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

Sponsor

Population Health Research Institute (Other)

Overall Status

Recruiting

CT.gov ID

NCT03950076

Collaborator

(none)

1,200

Enrollment

147

Locations

Arms

45.3

Anticipated Duration (Months)

8.2

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Intracranial Hemorrhages Atrial Fibrillation	Drug: Edoxaban Other: Non-anticoagulant medical therapy	Phase 4

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 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Prospective, randomized, open, blinded end-point (PROBE), multicenter international trialProspective, randomized, open, blinded end-point (PROBE), multicenter international trial

Masking:

Single (Outcomes Assessor)

Masking Description:

open label study where outcomes assessor is blinded to treatment allocation

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Sep 20, 2019

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Edoxaban 60/30mg daily Edoxaban 60/30 mg daily (lower dose depending on clinical criteria)	Drug: Edoxaban Edoxaban 60mg (or 30mg as determined by clinical criteria) Other Names: Lixiana Savaysa
Active Comparator: Non-anticoagulant medical therapy Non-anticoagulant medical therapy: no antithrombotic therapy or antiplatelet monotherapy (at discretion of local investigator)	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

Arm

Intervention/Treatment

Experimental: Edoxaban 60/30mg daily

Edoxaban 60/30 mg daily (lower dose depending on clinical criteria)

Drug: Edoxaban

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

Other Names:

Lixiana

Savaysa

Active Comparator: Non-anticoagulant medical therapy

Non-anticoagulant medical therapy: no antithrombotic therapy or antiplatelet monotherapy (at discretion of local investigator)

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

Outcome Measures

Primary Outcome Measures

Stroke [From randomization until the common study end date (median 2 years)]
composite of ischemic, hemorrhagic and unspecified
Major hemorrhage [From randomization until the common study end date (median 2 years)]
as defined byt the International Society on Thrombosis and Haemostasis (ISTH) criteria

Secondary Outcome Measures

Ischemic stroke [From randomization until the common study end date (median 2 years)]
development of an acute neurologic deficit in conjunction with brain imaging consistent with acute/subacute ischemic stroke.
Cardiovascular death [From randomization until the common study end date (median 2 years)]
Death related to cardiovascular cause
Hemorrhagic stroke [From randomization until the common study end date (median 2 years)]
development of an acute neurologic deficit in conjunction with brain imaging consistent with acute/subacute intraparenchymal, intraventricular or subarachnoid hemorrhage
Disabling/fatal stroke [From randomization until the common study end date (median 2 years)]
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.
Composite of all stroke, myocardial infarction, systemic thromboembolism, or all-cause death [From randomization until the common study end date (median 2 years)]
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
Net clinical benefit (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)]
Net clinical benefit is a composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area
modified Rankin Scale [12 months]
mRS as measured at 12 month visit
All intracranial hemorrhage (intracerebral hemorrhage, intraventricular hemorrhage, subdural hematoma, subarachnoid hemorrhage) [From randomization until the common study end date (median 2 years)]
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.
Fatal intracranial hemorrhage [From randomization until the common study end date (median 2 years)]
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
Subdural hemorrhage [From randomization until the common study end date (median 2 years)]
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
Hospitalization for any cause [From randomization until the common study end date (median 2 years)]
Minimum of one overnight stay in hospital.

Eligibility Criteria

Criteria

Ages Eligible for Study:

45 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent provided
Age ≥45 years, at the time of signing the informed consent
Previous intracranial hemorrhage (symptomatic, spontaneous and non-traumatic intraparenchymal, intraventricular, and/or cSAH, and symptomatic spontaneous or non-penetrating traumatic subdural hemorrhages) on or off antithrombotic therapy, and confirmed to have stabilized on neuroimaging.
Documented atrial fibrillation (paroxysmal, persistent, permanent)
CHA2DS2-VASc score ≥2

Exclusion Criteria:

Recent intracranial hemorrhage (within 14 days)
Secondary macrovascular, neoplastic or infectious causes of intracranial hemorrhage (except for antithrombotic treatment or non-penetrating traumatic subdural hemorrhages)
Traumatic or aneurysmal cSAH
Need for ongoing oral anticoagulant therapy for indication other than AF (e.g. mechanical heart valve, venous thromboembolic disease)
Need for ongoing antiplatelet therapy for indication where edoxaban would not be a suitable substitute
Plans for left atrial appendage occlusion
Estimated creatinine clearance (CrCl) < 15 mL/min or other creatinine clearance following local product monograph (Canada < 30mL/min)
Platelet count less than 100,000mm3 at enrollment or other bleeding diathesis
Persistent, uncontrolled hypertension (systolic BP averaging >150 mmHg)
Chronic use of NSAID
Clinically significant active bleeding, including gastrointestinal bleeding
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
Antiphospholipid antibody syndrome
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk
Known hypersensitivity to edoxaban
Estimated inability to adhere to study procedures
Pregnancy or breastfeeding
Estimated life expectancy < 6 months at the time of enrollment
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)

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alexian Brothers Medical Center	Elk Grove Village	Illinois	United States	60007
2	Presence Care Transformation Corporation	Lisle	Illinois	United States	60532
3	Tulane University Medical Center	New Orleans	Louisiana	United States	70112
4	New York Presbyterian - Queens	Queens	New York	United States	11355
5	The Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
6	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15218
7	The University of Texas at Austin, Dell Medical School	Austin	Texas	United States	78701
8	Texas Tech University Health Sciences Center at El Paso	El Paso	Texas	United States	79905
9	Baylor St. Luke's Medical Center	Houston	Texas	United States	77030
10	MultiCare Institute for Research & Innovation	Tacoma	Washington	United States	98405
11	Medical University of Innsbruck	Innsbruck		Austria
12	Institut für Akutneurologie und Stroke Unit (IANS), Landeskrankenhaus Feldkirch	Rankweil		Austria
13	Salzkammergutklinikum Vöcklabruck	Vocklabruck		Austria
14	Erasme Hospital	Brussel		Belgium
15	UZ Brussel	Brussel		Belgium
16	Universitair Ziekenhuis Antwerpen (UZA)	Edegem		Belgium
17	Ziekenhuis Oost-Limburg	Genk		Belgium
18	Jessa Hospital	Hasselt		Belgium
19	Groeninge Hospital	Kortrijk		Belgium
20	UZ Leuven	Leuven		Belgium
21	Clinique CHC MontLégia	Liège		Belgium
22	AZ Damiaan	Oostende		Belgium
23	AZ Delta	Roeselare		Belgium
24	Brandon Regional Health Centre	Brandon		Canada
25	University of Calgary / Foothills Medical Centre	Calgary		Canada
26	Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean	Chicoutimi		Canada
27	University of Alberta Hospital	Edmonton		Canada
28	Nova Scotia Health Authority	Halifax		Canada
29	Hamilton Health Sciences	Hamilton		Canada
30	Hamilton Health Sciences	Hamilton		Canada
31	Kingston General Hospital	Kingston		Canada
32	London Health Science Centre - University Hospital	London		Canada
33	CHUM Centre Hospitalier de l'Université de Montréal	Montreal		Canada
34	McGill University Health Centre	Montréal		Canada
35	The Ottawa Hospital Research Institute	Ottawa		Canada
36	The Rhema Research Institute	Owen Sound		Canada
37	CHUL Pavillon Enfant-Jésus	Québec		Canada
38	University of Saskatchewan	Saskatoon		Canada
39	Thunder Bay Regional Health Sciences Centre	Thunder Bay		Canada
40	Sunnybrook Health Science Centre	Toronto		Canada
41	University Health Network - Toronto Western Hospital	Toronto		Canada
42	Canadian Cardiac Research Centre	Windsor		Canada
43	Beijing Anzhen Hospital, Capital Medical University	Beijing		China
44	Punan Hospital	Shanghai		China
45	Shanghai Blue Cross Brain Hospital	Shanghai		China
46	Shanghai East Hospital, Tongji University	Shanghai		China
47	Shanghai Fengcheng Hospital	Shanghai		China
48	Xinhua Hospital, Chongming Branch	Shanghai		China
49	Yangpu Hospital, Tongji University	Shanghai		China
50	The First People's Hospital of Shenyang	Shenyang		China
51	St. Anne's University Hospital	Brno		Czechia
52	Neurological Department, General Hospital of Jihlava	Jihlava		Czechia
53	Cerebrovaskularni poradna s.r.o.	Ostrava		Czechia
54	Alexandria University Hospital	Alexandria		Egypt
55	Beni Suef University Hospital	Banī Suwayf		Egypt
56	Ain Shams Specialized Hospital	Cairo		Egypt
57	Ain Shams University Hospital	Cairo		Egypt
58	Fayoum General Hospital	Fayoum		Egypt
59	Mansoura University Hospital	Mansoura		Egypt
60	Tanta University Hospital	Tanta		Egypt
61	Zagazig University Hospital	Zagazig		Egypt
62	Charité - University Medicine Berlin	Berlin		Germany
63	Dresden University Hospital "Carl Gustav Carus"	Dresden		Germany
64	Universitätsklinikum Essen	Essen		Germany
65	Klinikum Friedrichshafen	Friedrichshafen		Germany
66	University Medicine Goettingen	Goettigen		Germany
67	Martha-Maria Hospital	Halle		Germany
68	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany
69	Klinikum Main-Spessart, Krankenhaus Lohr	Lohr		Germany
70	Klinik fur Neurologie, UKSH campus Lubeck	Lübeck		Germany
71	Medical Faculty Mannheim, Heidelberg University	Mannheim		Germany
72	Westfalische Wilhelms-Universitat Munster	Münster		Germany
73	Klinikum Osnabrück; Neurologie	Osnabrück		Germany
74	Department of Neurology, Klinikum Vest	Recklinghausen		Germany
75	Universitätsklinikum Tübingen	Tuebingen		Germany
76	Zydus Hospitals & Healthcare Research Pvt. Ltd.	Ahmedabad		India
77	Shree Krishna Hospital and Pramukhswami Medical College	Anand		India
78	Bangalore Baptist Hospital	Bangalore		India
79	Fortis Hospital Ltd	Bangalore		India
80	Mazumdar Shaw Medical Center - Unit of Narayana Health	Bangalore		India
81	St. John's Medical College Hospital	Bangalore		India
82	Post Graduate Institute of Medical Education &Research	Chandigarh		India
83	Sikkim Manipal Institute of Medical Sciences	Gangtok		India
84	GNRC Hospitals	Guwahati		India
85	Bangur Institute of Neurosciences	Kolkata		India
86	Caritas Hospital	Kottayam		India
87	Christian Medical College & Hospital	Ludhiāna		India
88	Dhadiwal Hospital in coalition with Shreeji Healthcare	Nashik		India
89	Bharati Vidyapeeth (DTU) Medical College & Hospital	Pune		India
90	Nanjappa Hospital	Shimoga		India
91	Sree Chitra Tirunal Institute for Medical Sciences and Technology	Thiruvananthapuram		India
92	Rhythm Heart Institute	Vadodara		India
93	Chitwan Everest Asptalal Private limited	Bharatpur		Nepal
94	Chitwan Medical College Teaching Hospital	Bharatpur		Nepal
95	Nobel Medical College & Teaching Hospital	Biratnagar		Nepal
96	B P Koirala Institute of Health Sciences	Dharān Bāzār		Nepal
97	B & C Medical College Teaching Hospital & Research Centre Pvt. Ltd.	Jhapa		Nepal
98	Annapurna Neurological institute and allied sciences	Kathmandu		Nepal
99	Grande International Hospital	Kathmandu		Nepal
100	Kathmandu Medical College	Kathmandu		Nepal
101	Upendra Devkota Memorial-National Institute of Neurological and Allied Sciences (UDMNINAS)	Kathmandu		Nepal
102	CHULN-Hospital Santa Maria	Lisboa		Portugal
103	Coruña University Hospital	A Coruña		Spain
104	University Hospital of Albacete	Albacete		Spain
105	Instituto de Investigacion Sanitaria Biocruces	Barakaldo		Spain
106	Hospital Clinic de Barcelona	Barcelona		Spain
107	Hospital de La Santa Creu Isant Pau	Barcelona		Spain
108	Hospital del Mar	Barcelona		Spain
109	Hospital Universitari Vall d'Hebron	Barcelona		Spain
110	Complejo Hospitalario Universitario de Cáceres	Cáceres		Spain
111	Hospital Donostia - Osidonostialdea	Donostia		Spain
112	Hospital u Arnau de Vilanova de Lleida	Lleida		Spain
113	Hospital General Universitario Gregorio Marañon	Madrid		Spain
114	Hospital Ramón y Cajal	Madrid		Spain
115	La Paz Univerity Hospital	Madrid		Spain
116	Hospital Universitario Central de Asturias-Finba	Oviedo		Spain
117	Hospital Universitario son Espases	Palma De Mallorca		Spain
118	Hospital Universitari i Politécnic La Fe.	Valencia		Spain
119	University Hospital Basel	Basel		Switzerland
120	Inselspital, University Hospital Bern	Bern		Switzerland
121	Aberdeen Royal Infirmary, NHS Grampian	Aberdeen		United Kingdom
122	Nevill Hall Hospital	Abergavenny		United Kingdom
123	NHS Lanarkshire Health Board - Monklands Hospital	Airdrie		United Kingdom
124	Arrowe Park Hospital	Birkenhead		United Kingdom
125	The Royal Bournemouth Hospital	Bournemouth		United Kingdom
126	Bradford Teaching Hospitals NHS Foundation Trust, at Bradford Royal Infirmary	Bradford		United Kingdom
127	Cambridge University Hospitals NHS Foundation Trust	Cambridge		United Kingdom
128	University Hospital of Wales	Cardiff		United Kingdom
129	East Suffolk and North Essex NHS Foundation Trust, at Colchester Hospital	Colchester		United Kingdom
130	Edinburgh Royal Infirmary	Edinburgh		United Kingdom
131	Queen Elizabeth Hospital - Gateshead Health NHS Foundation Trust	Gateshead		United Kingdom
132	Glasgow Royal Infirmary	Glasgow		United Kingdom
133	Queen Elizabeth University Hospital	Glasgow		United Kingdom
134	Gloucestershire Royal Hospital	Gloucester		United Kingdom
135	LNWUH - Northwick Park Hospital	Harrow		United Kingdom
136	Calderdale and Huddersfield NHS Foundation Trust	Huddersfield		United Kingdom
137	Victoria Hospital Kirkcaldy	Kirkcaldy		United Kingdom
138	Homerton University Hospital	London		United Kingdom
139	King's Mill Hospital	Mansfield		United Kingdom
140	The South Tees Hospitals NHS Foundation Trust	Middlesbrough		United Kingdom
141	Morriston Hospital	Morriston		United Kingdom
142	Royal Preston Hospital	Preston		United Kingdom
143	Royal Berkshire NHS Foundation Trust	Reading		United Kingdom
144	Royal Cornwall Hospital	Truro		United Kingdom
145	Hillingdon Hospital	Uxbridge		United Kingdom
146	Southend University Hospital Southend University Hospital NHS Foundation Trust	Westcliff-on-Sea		United Kingdom
147	Yeovil District Hospital	Yeovil		United Kingdom