The Cardiac Insufficiency BIsoprolol Study in Japanese Patients With Chronic Heart Failure (CIBIS-J)

Study Overview
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Brief Summary
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The purpose of this study is to investigate the non-inferiority of bisoprolol to carvedilol by evaluating tolerability (The probability that administered maintenance dose reaches the maximum will be determined as an indicator) as a primary endpoint when bisoprolol or carvedilol is administered for 48 weeks to Japanese chronic heart failure patients. In addition, the safety and efficacy of bisoprolol will be investigated.

Official Title
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The Cardiac Insufficiency BIsoprolol Study in Japanese Patients With Chronic Heart Failure (CIBIS-J)

Conditions
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Chronic Heart Failure

Intervention / Treatment
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* Drug: Bisoprolol
* Drug: Carvedilol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: As a result of diagnosis and tests before registration, a patient who is considered by an investigator to meet all requirements and to have ability to consent can be enrolled. Primary disease: In principle, ischemic heart disease or dilated cardiomyopathy. Heart failure patients with 40% or less of left ventricular ejection fraction (LVEF) . Patients in NYHA functional classification Class II, III, or IV (including a medical history). Basic treatment: In principle, patients undergoing treatment with an ACE inhibitor (or angiotensin receptor blocker (ARB)), a diuretic, a digitalis preparation, etc. Patients who had not undergone treatment with a beta-blocker (except eye drops) within 8 weeks before the registration date. Age: Patients aged 20 to less than 85 on the day of obtaining written informed consent. Hospitalized/outpatient: Either hospitalized or outpatient status. Gender: Male or Female Exclusion Criteria: Patients who meet any of the following exclusion criteria at the time of registration will be excluded: Patients who are considered not to be candidates for administration of bisoprolol or carvedilol. Patients who have developed acute myocardial infarction within 8 weeks before the registration day. Patients who have history of stroke or serious cerebrovascular accident within 1 year before the registration day. Patients with poor prognosis and life-threatening disease, such as malignant tumor, or such medical history within 5 years before the registration day. Patients who are scheduled to undergo coronary revascularization (Coronary artery bypass grafting; CABG, Percutaneous coronary intervention; PCI) during the study period. Patients who are pregnant, lactating, may become pregnant, or want to become pregnant during the study. Patients from whom written informed consent cannot be obtained. Patients who are judged by an investigator to be inappropriate for this study for any other reason.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 85 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bisoprolol group<br>Daily oral administration of bisoprolol 0.625 mg tablet once a day should be given (Step 1). If tolerability is confirmed by an investigator, the dose should be increased to 1.25 mg (bisoprolol 0.625 mg, 2 tablets; or bisoprolol 2.5 mg, half tablet; once daily) (Step 2). In the same manner, the doses should be increased to 2.5 mg (bisoprolol 2.5 mg, 1 tablet; or bisoprolol 5 mg, half tablet; once daily, Step 3), to 3.75 mg (bisoprolol 2.5 mg, 1.5 tablets once daily, Step 4), and to 5 mg (bisoprolol 2.5 mg, 2 tablets; or bisoprolol 5 mg, 1 tablet; once daily, Step 5). | Drug: Bisoprolol<br> <br> |
| Active Comparator: Carvedilol group<br>Daily oral administration of carvedilol 1.25 mg, 1 tablet twice a day (after breakfast and supper) should be given (Step 1). If tolerability is confirmed by an investigator after administering 2.5 mg/day of carvedilol, the dose should be increased to 5 mg (carvedilol 2.5 mg, 1 tablet twice daily) (Step 2). In the same manner, the dose should be increased to 10 mg (carvedilol 2.5 mg, 2 tablets twice daily, Step 3), to 15 mg (carvedilol 2.5 mg, 3 tablets twice daily, Step 4), and to 20 mg (carvedilol 10 mg, 1 tablet twice daily, Step 5). | Drug: Carvedilol<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability: The probability that administered maintenance dose reaches the maximum (bisoprolol 5 mg/day, carvedilol 20 mg/day) |  | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: New York Heart Association (NYHA) Functional Classification |  | 24 and 48 weeks | 
| Efficacy: Left Ventricular Ejection Fraction (LVEF) |  | 24 and 48 weeks | 
| Efficacy: Left Ventricular End Diastolic Volume (LVEDV), Left Ventricular End Systolic Volume (LVESV) |  | 24 and 48 weeks | 
| Efficacy: Heart rate |  | 24 and 48 weeks | 
| Efficacy: Plasma brain natriuretic peptide (BNP) |  | 24 and 48 weeks | 
| Safety: All deaths |  | 48 weeks | 
| Safety: Deaths with cardiovascular causes |  | 48 weeks | 
| Safety: Hospitalization for cardiovascular causes |  | 48 weeks | 
| Safety: Exacerbation of heart failure, resulting in hospitalization, and/or intensification of treatment (increase in dose of any diuretics, vasodilators or cardiotonics, in comparison with the dose-setting period), or administration of new drugs. |  | 48 weeks | 
| Safety: Deaths due to heart failure (pump-failure deaths, and deaths associated with exacerbation of heart failure) |  | 48 weeks | 
| Safety: Sudden deaths, including deaths due to arrhythmia |  | 48 weeks | 
| Safety: Deaths with non-cardiovascular causes |  | 48 weeks | 
| Safety: Adverse events |  | 48 weeks | 
| Safety: Changes in clinical laboratory test results |  | 48 weeks |