| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Atrial Fibrillation (an abnormal, rapid heart rhythm) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003658 |
| E.1.2 | Term | Atrial fibrillation |
| E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 β1389 arginine homozygous (β1389Arg/Arg) genotype. |
|
| E.2.2 | Secondary objectives of the trial |
| 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. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. AF Burden Substudy (cardiac rhythm monitored
continuously via a Medtronic implanted device) - part of the Clinical Study Protocol Version 4.0, Date: 29 January 2016
2. Optional Genetic Analyses (DNA Bank) - part of the Clinical Study Protocol Version 4.0, Date: 29 January 2016
|
|
| E.3 | Principal 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 β1389Arg/Arg genotype.
4. History of heart failure with reduced left ventricle ejection fraction (HFREF).
a. LVEF < 0.50 assessed at any time during the previous 12 months of the Screening Visit.
5. At least one symptomatic paroxysmal or persistent AF episode ≤ 180 days of the Screening Visit.
a. Qualifying AF episode may be documented by ECG, Holter, TTM, or implanted device. AF documented by implanted device must be a single episode ≥ 60 minutes in duration. Atrial flutter is not considered a qualifying AF episode.
b. Must have experienced AF symptoms ≤ 180 days of the Screening Visit, but these symptoms may overlap with HF symptoms, i.e. may be “arrhythmic” (e.g. palpitations, dizziness) or “heart failure” (e.g. breathlessness, fatigability) in nature.
6. Clinically appropriate for ECV if AF/AFL is present at the Week 0 Visit, including:
a. Patients with AF/AFL at randomization determined by the Investigator to require ECV.
b. Patients in SR at randomization determined by the Investigator to require ECV if AF/AFL recurs.
7. Receiving guideline indicated oral anticoagulation therapy at the Randomization Visit, which is considered optimal for stroke prevention in the opinion of the Investigator.
8. Systolic blood pressure > 90 mmHg and < 150 mmHg at the Randomization Visit.
9. Female of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Randomization Visit.
a. Female who is surgically sterile or post-menopausal for at least 12 months is not considered to be of childbearing potential.
10. Female of childbearing potential must agree to use a highly effective contraception for the duration of the trial and for at least 30 days following the last dose of study drug.
a. Female who is surgically sterile or post-menopausal for at least 12 months is not considered to be of childbearing potential.
11. Must agree not to participate in a clinical study involving another investigational drug or device throughout the duration of this study.
12. Must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved ICF. Must sign the ICF prior to the initiation of any study procedure and not withdraw consent prior to the Randomization Visit. |
|
| E.4 | Principal 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 < 7 days of the randomization Visit:
a. Amiodarone, disopyramide, dofetilide, dronedarone, flecainide, propafenone, sotalol, non-dihydropyridine calcium channel blockers, daily NSAIDS (e.g., ibuprofen, celecoxib), thiazolidinediones, or frequent use of short acting nitroglycerin (e.g., > 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 < 60 beats per minute at the Randomization Visit for patients who were not receiving β-blocker therapy during the screening period.
12. Heart rate > 180 beats per minute at the Randomization Visit.
13. Contraindication or previous history of intolerance to β-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 β2-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 requiring dialysis, serum creatinine > 2.5 mg/dL or an estimated creatinine clearance < 30 mL/min (Cockcroft-Gault) at the Screening Visit.
a. Lab values 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.
22. Significant intrinsic liver disease or a total bilirubin > 2.5 mg/dL 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.
23. Use of strong inhibitors of cytochrome P450 2D6 (e.g., fluoxetine, paroxetine, propafenone, quinidine, or ritonavir) < 7 days prior to the Randomization Visit for patients who are not receiving β-blocker therapy at screening.
24. Participation in a clinical study or treatment with an investigational drug or device within 30 days of the Screening Visit (or 5 half-lives of the investigational agent, whichever is longer).
25. Comorbid condition or illness which, in the opinion of the Investigator, may limit life expectancy to less than 1 year.
26. Serious or active medical or psychiatric condition
27. Treatment for a malignancy ≤ 2 years prior to randomization, the presence of a treated malignancy that has evidence of disease progression
28. History of alcohol, drug or chemical abuse |
|
| E.5 End points |
| E.5.1 | 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 Clinical Events Committee (CEC) examination of blinded data. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- in Phase 2b of the study: during the 24-Week Follow-up Period
- in Phase 3 of the study: during the Treatment Extension Period |
|
| E.5.2 | 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 be performed for the 24-week Follow-up Period only, for each endpoint component, and for each endpoint combination (i.e., AF/AFL+ACM, AF/AFL+HFH, HFH+ACM).
5. Proportion of patients with adequate ventricular rate control in the setting of AF/AFL. These patients will be identified by the CEC and the condition will be defined by (a) a ventricular response rate (VRR) between 40 and 80 beats per minute at rest on the last tracing demonstrating
AF/AFL during the 24-week Follow-up Period and (b) the absence of symptoms associated with bradycardia. This endpoint will be tested with a Cochran-Mantel-Haenszel statistic to control for the four stratification variables. A supportive analysis will also be performed to evaluate this
endpoint at the time of study drug discontinuation. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. during the Total Follow-up Period (24-Week Follow-up Period + Treatment Extension Period)
2. during the Total Follow-up Period (24-Week Follow-up Period + Treatment Extension Period)
3. during the Total Follow-up Period (24-Week Follow-up Period + Treatment Extension Period)
4. during the Total Follow-up Period (24-Week Follow-up Period + Treatment Extension Period)
5. during the 24-Week Follow-up Period and at the time of study drug discontinuation |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| genotype-directed, adaptive-design, superiority study |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Canada |
| Czech Republic |
| Hungary |
| Netherlands |
| Poland |
| Serbia |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 21 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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