API-CAT STUDY for APIxaban Cancer Associated Thrombosis

NCT ID: NCT03692065

Last Updated: 2025-02-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1766 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-10-11
• Study Completion Date: 2024-10-20

Brief Summary

The main objective is to determine whether a low-dose regimen of apixaban (2.5 mg bid) is non inferior to a full-dose regimen of apixaban (5 mg bid) for the prevention of recurrent venous thromboembolism (VTE) in patients with active cancer who have completed at least 6 months of anticoagulant therapy for treating a documented index event of proximal deep venous thrombosis (DVT) (symptomatic or incidental) or pulmonary embolism (symptomatic or incidental).

Detailed Description

For patients completing at least 6 months of anticoagulant therapy in whom the cancer is active, the thrombotic risk is arguably ongoing and indefinite anticoagulation seems required.

Given apixaban 5 mg bid is an alternative for the first 6 months of treatment, we intend to assess whether it is possible to lower the dose of apixaban (2.5 mg bid) after completing at least 6 months of anticoagulant treatment in a specific population of patients with cancer associated thrombosis (CAT) requiring extended anticoagulant treatment and with significant life expectancy. There are 2 conditions to be met : demonstrate the non-inferiority of the 2.5 mg bid regimen on the efficacy endpoint and then demonstrate the superiority of the 2.5 mg bid regimen as compared to the 5 mg bid on the safety endpoint.

It is a multicenter, international, prospective, randomized, parallel-group, double-blind non-inferiority trial with blinded adjudication of outcome events (approximately 160 centers in approximately 10 countries (France, Italy, Spain, Belgium, Greece, Netherlands, UK, Switzerland, Poland, Austria), with a number of expected inclusions of 11 patients per site.

Subjects should be randomized within 7 days after the last dose of their initial 6-month treatment, defined as the treatment ongoing after completing at least 6 months of anticoagulant treatment from the beginning of the anticoagulant treatment for the index event. This treatment may be low-molecular weight heparin (LMWH), direct oral anticoagulant (DOAC) or vitamin K antagonist (VKA). If a VKA was used as standard anticoagulant therapy, then an INR must be documented as 2 or less before randomization. Every attempt should be made to randomize subjects as soon as possible after the initial treatment has been discontinued.

Subjects will be stratified based on the cancer site and the type of disease treated (PE with/without DVT or DVT alone). If a subject had both symptomatic DVT and symptomatic PE, the subject will be stratified as having symptomatic PE.

Conditions

Cancer-associated Thrombosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Apixaban film coated tablets 2.5 mg

Patients randomized in the apixaban reduced dose group will receive an apixaban 2.5 mg tablet and a placebo of apixaban 5 mg tablet, twice daily for 12 months.

Group Type: ACTIVE_COMPARATOR

Apixaban 5 MG

Intervention Type: DRUG

Subjects will be randomized (1:1 ratio) to apixaban 5 mg bid (full dose) or apixaban 2.5 mg bid (reduced-dose) using a centralized IWRS (double blind study).

Apixaban film coated tablets 5 mg

Patients randomized in the apixaban full dose group will receive a placebo of apixaban 2.5 mg tablet and an apixaban 5 mg tablet, twice daily for 12 months.

Group Type: ACTIVE_COMPARATOR

Apixaban 5 MG

Intervention Type: DRUG

Subjects will be randomized (1:1 ratio) to apixaban 5 mg bid (full dose) or apixaban 2.5 mg bid (reduced-dose) using a centralized IWRS (double blind study).

Interventions

Apixaban 5 MG

Subjects will be randomized (1:1 ratio) to apixaban 5 mg bid (full dose) or apixaban 2.5 mg bid (reduced-dose) using a centralized IWRS (double blind study).

Intervention Type: DRUG

Other Intervention Names

Apixaban 2.5 MG

Eligibility Criteria

Inclusion Criteria

• Signed written informed consent
• Any cancer diagnosed histologically (other than basal-cell or squamous-cell carcinoma of the skin, primary brain tumor or intra-cerebral metastasis)
• Active cancer defined as the presence of measurable disease or ongoing (or planned) chemotherapy, radiotherapy, hormonotherapy, targeted therapy, immunotherapy at inclusion
• Objectively documented index event : Symptomatic or incidental proximal lower-limb, iliac, inferior vena cava DVT or symptomatic or incidental pulmonary embolism in a segmental or larger pulmonary artery or incidental PE in a segmental or larger pulmonary artery

1. Proximal DVT is defined as DVT that involves at least the popliteal vein or a more proximal vein, demonstrated by imaging with compression ultrasound (CUS), including grey-scale or color-coded Doppler, or ascending contrast venography or contrast enhanced computed tomography or magnetic resonance imaging

2. PE has to be demonstrated by imaging as follows:

• an intraluminal filling defect in segmental or more proximal branches on contrast enhanced chest computed tomography or on computed tomography pulmonary angiography; or
• an intraluminal filling defect or a sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram; or
• a perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS)

3. Incidental VTE is defined as proximal DVT or PE detected by imaging incidentally when a patient undergoes imaging studies as standard of care for the management of his or her malignancy or other reasons but not for a VTE suspicion(e.g. cancer diagnosis or staging).

• Completed at least 6 months of anticoagulant therapy at therapeutic dosage (whatever the drug and the dosing),or completed assigned a clinical trial study treatment, for the treatment of the index event and patient still receiving anticoagulant treatment 6 months after occurrence of the VTE index
• No objectively documented symptomatic recurrence of VTE between the index event and randomization.
• Anticipated duration of anticoagulant treatment of at least 12 months at the time of randomization
• Patient affiliated to social security for French centers.

Exclusion Criteria

• WOCBP who are unwilling or unable to use an acceptable method of birth control [such as oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (condoms)] to avoid pregnancy for the entire study
• Women who are pregnant or breastfeeding
• Women with a positive pregnancy test on enrollment or prior to investigational product administration
• Isolated sub-segmental (incidental or symptomatic) PE without associated DVT
• Isolated distal DVT of the legs
• Isolated upper-extremity DVT or superior vena cava thrombosis
• Isolated visceral thrombosis
• Isolated catheter thrombosis
• Objectively documented symptomatic recurrence of VTE after the index event under anticoagulant treatment
• VTE during anticoagulant treatment given at therapeutic dosage
• Subjects with indications for long-term treatment with a VKA, such as:
• Mechanical heart valve
• Antiphospholipid syndrome
• Subjects with indication for long-term anticoagulation with a VKA or a DOAC at therapeutic dosage
• Conditions increasing the risk of serious bleeding

1. intracranial or intraocular bleeding within the 6 months

2. major surgery within 2 weeks prior to randomization

3. overt major bleeding at time of randomization

• Life expectancy < 12 months
• Eastern Cooperative Oncology Group (ECOG) level 3 or 4
• Bacterial endocarditis
• Uncontrolled hypertension: systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg
• Platelet count < 75,000/mm3
• Hemoglobin < 8g /dl
• Creatinine clearance < 30 ml /min based on the Cockcroft Gault equation
• Acute hepatitis, chronic active hepatitis, liver cirrhosis; or an alanine aminotransferase level 3 times or more and/or bilirubin level 2 times or more higher the upper limit of the normal range
• Subjects requiring acetylsalicylic acid >165 mg/day at randomization or thienopyridine therapy (clopidogrel, prasugrel, or ticagrelor).
• Subjects requiring dual anti-platelet therapy (such as acetylsalicylic acid plus clopidogrel or acetylsalicylic acid plus ticlopidine) at randomization. Subjects who transition from dual antiplatelet therapy to monotherapy prior to randomization will be eligible for the trial.
• Concomitant use of strong inhibitors of both cytochrome P-450 3A4 and P Glycoprotein (e.g., human immunodeficiency virus protease inhibitors or systemic ketoconazole) or strong inducers of both cytochrome P450 3A4 and P Glycoprotein (e.g.,rifampicin, carbamazepine, or phenytoin).
• Prisoners or subjects who are involuntarily incarcerated
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
• Hypersensitivity to apixaban
• Subjects participating in another pharmaco therapeutic program with an experimental therapy that is known to affect the coagulation system
• Under 18 years old
• Patients under legal protection (guardianship).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Guy Meyer, Pr

Role: STUDY_DIRECTOR

APHP(ASSISTANCE PUBLIQUE DES HOPITAUX DE PARIS

Locations

Medical university of Graz

Graz, , Austria

Medical university of Innsbruck

Innsbruck, , Austria

Ordensklinikum Linz gmbH Elisabethinen

Linz, , Austria

Medical university of Vienna

Vienna, , Austria

Erasmus Hospital Brussel

Brussels, , Belgium

Institut Roi Albert II

Brussels, , Belgium

AZ Groeninge

Kortrijk, , Belgium

Uz Leuven

Leuven, , Belgium

CHC Saint-Joseph

Liège, , Belgium

CHR de la Citadelle

Liège, , Belgium

CHU de Liège

Liège, , Belgium

University of Calgary

Calgary, , Canada

University of Alberta

Edmonton, , Canada

Ottawa Hospital Research Institute OTTAWA

Ottawa, , Canada

Toronto General Hospital

Toronto, , Canada

Diamond Health Care Centre

Vancouver, , Canada

C.H.U. D'Amiens Picardie

Amiens, , France

Chu D'Angers

Angers, , France

HÔPITAL PRIVÉ ARRAS LES BONNETTES - Espace Artois Santé

Arras, , France

Centre Hospitalier d'Avignon

Avignon, , France

Institut Sainte Catherine

Avignon, , France

Hopital Jean Minjoz

Besançon, , France

Hôpital AVICENNE - APHP

Bobigny, , France

Hopital Saint Andre

Bordeaux, , France

Institut Bergonie

Bordeaux, , France

Hôpital d'Instruction des Armées Clermont Tonnerre

Brest, , France

Chru Brest - Hopital Morvan

Brest, , France

Chru Brest- Hopital Cavale Blanche

Brest, , France

Centre François Baclesse

Caen, , France

Centre de Recherche Clinique

Caen, , France

Hopital Cote de Nacre

Caen, , France

Clinique Du Parc

Castelnau-le-Lez, , France

Centre hospitalier Métropole Savoie

Chambéry, , France

Ch Cholet

Cholet, , France

Hia Percy

Clamart, , France

Hopital Gabriel Montpied

Clermont-Ferrand, , France

Hôpital BEAUJON - APHP

Clichy, , France

Hôpital Henri Mondor

Créteil, , France

Hôpital HENRI MONDOR - APHP

Créteil, , France

CHU DIJON BOURGOGNE - Hôpital François Mitterrand

Dijon, , France

Chu de Grenoble

Grenoble, , France

Chd Vendee

La Roche-sur-Yon, , France

Centre Hospitalier Du Mans

Le Mans, , France

Centre hospitalier Emile Roux

Le Puy-en-Velay, , France

Chu de Limoges

Limoges, , France

Centre Leon Berard

Lyon, , France

Hôpital Prive Jean Mermoz

Lyon, , France

Clinique de l'Infirmerie Protestante de Lyon

Lyon, , France

Hopital La Timone Adultes

Marseille, , France

Groupe hospitalier sud Ile de France

Melun, , France

Hopital Saint- Eloi

Montpellier, , France

C.H. Des Pays de Morlaix

Morlaix, , France

Centre D Oncologie de Gentilly

Nancy, , France

CHU DE Nantes - Site Hotel Dieu

Nantes, , France

Chu de Nice

Nice, , France

Institut Curie

Paris, , France

Hôpital Saint Antoine - APHP

Paris, , France

Hôpital PITIE SALPETRIERE - APHP

Paris, , France

Hôpital COCHIN - APHP

Paris, , France

Hôpital GEORGES POMPIDOU - APHP

Paris, , France

Hôpital Bichat Claude Bernard

Paris, , France

Hopital Tenon - Aphp

Paris, , France

Hopital Saint-Joseph

Paris, , France

Centre Hospitalier Lyon-Sud

Pierre-Bénite, , France

Polyclinique de Courlancy

Reims, , France

CHU de Rennes

Rennes, , France

Centre Anti-Cancereux E. Marquis

Rennes, , France

Chu de Rouen - Hopital Charles Nicolle

Rouen, , France

Centre Rene Huguenin

Saint-Cloud, , France

Hôpital Nord

Saint-Etienne, , France

C.H.I Poissy-Saint Germain

Saint-Germain-en-Laye, , France

Centre Hospitalier de Saint Malo

St-Malo, , France

Clinique de l' Estrée

Stains, , France

Clinique Saint Anne

Strasbourg, , France

Centre Paul Strauss

Strasbourg, , France

Hopital Foch

Suresnes, , France

Chi de Toulon La Seyne

Toulon, , France

Iuct Oncopole

Toulouse, , France

Hopital Andre Mignot

Versailles, , France

L'Hôpital Nord-Ouest

Villefranche-sur-Saône, , France

Hôpital Paul Brousse - APHP

Villejuif, , France

Institut Gustave Roussy

Villejuif, , France

Médipôle Hôpital Mutualiste

Villeurbanne, , France

Hopital Louis Mourier - APHP

Colombes, Île-de-France Region, France

Athens School of Medicine

Athens, , Greece

National and Kapodistrian University of Athens ALEXANDRA Hospital

Athens, , Greece

University General Hospital "Attikon"

Athens, , Greece

University of Athens

Athens, , Greece

Ospedale di Castelfranco Veneto

Castelfranco Veneto, , Italy

Opedale clinicizzato colle dell'ara

Chieti, , Italy

Universita di Perugia

Perugia, , Italy

Amsterdam university medical center

Amsterdam, , Netherlands

Gelre Ziekenhuizen Apeldoorn

Apeldoorn, , Netherlands

Rode Kruis Ziekenhuis

Beverwijk, , Netherlands

Albert Schweitzer Ziekenhuis

Dordrecht, , Netherlands

Tergooi Hospital Hilversum

Hilversum, , Netherlands

Leiden university medical center

Leiden, , Netherlands

Diakonessenhuis

Utrecht, , Netherlands

Centre of postgraduate medical education at the european health centre Otwock

Otwock, , Poland

Hospital genarl Univ de Albacete

Albacete, , Spain

Hospital Virgen de los lirios

Alicante, , Spain

Fundacio Hospital de L'Esperit Sant

Barcelona, , Spain

Hospital universitari Germans trias i Pujol

Barcelona, , Spain

Parc Santari Sant Joan de Deu - Hospital general

Barcelona, , Spain

Hospital general Universitario Santa Lucia

Cartagena, , Spain

Hospital general universitario de ciudad real

Ciudad Real, , Spain

Hospital Olot i Comarcal de ma Garrotxa

Girona, , Spain

Hospital universitari de Girona

Girona, , Spain

Hospital universitario Infanta Sofia

Madrid, , Spain

Hospital universitario Virgen del Rocio

Seville, , Spain

Istituto Oncologico della svizzera Italiana

Bellinzona, , Switzerland

Hopitaux universitaires de Genève

Geneva, , Switzerland

Lausanne university hospital - CHUV

Lausanne, , Switzerland

Queens centre castle hill hospital

Cottingham, , United Kingdom

Countries

Austria; Belgium; Canada; France; Greece; Italy; Netherlands; Poland; Spain; Switzerland; United Kingdom

References

Mahe I, Carrier M, Mayeur D, Chidiac J, Vicaut E, Falvo N, Sanchez O, Grange C, Monreal M, Lopez-Nunez JJ, Otero-Candelera R, Le Gal G, Yeo E, Righini M, Robert-Ebadi H, Huisman MV, Klok FA, Westerweel P, Agnelli G, Becattini C, Bamias A, Syrigos K, Szmit S, Torbicki A, Verhamme P, Maraveyas A, Cohen AT, Ay C, Chapelle C, Meyer G, Couturaud F, Mismetti P, Girard P, Bertoletti L, Laporte S; API-CAT Investigators. Extended Reduced-Dose Apixaban for Cancer-Associated Venous Thromboembolism. N Engl J Med. 2025 Apr 10;392(14):1363-1373. doi: 10.1056/NEJMoa2416112. Epub 2025 Mar 29.

Reference Type: DERIVED

PMID: 40162636 (View on PubMed)

Other Identifiers

P170604J

Identifier Type: -

Identifier Source: org_study_id