be conducted when all patients have been randomized and have 
all their data, at the minimum up to Week 26 (Visit 8), collected and validated. For this 
analysis the common cut-off date is 10 days after the date of last patient last Week 26 visit. 
The first step analyses will include: 
- 
Efficacy analyses up to Week 26, which are considered as the final analyses for 
primary and secondary endpoints. Analyses beyond week 26 will be descriptive, 
- 
Safety analysis of the key secondary safety endpoint of BMD at Week 26, 
- 
Interim safety analyses which will be performed on all safety data collected and 
validated at the time of the first step analyses. 
The first step analyses will not be used to change the conduct of the ongoing study in any aspect. 
Since the primary efficacy and secondary analyses would have been concluded at the time of the 
first step analyses, the significance level for the study remains at 0.05 (see Section 2.4.4.4). The 
first step analyses will be included in the submission dossier to health authorities. 
Individuals who are involved in the unblinding of the first step analysis will not be involved in the 
conduct of the study afterwards. 
 Second step: final analyses. 
The second step analyses will be conducted at the end of the study. The second step 
analyses will include the final analyses of efficacy endpoints at Week 52 and Week 104 
and safety endpoints on the 104-week entire treatment period, which will be descriptive 
only.  
Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses as appropriate. The following additional rules will apply for the first-step analyses: 
- 
Patients without end of treatment visit performed at the time of the cut-off date will be 
considered as ongoing and exposed up to the cut-off date. Therefore: 
- 
Any assessments within analysis windows up to Week 26 will be taken into account 
(may include few unscheduled data after the cut-off date), 
- 
Patients who did not complete 104-week entire treatment period nor prematurely 
discontinued the study treatment at cut-off date will be analyzed as “ongoing” in the 
disposition summary, 
- 
Their TEAE period, and on-study observation period will end at the cut-off date, 


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- 
Their treatment duration will be derived by considering date of cut-off as last 
administration date, 
- 
Analyses of percentage of days with under/above-planned dosing and compliance will 
be performed up to last administration reported in the e-CRF before the last visit taking 
into consideration of the cut-off date, 
- 
AEs occurring, worsening or becoming serious after the cut-off date will not be 
included in the analyses. However, any available outcome before database lock, 
regardless of timing in relation to the cut-off date, of an adverse event starting prior to 
the cut-off date will be taken into account. Medications, treatment 
discontinuations/completions, and deaths occurring after the cut-off date will not be 
included in the analyses, 
- 
For time to severe or documented symptomatic hypoglycemia at the 1st step analysis, 
the censoring date is min (EOT+1, EOS, common cut-off date), 
- 
Post-treatment epoch, post-study period are not applicable for ongoing patients. 
Analyses of post-treatment AEs, post-study deaths, and post-treatment medications 
will be performed for patients who either completed or prematurely discontinued the 
treatment before or at the cut-off date, 
- 
Status at last study contact will be provided for patients who either completed or 
prematurely discontinued the study before or at the cut-off date. 
An independent DMC will monitor and assess the safety of patients from this trial through 
periodic review of the accumulated safety data provided by an independent statistical group. 
Related details are provided in separate documents (DMC charter and DMC SAP). 


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4 
DATABASE LOCK 
Two database locks will be done: 
 First database lock (for first step analysis): will include all available data on all 
randomized patients up to the common cut-off date as defined in Section 3. This database 
lock is planned to be done approximately 4 weeks after the common cut-off date. 
 Final database lock (for second step analysis): will include all data, including follow-up, 
for all randomized patients. This database lock is planned to be done approximately 
4 weeks after last patient last visit. 


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


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6 
REFERENCES 
None. 


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7 
LIST OF APPENDICES 
 
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B: 
List of PTs for select EOSIs (MedDRA v22.0) 
Appendix C: 
Summary of statistical analyses  
Appendix D: 
Study Flow Chart  


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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. 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurement. 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
CLcr (mL/min) 
(Estimated 
creatinine clearance 
based on the 
Cokcroft-Gault 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥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 
 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
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) 
 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from Baseline ≥20 bpm 
≥120 bpm and increase from Baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from Baseline ≥20mmHg 
≥160 mmHg and increase from Baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from Baseline ≥10 mmHg 
≥110 mmHg and increase from Baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic 
Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from Baseline  
≥5% decrease from Baseline 
FDA Feb 2007. 


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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 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from Baseline 
Increase from Baseline ]30-60] ms 
Increase from Baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and QTc>60 ms are the 2 PCSA 
categories to be identified in individual 
subjects/patients listings. 
 
 


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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 


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EOSI 
Preferred term code 
Preferred term 
Urinary tract infections 
10048709 
Urosepsis 
Urinary tract infections 
10048837 
Cystitis glandularis 
Urinary tract infections 
10049059 
Urinary tract infection fungal 
Urinary tract infections 
10049100 
Pyelocystitis 
Urinary tract infections 
10051250 
Ureteritis 
Urinary tract infections 
10051350 
Cytomegalovirus urinary tract infection 
Urinary tract infections 
10051959 
Urinary bladder abscess 
Urinary tract infections 
10052238 
Escherichia urinary tract infection 
Urinary tract infections 
10054088 
Urinary tract infection bacterial 
Urinary tract infections 
10056351 
Emphysematous cystitis 
Urinary tract infections 
10058523 
Bladder candidiasis 
Urinary tract infections 
10058596 
Renal cyst infection 
Urinary tract infections 
10059517 
Bacterial pyelonephritis 
Urinary tract infections 
10061181 
Genitourinary tract gonococcal infection 
Urinary tract infections 
10061182 
Genitourinary tract infection 
Urinary tract infections 
10061395 
Ureter abscess 
Urinary tract infections 
10062279 
Urinary tract infection pseudomonal 
Urinary tract infections 
10062280 
Urinary tract infection staphylococcal 
Urinary tract infections 
10064825 
Urinary tract infection viral 
Urinary tract infections 
10064921 
Urinary tract inflammation 
Urinary tract infections 
10065197 
Cystitis viral 
Urinary tract infections 
10065198 
Cystitis bacterial 
Urinary tract infections 
10065199 
Cystitis helminthic 
Urinary tract infections 
10065213 
Pyelonephritis viral 
Urinary tract infections 
10065214 
Pyelonephritis fungal 
Urinary tract infections 
10065582 
Urogenital infection fungal 
Urinary tract infections 
10065583 
Urogenital infection bacterial 
Urinary tract infections 
10066757 
Urinary tract abscess 
Urinary tract infections 
10068822 
Emphysematous pyelonephritis 
Urinary tract infections 
10070300 
Streptococcal urinary tract infection 
Urinary tract infections 
10074409 
Escherichia pyelonephritis 
Urinary tract infections 
10075063 
Urethritis mycoplasmal 
Urinary tract infections 
10078665 
Bacterial urethritis 
Urinary tract infections 
10081163 
Fungal urethritis 
Urinary tract infections 
10081262 
Candida urethritis 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 74 of 90 
 
 
EOSI 
Preferred term code 
Preferred term 
Urinary tract infections 
10082040 
Nephritis bacterial 
Volume depletion 
10005697 
Blood osmolarity increased 
Volume depletion 
10005731 
Blood pressure ambulatory decreased 
Volume depletion 
10005734 
Blood pressure decreased 
Volume depletion 
10005737 
Blood pressure diastolic decreased 
Volume depletion 
10005748 
Blood pressure immeasurable 
Volume depletion 
10005758 
Blood pressure systolic decreased 
Volume depletion 
10005761 
Blood pressure systolic inspiratory decreased 
Volume depletion 
10007979 
Central venous pressure decreased 
Volume depletion 
10009192 
Circulatory collapse 
Volume depletion 
10012174 
Dehydration 
Volume depletion 
10013578 
Dizziness postural 
Volume depletion 
10021097 
Hypotension 
Volume depletion 
10021137 
Hypovolaemia 
Volume depletion 
10021138 
Hypovolaemic shock 
Volume depletion 
10026983 
Mean arterial pressure decreased 
Volume depletion 
10031127 
Orthostatic hypotension 
Volume depletion 
10036653 
Presyncope 
Volume depletion 
10037327 
Pulmonary arterial wedge pressure decreased 
Volume depletion 
10042772 
Syncope 
Volume depletion 
10046640 
Urine flow decreased 
Volume depletion 
10047235 
Venous pressure decreased 
Volume depletion 
10047239 
Venous pressure jugular decreased 
Volume depletion 
10047689 
Volume blood decreased 
Volume depletion 
10050760 
Blood urea nitrogen/creatinine ratio increased 
Volume depletion 
10050905 
Decreased ventricular preload 
Volume depletion 
10053356 
Blood pressure orthostatic decreased 
Volume depletion 
10059895 
Urine output decreased 
Volume depletion 
10060089 
Left ventricular end-diastolic pressure decreased 
Volume depletion 
10060231 
Pulmonary arterial pressure decreased 
Volume depletion 
10063080 
Postural orthostatic tachycardia syndrome 
Volume depletion 
10063927 
Orthostatic intolerance 
Volume depletion 
10066077 
Diastolic hypotension 
Volume depletion 
10069431 
Orthostatic heart rate response increased 
Volume depletion 
10069583 
Pulse volume decreased 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 75 of 90 
 
 
EOSI 
Preferred term code 
Preferred term 
Volume depletion 
10072370 
Prerenal failure 
Pancreatitis 
10033625 
Pancreatic haemorrhage 
Pancreatitis 
10033635 
Pancreatic pseudocyst 
Pancreatitis 
10033636 
Pancreatic pseudocyst drainage 
Pancreatitis 
10033645 
Pancreatitis 
Pancreatitis 
10033647 
Pancreatitis acute 
Pancreatitis 
10033649 
Pancreatitis chronic 
Pancreatitis 
10033650 
Pancreatitis haemorrhagic 
Pancreatitis 
10033654 
Pancreatitis necrotising 
Pancreatitis 
10033657 
Pancreatitis relapsing 
Pancreatitis 
10048984 
Pancreatic abscess 
Pancreatitis 
10052400 
Oedematous pancreatitis 
Pancreatitis 
10056277 
Pancreatorenal syndrome 
Pancreatitis 
10056975 
Pancreatic phlegmon 
Pancreatitis 
10056976 
Hereditary pancreatitis 
Pancreatitis 
10056977 
Alcoholic pancreatitis 
Pancreatitis 
10058096 
Pancreatic necrosis 
Pancreatitis 
10065189 
Pancreatitis helminthic 
Pancreatitis 
10066127 
Ischaemic pancreatitis 
Pancreatitis 
10069002 
Autoimmune pancreatitis 
Pancreatitis 
10074894 
Traumatic pancreatitis 
Pancreatitis 
10076058 
Haemorrhagic necrotic pancreatitis 
Venous thrombotic events 
10003192 
Arteriovenous fistula thrombosis 
Venous thrombotic events 
10003880 
Axillary vein thrombosis 
Venous thrombotic events 
10006537 
Budd-Chiari syndrome 
Venous thrombotic events 
10007830 
Cavernous sinus thrombosis 
Venous thrombotic events 
10008138 
Cerebral venous thrombosis 
Venous thrombotic events 
10014522 
Embolism venous 
Venous thrombotic events 
10019713 
Hepatic vein thrombosis 
Venous thrombotic events 
10023237 
Jugular vein thrombosis 
Venous thrombotic events 
10027402 
Mesenteric vein thrombosis 
Venous thrombotic events 
10034272 
Pelvic venous thrombosis 
Venous thrombotic events 
10034324 
Penile vein thrombosis 
Venous thrombotic events 
10036206 
Portal vein thrombosis 
Venous thrombotic events 
10037377 
Pulmonary embolism 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 76 of 90 
 
 
EOSI 
Preferred term code 
Preferred term 
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 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 77 of 90 
 
 
EOSI 
Preferred term code 
Preferred term 
Thyroid cancer 
10016935 
Follicular thyroid cancer 
Thyroid cancer 
10027105 
Medullary thyroid cancer 
Thyroid cancer 
10033701 
Papillary thyroid cancer 
Thyroid cancer 
10043744 
Thyroid neoplasm 
Thyroid cancer 
10055107 
Thyroid cancer metastatic 
Thyroid cancer 
10066136 
Huerthle cell carcinoma 
Thyroid cancer 
10066474 
Thyroid cancer 
Thyroid cancer 
10070567 
Thyroid cancer stage 0 
Thyroid cancer 
10071027 
Thyroid cancer stage I 
Thyroid cancer 
10071028 
Thyroid cancer stage II 
Thyroid cancer 
10071029 
Thyroid cancer stage III 
Thyroid cancer 
10071030 
Thyroid cancer stage IV 
Thyroid cancer 
10072162 
Thyroid cancer recurrent 
Thyroid cancer 
10072613 
Thyroid B-cell lymphoma 
Thyroid cancer 
10073153 
Familial medullary thyroid cancer 
Thyroid cancer 
10076603 
Poorly differentiated thyroid carcinoma 
Renal cell cancer 
10038389 
Renal cancer 
Renal cell cancer 
10038390 
Renal cancer recurrent 
Renal cell cancer 
10038391 
Renal cancer stage I 
Renal cell cancer 
10038392 
Renal cancer stage II 
Renal cell cancer 
10038393 
Renal cancer stage III 
Renal cell cancer 
10038394 
Renal cancer stage IV 
Renal cell cancer 
10038410 
Renal cell carcinoma recurrent 
Renal cell cancer 
10038411 
Renal cell carcinoma stage I 
Renal cell cancer 
10038412 
Renal cell carcinoma stage II 
Renal cell cancer 
10038413 
Renal cell carcinoma stage III 
Renal cell cancer 
10038414 
Renal cell carcinoma stage IV 
Renal cell cancer 
10050018 
Renal cancer metastatic 
Renal cell cancer 
10050513 
Metastatic renal cell carcinoma 
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 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 78 of 90 
 
 
EOSI 
Preferred term code 
Preferred term 
Pancreatic cancer 
10022498 
Insulinoma 
Pancreatic cancer 
10025997 
Malignant neoplasm of islets of Langerhans 
Pancreatic cancer 
10029341 
Neurotensinoma 
Pancreatic cancer 
10033609 
Pancreatic carcinoma 
Pancreatic cancer 
10033610 
Pancreatic carcinoma metastatic 
Pancreatic cancer 
10033613 
Pancreatic carcinoma recurrent 
Pancreatic cancer 
10041329 
Somatostatinoma 
Pancreatic cancer 
10047430 
Vipoma 
Pancreatic cancer 
10051709 
Gastrinoma malignant 
Pancreatic cancer 
10052747 
Adenocarcinoma pancreas 
Pancreatic cancer 
10055006 
Pancreatic sarcoma 
Pancreatic cancer 
10055007 
Carcinoid tumour of the pancreas 
Pancreatic cancer 
10059320 
Pancreatic carcinoma stage 0 
Pancreatic cancer 
10059321 
Pancreatic carcinoma stage I 
Pancreatic cancer 
10059322 
Pancreatic carcinoma stage II 
Pancreatic cancer 
10059323 
Pancreatic carcinoma stage III 
Pancreatic cancer 
10059326 
Pancreatic carcinoma stage IV 
Pancreatic cancer 
10061902 
Pancreatic neoplasm 
Pancreatic cancer 
10067517 
Pancreatic neuroendocrine tumour 
Pancreatic cancer 
10068909 
Pancreatic neuroendocrine tumour metastatic 
Pancreatic cancer 
10069345 
Solid pseudopapillary tumour of the pancreas 
Pancreatic cancer 
10073363 
Acinar cell carcinoma of pancreas 
Pancreatic cancer 
10073364 
Ductal adenocarcinoma of pancreas 
Pancreatic cancer 
10073365 
Intraductal papillary-mucinous carcinoma of pancreas 
Pancreatic cancer 
10073367 
Pancreatoblastoma 
Bladder cancer 
10004986 
Bladder adenocarcinoma recurrent 
Bladder cancer 
10004987 
Bladder adenocarcinoma stage 0 
Bladder cancer 
10004988 
Bladder adenocarcinoma stage I 
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 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 79 of 90 
 
 
EOSI 
Preferred term code 
Preferred term 
Bladder cancer 
10005007 
Bladder cancer stage 0, without cancer in situ 
Bladder cancer 
10005008 
Bladder cancer stage I, with cancer in situ 
Bladder cancer 
10005009 
Bladder cancer stage I, without cancer in situ 
Bladder cancer 
10005010 
Bladder cancer stage II 
Bladder cancer 
10005011 
Bladder cancer stage III 
Bladder cancer 
10005012 
Bladder cancer stage IV 
Bladder cancer 
10005056 
Bladder neoplasm 
Bladder cancer 
10005075 
Bladder squamous cell carcinoma recurrent 
Bladder cancer 
10005076 
Bladder squamous cell carcinoma stage 0 
Bladder cancer 
10005077 
Bladder squamous cell carcinoma stage I 
Bladder cancer 
10005078 
Bladder squamous cell carcinoma stage II 
Bladder cancer 
10005079 
Bladder squamous cell carcinoma stage III 
Bladder cancer 
10005080 
Bladder squamous cell carcinoma stage IV 
Bladder cancer 
10005081 
Bladder squamous cell carcinoma stage unspecified 
Bladder cancer 
10005084 
Bladder transitional cell carcinoma 
Bladder cancer 
10051690 
Urinary bladder sarcoma 
Bladder cancer 
10057352 
Metastatic carcinoma of the bladder 
Bladder cancer 
10066749 
Bladder transitional cell carcinoma stage 0 
Bladder cancer 
10066750 
Bladder transitional cell carcinoma recurrent 
Bladder cancer 
10066751 
Bladder transitional cell carcinoma stage I 
Bladder cancer 
10066752 
Bladder transitional cell carcinoma stage IV 
Bladder cancer 
10066753 
Bladder transitional cell carcinoma stage II 
Bladder cancer 
10066754 
Bladder transitional cell carcinoma stage III 
Bladder cancer 
10071664 
Bladder transitional cell carcinoma metastatic 
Bladder cancer 
10078341 
Neuroendocrine carcinoma of the bladder 
Potentially leading to amputation 
10003084 
Areflexia 
Potentially leading to amputation 
10003178 
Arterial thrombosis 
Potentially leading to amputation 
10003210 
Arteriosclerosis 
Potentially leading to amputation 
10003222 
Arteriosclerotic gangrene 
Potentially leading to amputation 
10006784 
Burning sensation 
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 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 80 of 90 
 
 
EOSI 
Preferred term code 
Preferred term 
Potentially leading to amputation 
10012665 
Diabetic gangrene 
Potentially leading to amputation 
10012679 
Diabetic neuropathic ulcer 
Potentially leading to amputation 
10012680 
Diabetic neuropathy 
Potentially leading to amputation 
10017711 
Gangrene 
Potentially leading to amputation 
10020937 
Hypoaesthesia 
Potentially leading to amputation 
10021137 
Hypovolaemia 
Potentially leading to amputation 
10021519 
Impaired healing 
Potentially leading to amputation 
10021784 
Infected skin ulcer 
Potentially leading to amputation 
10022562 
Intermittent claudication 
Potentially leading to amputation 
10024774 
Localised infection 
Potentially leading to amputation 
10028862 
Necrosis ischaemic 
Potentially leading to amputation 
10029331 
Neuropathy peripheral 
Potentially leading to amputation 
10031149 
Osteitis 
Potentially leading to amputation 
10031252 
Osteomyelitis 
Potentially leading to amputation 
10031253 
Osteomyelitis acute 
Potentially leading to amputation 
10031256 
Osteomyelitis chronic 
Potentially leading to amputation 
10031262 
Osteomyelitis salmonella 
Potentially leading to amputation 
10031264 
Osteonecrosis 
Potentially leading to amputation 
10033775 
Paraesthesia 
Potentially leading to amputation 
10034568 
Peripheral coldness 
Potentially leading to amputation 
10034576 
Peripheral ischaemia 
Potentially leading to amputation 
10034620 
Peripheral sensory neuropathy 
Potentially leading to amputation 
10034636 
Peripheral vascular disorder 
Potentially leading to amputation 
10036155 
Poor peripheral circulation 
Potentially leading to amputation 
10036410 
Postoperative wound infection 
Potentially leading to amputation 
10040026 
Sensory disturbance 
Potentially leading to amputation 
10040840 
Skin erosion 
Potentially leading to amputation 
10040872 
Skin infection 
Potentially leading to amputation 
10040943 
Skin ulcer 
Potentially leading to amputation 
10042343 
Subcutaneous abscess 
Potentially leading to amputation 
10043607 
Thrombosis 
Potentially leading to amputation 
10048031 
Wound dehiscence 
Potentially leading to amputation 
10048038 
Wound infection 
Potentially leading to amputation 
10049927 
Dry gangrene 
Potentially leading to amputation 
10050473 
Abscess limb 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 81 of 90 
 
 
EOSI 
Preferred term code 
Preferred term 
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 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 82 of 90 
 
 
EOSI 
Preferred term code 
Preferred term 
Potentially leading to amputation 
10065237 
Osteomyelitis bacterial 
Potentially leading to amputation 
10065239 
Osteomyelitis fungal 
Potentially leading to amputation 
10065240 
Wound infection bacterial 
Potentially leading to amputation 
10065242 
Wound infection fungal 
Potentially leading to amputation 
10068653 
Bone abscess 
Potentially leading to amputation 
10069379 
Peripheral arterial reocclusion 
Potentially leading to amputation 
10072170 
Skin wound 
Potentially leading to amputation 
10072557 
Peripheral artery restenosis 
Potentially leading to amputation 
10072560 
Peripheral endarterectomy 
Potentially leading to amputation 
10072561 
Peripheral artery bypass 
Potentially leading to amputation 
10072562 
Peripheral artery stent insertion 
Potentially leading to amputation 
10072563 
Peripheral artery stenosis 
Potentially leading to amputation 
10072564 
Peripheral artery thrombosis 
Potentially leading to amputation 
10074396 
Penetrating atherosclerotic ulcer 
Potentially leading to amputation 
10075118 
Subperiosteal abscess 
Potentially leading to amputation 
10075714 
Vasculitic ulcer 
Potentially leading to amputation 
10076246 
Spontaneous amputation 
 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 83 of 90 
 
Appendix C 
Summary of statistical analyses 
 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoint 
HbA1c: Change from 
Baseline at Week 26 
ITT 
ANCOVA (with missing values imputed  
by retrieved dropouts imputation 
method or by washout imputation 
method under MNAR): Trt, 
randomization strata (HbA1c, Sex) and 
country as fixed effects, and baseline 
HbA1c value as a covariate 
 
ANCOVA (with 
missing values 
imputed  by 
washout imputation 
method under 
MNAR 
Tipping point 
analysis; ANCOVA 
(with missing values 
imputed by retrieved 
dropouts imputation 
method or by 
washout imputation 
method under 
MNAR) 
Subgroups:  
race,  
ethnicity,  
age group,  
gender,  
baseline BMI, 
baseline HbA1c, 
baseline mean SBP, 
Duration of diabetes,  
Prior antidiabetic 
medication 
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. 
 
Key Secondary safety endpoint 
 
 
 
 
BMD (lumbar spine, total 
hip, and femoral neck): 
Percent change from 
Baseline at Week 26 
Safety 
ANCOVA (with missing values imputed  
using retrieved dropouts method or by 
ANCOVA (LOCF)): Trt, randomization 
strata (HbA1c, Sex) and country as 
fixed effects, and baseline BMD value 
as a covariate 
 
ANCOVA (LOCF)  
Subgroups:  
age group,  
gender,  
baseline BMI, 
baseline eGFR, 
Duration of diabetes. 
Summary statistics for observed values, changes 
and percent changes from Baseline by visit. 
Graphical presentations for mean percent changes 
from Baseline (±SE) and mean values (±SE) by 
visit. 
 
 
 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 84 of 90 
 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Secondary efficacy endpoints 
Continuous:  
HbA1c(sotagliflozin 200 mg 
vs placebo),FPG, body 
weight: Change from 
Baseline to Week 26; 
SBP:Change from Baseline 
at Week 12 
 
ITT 
ANCOVA (with missing values imputed 
by retrieved dropouts imputation 
method or by washout imputation 
method under MNAR): Trt, 
randomization strata (HbA1c, Sex) and 
country as fixed effects, and Baseline 
value as a covariate 
For Hba1c 
(sotagliflozin 200 
mg vs placebo) 
change from 
Baseline to Week 
26 only: 
ANCOVA (with 
missing values 
imputed by washout 
imputation method 
under MNAR 
Tipping point 
analysis; ANCOVA 
(with missing values 
imputed by retrieved 
dropouts mputation 
method or by 
washout imputation 
method under 
MNAR) 
 
For Hba1c 
sotagliflozin (200 mg 
vs placebo) change 
from Baseline to 
Week26 only: 
Subgroups:  
race,  
ethnicity,  
age group,  
gender,  
baseline BMI, 
baseline HbA1c, 
baseline mean SBP, 
Duration of diabetes,  
Prior antidiabetic 
medication 
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. 
Categorical: 
Proportion of patients with 
HbA1c <7% at Week 26 
ITT 
CMH stratified on randomization strata 
(HbA1c, Sex)  
CMH method 
stratified on 
randomization strata 
(HbA1c / Sex): 
excluding patients 
with Baseline 
HbA1c values <7% 
responders)  
 
 
No 
By-visit summary and graphs of HbA1c responders 
<7%). 
By-visit frequency summary and graphs of HbA1c 
responders (<7%) excluding patients with Baseline 
HbA1c values <7%. 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 85 of 90 
 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Other efficacy endpoints 
Continuous:  
HbA1c, FPG, body weight: 
Change from Baseline to 
weeks 52 & 104 
SBP (according to baseline 
SBP<130 mmHg/≥130 
mmHg & all), 
DBP(according to baseline 
DBP<80 mmHg/≥80 mmHg 
& all),: Change from 
Baseline to Weeks 12, 26 & 
104 
Serum estradiol, total body 
fat mass,  total lean mass, 
UACR, eGFR: Change from 
Baseline to Weeks 26, 52 & 
104 
 
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 
Categorical: 
Proportion of patients with 
HbA1c <7% at Weeks 52 & 
104  
Proportion of patients 
requiring rescue for 
hyperglycemia during the 
104 weeks 
 
ITT 
 
 
ITT 
 
By-visit summary and graphs of HbA1c 
responders <7%). 
 
Summary statistics  
 
No 
 
 
No 
 
No 
 
 
No 
 
 
 
 
KM plot , List of patients rescued 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 86 of 90 
 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Other safety endpoints 
 
 
 
 
BMD (lumbar spine, total 
hip, and femoral neck): 
Percent change from 
Baseline at Weeks 52 & 104 
Safety 
ANCOVA (with missing values imputed  
using retrieved dropouts method or by 
ANCOVA (MMRM) Trt, randomization 
strata (HbA1c, Sex), visit, trt-by-visit 
interaction and country as fixed effects, 
and Baseline BMD value-by-visit 
interaction as a covariate 
 
ANCOVA (MMRM) 
No 
Summary statistics for observed values, changes 
and percent changes from Baseline by visit. 
Graphical presentations for mean percent changes 
from Baseline (±SE) and mean values (±SE) by 
visit. 
 
SAFETY ANALYSES 
 
 
 
 
 
Hypoglycemia 
Safety 
Follow safety guidelines 
Number (%) of patients with any 
investigator reported hypoglycemia, 
severe hypoglycemia, documented 
symptomatic hypoglycemia during 
TEAE period, and incidence rates in 
100 patient-years. 
 
Severe 
hypoglycemia or 
documented 
symptomatic 
hypoglycemia by 
subgroups: race, 
age group, gender 
Severe hypoglycemia or documented symptomatic 
hypoglycemia: frequency summary of first event / 
recurrent event by weekly time intervals; frequency 
summary of any event by hour; KM plot time to first 
event 
Documented symptomatic hypoglycemia maybe 
presented by <54 mg/dL (3.0 mmol/L) as 
appropriate. 
Adverse events 
Safety 
Follow safety guidelines 
No 
Common TEAEs by 
subgroups: race, 
age, gender, 
baseline SBP, 
baseline eGFR 
 
Clinical laboratory data 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
Vital signs 
Safety 
Follow safety guidelines 
Descriptive 
No 
No 
ECG, Physical examination 
Safety 
Follow safety guidelines 
Frequency summary 
No 
No 
ITT = intent-to-treat;  ANCOVA = analysis of covariance 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 87 of 90 
 
Appendix D 
Study Flow Chart 
 
Screening Period 
Double-blind Treatment Perioda 
Follow-
up 
Periodb 
Screening 
Run-in 
Randomized Double-blind Core Treatment Period 
Randomized Double-blind Extension Period 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Week 
-4 
-2 
0 
3 
6 
12 
18 
26 
39 
52 
68 
86 
104 
106 
Day (window [days]) 
-28 
-14  
(±3) 
1  
 
21 
(±3) 
42  
(±3) 
84  
(±3) 
126  
(±3) 
182  
(±3) 
273  
(±7) 
364  
(±7) 
476  
(±7) 
602  
(±7) 
728 
(±3) 
742 
(±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight, heightc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Abbreviatede 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SMBGf 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diet & exercise instruction 
 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
Instruction on basic GU 
hygiene & hydration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 88 of 90 
 
 
Screening Period 
Double-blind Treatment Perioda 
Follow-
up 
Periodb 
Screening 
Run-in 
Randomized Double-blind Core Treatment Period 
Randomized Double-blind Extension Period 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Week 
-4 
-2 
0 
3 
6 
12 
18 
26 
39 
52 
68 
86 
104 
106 
Day (window [days]) 
-28 
-14  
(±3) 
1  
 
21 
(±3) 
42  
(±3) 
84  
(±3) 
126  
(±3) 
182  
(±3) 
273  
(±7) 
364  
(±7) 
476  
(±7) 
602  
(±7) 
728 
(±3) 
742 
(±3) 
IRT contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense glucose meter 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect/review diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense single-blind placebo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense double-blind IMP 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IMP accounting & compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGg 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Laboratory assessmentsh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 25 hydroxyvitamin D 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FPG i 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
HbA1c 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Safety laboratory 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Hematology 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Fasting lipids 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 89 of 90 
 
 
Screening Period 
Double-blind Treatment Perioda 
Follow-
up 
Periodb 
Screening 
Run-in 
Randomized Double-blind Core Treatment Period 
Randomized Double-blind Extension Period 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Week 
-4 
-2 
0 
3 
6 
12 
18 
26 
39 
52 
68 
86 
104 
106 
Day (window [days]) 
-28 
-14  
(±3) 
1  
 
21 
(±3) 
42  
(±3) 
84  
(±3) 
126  
(±3) 
182  
(±3) 
273  
(±7) 
364  
(±7) 
476  
(±7) 
602  
(±7) 
728 
(±3) 
742 
(±3) 
FSH and estradiol for 
documentation of 
menopausal statusj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estradiol (only for women) 
 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
Bone turnover markersk 
 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
Markers of calcium 
metabolisml 
 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
Collection of home 24-hour 
urine for albumin, creatinine, 
albumin-creatinine ratio, 
calcium, magnesium, and 
phosphorusm 
 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
Urinalysis w/microscopyn 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
DXA scan o 
 
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 
AE/SAE/AESI/EOSI 
recordingp 
To be assessed and reported throughout the study 


Statistical Analysis Plan 
Version: 3 
Date of Issue: 30 January 2020 
Lexicon Pharmaceuticals Protocol No. EFC15294 
 
Covance Study ID: 000000155848 
 
COVANCE INC. CONFIDENTIAL 
 
 
Page 90 of 90 
 
Abbreviations: AE = adverse event, AESI = adverse event of special interest, BMD = bone mineral density, BP = blood pressure, DXA = dual-energy X-ray absorptiometry, ECG = electrocardiogram, EOSI = event 
of special interest, EOT = End of Treatment, FPG = fasting plasma glucose, FSH = follicle-stimulating hormone, GU = genito-urinary, HbA1c = hemoglobin A1C, HR = heart rate, IMP = investigational medicinal 
product, iPTH = parathyroid hormone, IRT = Interactive Response Technology, NIMP = noninvestigational medicinal product, NTX = N-terminal telopeptide of Type 1 collagen, P1NP = Type 1 procollagen 
N-terminal propeptide, SAE = serious adverse event, SMBG = self-monitoring of blood glucose, β-CTX-1 = beta C-terminal telopeptide of Type 1 collagen. 
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 26 (Visit 8) and Week 104 (Visit 13). If the patient does not agree to a site visit, they will be contacted by telephone 
to inquire about safety status. 
b. The Follow-up Visit will take place 2 weeks ± 3 days after the last dose of IMP. All attempts will be made to contact the patient to inquire about safety status. 
c. Height to be measured only at Screening, Week 52, Week 104, and at the Premature EOT Visit. 
d. Vital sign measurements (sitting BP and HR): 3 separate seated BP and HR measurements should be taken with at least 1 minute between readings, following a 5-minute rest period and prior to phlebotomy. 
e. The abbreviated physical exam should focus on cardiac and respiratory systems, as well as any areas important for assessment of AEs if necessary. 
f. Patients will be instructed to measure their fasting glucose levels via SMBG and discuss results with site personnel at clinic visits or phone contacts. The frequency of the fasting SMBG measurements will be 
determined by the Investigator according to the clinical need and background diabetes treatment, but it is recommended to be done at least once a week. Patients will also be instructed to self-assess blood 
glucose levels whenever they experience any illnesses (eg, cold, flu), or symptoms of hyperglycemia or hypoglycemia. Note that the SMBG measurements obtained with glucose meters are displayed as plasma 
glucose concentration. The SMBGs ≤70 mg/dL will be reported on the hypoglycemia specific electronic case report form page. 
g. The 12-lead ECG recordings should be obtained prior to IMP administration. The ECG will be evaluated as “normal” or “abnormal”. 
h. All laboratory assessments occur prior to dose of double-blind IMP and NIMP. 
i. The FPG is performed in fasting status, ie, without any food intake (except for water) for at least 8 hours. 
j. The FSH and serum estradiol is performed in all women at Screening to confirm menopausal status as needed. 
k. Markers of bone turnover include: markers of bone resorption (serum NTX, serum β-CTX-1) and bone formation (serum P1NP and osteocalcin). 
l. Markers of calcium metabolism include: serum and urinary calcium (adjusted for creatinine), serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum and urinary phosphorus (adjusted for serum 
phosphorus, and creatinine), serum and urinary magnesium (adjusted for serum magnesium and creatinine), serum iPTH. 
m. 24-hour urine samples for calcium, phosphorus, and magnesium will be collected at Weeks 0, 26, 52, and 104. Patients will be instructed to initiate the 24-hour urine collection on the day before the visits. In 
exceptional situations, the 24-hour urine collection can be done up to 2 days maximum prior to or after the visit, and the specimen should be sent to the study site as soon as possible. 
n. Urinalysis will be done at central laboratory and includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte 
esterase. Microscopy includes detection of formed cellular elements, casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. In the event of abnormal urinalysis findings, urine cultures should 
be performed (microbial testing). Additionally, urine cultures should be performed if at any point the Principal Investigator suspects the presence of a urinary tract infection. 
o. Baseline DXA scans for BMD assessment will be performed during Run-in and centrally reviewed for eligibility assessment. All BMD assessments will be performed locally with a central review. Post-Baseline DXA 
scans will be performed within 2 weeks prior to the on-site visits at Weeks 26, 52, and 104, or no later than 7 days after the visit. Body composition by DXA will be performed at the same visits when the BMD is 
measured. 
p. All SAEs, AEs, AESI, and EOSI will be collected starting from signing informed consent and continue until the end of the study. All AEs that occur during treatment should be followed until study completion (or until 
patients leave the study) or until the event has resolved, the condition has stabilized or the patient is lost to follow-up. All patients will have a Follow-up Visit 2 weeks after the last dose of IMP to collect safety 
information.