1245.121

Boehringer Ingelheim

Binger Straße 173, Ingelheim am Rhein, Germany, 55216

Boehringer Ingelheim, Call Centre, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Boehringer Ingelheim, Call Centre, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

No

No

No

Final

14 Jul 2020

No

Yes

28 May 2020

No

The objective of this event-driven trial was to demonstrate superiority of empagliflozin 10 mg versus placebo on top of guideline-directed medical therapy in patients with symptomatic, chronic HF and reduced left ventricular ejection fraction (LVEF ≤40%).

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.

06 Apr 2017

No

Yes

Argentina: 911

Australia: 56

Belgium: 78

Brazil: 1629

Canada: 344

China: 278

Czechia: 194

Germany: 231

Spain: 73

France: 95

United Kingdom: 100

Hungary: 200

India: 261

Italy: 176

Japan: 343

Korea, Republic of: 150

Mexico: 184

Netherlands: 338

Poland: 874

United States: 705

7220

2259

0

0

0

0

0

0

3144

3909

167

Discontinuation from Treatment (overall period)

Randomised - controlled

Patients, investigators and everyone involved in the trial conduct or analysis or with any other interest in this double-blind trial remaind blinded with regard to the randomised treatment assignements until after database lock.

Yes

Placebo

Film-coated tablet

Oral use

1 film-coated tablet of matching placebo was administered orally once daily.

Empagliflozin

Film-coated tablet

Oral use

Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.

Placebo

10 mg Empagliflozin

Placebo

10 mg Empagliflozin

Time to the first event of adjudicated cardiovascular (CV) death or adjudicated hospitalisation for heart failure (HHF). The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Randomised Set (RS): All randomised patients. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

Primary

From randomisation until completion of the planned treatment period, up to 1040 days.

Model with terms for age, baseline eGFR (CKD-EPK)cr, region, baseline diabetes status, sex, baseline LVEF, and treatment. alpha = 0.0496 (resulting from interim analysis) eGFR (CKP-EPI)cr: Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement LVEF: Left ventricular ejection fraction.

Placebo v 10 mg Empagliflozin

3730

Pre-specified

0.75

2-sided

Reported is the total number of HHF events (first and recurrent) which occurred. All data up to the end of the planned treatment period (including the data after the end of treatment for patients not completing the treatment period as planned) from all randomised patients was used. Randomised Set (RS): All randomised patients.

Secondary

From randomisation until completion of the planned treatment phase, up to 1040 days.

Model accounts for dependence between recurrent HHF and cardiovascular death, with terms for age, baseline eGFR (CKD-EPK)cr, region, baseline diabetes status, sex, baseline LVEF, and treatment. eGFR (CKP-EPI)cr: Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement LVEF: Left ventricular ejection fraction.

Placebo v 10 mg Empagliflozin

3730

Pre-specified

0.7

2-sided

Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr) [mL/min/1.73m2] slope of change from baseline. Available on-treatment change-from-baseline data were to be used. Patients without on-treatment data after randomisation were not to be included in this analysis. Slope represents the long term effect on eGFR. Timepoints after baseline were included in calculation of slope of change from baseline. Descriptive statistic (mean(standard error)) is reported. Treated Set (TS): All patients treated with at least one dose of the study medication and at least one on-treatment measurement of eGFR.

Secondary

Assessed at baseline, week 4, 12, 32, 52, 76, 100, 124, 148 and at end of treatment (EOT), up to 1040 days.

Random coefficient model allowing for random intercept and random slope per patient, with the same factors used for the primary endpoint (age, baseline eGFR (CKD-EPK)cr, region, baseline diabetes status, sex, baseline LVEF, and treatment) and additional factors “time”, “treatment-by-time interaction”, and “baseline eGFR (CKD-EPI)cr-by-time interaction”. Only “on-treatment” data from treated patients were used. alpha=0.001

Placebo v 10 mg Empagliflozin

3591

Pre-specified

1.733

2-sided

Time to the first event in the composite renal endpoint: chronic dialysis (with a frequency of twice per week or more for at least 90 days), renal transplant, or sustained reduction in Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr). The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Randomised Set (RS): All randomised patients. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

Secondary

From randomisation until completion of the planned treatment period, up to 1040 days.

10 mg Empagliflozin v Placebo

3730

Pre-specified

0.5

2-sided

Time to first adjudicated Hospitalisation for Heart Failure (HHF). The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Randomised Set (RS): All randomised patients. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

Secondary

From randomisation until completion of the planned treatment period, up to 1040 days.

10 mg Empagliflozin v Placebo

3730

Pre-specified

0.69

2-sided

Time to adjudicated CV (Cardiovascular) death. The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Randomised Set (RS): All randomised patients. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

Secondary

From randomisation until completion of the planned treatment period, up to 1040 days.

10 mg Empagliflozin v Placebo

3730

Pre-specified

0.92

2-sided

Time to all-cause mortality. The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Randomised Set (RS): All randomised patients. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

Secondary

From randomisation until completion of the planned treatment period, up to 1040 days.

Placebo v 10 mg Empagliflozin

3730

Pre-specified

0.92

2-sided

Time to onset of DM (Glycated haemoglobin (HbA1c) ≥6.5% or as diagnosed by the investigator) in patients with pre-DM (no history of DM and no HbA1c ≥6.5% before treatment, and a pre-treatment HbA1c value of 5.7 to <6.5%). The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Patients in the randomised set with pre-DM. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

Secondary

From randomisation until completion of the planned treatment period, up to 1040 days.

10 mg Empagliflozin v Placebo

1268

Pre-specified

0.86

2-sided

The KCCQ is a 23-item self-administered questionnaire designed to evaluate physical limitations, symptoms (frequency, severity, and changes over time), social limitations, self efficacy, and quality of life in patients with Heart Failure. The KCCQ-clinical summary score comprises the following domains: Symptom frequency, symptom burden and physical limitation. The score is calculated by summing domain responses and then transforming scores to a 0-100 unit scale with higher scores indicating better health status. For patients who died, a worst score (score of 0) is imputed at all subsequent scheduled visits after the date of death. Standard error is adjusted standard error. Change from baseline in KCCQ-score at week 52 was modeled using a MMRM with visit (week 12, 32 and 52) as repeated measures, adjusted mean (standard error) at week 52 is reported. Patients in the randomized set (RS) with available data for this endpoint, including values obtained on treatment or post-treatment.

Secondary

Assessed at baseline, week 12, week 32 and week 52.

Mixed model with age, baseline eGFR (CKD-EPI) as linear covariate(s) and region, baseline diabetes status, sex, baseline LVEF, week reachable, treatment by visit interaction, baseline KCCQ - Clinical Summary Score by Visit interaction as fixed effects. An unstructured covariance structure has been used.

Placebo v 10 mg Empagliflozin

2796

Pre-specified

2.06

2-sided

Standard error of the mean

0.97

Number of all-cause hospitalizations (first and recurrent). Randomised Set (RS): All randomised patients.

Secondary

From randomisation until completion of the planned treatment phase, up to 1040 days.

Joint frailty model with terms for age, baseline eGFR (CDK-EPI), region, sex, baseline diabetes status and baseline LVEF. Model accounts for dependence between recurrent all-cause hospitalizations and all-cause mortality.

Placebo v 10 mg Empagliflozin

3730

Pre-specified

0.85

2-sided

[All-Cause Mortality]: From randomization until end of planned treatment period, up to 1040 days. [Serious/Other AE]: From first intake of study medication until end of planned treatment period + 7 days (Residual Effect Period), up to 1047 days.

[All-Cause Mortality]: Randomised Set: All randomised patients. The actual number of participants at risk for all-cause deaths is 1867 for Placebo group. [Serious Adverse Events and Other Adverse Events]: Treated Set: All patients treated with at least one dose of study drug.

23.0

Placebo

10mg Empagliflozin