| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Atrial fibrillation and underlying diastolic or systolic heart failure. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| 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 |
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| 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 |
To investigate whether in patients with early atrial fibrillation and mild to moderate early heart failure an aggressive upstream rhythm control approach, including aldosterone receptor antagonists and statins, dietary restrictions, counseling and cardiac rehabilitation programs, increases persistence of sinus rhythm compared with conventional rhythm control.
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| E.2.2 | Secondary objectives of the trial |
| To investigate whether in patients with early atrial fibrillation (AF) and mild to moderate early systolic or diastolic HF, aggressive upstream rhythm control, including aldosterone receptor antagonists (ARAs) and statins, dietary restrictions, counseling and cardiac rehabilitation programs, improves persistence of sinus rhythm without the need for class III ion-channel antiarrhythmic drugs or pulmonary vein isolation, quality of life, left ventricular function, and exercise capacity, and decreases number of patients with permanent AF, number of electrical cardioversions, number of radiofrequency and AV node ablations, hospitalizations for heart failure, hospitalizations for other cardiovascular reasons, and mortality. In addition, in this study the association between biomarkers, neurohormones, and genetics with recurrence of persistent AF will be investigated. Cost-effectiveness will also be studied. |
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| 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 |
Title: Routine versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure: RACE 3 Long term follow-up
Protocol date 2-5-2012, version 9
Study design:
Exploratory randomized long term extension of the RACE 3 study to study long term effects of the two treatment strategies.
Total follow-up: 5 years
Objective:To investigate whether in patients with early atrial fibrillation and mild to moderate early heart failure an aggressive upstream rhythm control approach, including aldosterone receptor antagonists and statins, dietary restrictions, counseling and cardiac rehabilitation programs (if needed repeated during long term follow up), and regular physical activity increases persistence of sinus rhythm and reduces cardiovascular morbidity and mortality compared with conventional rhythm control.
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| E.3 | Principal inclusion criteria |
1. Early persistent atrial fibrillation (total atrial fibrillation history < 5 years, total persistent atrial fibrillation duration > 7 days and < 6 months, and ≤ 1 previous electrical cardioversions during the last 2 years; neither electrical nor chemical cardioversion ≥ 2 years ago are allowed).
2. Mild to moderate early heart failure (Total heart failure history < 1 year, and normal pulmonary function and body mass index < 40 kg/m2, and either (1) left ventricular ejection fraction ≥ 45% and New York Heart Association functional class II-III and signs of heart failure [previously documented heart failure-related NT-proBNP elevation, ór evidence of structural heart disease, ór previous admission for heart failure, ór diastolic dysfunction on echocardiography] ór (2) left ventricular ejection fraction 25-45% and New York Heart Association functional class I-III). |
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| E.4 | Principal exclusion criteria |
1. On waiting list for pulmonary vein isolation (PVI) or expected to be placed on waiting list for PVI within one year.
2. Symptoms not allowing ECV to be delayed for 3 weeks.
3. Heart failure NYHA functional class IV.
4. Left ventricular ejection fraction < 25%.
5. Left atrial size > 50 mm (parasternal axis).
6. Severe valvular disease (previous valve repair/replacement is permitted).
7. Present ARA use.
8. Patients with cardiac resynchronization therapy.
9. Previous use of continuous prophylactic class I or class III antiarrhythmic drugs (except for sotalol, which should be discontinued at inclusion and replaced by a beta-blocker)
10. Postoperative AF.
11. Myocardial infarction within last 3 months.
12. Hypersensitivity against ARAs.
13. Unstable angina pectoris.
14. Open heart surgery within the last 3 months.
15. Serum potassium > 5 mmol/l.
16. Moderate to severe renal insufficiency (creatinine clearance less than 50 ml/min).
17. Patients with liver cirrhosis (Child-Pugh class C) or other significant liver disease.
18. Co-administration of strong CYP3A4 inhibitors or inductors.
19. Complex congenital heart disease. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The presence of the primary endpoint requires: a) the patient is still in a rhythm control strategy according to the attending physician, and b) sinus rhythm is present after 1 year of follow-up, defined as sinus rhythm during ≥ 6/7th of assessable time of continuous 7 days Holter monitoring during the last week of the study. |
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| E.5.2 | Secondary end point(s) |
Secondary endpoints
1. The presence of sinus rhythm after 1 year of follow-up during the 7 days Holter monitoring;Sinus rhythm on end of study ECG;
2. Sinus rhythm after 1 year of follow-up during the 7 days Holter monitoring without the need for class III ion-channel antiarrhythmic drugs;
3. Sinus rhythm after 1 year of follow-up during the 7 days Holter monitoring without the need for or pulmonary vein isolation;
4. Permanent AF during the 7 days Holter monitoring;
5. Number of ECVs;
6. Number of RF ablations;
7. AV node ablation;
8. Left ventricular function (systolic and diastolic function, left ventricular ejection fraction);
9. Exercise capacity (change in achieved number of Watts between baseline and follow-up);
10. Hospitalizations for HF;
11. Hospitalizations for other cardiovascular reasons including stroke, emboli, bleeding, myocardial infarction, PCI, CABG, life threatening arrhythmias, pacemaker or ICD/CRT(-D) therapy;
12. All cause mMortality (i.e. non-cardiovascular death, cardiovascular death including cardiac [sudden and non-sudden], vascular [sudden and non-sudden];
13. Biomarkers (i.e. markers of collagen/collagen metabolism, inflammatory mediators, thrombotic markers, neurohumoral factors, proteomic profiles) and genetics;
14. Quality of life;
15. Costs and cost-effectiveness
Follow-up protocol:
Endpoints:
1. Differences in treatment strategies between both randomization groups being still present after 5 years of follow up.
2. The presence of sinus rhythm at the end of long term follow up (5 years) defined as a) the patient is still in a rhythm control strategy according to the attending physician, and b) sinus rhythm is present at long term follow up, defined as sinus rhythm during ≥ 6/7th of assessable time of continuous 7 days Holter monitoring during the last week of the study
3. Composite of death from cardiovascular causes and cardiovascular morbidity including hospitalization for heart failure, stroke, systemic embolism, myocardial infarction, PCI, CABG, bleeding, life-threatening arrhythmic events, pacemaker, ICD or CRT therapy.. The duration of followup will be 5 years. This analysis is performed for descriptive purposes
4. Sinus rhythm at long term follow up during the 7 days Holter monitoring without the need for class III ion-channel antiarrhythmic drugs;
5. Sinus rhythm at long term follow up during the 7 days Holter monitoring without the need for pulmonary vein isolation;
6. Permanent atrial fibrillation during the 7 days Holter monitoring;
7. Number of electrical cardioversions;
8. Number of RF ablations;
9. AV node ablation;
10. Left ventricular function (systolic and diastolic function, left ventricular ejection fraction);
11. Exercise capacity;
12. Hospitalizations for heart failure;
13. Hospitalizations for other cardiovascular reasons including stroke, emboli, bleeding, myocardial infarction, PCI, CABG, life threatening arrhythmias, pacemaker or ICD/CRT(-D) therapy;
14. All cause mortality (i.e. non-cardiovascular death, cardiovascular death including cardiac [sudden and non-sudden], vascular [sudden and non-sudden];
15. Biomarkers (i.e. markers of collagen/collagen metabolism, inflammatory mediators, thrombotic markers, neurohumoral factors, proteomic profiles) and genetics;
16. Quality of life;
17. Costs and cost-effectiveness.
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| 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 | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Conventional rhythm control therapy for atrial fibrillation |
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| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
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| Last visit (1 year after electrical cardioversion) |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
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