Status:
Enrolling

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

Phase
III
Age
≥18
Sponsor
University Hospital, Brest
Enrollment code
1308
Last Updated
Mar 25, 2025
Locations
42 Countries

Overview

Condition/disease
Myeloproliferative Neoplasms
Modalities
[Not available]
Trial drugs
Clinicaltrials.gov ID

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.

Trial locations

Found 42 sites

CH de Morlaix

FR - Morlaix
Christophe NICOL, PH

CHU Bordeaux

FR - Bordeaux
Clémence MEDIAVILLA, PH

Médipôle Hôpital Mutualiste Villeurbanne

FR - Villeurbanne
Mathias BREHON, PH

CHIC de Quimper

FR - Quimper
Lénaïg LE CLECH, PH

CH Le Mans

FR - Le Mans
Kamel LARIBI, PH

CHU de Montpellier

FR - Montpellier
Franciane PAUL, PH

CH de Roubaix

FR - Roubaix

Hôpital privé Cesson-Sévigné

FR - Cesson-Sévigné
Benoît BAREAU, PH

Centre Léon Bérard Lyon

FR - Lyon
Franck-Emmanuel NICOLINI, PH

CHU Grenoble Alpes

FR - Grenoble
Mathieu MEUNIER, PH

Hôpital Cochin (APHP)

FR - Paris
Michaela FONTENAY, PH

CH de Béziers

FR - Béziers
Alain Radwan SAAD, PH

CHU d'Angers

FR - Angers

CHU Brest

FR - Brest
Jean-Christophe Ianotto, PUPH

CH de Versailles

FR - Versailles
Juliette LAMBERT, PH

CH d'Argenteuil

FR - Argenteuil

CHU de Rennes

FR - Rennes

CHD Vendée La Roche Sur Yon

FR - La Roche-sur-Yon
Bruno VILLEMAGNE, PH

CHU de Nancy

FR - Nancy
Dana RANTA, PH

CH Bretagne Atlantique Vannes

FR - Vannes

CH de Perpignan

FR - Perpignan

CH de Rochefort

FR - Rochefort

CH d'Avignon

FR - Avignon
Borhane SLAMA, PH

CHU de Clermont-Ferrand

FR - Clermont-Ferrand
Benoît DE RENZIS, PH

CHU de Tours

FR - Tours
Antoine MACHET, PH

Centre Henri Becquerel de Rouen

FR - Rouen

Hôpital Henri Mondor (APHP)

FR - Créteil
Lydia ROY, PH

CHR d'Orléans

FR - Orléans
Marlène OCHMANN, PH

CH de Périgueux

FR - Périgueux

CH Paul-Brousse (APHP)

FR - Villejuif
Laurence LE GROS, PH

CH de la Côte Basque Bayonne

FR - Bayonne
Frédéric BAUDUER, PH

CHU de Limoges - Hôpital Dupuytren

FR - Limoges
Amélie PENOT, PH

CH d'Annecy

FR - Annecy

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

FR - Saint-Priest-en-Jarez
Emilie CHALAYER, PH

Hôpital St-Louis (APHP)

FR - Paris
Jean-Jacques KILADJIAN, PUPH

CHU de Nantes - Hôtel-Dieu

FR - Nantes
Viviane DUBRUILLE, PH

Hôpital Privé du Confluent Nantes

FR - Nantes

CHU La Réunion - Site Sud

FR - Saint-Pierre
Raphaëlle DINE, PH

CHU Le Havre

FR - Le Havre
Pierre LEBRETON, PH

CH Libourne

FR - Libourne

Clinique Sainte Anne Strasbourg

FR - Strasbourg
Anaïse BLOUET, PH

CHU La Réunion - Site Nord Félix GUYON

FR - Saint-Denis
Stéphane VANDERBECKEN, PH

Eligibility criteria

Inclusion criteria:

  • 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:

    1. based on age (> 60-year-old)
    2. based on thrombotic history (compatible with antithrombotic randomization) but aged ≥ 18-year-old.
  • Length of time from MPN diagnostic to inclusion will not exceed 12 months.

Exclusion criteria:

  • 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.

Study plan

Experimental: Experimental group

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

Active Comparator: Control group

Patients randomized to receive Low-Dose Aspirin Aspirin 100 mg one per day
Drug
Low-dose aspirin
Patients allocated to receive LDA: Aspirin 100 mg OD once daily.
Allocation: Randomized

Outcome measures

Primary outcome measures

  • Time to occurrence of arterial or venous thromboembolic events. (Time to occurrence up to 24 months of patient follow-up)

Secondary outcome measures

  • 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)

More information

Official title

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

Estimated trial completion date

Jul 13, 2027
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