Clinical Study Of Eplerenone In Japanese Patients With Chronic Heart Failure

Study Overview
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Brief Summary
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A study to compare the efficacy and safety of eplerenone in Japanese chronic heart failure patients with placebo.

Detailed Description
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The aim of this study was to show consistency with the EMPHASIS-HF trial (NCT00232180), which was defined as a HR of the primary endpoint of below 1.

Official Title
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The Effect Of Eplerenone Versus Placebo On Cardiovascular Mortality And Heart Failure Hospitalization In Japanese Subjects With Chronic Heart Failure

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Eplerenone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Japanese chronic systolic heart failure patients with LVEF =<30% by echocardiography and NYHA II or more Patients who receive standard therapy (Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blocker or diuretic) Exclusion Criteria: Patients with a myocardial infarction, stroke, cardiac surgery or percutaneous coronary intervention within 30 days prior to randomization. Patients with serum potassium >5.0 mmol/L or eGFR <30 ml/min/1.73 m2.

Ages Eligible for Study
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Minimum Age: 55 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eplerenone arm<br>Add on standard heart failure therapy | Drug: Eplerenone<br>* Eplerenone 25 mg once every other day, 25mg once daily or 50 mg once daily<br>|
| Placebo Comparator: Placebo arm<br>Add on standard heart failure therapy | Drug: Placebo<br>* Placebo once daily or every once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) | CV mortality was defined as any death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With First Occurrence of Cardiovascular (CV) Mortality, Hospitalization Due to Heart Failure (HF), or Addition/Increase of Heart Failure (HF) Medication | CV mortality was defined as any death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Addition/ increase of HF medications was defined as administration of new HF medication or increase of 50 percentage (%) or more in dose of HF medication for >= 3 days. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With With First Occurrence of All-Cause Mortality | All-cause mortality was defined as any CV mortality, Non-CV mortality, including malignant tumor, pulmonary disease and trauma.CV mortality was defined as death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Mortality during treatment, within 30 days of treatment discontinuation and after 30 days of discontinuation was reported. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With With First Occurrence of Cardiovascular Mortality | CV mortality was defined as death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of All-cause Hospitalization | All cause hospitalization included all hospitalizations as CV hospitalization, which was defined as any hospitalization due to CV events including HF, myocardial infarction, arrhythmia, angina pectoris and non-CV hospitalizations which was defined as any hospitalization due to non-CV events including renal dysfunction, hyperkalaemia, malignant tumor and pulmonary disease. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of Hospitalization Due to Heart Failure (HF) | Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of All-cause Mortality or All-cause Hospitalization | All cause hospitalization included all hospitalizations as CV hospitalization, which was defined as any hospitalization due to CV events including HF, myocardial infarction, arrhythmia, angina pectoris and non-CV hospitalizations which was defined as any hospitalization due to non-CV events including renal dysfunction, hyperkalaemia, malignant tumor and pulmonary disease. All-cause mortality was defined as any CV mortality, Non-CV mortality, including malignant tumor, pulmonary disease and trauma.CV mortality was defined as death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization | HF mortality was defined as any death due to HF. Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of Cardiovascular (CV) Hospitalization | CV hospitalization, which was defined as any hospitalization due to CV events including HF, myocardial infarction, arrhythmia, angina pectoris. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of Addition/Increase of Heart Failure (HF) Medication Due to Heart Failure (HF) Worsening | Addition/ increase of HF medications was defined as administration of new HF medication or increase of 50 percent or more in dose of HF medication for >= 3 days. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of Fatal/Non-Fatal Stroke | Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of Fatal/Non-Fatal Myocardial Infarction (MI) | Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of New Onset Atrial Fibrillation/Flutter | New onset of atrial fibrillation or flutter was defined as the diagnosis of atrial fibrillation or flutter in a participant after randomization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of New Onset Diabetes Mellitus | New onset diabetes mellitus was defined as the diagnosis of diabetes mellitus in a participant after randomization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of Hospitalisation Due to Worsening Renal Function | Hospitalization due to worsening renal function (as per physician's decision) was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to worsening renal function as the primary reason for hospitalization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Number of Participants With First Occurrence of Hospitalization for Hyperkalemia | Hospitalization due to hyperkalemia (as per physician's decision) was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to hyperkalemia as the primary reason for hospitalization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model. | Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days) | 
| Change From Baseline in Plasma Concentration of Brain Natriuretic Peptide at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit |  | Baseline, Months 5,9,13,17,21,25,29,33,37,42,48, Final Visit (up to Month 48) | 
| Change From Baseline in Plasma Concentration of Serum N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit |  | Baseline, Months 5, 9, 13, 17, 21 ,25, 29, 33, 37, 42, 48 and Final Visit (up to Month 48) | 
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit | LVEF was calculated based on end-diastolic volume measured by two-dimensional echocardiography. | Baseline, Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48, Final Visit (up to Month 48) | 
| Change From Baseline in Urine Albumin-to-Creatinine Ratio at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit |  | Baseline, Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48, Final Visit (up to Month 48) | 
| Number of Participants With Change From Baseline in New York Heart Association (NYHA) Classification at Weeks 1, 4, Months 2, 3, 4, 5, 9, 13, 17 21, 25, 29, 33, 37, 42, 48 and Final Visit | NYHA: classified as 'class I' (participants with cardiac disease but without resulting limitations of physical activity), 'class II' (participants with cardiac disease resulting in slight limitation of physical activity), 'class III' (participants with cardiac disease resulting in marked limitation of physical activity), 'class IV' (participants with cardiac disease resulting in inability to carry on any physical activity without discomfort). Participants with change from baseline were classified as 'improved' (positive change), 'no change' or 'worsened' (negative change). | Baseline, Weeks 1, 4, Months 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit (up to Month 48) | 
| Change From Baseline in Specific Activity Scale (SAS) Score at Week 4, Months 2, 3, 4, 5, 9, 13, 17 21, 25, 29, 33, 37, 42, 48 and Final Visit | Specific activity scale was estimated by pre-specified questionnaire (for different activities) to assess the exercise capability of the participants. Answers provided by participants were transformed in terms of number of metabolic equivalents (METs).1 MET was defined as the amount of oxygen consumed while sitting at rest and is equal to 3.5 ml oxygen per kg body weight* minute. Scale ranged from 1 (less than (<) 2 METs) = lowest level of exercise tolerance to 6 (>=8METs) = highest level of tolerance and higher score indicated more tolerance. | Baseline, Week 4, Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48, Final Visit (up to Month 48) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Double-blind, eplerenone, Japanese