Reduction in the risk of stroke in people who have both a previous intracranial bleed and atrial fibrillation

• Register: EUCTR
• Last refreshed on: 6 November 2023
• Main ID: EUCTR2019-002075-33-DE
• Date of registration: 18/09/2019
• Prospective Registration: Yes
• Primary sponsor: Hamilton Health Sciences, through its Population Health Research Institute
• Public title: Reduction in the risk of stroke in people who have both a previous intracranial bleed and atrial fibrillation
• Scientific title: Edoxaban for intracranial hemorrhage survivors with atrial fibrillation - ENRICH-AF: EdoxabaN foR IntraCranial Hemorrhage survivors with Atrial Fibrillation
• Date of first enrolment: 06/10/2020
• Target sample size: 1200
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-002075-33
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Argentina, Austria, Belgium, Canada, China, Czech Republic, Czechia, Denmark, Egypt, Germany, Greece, India, Italy, Nepal, Norway, Portugal, Slovakia, Spain, Sri Lanka, Switzerland, United Kingdom, United States

Contacts

• Name: ENRICH-AF Research Coordinator
• Affiliation: Hamilton Health Sciences, through its Population Health Research Institute

• Name: ENRICH-AF Research Coordinator
• Affiliation: Hamilton Health Sciences, through its Population Health Research Institute

Key inclusion & exclusion 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 (Table 2)
4. Documented atrial fibrillation (paroxysmal, persistent, permanent)
5. CHA2DS2-VASc score =2
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 240
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 960

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 or other creatinine clearance following local product monograph (Canada < 30mL/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. Acute SARS-Co-V2 infection
21. Assgined to special institution by governmental or court order
22. 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).



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

High risk atrial fibrillation patients with previous intracranial hemorrhage
MedDRA version: 21.1 Level: PT Classification code 10018985 Term: Haemorrhage intracranial System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 20.0 Level: PT Classification code 10003658 Term: Atrial fibrillation System Organ Class: 10007541 - Cardiac disorders

Intervention(s)

Trade Name: Lixiana
Product Name: Edoxaban
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Edoxaban
CAS Number: 480449-71-6
Other descriptive name: EDOXABAN TOSYLATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-

Trade Name: Lixiana
Product Name: Edoxaban
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Edoxaban
CAS Number: 480449-71-6
Other descriptive name: EDOXABAN TOSYLATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 30-

Primary Outcome(s)

Main Objective: To determine whether edoxaban (60/30 mg daily) compared to non-anticoagulant 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 score =2) patients with previous intracranial hemorrhage.

Primary end point(s): The primary efficacy end point is stroke (composite of ischemic, hemorrhagic and unspecified).

The primary safety endpoint is major hemorrhage as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria

Secondary Objective: i) To assess whether edoxaban (60/30 mg daily) compared to non-anticoagulant medical therapy (either no antithrombotic therapy or antiplatelet monotherapy) reduces the risk of cardiovascular death in high-risk atrial fibrillation participants with previous intracranial hemorrhage.

ii) To assess whether edoxaban (60/30 mg daily) is associated with increased risk of major hemorrhage compared to standard of care (either no antithrombotic therapy or antiplatelet monotherapy).

Timepoint(s) of evaluation of this end point: Participants will be followed every 6 months until the common study end date. This trial is event driven to accrue 123 primary events, anticipated one year after the end of the recruitment. Follow up is anticipated to be an average of 24 months per participant (range 1 to 3 years).

Secondary Outcome(s)

Secondary end point(s): The secondary efficacy end points are:
1. Ischemic stroke
2. Cardiovascular death
3. Hemorrhagic stroke
4. Disabling/fatal stroke
5. Composite of all stroke, myocardial infarction, systemic thromboembolism or all-cause death
6. Net clinical benefit (composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area)
7. Modified Rankin scale (mRS) at 12 months

The secondary safety end point(s) are:
1. All intracranial hemorrhage (intracerebral hemorrhage, intraventricular hemorrhage, subdural hematoma, subarachnoid hemorrhage)
2. Fatal intracranial hemorrhage
3. Subdural hemorrhage
4. Hospitalization for any cause

Timepoint(s) of evaluation of this end point: Timepoints of evaluation will be every 6 months until the common study end date. Follow up is anticipated to be an average of 24 months per participant (range 1 to 3 years).

Secondary ID(s)

ENRICH-AF

2019-002075-33-GB

NCT03950076

Source(s) of Monetary Support

Daiichi Sankyo

Ethics review

Status: Approved
Approval date: 06/10/2020
Contact: