A Study to Evaluate Safety and Effects of Sotagliflozin 400 and 200 mg on Glucose Control in Participants With Type 2 Diabetes, Severe Impairment of Kidney Function and Inadequate Blood Sugar Control

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

• Placebo (Drug): Placebo tablet (identical to sotagliflozin 200 mg in appearance) orally, once daily.
• Sotagliflozin (Drug), also known as SAR439954: Sotagliflozin 200 mg, tablet, orally, once daily.

Primary outcomes

• Change From Baseline in HbA1c at Week 26 Comparing Sotagliflozin 400 mg Versus Placebo [Baseline to Week 26]: An analysis of covariance (ANCOVA) model was used for the analysis.

Secondary outcomes

• Change From Baseline in HbA1c at Week 26 Comparing Sotagliflozin 200 mg Versus Placebo [Baseline to Week 26]: An ANCOVA model was used for the analysis.
• Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 [Baseline to Week 26]: An ANCOVA model was used for the analysis.
• Change From Baseline in Body Weight at Week 26 [Baseline to Week 26]: An ANCOVA model was used for the analysis.
• Change From Baseline in SBP at Week 12 in Participants With Baseline SBP ≥130 mmHg [Baseline to Week 12]: An ANCOVA model was used for the analysis.
• Change From Baseline in SBP at Week 12 for All Participants [Baseline to Week 12]: An ANCOVA model was used for the analysis.
• Percentage Change From Baseline in the Urine Albumin: Creatinine Ratio (UACR) at Week 26 in Participants With Baseline UACR >30 Milligrams Per Gram (mg/g) [Baseline to Week 26]: An ANCOVA model was used for analysis. No Measure of Dispersion was pre-specified to be calculated.
• Percentage of Participants With HbA1c <6.5% at Week 26 [Week 26]
• Percentage of Participants With HbA1c <7.0% at Week 26 [Week 26]
• Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) [First dose of study drug to last dose of study drug (up to 56.3 weeks) + 4 weeks]: An adverse event (AE) is any untoward medical occurrence in a participants or clinical investigation participants administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the investigational medicinal product (IMP).

Other outcomes

• Percentage of Participants With Hypoglycemic Events [up to 56.3 weeks]: Percentage of participants with hypoglycemic events are reported for the following 3 categories: Any hypoglycemia (as reported in the Electronic Case Report Form); Documented symptomatic hypoglycemia \[typical symptoms of hypoglycemia (increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and/or coma) and plasma glucose ≤ 70 mg/dL (3.9 mmol/L)\]; Severe \[an event requiring assistance of another person to actively administer carbohydrate, glucagon, intravenous glucose or other resuscitative actions\] or documented symptomatic hypoglycemia \[typical symptoms of hypoglycemia and plasma glucose ≤ 70 mg/dL\].

Sex: All, ages: 18 Years to any

Inclusion criteria :

* Participants with Type 2 Diabetes (drug-naïve or on antidiabetic therapy) and documented severe renal insufficiency - CKD4 - defined by an estimated glomerular filtration rate (eGFR) equation (based on the 4 variable modification of diet in renal disease (MDRD) equation) of ≥15 and <30 milliliter per minute (mL/min)/1.73 per meter square (m\^2).
* Signed written informed consent to participate in the study in accordance with local regulations.

Exclusion criteria:

* At the time of screening, age <18 years.
* Hemoglobin A1c (HbA1c) <7% or >11%.
* Type 1 diabetes.
* 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 during the study.
* Treatment with an sodium-glucose cotransporter type 2 (SGLT2) inhibitor (canagliflozin, dapagliflozin, empagliflozin) during the last 12 months.
* Uncontrolled high blood pressure, severe anemia, severe cardiovascular problems, such as heart failure, active cancer, or other conditions that the Investigator believes with result in a short life expectancy, will preclude their safe participation in this study, or will make implementation of the protocol or interpretation of the study results difficult.
* Lower extremity complications (such as skin ulcers, infection, osteomyelitis and gangrene) identified during the Screening period, and still requiring treatment at Randomization.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Participant flow

Outcome results

• Change From Baseline in HbA1c at Week 26 Comparing Sotagliflozin 400 mg Versus Placebo (Primary), Least squares mean, percentage of HbA1c: Placebo -0.11 +/- 0.151; Sotagliflozin 400 mg -0.40 +/- 0.131 (p 0.0962)
• Change From Baseline in HbA1c at Week 26 Comparing Sotagliflozin 200 mg Versus Placebo (Secondary), Least squares mean, percentage of HbA1c: Placebo -0.11 +/- 0.151; Sotagliflozin 200 mg -0.07 +/- 0.162 (p 0.8124)
• Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 (Secondary), Least squares mean, millimole per liter (mmol/L): Placebo 0.069 +/- 0.4482; Sotagliflozin 200 mg -0.291 +/- 0.5056; Sotagliflozin 400 mg -0.644 +/- 0.4348 (p 0.5501)
• Change From Baseline in Body Weight at Week 26 (Secondary), Least squares mean, kilogram (kg): Placebo 0.39 +/- 0.615; Sotagliflozin 200 mg -0.43 +/- 0.480; Sotagliflozin 400 mg -1.02 +/- 0.490 (p 0.2432)
• Change From Baseline in SBP at Week 12 in Participants With Baseline SBP ≥130 mmHg (Secondary), Least squares mean, mmHg: Placebo -2.70 +/- 1.815; Sotagliflozin 200 mg -4.84 +/- 1.882; Sotagliflozin 400 mg -7.10 +/- 1.842 (p 0.3954)
• Change From Baseline in SBP at Week 12 for All Participants (Secondary), Least squares mean, mmHg: Placebo -2.50 +/- 1.762; Sotagliflozin 200 mg -5.74 +/- 1.752; Sotagliflozin 400 mg -7.86 +/- 1.794 (p 0.1232)
• Percentage Change From Baseline in the Urine Albumin: Creatinine Ratio (UACR) at Week 26 in Participants With Baseline UACR >30 Milligrams Per Gram (mg/g) (Secondary), Geometric mean, percent change: Placebo -4.56 +/- NA; Sotagliflozin 200 mg -26.99 +/- NA; Sotagliflozin 400 mg -30.66 +/- NA (p 0.222)
• Percentage of Participants With HbA1c <6.5% at Week 26 (Secondary), Number, percentage of participants: Placebo 2.2; Sotagliflozin 200 mg 5.4; Sotagliflozin 400 mg 8.7 (p 0.2420)
• Percentage of Participants With HbA1c <7.0% at Week 26 (Secondary), Number, percentage of participants: Placebo 4.3; Sotagliflozin 200 mg 16.3; Sotagliflozin 400 mg 17.4 (p 0.0066)
• Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) (Secondary), Number, percentage of participants: Placebo 82.8; Sotagliflozin 200 mg 86.2; Sotagliflozin 400 mg 81.1
• Percentage of Participants With Hypoglycemic Events (Other pre specified), Number, percentage of participants: Placebo 40.9; Sotagliflozin 200 mg 40.4; Sotagliflozin 400 mg 38.9

Adverse events

Time frame: Deaths: Up to approximately 60 weeks; Adverse Events: First dose of study drug to last dose of study drug (up to 56.3 weeks) + 4 weeks

Serious adverse events by term

15 more terms not shown.

Other adverse events by term

6 more sites not listed.

• Results publication: Natale P, Tunnicliffe DJ, Toyama T, Palmer SC, Saglimbene VM, Ruospo M, Gargano L, Stallone G, Gesualdo L, Strippoli GF. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev. 2024 May 21;5(5):CD015588. doi: 10.1002/14651858.CD015588.pub2. PMID 38770818
• Results publication: Cherney DZI, Ferrannini E, Umpierrez GE, Peters AL, Rosenstock J, Carroll AK, Lapuerta P, Banks P, Agarwal R. Efficacy and safety of sotagliflozin in patients with type 2 diabetes and severe renal impairment. Diabetes Obes Metab. 2021 Dec;23(12):2632-2642. doi: 10.1111/dom.14513. Epub 2021 Aug 20. PMID 34338408

• Study Protocol (PDF, 2017-12-15)
• Statistical Analysis Plan (PDF, 2019-11-25)

• Suman Wason, MD, Study director, Lexicon Pharmaceuticals, Inc.

NIH grants: 2016