Type 2 Diabetes Mellitus

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.

Sotagliflozin

Sotagliflozin

Tablet

200

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.

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.
• 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.
• 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.