Clinical trial NCT02387229: Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in AF
Official title: Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in AF (BRAIN-AF)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: ATRIAL FIBRILLATION
Keywords: Atrial Fibrillation
Stroke
Neurocognitive decline
Rivaroxaban
Acetylsalicylic acid
Anticoagulation
Montreal Cognitive Assesssment (MoCA)
Mini-Mental State Examination (MMSE)
Lead sponsor: Montreal Heart Institute
Sponsor class: OTHER
Collaborators: name: Canadian Stroke Prevention Intervention Network
name: The Montreal Health Innovations Coordinating Center (MHICC)
name: Bayer Healthcare Pharmaceuticals, Inc./Bayer Schering Pharma
name: Montreal Heart Institute Foundation
name: Canadian Institutes of Health Research (CIHR)
name: Hewitt Foundation
First posted: 2015-03-12
Enrollment: 1238
Sex: ALL
Minimum age (years): 30
Maximum age (years): 62
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a prospective, multicenter, randomized, double-blinded clinical trial exploring the efficacy and safety of rivaroxaban as compared to standard of care in reducing stroke, transient ischemic attack (TIA) and neurocognitive decline, in subjects with non-valvular AF and with low risk of stroke.

Detailed description: Subjects who qualify will be approached and those consenting will be enrolled to undergo a baseline evaluation. Subjects without a clinical diagnosis of dementia and with a Mini Mental State Examination score (MMSE) score ≥ 25 will undergo neurocognitive assessment (MoCA), psychosocial and QoL assessment before randomization.

Subjects will undergo regular visits (in-clinic, and/or by phone, or video conferencing) every 6 months during the treatment period. Subjects will take either rivaroxaban 15 mg or standard of care.

An independent clinical event committee will classify all endpoint events. An independent Data Safety Monitoring Committee (DSMC) was established to monitor the progress of the study and assure the safety of subjects enrolled in the trial.

Eligibility criteria: For entry into the study, the following criteria must be met:

Inclusion Criteria:

* Age at consent ≥30 to ≤62 years;
* Non-valvular atrial fibrillation (paroxysmal, persistent or permanent) documented by any electrical tracing or any device (i.e. routine 12-lead electrocardiogram, Holter monitor \[continuous ECG recording\] rhythm strip, intracardiac electrogram, or pacemaker or implantable cardiac defibrillator interrogation of at least 30 s, transcutaneous monitoring or other) in the last 2 years;
* Low risk of stroke as defined by the absence of all of the following:

  i. Prior stroke or Transient Ischemic Attack, ii. Hypertension, iii. Diabetes mellitus, iv. Congestive heart failure (New York Heart Association class II or higher at the time of enrolment or a known left ventricular ejection fraction \<35%);
* Signed informed consent

For entry into the study, none of the following criteria MUST be met

Exclusion Criteria:

* Known diagnosis of dementia;
* MMSE score \<25;
* Valvular AF \[mechanical heart valve, moderate to severe mitral stenosis (rheumatic or non rheumatic), or hypertrophic cardiomyopathy\];
* Other indication for antiplatelet therapy or anticoagulation;
* History of GI bleeding;
* Conditions associated with an increased risk of bleeding described as follows:

  1. Major surgery within the previous month;
  2. Planned surgery or intervention within the next 3 months;
  3. History of intracranial, intraocular, spinal, retroperitoneal or a traumatic intra-articular bleeding;
  4. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days;
  5. Haemorrhagic disorder or bleeding diathesis;
  6. Fibrinolytic agents within 48 hours of study entry;
  7. Recent malignancy or radiation therapy (within 6 months from the time of enrolment) and not expected to survive 3 years;
* Reversible cause of AF (e.g. cardiac surgery, pulmonary embolism, untreated hyperthyroidism);
* Absence of recurrence of AF 3 months after AF ablation;
* Severe renal impairment (creatinine clearance 30 mL/min or less);
* Active infective endocarditis;
* Active liver disease (e.g. acute clinical hepatitis, chronic active hepatitis, cirrhosis), or Alanine Transaminase (ALT) \>3 times the upper limit of normal;
* Women who are pregnant or of childbearing potential not using a medically acceptable form of contraception throughout the study;
* Women who are breastfeeding;
* Anemia or thrombocytopenia (according to the normal range values of the local laboratory);
* Participation in another study involving an investigational drug (under development) at the same time or within 30 days of randomization;
* Subjects considered unreliable, or having a life expectancy of less than 3 years or having any condition which, in the opinion of the investigator, would not allow safe participation in the study (e.g. drug addiction, alcohol abuse);
* History of allergic reaction to rivaroxaban.
* History of allergic reaction, in the absence of desensitization to acetylsalicylic acid in patients with vascular disease.

Primary outcomes:
measure: Composite endpoint of stroke, TIA and neurocognitive decline. Neurocognitive decline is defined by a decrease in the MoCA score greater than or equal to 2 at any follow-up visit from baseline.
timeFrame: estimated up to 84 months
Secondary outcomes:
measure: Death (total and cardiovascular)
timeFrame: estimated up to 84 months
measure: Composite including stroke/transient ischemic attack (TIA) and systemic embolic events
timeFrame: estimated up to 84 months
measure: Neurocognitive decline
timeFrame: estimated up to 84 months
measure: Hospitalization for cardiovascular (myocardial infarction, heart failure, AF, stroke or unstable angina or other cardiovascular events) or bleeding event
timeFrame: estimated up to 84 months
Other outcomes:
measure: Major clinical bleeding event
timeFrame: estimated up to 84 months
Locations:
city: Calgary
country: Canada
facility: CardiAi Inc.
state: Alberta
city: Calgary
country: Canada
facility: Libin Cardiovascular Institute of Alberta
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Abbotsford
country: Canada
facility: Office of Dr. TunZan Maung, MD
state: British Columbia
city: North Vancouver
country: Canada
facility: North Shore Heart Center
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital/UBC
state: British Columbia
city: Winnipeg
country: Canada
facility: Cardio 1
state: Manitoba
city: Winnipeg
country: Canada
facility: St. Boniface Hospital
state: Manitoba
city: Moncton
country: Canada
facility: Dr. Georges-L - Dumont University Hospital Center
state: New Brunswick
city: Halifax
country: Canada
facility: QEll Health Sciences Center-Halifax Infirmary
state: Nova Scotia
city: London
country: Canada
facility: Western University - London Health Sciences Centre
state: Onatrio
city: Newmarket
country: Canada
facility: PACE (Partners in Advanced Cardiac Evaluation)
state: Onatrio
city: Oakville
country: Canada
facility: Oakville Cardiovascular Research LP
state: Onatrio
city: Cambridge
country: Canada
facility: Cambridge Cardiac Care Center
state: Ontario
city: Cambridge
country: Canada
facility: Vizel Cardiac Research
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Sciences - General Site
state: Ontario
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Kitchener
country: Canada
facility: Cardiology Clinic
state: Ontario
city: Kitchener
country: Canada
facility: St. Mary's general Hospital
state: Ontario
city: Mississauga
country: Canada
facility: One Heart Care
state: Ontario
city: Ottawa
country: Canada
facility: University of Ottawa Heart Institute
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Brossard
country: Canada
facility: Viacar Recherche Clinique Inc.
state: Quebec
city: Chicoutimi
country: Canada
facility: CIUSSS du Saguenay-Lac-Saint-Jean
state: Quebec
city: Granby
country: Canada
facility: CIUSSS de l'Estrie-CHUS-Centre Haute-Yamaska (Hopital de Granby)
state: Quebec
city: Greenfield Park
country: Canada
facility: CISSSMC-Hopital Charles-Lemoyne
state: Quebec
city: Greenfield Park
country: Canada
facility: Viacar Recherche Clinique Inc.
state: Quebec
city: Laval
country: Canada
facility: Hopital de la Cite-de-la-Sante
state: Quebec
city: Levis
country: Canada
facility: Clinique Cardiologie de Levis
state: Quebec
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Montreal
country: Canada
facility: CHUM
state: Quebec
city: Montreal
country: Canada
facility: Hopital du Sacre Coeur de Montreal
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Rimouski
country: Canada
facility: CISSS BSL-Hopital de Rimouski
state: Quebec
city: Saint-Jerome
country: Canada
facility: CISSS des Laurentides-Unite de recherche clinique
state: Quebec
city: Sherbrooke
country: Canada
facility: CIUSSS de l'Estrie-CHUS
state: Quebec
city: Terrebonne
country: Canada
facility: CISSS de Lanaudiere-Hopital Pierre-Le Gardeur
state: Quebec
city: Trois-Rivières
country: Canada
facility: CIUSSS MCQ CHAUR- Centre Hospitalier regional de Trois-Rivieres
state: Quebec
city: Quebec
country: Canada
facility: CHU de Quebec-Universite Laval/Hotel Dieu de Quebec
city: Quebec
country: Canada
facility: Institut Universitaire de Cardiologie et de Pneumologie de Quebec
Study officials:
affiliation: Montreal Heart Institute
name: Lena Rivard, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Montreal health Innovations Coordinating Centre
name: Sophie Tanguay, M.Sc.
role: STUDY_DIRECTOR
References:
citation: Rivard L, Khairy P, Talajic M, Tardif JC, Nattel S, Bherer L, Black S, Healey J, Lanthier S, Andrade J, Massoud F, Nault I, Guertin MC, Dorian P, Kouz S, Essebag V, Ellenbogen KA, Wyse G, Racine N, Macle L, Mondesert B, Dyrda K, Tadros R, Guerra P, Thibault B, Cadrin-Tourigny J, Dubuc M, Roux JF, Mayrand H, Greiss I, Roy D. Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF): Methods and Design. Can J Cardiol. 2019 Aug;35(8):1069-1077. doi: 10.1016/j.cjca.2019.04.022. Epub 2019 May 7.