Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure
- Conditions
- Current or Recent History of Atrial Fibrillation
- Interventions
- Registration Number
- NCT01970501
- Lead Sponsor
- ARCA Biopharma, Inc.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 267
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description bucindolol hydrochloride 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. metoprolol succinate 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 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.
- Primary Outcome Measures
Name Time Method 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]. 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.
- Secondary Outcome Measures
Name Time Method 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 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.
Total Number of Hospitalization Days Per Patient (All-cause) During the Total Study Period (24 Weeks) 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.
Number of Patients With Adequate Ventricular Rate Control During the 24-week Follow-up Period 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
Trial Locations
- Locations (97)
ARCA Clinical Research Site #196
🇺🇸Puyallup, Washington, United States
ARCA Clinical Research Site #151
🇺🇸Columbus, Ohio, United States
ARCA Clinical Research Site #153
🇺🇸Aurora, Colorado, United States
ARCA Clinical Research Site #303
🇺🇸Hammond, Indiana, United States
ARCA Clinical Research Site #320
🇺🇸Pasadena, California, United States
ARCA Clinical Research Site #109
🇺🇸Lancaster, Pennsylvania, United States
ARCA Clinical Research Site #108
🇺🇸Saint Louis, Missouri, United States
ARCA Clinical Research Site #389
🇺🇸Atlanta, Georgia, United States
ARCA Clinical Research Site #380
🇺🇸Denver, Colorado, United States
ARCA Clinical Research Site #388
🇺🇸Iowa City, Iowa, United States
ARCA Clinical Research Site #390
🇺🇸Stanford, California, United States
ARCA Clinical Research Site #186
🇺🇸Loma Linda, California, United States
ARCA Clinical Research Site #201
🇺🇸Saint Louis, Missouri, United States
ARCA Clinical Research Site #184
🇺🇸Tampa, Florida, United States
ARCA Clinical Research Site #351
🇺🇸Athens, Georgia, United States
ARCA Clinical Research Site #342
🇺🇸Oakbrook Terrace, Illinois, United States
ARCA Clinical Research Site #133
🇺🇸Philadelphia, Pennsylvania, United States
ARCA Clinical Research Site #115
🇺🇸Portland, Oregon, United States
ARCA Clinical Research Site #174
🇺🇸Saint Paul, Minnesota, United States
ARCA Clinical Research Site #729
🇭🇺Budapest, Hungary
ARCA Clinical Research Site #782
🇳🇱Leiderdorp, Netherlands
ARCA Clinical Research Site #755
🇵🇱Lodz, Poland
ARCA Clinical Research Site #754
🇵🇱Warsaw, Poland
ARCA Clinical Research Site #195
🇺🇸Miami, Florida, United States
ARCA Clinical Research Site #156
🇺🇸Minneapolis, Minnesota, United States
ARCA Clinical Research Site #181
🇺🇸Durham, North Carolina, United States
ARCA Clinical Research Site #392
🇺🇸Cincinnati, Ohio, United States
ARCA Clinical Research Site #381
🇺🇸East Palo Alto, California, United States
ARCA Clinical Research Site #385
🇺🇸Phoenix, Arizona, United States
ARCA Clinical Research Site #398
🇺🇸Baltimore, Maryland, United States
ARCA Clinical Research Site #397
🇺🇸New York, New York, United States
ARCA Clinical Research Site #322
🇺🇸Cleveland, Ohio, United States
ARCA Clinical Research Site #173
🇺🇸Akron, Ohio, United States
ARCA Clinical Research Site #379
🇺🇸Salt Lake City, Utah, United States
ARCA Clinical Research Site #200
🇺🇸Manassas, Virginia, United States
ARCA Clinical Research Site #621
🇨🇦Cambridge, Ontario, Canada
ARCA Clinical Research Site #752
🇵🇱Bialystok, Poland
ARCA Clinical Research Site #726
🇭🇺Budapest, Hungary
ARCA Clinical Research Site #728
🇭🇺Budapest, Hungary
ARCA Clinical Site #393
🇺🇸Germantown, Tennessee, United States
ARCA Clinical Research Site #198
🇺🇸Jackson, Tennessee, United States
ARCA Clinical Research Site #730
🇭🇺Pecs, Hungary
ARCA Clinical Research Site #781
🇳🇱Capelle aan den IJssel, Netherlands
ARCA Clinical Research Site #783
🇳🇱Stadskanaal, Netherlands
ARCA Clinical Research Site #157
🇺🇸Anchorage, Alaska, United States
ARCA Clinical Research Site #383
🇺🇸Phoenix, Arizona, United States
ARCA Clinical Site #396
🇺🇸New Orleans, Louisiana, 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 #784
🇳🇱Tiel, Netherlands
ARCA Clinical Research Site #758
🇵🇱Lublin, Poland
ARCA Clinical Research Site #806
🇷🇸Belgrade, Serbia
ARCA Clinical Research Site #805
🇷🇸Niš, Serbia
ARCA Clinical Research Site #614
🇨🇦Montreal, Quebec, Canada
ARCA Clinical Research Site #732
🇭🇺Kaposvar, Hungary
ARCA Clinical Research Site #612
🇨🇦Calgary, Alberta, Canada
ARCA Clinical Research Site #733
🇭🇺Debrecen, Hungary
ARCA Clinical Research Site #731
🇭🇺Szeged, Hungary
ARCA Clinical Research Site #779
🇳🇱Gorinchem, Netherlands
ARCA Clinical Research Site #751
🇵🇱Lodz, Poland
ARCA Clinical Research Site #801
🇷🇸Kragujevac, Serbia
ARCA Clinical Research Site #607
🇨🇦Montreal, Quebec, Canada
ARCA Clinical Research Site #624
🇨🇦Vancouver, British Columbia, Canada
ARCA Clinical Research Site #603
🇨🇦Montreal, Quebec, Canada
ARCA Clinical Research Site #625
🇨🇦Saint-Jerome, Quebec, Canada
ARCA Clinical Research Site #734
🇭🇺Szolnok, Hungary
ARCA Clinical Research Site #776
🇳🇱Groningen, Netherlands
ARCA Clinical Research Site #757
🇵🇱Gdansk, Poland
ARCA Clinical Research Site #807
🇷🇸Belgrade, Serbia
ARCA Clinical Research Site #602
🇨🇦Sherbrooke, Quebec, Canada
ARCA Clinical Research Site #780
🇳🇱Helmond, Netherlands
ARCA Clinical Research Site #753
🇵🇱Krakow, Poland
ARCA Clinical Research Site #804
🇷🇸Niš, Serbia
ARCA Clinical Research Site #727
🇭🇺Budapest, Hungary
ARCA Clinical Research Site #626
🇨🇦Trois-Rivières, Quebec, Canada
ARCA Clinical Research Site #786
🇳🇱Roosendaal, Netherlands
ARCA Clinical Research Site #777
🇳🇱Sneek, Netherlands
ARCA Clinical Research Site #756
🇵🇱Wroclaw, Poland
ARCA Clinical Research Site #623
🇨🇦Newmarket, Ontario, Canada
ARCA Clinical Research Site #618
🇨🇦Oshawa, Ontario, Canada
ARCA Clinical Research Site #611
🇨🇦Cambridge, Ontario, Canada
ARCA Clinical Research Site #613
🇨🇦Ottawa, Ontario, Canada
ARCA Clinical Research Site #619
🇨🇦Toronto, Ontario, Canada
ARCA Clinical Research Site #615
🇨🇦Quebec, Canada
ARCA Clinical Research Site #616
🇨🇦Waterloo, Ontario, Canada
ARCA Clinical Research Site #127
🇺🇸Ypsilanti, Michigan, United States
ARCA Clinical Research Site #349
🇺🇸Greensboro, North Carolina, United States
ARCA Clinical Research Site # 189
🇺🇸Hershey, Pennsylvania, United States
ARCA Clinical Research Site #387
🇺🇸Dallas, Texas, United States
ARCA Research Site #131
🇺🇸Norfolk, Virginia, United States
ARCA Clinical Research Site #399
🇺🇸Oklahoma City, Oklahoma, United States
ARCA Clinical Research Site # 179
🇺🇸Albany, New York, United States
ARCA Clinical Site #391
🇺🇸Charlottesville, Virginia, United States
ARCA Clinical Research Site #386
🇺🇸Falls Church, Virginia, United States
ARCA Clinical Research Site #609
🇨🇦London, Ontario, Canada
ARCA Clinical Research Site #601
🇨🇦Hamilton, Ontario, Canada