Evaluation of Dabigatran Etexilate, Apixaban, Edoxaban, and Drug Combination for Secondary Prevention in Acute Ischemic Stroke Patients Without Atrial Fibrillation

The primary objective of the MOSES-study is to demonstrate that the efficacy of **DOACs** (Direct Oral Anticoagulants) is superior to the standard of care, which involves treatment with antiplatelets until study end or until atrial fibrillation (AF) is detected, for the prevention of stroke recurrence in patients with **acute ischemic stroke** who do not have known AF upon admission. This objective is clinically relevant as it aims to improve secondary stroke prevention strategies, potentially reducing the risk of recurrent strokes in this patient population. No secondary objectives are provided in the data.

The clinical trial involves a total of **400 participants** diagnosed with **acute ischemic stroke**. The study population includes both male and female subjects, aged 18 years and older. Participants were selected based on specific criteria, including an MR-proANP level of 200 pmol/L or higher within 72 hours from symptom onset, and a clinical diagnosis of ischemic stroke. The trial does not exclude vulnerable populations, indicating a diverse participant group. The general health status of participants is characterized by the acute nature of their condition, and lifestyle factors such as diet and physical activity are not specified. The selection process ensures that all participants have provided written informed consent according to country-specific regulations.

The clinical trial is designed as an international, multicenter, randomized-controlled, two-arm, assessor-blinded study. The primary objective is to evaluate the efficacy of Direct Oral Anticoagulants (DOACs) compared to the standard of care for preventing stroke recurrence in patients with **acute ischemic stroke** and elevated mid-regional pro-atrial natriuretic peptide (MR-proANP) levels, without known atrial fibrillation at admission. The trial will span approximately five years, with an estimated recruitment start date of June 1, 2021, and an estimated end date of January 31, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as MR-proANP levels, age, and clinical diagnosis of ischemic stroke. Following randomization, participants will be assigned to receive either DOACs or standard antiplatelet therapy. The trial includes regular follow-up visits to monitor treatment adherence, collect data on any recurrent strokes, and assess for adverse events. The primary endpoint is the time to any recurrent stroke within one year after the index ischemic stroke. Secondary endpoints include a composite of major bleeding, recurrent stroke, and/or vascular death within the same timeframe.

The expected length of participant involvement is up to 13 months, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The study will utilize **dabigatran etexilate**, **apixaban**, **edoxaban**, **acetylsalicylic acid**, and **clopidogrel** as investigational products, administered orally in various formulations such as hard capsules and film-coated tablets. The trial is not categorized as low intervention, given the expansion of DOAC applications in secondary stroke prevention. Participants will be closely monitored throughout the study to ensure safety and efficacy of the treatment regimens.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. The experimental medications include Pradaxa 110 mg and 150 mg hard capsules, which contain the active substance **dabigatran etexilate**. These medications are administered orally in the form of hard capsules. The maximum daily dose for Pradaxa 110 mg is 220 mg, while for Pradaxa 150 mg, it is 300 mg. The treatment period for both formulations is up to 13 weeks. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

Another experimental medication used in the trial is Eliquis, available in 2.5 mg and 5 mg film-coated tablets, containing the active substance **apixaban**. These tablets are administered orally, with a maximum daily dose of 5 mg for the 2.5 mg formulation and 10 mg for the 5 mg formulation. The treatment duration is also set at 13 weeks. Compliance monitoring is conducted to ensure participants adhere to the prescribed dosing regimen.

Lixiana, containing the active substance **edoxaban**, is administered in the form of 30 mg and 60 mg film-coated tablets. The oral administration of Lixiana 30 mg allows for a maximum daily dose of 30 mg, while the 60 mg formulation permits a maximum daily dose of 60 mg. The treatment period is consistent with other experimental medications, lasting up to 13 weeks. Participant adherence is monitored throughout the trial.

The trial also includes non-experimental treatments, such as Aspirine 100 mg tablets, containing **acetylsalicylic acid**, and Plavix 75 mg film-coated tablets, containing **clopidogrel**. Both medications are administered orally. Aspirine has a maximum daily dose of 100 mg, while Plavix allows for a maximum daily dose of 75 mg. These treatments serve as comparator therapies, and their administration is monitored to ensure compliance over the 13-week treatment period.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the time to any recurrent stroke within one year after the index **ischemic stroke**. This will be measured to determine the effectiveness of Direct Oral Anticoagulants (DOACs) compared to the standard of care, which involves treatment with antiplatelets until the study ends or until atrial fibrillation (AF) is detected. Secondary endpoints include a composite of major bleeding, recurrent stroke, and/or vascular death, whichever occurs first, within one year after the index ischemic stroke. The individual components of this composite outcome will also be analyzed.

The trial will involve the collection and analysis of data related to these endpoints over a specified period. The study is designed as an international, multicenter, randomized-controlled, two-arm, assessor-blinded trial. The efficacy parameters will be collected at various time points throughout the study, with the final analysis occurring at the end of the one-year follow-up period. The trial aims to demonstrate the superiority of DOACs over the standard of care in preventing stroke recurrence in patients with elevated midregional proatrial natriuretic peptide (MR-proANP) levels, who have experienced an acute ischemic stroke without known AF on admission.