Clinical trial NCT03718273: IvaBRAdine blocK of Funny Current for Heart Rate Control in permanEnt Atrial Fibrillation. (BRAKE-AF Study).
Official title: A Phase III Clinical Trial to Compare Ivabradine Versus Digoxin in the Heart Rate Control in Patients With Permanent Atrial Fibrillation Under Treatment With Beta-blockers or Calcium Antagonists.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Atrial Fibrillation
Heart Diseases
Keywords: Ivabradine
Digoxin
Atrial Fibrillation
Heart rate control
Lead sponsor: Hospital Universitario 12 de Octubre
Sponsor class: OTHER
Collaborators: name: Spanish Clinical Research Network - SCReN
name: Carlos III Health Institute
First posted: 2018-10-24
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The BRAKE-AF Study is a phase III, randomised, controlled, multicentric, open-label clinical trial to prove the noninferiority of ivabradine versus digoxin in the treatment of permanent atrial fibrillation. The total duration of the study is 3 years, with 24 months of enrolment, treatment and follow-up.

Detailed description: This is a non-commercial, investigator-driven clinical study funded through a public competitive call by Instituto de Salud Carlos III, Spanish Ministry of Economy (PI17/01272).

The study is coordinated by the main investigator from Hospital Universitario 12 de Octubre in Madrid; the sponsorship is performed by Dr. Adolfo Fontenla (Hospital Universitario 12 de Octubre). Several responsibilities are delegated to the Clinical Research Unit (Hospital 12 de Octubre, Madrid, Spain).

The study was planned according to the Good Clinical Practices. BRAKE-AF Study has been approved by the Ethics Committee and Spanish Health Authorities. All participating patients must give written informed consent before any study procedure occur.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years.
2. Permanent Atrial Fibrillation (AF) at the time of randomization, with no prospect of cardioversion, antiarrhythmic treatment with group I or III drugs, or pulmonary vein ablation.
3. Symptoms attributable to AF associated with the presence of at least one of the following inadequate Heart rate (HR) control criteria:

   1. HR at rest \> 110 bpm (on ECG -electrocardiogram- performed in the 14 days prior to inclusion).
   2. HR at rest between 80 and 110 bpm (on ECG performed in the 14 days prior to inclusion) and at least one of the following criteria:

   i. HR in exercise of moderate intensity \> 130 bpm (measured in an ergometry or in a Holter-ECG performed in the 60 days prior to inclusion).

   ii. Average daytime HR \> 80 bpm (measured on a Holter-ECG performed in the 60 days prior to inclusion).
4. Be receiving treatment with beta-blockers or non-dihydropyridine calcium channel blockers (verapamil or diltiazem) at the maximum dose recommended or tolerated by the patient.
5. Be able to voluntarily give their informed consent.
6. B\|ood test carried out in the 6 months prior to inclusion' including: blood count, thyroid hormones and creatinine, in order to rule out secondary causes of poor HR control. The creatinine figure will be used to calculate the creatinine clearance in order to adjust the dose of patients who are randomized to the Digoxin group.
7. Transthoracic echocardiogram to rule out, eg, severe valvular heart disease, hypertrophic cardiomyopathy. The one performed in the year prior to inclusion in the study will be considered acceptable provided that the patient's clinical situation has been stable in that period of time.

Exclusion Criteria:

1. Previous treatment or patients with a known contraindication to Ivabradine or Digoxin or to any excipient of both drugs.
2. Paroxysmal or intermittent complete atrioventricular (AV) block in patients not carrying a pacemaker.
3. Decompensated heart failure requiring inotropic and I or intravenous diuretics in the week prior to randomization or in New York Heart Association (NYHA) functional class IV or on the cardiac transplant waiting list,
4. Acute pericarditis, acute myocarditis or constrictive pericarditis.
5. Obstructive hypertrophic cardiomyopathy.
6. Valvular disease requiring surgical or percutaneous correction.
7. Medical causes that justify poor control of heart rate: fever' anemia, hyperthyroidism, pheochromocytoma' etc.
8. Severe hypotension (blood pressure \<90/50 mmHg).
9. Concomitant treatment with potent cytochrome P450 3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin) HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone.
10. Severe renal insufficiency (CrCl \<30 ml/Kg/min) or in a hemodialysis program.
11. Severe hepatic insufficiency.
12. Major surgery (including cardiac surgery) in the month prior to randomization.
13. Severe concomitant illness that supposes a llfe expectancy of less than one year.
14. Impossibility of carrying out scheduled visits to the protocol.
15. Woman of childbearing age (under 50 years of age, except for those who present a gynecological report that proves the presence of menopause) and women who are breastfeeding.
16. Participation in a clinical trial in the previous 6 months.
17. Patients with acute myocardial infarction or unstable angina.
18. Patient with a recent stroke.
19. Patients with congenital long QT syndrome or treated with drugs that prolong this interval.

Primary outcomes:
measure: Heart rate reduction.
timeFrame: 3 months
measure: Serious adverse events
timeFrame: 3 months
Secondary outcomes:
measure: Reduction in the scale of atrial fibrillation (AF) symptoms according to the European Hearth Rhythm Association (EHRA) Score modified.
timeFrame: Months 1 and 3.
measure: 6 minute walk test (6MWT).
timeFrame: Baseline and after 3 months.
measure: Quality-of-Life Short Form 36 (SF-36) Health Survey (QoL SF-36) Score.
timeFrame: At baseline and 3 months.
measure: The Atrial Fibrillation Effect on Quality-of-Life (QoL AFEQT) score.
timeFrame: At baseline and 3 months
measure: Reduction of the daytime Health rate.
timeFrame: 1 month
measure: Reduction of resting Health Rate.
timeFrame: 1 and 3 months
measure: Reduction of the maximum heart rate (HR) recorded.
timeFrame: 1 and 3 months
measure: Reduction of the mean HR recorded.
timeFrame: 1 and 3 months
measure: Reduction of the HR delta.
timeFrame: 1 and 3 months
measure: Reduction of HR in moderate exercise.
timeFrame: 3 months
measure: Percentage of patients with non-severe bradycardia.
timeFrame: 1 and 3 months
measure: Percentage of patients who experience any adverse reaction.
timeFrame: 1 and 3 months
measure: Percentage of patients who voluntarily abandon the study drugs.
timeFrame: 3 months
measure: Proportion of hospitalizations, emergency visits and mortality due to a major cardiovascular event.
timeFrame: 3 months
Other outcomes:
Locations:
city: Burgos
country: Spain
facility: Hospital Universitario de Burgos
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario de Getafe
city: Madrid
country: Spain
facility: Hospital Universitario Rey Juan Carlos
city: Toledo
country: Spain
facility: Hospital Virgen de la Salud
Study officials:
affiliation: Hospital Universitario 12 de Octubre
name: Adolfo Fontenla, MD, PhD
role: STUDY_CHAIR
References:
citation: Fontenla A, Lopez-Gil M, Tamargo-Menendez J, Matia-Frances R, Salgado-Aranda R, Rey-Blas JR, Miracle-Blanco A, Mejia-Martinez E, Pastor-Fuentes A, Toquero-Ramos J, Arias MA, Montilla I, Gomez de la Camara A, Arribas F; BRAKE-AF investigators. Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project. Rev Esp Cardiol (Engl Ed). 2020 May;73(5):368-375. doi: 10.1016/j.rec.2019.09.004. Epub 2019 Oct 17. English, Spanish.