Clinical trial NCT03950076: EdoxabaN for IntraCranial Hemorrhage Survivors with Atrial Fibrillation (ENRICH-AF)
Official title: EdoxabaN for IntraCranial Hemorrhage Survivors with Atrial Fibrillation (ENRICH-AF)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Intracranial Hemorrhages
Atrial Fibrillation
Keywords: Edoxaban
Intracranial Hemorrhage
Hemorrhagic Stroke
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
First posted: 2019-05-15
Enrollment: 948
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomized, open, blinded end-point (PROBE), multicenter international trial
Primary purpose: PREVENTION

Brief summary: To assess whether edoxaban (60/30 mg daily) compared to non-antithrombotic medical therapy (either no antithrombotic therapy or antiplatelet monotherapy) reduces the risk of stroke (composite of ischemic, hemorrhagic and unspecified stroke) or systemic embolism in high-risk atrial fibrillation (CHA2DS2-VASc ≥2) patients with previous intracranial hemorrhage.

Detailed description: The EdoxabaN foR IntraCranial Hemorrhage survivors with Atrial Fibrillation (ENRICH-AF) study is a prospective, randomized open-label, blinded end-point (PROBE), investigator-initiated, study that will define the efficacy and safety of edoxaban compared with non-anticoagulant medical therapy (no antithrombotic therapy or antiplatelet monotherapy) for stroke/systemic embolism prevention in high-risk AF patients and previous intracranial hemorrhage. Intracranial hemorrhage includes intracerebral hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage and subdural hematoma. Recruitment will occur at 250-300 stroke research centres in North and South America, Europe and Asia over 24 months, where 1200 adult participants with high-risk AF (CHA2DS2-VASc score ≥2) and previous spontaneous or traumatic intracranial hemorrhage (while on or off antithrombotic therapy) will be randomly assigned to receive edoxaban 60/30 mg daily or to non-anticoagulant medical therapy (no antithrombotic therapy or antiplatelet monotherapy). Consenting participants will be followed to a common study end-date in this event-driven trial once 123 primary efficacy events (stroke) have accrued; anticipated to be about 12 months after the end of recruitment.

ENRICH-AF will assess the safety and efficacy of anticoagulant therapy in AF participants after intracranial hemorrhage, an area where there currently exists huge interest within the stroke and cardiology research communities. Demonstrating safety comparable with non-anticoagulant medical therapy in AF patients who are particularly at high risk for intracranial hemorrhage is likely to have a more far-reaching clinical impact than solely within the proposed study population. ENRICH-AF will be the "ultimate safety test" of anticoagulation of AF patients, providing reassuring evidence favoring more widespread use of anticoagulation for stroke prevention in AF patients.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent provided
2. Age ≥45 years, at the time of signing the informed consent
3. Previous intracranial hemorrhage (symptomatic, spontaneous and non-traumatic non-lobar intraparenchymal or intraventricular hemorrhage, and symptomatic spontaneous or non-penetrating traumatic subdural hemorrhages) on or off antithrombotic therapy
4. Documented atrial fibrillation (paroxysmal, persistent, permanent)
5. CHA2DS2-VASc score ≥2

Exclusion Criteria:

1. Recent intracranial hemorrhage (within 14 days)
2. Secondary macrovascular, neoplastic or infectious causes of intracranial hemorrhage (except for antithrombotic treatment or non-penetrating traumatic subdural hemorrhages)
3. Isolated subarachnoid hemorrhage (convexity or basal); subarachnoid blood tracking onto convexity secondary to an intraventricular hemorrhage or as part of a multicompartment bleed in cases of traumatic subdural hemorrhages are eligible
4. Need for ongoing oral anticoagulant therapy for indication other than AF (e.g. mechanical heart valve, venous thromboembolic disease)
5. Need for ongoing antiplatelet therapy for indication where edoxaban would not be a suitable substitute
6. Plans for left atrial appendage occlusion
7. Estimated creatinine clearance (CrCl) \< 15 mL/min
8. Platelet count less than 100,000mm3 at enrollment or other bleeding diathesis
9. Persistent, uncontrolled hypertension (systolic BP averaging \>150 mmHg)
10. Chronic use of NSAID
11. Clinically significant active bleeding, including gastrointestinal bleeding
12. Lesions or conditions at increased risk of clinically significant bleeding, e.g. active peptic ulcer disease with recent bleeding, patients with spontaneous or acquired impairment of hemostasis
13. Antiphospholipid antibody syndrome
14. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk
15. Known hypersensitivity to edoxaban
16. Estimated inability to adhere to study procedures
17. Pregnancy or breastfeeding
18. Estimated life expectancy \< 6 months at the time of enrollment
19. Close affiliation with the investigational site; e.g. a close relative for the investigator, dependent person (e.g., employee or student of the investigational site)
20. Lobar intraparenchymal hemorrhage

    * Post menopausal female subjects must be amenorrheic for ≥12 months prior to screening or ≥6 weeks post-surgical bilateral oophorectomy (with or without hysterectomy) prior to screening. Women of childbearing potential must have negative serum pregnancy test within 7 days prior to randomization or urine pregnancy testing within 24 hours of randomization. Heterosexually active women of childbearing potential must use highly effective methods of contraception for 32 days after discontinuation (duration of study drug plus 30 days duration of one ovulatory cycle).

Primary outcomes:
measure: Stroke or Systemic Embolism
timeFrame: From randomization until the common study end date (average of 3 years)
measure: Major hemorrhage
timeFrame: From randomization until the common study end date (median 2 years)
Secondary outcomes:
measure: Ischemic stroke
timeFrame: From randomization until the common study end date (median 2 years)
measure: Cardiovascular death
timeFrame: From randomization until the common study end date (median 2 years)
measure: Hemorrhagic stroke
timeFrame: From randomization until the common study end date (median 2 years)
measure: Disabling/fatal stroke
timeFrame: From randomization until the common study end date (median 2 years)
measure: Composite of all stroke, myocardial infarction, systemic thromboembolism, or all-cause death
timeFrame: From randomization until the common study end date (median 2 years)
measure: Net clinical benefit (composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area)
timeFrame: From randomization until the common study end date (median 2 years)
measure: modified Rankin Scale
timeFrame: 12 months
measure: All intracranial hemorrhage (intracerebral hemorrhage, intraventricular hemorrhage, subdural hematoma, subarachnoid hemorrhage)
timeFrame: From randomization until the common study end date (median 2 years)
measure: Fatal intracranial hemorrhage
timeFrame: From randomization until the common study end date (median 2 years)
measure: Subdural hemorrhage
timeFrame: From randomization until the common study end date (median 2 years)
measure: Hospitalization for any cause
timeFrame: From randomization until the common study end date (median 2 years)
Other outcomes:
Locations:
city: Elk Grove Village
country: United States
facility: Alexian Brothers Medical Center
state: Illinois
city: Lisle
country: United States
facility: Presence Care Transformation Corporation
state: Illinois
city: New Orleans
country: United States
facility: Tulane University Medical Center
state: Louisiana
city: Queens
country: United States
facility: New York Presbyterian - Queens
state: New York
city: Philadelphia
country: United States
facility: The Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Austin
country: United States
facility: The University of Texas at Austin, Dell Medical School
state: Texas
city: El Paso
country: United States
facility: Texas Tech University Health Sciences Center at El Paso
state: Texas
city: Houston
country: United States
facility: Baylor St. Luke's Medical Center
state: Texas
city: Tacoma
country: United States
facility: MultiCare Institute for Research & Innovation
state: Washington
city: Buenos Aires
country: Argentina
facility: Stat Research S.A.
city: Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Buenos Aires
country: Argentina
facility: Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI)
city: Buenos Aires
country: Argentina
facility: Hospital Policial Churruca-Visca
city: Salta
country: Argentina
facility: Centro Instituto Neurologico Salta
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Rankweil
country: Austria
facility: Institut für Akutneurologie und Stroke Unit (IANS), Landeskrankenhaus Feldkirch
city: Vienna
country: Austria
facility: Medical University of Vienna, Dept. of Neurology
city: Vocklabruck
country: Austria
facility: Salzkammergutklinikum Vöcklabruck
city: Brussel
country: Belgium
facility: Erasme Hospital
city: Brussel
country: Belgium
facility: UZ Brussel
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen (UZA)
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg
city: Hasselt
country: Belgium
facility: Jessa Hospital
city: Kortrijk
country: Belgium
facility: Groeninge Hospital
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: Clinique CHC MontLégia
city: Oostende
country: Belgium
facility: AZ Damiaan
city: Roeselare
country: Belgium
facility: AZ Delta
city: Brandon
country: Canada
facility: Brandon Regional Health Centre
city: Calgary
country: Canada
facility: University of Calgary / Foothills Medical Centre
city: Chicoutimi
country: Canada
facility: Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean
city: Edmonton
country: Canada
facility: University of Alberta Hospital
city: Halifax
country: Canada
facility: Nova Scotia Health Authority
city: Hamilton
country: Canada
facility: Hamilton Health Sciences
city: Kingston
country: Canada
facility: Kingston General Hospital
city: London
country: Canada
facility: London Health Science Centre - University Hospital
city: Montreal
country: Canada
facility: CHUM Centre Hospitalier de l'Université de Montréal
city: Montréal
country: Canada
facility: McGill University Health Centre
city: Ottawa
country: Canada
facility: The Ottawa Hospital Research Institute
city: Owen Sound
country: Canada
facility: The Rhema Research Institute
city: Québec
country: Canada
facility: CHUL Pavillon Enfant-Jésus
city: Saskatoon
country: Canada
facility: University of Saskatchewan
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Sciences Centre
city: Toronto
country: Canada
facility: Sunnybrook Health Science Centre
city: Toronto
country: Canada
facility: University Health Network - Toronto Western Hospital
city: Windsor
country: Canada
facility: Canadian Cardiac Research Centre
city: Beijing
country: China
facility: Beijing Anzhen Hospital, Capital Medical University
city: Shanghai
country: China
facility: Punan Hospital
city: Shanghai
country: China
facility: Shanghai Blue Cross Brain Hospital
city: Shanghai
country: China
facility: Shanghai East Hospital, Tongji University
city: Shanghai
country: China
facility: Shanghai Fengcheng Hospital
city: Shanghai
country: China
facility: Xinhua Hospital, Chongming Branch
city: Shanghai
country: China
facility: Yangpu Hospital, Tongji University
city: Shenyang
country: China
facility: The First People's Hospital of Shenyang
city: Brno
country: Czechia
facility: St. Anne's University Hospital
city: Jihlava
country: Czechia
facility: Neurological Department, General Hospital of Jihlava
city: Ostrava
country: Czechia
facility: Cerebrovaskularni poradna s.r.o.
city: Alexandria
country: Egypt
facility: Alexandria University Hospital
city: Banī Suwayf
country: Egypt
facility: Beni Suef University Hospital
city: Cairo
country: Egypt
facility: Ain Shams Specialized Hospital
city: Cairo
country: Egypt
facility: Ain Shams University Hospital
city: Fayoum
country: Egypt
facility: Fayoum General Hospital
city: Mansoura
country: Egypt
facility: Mansoura University Hospital
city: Tanta
country: Egypt
facility: Tanta University Hospital
city: Zagazig
country: Egypt
facility: Zagazig University Hospital
city: Berlin
country: Germany
facility: Charité - University Medicine Berlin
city: Dresden
country: Germany
facility: Dresden University Hospital "Carl Gustav Carus"
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Friedrichshafen
country: Germany
facility: Klinikum Friedrichshafen
city: Goettigen
country: Germany
facility: University Medicine Goettingen
city: Halle
country: Germany
facility: Martha-Maria Hospital
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Lohr
country: Germany
facility: Klinikum Main-Spessart, Krankenhaus Lohr
city: Lübeck
country: Germany
facility: Klinik fur Neurologie, UKSH campus Lubeck
city: Mannheim
country: Germany
facility: Medical Faculty Mannheim, Heidelberg University
city: Münster
country: Germany
facility: Westfalische Wilhelms-Universitat Munster
city: Osnabrück
country: Germany
facility: Klinikum Osnabrück; Neurologie
city: Recklinghausen
country: Germany
facility: Department of Neurology, Klinikum Vest
city: Tuebingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ahmedabad
country: India
facility: Zydus Hospitals & Healthcare Research Pvt. Ltd.
city: Anand
country: India
facility: Shree Krishna Hospital and Pramukhswami Medical College
city: Bangalore
country: India
facility: Bangalore Baptist Hospital
city: Bangalore
country: India
facility: Fortis Hospital Ltd
city: Bangalore
country: India
facility: Mazumdar Shaw Medical Center - Unit of Narayana Health
city: Bangalore
country: India
facility: St. John's Medical College Hospital
city: Chandigarh
country: India
facility: Post Graduate Institute of Medical Education &Research
city: Gangtok
country: India
facility: Sikkim Manipal Institute of Medical Sciences
city: Guwahati
country: India
facility: GNRC Hospitals
city: Kolkata
country: India
facility: Bangur Institute of Neurosciences
city: Kottayam
country: India
facility: Caritas Hospital
city: Ludhiāna
country: India
facility: Christian Medical College & Hospital
city: Nashik
country: India
facility: Dhadiwal Hospital in coalition with Shreeji Healthcare
city: Pune
country: India
facility: Bharati Vidyapeeth (DTU) Medical College & Hospital
city: Shimoga
country: India
facility: Nanjappa Hospital
city: Thiruvananthapuram
country: India
facility: Sree Chitra Tirunal Institute for Medical Sciences and Technology
city: Vadodara
country: India
facility: Rhythm Heart Institute
city: Bharatpur
country: Nepal
facility: Chitwan Everest Asptalal Private limited
city: Bharatpur
country: Nepal
facility: Chitwan Medical College Teaching Hospital
city: Biratnagar
country: Nepal
facility: Nobel Medical College & Teaching Hospital
city: Dharān Bāzār
country: Nepal
facility: B P Koirala Institute of Health Sciences
city: Jhapa
country: Nepal
facility: B & C Medical College Teaching Hospital & Research Centre Pvt. Ltd.
city: Kathmandu
country: Nepal
facility: Annapurna Neurological institute and allied sciences
city: Kathmandu
country: Nepal
facility: Grande International Hospital
city: Kathmandu
country: Nepal
facility: Kathmandu Medical College
city: Kathmandu
country: Nepal
facility: Upendra Devkota Memorial-National Institute of Neurological and Allied Sciences (UDMNINAS)
city: Lisboa
country: Portugal
facility: CHULN-Hospital Santa Maria
city: A Coruña
country: Spain
facility: Coruña University Hospital
city: Albacete
country: Spain
facility: University Hospital of Albacete
city: Barakaldo
country: Spain
facility: Instituto de Investigacion Sanitaria Biocruces
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu Isant Pau
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Cáceres
country: Spain
facility: Complejo Hospitalario Universitario de Cáceres
city: Donostia
country: Spain
facility: Hospital Donostia - Osidonostialdea
city: Lleida
country: Spain
facility: Hospital u Arnau de Vilanova de Lleida
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: La Paz Univerity Hospital
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias-Finba
city: Palma De Mallorca
country: Spain
facility: Hospital Universitario son Espases
city: Valencia
country: Spain
facility: Hospital Universitari i Politécnic La Fe.
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bern
country: Switzerland
facility: Inselspital, University Hospital Bern
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary, NHS Grampian
city: Abergavenny
country: United Kingdom
facility: Nevill Hall Hospital
city: Airdrie
country: United Kingdom
facility: NHS Lanarkshire Health Board - Monklands Hospital
city: Birkenhead
country: United Kingdom
facility: Arrowe Park Hospital
city: Bournemouth
country: United Kingdom
facility: The Royal Bournemouth Hospital
city: Bradford
country: United Kingdom
facility: Bradford Teaching Hospitals NHS Foundation Trust, at Bradford Royal Infirmary
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Colchester
country: United Kingdom
facility: East Suffolk and North Essex NHS Foundation Trust, at Colchester Hospital
city: Edinburgh
country: United Kingdom
facility: Edinburgh Royal Infirmary
city: Gateshead
country: United Kingdom
facility: Queen Elizabeth Hospital - Gateshead Health NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Gloucester
country: United Kingdom
facility: Gloucestershire Royal Hospital
city: Harrow
country: United Kingdom
facility: LNWUH - Northwick Park Hospital
city: Huddersfield
country: United Kingdom
facility: Calderdale and Huddersfield NHS Foundation Trust
city: Kirkcaldy
country: United Kingdom
facility: Victoria Hospital Kirkcaldy
city: London
country: United Kingdom
facility: Homerton University Hospital
city: Mansfield
country: United Kingdom
facility: King's Mill Hospital
city: Middlesbrough
country: United Kingdom
facility: The South Tees Hospitals NHS Foundation Trust
city: Morriston
country: United Kingdom
facility: Morriston Hospital
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire NHS Foundation Trust
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
city: Uxbridge
country: United Kingdom
facility: Hillingdon Hospital
city: Westcliff-on-Sea
country: United Kingdom
facility: Southend University Hospital Southend University Hospital NHS Foundation Trust
city: Yeovil
country: United Kingdom
facility: Yeovil District Hospital
Study officials:
affiliation: Population Health Research Institute
name: Ashkan Shoamanesh, MD, FRCPC
role: PRINCIPAL_INVESTIGATOR
References:
citation: Li L, Poon MTC, Samarasekera NE, Perry LA, Moullaali TJ, Rodrigues MA, Loan JJM, Stephen J, Lerpiniere C, Tuna MA, Gutnikov SA, Kuker W, Silver LE, Al-Shahi Salman R, Rothwell PM. Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies. Lancet Neurol. 2021 Jun;20(6):437-447. doi: 10.1016/S1474-4422(21)00075-2.