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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.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    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:2005-000674-43
    Sponsor's Protocol Code Number:RituxRA version1
    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:2005-10-03
    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 number2005-000674-43
    A.3Full title of the trial
    AN OPEN LABEL STUDY OF THE EFFECT OF TREATMENT WITH RITUXIMAB ON RESISTANT RHEUMATOID ARTHRITIS:

    Clinical, radiological, synovial and immunological outcomes
    A.3.2Name or abbreviated title of the trial where available
    Rituximab in Rheumatoid Arthritis
    A.4.1Sponsor's protocol code numberRituxRA version1
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) Numbernot available
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Leeds
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Information not present in EudraCT
    D.2.1.1.1Trade name Mabthera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameMabthera
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNn/a
    D.3.9.1CAS number n/a
    D.3.9.2Current sponsor coden/a
    D.3.9.3Other descriptive namenone
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    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
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To confirm the efficacy and safety of rituximab in patients with resistant RA
    E.2.2Secondary objectives of the trial
    To explore the effects of rituximab on underlying structural joint disease, the synovium and B cell profiles in the peripheral circulation

    To explore why relapse occurs after rituximab therapy
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    1. Able and willing to give written informed consent and comply with the requirements of the study protocol.

    2. Patients with rheumatoid arthritis for at least 6 months, diagnosed according to the revised 1987 ACR criteria for the classification of rheumatoid arthritis

    3. Patients who have experienced an inadequate response to previous or current treatment with etanercept, infliximab or adalimumab because of toxicity or inadequate efficiency ( etanercept for>3 months at 25mg twice weekly, at least 4 infusions of infliximab at ≥ 3 mg/kg or adalimumab for ≥3 months at 40mg every other week) or be unsuitable for treatment with anti-TNF therapy because of contra-indication

    4. Patients who have been washed out from etanercept, infliximab or adalimumab for≥4 weeks prior to treatment with rituximab

    5. Patients must have received methotrexate at a dose of 10-25mg/week (po or parenteral) at a stable dose for 4 weeks prior to screening

    6. All DMARDs other than methotrexate should be withdrawn at least 4 weeks prior to rituximab therapy (see above for anti-TNF therapy)

    7. DAS28 >5.1

    8. Age 18-80 years

    9. Corticosteroids (≤10mg/day prednisolone or equivalent) permitted if stable for at least 4 weeks prior to screening and NSAIDs permitted if stable for at least 2 weeks prior to screening.

    10. Patients of reproductive potential (males and females) using a reliable means of contraception (eg contraceptive pill, IUD, physical barrier)

    11. Must be willing to receive oral folate

    12. If female and of childbearing potential, a negative urine pregnancy test within two weeks prior to therapy

    13. Presence of erosive joint disease of at least 1 joint on x-ray ( except if DIP joint of the hand)
    E.4Principal exclusion criteria
    1. Bone/joint surgery within 8 weeks prior to therapy or joint surgery planned within 24 weeks of therapy

    2. Rheumatic autoimmune disease other than RA or significant systemic involvement secondary to RA

    3. History of, or current, inflammatory joint disease other than RA or other systemic rheumatic disorder

    3.2.4 Excluded previous/concomitant medications:

    1. Concurrent treatment with any DMARD (apart from methotrexate) or any anti-TNF therapy or other biologic agent

    2. Treatment with any investigational agent within 4 weeks of screening or 5 half lives of the investigational drug

    3. Previous treatment with any cell depleting therapy therapies including investigational agents (eg CAMPATH, anti-CD4, anti-CD5, anti-CD3, antiCD19)


    4. Intra-articular or parenteral steroids within 4 weeks prior to therapy except for joints undergoing arthroscopy and/or MRI where IA steroids are not permitted within 12 weeks prior to therapy)

    5. Receipt of a live vaccine within 4 weeks prior to randomisation (?ever)

    3.2.5 Exclusions for General Safety:

    1. History of severe allergic or anaphylactic reactions to humanised or murine monoclonal antibodies (eg infliximab or adalimumab)

    2. Evidence of significant uncontrolled concomitant diseases such as cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders.

    3. Known active bacterial, viral, fungal mycobacterial infection (including tuberculosis, or atypical mycobacterial disease but excluding fungal infection of the nailbeds) or any episode of infection requiring hospitalisation or treatment with iv antibiotics within 4 weeks of therapy or oral antibiotics within 2 weeks of therapy

    4. History of , or currently active, primary or secondary immunodeficiency

    5. History of solid organ malignancy in the past 5 years (excluding basal cell or squamous cell carcinomas of the skin which have been excised and cured)

    6.Pregnant women or breastfeeding mothers

    7.History of alcohol, drug or chemical abuse within 6 months prior to screening

    8.Neuropathies or neurovasculopathies which might interfere with pain evaluation

    9.Intolerance or contraindications to po or iv steroids

    3.2.6 Laboratory Exclusion Criteria (at screening):

    1. Serum creatinine >140mmol/l

    2. AST or ALT > 2.5 times upper limit of normal

    3. platelet count <100

    4. haemoglobin <8.5

    5. neutrophils <1.5x10.3/μL

    6. Positive tests for hepatitis B surface antigen or hepatitis C antibody

    7. Levels of IgG and/or IgM below 5.65 and 0.55mg/mL respectively
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients achieving ACR50 response at Week 24.

    Secondary outcomes:

    These will be measured at weeks 12, 24, 36, 48, unless otherwise stated below.
    1. Disease Activity Response:
    a) Proportions of patients with ACR 20,ACR50 and ACR70
    b) Change in Disease Activity Score (DAS 28) from baseline
    c) Proportion of patients who are categorical DAS 28 responders(EULAR response)
    d) Change in swollen and tender joint counts from baseline
    e) Change in CRP and ESR
    f) Proportion of patients becoming seronegative for Rheumatoid Factor
    2. Disability outcomes:
    a) change in HAQ from baseline
    b) change in patient’s global assessment (VAS)
    c) change in physician’s global assessment (VAS)
    3. Quality of Life
    a) RA QoL change from baseline
    b) Pain Score (VAS) change from baseline
    4. Radiographic outcomes:
    a) X ray change in modified Sharp scores, erosion score (measured as grade 0-3.5 in 0.5 increments) and joint space narrowing score (measured as grade 0 – 4 with 0.5 increments)
    b) Ultrasound: changes in synovitis on grey scale and power doppler scores (measured 0-3)
    c) MRI: change in bone erosion (0-10) and bone oedema (0-3) as measured by EULAR-OMERACT scales
    5. B cell activity:
    a) Proportion of patients achieving full B cell depletion in peripheral blood
    b) Proportion of patients achieving B cell depletion in synovium ( defined as grades 0 and 1 on a standardised immunohistochemistry scale of 0-3) at week 26
    c) Proportion of patients who relapse with B cell depletion in peripheral blood but not in synovium

    Relapse is defined as having shown at least an ACR 20 response by week 24 and then subsequent deterioration with an increase in DAS 28 of at least 1.2
    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 Information not present in EudraCT
    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 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 Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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 initial phase of the study is 26 weeks (with treatment given at the beginning and end of the first 2 weeks). After this patients will be followed every 3 months for a total study duration of 24 months with one further safety assessment at 36 months.
    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 months0
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-10-03. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 15
    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 can continue to receive Rituximab through the standard NHS guidelines.
    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 Decision2005-04-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-03-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2009-09-01
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