Background
Methods/design
Overview
Study population
Inclusion criteria | |
1 | Men or women aged 20 years or older |
2 | Confirmed left ventricular ejection fraction ≤ 40% by echocardiography within the pre-analytical 6 months |
3 | NT-proBNP level ≥ 125 pg/ml or BNP level ≥ 35 pg/ml within the pre-analytical 3 months |
4 | Clinically stable patient without evidence of congestion or extracellular fluid retention |
5 | Patients providing written informed consent |
Exclusion criteria | |
1 | Systolic blood pressure in a sitting position < 90 mmHg or resting heart rate < 50 beats/min at screening |
2 | Patient has a contraindication to beta-blockers |
3 | Patient who are expected to take another beta-blocker after randomization |
4 | Cardiovascular diseases; Ischemic heart disease (unstable angina, myocardial infarction) within 1 month Hypertrophic cardiomyopathy Cor pulmonale Hemodynamically significant stenosis of the aorta, aortic valve, or mitral valve Acute myocardial infarction with complications |
5 | Severe cerebrovascular accident (for example, ischemic stroke or cerebral hemorrhage) within the pre-analytical within 6 months |
6 | Glottic edema, allergic rhinitis, respiratory diseases with bronchospasm such as asthma and chronic obstructive lung disease |
7 | Peripheral vascular disease (for example, Raynaud’s syndrome, intermittent claudication) |
8 | Patients who needs vasopressor support due to prominent volume retention/overload |
9 | Moderate-to-severe retinopathy (for example, retinal hemorrhage, visual disturbance, retinal microaneurysm within 6 months) |
10 | Impaired renal function (serum creatinine ≥ 2.5 mg/dL) or hepatic function (AST or ALT ≥ 3 × ULM) |
11 | Patients in a clinical status that can significantly influence absorption, distribution, metabolism, and secretion of drugs for clinical trials: History of major gastrointestinal surgery, such as gastrectomy or gastric bypass surgery Inflammatory bowel disease within 12 months Current gastric ulcer, pancreatic function abnormality including pancreatitis, gastrointestinal/rectal bleeding which requires treatment Current urologic stenosis or obstruction which requires treatment |
12 | Confirmed or suspected drug/alcohol abuse within 6 months |
13 | Pregnant or lactating women, suspected pregnant women or lactating women |
14 | Chronic inflammatory diseases which require anti-inflammatory treatment |
15 | Hypersensitivity to carvedilol |
16 | Malignant disease including lymphoma and leukemia within 5 years |
17 | Patients who were prescribed other medication for any other clinical trials within the pre-analytical 28 days |
18 | Patients who are expected to have prolonged hospital stay due to other medical problems other than chronic heart failure (for example, femoral neck fracture) |
19 | Patients who are considered inappropriate by researchers to participate in the clinical trial |
Endpoints
Endpoint details | |
---|---|
Primary endpoint | Change in of NT-proBNP level from baseline to 6 months after randomization |
Secondary endpoints | The frequency of NT-proBNP increment > 10% from baseline |
Composite of all-cause mortality and readmission | |
All-cause mortality rate and readmission rate | |
Change in systolic/diastolic blood pressure at sitting position, control/response rate of blood pressure | |
Quality of life assessment by the MLHFQ, Visual Analog Scale | |
Drug compliance |
Randomization
Carvedilol treatment protocol
Dose | ||||
---|---|---|---|---|
Carvedilol IR | 3.125 mg bid | 6.25 mg bid | 12.5 mg bid | 25 mg bid |
Carvedilol SR | 8 mg qd | 16 mg bid | 32 mg bid | 64 mg qd |
Bisoprolol | 1.25 mg qd | 2.5 mg qd | 5 mg qd | 10 mg qd |
Nebivolol | 1.25 mg qd | 2.5 mg qd | 5 mg qd | 10 mg qd |
Metoprolol succinate | 25 mg qd | 50 mg qd | 100 mg qd | 200 mg qd |
Prohibited drugs during the clinical trial
Contraindication details | |
---|---|
1 | Other beta-blockers except the study medication |
2 | Steroid medication (ACTH or corticosteroid). Locally applied drugs are allowed. |
3 | Non-steroidal anti-inflammatory drugs. They are allowed only for shor term use (≤7 days) according to the examiner’s decision, while their usage is absolutely prohibited 3 days before the scheduled visits. Low-dose aspirin (30 to 300 mg daily) for cardiovascular diseases is allowed. |
4 | Estrogen medications. If necessary, low-dose hormonal therapy can be continued for therapeutic purpose at the same dose during the study period |
5 | Sympathomimetic drugs such as catecholamines |
6 | Anti-psychotics: MAO inhibitors, anti-depressants (tri- and tetra-cyclic classes, selective serotonin reuptake inhibitors including lithium) Sedatives and anti-anxiolytics (benzodiazepines and their antagonists, barbiturates, hypnotics such as zolpidem) can be intermittently used according to the physician's decision, while their usage is absolutely prohibited 7 days before the scheduled visits |
7 | Immunosuppressants |
8 | Thyroid hormones. If necessary, thyroid hormonal therapy can be prescribed for therapeutic purpose at the same dose during the study period |
Clinical follow-up
Visit | Visit 1 | Visit 2 | Visit 3 | Visit 4 | Visit 5 |
---|---|---|---|---|---|
Status Period | Screening − 2 to 0 week | Baseline 0 months | 2 months (± 4 days) | 4 months (± 14 days) | 6 months (± 14 days) |
Inclusion/exclusion criteria | • | ||||
Informed consent | • | ||||
Demographic data | • | ||||
Past medical historya | • | ||||
Randomization | • | ||||
Physical examination | • | • | • | • | • |
Vital signs | • | • | • | • | • |
Height and weightb | • | • | • | • | • |
Blood analysisc | • | • | • | ||
Urinalysisd | • | • | • | ||
Pregnancy teste | • | • | • | ||
Chest x-rayf | • | ||||
12-lead electrocardiographg | • | • | |||
Echocardiographyh | • | • | • | ||
Concomitant medication | • | • | • | • | • |
Adverse events | • | • | • | • | |
Patient’s compliance | • | • | • | ||
Questionnaire for quality of life | • | • |