Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure (GENETIC-AF)

ARCA Biopharma

Status and phase: Completed; Phase 2

Conditions: Current or Recent History of Atrial Fibrillation

Treatments: Drug: bucindolol hydrochloride; Other: Placebo oral capsule; Drug: metoprolol succinate

Study type: Interventional

Funder types: Industry

Identifiers

NCT01970501

BUC-CLIN-303

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 267 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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267 participants in 2 patient groups

bucindolol hydrochloride

Experimental group

Description:

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.

Treatment:

Drug: bucindolol hydrochloride

metoprolol succinate

Active Comparator group

Description:

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.

Treatment:

Drug: metoprolol succinate

Other: Placebo oral capsule