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    Summary
    EudraCT Number:2004-005210-37
    Sponsor's Protocol Code Number:WA18063
    National Competent Authority:Czech Republic - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-06-30
    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 ConcernedCzech Republic - SUKL
    A.2EudraCT number2004-005210-37
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled, parallel group study of the safety and reduction of signs and symptoms during treatment with MRA versus placebo, in combination with traditional DMARD therapy in patients with moderate to severe active rheumatoid arthritis and an inadequate response to current DMARD therapy.
    A.4.1Sponsor's protocol code numberWA18063
    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 AG
    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 nameMRA
    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.3.9.1CAS number 375823-41-9
    D.3.9.2Current sponsor codeR04877533
    D.3.9.3Other descriptive nameMRA
    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 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
    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 assess the efficacy of treatment with MRA versus placebo, in combination with stable, ongoing therapy, with regard to signs and symptoms, in patients with moderate to severe active RA and inadequate response to current DMARD treatment.
    2. To assess the safety of MRA versus placebo in combination with stable, ongoing therapy, with regard to adverse events and laboratory assessments in patients with moderate to severe active RA and inadequate response to current DMARD treatment.
    E.2.2Secondary objectives of the trial
    To explore the pharmacokinetics, immunogenicity and pharmacodynamic parameters of MRA in this patient population.
    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 of ³ 6 months duration diagnosed according to the revised 1987 American College of Rheumatology (ACR; formerly American Rheumatism Association) criteria (Appendix 2).

    3. Receiving treatment on an outpatient basis.

    4. Prior to randomization, will have discontinued etanercept for ³ 2 weeks, infliximab or adalimumab for ³ 8 weeks (see exclusion # 5), anakinra for ³ 1 week.

    5. Have received permitted DMARDs, each at a stable dose, for at least 8 weeks prior to baseline.

    6. Swollen joint count (SJC) ³ 6 (66 joint count) and tender joint count (TJC) ³ 8 (68 joint count) at screening and baseline.

    7. At screening either CRP ³ 1 mg/dL (10 mg/L) or ESR ³ 28 mm/hr

    8. Age ³ 18 years

    9. Oral corticosteroids (£ 10 mg/day prednisone or equivalent) and NSAIDs (up to the maximum recommended dose) are permitted if the dose has been stable for at least 6 weeks prior to baseline.

    10. Females of child-bearing potential and males with female partners of child-bearing potential may participate in this trial only if using a reliable means of contraception (e.g. physical barrier (patient and partner), contraceptive pill or patch, spermicide and barrier, or IUD).

    11. If female and of childbearing potential, the patient must have a negative urine pregnancy test within three weeks prior to baseline.
    E.4Principal exclusion criteria
    General:

    1. Major surgery (including joint surgery) within eight weeks prior to screening or planned surgery within six months following randomization.

    2. Rheumatic autoimmune disease other than RA, including SLE, MCTD, scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty’s syndrome). Sjögren’s Syndrome with RA is allowable.

    3. Functional class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.

    4. Prior history of or current inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease).

    Excluded Previous or Concomitant Therapy:

    5. Unsuccessful treatment with an anti-TNF agent (i.e. significant safety issues or lack of efficacy; Patients who terminated previous anti-TNF treatment due to cost or discomfort with the subcutaneous injections, may participate in this study.) (See Inclusion #4 for anti-TNF agent washouts.)

    6. Treatment with any investigational agent within four weeks (or five half-lives, whichever is longer) of screening.

    7. Previous treatment with any cell depleting therapies, including investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20).

    8. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba ä column within six months of baseline.

    9. Intra-articular or parenteral corticosteroids within six weeks prior to baseline.

    10. Immunization with a live/attenuated vaccine within four weeks prior to baseline.

    11. Previous treatment with MRA (an exception to this criterion may be granted for single dose exposure upon application to the sponsor on a case by case basis).

    12. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation.


    Exclusions for General Safety

    13. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.

    14. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (incl. obstructive pulmonary disease), renal, hepatic, endocrine (incl. uncontrolled diabetes mellitus) or gastrointestinal disease.

    15. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids.

    16. Current liver disease as determined by principal investigator. (Patients with prior history of ALT elevation will not be excluded.)

    17. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, granulomatous disease on chest X-ray, Hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within four weeks of screening or oral antibiotics within two weeks prior to screening.

    18. Primary or secondary immunodeficiency (history of or currently active).

    19. History of malignancy, including solid tumors and hematologic malignancies (except basal cell carcinoma of the skin that has been excised and cured).

    20. Pregnant women or nursing (breast feeding) mothers.

    21. History of alcohol, drug or chemical abuse within the six months prior to screening.

    22. Neuropathies or other painful conditions that might interfere with pain evaluation.

    23. Patients with lack of peripheral venous access

    24. Body weight of > 150 kg


    Laboratory Exclusion criteria (at screening)

    25. Serum creatinine > 1.4 mg/dL in female patients and > 1.6 mg/dL in male patients

    26. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper limit of normal (ULN). (If initial sample yields ALT or AST > 1.5 times the ULN, a second sample may be taken and tested during the screening period.)

    27. Platelet count < 100,000/mm3

    28. Hemoglobin < 8.5 g/dL

    29. White Blood Cells < 3000/mm3

    30. Absolute Neutrophil Count < 2000/mm3

    31. Absolute Lymphocyte Count < 500/mm3

    32. Positive Hepatitis BsAg, or Hepatitis C antibody

    33. Total Bilirubin > ULN. (If initial sample yields Bilirubin > ULN, a second sample may be taken and tested during the screening period.)

    34. Triglycerides > 10 mmol/L (> 900 mg/dL) at screening (non-fasted)
    35. Patients with history of inlammatory lower GI disease, such as diverticulitis, colitis, enteritis, as well as symptomatic diverticulosis (with or without history of bleeding) are excluded.
    36. Patients who have a negative outcome to the risk/benefit assessment or who are not willing to undergo the additional tests will be withdrawn.
    E.5 End points
    E.5.1Primary end point(s)
    Primary:The primary endpoint is the proportion of patients with an ACR20 response at week 24
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    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 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.8.5The 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
    Last follow-up visit. All patients must return for a Safety Follow-up assessment 4 weeks after last dose of study medication. Patients who have not enrolled in a proposed long term extension study must also return for a Safety Follow-up assessment 8 and 12 weeks after last dose of study medication.
    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 years1
    E.8.9.2In all countries concerned by the trial months10
    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 2005-06-30. 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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 204
    F.4.2.2In the whole clinical trial 1200
    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 Decision2005-07-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-06-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2007-01-31
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