AVAJAK: Apixaban/Rivaroxaban Versus Aspirin for Primary Prevention of Thrombo-embolic Complications in JAK2V617F-positive Myeloproliferative Neoplasms

NCT05198960 | Recruiting Phase 3 DMC

• 1 other identifier: 29BRC20.0263 (AVAJAK)
• Study Type: interventional
• Target: 1,308
• Locations: 1 country
• Sites: 42

Brief Summary

Philadelphia-negative myeloproliferative neoplasms (MPN) are frequent and chronic myeloid malignancies including Polycythemia Vera (PV), essential thrombocythemia (ET), Primary Myelofibrosis (PMF) and Prefibrotic myelofibrosis (PreMF). These MPNs are caused by the acquisition of mutations affecting activation/proliferation pathways in hematopoietic stem cells. The principal mutations are JAK2V617F, calreticulin (CALR exon 9) and MPL W515. ET or MFP/PreMF patients who do not carry one of these three mutations are declared as triple-negative (3NEG) cases even if they are real MPN cases. These diseases are at high risk of thrombo-embolic complications and with high morbidity/mortality. This risk varies from 4 to 30% depending on MPN subtype and mutational status. In terms of therapy, all patients with MPNs should also take daily low-dose aspirin (LDA) as first antithrombotic drug, which is particularly efficient to reduce arterial but not venous events. Despite the association of a cytoreductive drug and LDA, thromboses still occur in 5-8% patients/year. All these situations have been explored in biological or clinical assays. All of them could increase the bleeding risk. We should look at different ways to reduce the thrombotic incidence: Direct Oral Anticoagulants (DOAC)? In the general population, in medical or surgical contexts, DOACs have demonstrated their efficiency to prevent or cure most of the venous or arterial thrombotic events. At the present time, DOAC can be used in cancer populations according to International Society on Thrombosis and Haemostasis (ISTH) recommendations, except in patients with cancer at high bleeding risk (gastro-intestinal or genito-urinary cancers). Unfortunately, in trials evaluating DOAC in cancer patients, most patients have solid rather than hematologic cancers (generally less than 10% of the patients, mostly lymphoma or myeloma). In cancer patients, DOAC are also highly efficient to reduce the incidence of thrombosis (-30 to 60%), but patients are exposed to a higher hemorrhagic risk, especially in digestive cancer patients. In the cancer population, pathophysiology of both thrombotic and hemorrhagic events may be quite different between solid cancers and MPN. If MPN patients are also considered to be cancer patients in many countries, the pathophysiology of thrombosis is quite specific (hyperviscosity, platelet abnormalities, clonality, specific cytokines…) and they are exposed to a lower risk of digestive hemorrhages. It is thus difficult to extend findings from the "general cancer population" to MPN patients. Unfortunately, only scarce, retrospective data regarding the use of DOAC in MPNs are available data. We were the first to publish a "real-life" study about the use, the impact, and the risks in this population. In this local retrospective study, 25 patients with MPN were treated with DOAC for a median time of 2.1 years. We observed only one thrombosis (4%) and three major hemorrhages (12%, after trauma or unprepared surgery). Furthermore, we have compared the benefit/risk balance compared to patients treated with LDA without difference. With the increasing evidences of efficacy and tolerance of DOAC in large cohorts of patients including cancer patients, with their proven efficacy on prevention of both arterial and venous thrombotic events and because of the absence of prospective trial using these drugs in MPN patients, we propose to study their potential benefit as primary thrombotic prevention in MPN.

Conditions

Essential Thrombocythemia; Prefibrotic/Early Primary Myelofibrosis; High-risk Patients; JAK2 V617F; Polycythemia Vera

Keywords

Venous ThromboEmbolism; Arterial Thrombosis; Hemorrhage

Outcome Measures

Primary Outcomes (1)

• Time to occurrence of arterial or venous thromboembolic events.

  Nb and type of thrombotic events during the FU

  Time to occurrence up to 24 months of patient follow-up

Secondary Outcomes (11)

• Time to occurrence of major and clinically relevant non-major bleedings as defined by International Society on Thrombosis and Haemostasis

  Time to occurrence up to 24 months of patient follow-up

• Time to occurrence of arterial thromboembolic events.

  Time to occurrence up to 24 months of patient follow-up

• Time to occurrence of venous thromboembolic

  Time to occurrence up to 24 months of patient follow-up

• Time to occurrence of thromboembolic and bleeding events according to the cytoreductive associated drugs

  Time to occurrence up to 24 months of patient follow-up

• Time to occurrence of serious adverse events others than thromboses and hemorrhages hemorrhages

  Time to occurrence up to 24 months of patient follow-up

Study Arms (2)

Experimental group

EXPERIMENTAL

Patients randomized to receive Direct Oral Anticoagulants, at the choice of the investigator Apixaban 2.5 mg both in day or Rivaroxaban 10 mg one per day, at the choice of the investigator

Drug: Direct Oral Anticoagulants

Control group

ACTIVE COMPARATOR

Patients randomized to receive Low-Dose Aspirin Aspirin 100 mg one per day

Drug: Low-dose aspirin

Interventions

Direct Oral Anticoagulants DRUG

Patients randomized to receive DOAC, at the choice of the investigator: Apixaban 2.5 mg both in day or Rivaroxaban 10 mg once daily.

Experimental group

Low-dose aspirin DRUG

Patients allocated to receive LDA: Aspirin 100 mg OD once daily.

Control group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with diagnosis of PV or ET or PreMF according to WHO or BSCH criteria (bone marrow biopsy not compulsory).
• Patients with JAK2V617F mutation (threshold allele burden \> 1%).
• Patients considered as "high-risk" patients:
• based on age (\> 60-year-old)
• based on thrombotic history (compatible with antithrombotic randomization) but aged ≥ 18-year-old.

You may not qualify if:

• Contra-indication to aspirin or DOAC due to allergic situation or recent history of major bleeding.
• Formal indication of treatment with aspirin or DOAC (thus precluding randomization).
• Inability to give informed consent.
• Patients under curatorship/guardianship
• Concomitant use of a strong inhibitor or inducer of CYP3A4 (like ruxolitinib).
• Chronic liver disease or chronic hepatitis.
• Renal insufficiency with creatinine \<30 ml/mn on Cockcroft and Gault Formula
• Patient considered at high-risk of bleeding: patients with current or recent major or clinical relevant non major bleeding gastrointestinal or cerebral bleedings
• Planned pregnancy within 24 months
• No appropriate contraception (estrogen contraception or no contraception) in women of childbearing age or breastfeeding woman
• PS\>2 or life expectancy \<12 months.

Sponsors & Collaborators

• University Hospital, Brest: lead

Study Sites (42)

CHU d'Angers

Angers, 49933, France

RECRUITING

CH d'Annecy

Annecy, 74374, France

NOT YET RECRUITING

CH d'Argenteuil

Argenteuil, 95100, France

NOT YET RECRUITING

CH d'Avignon

Avignon, 84000, France

RECRUITING

CH de la Côte Basque Bayonne

Bayonne, 64100, France

NOT YET RECRUITING

CH de Béziers

Béziers, 34500, France

NOT YET RECRUITING

CHU Bordeaux

Bordeaux, 33604, France

RECRUITING

CHU Brest

Brest, 29609, France

RECRUITING

Hôpital privé Cesson-Sévigné

Cesson-Sévigné, 35510, France

NOT YET RECRUITING

CHU de Clermont-Ferrand

Clermont-Ferrand, 63003, France

NOT YET RECRUITING

Hôpital Henri Mondor (APHP)

Créteil, 94010, France

RECRUITING

CHU Grenoble Alpes

Grenoble, 38043, France

RECRUITING

CHD Vendée La Roche Sur Yon

La Roche-sur-Yon, 85925, France

RECRUITING

CHU Le Havre

Le Havre, 76083, France

NOT YET RECRUITING

CH Le Mans

Le Mans, 72000, France

NOT YET RECRUITING

CH Libourne

Libourne, 33500, France

NOT YET RECRUITING

CHU de Limoges - Hôpital Dupuytren

Limoges, France

RECRUITING

Centre Léon Bérard Lyon

Lyon, 69000, France

NOT YET RECRUITING

CHU de Montpellier

Montpellier, 34295, France

NOT YET RECRUITING

CH de Morlaix

Morlaix, 29600, France

RECRUITING

CHU de Nancy

Nancy, 54511, France

RECRUITING

CHU de Nantes - Hôtel-Dieu

Nantes, 44093, France

NOT YET RECRUITING

Hôpital Privé du Confluent Nantes

Nantes, 44202, France

NOT YET RECRUITING

CHR d'Orléans

Orléans, 45100, France

RECRUITING

Hôpital St-Louis (APHP)

Paris, 75010, France

RECRUITING

Hôpital Cochin (APHP)

Paris, 75679, France

NOT YET RECRUITING

CH de Perpignan

Perpignan, 66000, France

NOT YET RECRUITING

CH de Périgueux

Périgueux, 24019, France

RECRUITING

CHIC de Quimper

Quimper, 29107, France

RECRUITING

CHU de Rennes

Rennes, 35033, France

NOT YET RECRUITING

CH de Rochefort

Rochefort, 17300, France

NOT YET RECRUITING

CH de Roubaix

Roubaix, 59100, France

RECRUITING

Centre Henri Becquerel de Rouen

Rouen, 76038, France

RECRUITING

CHU La Réunion - Site Nord Félix GUYON

Saint-Denis, 97405, France

NOT YET RECRUITING

CHU La Réunion - Site Sud

Saint-Pierre, 97410, France

NOT YET RECRUITING

Institut de Cancérologie Lucien Neuwirth St-Priest-en-Jarez

Saint-Priest-en-Jarez, 42271, France

RECRUITING

Clinique Sainte Anne Strasbourg

Strasbourg, 92210, France

NOT YET RECRUITING

CHU de Tours

Tours, 37044, France

RECRUITING

CH Bretagne Atlantique Vannes

Vannes, 56017, France

RECRUITING

CH de Versailles

Versailles, 78150, France

NOT YET RECRUITING

CH Paul-Brousse (APHP)

Villejuif, 94800, France

NOT YET RECRUITING

Médipôle Hôpital Mutualiste Villeurbanne

Villeurbanne, 69616, France

RECRUITING

MeSH Terms

Conditions

Polycythemia Vera; Thrombocythemia, Essential; Primary Myelofibrosis; Venous Thromboembolism; Hemorrhage

Interventions

N(4)-oleylcytosine arabinoside; Aspirin

Condition Hierarchy (Ancestors)

Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Myeloproliferative Disorders; Blood Coagulation Disorders; Thrombocytosis; Blood Platelet Disorders; Hemorrhagic Disorders; Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Central Study Contacts

Jean-Christophe IANOTTO, Pr

CONTACT

+33298223421; jean-christophe.ianotto@chu-brest.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: AVAJAK is an academic multicenter phase 3 prospective, randomized, and open label trial. \> Randomization of the patients: Patients corresponding to inclusion criteria will be randomized based on a 1:1 distribution. * Experimental group (Patients allocated to receive low-dose DOAC, at the choice of the investigator) * Apixaban 2.5 mg BID or * Rivaroxaban 10 mg OD, at the choice of the investigator. * Control group (Patients allocated to receive LDA) \- Aspirin 100 mg OD Dispensation of treatments every 6 months for 24 months * Stratification: * First stratification will be done by center * Second stratification will be done by pathology (PV/ET/ PreMF) * No stratification will be made based on DOAC drugs.

Study Record Dates

• First Submitted: November 9, 2021
• First Posted: January 20, 2022
• Study Start: July 13, 2022
• Primary Completion (Estimated): July 13, 2027
• Study Completion (Estimated): July 13, 2027
• Last Updated: March 20, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Data will be available beginning five years and ending fifteen years following the final study report completion.
• Access Criteria: Data access requests will be reviewed by the internal committee of Brest UH. Requestors will be required to sign and complete a data access agreement.

Locations

FR (42)