Heart Failure Clinical Trials

In November 2020, we reported results from both the SOLOIST and SCORED outcome studies, which achieved their primary endpoints by demonstrating statistically significant reductions in total cardiovascular deaths, hospitalizations for heart failure and urgent heart failure visits in patients treated with sotagliflozin as compared with placebo.

The key results from SOLOIST and SCORED were presented at the Late-Breaking Science Session of the American Heart Association (AHA) Scientific Sessions 2020 and simultaneously published in The New England Journal of Medicine (NEJM) in two separate articles titled: “Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure” and “Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease.” The articles may be accessed at www.nejm.org.

In January 2021, we received feedback from the FDA that the results of the studies can support the submission of an application for regulatory approval for an indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with type 2 diabetes with either worsening heart failure or additional risk factors for heart failure.

SOLOIST Clinical Trial

SOLOIST was a multi-center, randomized, double-blinded, placebo-controlled Phase 3 study evaluating the cardiovascular efficacy of sotagliflozin versus placebo when added to standard of care in 1,222 patients with type 2 diabetes who had recently been hospitalized for worsening heart failure. The primary endpoint was the total number of events comprised of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure in patients starting treatment with 200 mg sotagliflozin once daily compared with placebo, with dosing initiated either before or within 3 days of hospital discharge.

The first dose of sotagliflozin or placebo was administered prior to hospital discharge in 48.8% of the patients and a median of two days after discharge in 51.2% of the patients, with the benefits of sotagliflozin being consistent between those prespecified subgroups of patients. The initial 200 mg once daily dose of sotagliflozin was increased to 400 mg once daily if unacceptable side effects did not occur.

Treatment with sotagliflozin resulted in a significantly lower total number of cardiovascular deaths, heart failure hospitalizations and urgent visits as compared to placebo. A total of 600 primary endpoint events occurred in the study, with 245 events in the sotagliflozin treated group and 355 events in the placebo group. There were 51.0 primary endpoint events per 100 patient-years in the sotagliflozin treated group as compared to 76.3 events per 100 patient-years in the placebo group (HR=0.67; 95% confidence interval [CI]=0.52 to 0.85; p<0.001). There were 10.6 events of cardiovascular death per 100 patient-years in the sotagliflozin treated group as compared to 12.5 events per 100 patient-years in the placebo group (HR=0.84; 95% CI=0.58 to 1.22; p=0.36).

Of note, effects on the primary endpoint were consistent among patients suffering from heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), with a hazard ratio of 0.72 (95% CI=0.56 to 0.94) in patients with a left ventricular ejection fraction (LVEF) of less than 50% and a hazard ratio of 0.48 (95% CI=0.27 to 0.86) in patients with a LVEF of greater than or equal to 50%.

Serious adverse events that led to discontinuation of study drug, as determined by investigators, occurred in 3.0% (n=18) of the patients in the sotagliflozin treated group and in 2.8% (n=17) of the patients in the placebo group. Based on investigator reported events, the most common adverse events of special interest included hypotension (6.0% on sotagliflozin versus 4.6% on placebo), urinary tract infections (4.8% on sotagliflozin versus 5.1% on placebo), acute kidney injury (4.1% on sotagliflozin versus 4.4% on placebo), and diarrhea (6.1% on sotagliflozin versus 3.4% on placebo). Among other adverse events of interest, in SOLOIST, genital mycotic infections (0.8% on sotagliflozin vs. 0.2% on placebo) were infrequent, severe hypoglycemia (1.5% on sotagliflozin vs. 0.3% on placebo) was more common in the sotagliflozin treated group and diabetic ketoacidosis (0.3% on sotagliflozin vs. 0.7% on placebo) was similar between treatment groups.

The SOLOIST study was originally designed with a primary endpoint of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, as determined by independent adjudication, but was modified in connection with the early close out of the study to include urgent heart failure visits and reflect the total number of events, as determined by investigators, in order to enhance the statistical power of the comparison. The specification of the primary endpoint based on total events was implemented without any awareness of the study outcomes or study-group assignments and without information from an interim analysis.

The results for first occurrence of cardiovascular death or hospitalization for heart failure (HR=0.71; 95% CI=0.57 to 0.89; p=0.003) based on investigator reported events were consistent with those of the modified primary endpoint.

SCORED Clinical Trial

SCORED was a multi-center, randomized, double-blinded, placebo-controlled Phase 3 study evaluating the cardiovascular efficacy of sotagliflozin versus placebo when added to standard of care in 10,584 patients with type 2 diabetes, chronic kidney disease with eGFR of 25 to 60 ml per minute per 1.73 m2 of body-surface area, and risks for cardiovascular disease. The primary endpoint was the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure in patients treated with sotagliflozin compared with placebo. The initial 200 mg once daily dose of sotagliflozin was increased to 400 mg once daily if unacceptable side effects did not occur.

Treatment with sotagliflozin resulted in a significantly lower total number of cardiovascular deaths, heart failure hospitalizations and urgent visits as compared to placebo. A total of 930 primary endpoint events occurred in the study, with 400 events in the sotagliflozin treated group and 530 events in the placebo group. There were 5.6 primary endpoint events per 100 patient-years in the sotagliflozin treated group as compared to 7.5 events per 100 patient-years in the placebo group (HR=0.74; 95% CI=0.63 to 0.88; p<0.001). There were 2.2 events of cardiovascular death per 100 patient-years in the sotagliflozin treated group as compared to 2.4 events per 100 patient-years in the placebo group (HR=0.90; 95% CI=0.73 to 1.12; p=0.35).

Of note, over the course of the study, the data showed an average reduction in hemoglobin A1c of 0.56% in the sotagliflozin treated group as compared to a reduction of 0.25% in the placebo group in patients with severe chronic kidney disease, eGFR less than 30 ml per minute per 1.73 m2 of body-surface area (p<0.001). In patients with moderate chronic kidney disease, eGFR greater than or equal to 30 ml per minute per 1.73 m2 of body-surface area, the data showed an average reduction in hemoglobin A1c of 0.60% in the sotagliflozin treated group as compared to a reduction of 0.17% in the placebo group (p<0.001).

Serious adverse events that led to discontinuation of study drug, as determined by investigators, occurred in 2.1% (n=112) of the patients in the sotagliflozin treated group and in 1.8% (n=94) of the patients in the placebo group. Based on investigator reported events, the most common adverse events of special interest included urinary tract infections (11.5% on sotagliflozin versus 11.1% on placebo), diarrhea (8.5% on sotagliflozin versus 6.0% on placebo), volume depletion (5.3% on sotagliflozin versus 4.0% on placebo), bone fractures (2.1% on sotagliflozin versus 2.2% on placebo), and genital mycotic infections (2.4% on sotagliflozin versus 0.9% on placebo). Among other adverse events of interest, diabetic ketoacidosis (0.6% on sotagliflozin vs. 0.3% on placebo) was more common in the sotagliflozin treated group and severe hypoglycemia (1.0% on sotagliflozin vs. 1.0% on placebo) was similar between treatment groups.

The SCORED study was originally designed with co-primary endpoints, assessed in time-to-event analyses, of the first occurrence of a major adverse cardiovascular event (defined as death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, or 3-point MACE) and the first occurrence of death from cardiovascular causes or hospitalization for heart failure, as determined by independent adjudication, but were modified in connection with the early close out of the study to include urgent heart failure visits and reflect the total number of events, as determined by investigators, in order to enhance the statistical power of the comparison. The specification of the primary endpoint based on total events was implemented without any awareness of the study outcomes or study-group assignments and without information from an interim analysis.

In a time-to-event analysis, applying the original co-primary endpoints based on investigator reported events, the results for both the first occurrence of a MACE event (HR=0.84; 95% CI=0.72 to 0.99; p=0.035) and the first occurrence of death from cardiovascular causes or hospitalization for heart failure (HR=0.78; 95% CI=0.66 to 0.91; p=0.001) were consistent with those of the modified primary endpoint.