Study of Rivaroxaban for CeREbral Venous Thrombosis

Study Overview
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Brief Summary
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SECRET examines the safety of rivaroxaban versus standard-of-care for treatment of symptomatic cerebral venous thrombosis, initiated within 14 days of diagnosis.

Detailed Description
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SECRET is an open-label, randomized, controlled, phase II study that will assess the safety of rivaroxaban, a non-vitamin K antagonist oral anticoagulant (NOAC), compared with standard-of-care (unfractionated or low-molecular weight heparin with transition to warfarin [INR 2.0-3.0], or continued low molecular-weight heparin) for cerebral venous thrombosis. Recruitment will occur at 17 high-volume stroke research centres across Canada over 3 years. During the pilot phase, 50 adult patients within 14 days of symptomatic cerebral venous thrombosis diagnosis will be randomized to receive rivaroxaban 20 mg daily versus standard of care (warfarin or low-molecular weight heparin). Patients will be followed for 1 year. The feasibility of recruitment will be tested during the pilot phase and outcomes refined for a future Phase III trial.

Official Title
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Multicentre, Prospective Randomized Open Label, Blinded-endpoint (PROBE) Controlled Trial of Early Anticoagulation With Rivaroxaban Versus Standard of Care in Determining Safety at 365 Days in Symptomatic Cerebral Venous Thrombosis

Conditions
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Cerebral Venous Thrombosis

Intervention / Treatment
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* Drug: Rivaroxaban
* Drug: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients aged 18 and above New diagnosis of symptomatic cerebral venous thrombosis as confirmed on CT venogram or MR venogram Ability to randomize within 14 days of neuroimaging-confirmed diagnosis The treating clinician is of the opinion that the patient is appropriate for oral anticoagulation as per standard of care Patient or legally authorized representative is able to give written informed consent Exclusion criteria: Patient has known antiphospholipid antibody syndrome (APLS; lupus anticoagulant, anti-beta 2-glycoprotein I antibodies, and anticardiolipin antibody) by Sapporo-Sydney criteria with a previous history of venous or arterial thrombosis Patient is anticipated to require invasive procedure (e.g. lumbar puncture, thrombectomy, hemicraniectomy) prior to initiation of oral anticoagulation** Patient is unable to swallow due to depressed level of consciousness† Impaired renal function (i.e., CrCl < 30 mL/min using Cockroft-Gault equation) Pregnancy; if a woman is of childbearing potential a urine or serum beta human chorionic gonadotropin (β-hCG) test is positive Breastfeeding at the time of randomization Bleeding diathesis or other contraindication to anticoagulation Any concurrent medical condition requiring mandatory antiplatelet or anticoagulant use Concomitant use of strong CYP3A4 inducers (e.g., ongoing use of dilantin, carbamazepine, HIV protease inhibitors) or CYP3A4 inhibitors (e.g., diltiazem, ketoconazole) Patient has a severe or fatal comorbid illness that will prevent improvement, or cannot complete follow-up due to the same, or cannot complete follow-up due to co-morbid non-fatal illness, non-residence in the city, or for any other known reason for which follow-up would be impossible.

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban<br>Rivaroxaban | Drug: Rivaroxaban<br>* Rivaroxaban 20 mg daily (15 mg daily in participants with a CrCl 30-49 mL/min as per the Cockroft-Gault equation)<br>* Other names: Xarelto;|
| Active Comparator: Standard of care<br>Unfractionated heparin Low-molecular weight heparin (dalteparin, enoxaparin, tinzaparin) Warfarin | Drug: Standard of care<br>* Accepted standard of care as per American Heart Association/American Stroke Association Guidelines (initial use of unfractionated heparin or low-molecular weight heparin with transition to an oral vitamin K antagonist or continuation with low-molecular weight heparin) with choice of agent at the treating physician's discretion.<br>* Other names: Heparin, Coumadin, Fragmin, Lovenox, Innohep;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite rate of all-cause mortality, symptomatic intracranial bleeding, major extracranial bleeding | Symptomatic intracranial bleeding is defined as a new symptomatic intracranial hemorrhage OR worsening existing intracranial hemorrhage with a >33% change in hematoma volume, AND either an NIHSS score increase of 4 or more points, or a change in level of consciousness as per NIHSS item 1a, AND the clinical change is thought to be attributable to the hemorrhage. Major extracranial bleeding is defined as bleeding in a critical area or organ, including intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or bleeding causing a drop in hemoglobin by 20 g/L or more, leading to transfusion of 2 or more units of whole blood or red cells. | 180 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | Death from any cause | 180 days | 
| Symptomatic intracranial bleeding | Symptomatic intracranial bleeding is defined as a new symptomatic intracranial hemorrhage OR worsening existing intracranial hemorrhage with a >33% change in hematoma volume, AND either an NIHSS score increase of 4 or more points, or a change in level of consciousness as per NIHSS item 1a, AND the clinical change is thought to be attributable to the hemorrhage. | 180 days | 
| Major extracranial bleeding | Major extracranial bleeding is defined as bleeding in a critical area or organ, including intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or bleeding causing a drop in hemoglobin by 20 g/L or more, leading to transfusion of 2 or more units of whole blood or red cells. | 180 days | 
| Recurrent venous thromboembolism | any thrombosis at a new site including cerebral venous thrombosis in a separate localization from index event | 180 days or end of anticoagulation, whichever is sooner | 
| Major bleeding or clinically relevant non-major bleeding | A clinically relevant minor bleed is an acute or subacute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of: (a) a hospital admission for bleeding, or (b) a physician guided medical or surgical treatment for bleeding, or (c) a change in antithrombotic therapy (including interruption or discontinuation or study drug) | 180 days or end of anticoagulation, whichever is sooner | 
| Partial or complete recanalization | Partial or complete recanalization between baseline and last study venogram | 180 or 365 days | 
| Functional independence | modified Rankin Scale 0-1 | 365 days | 
| Reduced functional dependence | shift of one or more modified Rankin Scale categories to reduced functional dependence | 365 days | 
| Health care resource utilization | Cost in Canadian dollars of number of hospitalizations (length of stay, critical care unit use), emergency room visits, unscheduled outpatient consultations, postacute care (including home care, rehabilitation stays or long-term care) | 365 days | 
| Population Health Questionnaire (PHQ)-9 score | Change in PHQ-9 score between baseline and end of study | 365 days | 
| EuroQOL 5-Dimensions (EQ-5D) score | Change in EQ-5D score between baseline and end of study | 365 days | 
| Fatigue Assessment score | Change in fatigue assessment score between baseline and end of study | 365 days | 
| Headache Impact Test - 6 score | Change in Headache Impact Test - 6 score between baseline and Day 180 (score = 36-78, where a higher score indicates a worse outcome) | 365 days | 
| Montreal Cognitive Assessment score | Change in performance on the Montreal Cognitive Assessment between baseline and end of study (score = 0-30, where a higher score indicates a better outcome) | 365 days | 
| National Institutes of Health toolbox - Cognitive battery score | Change in performance on the cognitive battery of the National Institutes of Health toolbox between baseline and end of study (where a higher score indicates a better outcome) | 365 days | 
| Boston cookie theft picture description task | Change in spontaneous speech between baseline and end of study. Components of spontaneous speech include lexical features (part-of-speech, word types and frequencies), syntactic complexity, grammaticality, fluency, vocabulary richness, and acoustic features. | 365 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anticoagulation, cerebral venous thrombosis