API-CAT STUDY for APIxaban Cancer Associated Thrombosis

Cancer-associated Thrombosis Clinical Trial

— API-CAT  

Official title:

Long-term Treatment of Cancer Associated VTE: Reduced vs Full Dose of Apixaban : API-CAT STUDY for APIxaban Cancer Associated Thrombosis

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03692065
• Other study ID #: P170604J
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 11, 2018
• Est. completion date: October 6, 2024

Study information

• Verified date: September 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1767
• Est. completion date: October 6, 2024
• Est. primary completion date: September 6, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Cancer-associated Thrombosis
• Thrombosis

Intervention

Drug:
• 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).

Locations

Country	Name	City	State
Austria	Medical university of Graz	Graz
Austria	Medical university of Innsbruck	Innsbruck
Austria	Ordensklinikum Linz gmbH Elisabethinen	Linz
Austria	Medical university of Vienna	Vienna
Belgium	Erasmus Hospital Brussel	Brussel
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
Canada	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
France	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	Besancon
France	Hôpital AVICENNE - APHP	Bobigny
France	Hopital Saint Andre	Bordeaux
France	Institut Bergonie	Bordeaux
France	Chru Brest - Hopital Morvan	Brest
France	Chru Brest- Hopital Cavale Blanche	Brest
France	Hôpital d'Instruction des Armées Clermont Tonnerre	Brest
France	Centre de Recherche Clinique	Caen
France	Centre François Baclesse	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	Hopital Louis Mourier - APHP	Colombes	Ile De France
France	Hôpital HENRI MONDOR - APHP	Creteil
France	Hôpital Henri Mondor	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	Clinique de l'Infirmerie Protestante de Lyon	Lyon
France	Hôpital Prive Jean Mermoz	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	Hôpital Bichat Claude Bernard	Paris
France	Hôpital COCHIN - APHP	Paris
France	Hôpital GEORGES POMPIDOU - APHP	Paris
France	Hôpital PITIE SALPETRIERE - APHP	Paris
France	Hôpital Saint Antoine - APHP	Paris
France	Hopital Saint-Joseph	Paris
France	Hopital Tenon - Aphp	Paris
France	Institut Curie	Paris
France	Centre Hospitalier Lyon-Sud	Pierre Benite
France	Polyclinique de Courlancy	Reims
France	Centre Anti-Cancereux E. Marquis	Rennes
France	CHU de Rennes	Rennes
France	Chu de Rouen - Hopital Charles Nicolle	Rouen
France	C.H.I Poissy-Saint Germain	Saint Germain En Laye
France	Centre Hospitalier de Saint Malo	Saint Malo
France	Centre Rene Huguenin	Saint-Cloud
France	Hôpital Nord	Saint-Étienne
France	Clinique de l' Estrée	Stains
France	Centre Paul Strauss	Strasbourg
France	Clinique Saint Anne	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
Greece	University General Hospital "Attikon"	Athènes
Greece	Athens School of Medicine	Athens
Greece	National and Kapodistrian University of Athens ALEXANDRA Hospital	Athens
Greece	University of Athens	Athens
Italy	Ospedale di Castelfranco Veneto	Castelfranco Veneto
Italy	Opedale clinicizzato colle dell'ara	Chieti
Italy	Universita di Perugia	Pérouse
Netherlands	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
Poland	Centre of postgraduate medical education at the european health centre Otwock	Otwock
Spain	Hospital genarl Univ de Albacete	Albacete
Spain	Hospital Virgen de los lirios	Alicante
Spain	Hospital universitari Germans trias i Pujol	Barcelona
Spain	Parc Santari Sant Joan de Deu - Hospital general	Barcelona
Spain	Fundacio Hospital de L'Esperit Sant	Barcelone
Spain	Hospital general Universitario Santa Lucia	Carthagène
Spain	Hospital general universitario de ciudad real	Ciudad Real
Spain	Hospital Olot i Comarcal de ma Garrotxa	Gerona
Spain	Hospital universitari de Girona	Girona
Spain	Hospital universitario Infanta Sofia	Madrid
Spain	Hospital universitario Virgen del Rocio	Sevilla
Switzerland	Istituto Oncologico della svizzera Italiana	Bellinzona
Switzerland	Hopitaux universitaires de Genève	Geneve
Switzerland	Lausanne university hospital - CHUV	Lausanne
United Kingdom	Queens centre castle hill hospital	Cottingham

Sponsors (2)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Bristol-Myers Squibb

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The incidence of an an adjudicated composite endpoint	The incidence of an adjudicated composite of recurrent symptomatic VTE (proximal and/or distal DVT and/or symptomatic PE and/or upper limb or central venous catheter thrombosis or incidental VTE (proximal DVT or PE), or death due to PE during the treatment period.; 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 the malignancy or other reasons but not for a VTE suspicion.	During the treatment period (12 months)
Secondary	The incidence of adjudicated major and clinically relevant non-major bleeding	The definition of major bleeding described is adapted from the International Society on Thrombosis and Hemostasis (ISTH) definition (Schulman JTH 2005).	During the treatment period (12 months)
Secondary	Recurrent symptomatic VTE	Recurrent VTE objectively confirmed after clinical suspicion	During the treatment period (12 months)
Secondary	VTE related-death	VTE related-death: PE based on objective diagnostic testing, autopsy, or sudden death; i.e. death occurring within one hour of the onset of new symptoms which cannot be attributed to a documented cause (unexplained death) and for which PE/DVT cannot be ruled out as the cause.	During the treatment period (12 months)
Secondary	All-cause death	All deaths will be adjudicated by the ICAC and classified as either VTE-related, cancer death (including all deaths due to the underlying cancer), bleeding-related or others, including all deaths due to a clearly documented other cause, such as respiratory failure (e.g., terminal emphysema), infections/sepsis etc.	During the treatment period (12 months)
Secondary	Adjudicated major bleeding.	The definition of major bleeding described is adapted from the International Society on Thrombosis and Hemostasis (ISTH) definition (Schulman 2005) and includes; Acute clinically overt bleeding with one or more of the following: A decrease in hemoglobin (Hgb) of 2 g/dL or more; A transfusion of 2 or more units of packed red blood cells; Symptomatic bleeding that occurs in at least one of the following critical sites: Intracranial; Intraspinal; Intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed); Pericardial; Intra-articular; Intramuscular with compartment syndrome; Retroperitoneal; Bleeding that is fatal: bleeding event that the independent adjudication committee determines is the primary cause of death or contributes directly to death.	During the treatment period (12 months)
Secondary	Adjudicated composite of recurrent symptomatic VTE, VTE related-death, all-cause death, adjudicated major bleeding.	Adjudicated composite of recurrent symptomatic VTE, VTE related-death, all-cause death, adjudicated major bleeding.	During the treatment period (12 months)