Clinical trial NCT01970501: Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: ARCA Biopharma, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Medtronic
First posted: 2013-10-28
Enrollment: 267
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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].
timeFrame: end of treatment week 24
Secondary outcomes:
measure: 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]
timeFrame: end of treatment week 24
measure: Number of Patients With Adequate Ventricular Rate Control During the 24-week Follow-up Period
timeFrame: end of treatment week 24
measure: Total Number of Hospitalization Days Per Patient (All-cause) During the Total Study Period (24 Weeks)
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: ARCA Clinical Research Site #157
state: Alaska
city: Phoenix
country: United States
facility: ARCA Clinical Research Site #383
state: Arizona
city: Phoenix
country: United States
facility: ARCA Clinical Research Site #385
state: Arizona
city: East Palo Alto
country: United States
facility: ARCA Clinical Research Site #381
state: California
city: Loma Linda
country: United States
facility: ARCA Clinical Research Site #186
state: California
city: Pasadena
country: United States
facility: ARCA Clinical Research Site #320
state: California
city: Stanford
country: United States
facility: ARCA Clinical Research Site #390
state: California
city: Aurora
country: United States
facility: ARCA Clinical Research Site #153
state: Colorado
city: Denver
country: United States
facility: ARCA Clinical Research Site #380
state: Colorado
city: Miami
country: United States
facility: ARCA Clinical Research Site #195
state: Florida
city: Tampa
country: United States
facility: ARCA Clinical Research Site #184
state: Florida
city: Athens
country: United States
facility: ARCA Clinical Research Site #351
state: Georgia
city: Atlanta
country: United States
facility: ARCA Clinical Research Site #389
state: Georgia
city: Oakbrook Terrace
country: United States
facility: ARCA Clinical Research Site #342
state: Illinois
city: Hammond
country: United States
facility: ARCA Clinical Research Site #303
state: Indiana
city: Iowa City
country: United States
facility: ARCA Clinical Research Site #388
state: Iowa
city: New Orleans
country: United States
facility: ARCA Clinical Site #396
state: Louisiana
city: Baltimore
country: United States
facility: ARCA Clinical Research Site #398
state: Maryland
city: Ypsilanti
country: United States
facility: ARCA Clinical Research Site #127
state: Michigan
city: Minneapolis
country: United States
facility: ARCA Clinical Research Site #156
state: Minnesota
city: Saint Paul
country: United States
facility: ARCA Clinical Research Site #174
state: Minnesota
city: Saint Louis
country: United States
facility: ARCA Clinical Research Site #108
state: Missouri
city: Saint Louis
country: United States
facility: ARCA Clinical Research Site #201
state: Missouri
city: Lincoln
country: United States
facility: ARCA Clinical Research Site #152
state: Nebraska
city: Elmer
country: United States
facility: ARCA Clinical Research Site #161
state: New Jersey
city: Hillsborough
country: United States
facility: ARCA Clinical Research Site #202
state: New Jersey
city: Albany
country: United States
facility: ARCA Clinical Research Site # 179
state: New York
city: New York
country: United States
facility: ARCA Clinical Research Site #397
state: New York
city: Durham
country: United States
facility: ARCA Clinical Research Site #181
state: North Carolina
city: Greensboro
country: United States
facility: ARCA Clinical Research Site #349
state: North Carolina
city: Akron
country: United States
facility: ARCA Clinical Research Site #173
state: Ohio
city: Cincinnati
country: United States
facility: ARCA Clinical Research Site #392
state: Ohio
city: Cleveland
country: United States
facility: ARCA Clinical Research Site #322
state: Ohio
city: Columbus
country: United States
facility: ARCA Clinical Research Site #151
state: Ohio
city: Oklahoma City
country: United States
facility: ARCA Clinical Research Site #399
state: Oklahoma
city: Portland
country: United States
facility: ARCA Clinical Research Site #115
state: Oregon
city: Hershey
country: United States
facility: ARCA Clinical Research Site # 189
state: Pennsylvania
city: Lancaster
country: United States
facility: ARCA Clinical Research Site #109
state: Pennsylvania
city: Philadelphia
country: United States
facility: ARCA Clinical Research Site #133
state: Pennsylvania
city: Germantown
country: United States
facility: ARCA Clinical Site #393
state: Tennessee
city: Jackson
country: United States
facility: ARCA Clinical Research Site #198
state: Tennessee
city: Dallas
country: United States
facility: ARCA Clinical Research Site #387
state: Texas
city: Salt Lake City
country: United States
facility: ARCA Clinical Research Site #379
state: Utah
city: Charlottesville
country: United States
facility: ARCA Clinical Site #391
state: Virginia
city: Falls Church
country: United States
facility: ARCA Clinical Research Site #386
state: Virginia
city: Manassas
country: United States
facility: ARCA Clinical Research Site #200
state: Virginia
city: Norfolk
country: United States
facility: ARCA Research Site #131
state: Virginia
city: Puyallup
country: United States
facility: ARCA Clinical Research Site #196
state: Washington
city: Calgary
country: Canada
facility: ARCA Clinical Research Site #612
state: Alberta
city: Vancouver
country: Canada
facility: ARCA Clinical Research Site #624
state: British Columbia
city: Cambridge
country: Canada
facility: ARCA Clinical Research Site #611
state: Ontario
city: Cambridge
country: Canada
facility: ARCA Clinical Research Site #621
state: Ontario
city: Hamilton
country: Canada
facility: ARCA Clinical Research Site #601
state: Ontario
city: London
country: Canada
facility: ARCA Clinical Research Site #609
state: Ontario
city: Newmarket
country: Canada
facility: ARCA Clinical Research Site #623
state: Ontario
city: Oshawa
country: Canada
facility: ARCA Clinical Research Site #618
state: Ontario
city: Ottawa
country: Canada
facility: ARCA Clinical Research Site #613
state: Ontario
city: Toronto
country: Canada
facility: ARCA Clinical Research Site #619
state: Ontario
city: Waterloo
country: Canada
facility: ARCA Clinical Research Site #616
state: Ontario
city: Montreal
country: Canada
facility: ARCA Clinical Research Site #614
state: Quebec
city: Montreal
country: Canada
facility: ARCA Clinical Research Site #607
state: Quebec
city: Montreal
country: Canada
facility: ARCA Clinical Research Site #603
state: Quebec
city: Saint-Jerome
country: Canada
facility: ARCA Clinical Research Site #625
state: Quebec
city: Sherbrooke
country: Canada
facility: ARCA Clinical Research Site #602
state: Quebec
city: Trois-Rivières
country: Canada
facility: ARCA Clinical Research Site #626
state: Quebec
city: Quebec
country: Canada
facility: ARCA Clinical Research Site #615
city: Budapest
country: Hungary
facility: ARCA Clinical Research Site #726
city: Budapest
country: Hungary
facility: ARCA Clinical Research Site #727
city: Budapest
country: Hungary
facility: ARCA Clinical Research Site #728
city: Budapest
country: Hungary
facility: ARCA Clinical Research Site #729
city: Debrecen
country: Hungary
facility: ARCA Clinical Research Site #733
city: Kaposvar
country: Hungary
facility: ARCA Clinical Research Site #732
city: Pecs
country: Hungary
facility: ARCA Clinical Research Site #730
city: Szeged
country: Hungary
facility: ARCA Clinical Research Site #731
city: Szolnok
country: Hungary
facility: ARCA Clinical Research Site #734
city: Capelle aan den IJssel
country: Netherlands
facility: ARCA Clinical Research Site #781
city: Gorinchem
country: Netherlands
facility: ARCA Clinical Research Site #779
city: Groningen
country: Netherlands
facility: ARCA Clinical Research Site #776
city: Helmond
country: Netherlands
facility: ARCA Clinical Research Site #780
city: Leiderdorp
country: Netherlands
facility: ARCA Clinical Research Site #782
city: Roosendaal
country: Netherlands
facility: ARCA Clinical Research Site #786
city: Sneek
country: Netherlands
facility: ARCA Clinical Research Site #777
city: Stadskanaal
country: Netherlands
facility: ARCA Clinical Research Site #783
city: Tiel
country: Netherlands
facility: ARCA Clinical Research Site #784
city: Bialystok
country: Poland
facility: ARCA Clinical Research Site #752
city: Gdansk
country: Poland
facility: ARCA Clinical Research Site #757
city: Krakow
country: Poland
facility: ARCA Clinical Research Site #753
city: Lodz
country: Poland
facility: ARCA Clinical Research Site #755
city: Lodz
country: Poland
facility: ARCA Clinical Research Site #751
city: Lublin
country: Poland
facility: ARCA Clinical Research Site #758
city: Warsaw
country: Poland
facility: ARCA Clinical Research Site #754
city: Wroclaw
country: Poland
facility: ARCA Clinical Research Site #756
city: Belgrade
country: Serbia
facility: ARCA Clinical Research Site #807
city: Belgrade
country: Serbia
facility: ARCA Clinical Research Site #806
city: Kragujevac
country: Serbia
facility: ARCA Clinical Research Site #801
city: Niš
country: Serbia
facility: ARCA Clinical Research Site #804
city: Niš
country: Serbia
facility: ARCA Clinical Research Site #805
Study officials:
affiliation: Duke University
name: Jonathan Piccini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: ARCA Biopharma, Inc.
name: Michael Bristow, MD,PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.