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

September 14, 2022 updated by: ARCA Biopharma, Inc.

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Actual)

267

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
      • Quebec, Canada, G1V 4G5
        • ARCA Clinical Research Site #615
    • Alberta
      • Calgary, Alberta, Canada, T2N 4Z6
        • ARCA Clinical Research Site #612
    • British Columbia
      • Vancouver, British Columbia, Canada, V6E 1M7
        • ARCA Clinical Research Site #624
    • Ontario
      • Cambridge, Ontario, Canada, N1R 6V6
        • ARCA Clinical Research Site #611
      • Cambridge, Ontario, Canada, N1R 7R1
        • ARCA Clinical Research Site #621
      • Hamilton, Ontario, Canada, L8L 2X2
        • ARCA Clinical Research Site #601
      • London, Ontario, Canada, N6A 5A5
        • ARCA Clinical Research Site #609
      • Newmarket, Ontario, Canada, L3Y 2P6
        • ARCA Clinical Research Site #623
      • Oshawa, Ontario, Canada, L1H 1B9
        • ARCA Clinical Research Site #618
      • Ottawa, Ontario, Canada, K1Y 4W7
        • ARCA Clinical Research Site #613
      • Toronto, Ontario, Canada, M4N 3M5
        • ARCA Clinical Research Site #619
      • Waterloo, Ontario, Canada, N2J 1C4
        • ARCA Clinical Research Site #616
    • Quebec
      • Montreal, Quebec, Canada, H1T 1C8
        • ARCA Clinical Research Site #614
      • Montreal, Quebec, Canada, H2W 1T8
        • ARCA Clinical Research Site #607
      • Montreal, Quebec, Canada, H3G 1A3
        • ARCA Clinical Research Site #603
      • Saint-Jerome, Quebec, Canada, J7Z 5T3
        • ARCA Clinical Research Site #625
      • Sherbrooke, Quebec, Canada, J1H 5N4
        • ARCA Clinical Research Site #602
      • Trois-Rivières, Quebec, Canada, G8Z 3R9
        • ARCA Clinical Research Site #626
  • Hungary
      • Budapest, Hungary, 1096
        • ARCA Clinical Research Site #726
      • Budapest, Hungary, 1122
        • ARCA Clinical Research Site #727
      • Budapest, Hungary, 1134
        • ARCA Clinical Research Site #728
      • Budapest, Hungary, 1145
        • ARCA Clinical Research Site #729
      • Debrecen, Hungary, 4032
        • ARCA Clinical Research Site #733
      • Kaposvar, Hungary, 7400
        • ARCA Clinical Research Site #732
      • Pecs, Hungary, 7624
        • ARCA Clinical Research Site #730
      • Szeged, Hungary, 6725
        • ARCA Clinical Research Site #731
      • Szolnok, Hungary, 5000
        • ARCA Clinical Research Site #734
  • Netherlands
      • Capelle aan den IJssel, Netherlands, 2906 ZC
        • ARCA Clinical Research Site #781
      • Gorinchem, Netherlands, 4204 AA
        • ARCA Clinical Research Site #779
      • Groningen, Netherlands, 9713 GZ
        • ARCA Clinical Research Site #776
      • Helmond, Netherlands, 5707 HA
        • ARCA Clinical Research Site #780
      • Leiderdorp, Netherlands, 2334 CK
        • ARCA Clinical Research Site #782
      • Roosendaal, Netherlands, 4708 AE
        • ARCA Clinical Research Site #786
      • Sneek, Netherlands, 8601 ZK
        • ARCA Clinical Research Site #777
      • Stadskanaal, Netherlands, 9501 HE
        • ARCA Clinical Research Site #783
      • Tiel, Netherlands, 4002 WP
        • ARCA Clinical Research Site #784
  • Poland
      • Bialystok, Poland, 15-276
        • ARCA Clinical Research Site #752
      • Gdansk, Poland, 80-952
        • ARCA Clinical Research Site #757
      • Krakow, Poland, 31-501
        • ARCA Clinical Research Site #753
      • Lodz, Poland, 91-347
        • ARCA Clinical Research Site #755
      • Lodz, Poland, 92-213
        • ARCA Clinical Research Site #751
      • Lublin, Poland, 20-954
        • ARCA Clinical Research Site #758
      • Warsaw, Poland, 02-097
        • ARCA Clinical Research Site #754
      • Wroclaw, Poland, 50-981
        • ARCA Clinical Research Site #756
  • Serbia
      • Belgrade, Serbia, 11000
        • ARCA Clinical Research Site #807
      • Belgrade, Serbia, 11080
        • ARCA Clinical Research Site #806
      • Kragujevac, Serbia, 34000
        • ARCA Clinical Research Site #801
      • Niš, Serbia, 18000
        • ARCA Clinical Research Site #804
      • Niš, Serbia, 18000
        • ARCA Clinical Research Site #805
  • United States
    • Alaska
      • Anchorage, Alaska, United States, 99508
        • ARCA Clinical Research Site #157
    • Arizona
      • Phoenix, Arizona, United States, 85004
        • ARCA Clinical Research Site #383
      • Phoenix, Arizona, United States, 85018
        • ARCA Clinical Research Site #385
    • California
      • East Palo Alto, California, United States, 94303
        • ARCA Clinical Research Site #381
      • Loma Linda, California, United States, 92357
        • ARCA Clinical Research Site #186
      • Pasadena, California, United States, 91105
        • ARCA Clinical Research Site #320
      • Stanford, California, United States, 94305
        • ARCA Clinical Research Site #390
    • Colorado
      • Aurora, Colorado, United States, 80045
        • ARCA Clinical Research Site #153
      • Denver, Colorado, United States, 80120
        • ARCA Clinical Research Site #380
    • Florida
      • Miami, Florida, United States, 33136
        • ARCA Clinical Research Site #195
      • Tampa, Florida, United States, 33606
        • ARCA Clinical Research Site #184
    • Georgia
      • Athens, Georgia, United States, 30606
        • ARCA Clinical Research Site #351
      • Atlanta, Georgia, United States, 30322
        • ARCA Clinical Research Site #389
    • Illinois
      • Oakbrook Terrace, Illinois, United States, 60181
        • ARCA Clinical Research Site #342
    • Indiana
      • Hammond, Indiana, United States, 46320
        • ARCA Clinical Research Site #303
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • ARCA Clinical Research Site #388
    • Louisiana
      • New Orleans, Louisiana, United States, 70121
        • ARCA Clinical Site #396
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • ARCA Clinical Research Site #398
    • Michigan
      • Ypsilanti, Michigan, United States, 48197
        • ARCA Clinical Research Site #127
    • Minnesota
      • Minneapolis, Minnesota, United States, 55417
        • ARCA Clinical Research Site #156
      • Saint Paul, Minnesota, United States, 55102
        • ARCA Clinical Research Site #174
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • ARCA Clinical Research Site #108
      • Saint Louis, Missouri, United States, 63128
        • ARCA Clinical Research Site #201
    • Nebraska
      • Lincoln, Nebraska, United States, 68506
        • ARCA Clinical Research Site #152
    • New Jersey
      • Elmer, New Jersey, United States, 08318
        • ARCA Clinical Research Site #161
      • Hillsborough, New Jersey, United States, 08844
        • ARCA Clinical Research Site #202
    • New York
      • Albany, New York, United States, 12205
        • ARCA Clinical Research Site # 179
      • New York, New York, United States, 10029
        • ARCA Clinical Research Site #397
    • North Carolina
      • Durham, North Carolina, United States, 27705
        • ARCA Clinical Research Site #181
      • Greensboro, North Carolina, United States, 27401
        • ARCA Clinical Research Site #349
    • Ohio
      • Akron, Ohio, United States, 44304
        • ARCA Clinical Research Site #173
      • Cincinnati, Ohio, United States, 45219
        • ARCA Clinical Research Site #392
      • Cleveland, Ohio, United States, 44106
        • ARCA Clinical Research Site #322
      • Columbus, Ohio, United States, 43210
        • ARCA Clinical Research Site #151
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73135
        • ARCA Clinical Research Site #399
    • Oregon
      • Portland, Oregon, United States, 97201
        • ARCA Clinical Research Site #115
    • Pennsylvania
      • Hershey, Pennsylvania, United States, 17033
        • ARCA Clinical Research Site # 189
      • Lancaster, Pennsylvania, United States, 17603
        • ARCA Clinical Research Site #109
      • Philadelphia, Pennsylvania, United States, 19104
        • ARCA Clinical Research Site #133
    • Tennessee
      • Germantown, Tennessee, United States, 38138
        • ARCA Clinical Site #393
      • Jackson, Tennessee, United States, 38305
        • ARCA Clinical Research Site #198
    • Texas
      • Dallas, Texas, United States, 75230
        • ARCA Clinical Research Site #387
    • Utah
      • Salt Lake City, Utah, United States, 84132
        • ARCA Clinical Research Site #379
    • Virginia
      • Charlottesville, Virginia, United States, 22908
        • ARCA Clinical Site #391
      • Falls Church, Virginia, United States, 22042
        • ARCA Clinical Research Site #386
      • Manassas, Virginia, United States, 20109
        • ARCA Clinical Research Site #200
      • Norfolk, Virginia, United States, 23507
        • ARCA Research Site #131
    • Washington
      • Puyallup, Washington, United States, 98372
        • ARCA Clinical Research Site #196

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: 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.
Drug: bucindolol hydrochloride
Other Names:
  • bucindolol
ACTIVE_COMPARATOR: 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.
Drug: metoprolol succinate
Other Names:
  • Toprol-XL
  • metoprolol
Other: Placebo oral capsule
Other Names:
  • placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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 Frame: 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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
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]
Time Frame: end of treatment week 24
Number of days on study medication before participant experienced symptomatic or asymptomatic atrial fibrillation, atrial flutter, or all-cause mortality during the 24 week follow up period.
end of treatment week 24
Number of Patients With Adequate Ventricular Rate Control During the 24-week Follow-up Period
Time Frame: end of treatment week 24
Number of patients with adequate ventricular rate control following the start of medication 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)
Time Frame: 24 weeks
Total number of hospitalization days per patient (all-cause) following the start of study medication during the Total Study Period (24 weeks). Hospitalization was defined by a hospital admission (note that same day admit and discharge equates to 0 days duration), ER visits were not counted as events.
24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

ARCA Biopharma, Inc.

Collaborators

Medtronic

Investigators

  • Study Director: Michael Bristow, MD,PhD, ARCA Biopharma, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2014

Primary Completion (ACTUAL)

December 28, 2017

Study Completion (ACTUAL)

December 28, 2017

Study Registration Dates

First Submitted

October 23, 2013

First Submitted That Met QC Criteria

October 23, 2013

First Posted (ESTIMATE)

October 28, 2013

Study Record Updates

Last Update Posted (ACTUAL)

September 26, 2022

Last Update Submitted That Met QC Criteria

September 14, 2022

Last Verified

September 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BUC-CLIN-303

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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