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    Summary
    EudraCT Number:2005-002395-15
    Sponsor's Protocol Code Number:WA17047
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-06-19
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2005-002395-15
    A.3Full title of the trial
    A randomized, phase 3, controlled, double-blind, parallel-group, multicenter study to evaluate the safety and efficacy of rituximab in combination with methotrexate (MTX) compared to MTX alone, in methotrexate-naïve patients with active rheumatoid arthritis.
    A.4.1Sponsor's protocol code numberWA17047
    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 Information not present in EudraCT
    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 Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.11Herbal medicinal product Information not present in EudraCT
    D.3.11.12Homeopathic medicinal product Information not present in EudraCT
    D.3.11.13Another type of medicinal product Information not present in EudraCT
    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
    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
    1. To determine the efficacy of rituximab in the prevention of progression in structural joint damage and to evaluate the safety of rituximab in patients with active rheumatoid arthritis initiating treatment with MTX.
    2. To evaluate the efficacy of rituximab in improving patient’s physical function and signs and symptoms of RA.
    3. To investigate by a population analysis approach the pharmacokinetics (PK) of rituximab in the target RA patient population and the influence of covariates on the PK parameters.
    4. To explore the long-term efficacy and safety of further courses
    of rituximab.
    E.2.2Secondary objectives of the trial
    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 diagnosed for at least 8 weeks, but no more than 4 years, according to the revised 1987 American College of Rheumatology (ACR) criteria for the classification of rheumatoid arthritis.
    3. Patients naïve to, and considered to be candidates for, treatment with methotrexate.
    4. Swollen joint count (SJC) ≥ 8 (66 joint count), and tender joint count (TJC) ≥ 8 (68 joint count) at screening and baseline.
    5. At screening CRP ≥ 1.2 mg/dL (12 mg/L).
    6. Age 18-80 years.
    7. Glucocorticoids ≤ 10 mg/day prednisolone or equivalent is permitted if stable for at least 4 weeks prior to baseline.
    8. Use of NSAIDs is permitted if stable for at least 2 weeks prior to baseline.
    9. For patients of reproductive potential (males and females), use of a reliable means of contraception (e.g. hormonal contraceptive, patch, intrauterine device, physical barrier) throughout study participation.
    10. Must be willing to receive oral folate.
    11. For RF negative patients only, radiographic evidence of at least one joint with definite erosion attributable to RA.
    12. Patients who are to receive, or who are currently receiving, treatment on an outpatient basis.
    E.4Principal exclusion criteria
    1. Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis or Felty’s syndrome). Secondary Sjögren’s syndrome or secondary limited cutaneous vasculitis with RA is permitted.
    2. Functional class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
    3. History of, or current, inflammatory joint disease other than RA (including, but not limited to, gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune disorder (including, but not limited to, systemic lupus erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease or any overlap syndrome).
    4. Diagnosis of juvenile idiopathic arthritis (JIA) or juvenile rheumatoid arthritis (JRA) and/or RA before age 16.
    5. Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned during the study.
    6. Lack of peripheral venous access.
    7. Pregnancy or breast feeding.
    8. Significant and/or uncontrolled cardiac or pulmonary disease (including obstructive pulmonary disease).
    9. Evidence of significant concomitant disease, including but not limited to, nervous system, renal, hepatic, endocrine or gastrointestinal disorders which, in the investigator’s opinion, would preclude patient participation.
    10. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection.
    11. 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 baseline or completion of oral antiinfectives within 2 weeks prior to baseline.
    12. History of deep space/tissue infection (e.g. fasciitis, abscess, osteomyelitis) within 52 weeks prior to baseline.
    13. History of serious recurrent or chronic infection (for screening for a chest infection a chest radiograph will be performed at screening if not performed within 12 weeks prior to screening).
    14. History of cancer, including solid tumors, hematologic malignancies and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured).
    15. Any neurological (congenital or acquired), vascular or systemic disorder which could affect any of the efficacy assessments, in particular, joint pain and swelling (e.g. Parkinsons disease, cerebral palsy, diabetic neuropathy).
    16. Currently active alcohol or drug abuse or history of alcohol or drug abuse within 24 weeks prior to baseline.
    17.History of a severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of rituximab or to murine proteins.
    18. Previous treatment with any approved or investigational biologic agent for RA.
    19. Previous treatment with an anti-alpha 4 integrin antibody or co-stimulation modulator.
    20. Concurrent treatment with any biologic agent or DMARD other than MTX. Treatment must be discontinued 14 days prior to baseline, except for the following: azathioprine for ≥ 28 days; leflunomide for ≥ 8 weeks (or ≥ 14 days after 11 days of standard cholestyramine or activated charcoal washout).
    21. 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, BLys/ BAFF, and anti-CD20).
    22. Treatment with any investigational agent within 28 days of baseline or 5 half lives of the investigational drug (whichever is the longer).
    23. Receipt of a live/attenuated vaccine within 28 days prior to baseline (it is recommended that a patient’s vaccination record and the need for immunization prior to receiving rituximab/placebo should be carefully investigated)
    24. Intra-articular or parenteral glucocorticoids within 4 weeks prior to baseline.
    25. Intolerance or contraindications to i.v. glucocorticoids.
    26. Positive serum human chorionic gonadotropin (hCG) measured prior to the first rituximab infusion.
    27. Positive tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBsAb) or hepatitis C serology.
    28. Hemoglobin < 8.0 g/dL.
    29. Concentrations of serum IgG and/or IgM below 5.0 and 0.40 mg/mL, respectively.
    30. Absolute neutrophil count (ANC) < 1.5 × 103/µL.
    31. AST or ALT > 2.5 times upper limit of normal.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the change from screening in total modified Sharp score at week 52 using the modified ITT population.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Information not present in EudraCT
    E.6.2Prophylaxis Information not present in EudraCT
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence Information not present in EudraCT
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic Information not present in EudraCT
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of life
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Information not present in EudraCT
    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) Information not present in EudraCT
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) Information not present in EudraCT
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.5The trial involves multiple Member States Yes
    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
    Patients will receive study medication for a total of 3 years or until rituximab is commercially available for rheumatoid arthritis (whichever is the later). The end of treatment is therefore defined as the 3 year time point, following which there will be an additional period of at least a year of safety follow-up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    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 years6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Information not present in EudraCT
    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 Information not present in EudraCT
    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 2007-06-19. 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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 360
    F.4.2.2In the whole clinical trial 853
    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 Decision2006-01-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-12-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-07-22
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