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    Summary
    EudraCT Number:2012-002345-38
    Sponsor's Protocol Code Number:12/0033/CTU/IMM/001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-10-08
    Trial results View 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 number2012-002345-38
    A.3Full title of the trial
    A prospective randomised controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Comparison of rivaroxaban (Xarelto®; Bayer HealthCare), fixed-dose oral anticoagulant (blood thinner), versus warfarin in patients with antiphospholipid syndrome (called APS), with or without 'lupus' (systemic lupus erythematosus)
    A.3.2Name or abbreviated title of the trial where available
    Rivaroxaban in Antiphospholipid Syndrome (RAPS)
    A.4.1Sponsor's protocol code number12/0033/CTU/IMM/001
    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 supportArthritis Research UK
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportBayer plc
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity College London
    B.5.2Functional name of contact pointSimon Clawson
    B.5.3 Address:
    B.5.3.1Street AddressClinical Trials Unit, UCL, Gower Street
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeWC1E 6BT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02076795669
    B.5.6E-mailsimon.clawson@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 Xarelto
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Pharma AG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.9.1CAS number 366789-02-8
    D.3.9.3Other descriptive nameTrade name Xarelto
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15 to 20
    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 Information not present in EudraCT
    D.2.1.1.1Trade name The generic name is warfarin and many producers will be involved
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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
    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
    D.3.9.1CAS number 81-81-2
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    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 antiphospholipid syndrome (APS), with or without systemic lupus erythematosus (SLE).
    E.1.1.1Medical condition in easily understood language
    Patients with a condition where antibodies can affect the blood coagulation mechanisms leading to blood clots (antiphospholipid syndrome or APS), with or without ‘Lupus’ (systemic lupus erythematosus
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10002817
    E.1.2Term Antiphospholipid syndrome
    E.1.2System Organ Class 10021428 - Immune 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
    The primary aim of the trial is to assess whether the anticoagulant effects of rivaroxaban are not inferior to those of warfarin. This will be achieved by comparing the percentage change in endogenous thrombin potential (ETP), assessed by the thrombin generation test (TGT), from randomisation to day 42. The TGT is a global measure of anticoagulation, which can assess the anticoagulant effects of both rivaroxaban and warfarin (drugs with very different modes of action on the coagulation mechanism). The TGTs will be performed in the UCL Haemostasis Research Unit.
    E.2.2Secondary objectives of the trial
    1) To compare the effectiveness of the treatment between the two arms of the trial: i) Further blood clots in blood vessels (venous thromboembolism) ii) A combination of further venous thromboembolism and other thrombotic events 2) To compare serious adverse events and all bleeding events in patients on rivaroxaban versus those on warfarin 3) To compare the completed quality of life questionnaires at baseline and at day 180 for patients on rivaroxaban versus those on warfarin. 4) To assess compliance to the study drugs by performing assays in the plasma from the patients on rivaroxaban (anti-Xa assay) and in patients on warfarin (INR and factor X amidolytic assay as an antiphospholipid antibody-independent assessment of anticoagulation). Percentage time in therapeutic range (TTR) between baseline and day 180 will be calculated in patients on warfarin.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Patients with thrombotic APS, with or without SLE, who have had either a single episode of VTE whilst not on anticoagulation or recurrent episode(s) which occurred whilst off anticoagulation or on sub-therapeutic anticoagulant therapy 2) Patients with a target INR of 2.5 (range 2.0 – 3.0) 3) Treated with warfarin for a minimum period of six months since last VTE 4) Female patients must be using adequate contraception with exception to postmenopausal or sterilised women
    E.4Principal exclusion criteria
    1) Previous arterial thrombotic events due to APS 2) Recurrent venous thromboembolic events whilst on warfarin 3) Pregnant or lactating women 4) Severe renal impairment (creatinine clearance (calculated using the Cockcroft & Gault Equation Appendix A) < 30 mL/min (i.e. 29 mL/min or less)) 5) Liver function tests (ALT > 2 x ULN) 6) Thrombocytopenia (platelets < 75 x 10^9/L) 7) Non-compliance on warfarin (based on clinical assessment) 8) Patients on azole antifungals (e.g. ketoconazole, itraconazole, voriconazole and posaconazole) 9) Patents on Human Immunodeficiency Virus (HIV) protease inhibitors (e.g. ritonavir) 10) Patients on strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine or phenobarbital) 11) Patients less than 18 years of age
    E.5 End points
    E.5.1Primary end point(s)
    Percentage change in endogenous thrombin potential (ETP), assessed by the thrombin generation test (TGT), from randomisation to day 42.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The time point for the primary outcome is at the first trial visit, which will take place 42 days (±12days) after trial randomisation.
    E.5.2Secondary end point(s)
    a) Efficacy: i) recurrent venous thromboembolism (VTE) alone; ii) a composite of recurrent VTE and other thrombotic events. iii) The thrombin generation curve will also be quantified in terms of: the lag-time; the time to peak; and peak thrombin concentration. b) Safety: i) serious adverse events; ii) all bleeding events. c) Quality of life (QoL): EQ5D 5L. d) Laboratory assessment of compliance: i) anti-Xa assay in patients on rivaroxaban; ii) factor X amidolytic assay as an antiphospholipid antibody-independent assessment of anticoagulation, in addition to an International Normalised Ratio (INR) in patients on warfarin, iii) percentage time in therapeutic range (TTR) between baseline and day 180 in patients on warfarin.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All bleeding and thrombotic events are going to be collected at each visit (day 42 (±12 days), day 90 (±21 days), day 180 (±21 days) and day 210 (±21 days)). Quality of life will be measured at baseline and at six months using the EQ 5D 5L questionnaire. Laboratory measures of compliance will be measured at day 42 (±12 days) on trial treatment.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    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) No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Warfarin as an IMP
    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 concerned2
    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 No
    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 the trial will be declared on completion of entry of all clinical data.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 148
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state156
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 156
    F.4.2.2In the whole clinical trial 156
    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)
    After the interventional stage of the trial patients will be provided with the treatment that is considered appropriate care at the time. Rivaroxaban is licensed and commercially available for the treatment of deep vein thrombosis (DVT) and prevention of recurrent DVT and pulmonary embolism following acute DVT in adults. Therefore, although it would not be available via the trial, it will be available through private health care or may be available through the NHS
    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 Decision2012-10-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-10-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-06-08
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