GENETIC-AF - A Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients With Heart Failure
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 267
- 试验地点
- 97
- 主要终点
- Time to First Event of Symptomatic Atrial Fibrillation/Atrial Flutter (AF/AFL) or All Cause Mortality (ACM) During the 24-week Follow-up Period After Establishment of Stable Sinus Rhythm (SR) on Study Drug [End of Treatment Week 24].
研究概览
简要总结
This study is being done to compare the effects of bucindolol hydrochloride (bucindolol) to metoprolol succinate (Toprol-XL) on the recurrence of symptomatic atrial fibrillation/atrial flutter in patients with heart failure who have a specific genotype for the beta-1 adrenergic receptor.
详细描述
The goal of the GENETIC-AF trial is to demonstrate the superiority of pharmacogenetically targeted bucindolol compared to metoprolol for the prevention of symptomatic atrial fibrillation or atrial flutter in a genotype-defined population with heart failure and/or reduced left ventricular ejection fraction at high risk of atrial fibrillation/atrial flutter recurrence.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must weigh at least 40 kg
- •Possess the β1389 Arg/Arg genotype
- •Left Ventricular Ejection Fraction (LVEF) < 0.50 assessed within 12 months prior to Screening
- •At least one episode of symptomatic paroxysmal or persistent AF within 180 days of Screening
- •Clinically appropriate for electrical cardioversion (ECV) if AF/AFL is present after study drug initiation
- •Receiving appropriate anticoagulation therapy prior to Randomization
排除标准
- •NYHA Class IV symptoms at the time of Randomization
- •Significant fluid overload at Randomization
- •Permanent AF at Screening
- •More than two previous ECV within 6 months of Randomization or if the most recent ECV failed to produce SR
- •Presence of an LVAD, or likely to requirement LVAD placement within 6 months of Randomization
- •History of a successful atrioventricular (AV) node ablation
- •History of an AF/AFL ablation within 30 days of Randomization
- •Evidence of an appropriate firing of an implanted cardioverter-defibrillator (ICD) device for ventricular tachycardia (VT) or ventricular fibrillation (VF) within 90 days of Randomization
研究组 & 干预措施
bucindolol hydrochloride
bucindolol hydrochloride (bucindolol)
Participants were randomized (1:1) to blinded treatment with bucindolol or metoprolol and titrated weekly to target doses of 50 mg twice daily (BID; < 75 kg) or 100 mg BID (≥ 75 kg) for bucindolol or 200 mg once daily (QD) for metoprolol. 84% of bucindolol participants attained target dose and 72% of metoprolol participants attained target dose.
The lowest starting dose of bucindolol was 6.25 mg BID with weekly dose titrations to the weight-based target dose or to the maximum tolerated dose. The starting dose assigned was based on the patient's beta-blocker treatment prior to randomization. Capsules for titration were available in the following dosage strengths to be taken twice daily (with or without food): 6.25mg, 12.5mg, 25mg, 50mg, and 100mg.
干预措施: bucindolol hydrochloride (Drug)
metoprolol succinate
metoprolol succinate (Toprol-XL)
Participants were randomized (1:1) to blinded treatment with bucindolol or metoprolol and titrated weekly to target doses of 50 mg twice daily (BID; < 75 kg) or 100 mg BID (≥ 75 kg) for bucindolol or 200 mg once daily (QD) for metoprolol. 84% of bucindolol participants attained target dose and 72% of metoprolol participants attained target dose.
The lowest starting dose of metoprolol was 25 mg QD with weekly dose titrations to the target dose or to the maximum tolerated dose. The starting dose assigned was based upon the patient's beta-blocker treatment prior to randomization. Capsules for titration were available in the following dosage strengths to be taken twice daily (with or without food): 25mg, 50mg, 100mg, 200mg and/or matching placebo oral capsule to maintain blinded dosing.
干预措施: metoprolol succinate (Drug)
metoprolol succinate
metoprolol succinate (Toprol-XL)
Participants were randomized (1:1) to blinded treatment with bucindolol or metoprolol and titrated weekly to target doses of 50 mg twice daily (BID; < 75 kg) or 100 mg BID (≥ 75 kg) for bucindolol or 200 mg once daily (QD) for metoprolol. 84% of bucindolol participants attained target dose and 72% of metoprolol participants attained target dose.
The lowest starting dose of metoprolol was 25 mg QD with weekly dose titrations to the target dose or to the maximum tolerated dose. The starting dose assigned was based upon the patient's beta-blocker treatment prior to randomization. Capsules for titration were available in the following dosage strengths to be taken twice daily (with or without food): 25mg, 50mg, 100mg, 200mg and/or matching placebo oral capsule to maintain blinded dosing.
干预措施: Placebo oral capsule (Other)
结局指标
主要结局
Time to First Event of Symptomatic Atrial Fibrillation/Atrial Flutter (AF/AFL) or All Cause Mortality (ACM) During the 24-week Follow-up Period After Establishment of Stable Sinus Rhythm (SR) on Study Drug [End of Treatment Week 24].
时间窗: end of treatment week 24
Time-to-event is calculated as the date of the event minus the date of initiation of efficacy follow-up, with 1 added in order to include both the start date and end date of the interval. Cox's proportional hazards model will be used to calculate estimated hazard ratios and 95% confidence intervals. The calculations will be performed with the SAS PHREG procedure, with the stratification variables specified in the STRATA statement and the treatment group comparator and any covariates being examined specified in the MODEL statement. For the primary endpoint, the appropriateness of assuming proportional hazards will be explored by the graphing of log (-log(survival function)) over follow-up for each treatment group.
次要结局
- Time to First Event of Symptomatic or Asymptomatic AF/AFL or ACM During the 24-week Follow-up Period After Establishment of Stable SR on Study Drug [End of Treatment Week 24](end of treatment week 24)
- Total Number of Hospitalization Days Per Patient (All-cause) During the Total Study Period (24 Weeks)(24 weeks)
- Number of Patients With Adequate Ventricular Rate Control During the 24-week Follow-up Period(end of treatment week 24)