API-CAT STUDY for APIxaban Cancer Associated Thrombosis

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Cancer-associated Thrombosis

Intervention / Treatment
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* Drug: Apixaban 5 MG


Participation Criteria
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Eligibility Criteria
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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 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 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) 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 intracranial or intraocular bleeding within the 6 months major surgery within 2 weeks prior to randomization 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Apixaban film coated tablets 2.5 mg<br>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. | Drug: Apixaban 5 MG<br>* 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).<br>* Other names: Apixaban 2.5 MG;|
| Active Comparator: Apixaban film coated tablets 5 mg<br>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. | Drug: Apixaban 5 MG<br>* 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).<br>* Other names: Apixaban 2.5 MG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| Recurrent symptomatic VTE | Recurrent VTE objectively confirmed after clinical suspicion | During the treatment period (12 months) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Apixaban, Cancer, VTE, Thrombosis