An Exploratory, Randomized, Double-blind, Placebo-controlled, Parallel Arm Trial of the Safety and Pharmacodynamic Activity of Sotagliflozin in Hemodynamically Stable Patients with Worsening Heart Failure

Sotagliflozin (Sanofi code SAR439954, Lexicon code LX4211) is an orally administered small molecule, the first dual inhibitor of sodium-glucose co-transporter 1 and 2 (SGLT1 and SGLT2), formulated as 75 mg and 200 mg coated tablets. The compound, a member of the pharmaceutical class of SGLT-inhibitors known as gliflozins, lowers blood glucose by decreasing and delaying SGLT1-mediated glucose absorption in the gastrointestinal (GI) tract as well as enhancing glucose excretion in the urine by reducing renal glucose re-absorption via action of SGLT2 in the kidney. Sotagliflozin is being investigated as a therapy to improve glycemic control in adults with diabetes. In type 2 diabetes (T2DM) it is being developed as monotherapy or in combination with other classes of anti-diabetic agents. For type 1 diabetes (T1DM) it is being developed for adjunctive use with insulin. Recent clinical trial data support that SGLT2 inhibitors may reduce heart failure morbidity and mortality.

This study will be a randomized, double-blind, placebo-controlled, parallel arm trial of the safety, tolerability and pharmacodynamic activity of sotagliflozin in hemodynamically stable patients hospitalized with worsening heart failure. Study drug will be initiated (either in the hospital or outpatient facility) within 4 days following completion of intravenous diuretic therapy, and continued in an outpatient setting for a total of 14 days.

The primary objective of this study is the assessment of safety and tolerability of sotagliflozin, added to the standard of care treatment, in hemodynamically stable patients hospitalized for worsening of heart failure, compared to placebo. A co-primary objective of this trial is the estimation of the effect of sotagliflozin, when added to the standard of care treatment, on changes in plasma volume, as assessed by direct (indicator dilution) and indirect (hemoconcentration) methods, in hemodynamically stable patients hospitalized for worsening of heart failure, compared to placebo. 

Inclusion Criteria

I 01. Written informed consent;
I 02. 18 years of age or older
I 03. Patient 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 vein 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 lbs (2.27 kg)
AND
- Requiring treatment with IV diuretics
I 04. Estimated glomerular filtration rate (eGFR) ≥30
ml/min/1.73m2 at the screening or randomization visit by the 4 variable Modification of Diet in Renal Disease (MDRD) equation
I 05. Female subject 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.
I 06. 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 patient has a female partner of childbearing potential, the patient 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.
Inclusion criteria at randomization
I 07. Transitioning from intravenous (IV) to oral diuretics and oral diuretic treatment has been prescribed or administered
I 08. Hemodynamically stable, defined as:
- SBP ≥100 mmHg with no requirement for IV inotropes or IV vasodilators 

Exclusion Criteria

E01. History of Type 1 diabetes mellitus
E02. 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
E03. Current admission or visit for Worsening 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
E04. 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
E05. Patients who recently had or scheduled to have cardiac interventions may be eligible if:
-Stable 48 hours post procedure AND
-Have diuretic treatment planned for the duration of treatment in this study
E06. Current use of or recent suspension of digoxin therapy with high levels of digoxin (level should be obtained and must be <1.2 ng/mL) at screening.
E07. History of heart or kidney transplant
E08. Diagnosis of hypertrophic obstructive cardiomyopathy
E09. 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
E10. Pregnancy (demonstrated by serum pregnancy test at screening), breast-feeding, or inability or refusal to undergo pregnancy testing
E11. Use of any investigational drug(s) or prohibited therapy or sodium-glucose co-transporter 2 (SGLT2) inhibitor 5 half-lives prior to screening
E12. Patients 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
E13. 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
E14. Laboratory findings at the Screening Visit:
a. Alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) >3 times the upper limit of the normal laboratory range (ULN) (1 repeat lab allowed)
b. Total bilirubin >1.7 times the ULN (except in case of Gilbert’s syndrome) (1 repeat lab allowed)
c. Amylase and/or lipase > 3 times the ULN (1 repeat lab allowed)
E15. Patients with a severe or persistent in spite of optimal treatment genitourinary tract infection at time of randomization.
E16. Patient is the Investigator or any Subinvestigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol

Additional exclusion criteria for patients with diabetes:

E17. History of diabetic ketoacidosis or non-ketotic
hyperosmolar coma within 3 months prior to the
screening visit
E18. Lower extremity diabetic complications (such as skin ulcers, infection, osteomyelitis and gangrene) identified during the Screening period, and still requiring treatment at Randomization 

Conditions:
• Cardiology