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

Polycythemia Vera Clinical Trial

— AVAJAK  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05198960
• Other study ID #: 29BRC20.0263 (AVAJAK)
• Status: Recruiting
• Phase: Phase 3
• Start date: July 13, 2022
• Est. completion date: July 13, 2027

Study information

• Verified date: October 2023
• Source: University Hospital, Brest
• Contact: Jean-Christophe IANOTTO, Pr
• Phone: +33298223421
• Email: jean-christophe.ianotto[@]chu-brest.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1308
• Est. completion date: July 13, 2027
• Est. primary completion date: July 13, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Essential Thrombocythemia
• High-risk Patients
• Myeloproliferative Disorders
• Neoplasms
• Polycythemia
• Polycythemia Vera
• Prefibrotic/Early Primary Myelofibrosis
• Primary Myelofibrosis
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

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.
• Low-dose aspirin
Patients allocated to receive LDA: Aspirin 100 mg OD once daily.

Locations

Country	Name	City	State
France	CHU d'Angers	Angers
France	CH d'Annecy	Annecy
France	CH d'Argenteuil	Argenteuil
France	CH d'Avignon	Avignon
France	CH de la Côte Basque Bayonne	Bayonne
France	CH de Béziers	Béziers
France	CHU Bordeaux	Bordeaux
France	CHU Brest	Brest
France	Hôpital privé Cesson-Sévigné	Cesson-Sévigné
France	CHU de Clermont-Ferrand	Clermont-Ferrand
France	Hôpital Henri Mondor (APHP)	Créteil
France	CHU Grenoble Alpes	Grenoble
France	CHD Vendée La Roche Sur Yon	La Roche-sur-Yon
France	CHU Le Havre	Le Havre
France	CH Le Mans	Le Mans
France	CH Libourne	Libourne
France	CHU de Limoges - Hôpital Dupuytren	Limoges
France	Centre Léon Bérard Lyon	Lyon
France	CHU de Montpellier	Montpellier
France	CH de Morlaix	Morlaix
France	CHU de Nancy	Nancy
France	CHU de Nantes - Hôtel-Dieu	Nantes
France	Hôpital Privé du Confluent Nantes	Nantes
France	CHR d'Orléans	Orléans
France	Hôpital Cochin (APHP)	Paris
France	Hôpital St-Louis (APHP)	Paris
France	CH de Périgueux	Périgueux
France	CH de Perpignan	Perpignan
France	CHIC de Quimper	Quimper
France	CHU de Rennes	Rennes
France	CH de Rochefort	Rochefort
France	CH de Roubaix	Roubaix
France	Centre Henri Becquerel de Rouen	Rouen
France	CHU La Réunion - Site Nord Félix GUYON	Saint-Denis
France	CHU La Réunion - Site Sud	Saint-Pierre
France	Institut de Cancérologie Lucien Neuwirth St-Priest-en-Jarez	Saint-Priest-en-Jarez
France	Clinique Sainte Anne Strasbourg	Strasbourg
France	CHU de Tours	Tours
France	CH Bretagne Atlantique Vannes	Vannes
France	CH de Versailles	Versailles
France	CH Paul-Brousse (APHP)	Villejuif
France	Médipôle Hôpital Mutualiste Villeurbanne	Villeurbanne

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Brest

Country where clinical trial is conducted

France, 

Outcome

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