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    Summary
    EudraCT Number:2018-003588-69
    Sponsor's Protocol Code Number:W2018.034
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-11-08
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-003588-69
    A.3Full title of the trial
    The ENDURRANCE-1 Study.
    Exploring durable remission with rituximab in ANCA associated vasculitis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The ENDURRANCE-1 Study.
    Exploring durable remission with rituximab in ANCA associated vasculitis
    A.3.2Name or abbreviated title of the trial where available
    The ENDURRANCE-1 study
    A.4.1Sponsor's protocol code numberW2018.034
    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 SponsorLeiden University Medical Center
    B.1.3.4CountryNetherlands
    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 supportLUMC leiden
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden university medical centre
    B.5.2Functional name of contact pointTeng
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333ZA
    B.5.3.4CountryNetherlands
    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 Cyclophosphamide
    D.2.1.1.2Name of the Marketing Authorisation holderBaxter Médico-Farmacêutica, Lda., Sintra, Portugal
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameCyclophosphamide
    D.3.2Product code 5009111000001105
    D.3.4Pharmaceutical form Powder for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    ANCA associated vasculitis
    ANCA geassocieerde vasculitis
    E.1.1.1Medical condition in easily understood language
    Small vessel vasculitis
    kleine vaten vasculitis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    In this randomized study the primary objective is to prove the superiority of combination treatment RTX with cyclophosphamide to achieve a state of MRA in AAV patients as compared to RTX alone. The primary objective is to assess the time to an ANCA negative test.
    E.2.2Secondary objectives of the trial
    Secondary objectives are:
    - time to ANCA return
    - duration of B-cell depletion
    - composition of the memory B-cell and plasma cell compartment before and after treatment
    - to investigate whether MRA is associated with disease flares
    - to investigate whether MRA is associated with (a shorter) time to a disease flares
    - to investigate whether the presence or absence of MRA after RTX can guide a personalized treatment
    - to assess the safety parameters of each treatment arm including adverse events according to WHO toxicity criteria, time to immune reconstitution and recording of infectious events
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    4.1. Inclusion criteria
    Subjects enrolled in the study must meet the following inclusion criteria:
    1) Clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic Polyangiitis (MPA), consistent with Chapel-Hill Consensus Conference definitions26
    2) Aged at least 18 years, with newly-diagnosed or relapsed AAV with ‘generalised disease’, defined as involvement of at least one major organ (e.g. kidney, lung, heart, peripheral or central nervous system), requiring induction treatment with cyclophosphamide or rituximab
    3) Positive test for anti-PR3 or anti-MPO (current or historic)
    4) Willing and able to give written Informed Consent and to comply with the requirements of
    the study protocol
    E.4Principal exclusion criteria
    4.2. Exclusion criteria
    Subjects will be excluded from participation if they meet any of the following exclusion criteria:
    1) Pregnant or breast-feeding
    2) Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG
    3) Significant hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L)
    5) Active infection at time of screening, as follows:
    - Hospitalization for treatment of infection within previous 60 days of day 0 of the study
    - Use of parenteral (intravenous of intramuscular) antibiotics (including anti-bacterials, anti-virals, anti-fungals or anti-parasitic agents) within previous 60 days of day 0 of the study
    - Serological evidence of viral hepatitis defined as: patients positive for HbsAg
    test or HBcAb or a positive hepatitis C antibody not treated with antiviral medication
    - Have a historically positive HIV test or test positive at screening for HIV
    6) Have a history of a primary immunodeficiency
    7) Have a significant infection history that in the opinion of the investigator would make the candidate unsuitable for the study
    8) Have a neutrophil count of < 1.5x10E9/L
    9) Evidence of hepatic disease: AST, ALT, alkaline phosphatase, or bilirubin > 3 times the upper limit of normal before start of dosing
    10) Have a CD19 count of < 40x106 cells/L (equal to < 40 cells/uL; equal to < 40 cells/mm3)
    11) Have any other clinically significant abnormal laboratory value in the opinion of the investigator
    12) Required dialysis or plasma exchange within 12 weeks prior to screening
    13) Received intravenous glucocorticoids, >3000mg methylprednisolone equivalent, within 4 weeks prior to screening
    14) Immunization with a live vaccine 1 month before screening
    15) History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the patient at unacceptable risk for study participation.
    16) Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies
    E.5 End points
    E.5.1Primary end point(s)
    The primary immunological parameter will be the time to seroconversion of ANCA to negative, i.e. below the detection range of a high-quality ANCA immunoassay.
    E.5.1.1Timepoint(s) of evaluation of this end point
    SCR
    BL
    2
    4
    8
    12
    16
    20
    24
    32
    40
    48
    56
    64
    72
    80
    88
    96
    104
    EoS
    E.5.2Secondary end point(s)
    - assess the time to ANCA return defined as seroconversion to positive on at least 2 consecutive visits (the time of the first is then representative time of seroconversion) OR a doubling of the ANCA serum levels PR3 or MPO ELISA test compared to a previously achieved nadir
    - duration of B-cell depletion defined as time taken to detect a repopulation of B-cells above the detection limit of standard flowcytometry (i.e. > 1x106 cells/L)
    - composition of the memory B-cell and plasma cell compartment before and after treatment using standard and high-sensitivity flowcytometry
    - to investigate whether MRA is associated with disease flares where degrees of MRA are defined as seroconversion of ANCA to negative with or without B-cell depletion
    - to investigate whether MRA is associated with (a shorter) time to a disease flares
    - to assess the safety parameters of each treatment arm including adverse events according to WHO toxicity criteria and recording of infectious events
    E.5.2.1Timepoint(s) of evaluation of this end point
    SCR BL 2 4 8 12 16 20 24 32 40 48 56 64 72 80 88 96 104 EoS

    experimental high sensitivity flow cytometry:
    scr, bl, 4, 12, 24, 40, 56, 72, 88, 104, eos
    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 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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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
    end of study: week 104
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    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 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 state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 44
    F.4.2.2In the whole clinical trial 44
    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)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-11-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-07
    P. End of Trial
    P.End of Trial StatusOngoing
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