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

• Time to first event of AF/AFL (i.e., symptomatic or asymptomatic) or ACM during the 24-week Follow-up Period [ Time Frame: end of treatment week 24 ] [ Designated as safety issue: No ]
• Proportion of patients with ventricular tachycardia (VT), ventricular fibrillation (VF), or symptomatic supraventricular tachycardia (SVT) during the 24-week Follow-up Period [ Time Frame: end of treatment week 24 ] [ Designated as safety issue: No ]
• Total number of hospitalization days per patient (all-cause) during the Total Study Period [ Time Frame: 4 years ] [ Designated as safety issue: No ]
• Time to first event of AF/AFL (i.e., symptomatic or asymptomatic), heart failure (HF) hospitalization (as assessed by the Investigator), or ACM during the Total Study Period [ Time Frame: 4 years ] [ Designated as safety issue: No ]
• Proportion of patients who have AF on ECG at the end of study who demonstrate ventricular response rate (VRR) control [ Time Frame: 4 years ] [ Designated as safety issue: No ]

• Time to first event of AF/AFL (i.e., symptomatic or asymptomatic) or ACM during the 24-week Follow-up Period [ Time Frame: end of treatment week 24 ] [ Designated as safety issue: No ]
• Proportion of patients during the 24-week Follow-up Period with VT, VF, or symptomatic supraventricular tachycardia (SVT) [ Time Frame: end of treatment week 24 ] [ Designated as safety issue: No ]
• Total number of hospitalization (all-cause) days per patient during the Total Study Period [ Time Frame: 4 years ] [ Designated as safety issue: No ]
• Time to first event of ACM or HF hospitalization (as assessed by the Investigator) during the Total Study Period [ Time Frame: 4 years ] [ Designated as safety issue: No ]
• Proportion of patients who have AF on ECG at the end of the study who demonstrate ventricular response rate (VRR) control [ Time Frame: 4 years ] [ Designated as safety issue: No ]

• Incidence of ACM during the Total Study Period [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• Incidence of ACM, cardiovascular-related hospitalization (as assessed by the Investigator), or withdrawal of study drug due to an adverse event (AE) during the Drug Titration Period [ Time Frame: end of treatment week 8 ] [ Designated as safety issue: Yes ]
• Incidence of heart block during the Total Study Period. Defined as third degree heart block, second degree heart block requiring pacemaker implantation, or symptomatic second degree heart block as determined by the Clinical Events Committee. [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• Incidence and severity of treatment-emergent Adverse Events/Serious Adverse Events over time during the Total Study Period [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• Change from baseline (Visit 2) over time during the Total Study Period on: clinical laboratory tests, vital signs and weight [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• Proportion of patients attaining target study drug dose during the Drug Titration Period. Supportive analyses will also be performed for the subpopulations receiving and not receiving previous beta blocker therapy at randomization. [ Time Frame: end of treatment week 8 ] [ Designated as safety issue: Yes ]

• Incidence of ACM during the Total Study Period [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• Incidence of ACM, cardiovascular-related hospitalization (as assessed by the Investigator), or withdrawal of study drug due to an adverse event (AE) during the Drug Titration Period [ Time Frame: end of treatment week 8 ] [ Designated as safety issue: Yes ]
• Incidence during the Total Study Period of third degree heart block, second degree heart block requiring pacemaker implantation, or symptomatic second degree heart block as determined by the Clinical Events Committee [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• Incidence and severity of treatment-emergent AEs/SAEs over time [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• Incidence of neoplasm-related AEs/SAEs [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• Change from baseline (randomization) over time on clinical laboratory tests, vital signs and weight [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
• Proportion of patients attaining target study drug dose for the subpopulations receiving and not receiving previous beta blocker therapy at randomization [ Time Frame: end of treatment week 8 ] [ Designated as safety issue: Yes ]

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.

The goal of the GENETIC-AF trial is to demonstrate the superiority of pharmacogenetically targeted bucindolol compared to Toprol-XL 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 that has persistent symptomatic AF requiring electrical conversion to sinus rhythm.

• Atrial Fibrillation
• Atrial Flutter

• Drug: bucindolol hydrochloride
  Other Name: bucindolol
• Drug: metoprolol succinate
  Other Names:

  • Toprol-XL
  • metoprolol

• Experimental: bucindolol hydrochloride

  bucindolol hydrochloride (bucindolol)

  Capsules are available in the following dosage strengths to be taken twice daily (with or without food): 6.25mg, 12.5mg, 25mg, 50mg, and 100mg.

  Intervention: Drug: bucindolol hydrochloride
• Active Comparator: metoprolol succinate

  metoprolol succinate (Toprol-XL)

  Capsules are available in the following dosage strengths to be taken twice daily (with or without food): 25mg, 50mg, 100mg, 200mg and/or matching placebo to maintain blinded dosing.

  Intervention: Drug: metoprolol succinate

• Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, Hodne D, Nelson B, Morrison J, Domanski MJ, Wagoner LE, Abraham WT, Anderson JL, Carlquist JF, Krause-Steinrauf HJ, Lazzeroni LC, Port JD, Lavori PW, Bristow MR. A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11288-93. Epub 2006 Jul 14.
• O'Connor CM, Fiuzat M, Carson PE, Anand IS, Plehn JF, Gottlieb SS, Silver MA, Lindenfeld J, Miller AB, White M, Walsh R, Nelson P, Medway A, Davis G, Robertson AD, Port JD, Carr J, Murphy GA, Lazzeroni LC, Abraham WT, Liggett SB, Bristow MR. Combinatorial pharmacogenetic interactions of bucindolol and β1, α2C adrenergic receptor polymorphisms. PLoS One. 2012;7(10):e44324. doi: 10.1371/journal.pone.0044324. Epub 2012 Oct 10.
• Aleong RG, Sauer WH, Sauer WH, Murphy GA, Port JD, Anand IS, Fiuzat M, O'Connor CM, Abraham WT, Liggett SB, Bristow MR. Prevention of atrial fibrillation by bucindolol is dependent on the beta₁389 Arg/Gly adrenergic receptor polymorphism. JACC Heart Fail. 2013 Aug;1(4):338-44.
• Kao DP, Davis G, Aleong R, O'Connor CM, Fiuzat M, Carson PE, Anand IS, Plehn JF, Gottlieb SS, Silver MA, Lindenfeld J, Miller AB, White M, Murphy GA, Sauer W, Bristow MR. Effect of bucindolol on heart failure outcomes and heart rate response in patients with reduced ejection fraction heart failure and atrial fibrillation. Eur J Heart Fail. 2013 Mar;15(3):324-33. doi: 10.1093/eurjhf/hfs181. Epub 2012 Dec 7.

Key Inclusion Criteria:

• Must weigh ≥ 40 kg
• Symptomatic heart failure within 90 days of Visit 1
• Symptomatic AF at Visit 1 and Visit 2, determined by the Investigator to require electrical cardioversion (ECV)
• Possess the β1389Arg/Arg genotype
• Left Ventricular Ejection Fraction (LVEF) < 0.50 assessed ≤ 12 months prior to Visit 1
• Clinical euvolemia at the time of randomization
• Receiving appropriate anticoagulation therapy prior to randomization

Key Exclusion Criteria:

• Use of any of the following ≤ 7 days of Visit 2: amiodarone, disopyramide, dofetilide, dronedarone, flecainide, propafenone, sotalol, non-dihydropyridine calcium channel blockers, daily NSAIDS (e.g. ibuprofen, celecoxib), thiazolidinediones, or frequent use of nitroglycerin (i.e., > 6 sublingual tablets/week)
• More than two previous ECV ≤ 12 months of Visit 1 or if the most recent ECV failed to produce SR
• NYHA Class IV symptoms at Visit 1
• Permanent AF at Visit 1
• History of a successful atrioventricular (AV) node ablation
• History of an AF ablation within 3 months of Visit 1
• Myocardial infarction, unstable angina, acute coronary syndrome, cardiac surgery (including percutaneous transluminal coronary angioplasty or stent placement), or evidence of new ischemic changes as assessed by ECG within 90 days of Visit 2
• Evidence of an appropriate firing of an implanted cardioverter-defibrillator (ICD) device for ventricular tachycardia (VT) or ventricular fibrillation (VF) within 90 days of Visit 2