Safety, Tolerability and Pharmacodynamic Activity of Sotagliflozin in Hemodynamically Stable Participants With Worsening Heart Failure
Condition: Cardiac Failure Aggravated
MeSH terms: Heart Failure
Intervention: Sotagliflozin; Placebo
Intervention description: Pharmaceutical form: Tablet; Route of administration: Oral; Pharmaceutical form: Tablet; Route of administration: Oral
Intervention MeSH terms: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Primary Objectives:

        -  Assess the safety and tolerability of sotagliflozin in hemodynamically stable
           participants with worsening of heart failure, compared to placebo.

        -  Estimate the effects of sotagliflozin on plasma volume changes in hemodynamically stable
           participants with worsening of heart failure, compared to placebo.

      Secondary Objectives:

        -  Explore the effect of sotagliflozin on erythropoiesis, as assessed by changes in plasma
           erythropoietin levels, in hemodynamically stable participants with worsening of heart
           failure, compared to placebo.

        -  Explore the effect of sotagliflozin on changes in plasma N-terminal prohormone of brain
           natriuretic peptide (NT-proBNP) levels, in hemodynamically stable participants with
           worsening of heart failure, compared to placebo.
    

Eligibility criteria:

        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.