NCT03950076.

Study name	EdoxabaN foR IntraCranial Hemorrhage survivors with Atrial Fibrillation (ENRICH‐AF)
Methods	Design: randomised controlled PROBE parallel group trial Setting: multicentre, international Dates: September 2019 to July 2023
Participants	Sample size: 1200 participants Diagnosis: symptomatic, spontaneous and non‐traumatic ICH, IVH, and/or convexity SAH, and symptomatic spontaneous or non‐penetrating traumatic SDH Inclusion criteria Written informed consent provided Age ≥ 45 years, at the time of signing the informed consent Previous intracranial haemorrhage (symptomatic, spontaneous and non‐traumatic ICH, IVH, and/or cSAH, and symptomatic spontaneous or non‐penetrating traumatic SDH) on or off antithrombotic therapy, and confirmed to have stabilised on neuroimaging Documented AF (paroxysmal, persistent, permanent) CHA2DS2‐VASc score ≥ 2 Exclusion criteria Recent intracranial haemorrhage (within 14 days) Secondary macrovascular, neoplastic or infectious causes of intracranial haemorrhage (except for antithrombotic treatment or non‐penetrating traumatic SDH) 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 LAAO 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 haemostasis 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 participants must be amenorrhoeic 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 randomisation or urine pregnancy testing within 24 hours of randomisation. 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)
Interventions	Intervention: edoxaban 60 mg (or 30 mg as determined by clinical criteria) Comparator: non‐anticoagulant medical therapy as determined by the local investigator includes 1) no antithrombotic therapy, 2) antiplatelet monotherapy, including de novo indication for antiplatelet monotherapy during course of the study
Outcomes	Primary outcomes Stroke (composite of ischaemic, haemorrhagic and unspecified) Major haemorrhage as defined byt the International Society on Thrombosis and Haemostasis (ISTH) criteria Secondary outcomes Ischaemic stroke (development of an acute neurologic deficit in conjunction with brain imaging consistent with acute/subacute ischaemic stroke) Cardiovascular death Haemorrhagic stroke (development of an acute neurologic deficit in conjunction with brain imaging consistent with acute/subacute ICH, IVH or SAH) Disabling/fatal stroke (disabling stroke is defined as stroke resulting in a clinical outcome that is associated with a mRS 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 (components of composite outcome (adjudicated) includes stroke (ischaemic, haemorrhagic, and undefined stroke, TIA with positive neuroimaging), myocardial infarction, systemic thromboembolism or all‐cause death) Net clinical benefit (composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area) mRS at 12 month visit All intracranial haemorrhage (ICH, IVH, SDH, SAH). Intracranial haemorrhage as defined by signs or symptoms associated with an epidural, SDH, SAH, ICH or IVH on CT or MRI scan, or as demonstrated by surgery or autopsy Fatal intracranial haemorrhage (defined as signs or symptoms associated with an epidural, SDH, SAH, ICH or IVH on CT or MRI scan, or as demonstrated by surgery or autopsy with death occurring within 30 days of stroke) SDH (defined as signs or symptoms associated with a SDH on CT or MRI scan, or as demonstrated by surgery or autopsy) Hospitalisation for any cause Duration of follow‐up: median 2 years
Starting date	20 September 2019
Contact information	Kevin Reeh ENRICH-AF@phri.ca
Notes	Declarations of interest: not specified in trials register Sources of funding: not specified in trials register