Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure
NCT ID: NCT01970501
Last Updated: 2022-09-26
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
267 participants
INTERVENTIONAL
2014-04-30
2017-12-28
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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bucindolol hydrochloride
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.
bucindolol hydrochloride
metoprolol succinate
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.
metoprolol succinate
Placebo oral capsule
Interventions
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bucindolol hydrochloride
metoprolol succinate
Placebo oral capsule
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
Exclusion Criteria
* 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
18 Years
85 Years
ALL
No
Sponsors
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Medtronic
INDUSTRY
ARCA Biopharma, Inc.
INDUSTRY
Responsible Party
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Principal Investigators
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Jonathan Piccini, MD
Role: PRINCIPAL_INVESTIGATOR
Duke University
Michael Bristow, MD,PhD
Role: STUDY_DIRECTOR
ARCA Biopharma, Inc.
Locations
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ARCA Clinical Research Site #157
Anchorage, Alaska, United States
ARCA Clinical Research Site #383
Phoenix, Arizona, United States
ARCA Clinical Research Site #385
Phoenix, Arizona, United States
ARCA Clinical Research Site #381
East Palo Alto, California, United States
ARCA Clinical Research Site #186
Loma Linda, California, United States
ARCA Clinical Research Site #320
Pasadena, California, United States
ARCA Clinical Research Site #390
Stanford, California, United States
ARCA Clinical Research Site #153
Aurora, Colorado, United States
ARCA Clinical Research Site #380
Denver, Colorado, United States
ARCA Clinical Research Site #195
Miami, Florida, United States
ARCA Clinical Research Site #184
Tampa, Florida, United States
ARCA Clinical Research Site #351
Athens, Georgia, United States
ARCA Clinical Research Site #389
Atlanta, Georgia, United States
ARCA Clinical Research Site #342
Oakbrook Terrace, Illinois, United States
ARCA Clinical Research Site #303
Hammond, Indiana, United States
ARCA Clinical Research Site #388
Iowa City, Iowa, United States
ARCA Clinical Site #396
New Orleans, Louisiana, United States
ARCA Clinical Research Site #398
Baltimore, Maryland, United States
ARCA Clinical Research Site #127
Ypsilanti, Michigan, United States
ARCA Clinical Research Site #156
Minneapolis, Minnesota, United States
ARCA Clinical Research Site #174
Saint Paul, Minnesota, United States
ARCA Clinical Research Site #108
St Louis, Missouri, United States
ARCA Clinical Research Site #201
St Louis, Missouri, United States
ARCA Clinical Research Site #152
Lincoln, Nebraska, United States
ARCA Clinical Research Site #161
Elmer, New Jersey, United States
ARCA Clinical Research Site #202
Hillsborough, New Jersey, United States
ARCA Clinical Research Site # 179
Albany, New York, United States
ARCA Clinical Research Site #397
New York, New York, United States
ARCA Clinical Research Site #181
Durham, North Carolina, United States
ARCA Clinical Research Site #349
Greensboro, North Carolina, United States
ARCA Clinical Research Site #173
Akron, Ohio, United States
ARCA Clinical Research Site #392
Cincinnati, Ohio, United States
ARCA Clinical Research Site #322
Cleveland, Ohio, United States
ARCA Clinical Research Site #151
Columbus, Ohio, United States
ARCA Clinical Research Site #399
Oklahoma City, Oklahoma, United States
ARCA Clinical Research Site #115
Portland, Oregon, United States
ARCA Clinical Research Site # 189
Hershey, Pennsylvania, United States
ARCA Clinical Research Site #109
Lancaster, Pennsylvania, United States
ARCA Clinical Research Site #133
Philadelphia, Pennsylvania, United States
ARCA Clinical Site #393
Germantown, Tennessee, United States
ARCA Clinical Research Site #198
Jackson, Tennessee, United States
ARCA Clinical Research Site #387
Dallas, Texas, United States
ARCA Clinical Research Site #379
Salt Lake City, Utah, United States
ARCA Clinical Site #391
Charlottesville, Virginia, United States
ARCA Clinical Research Site #386
Falls Church, Virginia, United States
ARCA Clinical Research Site #200
Manassas, Virginia, United States
ARCA Research Site #131
Norfolk, Virginia, United States
ARCA Clinical Research Site #196
Puyallup, Washington, United States
ARCA Clinical Research Site #612
Calgary, Alberta, Canada
ARCA Clinical Research Site #624
Vancouver, British Columbia, Canada
ARCA Clinical Research Site #611
Cambridge, Ontario, Canada
ARCA Clinical Research Site #621
Cambridge, Ontario, Canada
ARCA Clinical Research Site #601
Hamilton, Ontario, Canada
ARCA Clinical Research Site #609
London, Ontario, Canada
ARCA Clinical Research Site #623
Newmarket, Ontario, Canada
ARCA Clinical Research Site #618
Oshawa, Ontario, Canada
ARCA Clinical Research Site #613
Ottawa, Ontario, Canada
ARCA Clinical Research Site #619
Toronto, Ontario, Canada
ARCA Clinical Research Site #616
Waterloo, Ontario, Canada
ARCA Clinical Research Site #614
Montreal, Quebec, Canada
ARCA Clinical Research Site #607
Montreal, Quebec, Canada
ARCA Clinical Research Site #603
Montreal, Quebec, Canada
ARCA Clinical Research Site #625
Saint-Jérôme, Quebec, Canada
ARCA Clinical Research Site #602
Sherbrooke, Quebec, Canada
ARCA Clinical Research Site #626
Trois-Rivières, Quebec, Canada
ARCA Clinical Research Site #615
Québec, , Canada
ARCA Clinical Research Site #726
Budapest, , Hungary
ARCA Clinical Research Site #727
Budapest, , Hungary
ARCA Clinical Research Site #728
Budapest, , Hungary
ARCA Clinical Research Site #729
Budapest, , Hungary
ARCA Clinical Research Site #733
Debrecen, , Hungary
ARCA Clinical Research Site #732
Kaposvár, , Hungary
ARCA Clinical Research Site #730
Pécs, , Hungary
ARCA Clinical Research Site #731
Szeged, , Hungary
ARCA Clinical Research Site #734
Szolnok, , Hungary
ARCA Clinical Research Site #781
Capelle aan den IJssel, , Netherlands
ARCA Clinical Research Site #779
Gorinchem, , Netherlands
ARCA Clinical Research Site #776
Groningen, , Netherlands
ARCA Clinical Research Site #780
Helmond, , Netherlands
ARCA Clinical Research Site #782
Leiderdorp, , Netherlands
ARCA Clinical Research Site #786
Roosendaal, , Netherlands
ARCA Clinical Research Site #777
Sneek, , Netherlands
ARCA Clinical Research Site #783
Stadskanaal, , Netherlands
ARCA Clinical Research Site #784
Tiel, , Netherlands
ARCA Clinical Research Site #752
Bialystok, , Poland
ARCA Clinical Research Site #757
Gdansk, , Poland
ARCA Clinical Research Site #753
Krakow, , Poland
ARCA Clinical Research Site #755
Lodz, , Poland
ARCA Clinical Research Site #751
Lodz, , Poland
ARCA Clinical Research Site #758
Lublin, , Poland
ARCA Clinical Research Site #754
Warsaw, , Poland
ARCA Clinical Research Site #756
Wroclaw, , Poland
ARCA Clinical Research Site #807
Belgrade, , Serbia
ARCA Clinical Research Site #806
Belgrade, , Serbia
ARCA Clinical Research Site #801
Kragujevac, , Serbia
ARCA Clinical Research Site #804
Niš, , Serbia
ARCA Clinical Research Site #805
Niš, , Serbia
Countries
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References
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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. doi: 10.1073/pnas.0509937103. 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 beta1, alpha2C 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 beta(1)389 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.
Carroll IA, Piccini JP, Steinberg BA, Tzou WS, Richards JC, DeMets DL, Bristow MR. Symptoms Burden as a Clinical Outcomes Assessment in Heart Failure Patients With Atrial Fibrillation. JACC Heart Fail. 2025 Apr;13(4):573-585. doi: 10.1016/j.jchf.2024.08.023. Epub 2024 Nov 20.
Piccini JP, Dufton C, Carroll IA, Healey JS, Abraham WT, Khaykin Y, Aleong R, Krueger SK, Sauer WH, Wilton SB, Rienstra M, van Veldhuisen DJ, Anand IS, White M, Camm AJ, Ziegler PD, Marshall D, Bristow MR, Connolly SJ; Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL for Prevention of Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure Trial Investigators*. Bucindolol Decreases Atrial Fibrillation Burden in Patients With Heart Failure and the ADRB1 Arg389Arg Genotype. Circ Arrhythm Electrophysiol. 2021 Aug;14(8):e009591. doi: 10.1161/CIRCEP.120.009591. Epub 2021 Jul 16.
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.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Document Type: Informed Consent Form
Other Identifiers
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BUC-CLIN-303
Identifier Type: -
Identifier Source: org_study_id
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