Sotagliflozin in Heart Failure With Preserved Ejection Fraction (HFpEF) Patients

Study Overview
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Brief Summary
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The clinical benefits of the dual Sodium-Glucose cotransporter (SGLT) 1 and 2-inhibition have recently been reported in two clinical trials. The SOLOIST reported the benefits of sotagliflozin in Type-2 Diabetes Mellitus (T2DM) patients hospitalized for worsening of Heart Failure (HF), while the SCORED involved T2DM patients with Chronic Kidney Disease (CKD). It is worth noting that not only did the event curves separate within the first week post-treatment, but the effects of sotagliflozin on HF-related outcomes were observed regardless of Left Ventricular Ejection Fraction (LVEF) values and did not seem to attenuate with increasing LVEF as seen with empagliflozin and sacubitril/valsartan. Despite the favorable outcomes, the mechanism(s) of action through which sotagliflozin exerts these benefits remains unclear. The present study aims to investigate the potential (non-glucose dependent) cardio-renal pleiotropic effects of sotagliflozin in a mechanistic, randomized, double blind, placebo-control trial in HF patients with preserved ejection fraction (HFpEF). Comparisons between treatment groups will be made using cardiac MRI, CPET, 6-MWT and KCCQ-12.

Official Title
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SOTA-P-CARDIA Trial: A Randomized Trial of Sotagliflozin in HFpEF Patients Without Diabetes

Conditions
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Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: Sotagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients should meet all of the following criteria Ambulatory patients age ≥ 18 years Written informed consent prior to admission to the trial. No diabetes as confirmed by HbA1c <6.5%, fasting serum glucose <126 mg/dL, and review of concomitant medications and medical history Diagnosis of Heart failure (NYHA II to III) LVEF > 50% On medical therapy for heart failure consistent with prevailing cardiovascular guidelines at a stable dose for ≥4 weeks prior to screening, except for diuretics which must have been stable for ≥2 weeks prior to screening Women of child-bearing potential must agree to use birth control measures with a failure rate of <1% per year during the treatment period of the study Exclusion Criteria: Type 1 and Type 2 diabetes Acute coronary syndrome (ACS) or cardiac surgery within the last week. Pregnant or lactating women, Acute decompensated HF or hospitalized for HF within 1 month from screening visit Glomerular Filtration Rate (GFR) < 25 ml/ min/1.73m2, Patients on drugs with potential interaction with sotagliflozin including digoxin, phenytoin, HIV medication and rifampin. Receiving SGLT2-I 3-months prior to randomization. non-MRI compatible PM or ICD and any other medical or physical condition considered unappropriated by a study physician.

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<br>Daily administration of sotagliflozin (2x200 mg, orally, once a day) for 6 months. | Drug: Sotagliflozin<br>* Daily administration of sotagliflozin (2x200 mg, PO, OD) for 6 months.<br>|
| Placebo Comparator: Placebo<br>Daily administration of placebo (2 tablet identical in appearance and color to sotagliflozin tablets, orally, once a day) for 6 months. | Drug: Placebo<br>* Matching placebo for 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Left Ventricular mass in CMRI | Changes in Left Ventricular (LV) mass at 6 months compared to baseline | Baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Left Ventricular end-systolic volume | Changes in left ventricular end-systolic volume (LVESV) in CMRI at 6 months compared to baseline | Baseline and 6 months | 
| Changes in Left Ventricular end-diastolic volume | Changes in left ventricular end-diastolic volume (LVEDV) in CMRI at 6 months compared to baseline | Baseline and 6 months | 
| Changes in extracellular volume (ECV) | Changes in extracellular volume (ECV) to assess Left Ventricular interstitial myocardial fibrosis as quantified using T1 mapping at 6 months compared to baseline | Baseline and 6 months | 
| Changes in Left atrial volume index | Changes in Left atrial volume index measured by CMRI at 6 months compared to baseline | Baseline and 6 months | 
| Changes in Peak oxygen consumption (peakVO2) | Changes in exercise capacity as assessed by peak oxygen consumption in Cardiopulmonary exercise test (CPET) at 6 months compared to baseline | Baseline and 6 months | 
| Changes 6 minute walk test | Changes in exercise tolerance as assessed by 6 minute walk test, or the distance covered over a time of 6 minutes, at 6 months compared to baseline | Baseline and 6 months | 
| Changes in The Kansas City Cardiomyopathy Questionnaire (KCCQ) | Changes in The KCCQ at 6 months compared to baseline. The KCCQ is the most widely used instrument to evaluate quality of life in Heart Failure (HF). The KCCQ is a 12-item self-administered questionnaire used to measure the patient's perception of their health status. The KCCQ is a disease-specific health status instrument composed of 12 items that quantifies the domains of physical limitations, symptoms, self-efficacy, social limitation and quality of life from heart failure. Full scale range is from 0 to 100; higher scores reflect better health status. | Baseline and 6 months |