EdoxabaN foR IntraCranial Hemorrhage Survivors With Atrial Fibrillation (ENRICH-AF)

Atrial Fibrillation Clinical Trial

— ENRICH-AF  

Official title:

EdoxabaN foR IntraCranial Hemorrhage Survivors With Atrial Fibrillation (ENRICH-AF)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03950076
• Other study ID #: ENRICH-AF
• Status: Recruiting
• Phase: Phase 4
• Start date: September 20, 2019
• Est. completion date: October 2024

Study information

• Verified date: February 2024
• Source: Population Health Research Institute
• Contact: Kevin Reeh, MSc
• Phone: 905-521-2100
• Email: ENRICH-AF[@]phri.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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) in high-risk atrial fibrillation (CHA2DS2-VASc ≥2) patients with previous intracranial hemorrhage.

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 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1200
• Est. completion date: October 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Atrial Fibrillation
• Hemorrhage
• Intracranial Hemorrhages

Intervention

Drug:
• Edoxaban
Edoxaban 60mg (or 30mg as determined by clinical criteria)

Other:
• Non-anticoagulant medical therapy
Non-anticoagulant medical therapy as determined by the local investigator includes i) No antithrombotic therapy ii) Antiplatelet monotherapy, including de novo indication for antiplatelet monotherapy during course of the study

Locations

Country	Name	City	State
Argentina	Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI)	Buenos Aires
Argentina	Hospital Italiano de Buenos Aires	Buenos Aires
Argentina	Hospital Policial Churruca-Visca	Buenos Aires
Argentina	Stat Research S.A.	Buenos Aires
Argentina	Centro Instituto Neurologico Salta	Salta
Austria	Medical University of Innsbruck	Innsbruck
Austria	Institut für Akutneurologie und Stroke Unit (IANS), Landeskrankenhaus Feldkirch	Rankweil
Austria	Medical University of Vienna, Dept. of Neurology	Vienna
Austria	Salzkammergutklinikum Vöcklabruck	Vocklabruck
Belgium	Erasme Hospital	Brussel
Belgium	UZ Brussel	Brussel
Belgium	Universitair Ziekenhuis Antwerpen (UZA)	Edegem
Belgium	Ziekenhuis Oost-Limburg	Genk
Belgium	Jessa Hospital	Hasselt
Belgium	Groeninge Hospital	Kortrijk
Belgium	UZ Leuven	Leuven
Belgium	Clinique CHC MontLégia	Liège
Belgium	AZ Damiaan	Oostende
Belgium	AZ Delta	Roeselare
Canada	Brandon Regional Health Centre	Brandon
Canada	University of Calgary / Foothills Medical Centre	Calgary
Canada	Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean	Chicoutimi
Canada	University of Alberta Hospital	Edmonton
Canada	Nova Scotia Health Authority	Halifax
Canada	Hamilton Health Sciences	Hamilton
Canada	Hamilton Health Sciences	Hamilton
Canada	Kingston General Hospital	Kingston
Canada	London Health Science Centre - University Hospital	London
Canada	CHUM Centre Hospitalier de l'Université de Montréal	Montreal
Canada	McGill University Health Centre	Montréal
Canada	The Ottawa Hospital Research Institute	Ottawa
Canada	The Rhema Research Institute	Owen Sound
Canada	CHUL Pavillon Enfant-Jésus	Québec
Canada	University of Saskatchewan	Saskatoon
Canada	Thunder Bay Regional Health Sciences Centre	Thunder Bay
Canada	Sunnybrook Health Science Centre	Toronto
Canada	University Health Network - Toronto Western Hospital	Toronto
Canada	Canadian Cardiac Research Centre	Windsor
China	Beijing Anzhen Hospital, Capital Medical University	Beijing
China	Punan Hospital	Shanghai
China	Shanghai Blue Cross Brain Hospital	Shanghai
China	Shanghai East Hospital, Tongji University	Shanghai
China	Shanghai Fengcheng Hospital	Shanghai
China	Xinhua Hospital, Chongming Branch	Shanghai
China	Yangpu Hospital, Tongji University	Shanghai
China	The First People's Hospital of Shenyang	Shenyang
Czechia	St. Anne's University Hospital	Brno
Czechia	Neurological Department, General Hospital of Jihlava	Jihlava
Czechia	Cerebrovaskularni poradna s.r.o.	Ostrava
Egypt	Alexandria University Hospital	Alexandria
Egypt	Beni Suef University Hospital	Bani Suwayf
Egypt	Ain Shams Specialized Hospital	Cairo
Egypt	Ain Shams University Hospital	Cairo
Egypt	Fayoum General Hospital	Fayoum
Egypt	Mansoura University Hospital	Mansoura
Egypt	Tanta University Hospital	Tanta
Egypt	Zagazig University Hospital	Zagazig
Germany	Charité - University Medicine Berlin	Berlin
Germany	Dresden University Hospital "Carl Gustav Carus"	Dresden
Germany	Universitätsklinikum Essen	Essen
Germany	Klinikum Friedrichshafen	Friedrichshafen
Germany	University Medicine Goettingen	Goettigen
Germany	Martha-Maria Hospital	Halle
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Klinikum Main-Spessart, Krankenhaus Lohr	Lohr
Germany	Klinik fur Neurologie, UKSH campus Lubeck	Lübeck
Germany	Medical Faculty Mannheim, Heidelberg University	Mannheim
Germany	Westfalische Wilhelms-Universitat Munster	Münster
Germany	Klinikum Osnabrück; Neurologie	Osnabrück
Germany	Department of Neurology, Klinikum Vest	Recklinghausen
Germany	Universitätsklinikum Tübingen	Tuebingen
India	Zydus Hospitals & Healthcare Research Pvt. Ltd.	Ahmedabad
India	Shree Krishna Hospital and Pramukhswami Medical College	Anand
India	Bangalore Baptist Hospital	Bangalore
India	Fortis Hospital Ltd	Bangalore
India	Mazumdar Shaw Medical Center - Unit of Narayana Health	Bangalore
India	St. John's Medical College Hospital	Bangalore
India	Post Graduate Institute of Medical Education &Research	Chandigarh
India	Sikkim Manipal Institute of Medical Sciences	Gangtok
India	GNRC Hospitals	Guwahati
India	Bangur Institute of Neurosciences	Kolkata
India	Caritas Hospital	Kottayam
India	Christian Medical College & Hospital	Ludhiana
India	Dhadiwal Hospital in coalition with Shreeji Healthcare	Nashik
India	Bharati Vidyapeeth (DTU) Medical College & Hospital	Pune
India	Nanjappa Hospital	Shimoga
India	Sree Chitra Tirunal Institute for Medical Sciences and Technology	Thiruvananthapuram
India	Rhythm Heart Institute	Vadodara
Nepal	Chitwan Everest Asptalal Private limited	Bharatpur
Nepal	Chitwan Medical College Teaching Hospital	Bharatpur
Nepal	Nobel Medical College & Teaching Hospital	Biratnagar
Nepal	B P Koirala Institute of Health Sciences	Dharan Bazar
Nepal	B & C Medical College Teaching Hospital & Research Centre Pvt. Ltd.	Jhapa
Nepal	Annapurna Neurological institute and allied sciences	Kathmandu
Nepal	Grande International Hospital	Kathmandu
Nepal	Kathmandu Medical College	Kathmandu
Nepal	Upendra Devkota Memorial-National Institute of Neurological and Allied Sciences (UDMNINAS)	Kathmandu
Portugal	CHULN-Hospital Santa Maria	Lisboa
Spain	Coruña University Hospital	A Coruña
Spain	University Hospital of Albacete	Albacete
Spain	Instituto de Investigacion Sanitaria Biocruces	Barakaldo
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital de La Santa Creu Isant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Complejo Hospitalario Universitario de Cáceres	Cáceres
Spain	Hospital Donostia - Osidonostialdea	Donostia
Spain	Hospital u Arnau de Vilanova de Lleida	Lleida
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Ramón y Cajal	Madrid
Spain	La Paz Univerity Hospital	Madrid
Spain	Hospital Universitario Central de Asturias-Finba	Oviedo
Spain	Hospital Universitario son Espases	Palma De Mallorca
Spain	Hospital Universitari i Politécnic La Fe.	Valencia
Switzerland	University Hospital Basel	Basel
Switzerland	Inselspital, University Hospital Bern	Bern
United Kingdom	Aberdeen Royal Infirmary, NHS Grampian	Aberdeen
United Kingdom	Nevill Hall Hospital	Abergavenny
United Kingdom	NHS Lanarkshire Health Board - Monklands Hospital	Airdrie
United Kingdom	Arrowe Park Hospital	Birkenhead
United Kingdom	The Royal Bournemouth Hospital	Bournemouth
United Kingdom	Bradford Teaching Hospitals NHS Foundation Trust, at Bradford Royal Infirmary	Bradford
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	East Suffolk and North Essex NHS Foundation Trust, at Colchester Hospital	Colchester
United Kingdom	Edinburgh Royal Infirmary	Edinburgh
United Kingdom	Queen Elizabeth Hospital - Gateshead Health NHS Foundation Trust	Gateshead
United Kingdom	Glasgow Royal Infirmary	Glasgow
United Kingdom	Queen Elizabeth University Hospital	Glasgow
United Kingdom	Gloucestershire Royal Hospital	Gloucester
United Kingdom	LNWUH - Northwick Park Hospital	Harrow
United Kingdom	Calderdale and Huddersfield NHS Foundation Trust	Huddersfield
United Kingdom	Victoria Hospital Kirkcaldy	Kirkcaldy
United Kingdom	Homerton University Hospital	London
United Kingdom	King's Mill Hospital	Mansfield
United Kingdom	The South Tees Hospitals NHS Foundation Trust	Middlesbrough
United Kingdom	Morriston Hospital	Morriston
United Kingdom	Royal Preston Hospital	Preston
United Kingdom	Royal Berkshire NHS Foundation Trust	Reading
United Kingdom	Royal Cornwall Hospital	Truro
United Kingdom	Hillingdon Hospital	Uxbridge
United Kingdom	Southend University Hospital Southend University Hospital NHS Foundation Trust	Westcliff-on-Sea
United Kingdom	Yeovil District Hospital	Yeovil
United States	The University of Texas at Austin, Dell Medical School	Austin	Texas
United States	Texas Tech University Health Sciences Center at El Paso	El Paso	Texas
United States	Alexian Brothers Medical Center	Elk Grove Village	Illinois
United States	Baylor St. Luke's Medical Center	Houston	Texas
United States	Presence Care Transformation Corporation	Lisle	Illinois
United States	Tulane University Medical Center	New Orleans	Louisiana
United States	The Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	New York Presbyterian - Queens	Queens	New York
United States	MultiCare Institute for Research & Innovation	Tacoma	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Population Health Research Institute

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  Canada,  China,  Czechia,  Egypt,  Germany,  India,  Nepal,  Portugal,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Stroke	composite of ischemic, hemorrhagic and unspecified	From randomization until the common study end date (median 2 years)
Primary	Major hemorrhage	as defined byt the International Society on Thrombosis and Haemostasis (ISTH) criteria	From randomization until the common study end date (median 2 years)
Secondary	Ischemic stroke	development of an acute neurologic deficit in conjunction with brain imaging consistent with acute/subacute ischemic stroke.	From randomization until the common study end date (median 2 years)
Secondary	Cardiovascular death	Death related to cardiovascular cause	From randomization until the common study end date (median 2 years)
Secondary	Hemorrhagic stroke	development of an acute neurologic deficit in conjunction with brain imaging consistent with acute/subacute intraparenchymal, intraventricular or subarachnoid hemorrhage	From randomization until the common study end date (median 2 years)
Secondary	Disabling/fatal stroke	Disabling stroke is defined as stroke resulting in a clinical outcome that is associated with a modified Rankin scale of 4 or 5. Fatal stroke is defined as death occurring within 30 days of stroke.	From randomization until the common study end date (median 2 years)
Secondary	Composite of all stroke, myocardial infarction, systemic thromboembolism, or all-cause death	Components of composite outcome (adjudicated) includes stroke (ischemic, hemorrhagic, and undefined stroke, TIA with positive neuroimaging),myocardial infarction, systemic thromboembolism or all-cause death. Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred	From randomization until the common study end date (median 2 years)
Secondary	Net clinical benefit (composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area)	Net clinical benefit is a composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area	From randomization until the common study end date (median 2 years)
Secondary	modified Rankin Scale	mRS as measured at 12 month visit	12 months
Secondary	All intracranial hemorrhage (intracerebral hemorrhage, intraventricular hemorrhage, subdural hematoma, subarachnoid hemorrhage)	Intracranial hemorrhage as defined by Signs or symptoms associated with an epidural, subdural, subarachnoid, intraparenchymal or intraventricular hemorrhage on computed tomography (CT) or MRI scan, or as demonstrated by surgery or autopsy.	From randomization until the common study end date (median 2 years)
Secondary	Fatal intracranial hemorrhage	Inctracranial hemorrhage defined as Signs or symptoms associated with an epidural, subdural, subarachnoid, intraparenchymal or intraventricular hemorrhage on computed tomography (CT) or MRI scan, or as demonstrated by surgery or autopsy with death occurring within 30 days of stroke	From randomization until the common study end date (median 2 years)
Secondary	Subdural hemorrhage	Subdural hemorrhage as defined as Signs or symptoms associated with a subdural hemorrhage on computed tomography (CT) or MRI scan, or as demonstrated by surgery or autopsy	From randomization until the common study end date (median 2 years)
Secondary	Hospitalization for any cause	Minimum of one overnight stay in hospital.	From randomization until the common study end date (median 2 years)