Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Current or Recent History of Atrial Fibrillation

Intervention / Treatment
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* Drug: bucindolol hydrochloride
* Drug: metoprolol succinate
* Other: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 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 Key Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: bucindolol hydrochloride<br>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. | Drug: bucindolol hydrochloride<br> <br> * Other names: bucindolol;|
| Active Comparator: metoprolol succinate<br>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. | Drug: metoprolol succinate<br> <br> * Other names: metoprolol;Other: Placebo oral capsule<br> <br> * Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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]. | 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. | end of treatment week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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] | Number of days on study medication before participant experienced symptomatic or asymptomatic atrial fibrillation, atrial flutter, or all-cause mortality during the 24 week follow up period. | end of treatment week 24 | 
| Number of Patients With Adequate Ventricular Rate Control During the 24-week Follow-up Period | Number of patients with adequate ventricular rate control following the start of medication during the 24-week Follow-up Period | end of treatment week 24 | 
| Total Number of Hospitalization Days Per Patient (All-cause) During the Total Study Period (24 Weeks) | Total number of hospitalization days per patient (all-cause) following the start of study medication during the Total Study Period (24 weeks). Hospitalization was defined by a hospital admission (note that same day admit and discharge equates to 0 days duration), ER visits were not counted as events. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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atrial fibrillation, atrial flutter, heart failure, reduced left ventricle ejection fraction, electrical cardioversion, GENETIC-AF, Medtronic, bucindolol, pharmacogenetic, ARCA, Toprol, Toprol-XL, Metoprolol, Metoprolol succinate