Heart Failure, Type 2 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: To compare the effect of sotagliflozin to placebo on the total occurrences of cardiovascular (CV) death, hospitalization for heart failure (HHF), and urgent visit for heart failure (HF) in hemodynamically stable participants after admission for worsening heart failure (WHF) Secondary Objectives: To compare the effects of sotagliflozin to placebo on: * The total occurrences of HHF and urgent visit for HF * The occurrence of CV death * The occurrence of all-cause mortality * The total occurrences of CV death, HHF, urgent visit for HF, non-fatal myocardial infarction (MI), and non-fatal stroke * Change in Kansas City Cardiomyopathy Questionnaire-12(KCCQ-12) score * Change in estimated glomerular filtration rate (eGFR)
Detailed description
The estimated study duration for a given participants will be approximately 3 to 24 months.
Interventions
DRUGSotagliflozin
Pharmaceutical form: tablet Route of administration: oral
DRUGPlacebo
Pharmaceutical form: tablet Route of administration: oral
Sponsors
Sanofi
Lexicon Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 Diabetes Mellitus. * Admitted to the hospital, or urgent heart failure visit for worsening heart failure. * Prior diagnosis of heart failure (\> 3 months). * Prior chronic treatment for heart failure with a loop diuretic (eg furosemide, torsemide, bumetanide) for \> 30 days. * Randomized when hemodynamically stable, prior to hospital discharge or within 3 days of discharge. * Brain natriuretic peptide (BNP) ≥150 picograms per milliliter (pg/mL) (≥450 pg/mL for participants with atrial fibrillation) or N-terminal B-type natriuretic peptide ≥600 pg/mL (≥1800 pg/mL for participants with atrial fibrillation). * Participants with Left Ventricular Ejection Fraction \<40% should be on beta-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors as per local guidelines unless contraindicated. * Signed written informed consent.
Exclusion criteria
* Age \< 18 years or \> 85 years. * Worsening heart failure attributed to other causes such as pulmonary embolism, stroke, heart attack. * Cardiac surgery or coronary procedure within 1 month or planned during study. * Lower extremity complications (such as skin ulcer, infection, osteomyelitis, and gangrene) identified during screening and requiring treatment at randomization. * Planning to start a sodium-glucose linked transporter-2 (SGLT2) inhibitor during the study. * Acute coronary syndromes within 3 months prior to Randomization. * Hemodynamically significant uncorrected primary valvular disease. * Significant pulmonary disease contributing substantially to the participant's dyspnea. * End stage Heart Failure. * History of diabetic ketoacidosis (DKA) or nonketotic hyperosmolar coma within 3 months prior to screening. * History of stroke within 3 months prior to randomization. * History of dialysis within 1 year prior to randomization. * History of solid organ transplant or on a transplant list (if heart transplant, defined as status 1 transplant). * Severe kidney disease as defined by glomerular filtration rate (eGFR) \<30 milliliter per minute per 1.72 meter square (mL/min/1.73 m\^2). * Pregnancy. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Total Occurrences of Cardiovascular (CV) Death, Hospitalizations for Heart Failure (HHF) and Urgent Visits for Heart Failure (HF) | Up to 21.9 months | Combined endpoint of the total number of occurrences (first and potentially subsequent) of CV death, HHF, and urgent HF visits after randomization. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Deaths From Cardiovascular Causes | Up to 21.9 months | Number of events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. |
| Total Number of Occurrences of CV Death, HHF, Non-fatal Myocardial Infarction and Non-fatal Stroke | Up to 21.9 months | Combined endpoint of the total number of occurrences (first and potentially subsequent) of CV death, HHF, non-fatal stroke, and non-fatal myocardial infarction after randomisation. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. |
| Total Number of Occurrences of HHF, Urgent HF Visit, CV Death, and HF While Hospitalized | Up to 21.9 months | Combined endpoint of the total number of occurrences (first and potentially subsequent) after randomisation of HHF, urgent HF visits, CV Death and HF while hospitalised. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. |
| Total Number of Occurrences of HHF and Urgent HF Visits | Up to 21.9 months | Combined endpoint of the total occurrences (first and potentially subsequent) of HHF and urgent HF visits after randomization. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. |
| Change From Baseline in Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) Scores at Month 4 | Baseline to Month 4 | KCCQ-12 is a 12 question questionnaire, participants completed questionnaire about how heart failure affected their life over the past 2 weeks. The scale has 4 domains: symptom frequency, physical limitation, social limitations and quality of life for a total possible transformed score of 0 to 100 where 100 denotes the highest health status. A positive change from baseline indicates improvement. An analysis of covariance (ANCOVA) model was used for analysis. |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Baseline up to 21.9 months | eGFR is a test for renal function. A blood sample was collected and was sent to a central laboratory. eGFR was calculated by the Modification of Diet in Renal Disease (MDRD) equation reported as milliliters/minute/1.73 meter squared (mL/min/1.73 m\^2). A mixed model for repeated measures (MMRM) was used for analysis. |
| Total Number of Deaths From Any Cause | Up to 21.9 months | Number of events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, Israel, Italy, Latvia, Lithuania, Netherlands, New Zealand, Poland, Portugal, Romania, Russia, Slovakia, South Korea, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 306 investigative sites in North America, Latin America, Western Europe, Eastern Europe, and the Rest of the World from 15 June 2018 to 05 June 2020.
Pre-assignment details
Participants with a diagnosis of Type 2 Diabetes post Worsening Heart Failure were enrolled equally in 1 of 2 treatment groups, sotagliflozin or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Sotagliflozin Sotagliflozin 200 mg tablet once daily, with possible up-titration in the first 8 months to 400 mg, for up to 21.2 months. | 608 |
| Placebo Matching placebo to sotagliflozin 200 mg once daily, with possible up-titration in the first 8 months to matching placebo to sotagliflozin 400 mg, for up to 21.6 months. | 614 |
| Total | 1,222 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 65 | 73 |
| Overall Study | Reason not Specified | 3 | 6 |
| Overall Study | Site Terminated by Sponsor | 39 | 35 |
| Overall Study | Study Terminated by Sponsor | 483 | 477 |
| Overall Study | Withdrawal by Subject | 18 | 23 |
Baseline characteristics
| Characteristic | Placebo | Total | Sotagliflozin |
|---|---|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 8.8 | 68.9 years STANDARD_DEVIATION 9.1 | 68.6 years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 157 Participants | 320 Participants | 163 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 455 Participants | 893 Participants | 438 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 9 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 15 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 25 Participants | 50 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 12 Participants | 6 Participants |
| Race (NIH/OMB) White | 572 Participants | 1139 Participants | 567 Participants |
| Sex: Female, Male Female | 214 Participants | 412 Participants | 198 Participants |
| Sex: Female, Male Male | 400 Participants | 810 Participants | 410 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 65 / 608 | 76 / 614 |
| other Total, other adverse events | 101 / 605 | 90 / 611 |
| serious Total, serious adverse events | 235 / 605 | 251 / 611 |
Outcome results
Primary
Number of Total Occurrences of Cardiovascular (CV) Death, Hospitalizations for Heart Failure (HHF) and Urgent Visits for Heart Failure (HF)
Combined endpoint of the total number of occurrences (first and potentially subsequent) of CV death, HHF, and urgent HF visits after randomization. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up.
Time frame: Up to 21.9 months
Population: ITT population includes all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Number of Total Occurrences of Cardiovascular (CV) Death, Hospitalizations for Heart Failure (HHF) and Urgent Visits for Heart Failure (HF) | 51 events per 100-person years |
| Placebo | Number of Total Occurrences of Cardiovascular (CV) Death, Hospitalizations for Heart Failure (HHF) and Urgent Visits for Heart Failure (HF) | 76.3 events per 100-person years |
Comparison: The estimates of the hazard ratio (HR) and corresponding 2-sided 95% confidence interval (CI) was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction, with non-cardiovascular (non-CV) death treated as a competing event.p-value: <0.00195% CI: [0.52, 0.85]Cox proportional hazards model
Secondary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
eGFR is a test for renal function. A blood sample was collected and was sent to a central laboratory. eGFR was calculated by the Modification of Diet in Renal Disease (MDRD) equation reported as milliliters/minute/1.73 meter squared (mL/min/1.73 m\^2). A mixed model for repeated measures (MMRM) was used for analysis.
Time frame: Baseline up to 21.9 months
Population: ITT population includes all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sotagliflozin | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | -0.34 mL/min/1.73 m^2 | Standard Error 1.33 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | -0.18 mL/min/1.73 m^2 | Standard Error 1.33 |
Comparison: Rate of decline in eGFR observed over time was analyzed by MMRM with absolute change in eGFR from baseline as the outcome, a random effect for intercept, and fixed effects for treatment, baseline value, and time.95% CI: [-1.3, 0.98]
Secondary
Change From Baseline in Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) Scores at Month 4
KCCQ-12 is a 12 question questionnaire, participants completed questionnaire about how heart failure affected their life over the past 2 weeks. The scale has 4 domains: symptom frequency, physical limitation, social limitations and quality of life for a total possible transformed score of 0 to 100 where 100 denotes the highest health status. A positive change from baseline indicates improvement. An analysis of covariance (ANCOVA) model was used for analysis.
Time frame: Baseline to Month 4
Population: ITT population includes all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sotagliflozin | Change From Baseline in Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) Scores at Month 4 | 17.7 score on a scale | Standard Error 0.41 |
| Placebo | Change From Baseline in Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) Scores at Month 4 | 13.6 score on a scale | Standard Error 0.41 |
Comparison: The change from baseline to Month 4 was analyzed using an ANCOVA model with treatment groups as factor and baseline KCCQ-12 score and randomization stratification factors as covariates.95% CI: [1.3, 7]
Secondary
Total Number of Deaths From Any Cause
Number of events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up.
Time frame: Up to 21.9 months
Population: ITT population includes all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Total Number of Deaths From Any Cause | 13.5 events per 100-person years |
| Placebo | Total Number of Deaths From Any Cause | 16.3 events per 100-person years |
Comparison: The estimates of the HR and corresponding 2-sided 95% CI was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction.95% CI: [0.59, 1.14]
Secondary
Total Number of Deaths From Cardiovascular Causes
Number of events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up.
Time frame: Up to 21.9 months
Population: ITT population includes all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Total Number of Deaths From Cardiovascular Causes | 10.6 events per 100-person years |
| Placebo | Total Number of Deaths From Cardiovascular Causes | 12.5 events per 100-person years |
Comparison: The estimates of the HR and corresponding 2-sided 95% CI was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction, with non-CV death treated as a competing event.p-value: =0.3695% CI: [0.58, 1.22]Cox proportional hazards model
Secondary
Total Number of Occurrences of CV Death, HHF, Non-fatal Myocardial Infarction and Non-fatal Stroke
Combined endpoint of the total number of occurrences (first and potentially subsequent) of CV death, HHF, non-fatal stroke, and non-fatal myocardial infarction after randomisation. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up.
Time frame: Up to 21.9 months
Population: ITT population includes all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Total Number of Occurrences of CV Death, HHF, Non-fatal Myocardial Infarction and Non-fatal Stroke | 51.4 events per 100-person years |
| Placebo | Total Number of Occurrences of CV Death, HHF, Non-fatal Myocardial Infarction and Non-fatal Stroke | 71.0 events per 100-person years |
Comparison: The estimates of the HR and corresponding 2-sided 95% CI was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction, with non-CV death treated as a competing event.95% CI: [0.56, 0.92]
Secondary
Total Number of Occurrences of HHF and Urgent HF Visits
Combined endpoint of the total occurrences (first and potentially subsequent) of HHF and urgent HF visits after randomization. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up.
Time frame: Up to 21.9 months
Population: ITT population includes all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Total Number of Occurrences of HHF and Urgent HF Visits | 40.4 events per 100-person years |
| Placebo | Total Number of Occurrences of HHF and Urgent HF Visits | 63.9 events per 100-person years |
Comparison: The estimates of the HR and corresponding 2-sided 95% CI was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction, with non-CV death treated as a competing event.p-value: <0.00195% CI: [0.49, 0.83]Cox proportional hazards model
Secondary
Total Number of Occurrences of HHF, Urgent HF Visit, CV Death, and HF While Hospitalized
Combined endpoint of the total number of occurrences (first and potentially subsequent) after randomisation of HHF, urgent HF visits, CV Death and HF while hospitalised. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up.
Time frame: Up to 21.9 months
Population: ITT population includes all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Total Number of Occurrences of HHF, Urgent HF Visit, CV Death, and HF While Hospitalized | 54.7 events per 100-person years |
| Placebo | Total Number of Occurrences of HHF, Urgent HF Visit, CV Death, and HF While Hospitalized | 80.6 events per 100-person years |
Comparison: The estimates of the HR and corresponding 2-sided 95% CI was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction, with non-CV death treated as a competing event.95% CI: [0.54, 0.86]