IvaBRAdine blocK of Funny Current for Heart Rate Control in permanEnt Atrial Fibrillation. (BRAKE-AF Study). (BRAKE-AF)

October 6, 2022 updated by: Adolfo Fontenla

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.

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.

Study Overview

Status

Completed

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

68

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Burgos, Spain, 09006
        • Hospital Universitario de Burgos
      • Madrid, Spain, 28040
        • Fundación Jiménez Díaz
      • Madrid, Spain, 28034
        • Hospital Universitario Ramon y Cajal
      • Madrid, Spain, 28040
        • Hospital Clinico San Carlos
      • Madrid, Spain, 28041
        • Hospital Universitario 12 de Octubre
      • Madrid, Spain, 28046
        • Hospital Universitario La Paz
      • Madrid, Spain, 28905
        • Hospital Universitario de Getafe
      • Madrid, Spain, 28022
        • Hospital Universitario Puerta de Hierro
      • Madrid, Spain, 28933
        • Hospital Universitario Rey Juan Carlos
      • Toledo, Spain, 45004
        • Hospital Virgen de la Salud

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Digoxin
Digoxin 0,25 mg. The initial dose will be based on whether there are factors such as age over 80 years, weight under 60 kg and creatinine clearance <60ml / min,
The initial dose will be based on whether there are factors such as age over 80 years, weight less than 60 kg and creatinine clearance <60ml / min, if there is no factor, the oral dose will be 0.25mg / 24h. If there are 2 factors, the dose will be 0.15 mg / 24 h. and if there are 2 or 3 factors, the dose will be 0.10 mg / 24 h.
Other Names:
  • Digoxin 0,25 mg
Experimental: Ivabradine
Ivabradine 5 mg, twice a day the first month administered by mouth. If the tolerance is good, the dose will be increased to 7.5 mg on month 2 and will continue until the third month.

Ivabradine 5 mg, twice a day the first month administered by mouth. If the tolerance is good, the dose will be increased to 7.5 mg on month 2 and will continue until the third month.

Patients with 75 or more years of age will receive an initial dose of 2.5 mg / twice a day, which can be increased to 5 mg / twice a day in week 7 and to 7.5 mg in month 1 if the tolerance has been good

Other Names:
  • Ivabradine 5 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Heart rate reduction.
Time Frame: 3 months
Reduction of the mean daytime heart rate registered in Holter- electrocardiogram (ECG) after treatment with Ivabradine or Digoxin.
3 months
Serious adverse events
Time Frame: 3 months
Proportion of patients experiencing syncope, severe bradycardia or any serious adverse reaction requiring hospitalization, emergency visit or death of the patient during treatment with Ivabradine or Digoxin.
3 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Reduction in the scale of atrial fibrillation (AF) symptoms according to the European Hearth Rhythm Association (EHRA) Score modified.
Time Frame: Months 1 and 3.
Percentage of patients who experience a reduction in the scale of atrial fibrillation. symptoms according to the EHRA Score modified.
Months 1 and 3.
6 minute walk test (6MWT).
Time Frame: Baseline and after 3 months.
Increase in meters in the 6MWT.
Baseline and after 3 months.
Quality-of-Life Short Form 36 (SF-36) Health Survey (QoL SF-36) Score.
Time Frame: At baseline and 3 months.
Increase in the score obtained in global quality of life parameters analyzed by the SF-36 questionnaire.
At baseline and 3 months.
The Atrial Fibrillation Effect on Quality-of-Life (QoL AFEQT) score.
Time Frame: At baseline and 3 months
Increase in the score obtained in parameters of quality of life quality of life associated with AF analyzed by the AFEQT questionnaire.
At baseline and 3 months
Reduction of the daytime Health rate.
Time Frame: 1 month
Reduction of the average daytime Heart Rate (HR) recorded in Holter-ECG
1 month
Reduction of resting Health Rate.
Time Frame: 1 and 3 months
Reduction of resting heart rate (HR) recorded on one electrocardiogram (ECG).
1 and 3 months
Reduction of the maximum heart rate (HR) recorded.
Time Frame: 1 and 3 months
Reduction of the maximum HR recorded in Holter-ECG
1 and 3 months
Reduction of the mean HR recorded.
Time Frame: 1 and 3 months
Reduction of the mean HR in 24 hours recorded in Holter-ECG .
1 and 3 months
Reduction of the HR delta.
Time Frame: 1 and 3 months
Reduction of the HR delta (difference between maximum HR and mean HR in 24 hours) recorded in Holter-ECG.
1 and 3 months
Reduction of HR in moderate exercise.
Time Frame: 3 months
Reduction of HR in moderate exercise (maximum HR measured by Holter-ECG during the 6-minute walk test.
3 months
Percentage of patients with non-severe bradycardia.
Time Frame: 1 and 3 months
Percentage of patients who experience non-severe bradycardia during the study treatment.
1 and 3 months
Percentage of patients who experience any adverse reaction.
Time Frame: 1 and 3 months
Percentage of patients who experience any adverse reaction to the study drugs.
1 and 3 months
Percentage of patients who voluntarily abandon the study drugs.
Time Frame: 3 months
Percentage of patients who voluntarily abandon the study drugs.
3 months
Proportion of hospitalizations, emergency visits and mortality due to a major cardiovascular event.
Time Frame: 3 months
Proportion of patients experiencing hospitalizations, emergency visits and mortality due to a major cardiovascular event during treatment with the study drug.
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Study Chair: Adolfo Fontenla, MD, PhD, Hospital Universitario 12 de Octubre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 19, 2018

Primary Completion (Actual)

February 22, 2022

Study Completion (Actual)

June 30, 2022

Study Registration Dates

First Submitted

October 18, 2018

First Submitted That Met QC Criteria

October 22, 2018

First Posted (Actual)

October 24, 2018

Study Record Updates

Last Update Posted (Actual)

October 7, 2022

Last Update Submitted That Met QC Criteria

October 6, 2022

Last Verified

October 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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