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    Summary
    EudraCT Number:2006-001682-42
    Sponsor's Protocol Code Number:ML 20381
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-06-07
    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 ConcernedSweden - MPA
    A.2EudraCT number2006-001682-42
    A.3Full title of the trial
    Rituximab phase IIIb open-label, multi-centre assessment of safety and effectiveness in patients with RA following inadequate response to one prior anti-TNF inhibitor (RESET).
    A.3.2Name or abbreviated title of the trial where available
    RESET
    A.4.1Sponsor's protocol code numberML 20381
    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 SponsorRoche AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    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 Yes
    D.2.1.1.1Trade name Mabthera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Reistration Limited
    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 nameMabthera
    D.3.2Product code Ro 45-2294
    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 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
    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) No
    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
    Active reumathoid 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
    The primary objective of this study is to evaluate the safety of rituximab in patients with active RA who are receiving MTX and who have a previous or current inadequate response or were intolerant to treatment with one prior anti–TNF–alfa therapy.
    E.2.2Secondary objectives of the trial
    To evaluate:
    To evaluate the safety of re treatment with rituximab in combination with MTX.
    The effectiveness of initial treatment with rituximab in combination with MTX
    Changes in patient reported outcomes following treatment or re treatment with rituximab.
    The timing of retreatment with rituximab in routine patient care
    The factors which influence the clinical judgment to re treat with rituximab including:
    • Disease Activity Score (DAS 28)
    • DAS, and ACR core component values
    • presence or absence of disease flare
    • additional clinical or laboratory factors influencing re treatment
    Further exploratory endpoints (for example complete clinical response, duration of remission) will be analyzed descriptively during the period following the Week 24 visit. Response to rituximab based on the patient’s prior historical response to anti-TNF therapy (lack of initial response, loss of response, tolerability) will also be explored.
    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. Ages 18-80 years, inclusive.
    3. Patients with documented moderate to severe active rheumatoid arthritis at screening as follows:
    • tender joint count ≥ 6 (28 joint count)
    • swollen joint count ≥ 6 (28 joint count)
    • C-reactive protein (CRP) or Erythrocyte sedimentation rate (ESR) levels elevated above the upper limit of normal (as per local laboratory), or morning stiffness lasting ≥30 minutes.
    4. Patients who are to receive, or who are currently receiving treatment for RA on an outpatient basis.
    5. Documented inadequate response to a single previous or current treatment with the anti–TNF–alfa agents etanercept, infliximab, or adalimumab because of toxicity or inadequate efficacy (inadequate efficacy requires treatment with etanercept for >= 3 months at 25 mg twice a week or 50 mg weekly; or at least 3 infusions of infliximab at >= 3 mg/kg; or adalimumab for >= 3 months at 40 mg every other week).
    6. Must have received MTX at a dose of 10-25 mg/week (p.o. or parenteral) for at least 12 weeks prior to screening, at a stable dose over the last 4 weeks prior to day 1.
    7. Corticosteroids (<= 10 mg/day prednisone or equivalent) are permitted if stable for at least 4 weeks prior to day 1 and NSAIDs permitted if stable for at least 2 weeks prior to day 1.
    8. Must be willing to receive oral folate.
    9. Patients of reproductive potential (males and females) must be willing to use a reliable means of contraception (e.g., hormonal contraceptive, intrauterine device, physical barrier) during the study.
    10. If female and of childbearing potential, a negative serum pregnancy test.
    E.4Principal exclusion criteria
    Exclusion Criteria Related to RA
    1. Patients with severe rheumatoid arthritis (functional class IV as defined by the ACR Classification of Functional Status in RA) that requires either a wheelchair or results in the patient being bed bound.
    2. Bone/joint surgery within 8 weeks prior to day 1, or joint surgery planned within 48 weeks of day 1.

    Exclusions Related to Medications
    1. History of severe allergic or anaphylactic reactions to monoclonal antibodies
    2. Previous treatment with rituximab (Rituxan/Mabthera).
    3. Use of an anti–TNF–alfa agent within 8 weeks of Day 1 (or 4 weeks in the case of etanercept).
    4. Concurrent treatment with any DMARD other than methotrexate. Treatment with all DMARDS must be discontinued at least 14 days prior to Day 1 except for the following:
    • azathioprine for ≥4 weeks;
    • etanercept for ≥4 weeks;
    • leflunomide for ≥8 weeks;
    • infliximab or adalimumab for ≥8 weeks
    5. In the event that abatacept is approved as a treatment for RA during the course of this study, this must also be discontinued for ≥8 weeks prior to day 1.
    6. Receipt of any vaccine within 4 weeks prior to day 1 (it is recommended that a patient’s vaccination record and the need for immunization prior to receiving rituximab should be carefully investigated).
    7. Intra-articular or parenteral glucocorticoids within 4 weeks prior to day 1.
    8. Treatment with any investigational agent within 4 weeks of day 1 or within 5 half-lives of the investigational drug (which ever is the longer).
    9. Previous treatment with any cell-depleting therapies, including investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti-CD11a, anti-CD22, anti-BLys/BAFF)
    Exclusions for General Safety/Health
    1. Evidence of any severe or significant medical condition(s) or disease(s) that, in the view of the investigator, prohibits participation in the study.
    2. Significant cardiac or pulmonary disease (including obstructive pulmonary disease).
    3. Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with i.v. anti-infectives within 4 weeks of day 1 or oral anti-infectives within 2 weeks prior to day 1.
    4. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection.
    5. History of serious recurrent or chronic infection.
    6. Pregnancy or lactation.
    7. History of cancer, including solid tumours, hematological malignancies and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured).
    8. Currently active alcohol or drug abuse or history of alcohol or drug abuse within 24 weeks prior to baseline.
    Exclusions Related to Laboratory Findings
    1. Hemoglobin < 9.0 g/dL.
    2. Absolute neutrophil count < 1.5 x 103/µL.
    3. Levels of IgG <5.0 mg/mL.
    4. Levels of IgM < 0.40 mg/mL.
    5. Positive tests for hepatitis B surface antigen (HBsAg) and/or positive tests for hepatitis B core antibody (HBcAb) associated with detectable hepatitis B viral DNA (HBV DNA) or hepatitis C serology.
    6. Positive serum test for human chorionic gonadotropin (pregnancy).
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective of this study is to evaluate the safety of rituximab in patients with active RA who are receiving MTX and who have a previous or current inadequate response or were intolerant to treatment with one prior anti–TNF– therapy
    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) Yes
    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 No
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    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 Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    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 2006-06-07. 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 Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 100
    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 Decision2006-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-07-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2009-05-01
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