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    Summary
    EudraCT Number:2008-003011-12
    Sponsor's Protocol Code Number:RR08/8613
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-04-27
    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 ConcernedUK - MHRA
    A.2EudraCT number2008-003011-12
    A.3Full title of the trial
    Prospective Randomised Double-Blind Placebo Controlled Study Assessing the Efficacy of Tocilizumab with Synovial Analysis in Patients with Rheumatoid Arthritis
    A.3.2Name or abbreviated title of the trial where available
    TOCRA
    A.4.1Sponsor's protocol code numberRR08/8613
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Leeds
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    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®EV Product Code: PRD82321
    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 No
    D.3.7Routes of administration for this IMPIntravenous use
    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) No
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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
    To assess changes in synovial tissue to identify onset of action and potential predictors of response to tocilizumab based on changes in: • synovial volume, bone oedema on knee MRI at 4 weeks • synovial tissue histology and immunohistochemistry
    E.2.2Secondary objectives of the trial
    o To evaluate the safety of tocilizumab and MTX combination for the treatment of rheumatoid arthritis by assessment of: Incidence of adverse events, Vital signs and urinalysis, Blood haematology and chemistry, and ECG o To evaluate efficacy of tocilizumab and MTX/DMARD combination by: Clinical assessment (Composite scores: ACR and DAS28/EULAR response, 28 joint counts, Patient pain and general health VAS, Duration of morning stiffness, HAQ and RAQol, Physician Global VAS, and hsCRP and ESR), Radiological Assessment (MRI and ultrasonographical features, Plain radiology, and Bone densitometry, and Synovial Assessment (Macroscopic synovitis and vascularity scores, Change in histological score and pro-inflammatory cytokine expression in biopsies).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Diagnosis of rheumatoid arthritis (1987 revised ACR criteria) confirmed at least 6 months prior to screening. 2.Persistent RA disease activity not responsive (ACR 0 and / or EULAR None-response) whilst being treated with an anti-TNF agent for at least 12 weeks. 3.Patients who have previously discontinued anti-TNF due to toxicity. 4.Patients have previously qualified for anti-TNF (NICE / BSR criteria) but therapy is contra-indicated. 5.Methotrexate dose stable for 12 weeks prior to screening and to be continued for the duration of the study. 6.Subjects with active RA at baseline are defined as: DAS28 > 5.1 7.Female patients will only be enrolled into the study if they are of non child bearing potential (surgically sterile or at least 2 years postmenopausal) or have satisfied the investigator as having an adequate form of contraception. Male patients must consent to practice contraception during the study. 8.Patients on NSAIDs and / or corticosteroids must have remained on an unchanged regimen for at least 28 days prior to study drug administration. 9. Discontinuation of a prohibited DMARD (e.g. oral or injectable gold, chloroquine, hydroxychloroquine, cyclosporine, azathioprine, leflunomide, sulphasalazine) or TNF-blocker (infliximab, etanercept or adalimumab) must occur at least 28 days prior to study drug administration (week 0). 10. Patients must be able and willing to comply with the terms of this protocol including attending for arthroscopy and imaging assessments. 11. Informed consent must be obtained in writing for all subjects at enrolment into the study. 4.3 EXCLUSION CRITERIA 1. Patients unwilling or unable to receive MTX for the duration of the study. 2. Patients with inflammatory joint disease of different origin, mixed connective tissue disease, Reiter’s syndrome, psoriatic arthritis, systemic lupus erythematosus, or any arthritis with onset prior to 16 years of age. 3. Suspicion of diagnosis of tuberculosis (positive tuberculosis test (>5mm induration if previous BCG or >10mm if no previous BCG) or abnormal chest x-ray)…
    E.4Principal exclusion criteria
    1. Patients unwilling or unable to receive MTX for the duration of the study. 2. Patients with inflammatory joint disease of different origin, mixed connective tissue disease, Reiter’s syndrome, psoriatic arthritis, systemic lupus erythematosus, or any arthritis with onset prior to 16 years of age. 3. Suspicion of diagnosis of tuberculosis (positive tuberculosis test (>5mm induration if previous BCG or >10mm if no previous BCG) or abnormal chest x-ray). 4. Patients with concomitant medical condition which would in the investigator’s opinion compromise the patient’s ability to tolerate, absorb, metabolise or excrete the study medication. 5. Patients with serious infections within 3 month of enrolment (screening) or persistent infections. 6. Patients at significant risk of infection (e.g. leg ulceration, indwelling urinary catheter, septic joint within 1 year (or ever if prosthetic joint still in situ)). 7. Patients with malignancy (other than excised basal cell carcinoma) within the last 5 years before study entry (screening). 8. Patients with history of Felty’s syndrome, uncontrolled diabetes, uncontrolled hypertension, unstable ischaemic heart disease, active bowel disease, active peptic ulcer disease, recent stroke (within three month before study entry (screening)), or other condition which, in the opinion of the investigator, would put the patient at risk to participate in the study. 9. Known positive serology for hepatitis B or C, or HIV 10. Patients with acute major trauma. 11. Patients with body weight < 45 kg. 12. Clinically relevant cardiovascular, hepatic, neurologic (such as multiple sclerosis, optic neuritis etc.), endocrine, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult. 13. Impaired hepatic function, as shown by • ALT or ALP ? 2 times the laboratory upper limit of normal or • Serum albumin < 30 g/l. 14. Patients with significantly impaired bone marrow function as for example significant anaemia, leukopenia, neutropenia or thrombocytopenia as shown by the following laboratory values : • Haemoglobin < 8.5 g/dl • Hematocrit < 30% • Platelet count < 100 x 109 / L • White blood cell count < 3.5 x 109 / L • Neutrophils count < 1 x 109 / L 15. Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome or impaired renal function, as shown by: • Serum Creatinine > 150 umol / L • Creatinine Clearance ? 50 ml/min 16. Therapy within the previous 28 days before study drug administration with: • Other biological agents, e.g. anti-TNF, interferon, monoclonal antibodies, growth factor, cytokines. • Other DMARDs (e.g. oral or injectable gold, chloroquine, hydroxychloroquine, cyclosporine, azathioprine, leflunomide, sulfasalazine, D-penicillamine, alkylating agents, e.g. cyclophosphamide, chlorambucil) 17. Doses of prednisolone > 10mg/d within the previous 28 days before study drug administration (week 0). 18. Intra-articular or intra-muscular steroid administration within 28 days before screening. Intra-articular steroid into joint to be scanned / biopsied within 12 weeks of baseline assessments. 19. Previous treatment with total lymphoid irradiation or anti - CD4 or CAMPATH 1-H monoclonal antibodies, resulting in CD4-Lymphopenia and possible immunosuppression (CD4 lymphocytes < 500/mm3). 20. Pregnant women or women of childbearing potential. Pregnancy must be excluded before start of treatment with the study drug. 21. Women who are Breast-feeding 22. Male patients of procreation potential who are not using reliable contraception during treatment with the study drug. 23. History of hypersensitivity to the study medication or to drugs with similar chemical structures or to any of the contents in the tablets (especially previous Stevens-Johnson Syndrome, toxic epidermal necrolysis, erythema multiform). 24. History of drug or alcohol abuse. 25. Any known condition or circumstance which would prevent compliance or completion of the study, scheduled or anticipated surgery (particularly surgery to the involved knee joint within the study period). 26. Likelihood of requiring treatment during the study period with drugs not permitted by the study protocol. 27. Planned surgery within 12 months of study initiation. 28. Treatment with any investigational drug in the last 90 days before study entry 29. Any contra-indication to MRI such as pacemaker as per local protocol
    E.5 End points
    E.5.1Primary end point(s)
    To assess changes in synovial tissue to identify onset and mechanism of action and potential predictors of response to tocilizumab based on changes in: • synovial volume, bone oedema on knee MRI at 4 weeks • synovial tissue histology and immunohistochemistry
    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 No
    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 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) 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 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 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 No
    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 No
    E.8.7Trial has a data monitoring committee Yes
    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
    End of trial is defined as Last Patient Last Visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 30
    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)
    If patients respond well to the IMP we will apply for compassionate use from the manufacturer.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2009-03-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-02-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-12-27
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