Clinical trial NCT05198960: AVAJAK: Apixaban/Rivaroxaban Versus Aspirin for Primary Prevention of Thrombo-embolic Complications in JAK2V617F-positive Myeloproliferative Neoplasms
Official title: AVAJAK: Apixaban/Rivaroxaban Versus Aspirin for Primary Prevention of Thrombo-embolic Complications in JAK2V617F-positive Myeloproliferative Neoplasms
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Polycythemia Vera
Essential Thrombocythemia
Prefibrotic/Early Primary Myelofibrosis
JAK2 V617F
High-risk Patients
Keywords: Venous ThromboEmbolism
Arterial Thrombosis
Hemorrhage
Lead sponsor: University Hospital, Brest
Sponsor class: OTHER
First posted: 2022-01-20
Enrollment: 1308
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: PREVENTION

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.


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.

Primary outcomes:
measure: Time to occurrence of arterial or venous thromboembolic events.
timeFrame: Time to occurrence up to 24 months of patient follow-up
Secondary outcomes:
measure: Time to occurrence of major and clinically relevant non-major bleedings as defined by International Society on Thrombosis and Haemostasis
timeFrame: Time to occurrence up to 24 months of patient follow-up
measure: Time to occurrence of arterial thromboembolic events.
timeFrame: Time to occurrence up to 24 months of patient follow-up
measure: Time to occurrence of venous thromboembolic
timeFrame: Time to occurrence up to 24 months of patient follow-up
measure: Time to occurrence of thromboembolic and bleeding events according to the cytoreductive associated drugs
timeFrame: Time to occurrence up to 24 months of patient follow-up
measure: Time to occurrence of serious adverse events others than thromboses and hemorrhages hemorrhages
timeFrame: Time to occurrence up to 24 months of patient follow-up
measure: Overall survival and event-free survival
timeFrame: 24 months
measure: Therapeutic adherence
timeFrame: 24 months
measure: Occurrence of atrial fibrillation episode (time to occurrence).
timeFrame: 24 months
measure: Evaluation of Quality of life under antithrombotic drugs
timeFrame: 24 months
measure: Evaluation of costs and incremental cost utility ratio of low-dose DOAC compared to low-dose aspirin
timeFrame: 24 months
measure: Evaluation of Quality of life under antithrombotic drugs
timeFrame: 24 months
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU d'Angers
city: Annecy
country: France
facility: CH d'Annecy
city: Argenteuil
country: France
facility: CH d'Argenteuil
city: Avignon
country: France
facility: CH d'Avignon
city: Bayonne
country: France
facility: CH de la Côte Basque Bayonne
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Brest
country: France
facility: CHU Brest
city: Béziers
country: France
facility: CH de Béziers
city: Cesson-Sévigné
country: France
facility: Hôpital privé Cesson-Sévigné
city: Clermont-Ferrand
country: France
facility: CHU de Clermont-Ferrand
city: Créteil
country: France
facility: Hôpital Henri Mondor (APHP)
city: Grenoble
country: France
facility: CHU Grenoble Alpes
city: La Roche-sur-Yon
country: France
facility: CHD Vendée La Roche Sur Yon
city: Le Havre
country: France
facility: CHU Le Havre
city: Le Mans
country: France
facility: CH Le Mans
city: Libourne
country: France
facility: CH Libourne
city: Limoges
country: France
facility: CHU de Limoges - Hôpital Dupuytren
city: Lyon
country: France
facility: Centre Léon Bérard Lyon
city: Montpellier
country: France
facility: CHU de Montpellier
city: Morlaix
country: France
facility: CH de Morlaix
city: Nancy
country: France
facility: CHU de Nancy
city: Nantes
country: France
facility: CHU de Nantes - Hôtel-Dieu
city: Nantes
country: France
facility: Hôpital Privé du Confluent Nantes
city: Orléans
country: France
facility: CHR d'Orléans
city: Paris
country: France
facility: Hôpital St-Louis (APHP)
city: Paris
country: France
facility: Hôpital Cochin (APHP)
city: Perpignan
country: France
facility: CH de Perpignan
city: Périgueux
country: France
facility: CH de Périgueux
city: Quimper
country: France
facility: CHIC de Quimper
city: Rennes
country: France
facility: CHU de Rennes
city: Rochefort
country: France
facility: CH de Rochefort
city: Roubaix
country: France
facility: CH de Roubaix
city: Rouen
country: France
facility: Centre Henri Becquerel de Rouen
city: Saint-Denis
country: France
facility: CHU La Réunion - Site Nord Félix GUYON
city: Saint-Pierre
country: France
facility: CHU La Réunion - Site Sud
city: Saint-Priest-en-Jarez
country: France
facility: Institut de Cancérologie Lucien Neuwirth St-Priest-en-Jarez
city: Strasbourg
country: France
facility: Clinique Sainte Anne Strasbourg
city: Tours
country: France
facility: CHU de Tours
city: Vannes
country: France
facility: CH Bretagne Atlantique Vannes
city: Versailles
country: France
facility: CH de Versailles
city: Villejuif
country: France
facility: CH Paul-Brousse (APHP)
city: Villeurbanne
country: France
facility: Médipôle Hôpital Mutualiste Villeurbanne
Study officials:
References: