Efficacy and Safety of Sotagliflozin Versus Glimepiride and Placebo in Participants With Type 2 Diabetes Mellitus That Are Taking Metformin Monotherapy

Study Overview
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Brief Summary
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Primary Objective: To demonstrate the non-inferiority of Sotagliflozin 400 milligrams (mg) compared to Glimepiride on hemoglobin A1c (HbA1c) reduction at Week 52 in participants with Type 2 Diabetes (T2D) who have inadequate glycemic control with metformin. Secondary Objectives: To demonstrate the superiority of Sotagliflozin 400 mg compared to Glimepiride on change in body weight, systolic blood pressure (SBP) in participants with baseline SBP ≥130 millimeter of mercury (mmHg), SBP in all participants, and proportion of participants with at least 1 documented symptomatic hypoglycemic event (≤70 milligrams per deciliter [mg/dL]). To demonstrate the superiority of Sotagliflozin 400 mg compared to placebo on change in HbA1c, body weight, SBP in participants with baseline SBP ≥130 mmHg, SBP in all participants. To demonstrate the superiority of Sotagliflozin 200 mg compared to placebo on change in HbA1c. To demonstrate the non-inferiority of Sotagliflozin 400 mg compared to Glimepiride on change in HbA1c. To demonstrate the superiority of Sotagliflozin 400 mg compared to Glimepiride on change in HbA1c. To evaluate the safety and tolerability of Sotagliflozin compared to Glimepiride and placebo.

Detailed Description
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Up to 58 weeks, including a Screening Period consisting of a Screening phase of up to 2 weeks, a 2-week single-blind placebo Run-in phase, a 52-week double-blind Treatment Period, and a 2-week post-treatment Follow-up period to collect safety information.

Official Title
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A 52-week Randomized, Double-blind, Double-dummy, Active and Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin Compared to Glimepiride or Placebo Added to Metformin in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control With Metformin Monotherapy

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Sotagliflozin (SAR439954)
* Drug: Glimepiride
* Drug: Metformin
* Drug: Placebo
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Participants with Type 2 Diabetes (T2D) treated with metformin at a stable dose ≥1500 milligrams per day (mg/day) or maximum tolerated dose (documented) for at least 12 weeks prior to Screening Visit; in case of documented lack of tolerance, metformin dose <1500 mg/day is acceptable, and the dose should be stable for at least 12 weeks prior to Screening Visit. Participants has given written informed consent to participate in the study in accordance with local regulations. Exclusion criteria: Age <18 years at the Screening Visit or <legal age of majority, whichever is greater. Type 1 diabetes mellitus. HbA1c, HbA1c <7.0% or HbA1c >10% at Screening. Fasting Plasma Glucose (FPG) >15 millimoles per liter (mmol/L) (>270 milligram per deciliter [mg/dL]) measured by the central laboratory at Screening (Visit 1) and confirmed by a repeat test (>15 mmol/L [>270 mg/dL]) before randomization. Body mass index ≤20 or >45 kilogram per meter square (kg/m^2) at Screening. Pregnant (confirmed by pregnancy test at the Screening) or breast-feeding women. Women of childbearing potential (WOCBP) not willing to use highly effective method(s) of birth control during the study treatment period and the follow-up period, or who are unwilling or unable to be tested for pregnancy (see Appendix A) during the study. Previous use of any antidiabetic drug other than Metformin within 12 weeks preceding the Screening Visit. Use of a selective Sodium-glucose co-transporter-2 (SGLT2) inhibitor (e.g., Canagliflozin, Dapagliflozin, or Empagliflozin) within 3 months prior to the Screening visit. Use of systemic glucocorticoids (excluding topical, or ophthalmic application, intra-articular, nasal spray or inhaled forms) for more than 10 consecutive days within 90 days prior to the Screening Visit. Previous insulin use >1 month (at any time, except for treatment of gestational diabetes). History of prior gastric surgical procedure, including gastric banding, or inflammatory bowel disease within 3 years prior to the Screening Visit. Difficulty swallowing such that the participants cannot take the investigational medicinal product (IMP). History of diabetic ketoacidosis or nonketotic hyperosmolar coma within 12 weeks prior to the Screening Visit. Mean of 3 separate blood pressure measurements >180 millimeter of mercury (mmHg) (SBP) or >100 mmHg (DBP). History of hypertensive emergency within 12 weeks prior to Screening. Participants who have previously been randomized in any clinical trial of Sotagliflozin/LX4211. Participants with severe renal disease as defined by an estimated glomerular filtration rate (eGFR) of <30 milliliter per minute per meter square (mL/min/1.73 m^2) at Screening, based on the 4 variable Modification of Diet in Renal Disease (MDRD) equation (or according to the renal function restrictions of metformin use defined in the local approved label). Participants with severe anemia, severe cardiovascular (including congestive heart failure New York Heart Association IV), respiratory, hepatic, neurological, psychiatric, or active malignant tumor or other major systemic disease that, according to 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 ULN (except in case of Gilbert's syndrome). Participants who have taken other investigational drugs within 12 weeks or 5 half-lives from Screening whichever is longer. Participants unwilling or unable to perform self-monitoring blood glucose (SMBG), complete the participant diary, or comply with study visits and other study procedures as required per protocol. Participants with contraindication to glimepiride as per local labelling. Participants with contraindication to metformin as per local labelling. The above information is not intended to contain all considerations relevant to a Participants potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sotagliflozin 400 mg<br>Following a 2-week run-in period, two Sotagliflozin 200 mg, tablets, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks. | Drug: Sotagliflozin (SAR439954)<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Metformin<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Placebo<br>* Pharmaceutical form: capsule Route of administration: oral<br>|
| Experimental: Sotagliflozin 200 mg<br>Following a 2-week run-in period, one Sotagliflozin 200 mg, tablet and one Sotagliflozin-matching placebo tablet, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks. | Drug: Sotagliflozin (SAR439954)<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Metformin<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Placebo<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Placebo<br>* Pharmaceutical form: capsule Route of administration: oral<br>|
| Active Comparator: Glimepiride<br>Following a 2-week run-in period, two Sotagliflozin-matching placebo tablets, and combination of two Glimepiride capsules with adequate dose strengths per dose titration (titrated up to 6mg), taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks. | Drug: Glimepiride<br>* Pharmaceutical form: capsule Route of administration: oral<br>Drug: Metformin<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Placebo<br>* Pharmaceutical form: tablet Route of administration: oral<br>|
| Placebo Comparator: Placebo<br>Following a 2-week run-in period, two Sotagliflozin-matching placebo tablets and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks. | Drug: Metformin<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Placebo<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: Placebo<br>* Pharmaceutical form: capsule Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c at Week 52 | An analysis of covariance (ANCOVA) model was used for the analysis. | Baseline, Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c at Week 26 | An ANCOVA model was used for the analysis. | Baseline, Week 26 | 
| Change From Baseline in Body Weight at Week 26 and 52 | An ANCOVA model was used for the analysis. | Baseline, Week 26, Week 52 | 
| Change From Baseline in Systolic Blood Pressure (SBP) for Participants With SBP ≥130 mmHg at Week 12 | An ANCOVA model was used for the analysis. | Baseline, Week 12 | 
| Change From Baseline in Systolic Blood Pressure (SBP) for All Participants at Week 12 | An ANCOVA model was used for the analysis. | Baseline, Week 12 | 
| Percentage of Participants With At Least One Documented Symptomatic Hypoglycemic Event | Documented symptomatic hypoglycemia includes the typical symptoms of hypoglycemia (increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and/or coma) and plasma glucose ≤ 70 mg/dL (3.9 mmol/L). | Up to Week 52 | 
| Percentage of Participants With Adverse Events (AEs) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. | Up to Week 52 |