Evaluation of Edoxaban Versus Nonanticoagulant Therapy in High-Risk Atrial Fibrillation Patients with Prior Intracranial Hemorrhage

The primary objective of this study is to evaluate whether **edoxaban** (60/30 mg daily) compared to non-anticoagulant medical therapy (either no antithrombotic therapy or antiplatelet monotherapy) reduces the composite risk of stroke (ischemic, hemorrhagic, and unspecified stroke) or systemic embolism in high-risk atrial fibrillation participants with previous intracranial hemorrhage. This is clinically relevant as it addresses the management of stroke risk in a vulnerable population with a history of intracranial bleeding, where balancing the benefits of anticoagulation against the risk of further hemorrhage is critical.

Secondary objectives include: - To assess whether edoxaban (60/30 mg daily) compared to non-anticoagulant medical therapy reduces the risk of cardiovascular death in high-risk atrial fibrillation participants with previous intracranial hemorrhage. - To evaluate whether edoxaban (60/30 mg daily) is associated with an increased risk of major hemorrhage compared to standard of care (either no antithrombotic therapy or antiplatelet monotherapy).

The clinical trial involves a total of **570 participants** who are high-risk patients with **atrial fibrillation** and have a history of previous intracranial hemorrhage. The study population includes both male and female subjects, aged 45 years and older, with a CHA2DS2-VASc score of 2 or higher. Participants were selected based on their documented history of atrial fibrillation, which could be paroxysmal, persistent, or permanent, and their previous experience of symptomatic, spontaneous, and non-traumatic non-lobar intraparenchymal or intraventricular hemorrhage, or symptomatic spontaneous or non-penetrating traumatic subdural hemorrhages. The trial population is considered vulnerable, and the selection process ensured that all participants provided written informed consent. The study does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status or specific lifestyle habits of the participants.

The clinical trial is designed to evaluate the efficacy and safety of **edoxaban** in high-risk patients with **atrial fibrillation** who have previously experienced an intracranial hemorrhage. This study employs a prospective, randomized, open-label, blinded end-point (PROBE) design, which is a standard approach for phase III-IV trials. The trial aims to compare the effects of edoxaban (60 mg or 30 mg daily) against non-anticoagulant medical therapy, which may include no antithrombotic therapy or antiplatelet monotherapy. The primary objective is to assess whether edoxaban reduces the composite risk of stroke (ischemic, hemorrhagic, and unspecified) or systemic embolism in the target population. The trial is expected to run from September 24, 2020, to April 30, 2026, with a maximum treatment period of 84 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥45 years), documented atrial fibrillation, and a CHA2DS2-VASc score of ≥2. Following the screening, eligible participants will be randomized to receive either edoxaban or the comparator therapy. Follow-up visits will be scheduled to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will conclude the trial for each participant, during which final assessments will be conducted to evaluate the primary and secondary endpoints, including the incidence of major hemorrhage as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria.

Participant involvement is expected to last for the duration of the treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial's primary efficacy endpoint is the composite risk of stroke or systemic embolism, while secondary endpoints include ischemic stroke, cardiovascular death, and net clinical benefit, among others. The trial will also assess safety endpoints such as all intracranial hemorrhage and hospitalization for any cause.

The clinical trial involves the administration of **Lixiana 60 mg film-coated tablets**, which contain the active substance **edoxaban**. The pharmaceutical form is a film-coated tablet, and the medication is administered orally. The maximum daily dose is 60 mg, with a total treatment period of up to 84 days. The commercial supply of the product will be overlabelled or relabelled for the purpose of this trial, which is the only modification to the product. The active substance, edoxaban, is of chemical origin and is classified under the ATC code B01AF03. The product is manufactured by Daiichi Sankyo Europe GmbH and holds the marketing authorization number EU/1/15/993/024.

Additionally, the trial includes the use of **Lixiana 30 mg film-coated tablets**, also containing the active substance **edoxaban**. This medication is similarly administered in the form of film-coated tablets for oral use. The maximum daily dose for this formulation is 30 mg, with the same treatment duration of up to 84 days. As with the 60 mg tablets, the commercial supply will be overlabelled or relabelled for trial purposes. The product is also manufactured by Daiichi Sankyo Europe GmbH and is authorized under the marketing authorization number EU/1/15/993/011.

In this study, the experimental medications are compared to non-experimental treatments, which include non-anticoagulant medical therapy options such as no antithrombotic therapy or antiplatelet monotherapy. The trial aims to evaluate the efficacy of edoxaban in reducing the composite risk of stroke or systemic embolism in high-risk atrial fibrillation participants with a history of intracranial hemorrhage. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of the clinical trial titled "EdoxabaN foR IntraCranial Hemorrhage survivors with Atrial Fibrillation" will be assessed using a primary efficacy endpoint that focuses on the composite risk of stroke, including ischemic, hemorrhagic, and unspecified stroke, or systemic embolism. This trial aims to evaluate whether **edoxaban** (60/30 mg daily) is more effective than non-anticoagulant medical therapy in reducing these risks in high-risk atrial fibrillation participants with a history of intracranial hemorrhage.

Secondary efficacy endpoints include the occurrence of ischemic stroke, cardiovascular death, hemorrhagic stroke, disabling or fatal stroke, systemic embolism, and a composite of all stroke, myocardial infarction, systemic embolism, or all-cause death. Additionally, the net clinical benefit, which is a composite of stroke, systemic embolism, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area, will be evaluated. The Modified Rankin Scale (mRS) at 12 months will also be used to assess functional outcomes.

The trial employs a standard prospective, randomized, open-label, blinded end-point (PROBE) design. The efficacy parameters will be measured and collected at specified time points throughout the trial, with the primary and secondary endpoints being analyzed to determine the overall efficacy of the treatment. The trial is expected to conclude by April 2026, with data collection and analysis continuing until the end of the study period.