Comparison of Apixaban, Rivaroxaban, and Acetylsalicylic Acid for Thromboembolic Prevention in JAK2V617F-Positive Myeloproliferative Neoplasms

The primary objective of this study is to demonstrate that low-dose **DOAC** (Direct Oral Anticoagulant) is more effective than low-dose aspirin (LDA) in the primary prevention of arterial or venous thrombosis in patients with JAK2V617F-positive high-risk myeloproliferative neoplasms (MPN). This is clinically relevant as it aims to improve the management of thrombo-embolic complications in this patient population, potentially reducing morbidity and mortality associated with these conditions.

Secondary objectives include:

• Comparing the risk of antithrombotic-related bleeding between patients receiving low-dose DOAC and those receiving LDA.
• Assessing the efficacy of low-dose DOAC versus LDA in preventing arterial and venous thrombosis.
• Evaluating the efficacy and toxicity of low-dose DOAC versus LDA in relation to MPN subtypes and cytoreductive associated drugs.
• Evaluating the risk of other adverse events and the benefit of prevention by low-dose DOAC versus LDA in terms of overall survival and event-free survival.
• Assessing non-cardiovascular and cardiovascular deaths, treatment compliance, incidence of atrial fibrillation, and quality of life in patients treated with low-dose DOAC versus LDA.
• Providing an economic evaluation of the use of low-dose DOACs for thrombosis prevention.

The clinical trial involves participants diagnosed with **Philadelphia-negative myeloproliferative neoplasms**, specifically Polycythemia Vera, Essential Thrombocythemia, or Prefibrotic myelofibrosis, as per WHO or BSCH criteria. The study population includes both male and female subjects, aged 18 years and older, with a focus on those over 60 years old or with a thrombotic history, categorized as high-risk due to the presence of the JAK2V617F mutation with an allele burden greater than 1%. Participants must have been diagnosed with the condition within the last 12 months. The trial does not include vulnerable populations, and the sponsor has not provided the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of low-dose direct oral anticoagulants (DOACs) compared to low-dose aspirin (LDA) in the primary prevention of arterial or venous thrombosis in patients with JAK2V617F-positive high-risk Philadelphia-negative **myeloproliferative neoplasms**. This study is a randomized, double-blind, controlled trial, conducted over an estimated duration of 72 months, with participant involvement expected to last up to 24 months. The trial will include a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as a diagnosis of Polycythemia Vera, Essential Thrombocythemia, or Prefibrotic myelofibrosis, and the presence of the JAK2V617F mutation with a threshold allele burden greater than 1%. Participants must be considered high-risk due to age or thrombotic history and must be within 12 months of their MPN diagnosis.

Following the screening visit, participants will be randomized to receive either DOACs or LDA, administered orally in the form of film-coated or gastro-resistant tablets. The trial will include regular follow-up visits to monitor the occurrence of primary endpoints, such as arterial or venous thromboembolic events, and secondary endpoints, including major bleeding events, overall survival, and quality of life assessments. The end-of-study visit will conclude the participant's involvement, with data collected on therapeutic adherence and any adverse events experienced during the trial period. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial aims to provide comprehensive data on the comparative effectiveness and safety of DOACs versus LDA in this patient population.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. The first experimental medication is **Xarelto** 10 mg, a film-coated tablet containing the active substance **rivaroxaban**. This medication is administered orally with a maximum daily dose of 10 mg and a total maximum dose of 18,250 mg over a treatment period of 72 weeks. The pharmaceutical form is a film-coated tablet, and the medication is produced by Bayer AG. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

Another experimental medication used in the trial is **Eliquis** 2.5 mg, a film-coated tablet containing the active substance **apixaban**. This medication is also administered orally, with a maximum daily dose of 5 mg and a total maximum dose of 10,000 mg over the same treatment period of 72 weeks. The pharmaceutical form is a film-coated tablet, and it is manufactured by Bristol-Myers Squibb/Pfizer EEIG. Compliance monitoring is conducted to ensure participants adhere to the prescribed dosing regimen.

The trial includes several comparator treatments, primarily involving **acetylsalicylic acid** in various formulations. **Aspirine Protect** 100 mg is a gastro-resistant tablet containing acetylsalicylic acid, administered orally with a maximum daily dose of 300 mg and a total maximum dose of 21,600 mg over 72 weeks. This product is manufactured by Bayer Healthcare. Similarly, **Aspirine Arrow** 100 mg, **Resitune** 100 mg, and **Acide Acetylsalicylique Viatris** 100 mg are all gastro-resistant tablets containing acetylsalicylic acid, each with a maximum daily dose of 100 mg and a total maximum dose of 182,500 mg over the treatment period. These products are manufactured by Arrow Generiques, Pfizer Holding France, and Viatris Sante, respectively. The administration route for all these comparator treatments is oral, and compliance is monitored to ensure proper adherence to the dosing schedule.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the time to occurrence of arterial or venous thromboembolic events. Secondary endpoints include the time to occurrence of major and clinically relevant non-major bleedings as defined by the International Society on Thrombosis and Haemostasis (ISTH), time to occurrence of arterial and venous thromboembolic events, and time to occurrence of thromboembolic and bleeding events according to Polycythemia Vera (PV), Essential Thrombocythemia (ET), or Prefibrotic Myelofibrosis (PreMF) status. Additional secondary endpoints involve the time to occurrence of thromboembolic and bleeding events according to the cytoreductive associated drugs, time to occurrence of serious adverse events other than thromboses and hemorrhages, occurrence of atrial fibrillation episodes, overall survival and event-free survival at 24 months, and adjudicated mortality (non-cardiovascular and cardiovascular).

Therapeutic adherence will be evaluated using the Girerd auto-questionnaire during the study treatment period of 24 months. Quality of life assessments will be conducted using the EQ-5D-5L and MPN-SAF-TSS auto-questionnaires over the same period. Additionally, the evaluation of costs and incremental cost utility ratio (cost per Quality-Adjusted Life Year, QALY) of low-dose Direct Oral Anticoagulants (DOAC) compared to Low-Dose Aspirin (LDA) will be performed. The trial is designed to demonstrate that low-dose DOAC is more effective than LDA in the primary prevention of arterial or venous thrombosis in patients with JAK2V617F-positive high-risk myeloproliferative neoplasms (MPN).