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

October 27, 2023 updated by: University Hospital, Brest

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

1308

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • France
      • Angers, France, 49933
        • Recruiting
        • CHU d'Angers
        • Contact:
        • Principal Investigator:
          • Corentin ORVAIN, PH
      • Annecy, France, 74374
        • Not yet recruiting
        • CH d'Annecy
        • Contact:
        • Principal Investigator:
          • Anne PARRY, PH
      • Argenteuil, France, 95100
      • Avignon, France, 84000
        • Recruiting
        • CH d'Avignon
        • Contact:
        • Principal Investigator:
          • Borhane SLAMA, PH
      • Bayonne, France, 64100
        • Not yet recruiting
        • CH de la Côte Basque Bayonne
        • Contact:
        • Principal Investigator:
          • Frédéric BAUDUER, PH
      • Bordeaux, France, 33604
      • Brest, France, 29609
      • Béziers, France, 34500
        • Not yet recruiting
        • CH de Béziers
        • Contact:
        • Principal Investigator:
          • Alain Radwan SAAD, PH
      • Cesson-Sévigné, France, 35510
        • Not yet recruiting
        • Hôpital privé Cesson-Sévigné
        • Contact:
        • Principal Investigator:
          • Benoît BAREAU, PH
      • Clermont-Ferrand, France, 63003
        • Not yet recruiting
        • CHU de Clermont-Ferrand
        • Contact:
        • Principal Investigator:
          • Benoît DE RENZIS, PH
      • Créteil, France, 94010
        • Recruiting
        • Hôpital Henri Mondor (APHP)
        • Contact:
        • Principal Investigator:
          • Lydia ROY, PH
      • Grenoble, France, 38043
        • Recruiting
        • CHU Grenoble Alpes
        • Contact:
        • Principal Investigator:
          • Mathieu MEUNIER, PH
      • La Roche-sur-Yon, France, 85925
        • Recruiting
        • Chd Vendee La Roche Sur Yon
        • Contact:
        • Principal Investigator:
          • Bruno VILLEMAGNE, PH
      • Le Havre, France, 76083
        • Not yet recruiting
        • CHU Le Havre
        • Contact:
        • Principal Investigator:
          • Pierre LEBRETON, PH
      • Le Mans, France, 72000
        • Not yet recruiting
        • CH Le Mans
        • Contact:
        • Principal Investigator:
          • Kamel LARIBI, PH
      • Libourne, France, 33500
        • Not yet recruiting
        • Ch Libourne
        • Contact:
        • Principal Investigator:
          • Diane LARA, PH
      • Limoges, France
        • Recruiting
        • CHU de Limoges - Hôpital Dupuytren
        • Contact:
        • Principal Investigator:
          • Amélie PENOT, PH
      • Lyon, France, 69000
      • Montpellier, France, 34295
        • Not yet recruiting
        • CHU de Montpellier
        • Contact:
        • Principal Investigator:
          • Franciane PAUL, PH
      • Morlaix, France, 29600
        • Recruiting
        • CH de Morlaix
        • Contact:
        • Principal Investigator:
          • Christophe NICOL, PH
      • Nancy, France, 54511
        • Recruiting
        • Chu de Nancy
        • Contact:
        • Principal Investigator:
          • Dana RANTA, PH
      • Nantes, France, 44093
        • Not yet recruiting
        • CHU de Nantes - Hôtel-Dieu
        • Contact:
        • Principal Investigator:
          • Viviane DUBRUILLE, PH
      • Nantes, France, 44202
        • Not yet recruiting
        • Hôpital Privé du Confluent Nantes
        • Contact:
        • Principal Investigator:
          • Katell LE DU, PH
      • Orléans, France, 45100
      • Paris, France, 75679
        • Not yet recruiting
        • Hôpital Cochin (APHP)
        • Contact:
        • Principal Investigator:
          • Michaela FONTENAY, PH
      • Paris, France, 75010
        • Recruiting
        • Hôpital St-Louis (APHP)
        • Contact:
        • Principal Investigator:
          • Jean-Jacques KILADJIAN, PUPH
      • Perpignan, France, 66000
      • Périgueux, France, 24019
      • Quimper, France, 29107
        • Recruiting
        • CHIC de Quimper
        • Contact:
        • Principal Investigator:
          • Lénaïg LE CLECH, PH
      • Rennes, France, 35033
        • Not yet recruiting
        • CHU de Rennes
        • Contact:
        • Principal Investigator:
          • Marc BERNARD, PH
      • Rochefort, France, 17300
      • Roubaix, France, 59100
      • Rouen, France, 76038
      • Saint-Denis, France, 97405
        • Not yet recruiting
        • CHU La Réunion - Site Nord Félix GUYON
        • Principal Investigator:
          • Stéphane VANDERBECKEN
        • Contact:
      • Saint-Pierre, France, 97410
        • Not yet recruiting
        • CHU La Réunion - Site Sud
        • Contact:
        • Principal Investigator:
          • Raphaëlle DINE, PH
      • Saint-Priest-en-Jarez, France, 42271
        • Recruiting
        • Institut de Cancérologie Lucien Neuwirth St-Priest-en-Jarez
        • Contact:
        • Principal Investigator:
          • Emilie CHALAYER, PH
      • Strasbourg, France, 92210
        • Not yet recruiting
        • Clinique Sainte Anne Strasbourg
        • Contact:
        • Principal Investigator:
          • Anaïse BLOUET, PH
      • Tours, France, 37044
        • Recruiting
        • CHU de Tours
        • Contact:
        • Principal Investigator:
          • Antoine MACHET, PH
      • Vannes, France, 56017
      • Versailles, France, 78150
        • Not yet recruiting
        • CH de Versailles
        • Contact:
        • Principal Investigator:
          • Juliette LAMBERT, PH
      • Villejuif, France, 94800
        • Not yet recruiting
        • CH Paul-Brousse (APHP)
        • Contact:
        • Principal Investigator:
          • Laurence LE GROS, PH
      • Villeurbanne, France, 69616
        • Recruiting
        • Médipôle Hôpital Mutualiste Villeurbanne
        • Contact:
        • Principal Investigator:
          • Mathias BREHON, PH

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to occurrence of arterial or venous thromboembolic events.
Time Frame: Time to occurrence up to 24 months of patient follow-up
Nb and type of thrombotic events during the FU
Time to occurrence up to 24 months of patient follow-up

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival and event-free survival
Time Frame: 24 months
Time to last news and time to first event
24 months
Therapeutic adherence
Time Frame: 24 months
Therapeutic adherence by Girerd auto-questionnaire
24 months
Evaluation of Quality of life under antithrombotic drugs
Time Frame: 24 months
Evaluation of QoL by the use of MPN-SAF Quality of life
24 months
Evaluation of costs and incremental cost utility ratio of low-dose DOAC compared to low-dose aspirin
Time Frame: 24 months
Evaluation of benefits/costs under antithrombotic drugs
24 months
Evaluation of Quality of life under antithrombotic drugs
Time Frame: 24 months
Evaluation of QoL by the use of EQ-5D-5L Quality of life
24 months
Time to occurrence of major and clinically relevant non-major bleedings as defined by International Society on Thrombosis and Haemostasis
Time Frame: Time to occurrence up to 24 months of patient follow-up
Nb and type of new hemorrhagic events
Time to occurrence up to 24 months of patient follow-up
Time to occurrence of arterial thromboembolic events.
Time Frame: Time to occurrence up to 24 months of patient follow-up
Nb and type of new arterial events
Time to occurrence up to 24 months of patient follow-up
Time to occurrence of venous thromboembolic
Time Frame: Time to occurrence up to 24 months of patient follow-up
Nb and type of new venous events
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 Frame: Time to occurrence up to 24 months of patient follow-up
Nb and type of new thromboembolic and hemorrhage events
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 Frame: Time to occurrence up to 24 months of patient follow-up
Nb, type and grade of adverse events observed
Time to occurrence up to 24 months of patient follow-up
Occurrence of atrial fibrillation episode (time to occurrence).
Time Frame: 24 months
Nb and timing of atrial fibrillation event
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Brest

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 13, 2022

Primary Completion (Estimated)

July 13, 2027

Study Completion (Estimated)

July 13, 2027

Study Registration Dates

First Submitted

November 9, 2021

First Submitted That Met QC Criteria

January 5, 2022

First Posted (Actual)

January 20, 2022

Study Record Updates

Last Update Posted (Actual)

October 30, 2023

Last Update Submitted That Met QC Criteria

October 27, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 29BRC20.0263 (AVAJAK)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All collected data that underlie results in a publication

IPD Sharing Time Frame

Data will be available beginning five years and ending fifteen years following the final study report completion.

IPD Sharing 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.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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