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    The EU Clinical Trials Register currently displays   41189   clinical trials with a EudraCT protocol, of which   6743   are clinical trials conducted with subjects less than 18 years old.
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    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .
     
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    Summary
    EudraCT Number:2020-002507-19
    Sponsor's Protocol Code Number:RTX-SC
    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:2020-09-03
    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 number2020-002507-19
    A.3Full title of the trial
    Comparison of subcutaneous and intravenous continued treatment with ultra-low dose Rituximab in rheumatoid arthritis: a randomised open-label non-inferiority trial
    Vergelijking tussen subcutane en intraveneuze toediening van ultra-lage doseringen rituximab bij reumatoïde artritis: een gerandomiseerde open-label non-inferiority trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Research into administration of lower dosed rituximab with an injection
    Onderzoek naar het toedienen van lagere doseringen rituximab via een injectie
    A.3.2Name or abbreviated title of the trial where available
    RTX-SC
    A.4.1Sponsor's protocol code numberRTX-SC
    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 SponsorSint Maartenskliniek
    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 supportSint Maartenskliniek
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSint Maartenskliniek
    B.5.2Functional name of contact pointPrincipal investigator
    B.5.3 Address:
    B.5.3.1Street AddressHengstdal 3
    B.5.3.2Town/ cityUbbergen
    B.5.3.3Post code6574 NA
    B.5.3.4CountryNetherlands
    B.5.6E-maila.denbroeder@maartenskliniek.nl
    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 MabThera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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 namerituximab
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    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.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 Rixathon
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz GmbH
    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 namerituximab
    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.3.11 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.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
    rheumatoid arthritis
    reumatoïde artritis
    E.1.1.1Medical condition in easily understood language
    rheumatic disease
    reuma
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate non-inferiority of rituximab SC 336 mg to rituximab IV 200 mg, with the lower boundary of the 95% confidence interval of AUC0-6mnd,SC : AUC0-6mnd,IV exceeding the non-inferiority margin of 0.8.
    E.2.2Secondary objectives of the trial
    1. To describe the relevant pharmacokinetic parameters of rituximab 336 mg SC compared to 200 mg IV: peak level, trough level, Cavg;
    2. To evaluate the between group difference in changes in disease activity (DAS28-CRP) after 6 months, compared to a NI margin of 0.6;
    3. To evaluate the between group differences on on B-cell counts;
    4. To assess the differences in incidence of anti-drug antibodies (ADAs);
    5. To assess the incidence of AEs in both groups;
    6. To assess patient preferences for either SC or IV formulation.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Rheumatoid arthritis: either 2010 EULAR/ACR RA and/or 1987 ACR RA criteria and/or clinical diagnosis of the treating rheumatologist;
    2. Patients using rituximab in ultra-low dose: either 200 mg or 500 mg as previous dose, given every 6 months, with or without concomitant methotrexate;
    3. Having sufficient response to rituximab treatment, operationalized as a DAS28-CRP < 2.9 3-6 months after the last infusion and/or judgment of low disease activity by the treating rheumatologist;
    4. ≥16 years old and mentally competent;
    5. Ability to read and communicate well in Dutch.
    E.4Principal exclusion criteria
    1. Previous non-response to ultra-low dose rituximab (DAS28-CRP > 2.9);
    2. Objection or contraindication to either of the treatment options;
    E.5 End points
    E.5.1Primary end point(s)
    The main study endpoint is non-inferiority of rituximab 336 mg SC to rituximab 200 mg IV, based on AUC0-6 months. The AUC will be calculated using the four samples with the trapezoid method.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Blood samples will be drawn pre-dose, post-dose (for IV directly after infusion, for SC 2-4 days after injection), at 3 months, and at 6 months.
    E.5.2Secondary end point(s)
    Additional PK parameters
    In addition to the AUC0-6months, the peak level, the trough level and the average concentration (Cavg) are considered relevant PK parameters to compare both formulas. Those parameters will be calculated using (some of) the four RTX samples drawn, analysed by the RTX assay of Sanquin.

    Efficacy
    Disease activity will be measured at baseline, at three months and at six months, using the DAS28-CRP score. Therefore, we collect the following parameters:
    - Physical examination: swollen joint count, tender joint count;
    - Patient Global Assessment of disease activity (VAS);
    - Acute phase reactants: CRP.

    B-cell count
    B-cell count will be performed at baseline, at three months and at six months. For this analysis, blood will be drawn in a 3 ml EDTA tube. B-cell count will be performed at the Radboudumc immunology laboratory. The percentages and absolute number of B-cells will be determined within 24 hours after blood collection by using a combination of fluorochrome-labelled monoclonal antibodies, CD45, CD3, CD19 and CD16/56 (Tetra 2 combi from Beckman Coulter). With the use of a fully standardized volumetric counting flow cytometer, the Aquios (Beckman Coulter), samples will be incubated with MoAbs, erythrocytes will be lysed and subsequently the analysis will be automatically performed. Samples will be calibrated using standardized fixed cells samples (Aquios Immuno-Trol cells, Beckman Coulter). Quality control assessment is performed by participating in the regular program of the UK Neqas (Sheffield), the Alternative Immunomonitoring Program (12 samples per year).

    Anti-drug antibodies
    Presence of anti-drug antibodies against rituximab will be measured in the proportion of patients with undetectable rituximab levels. This means that in patients with rituximab levels < 0.1 mg/L anti-drug antibodies will be measured in serum. Samples will then be analysed using a validated ADA radio-immune assay at the bioanalytical laboratory of Sanquin.

    Adverse Events
    The occurrence of adverse events during the study period will be registered using the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.21 AEs that can occur using rituximab IV or SC are an increased risk for infections and (skin) malignancies. AEs will be monitored throughout the study.

    Patient preferences
    In the intervention group, patient preference for IV or SC RTX therapy will be assessed on the last visit in a small questionnaire, using a 7-point Likert-scale, with one end representing SC therapy and the other end IV therapy.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - PK parameters: Blood samples will be drawn pre-dose, post-dose (for IV directly after infusion, for SC 2-4 days after injection), at 3 months, and at 6 months.
    - Efficacy: at baseline, at 3 months and at 6 months
    - B-cell count: at baseline, at 3 months and at 6 months
    - Anti-drug antibodies: antibodies will be determined for low RTX serum levels. Blood samples will be drawn pre-dose, post-dose (for IV directly after infusion, for SC 2-4 days after injection), at 3 months, and at 6 months.
    - Adverse Events: throughout the study
    - Patient preferences: for the SC group, at 6 months
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    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) 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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    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: 36
    F.1.3Elderly (>=65 years) No
    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 state36
    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)
    Patients will receive the next dose of rituximab as 200 mg rituximab IV (standard care).
    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 Decision2020-09-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-09-07
    P. End of Trial
    P.End of Trial StatusOngoing
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