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

Study Overview
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Brief Summary
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This is a study in adults with chronic heart failure. People with chronic heart failure may need to be hospitalised for their condition. Some people with chronic heart failure may eventually die from their condition. The purpose of the study is to find out whether a medicine called empagliflozin lowers the chances of patients having to go to hospital for heart failure and whether it improves their survival. The study is open to patients with a type of chronic heart failure called chronic heart failure with preserved ejection fraction. Participants stay in the study until researchers have enough information about how effective empagliflozin is. It is expected that participants who enter at the very beginning of the enrolment period may be in the study for over 3 years, while participants who enter near the end of the enrolment period may be in the study for less than 2 years. The participants are put into 2 groups. It is decided by chance who gets into which group. One group gets empagliflozin tablets every day and the other group gets placebo tablets every day. Placebo tablets look like empagliflozin tablets but contain no medicine. Participants visit the doctors regularly. During these visits, the doctors collect information about the participant's health. The doctors want to know how many patients had to go to hospital because of heart failure or who died from cardiovascular disease.

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 Preserved Ejection Fraction (HFpEF)

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 preserved EF (Ejection Fraction)(LVEF (Left Ventricular Ejection Fraction) > 40 %) and elevated NT-proBNP (N-terminal of the prohormone brain natriuretic peptide) > 300 pg/ml for patients without AF, OR > 900 pg/ml for patients with AF, analysed at the Central laboratory at Visit 1 Structural heart disease within 6 months prior to Visit 1, OR documented HHF (Hospitalisation for Heart Failure) within 12 months prior to Visit 1 Stable dose of oral diuretics, if prescribed 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 (Heart Failure) 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))cr 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 trial 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 may 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: 10 mg 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 First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF) | 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. | From randomization until completion of the planned treatment phase, up to 1403 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 adjudicated HHF events (first and recurrent) which occurred. | From randomization until completion of the planned treatment phase, up to 1403 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) slope of change from baseline. Available on-treatment change-from-baseline data were used. The slope represents the long term effect of eGFR change from baseline and provides the yearly rate of decline. Timepoints after baseline were included in calculation of slope of change from baseline. The slope per patient was calculated using a random coefficient model 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 (eGFR (CKD-EPI)cr) at baseline and in addition the factors time, treatment-by-time interaction, and baseline eGFR (CKD-EPI)cr-by-time interaction. | At baseline, week 4, 12, 32, 52, 76, 100, 124, 148, 172 and week 196, up to 1043 days. | 
| Time to the First Event in the Composite Renal Endpoint: Chronic Dialysis, Renal Transplant, or Sustained Reduction in eGFR (CKD-EPI)cr | 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. Abbreviation: Patient-years (pt-yrs). | From randomization until completion of the planned treatment phase, up to 1403 days. | 
| Time to First Adjudicated Hospitalisation for Heart Failure (HHF) | 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. | From randomization until completion of the planned treatment phase, up to 1403 days. | 
| Time to Adjudicated Cardiovascular (CV) Death | 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. | From randomization until completion of the planned treatment phase, up to 1403 days. | 
| Time to All-cause Mortality | 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 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. | From randomization until completion of the planned treatment phase, up to 1403 days. | 
| Time to Onset of Diabetes Mellitus (DM) in Patients With Pre-DM | 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 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. | From randomization until completion of the planned treatment phase, to 1403 days. | 
| Change From Baseline in Kansas City Cardiomyopathy Questionaire (KCCQ) 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, 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) was imputed for the score at all subsequent scheduled visits after the date of death where the score would have been assessed. 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. | At baseline and at week 12, week 32 and week 52. | 
| Occurrence of All-cause Hospitalisation (First and Recurrent) | Occurrence of all-cause hospitalisation (first and recurrent). Total number of all cause hospitalisations is reported. | From randomization until completion of the planned treatment phase, up to 1403 days. |