EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced)

Study Overview
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Brief Summary
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The aim of the study is to investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction.

Official Title
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A Phase III Randomised, Double-blind Trial to Evaluate Efficacy and Safety of Once Daily Empagliflozin 10 mg Compared to Placebo, in Patients With Chronic Heart Failure With Reduced Ejection Fraction (HFrEF)

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patient age >= 18 years at screening. For Japan only: Age >= 20 years at screening Patients with chronic HF (Chronic Heart Failure) NYHA (New York Heart Association Classification) class II-IV and reduced EF (Ejection Fraction) (LVEF (Left Ventricular Ejection Fraction) <=40%) and elevated NT-proBNP (N-terminal of the prohormone brain natriuretic peptide) If EF >= 36% to <= 40%: NT-proBNP >= 2500 pg/ml or patients without AF (atrial fibrillation/atrial flutter) and NT-proBNP >= 5000 pg/ml for patients with AF If EF >= 31% to <= 35%: NT-proBNP >= 1000 pg/ml for patients without AF and NT-proBNP >=2000 pg/ml for patients with AF If EF<= 30%: NT-proBNP >= 600 pg/ml for patients without AF and NT-proBNP >=1200 pg/ml for patients with AF EF ≤ 40% and hospitalization for heart failure in the past 12 months: NTproBNP ≥ 600 pg/ml for patients without AF and NT-proBNP >= 1200 pg/ml for patients with AF Appropriate dose of medical therapy for HF consistent with prevailing local and international CV (Cardiovascular) guidelines, stable for at least 1 week prior to Visit 1 Appropriate use of medical devices such as cardioverter defibrillator (ICD) or a cardiac resynchronization therapy (CRT) consistent with prevailing local or international CV guidelines Signed and dated written ICF (Informed Consent Form) Further inclusion criteria apply Exclusion criteria: Myocardial infarction, coronary artery bypass graft surgery, or other major cardiovascular surgery, stroke or TIA (Transient Ischaemic Attack) in past 90 days prior to Visit 1 Heart transplant recipient, or listed for heart transplant Acute decompensated HF Systolic blood pressure (SBP) >= 180 mmHg at Visit 2. Symptomatic hypotension and/or a SBP < 100 mmHg Indication of liver disease Impaired renal function, defined as eGFR (Estimated Glomerular Filtration Rate) < 20 mL/min/1.73 m2 (CKD-EPI (Chronic Kidney Disease - Epidemiology Collaboration Equation)) or requiring dialysis History of ketoacidosis Current use or prior use of a SGLT (Sodium-glucose co-transporter)-2 inhibitor or combined SGLT-1 and 2 inhibitor Currently enrolled in another investigational device or drug study Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors Women who are pregnant, nursing, or who plan to become pregnant while in the trial Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br> | Drug: Empagliflozin<br>* once daily<br>* Other names: JARDIANCE, JARDIANZ, GIBTULIO;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF) | 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. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk. | From randomisation until completion of the planned treatment period, up to 1040 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Adjudicated Hospitalisation for Heart Failure (HHF) (First and Recurrent) | 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. | From randomisation until completion of the planned treatment phase, up to 1040 days. | 
| eGFR (CKD-EPI) cr Slope of Change From Baseline | 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. | Assessed at baseline, week 4, 12, 32, 52, 76, 100, 124, 148 and at end of treatment (EOT), up to 1040 days. | 
| Time to First Event in Composite Renal Endpoint: Chronic Dialysis, Renal Transplant or Sustained Reduction of eGFR(CKD-EPI)cr | 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. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk. | From randomisation until completion of the planned treatment period, up to 1040 days. | 
| Time to First Adjudicated Hospitalisation for Heart Failure (HHF) | 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. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk. | From randomisation until completion of the planned treatment period, up to 1040 days. | 
| Time to Adjudicated Cardiovascular (CV) Death | 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. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk. | From randomisation until completion of the planned treatment period, up to 1040 days. | 
| Time to All-cause Mortality | 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. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk. | From randomisation until completion of the planned treatment period, up to 1040 days. | 
| Time to Onset of Diabetes Mellitus (DM) | 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. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk. | From randomisation until completion of the planned treatment period, up to 1040 days. | 
| Change From Baseline in KCCQ (Kansas City Cardiomyopathy Questionnaire) Clinical Summary Score at Week 52 | Change from baseline in KCCQ (Kansas City cardiomyopathy questionnaire) clinical summary score at Week 52. The KCCQ is a 23-item self-administered questionnaire designed to evaluate physical limitations, symptoms (frequency, severity, and changes over time), social limitations, selfefficacy, 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. | Assessed at baseline, week 12, week 32 and week 52. | 
| Number of All-cause Hospitalizations (First and Recurrent) | Number of all-cause hospitalizations (first and recurrent). | From randomisation until completion of the planned treatment phase, up to 1040 days. |