Chronic Kidney Diseases, Heart Failure, Type 2 Diabetes Mellitus
Conditions
Brief summary
The primary objective of the study was to compare the effect of sotagliflozin to placebo on total occurrences of cardiovascular (CV) death, hospitalization for heart failure \[HHF\], and urgent visit for heart failure \[HF\] in participants with type 2 diabetes, cardiovascular risk factors, and moderate to severely impaired renal function.
Interventions
DRUGPlacebo
Placebo was administered as a tablet(s) (identical to the sotagliflozin tablet in appearance), orally once daily.
DRUGSotagliflozin
Sotagliflozin was administered as a tablet(s), orally once daily.
Sponsors
Sanofi
Lexicon Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * Type 2 Diabetes Mellitus with glycosylated hemoglobin (HbA1c) ≥7%. * Estimated glomerular filtration rate (eGFR) ≥25 and ≤60 milliliter/minute (mL/min)/1.73 square meter (m\^2). * Age 18 years or older with at least one major cardiovascular risk factor or age 55 years or older with at least two minor cardiovascular risk factors. * Signed written informed consent.
Exclusion criteria
* Antihyperglycemic treatment has not been stable within 12 weeks prior to screening. * Planned coronary procedure or surgery after randomization. * 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. 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 30 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 |
|---|---|---|
| Number of Deaths From Cardiovascular Causes | Up to 30 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 30 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 randomization. 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 30 months | Combined endpoint of the total number of occurrences (first and potentially subsequent) after randomization of HHF, urgent HF visits, CV Death, and HF while hospitalized. 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 30 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. |
| Number of Deaths From Any Cause | Up to 30 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, Non-fatal Myocardial Infarction and Non-fatal Stroke | Up to 30 months | Combined endpoint of the total number of occurrences (first and potentially subsequent) of CV death 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. |
| Number of Occurrences After Randomization of the Composite of Sustained ≥50% Decrease in Estimated Glomerular Filtration Rate (eGFR) From Baseline (for ≥30 Days), Chronic Dialysis, Renal Transplant, or Sustained eGFR <15 mL/Min/1.73 m^2 (for ≥30 Days) | Up to 30 months | Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, China, Czechia, Denmark, Estonia, France, Georgia, Germany, Greece, Guatemala, Hungary, India, Israel, Italy, Latvia, Lithuania, Mexico, Netherlands, New Zealand, North Macedonia, Norway, Peru, Poland, Portugal, Puerto Rico, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 723 study centers in North America, Latin America, Western Europe, Eastern Europe, and the Rest of the World from 19 December 2017 to 08 July 2020.
Pre-assignment details
Participants with a diagnosis of Type 2 diabetes (T2D), CV risk factors, and moderately impaired renal function 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 6 months to 400 mg, for up to 28.9 months. | 5,292 |
| Placebo Matching placebo to sotagliflozin 200 mg once daily, with possible up-titration in the first 6 months to matching placebo to sotagliflozin 400 mg, for up to 29.6 months. | 5,292 |
| Total | 10,584 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 240 | 246 |
| Overall Study | Reason not Specified | 16 | 32 |
| Overall Study | Site Terminated by Sponsor | 256 | 282 |
| Overall Study | Study Terminated by Sponsor | 4,723 | 4,664 |
| Overall Study | Withdrawal by Subject | 57 | 68 |
Baseline characteristics
| Characteristic | Placebo | Total | Sotagliflozin |
|---|---|---|---|
| Age, Continuous | 68.2 years STANDARD_DEVIATION 8.4 | 68.3 years STANDARD_DEVIATION 8.4 | 68.4 years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1678 Participants | 3349 Participants | 1671 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3581 Participants | 7174 Participants | 3593 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 33 Participants | 61 Participants | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 216 Participants | 421 Participants | 205 Participants |
| Race (NIH/OMB) Asian | 365 Participants | 682 Participants | 317 Participants |
| Race (NIH/OMB) Black or African American | 187 Participants | 363 Participants | 176 Participants |
| Race (NIH/OMB) More than one race | 114 Participants | 243 Participants | 129 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 15 Participants | 40 Participants | 25 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 66 Participants | 123 Participants | 57 Participants |
| Race (NIH/OMB) White | 4329 Participants | 8712 Participants | 4383 Participants |
| Sex: Female, Male Female | 2407 Participants | 4754 Participants | 2347 Participants |
| Sex: Female, Male Male | 2885 Participants | 5830 Participants | 2945 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 246 / 5,292 | 246 / 5,292 |
| other Total, other adverse events | 705 / 5,291 | 609 / 5,286 |
| serious Total, serious adverse events | 1,236 / 5,291 | 1,331 / 5,286 |
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 30 months
Population: ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.
| 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) | 5.6 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) | 7.5 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: [0.63, 0.88]Cox proportional hazards model
Secondary
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 30 months
Population: ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Number of Deaths From Any Cause | 3.5 events per 100-person years |
| Placebo | Number of Deaths From Any Cause | 3.5 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.95% CI: [0.83, 1.18]
Secondary
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 30 months
Population: ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Number of Deaths From Cardiovascular Causes | 2.2 events per 100-person years |
| Placebo | Number of Deaths From Cardiovascular Causes | 2.4 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: =0.3595% CI: [0.73, 1.12]Cox proportional hazards model
Secondary
Number of Occurrences After Randomization of the Composite of Sustained ≥50% Decrease in Estimated Glomerular Filtration Rate (eGFR) From Baseline (for ≥30 Days), Chronic Dialysis, Renal Transplant, or Sustained eGFR <15 mL/Min/1.73 m^2 (for ≥30 Days)
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 30 months
Population: ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Number of Occurrences After Randomization of the Composite of Sustained ≥50% Decrease in Estimated Glomerular Filtration Rate (eGFR) From Baseline (for ≥30 Days), Chronic Dialysis, Renal Transplant, or Sustained eGFR <15 mL/Min/1.73 m^2 (for ≥30 Days) | 0.5 events per 100-person years |
| Placebo | Number of Occurrences After Randomization of the Composite of Sustained ≥50% Decrease in Estimated Glomerular Filtration Rate (eGFR) From Baseline (for ≥30 Days), Chronic Dialysis, Renal Transplant, or Sustained eGFR <15 mL/Min/1.73 m^2 (for ≥30 Days) | 0.7 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: [0.46, 1.08]
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 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 30 months
Population: ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Total Number of Occurrences of CV Death, HHF, Non-fatal Myocardial Infarction and Non-fatal Stroke | 7.6 events per 100-person years |
| Placebo | Total Number of Occurrences of CV Death, HHF, Non-fatal Myocardial Infarction and Non-fatal Stroke | 10.4 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: [0.63, 0.83]
Secondary
Total Number of Occurrences of CV Death, Non-fatal Myocardial Infarction and Non-fatal Stroke
Combined endpoint of the total number of occurrences (first and potentially subsequent) of CV death 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 30 months
Population: ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Total Number of Occurrences of CV Death, Non-fatal Myocardial Infarction and Non-fatal Stroke | 4.8 events per 100-person years |
| Placebo | Total Number of Occurrences of CV Death, Non-fatal Myocardial Infarction and Non-fatal Stroke | 6.3 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, with non-CV death treated as a competing event.95% CI: [0.65, 0.91]
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 30 months
Population: ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Total Number of Occurrences of HHF and Urgent HF Visits | 3.5 events per 100-person years |
| Placebo | Total Number of Occurrences of HHF and Urgent HF Visits | 5.1 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: [0.55, 0.82]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 randomization of HHF, urgent HF visits, CV Death, and HF while hospitalized. 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 30 months
Population: ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin | Total Number of Occurrences of HHF, Urgent HF Visit, CV Death, and HF While Hospitalized | 6.4 events per 100-person years |
| Placebo | Total Number of Occurrences of HHF, Urgent HF Visit, CV Death, and HF While Hospitalized | 8.3 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, with non-CV death treated as a competing event.95% CI: [0.65, 0.89]