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    Summary
    EudraCT Number:2018-001735-49
    Sponsor's Protocol Code Number:CTU/2015/174
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-01-22
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2018-001735-49
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    RIvaroxaban for Stroke patients with AntiPhospholipid Syndrome
    A.3.2Name or abbreviated title of the trial where available
    RIvaroxaban for Stroke patients with AntiPhospholipid Syndrome
    A.4.1Sponsor's protocol code numberCTU/2015/174
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03684564
    A.5.4Other Identifiers
    Name:Sponsor Number Number:CTU/2015/174
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity College London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportVersus Arthritis (formerly Arthritis Research UK)
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationComprehensive Clinical Trials Unit at UCL
    B.5.2Functional name of contact pointJade Dyer
    B.5.3 Address:
    B.5.3.1Street AddressCCTU at UCL, Institute of Clinical Trials & Methodology
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeWC1V 6LJ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02079074674
    B.5.6E-mailrisaps@ucl.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Rivaroxaban
    D.2.1.1.2Name of the Marketing Authorisation holderBayer AG
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRivaroxaban
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRivaroxaban
    D.3.9.3Other descriptive nameTrade Name Xarelto
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Warfarin Sodium
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameWarfarin Sodium
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNWarfarin sodium
    D.3.9.1CAS number 81-81-2
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with stroke or other ischaemic brain injury who have antiphospholipid syndrome (APS), with or without systemic lupus erythematosus (SLE)
    E.1.1.1Medical condition in easily understood language
    Patients with APS (an immune system disorder causing blood clots), with/without lupus, with ischaemic stroke (occurring when blood flow to an area of brain is cut off) or other ischaemic brain injury
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10002817
    E.1.2Term Antiphospholipid syndrome
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    We hypothesise that rivaroxaban is no worse that warfarin for the prevention of recurrent ischaemic stroke (which occurs when blood flow to an area of brain is cut off) or other ischaemic brain damage in APS 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 (antiphospholipid syndrome) patients, with or without lupus, 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).

    The primary outcome measure will be changes in the volume of brain white matter hyperintensities (WMH; small brain lesions that are a sensitive marker of ischaemic damage), as a surrogate marker of ischaemic brain damage, before the trial treatment starts and after 24 months of the trial treatment.

    If rivaroxaba
    E.2.2Secondary objectives of the trial
    The trial will also compare the following secondary outcomes between patients on rivaroxaban versus warfarin:

    Efficacy:
    - Other brain MRI scan appearances, including detailed assessment of alterations in brain structure indicative of ischaemic brain damage
    - Thrombosis (blood clots), including in arteries (e.g. stroke) or in veins, death; and change in cognitive (thinking) function based on assessment at trial visits

    Safety
    - All bleeding events: major, clinically relevant or minor
    - Serious Adverse Events (SAE) other than major bleeding
    - Brain microbleeds (tiny brain bleeds, visible on MRI brain scans), will be assessed as a surrogate marker of bleeding risk

    Health Economics:
    - The cost of the two treatment groups using quality of life questionnaires and health economics

    Anticoagulation (blood thinning) intensity:
    - Rivaroxaban blood levels will be measure in patients on rivaroxaban
    - In patients on warfarin, the percentage of time that the patient is within the target INR r
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion 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 at least two consecutive 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 MRI (including diffusion weighted imaging (DWI) 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 (WMH) 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.
    NB: patients weighing <50kg or >120kg may be included in RISAPS on a case by case basis, following assessment by the Investigator (PI) and consultation with the Chief Investigator (CI)/delegate before enrolment.
    E.4Principal exclusion criteria
    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
    a. Systemic azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, posaconazole)
    b. Patients on 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 GP and healthcare professional responsible for anticoagulation care, of participation
    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. Patients with known galactose intolerance, total lactase deficiency or galactose malabsorption.
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective of RISAPS is 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.

    The primary outcome measure is the rate of change in brain WMH volume between baseline and 24 months follow up, assessed on MRI, a surrogate marker of ischaemic damage.

    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary end point will be analysed after the last patient recruited has undergone their last trial visit and 24 month MRI.
    E.5.2Secondary end point(s)
    A. Efficacy
    1. Neuroradiological markers
    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 T1w volumetric images
    iii) Brain infarcts
    a) cortical or subcortical
    b) assessment of volume
    iv) Cerebral venous occlusions
    2. Clinical
    i) Vascular events
    a) Ischaemic stroke or TIA
    b) Occlusive arterial events in other sites including systemic embolism
    c) Cerebral venous thrombosis
    d) Venous thromboembolism in other sites
    e) Microvascular thrombosis
    f) Superficial venous thrombosis
    ii) Death
    iii) Composite clinical outcomes
    a) A composite of all thrombotic events: arterial, venous microvascular; and death
    b) Major adverse cardiac and cerebrovascular events (MACCE)
    iv) The rate of change in cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA)
    B. Safety
    1. Bleeding: All bleeding events: major, clinically relevant or minor
    2. Serious adverse events other than major bleeding
    3. Cerebral microbleeds (CMB) assessed with susceptibility-weighted imaging (SWI) as a surrogate marker of bleeding risk.
    C. Health Economics
    1. Quality of life (QoL) will be assessed using EQ-5D-5L
    2. Mean incremental cost per quality adjusted life year (QALY)
    D. Anticoagulation intensity
    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
    E. Exploratory Outcomes
    1. Rivaroxaban pharmacokinetic (PK) modelling
    2. Cerebral blood flow (CBF) derived from MR perfusion imaging using an arterial spin labelling (ASL) technique
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary endpoints will be analysed after the last patient recruited has had their final follow-up visit.

    Unless an interim analysis of safety endpoints is requested by the IDMC following any concerns regarding participant safety.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence Yes
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of trial will be defined as the date when all outstanding data queries have been resolved following the last participant’s last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 120
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state140
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Participants randomised to rivaroxaban will be invited to discuss with their treating trial investigator/main doctor about continuing on rivaroxaban at the end of the trial if they wish to do so.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-01
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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