Current or Recent History of Atrial Fibrillation
Conditions
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
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.
Interventions
DRUGbucindolol hydrochloride
DRUGmetoprolol succinate
OTHERPlacebo oral capsule
Sponsors
Medtronic
ARCA Biopharma, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
Countries
Canada, Hungary, Netherlands, Poland, Serbia, United States
Participant flow
Recruitment details
The study recruitment period began in Feb 2014 and the first participant screen was Apr 2014 and first randomization was Jun 2014. Recruitment continued through Jul 2017. Recruitment periods by country as follows: Canada: Mar 15 - Jul 17 Hungary: Sep 16 - Jun 17 Netherlands: May 1 - Jul 17 Poland: Jan 17 - Jul 17 Serbia: May 17 - Jun 17 United States: Feb 14 - Jul 17
Pre-assignment details
During the drug lead in period, participants were uptitrated to target doses of each drug. Bucindolol target dose was 50 mg bid (subjects \< 75 kg) or 100 mg bid (subjects \>= 75 kg) or maximum tolerated dose. Metoprolol succinate target dose was 200 mg once daily or the maximum tolerated dose. Within each treatment arm, participants were combined for analysis.
Participants by arm
| Arm | Count |
|---|---|
| Bucindolol Hydrochloride bucindolol hydrochloride (bucindolol)
Capsules are 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 | 134 |
| Metoprolol Succinate metoprolol succinate (Toprol-XL)
Capsules are 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 | 133 |
| Total | 267 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | Death | 1 | 3 |
| Overall Study | Discontinuation of study by sponsor | 16 | 14 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 7 |
Baseline characteristics
| Characteristic | Total | Bucindolol Hydrochloride | Metoprolol Succinate |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 158 Participants | 78 Participants | 80 Participants |
| Age, Categorical Between 18 and 65 years | 109 Participants | 56 Participants | 53 Participants |
| Age, Continuous | 65 years | 65 years | 65 years |
| Average Left Ventricular Ejection Fraction (LVEF) (%) | 36 % | 36 % | 36 % |
| Ischemic Heart Failure | 86 Participants | 42 Participants | 44 Participants |
| New York Heart Association (NYHA) Functional Class at screen NYHA I | 75 Participants | 40 Participants | 35 Participants |
| New York Heart Association (NYHA) Functional Class at screen NYHA II | 152 Participants | 80 Participants | 72 Participants |
| New York Heart Association (NYHA) Functional Class at screen NYHA III | 40 Participants | 14 Participants | 26 Participants |
| New York Heart Association (NYHA) Functional Class at screen NYHA IV | 0 Participants | 0 Participants | 0 Participants |
| Non-Ischemic Heart Failure | 181 Participants | 92 Participants | 89 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 257 Participants | 129 Participants | 128 Participants |
| Region of Enrollment Canada | 59 participants | 32 participants | 27 participants |
| Region of Enrollment Hungary | 33 participants | 18 participants | 15 participants |
| Region of Enrollment Netherlands | 4 participants | 2 participants | 2 participants |
| Region of Enrollment Poland | 23 participants | 13 participants | 10 participants |
| Region of Enrollment Serbia | 21 participants | 9 participants | 12 participants |
| Region of Enrollment United States | 127 participants | 60 participants | 67 participants |
| Rhythm at randomization Atrial Fibrillation | 135 Participants | 66 Participants | 69 Participants |
| Rhythm at randomization Sinus Rhythm | 132 Participants | 68 Participants | 64 Participants |
| Sex: Female, Male Female | 48 Participants | 23 Participants | 25 Participants |
| Sex: Female, Male Male | 219 Participants | 111 Participants | 108 Participants |
| Type of Atrial Fibrillation Paroxysmal | 131 Participants | 66 Participants | 65 Participants |
| Type of Atrial Fibrillation Persistent | 136 Participants | 68 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 134 | 3 / 133 |
| other Total, other adverse events | 100 / 134 | 95 / 133 |
| serious Total, serious adverse events | 33 / 134 | 26 / 133 |
Outcome results
Primary
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.
Time frame: end of treatment week 24
Population: 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 \[end of treatment week 24\]. Results from participants were combined for analysis within each treatment arm. Mean time to event (days) is presented for the participants experiencing an event.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Bucindolol Hydrochloride | 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]. | 35.9 days |
| Metoprolol Succinate | 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]. | 33.2 days |
p-value: 0.90595% CI: [0.72, 1.45]Log Rank
Secondary
Number of Patients With Adequate Ventricular Rate Control During the 24-week Follow-up Period
Number of patients with adequate ventricular rate control following the start of medication during the 24-week Follow-up Period
Time frame: end of treatment week 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bucindolol Hydrochloride | Number of Patients With Adequate Ventricular Rate Control During the 24-week Follow-up Period | 84 Participants |
| Metoprolol Succinate | Number of Patients With Adequate Ventricular Rate Control During the 24-week Follow-up Period | 116 Participants |
Secondary
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]
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.
Time frame: end of treatment week 24
Population: Time to first event of symptomatic or asymptomatic 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 \[end of treatment week 24\]. Mean time to event (days) is presented for the participants experiencing an event.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Bucindolol Hydrochloride | 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] | 37.86 days |
| Metoprolol Succinate | 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] | 31.06 days |
p-value: 0.96195% CI: [0.71, 1.42]Log Rank
Secondary
Total Number of Hospitalization Days Per Patient (All-cause) During the Total Study Period (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.
Time frame: 24 weeks
Population: A summary of all-cause and HF hospitalizations by treatment group over the 24-week study period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bucindolol Hydrochloride | Total Number of Hospitalization Days Per Patient (All-cause) During the Total Study Period (24 Weeks) | 2 days |
| Metoprolol Succinate | Total Number of Hospitalization Days Per Patient (All-cause) During the Total Study Period (24 Weeks) | 2 days |