Study of Rivaroxaban for CeREbral Venous Thrombosis (SECRET)

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

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

Study Overview

• Status: Completed
• Conditions: Cerebral Venous Thrombosis
• Intervention / Treatment: Drug: Rivaroxaban; Drug: Standard of care

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Foothills Medical Centre
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 1T2
      • Kelowna General Hospital
    • Vancouver, British Columbia, Canada, V5Z1M9
      • Vancouver General Hospital
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton Health Sciences Centre
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1Y 4E9
      • The Ottawa Hospital Research Institute
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5T 2S8
      • Toronto Western Hospital
  • Quebec
    • Montréal, Quebec, Canada, H2X 0A9
      • Centre Hospitalier de l'Universite de Montreal
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • Royal University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Patients aged 18 and above
2. New diagnosis of symptomatic cerebral venous thrombosis as confirmed on CT venogram or MR venogram
3. Ability to randomize within 14 days of neuroimaging-confirmed diagnosis
4. The treating clinician is of the opinion that the patient is appropriate for oral anticoagulation as per standard of care
5. Patient or legally authorized representative is able to give written informed consent

Exclusion criteria:

1. 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
2. Patient is anticipated to require invasive procedure (e.g. lumbar puncture, thrombectomy, hemicraniectomy) prior to initiation of oral anticoagulation**
3. Patient is unable to swallow due to depressed level of consciousness†
4. Impaired renal function (i.e., CrCl < 30 mL/min using Cockroft-Gault equation)
5. Pregnancy; if a woman is of childbearing potential a urine or serum beta human chorionic gonadotropin (β-hCG) test is positive
6. Breastfeeding at the time of randomization
7. Bleeding diathesis or other contraindication to anticoagulation
8. Any concurrent medical condition requiring mandatory antiplatelet or anticoagulant use
9. Concomitant use of strong CYP3A4 inducers (e.g., ongoing use of dilantin, carbamazepine, HIV protease inhibitors) or CYP3A4 inhibitors (e.g., diltiazem, ketoconazole)
10. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivaroxaban	Drug: Rivaroxaban; Rivaroxaban 20 mg daily (15 mg daily in participants with a CrCl 30-49 mL/min as per the Cockroft-Gault equation); Other Names: Xarelto
Active Comparator: Standard of care; Unfractionated heparin Low-molecular weight heparin (dalteparin, enoxaparin, tinzaparin) Warfarin	Drug: Standard of care; 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.; Other Names: Heparin, Coumadin, Fragmin, Lovenox, Innohep

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of British Columbia
• Investigators: Principal Investigator: Thalia S Field, MD FRCPC, University of British Columbia

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2019
• Primary Completion (Actual): October 5, 2022
• Study Completion (Actual): October 5, 2022

Study Registration Dates

• First Submitted: June 1, 2017
• First Submitted That Met QC Criteria: June 5, 2017
• First Posted (Actual): June 7, 2017

Study Record Updates

• Last Update Posted (Estimate): December 14, 2022
• Last Update Submitted That Met QC Criteria: December 12, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: anticoagulation; cerebral venous thrombosis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Venous Thrombosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Heparin
• Other Study ID Numbers: H17-00440

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Upon completion of the SECRET Trial, a public use database will be prepared by stripping any and all personal identifiers. The public use database, consisting of several data files, should contain: (1) baseline and demographic characteristics; (2) outcomes assessments; (3) CT/MRI data; (4) concomitant medications and procedures; and (5) adverse events. Each data file is made available as a formatted SAS dataset or other electronic format. The data files are distributed along with the data dictionary and a brief instruction ("Readme") file. These data files will be made available to the public only after all major manuscripts (including secondary analysis papers) of the Trial are accepted for publication in peer-reviewed journals.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No