Clinical trial NCT03692065: API-CAT STUDY for APIxaban Cancer Associated Thrombosis
Official title: Long-term Treatment of Cancer Associated VTE: Reduced vs Full Dose of Apixaban : API-CAT STUDY for APIxaban Cancer Associated Thrombosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cancer-associated Thrombosis
Keywords: Cancer
VTE
Apixaban
Thrombosis
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2018-10-02
Enrollment: 1766
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Minimum Age: 18 Years

Maximum Age:

Sex: All Gender Based: No Accepts Healthy Volunteers: No

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).

Primary outcomes:
measure: The incidence of an an adjudicated composite endpoint
timeFrame: During the treatment period (12 months)
Secondary outcomes:
measure: The incidence of adjudicated major and clinically relevant non-major bleeding
timeFrame: During the treatment period (12 months)
measure: Recurrent symptomatic VTE
timeFrame: During the treatment period (12 months)
measure: VTE related-death
timeFrame: During the treatment period (12 months)
measure: All-cause death
timeFrame: During the treatment period (12 months)
measure: Adjudicated major bleeding.
timeFrame: During the treatment period (12 months)
measure: Adjudicated composite of recurrent symptomatic VTE, VTE related-death, all-cause death, adjudicated major bleeding.
timeFrame: During the treatment period (12 months)
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical university of Graz
city: Innsbruck
country: Austria
facility: Medical university of Innsbruck
city: Linz
country: Austria
facility: Ordensklinikum Linz gmbH Elisabethinen
city: Vienna
country: Austria
facility: Medical university of Vienna
city: Brussels
country: Belgium
facility: Institut Roi Albert II
city: Brussel
country: Belgium
facility: Erasmus Hospital Brussel
city: Kortrijk
country: Belgium
facility: AZ Groeninge
city: Leuven
country: Belgium
facility: Uz Leuven
city: Liège
country: Belgium
facility: CHC Saint-Joseph
city: Liège
country: Belgium
facility: CHR de la Citadelle
city: Liège
country: Belgium
facility: CHU de Liège
city: Calgary
country: Canada
facility: University of Calgary
city: Edmonton
country: Canada
facility: University of Alberta
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute OTTAWA
city: Toronto
country: Canada
facility: Toronto General Hospital
city: Vancouver
country: Canada
facility: Diamond Health Care Centre
city: Colombes
country: France
facility: Hopital Louis Mourier - APHP
state: Ile De France
city: Amiens
country: France
facility: C.H.U. D'Amiens Picardie
city: Angers
country: France
facility: Chu D'Angers
city: Arras
country: France
facility: HÔPITAL PRIVÉ ARRAS LES BONNETTES - Espace Artois Santé
city: Avignon
country: France
facility: Centre Hospitalier d'Avignon
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Besancon
country: France
facility: Hopital Jean Minjoz
city: Bobigny
country: France
facility: Hôpital AVICENNE - APHP
city: Bordeaux
country: France
facility: Hopital Saint Andre
city: Bordeaux
country: France
facility: Institut Bergonie
city: Brest
country: France
facility: Hôpital d'Instruction des Armées Clermont Tonnerre
city: Brest
country: France
facility: Chru Brest - Hopital Morvan
city: Brest
country: France
facility: Chru Brest- Hopital Cavale Blanche
city: Caen
country: France
facility: Centre François Baclesse
city: Caen
country: France
facility: Centre de Recherche Clinique
city: Caen
country: France
facility: Hopital Cote de Nacre
city: Castelnau Le Lez
country: France
facility: Clinique Du Parc
city: Chambéry
country: France
facility: Centre hospitalier Métropole Savoie
city: Cholet
country: France
facility: Ch Cholet
city: Clamart
country: France
facility: Hia Percy
city: Clermont Ferrand
country: France
facility: Hopital Gabriel Montpied
city: Clichy
country: France
facility: Hôpital BEAUJON - APHP
city: Creteil
country: France
facility: Hôpital HENRI MONDOR - APHP
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: CHU DIJON BOURGOGNE - Hôpital François Mitterrand
city: Grenoble
country: France
facility: Chu de Grenoble
city: La Roche Sur Yon
country: France
facility: Chd Vendee
city: Le Mans
country: France
facility: Centre Hospitalier Du Mans
city: Le Puy-en-Velay
country: France
facility: Centre hospitalier Emile Roux
city: Limoges
country: France
facility: Chu de Limoges
city: Lyon
country: France
facility: Centre Leon Berard
city: Lyon
country: France
facility: Hôpital Prive Jean Mermoz
city: Lyon
country: France
facility: Clinique de l'Infirmerie Protestante de Lyon
city: Marseille
country: France
facility: Hopital La Timone Adultes
city: Melun
country: France
facility: Groupe hospitalier sud Ile de France
city: Montpellier
country: France
facility: Hopital Saint- Eloi
city: Morlaix
country: France
facility: C.H. Des Pays de Morlaix
city: Nancy
country: France
facility: Centre D Oncologie de Gentilly
city: Nantes
country: France
facility: CHU DE Nantes - Site Hotel Dieu
city: Nice
country: France
facility: Chu de Nice
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: Hôpital Saint Antoine - APHP
city: Paris
country: France
facility: Hôpital PITIE SALPETRIERE - APHP
city: Paris
country: France
facility: Hôpital COCHIN - APHP
city: Paris
country: France
facility: Hôpital GEORGES POMPIDOU - APHP
city: Paris
country: France
facility: Hôpital Bichat Claude Bernard
city: Paris
country: France
facility: Hopital Tenon - Aphp
city: Paris
country: France
facility: Hopital Saint-Joseph
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon-Sud
city: Reims
country: France
facility: Polyclinique de Courlancy
city: Rennes
country: France
facility: CHU de Rennes
city: Rennes
country: France
facility: Centre Anti-Cancereux E. Marquis
city: Rouen
country: France
facility: Chu de Rouen - Hopital Charles Nicolle
city: Saint Germain En Laye
country: France
facility: C.H.I Poissy-Saint Germain
city: Saint Malo
country: France
facility: Centre Hospitalier de Saint Malo
city: Saint-Cloud
country: France
facility: Centre Rene Huguenin
city: Saint-Étienne
country: France
facility: Hôpital Nord
city: Stains
country: France
facility: Clinique de l' Estrée
city: Strasbourg
country: France
facility: Clinique Saint Anne
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Suresnes
country: France
facility: Hopital Foch
city: Toulon
country: France
facility: Chi de Toulon La Seyne
city: Toulouse
country: France
facility: Iuct Oncopole
city: Versailles
country: France
facility: Hopital Andre Mignot
city: Villefranche Sur Saône
country: France
facility: L'Hôpital Nord-Ouest
city: Villejuif
country: France
facility: Hôpital Paul Brousse - APHP
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Villeurbanne
country: France
facility: Médipôle Hôpital Mutualiste
city: Athens
country: Greece
facility: Athens School of Medicine
city: Athens
country: Greece
facility: National and Kapodistrian University of Athens ALEXANDRA Hospital
city: Athens
country: Greece
facility: University of Athens
city: Athènes
country: Greece
facility: University General Hospital "Attikon"
city: Castelfranco Veneto
country: Italy
facility: Ospedale di Castelfranco Veneto
city: Chieti
country: Italy
facility: Opedale clinicizzato colle dell'ara
city: Pérouse
country: Italy
facility: Universita di Perugia
city: Amsterdam
country: Netherlands
facility: Amsterdam university medical center
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen Apeldoorn
city: Beverwijk
country: Netherlands
facility: Rode Kruis Ziekenhuis
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Ziekenhuis
city: Hilversum
country: Netherlands
facility: Tergooi Hospital Hilversum
city: Leiden
country: Netherlands
facility: Leiden university medical center
city: Utrecht
country: Netherlands
facility: Diakonessenhuis
city: Otwock
country: Poland
facility: Centre of postgraduate medical education at the european health centre Otwock
city: Albacete
country: Spain
facility: Hospital genarl Univ de Albacete
city: Alicante
country: Spain
facility: Hospital Virgen de los lirios
city: Barcelona
country: Spain
facility: Hospital universitari Germans trias i Pujol
city: Barcelona
country: Spain
facility: Parc Santari Sant Joan de Deu - Hospital general
city: Barcelone
country: Spain
facility: Fundacio Hospital de L'Esperit Sant
city: Carthagène
country: Spain
facility: Hospital general Universitario Santa Lucia
city: Ciudad Real
country: Spain
facility: Hospital general universitario de ciudad real
city: Gerona
country: Spain
facility: Hospital Olot i Comarcal de ma Garrotxa
city: Girona
country: Spain
facility: Hospital universitari de Girona
city: Madrid
country: Spain
facility: Hospital universitario Infanta Sofia
city: Sevilla
country: Spain
facility: Hospital universitario Virgen del Rocio
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della svizzera Italiana
city: Geneve
country: Switzerland
facility: Hopitaux universitaires de Genève
city: Lausanne
country: Switzerland
facility: Lausanne university hospital - CHUV
city: Cottingham
country: United Kingdom
facility: Queens centre castle hill hospital
Study officials:
affiliation: APHP(ASSISTANCE PUBLIQUE DES HOPITAUX DE PARIS
name: Guy Meyer, Pr
role: STUDY_DIRECTOR
References: