Clinical Trials Register

Summary
EudraCT Number:	2020-004652-15
Sponsor's Protocol Code Number:	29BRC20.0263
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-04-16
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2020-004652-15

A.3

Full title of the trial

AVAJAK: Apixaban/rivaroxaban Versus Aspirin for primary prevention of thrombo-embolic complications in JAK2V617F-positive myelo-proliferative neoplasms

AVAJAK: Apixaban/rivaroxaban Versus Aspirine en prévention primaire des complications thromboemboliques des néoplasies myéloprolifératives mutées pour JAK2V617F

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

AVAJAK: Apixaban/rivaroxaban Versus Aspirin for primary prevention of thrombo-embolic complications in JAK2V617F-positive myelo-proliferative neoplasms

AVAJAK: Apixaban/rivaroxaban Versus Aspirine en prévention primaire des complications thromboemboliques des néoplasies myéloprolifératives mutées pour JAK2V617F

A.3.2

Name or abbreviated title of the trial where available

AVAJAK

A.4.1

Sponsor's protocol code number

29BRC20.0263

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	CHRU de Brest
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	PHRC-K
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHRU de Brest
B.5.2	Functional name of contact point	Dauphou EDDI
B.5.3	Address:
B.5.3.1	Street Address	DRCI – Hôpital Morvan – 2 avenue Foch
B.5.3.2	Town/ city	Brest Cedex
B.5.3.3	Post code	29609
B.5.3.4	Country	France
B.5.4	Telephone number	003302 29 02 01 10
B.5.5	Fax number	003302 98 22 31 83
B.5.6	E-mail	promotion-interne@chu-brest.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Eliquis
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb/Pfizer EEIG
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Xarelto
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer AG
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Aspirine Protec
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Healthcare
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Gastro-resistant capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Myelo-proliferative neoplasms including essential thrombocythemia, Polycythemia Vera, Prefibrotic myelofibrosis

Néoplasies myéloprolifératives incluant les thrombocytémies essentielles, polyglobulies de Vaquez et pyélofibroses préfibrotiques

E.1.1.1

Medical condition in easily understood language

Myelo-proliferative neoplasms including essential thrombocythemia, Polycythemia Vera, Prefibrotic myelofibrosis

Néoplasies myéloprolifératives incluant les thrombocytémies essentielles, polyglobulies de Vaquez et pyélofibroses préfibrotiques

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10077465
E.1.2	Term	Myeloproliferative neoplasm
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10015494
E.1.2	Term	Essential thrombocythemia
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10036061
E.1.2	Term	Polycythemia vera
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10028537
E.1.2	Term	Myelofibrosis
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate that low-dose DOAC is more effective than LDA in the primary prevention of arterial or venous thrombosis in JAK2V617F-positive high-risk MPN patients.

Démontrer la supériorité d’une faible dose d’AOD par rapport à de faible dose d’aspirine dans la prévention primaire antithrombotique des patients NMP JAK2V617F de haut-risque.

E.2.2

Secondary objectives of the trial

Secondary objectives greater than 1000 characters (refer to the protocol)

Objectifs secondaires supérieures à 1000 caractères (se référer au protocole)

E.2.3

Trial contains a sub-study

E.3

Principal 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.

- Patients avec un diagnostic de PV ou ET ou PreMF en accord avec les classifications internationales (pas de BOM obligatoire).
- Patients mutés pour JAK2V617F (seuil de charge allélique >1%).
- Patients considérés à haut-risque :
- 1°) du fait de l’âge > 60 ans
- 2°) du fait d’un antécédent thrombotique (mais compatible avec la randomisation antithrombotique) et d’âge ≥18 ans
- Diagnostic néoplasies myéloprolifératives datant de moins d’un an.

E.4

Principal exclusion criteria

- Contra-indication to aspirin or DOAC due to allergic situation or recent history of major bleeding
- Formal indication of treatment with LDA 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 <25 ml/mn on Cockcroft and Gault Formula
- Patient considered at high-risk of bleeding
- Active or expected pregnancy
- No effective contraception in women of childbearing age
- PS>2 or life expectancy <12 months

- Contre-indication à l’aspirine ou à l’AOD pour allergie ou antécédent d’hémorragie majeure récente.
- Indication formelle à traiter par aspirine ou AOD avant l’inclusion.
- Incapacité à donner son consentement éclairé.
- Personne en curatelle ou tutelle.
- Utilisation concomitante d’un puissant inhibiteur ou inducteur du CYTP3A4 (comme le ruxolitinib).
- Insuffisance chronique hépatique.
- Insuffisance rénale chronique avec une clairance <25 ml/mn selon la formule de Cockcroft et Gault.
- Grossesse en cours ou à venir.
- Absence de contraception ou femme allaitante.
- Performans status > 2 ou espérance de vie < 12 mois.

E.5 End points

E.5.1

Primary end point(s)

Occurrence of arterial or venous thromboembolic events at 24 months.

Survenue d’un évènement thromboembolique artériel ou veineux à 24 mois de suivi.

E.5.1.1

Timepoint(s) of evaluation of this end point

3, 6, 12, 18 and 24 month

3, 6, 12, 18 et 24 mois

E.5.2

Secondary end point(s)

- Occurrence of major and clinically relevant non-major bleedings as defined by ISTH at 24 months.
- Occurrence of arterial thromboembolic events at 24 months.
- Occurrence of venous thromboembolic events at 24 months.
- Occurrence of serious adverse events others than thrombosis and bleedings at 24 months.
- Occurrence of atrial fibrillation episodes at 24 months.
- Overall survival and event free survival (events defined above) at 24 months.
- Occurrence of adjudicated mortality (non cardiovascular and cardiovascular) at 24 months
- Therapeutic adherence will be studied (Girerd auto-questionnaire) during the study treatment period of 24 months.
- Quality of life will be studied (EQ-5D-5L and MPN-SAF auto-questionnaire) during the study treatment period of 24 months.
- Evaluation of costs and incremental cost utility ratio (cost per QALY) of low-dose DOAC compared to LDA.

- Survenue d’épisode d’hémorragie majeure ou de signification clinique mais non-majeure, tel que définies par l’ISTHà 24 mois de suivi.
- Survenue d’épisode thrombotique artériel à 24 mois de suivi.
- Survenue d’épisode thrombotique veineux à 24 mois de suivi.
- Survenue d’épisode thrombotique ou hémorragique à 24 mois de suivi en fonction du type de NMP.
- Survenue d’épisode thrombotique ou hémorragique à 24 mois de suivi en fonction du type de cytoréducteur utilisé.
- Survenue d’effets secondaires (non-thrombotique ou hémorragique) à 24 mois.
- Survenue d’épisode d’arythmie cardiaque à 24 mois de suivi.
- Survie globale et sans événement thrombo-hémorragique à 24 mois de suivi.
- Survenue d’un décès (quel que soit la cause) à 24 mois de suivi.
- Analyse de la compliance aux traitements par auto-questionnaire Girerd pendant 24 mois.
- Analyse de la qualité de vie par utilisation d’auto-questionnaires (EQ-5D-5L et MPN-SAF) pendant 24 mois.
- Évaluation des coûts et du rapport coût-efficacité différentiel (coût par méthode QALY) des AOD à faible dose par rapport à l’aspirine faible dose.

E.5.2.1

Timepoint(s) of evaluation of this end point

3, 6, 12, 18 and 24 month

3, 6, 12, 18 et 24 mois

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last visit of the last patient

Dernière visite du dernier patient

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

1040

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

1340

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Aucun

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-06-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-06-03

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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