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

Sponsor

University Hospital, Brest (Other)

Overall Status

Recruiting

CT.gov ID

NCT05198960

Collaborator

(none)

1,340

Enrollment

Locations

Arms

Anticipated Duration (Months)

36.2

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Polycythemia Vera Essential Thrombocythemia Prefibrotic/Early Primary Myelofibrosis JAK2 V617F High-risk Patients	Drug: Direct Oral Anticoagulants Drug: Low-dose aspirin	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1340 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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.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 monthsStratification: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.

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

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

Anticipated Study Start Date :

Jul 1, 2022

Anticipated Primary Completion Date :

Jul 1, 2027

Anticipated Study Completion Date :

Jul 1, 2027

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Occurrence of arterial or venous thrombo-embolic events [24 months]
Nb and type of thrombotic events during the FU

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

based on age (> 60-year-old)
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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	CHU d'Angers	Angers	France	49933
2	CH d'Annecy	Annecy	France	74374
3	CH d'Argenteuil	Argenteuil	France	95100
4	CH d'Avignon	Avignon	France	84000
5	CH de la Côte Basque Bayonne	Bayonne	France	64100
6	CHU Bordeaux	Bordeaux	France	33604
7	CHU Brest	Brest	France	29609
8	CH de Béziers	Béziers	France	34500
9	Hôpital privé Cesson-Sévigné	Cesson-Sévigné	France	35510
10	CHU de Clermont-Ferrand	Clermont-Ferrand	France	63003
11	Hôpital Henri Mondor (APHP)	Créteil	France	94010
12	CHU Grenoble Alpes	Grenoble	France	38043
13	CHD Vendée La Roche Sur Yon	La Roche-sur-Yon	France	85925
14	CH Le Mans	Le Mans	France	72000
15	CHU de Limoges - Hôpital Dupuytren	Limoges	France
16	Centre Léon Bérard Lyon	Lyon	France	69000
17	CHU de Montpellier	Montpellier	France	34295
18	CH de Morlaix	Morlaix	France	29600
19	CHU de Nancy	Nancy	France	54511
20	CHU de Nantes - Hôtel-Dieu	Nantes	France	44093
21	CHR d'Orléans	Orléans	France	45100
22	Hôpital St-Louis (APHP)	Paris	France	75010
23	Hôpital Cochin (APHP)	Paris	France	75679
24	CH de Perpignan	Perpignan	France	66000
25	CH de Périgueux	Périgueux	France	24019
26	CHIC de Quimper	Quimper	France	29107
27	CHU de Rennes	Rennes	France	35033
28	CH de Rochefort	Rochefort	France	17300
29	CH de Roubaix	Roubaix	France	59100
30	Centre Henri Becquerel de Rouen	Rouen	France	76038
31	Institut Curie - Hôpital René Huguenin	Saint-Cloud	France	92210
32	Institut de Cancérologie Lucien Neuwirth St-Priest-en-Jarez	Saint-Priest-en-Jarez	France	42271
33	CHU de Tours	Tours	France	37044
34	CH Bretagne Atlantique Vannes	Vannes	France	56017
35	CH de Versailles	Versailles	France	78150
36	CH Paul-Brousse (APHP)	Villejuif	France	94800
37	Médipôle Hôpital Mutualiste Villeurbanne	Villeurbanne	France	69616