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    The EU Clinical Trials Register currently displays   44334   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2010-022049-88
    Sponsor's Protocol Code Number:ML22985
    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:2010-11-11
    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 number2010-022049-88
    A.3Full title of the trial
    "Efficacy and safety study of a sequential therapy of tocilizumab (TCZ) and, if initially inade-quately responded to tocilizumab (TCZ), followed by rituximab (RTX) in DMARD-IR patients with rheumatoid arthritis (MIRAI)"
    A.3.2Name or abbreviated title of the trial where available
    MIRAI
    A.4.1Sponsor's protocol code numberML22985
    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 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 20 mg/ml Concentrate for solution for infusion
    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.3.8 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) No
    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 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 Yes
    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 typeIl-6-Receptor Inhibitor, Humanized Monoclonal Antibody
    D.IMP: 2
    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 Mabthera 500 mg Concentrate for solution for infusion
    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 nameRituximab
    D.3.2Product code RO045-2294
    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 174722-31-7
    D.3.9.2Current sponsor codeRO045-2294
    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 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 typeChimeric 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 (RA)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    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 early efficacy of TCZ at week 16 defined as DAS28 remission (<2.6), after 4 courses of 8mg/kg TCZ treatment.
    E.2.2Secondary objectives of the trial
    To assess: - the efficacy of RTX treatment in terms of improvement in commonly used RA outcome measures (DAS28 remission (<2.6), EULAR responses, ACR responses) at week 32 in patients not having responded to 4 courses of TCZ. The efficacy of TCZ treatment (EULAR responses especially late clinical remission, ACR responses) at week 32 in DMARD-IR patients.The effects of TCZ and RTX treatment on patient-reported outcomes.
    ?Safety will be assessed via reporting of incidences of adverse events and serious adverse events and the number and percentage of patients who discontinue study treatment due to AEs and SAEs.
    ?To correlate DAS28 response with B-cell panels.
    Due to character limitation - details see protocol
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients at baseline with active rheumatoid arthritis (RA) and a DAS28 (ESR) of >3.2 and of ≥6 months duration, diagnosed according to the ACR (American College of Rheumatology) criteria of 1987.
    2. Patients able and willing to give written informed consent to participate and comply with the requirements of the study; in addition, written consent for data protection (legal requirement in Germany: Datenschutz-rechtliche Einwilligung) must be provided.
    3. Receiving treatment on an outpatient basis.
    4. Age ≥18 years.
    5. At screening and/or baseline either ESR ≥28mm/h or CRP ≥0.7mg/dL (SI: ≥7mg/L).
    6. Receiving permitted DMARDs, one or more; current DMARD therapy must have been at a stable dose for at least 4 weeks prior to baseline.
    7. Oral corticosteroids (≤10mg/day prednisone or equivalent) are permitted if dose was stable for at least 4 weeks prior to baseline.
    8. Women of child-bearing potential are allowed to participate in this trial only if using reliable, highly effective contraceptives (allowed methods of birth control, i.e. with a failure rate of less than 1 % per year, are implants, injectables, combined oral contraceptives, IUSs (only hormonal contraceptive coil), sexual abstinence or vasectomized partner.
    9. Women of childbearing potential or less than one year after menopause (unless surgically steril) must have a negative pregnancy test (urine β-HCG) at screening. Pregnancy test has to be repeated at baseline in case of ab-sence of menstruation or irregular menstrual cycle.
    E.4Principal exclusion criteria
    Exclusion criteria related to general health
    1. Major surgery (including joint surgery) within eight weeks prior to baseline or planned major surgery within the study duration (a maximum of 32 weeks following baseline)
    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 significant 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, active Lyme disease).
    Exclusion criteria related to medications
    5. Patients currently participating in another clinical trial or patients who have participated in another clinical trial within 30 days prior to screening (or five half-lifes of the IMP, whichever is longer) or patients who participated in this trial before.
    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 base-line.
    8. Intra-articular or parenteral corticosteroids within four weeks prior to baseline. Injection of intra-articular steroids while on study medication is discouraged, but may be used in a limited fashion.
    9. Immunization with a live/attenuated vaccine within four weeks prior to baseline.
    10. Previous treatment with TCZ, RTX, or other biologic DMARDs such as TNF-blockers.
    11. Combination therapy with methotrexate (MTX) and leflunomide within 4 weeks prior to baseline.
    12. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation.
    Exclusion criteria related to general safety
    13. Severe heart failure (NYHA class IV) or severe, uncontrolled cardiac diseases.
    14. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
    15. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (incl. obstructive pulmonary disease), renal, hepatic, endocrine (incl. uncontrolled diabetes mellitus) or gastrointestinal disease.
    16. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids.
    17. 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.
    18. Current liver disease as determined by principal investigator (patients with prior history of ALT elevation will not be excluded.)
    19. 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.
    20. Active tuberculosis (TB) requiring treatment
    within the previous 3 years. Quantiferon testing
    (IGRA) should be used in preference to protein derivative tuberculin skin (PPD) or ELISPOT testing and must be negative. Patients also must have a negative CXR.
    20. Exception: If a PPD test was performed and the test result is positive, treatment for latent TB must be completed and
    patients must have a negative CXR. In addition, retesting with IGRA or ELISPOT must be performed and the result must be negative.
    21. Primary or secondary immunodeficiency (history of or currently active).
    22. History of malignancy, including solid tumors and hematologic malignancies (except basal cell carcinoma of the skin that has been excised and cured).
    23. Pregnant or nursing (breast feeding) women.
    24. History of alcohol, drug or chemical abuse within the six months prior to screening.
    25. Neuropathies or other painful conditions (only referred to joint status) that might interfere with pain evaluation.
    26. Any severe neurological diseases and any history of or actual demyelinating diseases
    27. Patients with lack of peripheral venous access.
    28. Body weight of >130 kg.
    Exclusion criteria related to lab findings and Exclusion criteria related to formal aspects ->due to character limitation -> please refer to protocol
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the rate of patients achieving DAS28 remission (<2.6) at week 16.
    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 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 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 concerned80
    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 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 years3
    E.8.9.1In the Member State concerned months5
    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 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.1.2.1Number of subjects for this age range: 385
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 115
    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 state500
    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 Decision2010-12-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-01-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-02-19
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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