Safety, Tolerability and Pharmacodynamic Activity of Sotagliflozin in Hemodynamically Stable Participants With Worsening Heart Failure

The total study duration will be approximately 27-40 days, including a screening period of 1-10 days, a treatment period of 14 days, and a follow-up period of 14±2 days.

• Sotagliflozin (Drug), also known as SAR439954: Pharmaceutical form: Tablet; Route of administration: Oral
• Placebo (Drug): Pharmaceutical form: Tablet; Route of administration: Oral

Primary outcomes

• Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), AEs Leading to Discontinuation From the Investigational Medicinal Product (IMP) and Deaths [Baseline up to Day 14]: AE: is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the participants at immediate risk of death (a life-threatening event); an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a participant; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. AESI: is an adverse event (serious or nonserious) of scientific and medical concern, specific to the IMP or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor may be appropriate.
• Change From Baseline in Hemoconcentration as Assessed by Changes in Albumin to Day 14 [Baseline to Day 14]
• Change From Baseline in Hemoconcentration as Assessed by Changes in Hematocrit to Day 14 [Baseline to Day 14]
• Change From Baseline in Hemoconcentration as Assessed by Changes in Hemoglobin to Day 14 [Baseline to Day 14]
• Change From Baseline in Hemoconcentration as Assessed by Changes in Total Protein to Day 14 [Baseline to Day 14]
• Changes From Baseline in Plasma Volume to Day 14 [Baseline to 14 Days]: Change in plasma volume in milliliters (mL) was assessed by the indicator dilution method using 131I-labelled human albumin.

Secondary outcomes

• Change From Baseline in Erythropoietin to Day 14 [Baseline to Day 14]: Change in erythropoietin international units per liter (IU/L) was measured by chemiluminescent enzyme-labelled immunometric assay.
• Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) to Day 14 [Baseline to Day 14]: Change in NT-proBNP picomoles per liter (pmol/L) was measured by standard electrochemiluminescence immunoassay.

Sex: All, ages: 18 Years to any

Inclusion criteria:

* Written informed consent.
* 18 years of age or older.
* Participants admitted to the hospital or had urgent visit to emergency department or heart failure unit/clinic or infusion center for Congestive Heart Failure (CHF), defined by:
* Presence of ≥2 of the following clinical signs and symptoms of congestion: jugular venous distension, pitting edema in lower extremities greater than trace, dyspnea, rales heard on auscultation, radiographic pulmonary congestion, weight gain above historical dry weight of at least 5 pounds (lbs) (2.27 Kilograms (kg)).
* Requiring treatment with intravenous (IV) diuretics.
* Estimated glomerular filtration rate (eGFR) ≥30 milliliter per minute (mL/min)/1.73 square meter (m\^2) at the screening or randomization visit by the 4 variable Modification of Diet in Renal Disease (MDRD) equation.
* Female participants must use a double contraception method during the study including a highly effective method of birth control, except if she has undergone sterilization at least 3 months earlier or is postmenopausal.
* Male participants, unless vasectomized and confirmed sterile by sperm analysis, must use condoms during the study and refrain from donating sperm up to 90 days after the day of last dose. If the participant has a female partner of childbearing potential, the participant must wear a condom and female partner must use at least 1 highly effective method of birth control during the study treatment period and the Follow-up period.
* Transitioning from IV to oral diuretics, and oral diuretic treatment has been prescribed or administered.
* Hemodynamically stable, defined as systolic blood pressure (SBP) >100 millimeters of mercury (mmHg) with no requirement for IV inotropes or IV vasodilators.

Exclusion criteria :

* History of Type 1 diabetes mellitus.
* Appears unlikely or unable to participate in the required study procedures, as assessed by the study Investigator, study coordinator, or designee (ex: clinically-significant psychiatric, addictive, or neurological disease), or sectioned due to an official or court order.
* Current admission or visit for Worsening Heart Failure (HF) that is clearly and primarily triggered by causes such as tachyarrhythmia (example: sustained ventricular tachycardia, or atrial fibrillation/flutter with sustained ventricular response > 130 beats per minute), acute coronary syndrome, pulmonary embolism, cerebrovascular accident, heart valve disorders (such as severe aortic stenosis), as determined by the Investigator.
* Clinically significant myocardial infarction (MI) within past 1 month as determined by Investigator and with objective evidence from ECG, and/or cardiac imaging and/or coronary angiography. Small isolated elevations in troponin that often accompany HF hospitalization are not an exclusion, nor are clinically significant MIs that have been revascularized without complications.
* Participants who recently had or scheduled to have cardiac interventions may be eligible if:
* Stable 48 hours post procedure.
* Have diuretic treatment planned for the duration of treatment in this study.
* Current use of or recent suspension of digoxin therapy with high levels of digoxin (level should be obtained and must be <1.2 nanograms per milliliter (ng/mL) at screening.
* History of heart or kidney transplant.
* Diagnosis of hypertrophic obstructive cardiomyopathy.
* End-stage HF defined as requiring left ventricular assist device insertion, intra-aortic balloon placement (IABP), or any type of mechanical support during the study period.
* Pregnancy (demonstrated by serum pregnancy test at screening), breast-feeding, or inability or refusal to undergo pregnancy testing.
* Use of any investigational drug(s) or prohibited therapy or sodium-glucose co-transporter 2 (SGLT2) 5 half-lives prior to screening.
* Participants with moderate or severe respiratory, hepatic, neurological, psychiatric, active malignant tumor or other major systemic disease (including any diseases with evidence of malabsorption), making implementation of the protocol and/or the interpretation of the study results difficult.
* Known allergies, hypersensitivity, or intolerance to sotagliflozin or any inactive component of sotagliflozin or placebo (ie, microcrystalline cellulose, croscarmellose sodium \[disintegrant\], talc, silicon dioxide, and magnesium stearate \[non-bovine\]), unless the reaction is deemed irrelevant to the study by the PI.
* Laboratory findings at the Screening Visit:
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper limit of the normal laboratory range (ULN) (1 repeat lab allowed).
* Total bilirubin >1.7 times the ULN (except in case of Gilbert's syndrome) (1 repeat lab allowed).
* Amylase and/or lipase >3 times the ULN (1 repeat lab allowed).
* Participants with a severe or persistent in spite of optimal treatment genitourinary tract infection at time of randomization.
* Participant is the Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol.
* History of diabetic ketoacidosis or non-ketotic hyperosmolar coma within 3 months prior to the screening visit.
* Lower extremity diabetic 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

• Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), AEs Leading to Discontinuation From the Investigational Medicinal Product (IMP) and Deaths (Primary), Number, percentage of participants: Placebo 40; Sotagliflozin 200 mg 30; Sotagliflozin 400 mg 45.5
• Change From Baseline in Hemoconcentration as Assessed by Changes in Albumin to Day 14 (Primary), Least squares mean, g/L: Placebo 1.17 +/- 2.71; Sotagliflozin 200 mg 2.44 +/- 2.40; Sotagliflozin 400 mg 0.15 +/- 2.14 (p 0.736)
• Change From Baseline in Hemoconcentration as Assessed by Changes in Hematocrit to Day 14 (Primary), Least squares mean, percentage of red blood cells: Placebo 0.02 +/- 0.02; Sotagliflozin 200 mg -0.02 +/- 0.02; Sotagliflozin 400 mg -0.01 +/- 0.02 (p 0.184)
• Change From Baseline in Hemoconcentration as Assessed by Changes in Hemoglobin to Day 14 (Primary), Least squares mean, g/L: Placebo 8.16 +/- 6.80; Sotagliflozin 200 mg -8.91 +/- 6.02; Sotagliflozin 400 mg -3.94 +/- 5.37 (p 0.094)
• Change From Baseline in Hemoconcentration as Assessed by Changes in Total Protein to Day 14 (Primary), Least squares mean, g/L: Placebo 5.31 +/- 4.32; Sotagliflozin 200 mg 0.49 +/- 3.83; Sotagliflozin 400 mg -1.05 +/- 3.41 (p 0.4269)
• Changes From Baseline in Plasma Volume to Day 14 (Primary), Least squares mean, mL: Placebo -525.00 +/- 433.19; Sotagliflozin 200 mg 322.20 +/- 359.23; Sotagliflozin 400 mg -35.67 +/- 392.43 (p 0.1761)
• Change From Baseline in Erythropoietin to Day 14 (Secondary), Least squares mean, IU/L: Placebo 0.03 +/- 5.92; Sotagliflozin 200 mg 13.78 +/- 6.26; Sotagliflozin 400 mg -0.07 +/- 5.04 (p 0.1242)
• Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) to Day 14 (Secondary), Least squares mean, pmol/L: Placebo 91.36 +/- 78.04; Sotagliflozin 200 mg -59.53 +/- 81.28; Sotagliflozin 400 mg 86.10 +/- 65.87 (p 0.2121)

Adverse events

Time frame: First dose of study drug to last dose of study drug (up to Day 14) + 2 weeks

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2019-08-02)
• Statistical Analysis Plan (PDF, 2018-04-19)

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

NIH grants: 2017