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RIvaroxaban for Stroke Patients With AntiPhospholipid Syndrome (RISAPS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03684564
Recruitment Status : Not yet recruiting
First Posted : September 25, 2018
Last Update Posted : July 20, 2020
Sponsor:
Collaborators:
Arthritis Research UK
King's College London
University College London Hospitals
Hammersmith Hospitals NHS Trust
Guy's and St Thomas' NHS Foundation Trust
Barts & The London NHS Trust
King's College Hospital NHS Trust
Manchester University NHS Foundation Trust
Barking, Havering and Redbridge University Hospitals NHS Trust
St George's University Hospitals NHS Foundation Trust
Information provided by (Responsible Party):
University College, London

Brief Summary:

Rivaroxaban Versus Warfarin for Stroke Patients With Antiphospholipid Syndrome, With or Without SLE (RISAPS): a Randomised, Controlled, Open label, Phase II/III, Non-inferiority Trial.

140 patients will be randomised with a ratio of 1:1 to receive either:

  • Rivaroxaban 15mg twice daily orally for 24 months or
  • Warfarin (standard of care in the RISAPS trial) to maintain a target INR of 3.5 (range 3.0-4.0) for 24 months.

The primary outcome of the trial is the rate of change in brain white matter hyperintensity (WMH) volume between baseline and 24 months follow up, assessed on brain magnetic resonance imaging (MRI), a surrogate marker of ischaemic damage.


Condition or disease Intervention/treatment Phase
Antiphospholipid Syndrome Systemic Lupus Erythematosus Stroke Ischemic Stroke Brain Ischemia Drug: Rivaroxaban Drug: Warfarin Phase 2 Phase 3

Detailed Description:

The RISAPS trial follows on from the RAPS (Rivaroxaban in Antiphospholipid Syndrome) study that showed that rivaroxaban could offer a potentially effective alternative to warfarin for patients with antiphospholipid syndrome (APS) who have thrombosis (blood clots) in their veins, rather than in their arteries and require standard intensity anticoagulation (blood thinning).

Currently, APS patients who have had an ischaemic stroke (which occurs when blood flow to an area of brain is cut off) are treated with warfarin to reduce the risk of a recurrence. Warfarin tends to have a variable 'blood thinning' effect in patients with APS, necessitating frequent (usually weekly) INR blood tests to monitor the effect of the warfarin, which is inconvenient for patients.

The RISAPS trial will compare higher intensity (higher dose) rivaroxaban versus higher intensity warfarin (current standard of care treatment) for 24 months, in APS patients, with or without lupus (systemic lupus erythematosus; SLE), requiring higher intensity anticoagulation after experiencing a stroke, a 'mini stroke' (also known as a transient ischaemic attack) or other ischaemic brain damage (caused by blood clots in the brain arteries or smaller blood vessels). Rivaroxaban, unlike warfarin, does not require regular blood tests, because it has a more predictable blood thinning effect.

Furthermore, rivaroxaban does not interact with food or alcohol and has fewer interactions than warfarin with other drugs. If rivaroxaban is no worse than warfarin for anticoagulation of APS patients with stroke or other ischaemic brain manifestations, it could become the standard of care for the treatment of APS patients, with or without lupus, who have experienced stroke or other ischaemic brain manifestations and improve patients' quality of life.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants enrolled in RISAPS will be randomly allocated 1:1 to receive either oral rivaroxaban 15mg twice daily or oral warfarin (standard of care in the RISAPS trial) to maintain a target INR of 3.5 (range 3.0-4.0) for 24 months.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Rivaroxaban Versus Warfarin for Stroke Patients With Antiphospholipid Syndrome, With or Without SLE (RISAPS): a Randomised, Controlled, Open Label, Phase II/III, Non-inferiority Trial
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023


Arm Intervention/treatment
Experimental: Rivaroxaban (Treatment Arm) Drug: Rivaroxaban
Oral tablet 15 mg twice daily for 24 months

Active Comparator: Warfarin (Control Arm) Drug: Warfarin
Oral anticoagulant given as standard of care in the RISAPS trial to maintain a target INR of 3.5 (range 3.0-4.0) for 24 months




Primary Outcome Measures :
  1. To compare the efficacy of high-intensity oral rivaroxaban (15mg twice daily) vs high-intensity warfarin, target INR 3.5 (range 3.0-4.0), in patients with APS with or without SLE who have had a stroke or other ischaemic brain manifestations. [ Time Frame: 24 months ]
    The comparison of efficacy will be based on the rate of change in brain white matter hyperintensity (WMH) volume on MRI, a surrogate marker of ischaemic damage, between baseline and 24 months follow up.


Secondary Outcome Measures :
  1. A) Efficacy - Neuroradiological markers [ Time Frame: 24 months ]

    i) Mean diffusivity and fractional anisotropy as a measure of microstructural white matter damage derived from diffusion tensor imaging (DTI) ii) Changes in total brain volume, white matter volume and grey matter volume on T1 weighted volumetric images iii) Brain infarcts

    1. cortical or subcortical
    2. assessment of volume iv) Cerebral venous occlusions

  2. Clinical [ Time Frame: 24 months ]

    (i) Vascular events

    1. Ischaemic stroke or transient ischaemic attack
    2. Occlusive arterial events in other sites including systemic embolism
    3. Cerebral venous thrombosis
    4. Venous thromboembolism in other sites
    5. Microvascular thrombosis
    6. Superficial venous thrombosis

    The following events defined and reported according to CTCAE v5.

    ii) Death

    iii) Composite clinical outcomes

    1. A composite of all thrombotic events: arterial, venous, microvascular and death.
    2. Major adverse cardiac and cerebrovascular events (MACCE)

    iv) Rate of change in cognitive function assessed by the Montreal Cognitive Assessment (MoCA) in conjunction with the Queen Square Cognitive Assessment score


  3. B) Safety [ Time Frame: 24 months ]
    (i) Bleeding: All bleeding events: major, clinically relevant non-major or minor (ii) Serious adverse events other than major bleeding (iii) Cerebral microbleeds (CMB) assessed with susceptibility-weighted imaging (SWI) as a surrogate marker of bleeding risk.

  4. C) Health Economics [ Time Frame: 24 months ]
    1. Quality of life (QoL) assessed using EQ-5D-5L
    2. Health and social care resource use assessed using trial follow-up visit case report forms (CRFs)
    3. Mean incremental cost per quality adjusted life year (QALY)

    Serious adverse events other than major bleeding using the criteria within the CTCAE version 5.


  5. D) Anticoagulation intensity [ Time Frame: 24 months ]
    1. Rivaroxaban i) Rivaroxaban anti-Xa levels
    2. Warfarin i) Time in target therapeutic range (TTR) ii) Amidolytic factor X as a lupus anticoagulant independent assessment of warfarin anticoagulant effect

  6. ii) Changes in total brain volume, white matter volume and grey matter volume on T1w volumetric images on MRI [ Time Frame: 24 Months ]
    This will be used as a marker for neurological efficacy of the IMP compared with current standard of care.


Other Outcome Measures:
  1. E. Exploratory Outcomes [ Time Frame: 24 months ]
    1. Rivaroxaban pharmacokinetic (PK) modelling
    2. Cerebral blood flow (CBF) derived from MR perfusion imaging using an arterial spin labelling (ASL) technique



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Patients must be confirmed as having persistent antiphospholipid antibodies (aPL), defined as: positivity of one or more aPL, i.e. lupus anticoagulant, IgG and/or IgM anticardiolipin and/or anti beta 2 glycoprotein I antibodies at >40 GPL or MPL units or > the 99th centile of normal, on two or more occasions, at least 12 weeks apart.
  2. One or more of: a) Ischaemic stroke; b) transient ischaemic attack (TIA) with evidence of either acute or chronic ischaemic injury on brain magnetic resonance imaging (MRI) (including diffusion-weighted magnetic resonance imaging lesion(s), previous cortical or subcortical infarction(s), or white matter hyperintensities) and diagnosed by a clinician with expertise in stroke; c) brain infarcts (territorial or subcortical) or white matter hyperintensities of presumed vascular origin on brain MRI, with or without cognitive impairment; and an expert clinical opinion that anticoagulation is a reasonable treatment option (with the aim of preventing ischaemic brain injury).
  3. Women must be on adequate contraception, barrier or hormonal, unless postmenopausal or sterilised.

Exclusion Criteria

  1. Pregnant or lactating women
  2. Severe renal impairment with creatinine clearance <30 mL/min (i.e. 29 mL/min or less)
  3. Liver function tests ALT > 3 x ULN
  4. Cirrhotic patients with Child Pugh B or C
  5. Thrombocytopenia (platelets < 75 x 109/L)
  6. Non-adherence on warfarin (based on clinical assessment)
  7. Patients taking strong inhibitors of both CYP3A4 and P-gp pathways such as

    1. Systemic azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, posaconazole)
    2. Patients on human immunodeficiency virus (HIV) protease inhibitors (e.g. ritonavir)
  8. Patients on strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort)
  9. Patients on dronedarone
  10. Patients less than 18 years of age
  11. Refusal to consent to the site informing General Practitioner and Healthcare Professional responsible for anticoagulation care of the participant
  12. Contraindications to MRI (e.g. cardiac pacemaker, severe claustrophobia, inability to lie flat: patients who do not meet local safety rules for MRI).
  13. Patients at high risk of bleeding and not suitable for anticoagulation therapy.
  14. Previous known allergy or intolerance to warfarin or rivaroxaban.
  15. Women planning to become pregnant within the 2-year follow-up period.
  16. Patients with known galactose intolerance, total lactase deficiency or galactose malabsorption.
  17. Any other reason that the PI considers would make the patient unsuitable to enter RISAPS.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03684564


Contacts
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Contact: RISAPS Trial Manager 020 3108 8040 risaps@ucl.ac.uk

Sponsors and Collaborators
University College, London
Arthritis Research UK
King's College London
University College London Hospitals
Hammersmith Hospitals NHS Trust
Guy's and St Thomas' NHS Foundation Trust
Barts & The London NHS Trust
King's College Hospital NHS Trust
Manchester University NHS Foundation Trust
Barking, Havering and Redbridge University Hospitals NHS Trust
St George's University Hospitals NHS Foundation Trust
Investigators
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Principal Investigator: Hannah Cohen University College London Hospitals NHS Foundation Trust/University College London
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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT03684564    
Other Study ID Numbers: CTU/2015/174
First Posted: September 25, 2018    Key Record Dates
Last Update Posted: July 20, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Stroke
Ischemic Stroke
Brain Ischemia
Lupus Erythematosus, Systemic
Antiphospholipid Syndrome
Syndrome
Ischemia
Disease
Pathologic Processes
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Warfarin
Rivaroxaban
Anticoagulants
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action