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    Summary
    EudraCT Number:2008-000105-11
    Sponsor's Protocol Code Number:ML21469
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-05-16
    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 ConcernedGermany - PEI
    A.2EudraCT number2008-000105-11
    A.3Full title of the trial
    Effectiveness after 4 and 24 weeks and safety of tocilizumab in patients with active RA
    A.3.2Name or abbreviated title of the trial where available
    TAMARA - Tocilizumab And DMARDs: Achievements in Rheumatoid Arthritis
    A.4.1Sponsor's protocol code numberML21469
    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 Pharma AG
    B.1.3.4CountryGermany
    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 RoActemra
    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 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.3.9.1CAS number 375823-41-9
    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 typeHumanized monoclonal antibody
    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.1.2 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 determine the effectiveness of tocilizumab in combination with traditional DMARDs with regard to the clinical improvement in disease activity (achievement of LDAS) after 24 weeks' treatment in patients with active RA who have had an inadequate response to current traditional DMARD and/or anti-TNF therapy.
    E.2.2Secondary objectives of the trial
    To assess the treatment effects in terms of improvement in the commonly used RA outcome measures (EULAR response, ACR responses).
    To assess the safety of tocilizumab in combination with stable traditional DMARD therapy, with regard to adverse events and laboratory assessments and physical examination including vital signs.
    To assess the effects on health-related quality of life outcomes (SF-36, HAQ-DI, FACIT-F and PTHFs) in this patient population.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with rheumatoid arthritis of ≥6 months duration, diagnosed according to the revised 1987 American College of Rheumatology (ACR) criteria.
    2. Willingness to give written informed consent, written consent for data protection (legal requirement in Germany: datenschutz-rechtliche Einwilligung) and willingness to participate and to comply with the requirements of the study protocol.
    3. Receiving treatment on an outpatient basis.
    4. Age ≥18 years.
    5. DAS28 of >3.2.
    6. At screening either ESR ≥28 mm/h or
    CRP ≥1 mg/dL.
    7. Prior to baseline, will have discontinued: etanercept for ≥2 weeks, infliximab or adalimumab for ≥8 weeks, anakinra for ≥1 week.
    8. Have received permitted DMARDs, 1 or more; current DMARD therapy must have been at a stable dose for at least 8 weeks prior to baseline.
    9. Oral corticosteroids (≤10 mg/day prednisone or equivalent) and NSAIDs (up to the maximum recommended dose) are permitted if dose stable for at least 4 weeks prior to baseline.
    10. Women of child-bearing potential may participate in this trial only if using a reliable means of highly effective contraceptive method (allowed methods of birth control, i.e. with a failure rate of less than 1 % per year, are implants, injectables, combined oral contraceptives, IUDs (only hormonspirals), sexual abstinence or vasectomized partner).
    11. Women of childbearing potential or less than one year after menopause (unless surgically steril) must have a negative pregnancy test (serum, β-HCG) at screening.
    E.4Principal exclusion criteria
    1. Major surgery (including joint surgery) within eight weeks prior to screening or planned major surgery within six months following screening.
    2. Functional class IV as identified by the ACR classification of Functional Status in Rheumatoid Arthritis.
    3. Rheumatic autoimmune disease other than RA, including SLE, mixed connective tissue disease, scleroderma, polymyositis, or sig-nificant systemic involvement secondary to RA (e.g. vasculitis, pulmonary fibrosis or Felty’s syndrome). Sjögren’s syndrome with RA is allowable.
    4. Prior history of or current inflammatory joint disease other than RA (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease).
    Exclusion criteria related to medications:
    5. Patients who participate currently in another clinical trial or patients who participated in another clinical trial during the last 30 days (or five half-lives, whichever is longer).
    6. Previous treatment with any cell depleting therapies, including investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20).
    7. Treatment with intravenous gamma globulin plasmapheresis or immunosorbent column (e.g. Prosorba®) within six months of baseline.
    8. Intraarticular or parenteral corticosteroids within six weeks prior to baseline.
    9. Immunization with a live/attenuated vaccine within four weeks prior to baseline.
    10. Previous treatment with tocilizumab.
    11. Previous treatment with rituximab or abatacept.
    12. Any previous treatment with alkylating agents such as cyclophosphamide or
    chlorambucil, or with total lymphoid irradiation.
    Exclusion criteria related to 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 gastrointestine disease.
    15. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids.
    16. History of diverticulitis, diverticulosis requir-ing antibiotic treatment or chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis or other symptomatic lower GI conditions that might predispose to perforations OR evidence of serious uncontrolled concomitant gastrointestinal disease.
    17. Current liver disease as determined by principal investigator. (Patients with prior history of ALT elevation will not be excluded.)
    18. 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 (X-ray should not be older than 90 days related to treatment start), 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.
    19. Active tuberculosis (TB) requiring treatment within the previous 3 years. Subjects with a positive purified protein derivative tuberculin skin test (PPD) at screening are not eligible for the study unless they completed treatment for latent TB and had a negative CXR at enrollment.
    20. Primary or secondary immunodeficiency (history of or currently active).
    21. History of malignancy, including solid tumors and hematologic malignancies (except basal cell carcinoma of the skin that has been excised and cured).
    22. Pregnant women or nursing (breast feeding) mothers.
    23. History of alcohol, drug or chemical abuse within the six months prior to screening.
    24. Neuropathies or other painful conditions that might interfere with pain evaluation.
    25. Patients with lack of peripheral venous access.
    26. Body weight of >150 kg.
    Exclusion criteria related to lab findings:
    27. Serum creatinine >1.4 mg/dL in female pa-tients and >1.6 mg/dL in male patients.
    28. 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.)
    29. Platelet count <100,000/mm³.
    30. Hemoglobin <8.5 g/dL.
    31. White Blood Cells <3000/mm³.
    32. Absolute neutrophil count <2000/mm³.
    33. Absolute lymphocyte count <500/mm³.
    34. Positive Hepatitis BsAg, or Hepatitis C anti-body.
    35. Total Bilirubin >ULN. (If initial sample yields Bilirubin >ULN, a second sample may be taken and tested during the screening period.)
    36. Triglycerides >10 mmol/L (>900 mg/dL) at screening (non-fasted).
    Exclusion criteria related to formal aspects:
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the rate of patients reaching DAS28 low disease (≤3.2) 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 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 No
    E.6.11Pharmacogenomic No
    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 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) 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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned85
    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 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
    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 months20
    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 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 state258
    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 Decision2008-07-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-08-19
    P. End of Trial
    P.End of Trial StatusCompleted
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