Atrial Fibrillation MedDRA version: 19.0 Level: PT Classification code 10003658 Term: Atrial fibrillation System Organ Class: 10007541 - Cardiac disorders
Conditions
Sponsors
ARCA biopharma, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients must meet all of the following inclusion criteria to be eligible for randomization in this study. 1. Age = 18 years and = 85 years at the Screening Visit. 2. Weight = 40 kg at the Randomization Visit. 3. Possess the ß1389Arg/Arg genotype. 4. History of heart failure with reduced left ventricle ejection fraction (HFREF). a. LVEF 90 mmHg and =65 years) yes F.1.3.1 Number of subjects for this age range 465
Exclusion criteria
Exclusion criteria: 1. NYHA Class IV symptoms at the Randomization Visit. 2. Significant fluid overload at the Randomization Visit, in the opinion of the Investigator. Evidence of significant fluid overload may include: a. Mean jugular venous pressure above the clavicle at 90°. b. Liver congestion. c. Moist pulmonary rales post-cough. d. Peripheral edema beyond 1+ pedal not explained by local factors. 3. Permanent AF at the Screening Visit. a. Permanent AF is defined as an ongoing AF event 1 year or longer in duration in which there is no intervening evidence of SR. 4. More than two ECV procedures within 6 months of the Randomization Visit or if the most recent ECV within 6 months of the Randomization Visit failed to produce SR. 5. Use of any of the following 6 sublingual tablets/week). b. Note: Amiodarone and dofetilide can be restarted after the start of follow-up if the patient experiences an AF/AFL event or after failure to convert to SR following ECV (see protocol Section 5.8). 6. The presence of a left ventricular assist device (LVAD) or a condition that is likely to require LVAD placement within 6 months of the Randomization Visit. 7. History of a successful atrioventricular node ablation. 8. History of an AF ablation or AFL ablation within 30 days of the Randomization Visit. 9. History of untreated second degree Mobitz II or third degree heart block. 10. History of untreated symptomatic bradycardia or if symptomatic bradycardia is likely on full dose of study drug in the opinion of the Investigator. 11. Heart rate 180 beats per minute at the Randomization Visit. 13. Contraindication or previous history of intolerance to ß-blocker therapy (e.g., untreated valvular disease) or Toprol-XL (e.g., inability to tolerate at least 25mg QD). 14. Myocardial infarction, unstable angina, acute coronary syndrome, cardiac surgery (including PTCA or stent placement), or evidence of new ischemic changes as assessed by ECG = 90 days of the Randomization Visit. 15. Moderate to severe asthma or other obstructive lung disease requiring chronic use (> 2 days/week) of an inhaled ß2-selective adrenergic agonist < 7 days of the Randomization Visit. 16. History of pulmonary hypertension, defined as a systolic pulmonary arterial pressure = 70 mmHg at rest as assessed by echocardiography or right heart catheterization. 17. Known reversible causes of AF such as alcohol intoxication, pulmonary embolism, hyperthyroidism, acute pericarditis, or hypoxemia. 18. Evidence of an appropriate firing of an ICD device for ventricular tachycardia (VT) or ventricular fibrillation (VF) = 90 days of the Randomization Visit. a. Exception: does not include anti-tachycardia pacing. 19. Untreated thyroid disease, in the opinion of the Investigator, at the Randomization Visit. 20. Serum potassium < 3.5 mmol/L at the Screening Visit. a. Lab value will be assessed by the central lab at the Screening Visit and any exclusionary results must be corrected prior to randomization as documented by either the central or local lab. 21. Renal failure
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to compare the effects of bucindolol and metoprolol on the recurrence of symptomatic Atrial Fibrillation (AF)/Atrial Flutter (AFL) in patients with HFREF (heart failure with reduced left ventricle ejection fraction) who have a ß1389 arginine homozygous (ß1389Arg/Arg) genotype.;Secondary Objective: The secondary objectives of this study are to compare the effects of bucindolol and metoprolol on clinical outcomes and other electrocardiographic parameters, and to assess the effects on rate control in patients who have developed recurrent AF/AFL. The safety and tolerability of bucindolol and metoprolol will also be evaluated.;Primary end point(s): The primary endpoint is elapsed time to first event of symptomatic atrial fibrillation/atrial flutter (AF/AFL) or all cause mortality (ACM) during the 24-week Follow-up Period. This is a time to event endpoint censored at 24 weeks of follow-up after establishment of stable SR on study drug. Both calculations will be stratified by the pre-specified randomization strata: HF etiology (ischemic/non-ischemic); LVEF (< 0.35 / = 0.35); type of Medtronic device (Reveal/Non-Reveal/No Device), and; rhythm status at randomization (SR vs. AF/AFL). The analysis methodology will also be applied separately to each component of this compound endpoint (i.e., time to first event of symptomatic AF/AFL and time to ACM). The following definitions apply to this endpoint: - Stable SR on study drug is defined as any of the following: o SR confirmed = 1 hour after ECV. o SR confirmed = 1 hour after spontaneous conversion from AF/AFL. o SR confirmed = 1 hour at the Week 0 Visit for patients randomized in SR. - An AF/AFL event is defined as AF or AFL observed on two consecutive measures separated by at least 10 minutes as assessed by ECG. - A symptomatic AF/AFL event is defined as an AF/AFL event that is associated with a clinically relevant change in patient-reported symptoms, as determined by the | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The following endpoints will be tested for superiority of bucindolol benefit relative to metoprolol by fixed sequence provided that bucindolol meets the superiority criteria on the primary endpoint. 1. Time to first event of AF/AFL (i.e., symptomatic or asymptomatic) or ACM during the 24-week Follow-up Period. A supportive analysis will involve the same analysis methodology applied to each component (i.e., AF, AFL and ACM). Supportive analysis will also be conducted to examine this endpoint and its components for the Total Follow-up Period. 2. Proportion of patients with ventricular tachycardia (VT), ventricular fibrillation (VF), or symptomatic supraventricular tachycardia (SVT) during the 24-week Follow-up Period. Includes VF and symptomatic SVT events of any duration, VT events of = 15 seconds, and VT events that result in appropriate firing of an ICD. This endpoint will be tested with a Cochran-Mantel-Haenszel statistic to control for the four stratification variables. The components will also be examined individually with the same methodology. A supportive analysis will also be conducted to examine this endpoint and its components for the Total Follow-up Period. 3. Total number of hospitalization days per patient (all-cause) during the Total Study Period. This count will be normalized for the total number of days of follow-up prior to testing with the Wilcoxon Rank Sum statistic. A supportive analysis for this endpoint will also be conducted that compares patients who are in AF at the EOS Visit and have VRR control to patients who are in AF at the EOS Visit without VRR control. A supportive analysis for this endpoint will also be conducted for the subset of heart-failure related hospitalization days per patient during the Total Study Period. 4. Time to first event of AF/AFL (i.e., symptomatic or asymptomatic), HF hospitalization (as assessed by the Investigator), or ACM during the Total Study Period. Supportive analyses will also b | — |
Countries
Bulgaria, Canada, Czech Republic, Hungary, Netherlands, Poland, United States
Contacts
Public ContactGENETIC-AF helpdesk
ARCA biopharma, Inc.
Outcome results
None listed