Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure - Full Text View

Purpose

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.

Condition	Intervention	Phase
Atrial Fibrillation Atrial Flutter	Drug: bucindolol hydrochloride Drug: metoprolol succinate	Phase 2 Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	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

Resource links provided by NLM:

Genetics Home Reference related topics: familial atrial fibrillation

MedlinePlus related topics: Atrial Fibrillation Heart Failure

Drug Information available for: Succinic acid Metoprolol Metoprolol tartrate Metoprolol succinate Metoprolol fumarate

U.S. FDA Resources

Further study details as provided by ARCA Biopharma, Inc.:

Primary Outcome Measures:

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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

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 ]

Other Outcome Measures:

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 ]


Estimated Enrollment:	620
Study Start Date:	April 2014
Estimated Study Completion Date:	December 2017
Estimated Primary Completion Date:	December 2017 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.	Drug: bucindolol hydrochloride Other Name: bucindolol
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.	Drug: metoprolol succinate Other Names: Toprol-XL metoprolol

Detailed Description:

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.

Eligibility


Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01970501

Contacts


Contact: Jennifer Meriwether	720-940-2132	jennifer.meriwether@arcabiopharma.com

Show 37 Study Locations

Sponsors and Collaborators

ARCA Biopharma, Inc.

Medtronic

Investigators


Principal Investigator:	Jonathan Piccini, MD	Duke University
Study Director:	Chris Dufton, PhD	ARCA Biopharma, Inc.

More Information

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, 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.


Responsible Party:	ARCA Biopharma, Inc.
ClinicalTrials.gov Identifier:	NCT01970501 History of Changes
Other Study ID Numbers:	BUC-CLIN-303
Study First Received:	October 23, 2013
Last Updated:	February 19, 2015
Health Authority:	United States: Food and Drug Administration

Keywords provided by ARCA Biopharma, Inc.:


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

Additional relevant MeSH terms:


Atrial Fibrillation Atrial Flutter Arrhythmias, Cardiac Cardiovascular Diseases Heart Diseases Pathologic Processes Bucindolol Metoprolol Metoprolol succinate Adrenergic Agents Adrenergic Antagonists Adrenergic alpha-1 Receptor Antagonists Adrenergic alpha-Antagonists Adrenergic beta-1 Receptor Antagonists	Adrenergic beta-Antagonists Anti-Arrhythmia Agents Antihypertensive Agents Autonomic Agents Cardiovascular Agents Molecular Mechanisms of Pharmacological Action Neurotransmitter Agents Peripheral Nervous System Agents Pharmacologic Actions Physiological Effects of Drugs Sympatholytics Sympathomimetics Therapeutic Uses Vasodilator Agents

ClinicalTrials.gov processed this record on March 03, 2015

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