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    EudraCT Number:2016-002478-11
    Sponsor's Protocol Code Number:2.0
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-07-01
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedAustria - BASG
    A.2EudraCT number2016-002478-11
    A.3Full title of the trial
    Very low doses of Rituximab for off-label treatment – a Pilot Trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Very low doses of Rituximab for autoimmune diseases, for which rituximab is not approved for - a Pilot Trial
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code number2.0
    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 SponsorMedical University of Vienna, Department of Internal medicine I
    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 supportMedical University of Vienna, Department of Clinical Pharmacology
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedical University of Vienna, Department of Clinical Pharmacology
    B.5.2Functional name of contact pointDepartment of Clinical Pharmacology
    B.5.3 Address:
    B.5.3.1Street AddressWähringer Gürtel 18-20
    B.5.3.2Town/ cityVienna
    B.5.3.3Post code1090
    B.5.4Telephone number004314040029810
    B.5.5Fax number004314040029980
    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. name Mabthera or biosimilar Rituximab
    D. of the Marketing Authorisation holderRoche Registration Limited or Producer of biosimilar Rituximab
    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 nameRituximab
    D.3.2Product code Rituximab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.2Current sponsor codeRituximab
    D.3.9.3Other descriptive nameRituximab
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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) Yes
    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
    Autoimmune-haemolytic Anemia
    Antiphospholipid Syndrome
    Immune-mediated Thrombocytopenia
    E.1.1.1Medical condition in easily understood language
    antibodies directed against
    - red blood cells
    - phospholipids or phospholipid-binding proteins
    - platelets

    with consecutive anemia, thrombocytopenia or risk to experience thromboembolic events
    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 LLT
    E.1.2Classification code 10003825
    E.1.2Term Autoimmune hemolytic anemia
    E.1.2System Organ Class 100000154058
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10023095
    E.1.2Term ITP
    E.1.2System Organ Class 100000157088
    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
    Autoimmune haemolytic anaemia, antiphospholipid syndrome: To investigate whether 5mg/m2, 20mg or 50mg rituximab suffice to suppress CD20+ cells over a defined period of time

    Immune-mediated thrombocytopenia:
    to investigate whether repetitive infusions of 50mg rituximab over 2 years (8 every 3 months) reduce the relapse rate of rituximab treated patients, which according to published data is 38%.
    E.2.2Secondary objectives of the trial
    To investigate the Pharmacokinetics of very low doses of Rituximab
    To investigate the immunogenicity of very low doses of Rituximab
    To calculate the drug cost reduction of our treatment regimen
    To investigate the safety of very low doses of Rituximab
    To investigate the effects of very low doses of Rituximab on hemolysis specific parameters and hemoglobin
    To investigate CD20+ cell counts in patients with immune-mediated thrombocytopenia
    To investigate platelet counts and response to rituximab treatment in patients with immune-mediated thrombocytopenia
    To investigate platelet function after infusion of rituximab
    To investigate antibody levels directed against platelets (immune-mediated thrombocytopenia)
    To investigate Cardiolipin-, beta2-glycoprotein-I-, antiphospholipid- antibody levels and lupus anticoagulant in patients with anitphospholipid syndrome
    To investigate coagulation specific biomarkers in those patients with antiphospholipid syndrome
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Signed informed consent obtained before any trial related activities
    • Ability to understand the nature and the purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the trial
    • Men or women aged ≥18 years of age with a diagnosis of autoimmune-mediated haemolytic anemia, antiphospholipid syndrome or immune-mediated thrombocytopenia
    • In female subjects either childbearing potential terminated by surgery or one year post- menopausal, or a negative urine pregnancy test during screening and the willingness not to become pregnant during the entire study period by practicing reliable methods of contraception
    • Normal findings in medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant
    • Normal laboratory values unless the investigator considers an abnormality to be clinically irrelevant
    E.4Principal exclusion criteria
    • Previous treatment with rituximab, obinutuzumab, ofatumumab or ocrelizumab within 12 months
    • Clinically relevant infection (<1 week)
    • Intravenous immunoglobulins, unless cyclic thrombocytopenia occures
    • Relevant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, hematological, endocrine, inflammatory or neurological diseases, that may interfere with the aim of the study
    • Ascertained or presumed hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs or major allergic reactions in general, which the investigator considers may compromise the safety of the participants
    • Use of medication during 2 weeks before the start of the study, which the investigator considers may affect the validity of the study
    • Drug abuse, alcohol (>1 drinks/day, defined according to USDA Dietary Guidelines)
    • Pregnancy (positive pregnancy test at screening or during study phase), lactation or unreliable contraception in female subjects with child-bearing potential
    E.5 End points
    E.5.1Primary end point(s)
    Antiphospholipid Syndrome and Autoimmune haemolytic anaemia: CD19/20+ cell counts
    Immune-mediated Thrombocytopenia:
    Relapse rate
    E.5.1.1Timepoint(s) of evaluation of this end point
    Antiphospholipid Syndrome, Autoimmune-haemolytic anaemia:
    baseline, End of each infusion, +2h after infusion
    potentially +24h and +7d after first infusion
    before 2nd infusion
    before 3rd infusion
    during end-of-study visit

    Immune-mediated Thrombocytopenia:
    End of study visit (2 years)
    E.5.2Secondary end point(s)
    - plasma concentrations of rituximab
    - Immunogenicity (neutralizing anti-drug antibodies, human antichimeric antibodies)
    - Safety (Laboratory data and adverse events)
    - Platelet counts and reticulated platelets
    - hemoglobin levels, hemolysis specific parameters
    -antibody levels (antiphospholipid-specific antibodies, anti-platelet antibodies)
    - platelet function
    - coagulation specific tests in patients with immune-mediated thrombocytopenia
    - immune-mediated thrombocytopenia: response: permanent suppression of CD20+ cell counts, platelet counts, complete response (defined as platelets above 100 G/L), complete sustained response (permanent platelet count >100 G/L), partial response (platelets 50-100 G/L) for patients with initial platelet counts <50 G/L, as stable patients will also be included a 50% increase in platelet counts from baseline platelet count will be considered as response, overall response (includes the before mentioned responses), patients with platelets <30 G/L are defined as non-responders; response at 1, 3, 6 months, time to complete response, relapse will be defined as >50% reduction in platelet counts or platelet counts <30G/L after initial response or need for further treatment, relapse-free survival, treatment free survival (need for further treatment, usually at <30 G/L)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - PK at each visit to the ward (baseline, end of each infusion and 1 and 2h thereafter, control visits)
    - AE, Safety, (baseline, end of each infusion and 1 and 2h thereafter, control visits)
    - Immunogenicity: Baseline of each study day
    -hemoglobin levels: Trial day 1 each time-point, and baseline of all other trial days, all control visits
    - hemolysis specific data: baseline of each study day and all control visits
    - antibody levels: at each visit
    - platelet function: during first two infusions
    - coagulation specific biomarkers: every visit
    - response at 1, 3, 6 months
    -CD20+ cells: each visit
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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. 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 No
    E.8.1.1Randomised No
    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 No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    We plan to include 8-12 patients with anti-phospholipid syndrome and 8-12 patients with autoimmune hemolytic anaemia in this pilot trial.

    We plan to include a minimum of 24 patients with immune-mediated thrombocytopenia
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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: 24
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 24
    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 state48
    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)
    We will recruit patients in collaboration with the Department of Hematology. Treatment of patients will be continued by this department after the end of the trial.
    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 Decision2016-07-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-08-12
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