1245.110

Boehringer Ingelheim

Binger Straße 173, Ingelheim am Rhein, Germany, 55216

Boehringer Ingelheim, Call Centre, Boehringer Ingelheim, 001 018002430127, clintriage.rdg@boehringer-ingelheim.com

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

No

No

No

Final

01 Jun 2021

Yes

26 Apr 2021

Yes

26 Apr 2021

No

The objective of this event-driven trial was to demonstrate superiority of empagliflozin 10 mg versus placebo in patients with symptomatic, chronic heart failure and preserved left ventricular ejection fraction (LVEF >40%) under stable treatment of heart failure symptoms.

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.

27 Mar 2017

No

Yes

Argentina: 825

Australia: 233

Belgium: 61

Brazil: 2038

Canada: 393

China: 255

Colombia: 455

Czechia: 845

Germany: 569

Hungary: 610

India: 181

Italy: 223

Japan: 526

Korea, Republic of: 151

Mexico: 318

Netherlands: 225

Poland: 1588

Romania: 234

Singapore: 36

South Africa: 365

Spain: 160

United Kingdom: 53

United States: 1239

11583

4515

0

0

0

0

0

0

3258

7755

570

Overall Study (overall period)

Randomised - controlled

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

Yes

Placebo

Film-coated tablet

Oral use

1 film-coated tablet of matching placebo was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF).

Jardiance®

BI 10773

Film-coated tablet

Oral use

1 film-coated tablet of 10 milligram (mg) of empagliflozin was administered orally once daily in patients with chronic heart failure with preserved ejection fraction (HFpEF).

Placebo

10 mg Empagliflozin

Placebo

10 mg Empagliflozin

Composite primary endpoint - Time to first event of adjudicated CV death or adjudicated HHF in patients with Heart Failure with preserved Ejection Fraction (HFpEF). The incidence rate per 100 patient years (pt-yrs) is presented and calculated as followed: Incidence rate per 100 pt-yrs = 100 * number of patients with event / time at risk [years]. Time at risk [years] = 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), including all randomised patients.

Primary

From randomization until completion of the planned treatment phase, up to 1403 days.

Cox regression, with terms for treatment, region, baseline status of diabetes, age, sex, left ventricular ejection fraction (LVEF) and glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr) at baseline. alpha=0.0497 (resulting from interim analysis).

10 mg Empagliflozin v Placebo

5988

Pre-specified

0.79

2-sided

Reported is the total number of adjudicated HHF events (first and recurrent) which occurred. Randomised Set (RS), including all randomised patients.

Secondary

From randomization until completion of the planned treatment phase, up to 1403 days.

Joint frailty model that accounts for dependence between recurrent HHF and cardiovascular death, with terms for age, baseline eGFR (CKD-EPK)cr, baseline LVEF, region, baseline diabetes status, sex, 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. alpha=0.0497 (resulting from interim analysis).

Placebo v 10 mg Empagliflozin

5988

Pre-specified

0.73

2-sided

Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR(CKD-EPI)cr) slope of change from baseline. Available on-treatment change-from-baseline data were used. 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. Only patients included in the treated set (TS) and with available data for this endpoint.

Secondary

Assessed at baseline, week 4, 12, 32, 52, 76, 100, 124, 148, 172 and 196, up to 1043 days.

Random coefficient model allowing for random intercept and random slope per patient, with factors age, baseline eGFR (CKD-EPI), baseline LVEF as linear covariate(s) and region, baseline diabetes status, sex, baseline-by-time interaction, treatment-by-time interaction and treatment as fixed effects. Only ‘on-treatment’ data from treated patients were used. alpha=0.001. covariance structure: Unstructured.

Placebo v 10 mg Empagliflozin

5836

Pre-specified

1.363

2-sided

Chronic dialysis was defined as dialysis with a frequency of twice per week or more for at least 90 days. Sustained was determined by two or more consecutive post-baseline central laboratory measurement separated by at least 30 days. Reduction in glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr) was defined as reduction in eGFR from baseline ≥40%, eGFR <15 mL/min/1.73 m^2 for patients with baseline eGFR ≥30 mL/min/1.73 m^2, or eGFR <10 mL/min/1.73 m^2 for patients with baseline eGFR <30 mL/min/1.73 m^2. The incidence rate per 100 patient years (100 * number of patients with event / time at risk [years]) is reported. Time at risk [year] is calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Randomised Set (RS), including all randomised patients. Abbreviation: Patient-years (pt-yrs).

Secondary

From randomization until completion of the planned treatment phase, up to 1403 days.

Cox regression model included terms age, baseline glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr), region, baseline diabetes status, sex, baseline Left ventricular ejection fraction (LVEF) and treatment.

Placebo v 10 mg Empagliflozin

5988

Pre-specified

0.95

2-sided

Time to first adjudicated HHF. The incidence rate per 100 patient years (pt-yrs) is presented and calculated as followed: Incidence rate per 100 pt-yrs = 100 * number of patients with event / time at risk [years]. Time at risk [years] = 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), including all randomised patients.

Secondary

From randomization until completion of the planned treatment phase, up to 1403 days.

Cox regression model included terms age, baseline glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr), region, baseline diabetes status, sex, baseline Left ventricular ejection fraction (LVEF) and treatment.

Placebo v 10 mg Empagliflozin

5988

Pre-specified

0.71

2-sided

Time to adjudicated CV death. The incidence rate per 100 patient years (pt-yrs) is presented and calculated as followed: Incidence rate per 100 pt-yrs = 100 * number of patients with event / time at risk [years]. Time at risk [years] = 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), including all randomised patients.

Secondary

From randomization until completion of the planned treatment phase, up to 1403 days.

Cox regression model included terms age, baseline glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr), region, baseline diabetes status, sex, baseline Left ventricular ejection fraction (LVEF) and treatment.

Placebo v 10 mg Empagliflozin

5988

Pre-specified

0.91

2-sided

Time to all-cause mortality. The incidence rate per 100 patient years (pt-yrs) is presented and calculated as followed: Incidence rate per 100 pt-yrs = 100 * number of patients with events / time at risk [years]. Time at risk [years] = 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), including all randomised patients.

Secondary

From randomization until completion of the planned treatment phase, up to 1403 days.

Cox regression model included factors age, baseline glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr), region, baseline diabetes status, sex, baseline Left ventricular ejection fraction (LVEF) and treatment.

Placebo v 10 mg Empagliflozin

5988

Pre-specified

1

2-sided

Time to onset of DM (defined as HbA1c ≥6.5% or as diagnosed by the investigator) in patients with pre-DM. Pre-DM was defined as no history of DM and no HbA1c ≥6.5% before treatment, and a pre-treatment HbA1c value of ≥5.7% and <6.5%. The incidence rate per 100 patient years (pt-yrs) is presented and calculated as followed: Incidence rate per 100 pt-yrs = 100 * number of patients with events / time at risk [years]. Time at risk [years] = 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), including all randomised patients.

Secondary

From randomization until completion of the planned treatment phase, up to 1403 days.

Cox regression model included factors age, baseline glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr), region, baseline diabetes status, sex, baseline Left ventricular ejection fraction (LVEF) and treatment.

Placebo v 10 mg Empagliflozin

1980

Pre-specified

0.84

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. 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. Only patients included in the treated set (TS) including values obtained on treatment.

Secondary

At baseline, week 12, week 32 and week 52.

Model includes age, baseline glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula (eGFR (CKD-EPI)), baseline Left ventricular ejection fraction (LVEF) as linear covariate(s) and region, baseline diabetes status, sex, week reachable, treatment-by-visit interaction, baseline KCCQ-Clinical-Summary-Score-by-visit interaction as fixed effect(s). Unstructured covariance structure.

Placebo v 10 mg Empagliflozin

4668

Pre-specified

1.32

2-sided

Standard error of the mean

0.44

Occurrence of all-cause hospitalisation (first and recurrent). Total number of all cause hospitalisations is reported. Randomised Set (RS), including all randomised patients.

Secondary

From randomization until completion of the planned treatment phase, up to 1403 days.

Joint frailty model that accounts for the dependence between recurrent all-cause hospitalisation and all-cause mortality was used. Joint frailty model with terms for age, baseline glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula (eGFR (CKD-EPI)), baseline Left ventricular ejection fraction (LVEF), treatment, region, baseline diabetes status and sex.

Placebo v 10 mg Empagliflozin

5988

Pre-specified

0.93

2-sided

[All-cause Mortality]: From study start until end of study, up to 1438 days. [Serious adverse events (AE) and other AE]:From time of the first drug intake until 7 days (Residual Effect Period) after the last drug intake, up to 1410 days.

[All-cause mortality]: Randomised Set (RS), including all randomised patients. The actual number of participants at risk for all-cause deaths is 2991 for Placebo group and 2997 for Empagliflozin group. [Serious AE and other AE]: Treated Set (TS), including all patients treated with at least one dose of the study medication.

23.1

10 mg Empagliflozin

Placebo