Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure

NCT01970501 | Completed Phase 2 Results DMC

• 1 other identifier: BUC-CLIN-303
• Study Type: interventional
• Target: 267
• Locations: 6 countries
• Sites: 97

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.

Conditions

Current or Recent History of Atrial Fibrillation

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Establishment of Stable Sinus Rhythm (SR) on Study Drug [End of Treatment Week 24].

  Time-to-event is calculated as the date of the event minus the date of initiation of efficacy follow-up, with 1 added in order to include both the start date and end date of the interval. Cox's proportional hazards model will be used to calculate estimated hazard ratios and 95% confidence intervals. The calculations will be performed with the SAS PHREG procedure, with the stratification variables specified in the STRATA statement and the treatment group comparator and any covariates being examined specified in the MODEL statement. For the primary endpoint, the appropriateness of assuming proportional hazards will be explored by the graphing of log (-log(survival function)) over follow-up for each treatment group.

  end of treatment week 24

Secondary Outcomes (3)

• Time to First Event of Symptomatic or Asymptomatic AF/AFL or ACM During the 24-week Follow-up Period After Establishment of Stable SR on Study Drug [End of Treatment Week 24]

  end of treatment week 24

• Number of Patients With Adequate Ventricular Rate Control During the 24-week Follow-up Period

  end of treatment week 24

• Total Number of Hospitalization Days Per Patient (All-cause) During the Total Study Period (24 Weeks)

  24 weeks

Study Arms (2)

bucindolol hydrochloride

EXPERIMENTAL

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.

Drug: bucindolol hydrochloride

metoprolol succinate

ACTIVE COMPARATOR

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.

Drug: metoprolol succinate; Other: Placebo oral capsule

Interventions

bucindolol hydrochloride DRUG

Also known as: bucindolol

bucindolol hydrochloride

metoprolol succinate DRUG

Also known as: Toprol-XL, metoprolol

metoprolol succinate

Placebo oral capsule OTHER

Also known as: placebo

metoprolol succinate

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• ARCA Biopharma, Inc.: lead
• Medtronic: collaborator

Study Sites (97)

ARCA Clinical Research Site #157

Anchorage, Alaska, 99508, United States

Location

ARCA Clinical Research Site #383

Phoenix, Arizona, 85004, United States

Location

ARCA Clinical Research Site #385

Phoenix, Arizona, 85018, United States

Location

ARCA Clinical Research Site #381

East Palo Alto, California, 94303, United States

Location

ARCA Clinical Research Site #186

Loma Linda, California, 92357, United States

Location

ARCA Clinical Research Site #320

Pasadena, California, 91105, United States

Location

ARCA Clinical Research Site #390

Stanford, California, 94305, United States

Location

ARCA Clinical Research Site #153

Aurora, Colorado, 80045, United States

Location

ARCA Clinical Research Site #380

Denver, Colorado, 80120, United States

Location

ARCA Clinical Research Site #195

Miami, Florida, 33136, United States

Location

ARCA Clinical Research Site #184

Tampa, Florida, 33606, United States

Location

ARCA Clinical Research Site #351

Athens, Georgia, 30606, United States

Location

ARCA Clinical Research Site #389

Atlanta, Georgia, 30322, United States

Location

ARCA Clinical Research Site #342

Oakbrook Terrace, Illinois, 60181, United States

Location

ARCA Clinical Research Site #303

Hammond, Indiana, 46320, United States

Location

ARCA Clinical Research Site #388

Iowa City, Iowa, 52242, United States

Location

ARCA Clinical Site #396

New Orleans, Louisiana, 70121, United States

Location

ARCA Clinical Research Site #398

Baltimore, Maryland, 21287, United States

Location

ARCA Clinical Research Site #127

Ypsilanti, Michigan, 48197, United States

Location

ARCA Clinical Research Site #156

Minneapolis, Minnesota, 55417, United States

Location

ARCA Clinical Research Site #174

Saint Paul, Minnesota, 55102, United States

Location

ARCA Clinical Research Site #108

St Louis, Missouri, 63110, United States

Location

ARCA Clinical Research Site #201

St Louis, Missouri, 63128, United States

Location

ARCA Clinical Research Site #152

Lincoln, Nebraska, 68506, United States

Location

ARCA Clinical Research Site #161

Elmer, New Jersey, 08318, United States

Location

ARCA Clinical Research Site #202

Hillsborough, New Jersey, 08844, United States

Location

ARCA Clinical Research Site # 179

Albany, New York, 12205, United States

Location

ARCA Clinical Research Site #397

New York, New York, 10029, United States

Location

ARCA Clinical Research Site #181

Durham, North Carolina, 27705, United States

Location

ARCA Clinical Research Site #349

Greensboro, North Carolina, 27401, United States

Location

ARCA Clinical Research Site #173

Akron, Ohio, 44304, United States

Location

ARCA Clinical Research Site #392

Cincinnati, Ohio, 45219, United States

Location

ARCA Clinical Research Site #322

Cleveland, Ohio, 44106, United States

Location

ARCA Clinical Research Site #151

Columbus, Ohio, 43210, United States

Location

ARCA Clinical Research Site #399

Oklahoma City, Oklahoma, 73135, United States

Location

ARCA Clinical Research Site #115

Portland, Oregon, 97201, United States

Location

ARCA Clinical Research Site # 189

Hershey, Pennsylvania, 17033, United States

Location

ARCA Clinical Research Site #109

Lancaster, Pennsylvania, 17603, United States

Location

ARCA Clinical Research Site #133

Philadelphia, Pennsylvania, 19104, United States

Location

ARCA Clinical Site #393

Germantown, Tennessee, 38138, United States

Location

ARCA Clinical Research Site #198

Jackson, Tennessee, 38305, United States

Location

ARCA Clinical Research Site #387

Dallas, Texas, 75230, United States

Location

ARCA Clinical Research Site #379

Salt Lake City, Utah, 84132, United States

Location

ARCA Clinical Site #391

Charlottesville, Virginia, 22908, United States

Location

ARCA Clinical Research Site #386

Falls Church, Virginia, 22042, United States

Location

ARCA Clinical Research Site #200

Manassas, Virginia, 20109, United States

Location

ARCA Research Site #131

Norfolk, Virginia, 23507, United States

Location

ARCA Clinical Research Site #196

Puyallup, Washington, 98372, United States

Location

ARCA Clinical Research Site #612

Calgary, Alberta, T2N 4Z6, Canada

Location

ARCA Clinical Research Site #624

Vancouver, British Columbia, V6E 1M7, Canada

Location

ARCA Clinical Research Site #611

Cambridge, Ontario, N1R 6V6, Canada

Location

ARCA Clinical Research Site #621

Cambridge, Ontario, N1R 7R1, Canada

Location

ARCA Clinical Research Site #601

Hamilton, Ontario, L8L 2X2, Canada

Location

ARCA Clinical Research Site #609

London, Ontario, N6A 5A5, Canada

Location

ARCA Clinical Research Site #623

Newmarket, Ontario, L3Y 2P6, Canada

Location

ARCA Clinical Research Site #618

Oshawa, Ontario, L1H 1B9, Canada

Location

ARCA Clinical Research Site #613

Ottawa, Ontario, K1Y 4W7, Canada

Location

ARCA Clinical Research Site #619

Toronto, Ontario, M4N 3M5, Canada

Location

ARCA Clinical Research Site #616

Waterloo, Ontario, N2J 1C4, Canada

Location

ARCA Clinical Research Site #614

Montreal, Quebec, H1T 1C8, Canada

Location

ARCA Clinical Research Site #607

Montreal, Quebec, H2W 1T8, Canada

Location

ARCA Clinical Research Site #603

Montreal, Quebec, H3G 1A3, Canada

Location

ARCA Clinical Research Site #625

Saint-Jérôme, Quebec, J7Z 5T3, Canada

Location

ARCA Clinical Research Site #602

Sherbrooke, Quebec, J1H 5N4, Canada

Location

ARCA Clinical Research Site #626

Trois-Rivières, Quebec, G8Z 3R9, Canada

Location

ARCA Clinical Research Site #615

Québec, G1V 4G5, Canada

Location

ARCA Clinical Research Site #726

Budapest, 1096, Hungary

Location

ARCA Clinical Research Site #727

Budapest, 1122, Hungary

Location

ARCA Clinical Research Site #728

Budapest, 1134, Hungary

Location

ARCA Clinical Research Site #729

Budapest, 1145, Hungary

Location

ARCA Clinical Research Site #733

Debrecen, 4032, Hungary

Location

ARCA Clinical Research Site #732

Kaposvár, 7400, Hungary

Location

ARCA Clinical Research Site #730

Pécs, 7624, Hungary

Location

ARCA Clinical Research Site #731

Szeged, 6725, Hungary

Location

ARCA Clinical Research Site #734

Szolnok, 5000, Hungary

Location

ARCA Clinical Research Site #781

Capelle aan den IJssel, 2906 ZC, Netherlands

Location

ARCA Clinical Research Site #779

Gorinchem, 4204 AA, Netherlands

Location

ARCA Clinical Research Site #776

Groningen, 9713 GZ, Netherlands

Location

ARCA Clinical Research Site #780

Helmond, 5707 HA, Netherlands

Location

ARCA Clinical Research Site #782

Leiderdorp, 2334 CK, Netherlands

Location

ARCA Clinical Research Site #786

Roosendaal, 4708 AE, Netherlands

Location

ARCA Clinical Research Site #777

Sneek, 8601 ZK, Netherlands

Location

ARCA Clinical Research Site #783

Stadskanaal, 9501 HE, Netherlands

Location

ARCA Clinical Research Site #784

Tiel, 4002 WP, Netherlands

Location

ARCA Clinical Research Site #752

Bialystok, 15-276, Poland

Location

ARCA Clinical Research Site #757

Gdansk, 80-952, Poland

Location

ARCA Clinical Research Site #753

Krakow, 31-501, Poland

Location

ARCA Clinical Research Site #755

Lodz, 91-347, Poland

Location

ARCA Clinical Research Site #751

Lodz, 92-213, Poland

Location

ARCA Clinical Research Site #758

Lublin, 20-954, Poland

Location

ARCA Clinical Research Site #754

Warsaw, 02-097, Poland

Location

ARCA Clinical Research Site #756

Wroclaw, 50-981, Poland

Location

ARCA Clinical Research Site #807

Belgrade, 11000, Serbia

Location

ARCA Clinical Research Site #806

Belgrade, 11080, Serbia

Location

ARCA Clinical Research Site #801

Kragujevac, 34000, Serbia

Location

ARCA Clinical Research Site #804

Niš, 18000, Serbia

Location

ARCA Clinical Research Site #805

Niš, 18000, Serbia

Location

Related Publications (7)

• 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.

  PMID: 16844790 BACKGROUND

• 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.

  PMID: 23071495 BACKGROUND

• 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.

  PMID: 24159564 BACKGROUND

• 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.

  PMID: 23223178 BACKGROUND

• 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.

  PMID: 39570238 DERIVED

• 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.

  PMID: 34270905 DERIVED

• 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.

  PMID: 29754666 DERIVED

MeSH Terms

Conditions

Atrial Fibrillation; Atrial Flutter; Heart Failure

Interventions

bucindolol; Metoprolol

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines

Results Point of Contact

• Title: Dr. Michael Bristow
• Organization: Arca biopharma Inc.

Michael.Bristow@arcabio.com

7209412100

Study Officials

• Jonathan Piccini, MD

  Duke University

  PRINCIPAL INVESTIGATOR

• Michael Bristow, MD,PhD

  ARCA Biopharma, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 23, 2013
• First Posted: October 28, 2013
• Study Start: April 1, 2014
• Primary Completion: December 28, 2017
• Study Completion: December 28, 2017
• Last Updated: September 26, 2022
• Results First Posted: September 15, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

SE (5); CA (18); US (48); PL (8); HU (9); NL (9)