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

Tracking Information
First Submitted Date ICMJE	October 23, 2013
First Posted Date ICMJE	October 28, 2013
Last Update Posted Date	January 9, 2018
Study Start Date ICMJE	April 2014
Actual Primary Completion Date	December 28, 2017 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: January 8, 2018)	Time to first event of symptomatic or asymptomatic 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 Frame: end of treatment week 24 ]
Original Primary Outcome Measures ICMJE; (submitted: October 23, 2013)	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 conversion to stable sinus rhythm (SR) [ Time Frame: end of treatment week 24 ]
Change History	Complete list of historical versions of study NCT01970501 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: January 8, 2018)	Time to first event of symptomatic AF/AFL or ACM during the 24-week Follow-up Period after establishment of stable SR on study drug [end of treatment week 24] [ Time Frame: end of treatment week 24 ]; 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 ]; Total number of hospitalization days per patient (all-cause) during the Total Study Period [ Time Frame: 4 years ]; 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 ]; Proportion of patients with adequate ventricular rate control in the setting of AF/AFL [ Time Frame: 4 years ]
Original Secondary Outcome Measures ICMJE; (submitted: October 23, 2013)	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 ]; 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 ]; Total number of hospitalization (all-cause) days per patient during the Total Study Period [ Time Frame: 4 years ]; Time to first event of ACM or HF hospitalization (as assessed by the Investigator) during the Total Study Period [ Time Frame: 4 years ]; 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 ]
Current Other Outcome Measures ICMJE; (submitted: March 17, 2015)	Incidence of ACM during the Total Study Period [ Time Frame: 4 years ]; 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 ]; Incidence of heart block during the Total Study Period [ Time Frame: 4 years ]; Incidence and severity of treatment-emergent Adverse Events/Serious Adverse Events over time during the Total Study Period [ Time Frame: 4 years ]; Change from baseline (Visit 2) over time during the Total Study Period on: clinical laboratory tests, vital signs and weight, quantitative ECG parameters [ Time Frame: 4 years ]; Proportion of patients attaining target study drug dose during the Drug Titration Period [ Time Frame: end of treatment week 8 ]
Original Other Outcome Measures ICMJE; (submitted: October 23, 2013)	Incidence of ACM during the Total Study Period [ Time Frame: 4 years ]; 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 ]; 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 ]; Incidence and severity of treatment-emergent AEs/SAEs over time [ Time Frame: 4 years ]; Incidence of neoplasm-related AEs/SAEs [ Time Frame: 4 years ]; Change from baseline (randomization) over time on clinical laboratory tests, vital signs and weight [ Time Frame: 4 years ]; 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 ]
Descriptive Information
Brief Title ICMJE	Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure
Official Title ICMJE	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
Brief Summary	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	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.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Current or Recent History of Atrial Fibrillation
Intervention ICMJE	Drug: bucindolol hydrochloride Other Name: bucindolol; Drug: metoprolol succinate Other Names: Toprol-XL metoprolol
Study Arms	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
Publications *	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, Davis G, 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):338-344. doi: 10.1016/j.jchf.2013.04.002.; 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.; Piccini JP, Connolly SJ, Abraham WT, Healey JS, Steinberg BA, Al-Khalidi HR, Dignacco P, van Veldhuisen DJ, Sauer WH, White M, Wilton SB, Anand IS, Dufton C, Marshall DA, Aleong RG, Davis GW, Clark RL, Emery LL, Bristow MR. A genotype-directed comparative effectiveness trial of Bucindolol and metoprolol succinate for prevention of symptomatic atrial fibrillation/atrial flutter in patients with heart failure: Rationale and design of the GENETIC-AF trial. Am Heart J. 2018 May;199:51-58. doi: 10.1016/j.ahj.2017.12.001. Epub 2017 Dec 6.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: January 8, 2018)	267
Original Estimated Enrollment ICMJE; (submitted: October 23, 2013)	620
Actual Study Completion Date	December 28, 2017
Actual Primary Completion Date	December 28, 2017 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years to 85 Years (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Canada, Hungary, Netherlands, Poland, Serbia, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01970501
Other Study ID Numbers ICMJE	BUC-CLIN-303
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Plan to Share IPD: No
Responsible Party	ARCA Biopharma, Inc.
Study Sponsor ICMJE	ARCA Biopharma, Inc.
Collaborators ICMJE	Medtronic
Investigators ICMJE	Principal Investigator: Jonathan Piccini, MD Duke University Study Director: Chris Dufton, PhD ARCA Biopharma, Inc.
PRS Account	ARCA Biopharma, Inc.
Verification Date	January 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP