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    Summary
    EudraCT Number:2009-012185-32
    Sponsor's Protocol Code Number:ML22413
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-06-25
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2009-012185-32
    A.3Full title of the trial
    Open label, multicentric phase IIIb study to evaluate the effect of tocilizumab in combination with DMARDs in the inhibition of progression of synovitis, bone marrow edema, and erosions evaluated by dedicated magnetic resonance imaging (MRI) in the hand of patients with rheumatoid arthritis (RA)
    A.3.2Name or abbreviated title of the trial where available
    ND
    A.4.1Sponsor's protocol code numberML22413
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    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
    B.1.3.4CountryItaly
    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 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 Ro487-7533
    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 INNRoActemra
    D.3.9.1CAS number 375823-41-9
    D.3.9.2Current sponsor codeRo487-7533
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 typeInibitore del recettore IL6, anticorpo monoclonale umanizzato
    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
    Moderate to severe active rheumatoid arthritis (RA), who are inadequate responders to DMARDs.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.0
    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 assess the effects of tocilizumab in changes of the synovial membrane enhancement in the wrist joints of RA patients with inadequate clinical response to treatment with traditional DMARDs, defined as a baseline DAS28 > 3.2.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to assess the effects of tocilizumab on the following parameters: 1.Extent of bone marrow edema, and number and extent of erosions in the wrist and metacarpo-phalangeal joints using dedicated MRI; 2.Radiographic changes in the hands evaluated by the modified Sharp score; 3.Ritchie articular index; 4.HAQ; 5.Pain by using a visual-analogue scale; 6.General health by using a visual-analogue scale; 7.DAS 28-CRP; 8.VEGF concentrations; 9.ESR and hsCRP concentration; 10.Hb and soluble transferrin receptor concentrations; 11.Immunological and inflammatory parameters 12.Tolerability and safety parameters. To assess early effects (Day 2) of tocilizumab on immunological and inflammatory parameters, an additional laboratory assessment will be performed only on patients who will agree to give a supplementary written informed consent.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Men and women &amp;#8805; 18 years of age with a diagnosis of RA of &amp;#8805; 6 months duration, who are currently experiencing moderate to severe active RA (DAS28 > 3.2) and an inadequate clinical response to a stable dose of non-biologic DMARD therapy - Inclusion criteria 1.Male or non-pregnant, non-nursing female 2.Age &amp;#8805; 18 years 3.Patients with diagnosis of RA of &amp;#8805; 6 months duration 4.Patients currently experiencing moderate to severe active RA (DAS28 > 3.2) 5.Patients with: SJ &amp;#8805; 6; TJ &amp;#8805; 8 6.Patients receiving treatment on an outpatient basis 7.Patients with inadequate clinical response to a stable dose of non-biologic DMARD for at least 2 months 8.If patients are receiving an oral corticosteroid, the dose must have been stable for at least 25 out of 28 days prior to treatment (baseline) 9.Subjects able and willing to give written informed consent and comply with the requirements of the study protocol.
    E.4Principal exclusion criteria
    Disease-specific criteria: 1.Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization 2.Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), systemic sclerosis, polymyositis, or significant systemic involvement secondary to RA (e.g. vasculitis, pulmonary fibrosis or Felty�s syndrome). Patient with interstitial pulmonary fibrosis and still able to tolerate MTX therapy can be included in the study. Patients with secondary Sj�gren�s Syndrome associated with RA can be included in the study 3.Functional class IV as defined by the ACR Classification of Functional Status in RA (largely or wholly incapacitated with patient bedridden or confined to wheel chair, permitting little or no self-care) 4.Prior history of or current inflammatory joint disease other than RA (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) Drug-specific criteria: 5.Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational agent, whichever is longer) before screening 6.Previous inadequate response to treatment with biologic DMARDs Previous biologic treatment allowed if assumed for no more than 1 month and stopped for tolerability reasons at least 6 months before the enrollment in the study. 7.Intraarticular or parenteral corticosteroids within 6 weeks prior to baseline 8.Immunization with a live/attenuated vaccine within 4 weeks prior to baseline 9.Previous treatment with tocilizumab (an exception to this criterion may be granted for single-dose exposure upon application to the sponsor on a case by case basis) 10.Any previous treatment with alkylating agents, such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation Laboratory-specific criteria (at screening): 11.Serum creatinine > 142 &amp;#956;mol/L (1.6 mg/dL) in female patients and > 168 &amp;#956;mol/L (1.9 mg/dL) in male patients 12.ALT (SGPT) or AST (SGOT) > 1.5 ULN (If initial sample yields ALT [SGPT] or AST [SGOT] > 1.5 ULN, a second sample may be taken and tested during the screening period) 13.Platelet count < 100 x 109/L (100,000/mm3) 14.Hemoglobin < 80 g/L (8 g/dL) 15.WBC count <1.0 x 109/L (1000/mm3), ANC < 0.5 x 109/L (500/mm3) 16.ALC < 0.5 x 109/L (500/mm3) 17.Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody 18.Total bilirubin > ULN (If initial sample yields bilirubin > ULN, a second sample may be taken and tested during the screening period) 19.Triglycerides > 10 mmol/L (> 900 mg/dL) at screening (non-fasted) General medical: 20.Pregnant women or nursing (breastfeeding) mothers 21.Females of child-bearing potential who are not using a reliable method of contraception 22.History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies 23.History of severe or anaphylactic reactions to gadolinium. 24.Chest X-ray evidence of any clinically significant abnormality. 25.Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or GI disease. Et al.
    E.5 End points
    E.5.1Primary end point(s)
    ASSESSMENTS OF: -EFFICACY 1.Changes from baseline of the synovial membrane enhancement, in the wrist joints of RA, as follows: i.Extension and degree of synovitis of the wrist according to the RAMRIS score developed by OMERACT ii.Number of bones with, and extension of bone marrow oedema in the wrist and in the metacarpo-phalangeal area according to the RAMRIS score developed by OMERACT iii.Quantitative assessment of the degree of synovitis by dynamic, gadolinium-enhanced MRI (DCE-MRI) of the wrist 2.Radiographic changes in the hands evaluated by the modified Sharp score; 3.Changes from baseline of the Ritchie articular index 4.Changes from baseline of pain by using a visual-analogue scale (VAS) 5.Changes from baseline of general health by using a VAS 6.Changes from baseline of the DAS 28-CRP 7.Changes from baseline of VEGF concentrations 8.Changes from baseline of ESR and hsCRP concentrations 9.Changes from baseline of Hb and soluble transferring receptor concentrations 10.Changes from baseline of immunological and inflammatory parameters 11.Assessment of the early effects (Day 2) of tocilizumab on immunological and inflammatory parameters. An additional laboratory assessment will be performed only on patients who will agree to give a supplementary written informed consent. -SAFETY 1.Standard adverse events (AEs), drug-related AEs, serious adverse events (SAEs) and study discontinuations due to AEs. Additional information about AEs of special interest (serious and non-serious) such as lipid elevations, infections, neutrophil count and raised transaminases, will be captured 2.Physical examination 3.Vital signs (pulse rate, blood pressure, body temperature and body weight) 4.Routine safety laboratory parameters (haematology, blood chemistry) -QUALITY OF LIFE
    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 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 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 No
    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) 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 concerned12
    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
    La sperimentazione si conclude con l`ultima visita dell`ultimo paziente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months12
    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) 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 state70
    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 Decision2009-11-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-06-19
    P. End of Trial
    P.End of Trial StatusCompleted
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