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    The EU Clinical Trials Register currently displays   43974   clinical trials with a EudraCT protocol, of which   7312   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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    EudraCT Number:2008-007180-16
    Sponsor's Protocol Code Number:RITIS
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2008-11-24
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2008-007180-16
    A.3Full title of the trial
    A.3.2Name or abbreviated title of the trial where available
    RItuximab In Scleroderma ( RITIS)
    A.4.1Sponsor's protocol code numberRITIS
    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 SponsorLUMC
    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.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. name Rituximab
    D. of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameMabthera
    D.3.4Pharmaceutical form Powder for infusion*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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) Information not present in EudraCT
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. 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) Yes
    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 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 placeboSolution 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
    systemic sclerosis
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level PT
    E.1.2Classification code 10039710
    E.1.2Term Scleroderma
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and efficacy of anti-CD20 therapy with respect to:
    - Clinical and laboratory adverse events, as measured every three months.
    - Survival and prevention of major organ failure (referred to as ‘event-free survival’ which is considered the primary endpoint).
    - Impact on skin thickening, visceral involvement, functional status, and quality of life.
    E.2.2Secondary objectives of the trial
    - To evaluate whether disease activity correlates with immunological parameters, including immunopathology of skin, immune reconstitution, and autoantibodies.
    - To search for predictive factors (clinical and immunological) of response.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age between 18 and 70 years.
    2. Established diagnosis of systemic sclerosis according to ARA-criteria (appendix).
    3. Informed consent

    Appendix . Definition and classification of systemic sclerosis

    Systemic sclerosis can be classified according to criteria set up by the American Rheumatism Association:

    ARA scleroderma criteria cooperative study: Preliminary criteria for the classifica¬tion of
    syste¬mic sclerosis (scleroderma)

    1. Major criterion: - Proximal scleroderma
    2. Minor criteria : - Sclerodactyly
    - Digital pitting scars or loss of substance of the digital finger pad
    - Bibasilar pulmonary fibrosis

    One major or two or more minor criteria are necessary to establish a diagnosis of SSc. A further subclas¬sification can be made in limited (cuta¬neous) SSc (lSSc) and diffuse (cutaneous) SSc (dSSc).
    Limited SSc is characterized by skin involvement limited to hands, feet, face and/or fore¬arms, is associ¬ated with a high incidence of anticentro¬mere autoantibodies (70-80%), the existen¬ce for years of Ray¬naud's phenomenon and a significant late incidence of pulmonary hyper¬tensi¬on. The acronym CREST (Ca¬lcinosis, Raynaud's phenom¬enon, Esophageal dysmo¬tility, Sclero¬dac¬tyly and Telean¬giectasia) fits into this subclassification.
    Diffuse SSc is characterized by skin involvement on upperarms and trunk, is as¬sociated with an early incidence of interstitial lung disease, hypertensive crisis and renal failure, diffuse gastrointesti¬nal disease and myocardial involvement.


    Subcommittee for scleroderma criteria of the American Rheumatism Association diagnostic and therapeutic criteria commit¬tee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581-590.
    E.4Principal exclusion criteria
    . Pregnancy or unwillingness to use adequate contraception during study
    2. Previous treatments with biological agents, cell depleting therapies including investigational
    3. Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica; eosinophilic myalgia syndrome; eosinophilic fasciitis.
    5. History of allergic or anaphylactic reaction to a biological agent or known hypersensitivity to any component of anti-CD20 monoclonal antibodies or to murine proteins.
    6. History of deep tissue infection (e.g. Fasciitis, abscess, osteomyelitis) within 1 year prior to baseline.
    7. History of serious chronic or recurrent infection within 12 weeks prior to baseline, including HIV, HTLV-1,2 positivity.
    8. History of cancer, including solid tumors, hematological malignancies and carcinoma in situ (except for basal cell and squamous cell carcinoma of the skin that have been treated and cured).
    9. Concurrent liver failure as defined by a sustained 3-fold increase in serum transaminase or bilirubin.
    10. Active drug or alcohol abuse or persistent psychiatric disorders that prevent inclusion.
    11. Uncontrolled hypertension.
    12. Poor compliance of the patient as assessed by the referring physicians.
    13. Receipt of any vaccine 28 days prior to baseline.
    14. Intolerance or contraindications to IV glucocorticoids.
    15. Positive tests for HbsAg, Hepatitis core antibody or hepatitis C serology.
    16. Concentrations of serum IgG and /or IgM below 5.0 and 0.40 mg/ mL.
    17. Absolute neutrophil count of less than 1.0x 109/L.
    E.5 End points
    E.5.1Primary end point(s)
    - The major endpoints of the study are treatment related mortality and treatment toxicity, and efficacy of rituximab.
    Treatment related mortality is defined as any death during the study period that cannot be attributed to progression of the disease according to the consensus opinion.
    Treatment toxicity will be assessed using WHO toxicity parameters (expressed as maximum grade toxicity per organ system) (Appendix) in consecutive 3-month periods following randomization.

    Efficacy will be assessed as progression-free survival, defined as the time in days since the day of randomization until any of the following changes from baseline has been documented at two consecutive 3-month evaluations:
    - death,
    - > 10% drop in (F)VC and/or  15% drop in DLCO (of predicted values),
    - > 15% drop in LVEF by MUGA,
    - > 15% drop in body weight,
    - > 30% drop in creatinine clearance,
    - > 30% increase in Modified Rodnan skin score,
    - > 0.5 increase in SHAQ
    Changes during the study period (from baseline until completion of 2 years follow-up) in the following parameters :
    - Modified Rodnan Skin score
    - (F)VC and DLCO
    - LVEF
    - Weight (Kg)
    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 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. 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 Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    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 Information not present in EudraCT
    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
    after the last visit at t= 24months of the last subject in the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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 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 state20
    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 Decision2008-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-05-13
    P. End of Trial
    P.End of Trial StatusOngoing
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