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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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    Summary
    EudraCT Number:2008-005525-11
    Sponsor's Protocol Code Number:WX21956
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-11-17
    Trial results Removed from public view
    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 ConcernedGreece - EOF
    A.2EudraCT number2008-005525-11
    A.3Full title of the trial
    A randomized, placebo controlled, double-blind, parallel group study to compare the safety and efficacy of the combination of rituximab (MabThera) and tocilizumab (Actemra) versus tocilizumab therapy in patients with active rheumatoid arthritis with an incomplete response to methotrexate.
    A.4.1Sponsor's protocol code numberWX21956
    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 SponsorF Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    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 500mg
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration 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 namerituximab
    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.3.9.2Current sponsor codeRo 45-2294
    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 No
    D.3.11.8Extractive medicinal product No
    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 Yes
    D.3.11.13.1Other medicinal product typemonoclonal antibody, recombinant
    D.IMP: 2
    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 No
    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 nametocilizumab
    D.3.2Product code RO4877533
    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 INNtocilizumab
    D.3.9.2Current sponsor codeRo4877533
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 No
    D.3.11.8Extractive medicinal product No
    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 Yes
    D.3.11.13.1Other medicinal product typemonoclonal antibody
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    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 the safety, tolerability and efficacy of rituximab in combination with tocilizumab in patients with active RA despite a stable dose of methotrexate.
    E.2.2Secondary objectives of the trial
    To investigate the pharmacokinetics of rituximab and tocilizumab when given in combination to rheumatoid arthritis patients.
    To explore the effect of the combination of rituxmab and tocilizumab upon exploratory pharmacodynamic endpoints in rheumatoid arthritis.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Roche Sample Respository Research Project in association with WX21956
    E.3Principal inclusion criteria
    1. Able and willing to give written informed consent and comply with the requirements of the study protocol
    2. Age 18 - 65 years
    3. Rheumatoid arthritis diagnosed according to the American Rheumatism Association 1987 revised criteria for the classification of RA
    4. Functional Status I-III according to the 1991 ACR revised criteria for the classification of global functional status in RA
    5. Swollen joint count (SJC) ≥ 4 (28 joint count) and tender joint count (TJC) ≥ 4 (28 joint count) at screening and baseline
    6. DAS28-ESR > 3.2 at screening
    7. CRP ≥ 0.6 mg/dL using a high-sensitivity assay and/or ESR ≥ 30 mm/h at screening
    8. RF positive and/or anti-CCP positive
    9. Must have an inadequate response to MTX and have been receiving and tolerating this at a dose of 7.5 - 25 mg weekly (p.o. or parenterally) for at least 12 weeks, with the last 4 weeks prior to screening at a stable dose
    10. Patients may have failed (through lack of efficacy or tolerability) up to 1 approved anti-TNF agent (infliximab, etanercept or adalimumab), and up to 6 non-biologic disease-modifying antirheumatic drugs (DMARDs), including MTX. The following non-biologic DMARDS are considered as a single agent for this count:
    - All forms of gold
    - Leflunomide
    - Chloroquine and hydroxychloroquine
    - Dapsone or azathioprine
    - Sulfasalazine and mesalazine
    - Cyclosporine A
    11. All DMARDs other than methotrexate must be withdrawn at least 4 weeks prior to randomization except as follows: 2 weeks for etanercept, 8 weeks for infliximab, and 12 weeks for leflunomide (8 weeks if cholestyramine or activated charcoal is used to accelerate leflunomide withdrawal)
    12. Oral corticosteroids (≤ 10 mg/day prednisolone or equivalent) and NSAIDs (up to the maximum recommended dose, including COX-2 inhibitors) are permitted if the dose has been stable for at least 4 weeks prior to baseline. No patient may be using more than one NSAID simultaneously (with the exception of low-dose aspirin for cardioprotection)
    13. Patients must be willing to receive oral folic acid at a stable dose of at least 5 mg/week
    14. Current treatment for RA on an outpatient basis
    15. Female patients of child bearing potential may participate in this study if using reliable means of contraception for the duration of the study, and for up to 3 months after their last dose of tocilizumab, and up to 1 year after their last dose of rituximab, or until their peripheral CD20+ B cells have repleted
    16. Female patients of childbearing age must have a negative serum pregnancy test at screening
    17. Male patients with female partners of child bearing potential may participate in this study only if the patient or the partner are using reliable means of contraception for the duration of the study, and for up to 3 months after their last dose of tocilizumab, and up to 1 year after their last dose of rituximab, or until their peripheral CD20+ B cells have repleted.
    E.4Principal exclusion criteria
    1. Functional Status IV - 1991 ACR criteria
    2. Rheumatic AI disease other than RA (e.g SLE, Mixed Connective Tissue Disease, scleroderma/variants, polymyositis) or significant systemic involvement secondary to RA (e.g. vasculitis, pulmonary fibrosis, Felty’s syndrome); Secondary Sjögren’s and limited cutaneous vasculitis or nodulosis with RA allowed
    3. History of/current inflammatory joint disease other than RA (e.g: gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease, pseudogout, arthropathy of inflammatory bowel disease)
    4. Diagnosis of JIA/JRA and/or RA before age 16
    5. Significant +/or uncontrolled concomitant disease e.g cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or GI disorders (including previous complicated diverticulitis) which, in Investigator’s opinion, would preclude participation or impact benefit-risk
    6. Any condition or general state of health which, in Investigator’s opinion, would preclude participation
    7. Significant cardiac disease (NYHA Class III/IV), known severe COPD (FEV1 < 50% predicted or Functional dyspnea ≥ Grade 3 on MRC Scale) or other significant pulmonary disease
    8. Uncontrolled disease (e.g asthma, psoriasis or inflammatory bowel disease) where flares commonly treated with oral or injectable steroids
    9. Known active infection of any kind (excluding fungal infections of nail bed), or major episode of infection requiring hospitalization/treatment with i.v. anti-infectives within 4 weeks of baseline or completion of oral anti-infectives within 2 weeks of baseline
    10. History of deep space/tissue infection within 52 weeks of baseline
    11. Any surgical procedure, including bone/joint surgery/ synovectomy within 8 weeks of baseline or planned during the study
    12. History of serious recurrent or chronic infection
    13. Active tuberculosis requiring treatment within 2 years of screening
    14. Positive TB test result at screening, unless treated with anti-TB therapy for at least 4 weeks prior to receiving study medication and chest radiograph negative for active TB
    15. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection
    16. History of malignancy, including solid tumors, hematologic malignancies and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin, and melanoma in situ, or cervical carcinoma in situ with no stromal invasion, that have been completely excised and are considered cured)
    17. Any neurological, vascular or systemic disorder which could affect efficacy assessments, in particular, joint pain and swelling (e.g. Parkinsons, cerebral palsy, diabetic neuropathy)
    18. Current evidence for alcohol, drug or chemical abuse, or recent history of such abuse within 24 weeks of screening
    19. Lack of peripheral venous access
    20. Pregnancy or breast feeding
    21. Body weight > 150 kg or BMI > 35
    22. Previous treatment with any biological agent for RA other than infliximab, etanercept or adalimumab
    23. Previous treatment with tocilizumab or rituximab
    24. Previous/concurrent treatment with anti-alpha 4 integrin inhibitors (e.g. natalizumab)
    25. Previous/concurrent 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, anti-CD20)
    26. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba® column within 6 months of baseline
    27. Any previous treatment with alkylating agents e.g. cyclophosphamide or chlorambucil, or with total lymphoid irradiation
    28. Treatment with any investigational agent within 28 days of screening or 5 half-lives of investigational drug (whichever is longer)
    29. Previous/current significant safety issues experienced with another biological agent
    30. History of severe allergic or anaphylactic reaction to any biologic agent or known hypersensitivity to any component of tocilizumab or rituximab
    31. Receipt of any vaccine within 28 days of baseline
    32. Intra-articular or parenteral glucocorticoids within 4 weeks of baseline
    33. Intolerance or contraindications to i.v. glucocorticoids
    34. Positive tests for hepatitis B surface antigen, Hepatitis B core antibody or hepatitis C serology
    35. Absolute neutrophil count < 2.0 × 103/μL, white blood cells < 2.5 × 103/μL, platelet count < 100,000/μL
    36. Hemoglobin < 8.0 g/dL
    37. Serum IgG and/or IgM below 5.0 mg/mL and 0.40 mg/mL, respectively
    38. Serum creatinine > 2.0 mg/dL (200 μmol/L)
    39. ALT or AST > 1.5 times upper limit of normal.
    40. Total bilirubin > 1.5 times upper limit of normal
    41. Triglycerides > 400 mg/dL (non-fasted) or > 250 mg/dL (fasted) at screening
    42. Positive serum human chorionic gonadotropin measured prior to the first rituximab/placebo infusion
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients with a low DAS (DAS </= 3.2) at week 16 using DAS-ESR.
    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 Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other 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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    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.8.4.1Number 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 EEA28
    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 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
    Last Patient Last Visit (see protocol section 3.1.6)
    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.1.3Elderly (>=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 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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 75
    F.4.2.2In the whole clinical trial 81
    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)
    Standard of 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 Decision2009-04-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-07-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-03-13
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