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    EudraCT Number:2012-002067-10
    Sponsor's Protocol Code Number:MSC-JIA
    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:2013-09-24
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2012-002067-10
    A.3Full title of the trial
    Mesenchymal stromal cells for treatment of drug resistant
    pediatric Juvenile idiopathic arthritis
    Mesenchymale stromale cellen voor de behandeling van therapie-resistente juveniele idiopathische artritis op de kinderleeftijd
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Adult bonemarrow stem cells for treatment of juvenile arthritis in childhood
    Volwassen beenmergstamcellen voor de behandeling van therapie-resistente jeugdreuma op de kinderleeftijd
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberMSC-JIA
    A.5.4Other Identifiers
    Name:Nederlands Trial RegisterNumber:NTR4146
    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 Medical Center Utrecht
    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 supportUniversity Medical Center Utrecht
    B.4.1Name of organisation providing supportZonMw (The Netherlands Organisation for Health Research and Development)
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Utrecht
    B.5.2Functional name of contact pointBusiness Manager
    B.5.3 Address:
    B.5.3.1Street AddressPO Box 85090, intern mail address KB 03.057.1
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3508 AB
    B.5.4Telephone number31887554250
    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 nameMesenchymal Stromal Cells
    D.3.2Product code TC-MSC
    D.3.4Pharmaceutical form Suspension and solvent for suspension for injection
    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 INNmesenchymal stromal cells
    D.3.9.4EV Substance CodeSUB27304
    D.3.10 Strength
    D.3.10.1Concentration unit million CFU million colony forming units
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number2 million CFU/kg
    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) Yes
    D. cell therapy medicinal product Yes
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    juvenile idiopathic arthritis
    juveniele idiopathische artritis
    E.1.1.1Medical condition in easily understood language
    juvenile rheumatoid arthritis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10059176
    E.1.2Term Juvenile idiopathic arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Onderzoeken of intraveneuze MSC een veilige behandeling is voor kinderen met therapie-resistente jeugdreuma.
    To find out if intravenous MSC is a safe treatment for children with therapy-resistant JIA
    E.2.2Secondary objectives of the trial
    1. Effectiveness as measured by the percentage of individual change by ACR Pediatric 30 criteria (see 6.1.2)
    2. Effectiveness as measured by the a composite disease activity score for JIA, the Juvenile Arthritis Disease Activity Score (JADAS) which has the advantage of the measurement of actual disease activity and the comparison of one patient's absolute response with that of another patient's since it quantifies the absolute level of disease activity by providing one summary number on a continuous scale.
    3. Does infusion of MSC induce remission of inflammation as seen on MRI?
    4. Does infusion of MSC induce immunoregulatory mechanisms leading to a less pro-inflammatory milieu in the serum?
    1. Effectiviteit zoals gemeten met het percentage van de individuele verandering door ACR Pediatric 30 criteria (zie 6.1.2)
    2. Doeltreffendheid gemeten door een samengestelde ziekteactiviteit score JIA, de Juveniele Artritis Disease Activity Score (Jadas) hetgeen het voordeel heeft dat de werkelijke ziekteactiviteit wordt gemeten en een vergelijking van absolute respons van een patiënt met die van een andere patiënt mogelijk is omdat deze score het absolute niveau van de ziekte-activiteit kwantificeert door middel van een samengesteld getal op een continue schaal.
    3. Kan infusie van MSCremissie induceren van ontsteking zoals te zien op de MRI?
    4. Kan infusie van MSC immuunmodulatie geven leidend tot een minder pro-inflammatoire milieu in het serum?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must meet all of the following criteria: Patients (4-18 years of age) diagnosed with juvenile idiopathic arthritis according to the ILAR-criteria with active arthritis resistant to intra-articular steroids and systemic use of methotrexate and for whom no on-label indication exists for (not yet used) biologicals. The patient is followed for adverse events via the Pharmachild database.
    Patiënten (4-18 jaar) gediagnosticeerd met juveniele idiopathische artritis op basis van de Ilar-criteria met actieve artritis resistent tegen intra-articulaire steroïden en systemisch gebruik van methotrexaat voor wie er geen (nog niet gebruikt) on-label biological beschikbaar is. De patient wordt gevolgd voor bijwerkingen via Pharmachild database.
    E.4Principal exclusion criteria
    Concurrent use of biological response modifiers.
    Concurrent infection, febrile illness or malignancy.
    Gelijktijdig gebruik van biological response modifiers.
    Gelijktijdige infectie, met koorts gepaard gaande ziekte of een maligniteit.
    E.5 End points
    E.5.1Primary end point(s)
    Total number of adverse events in the 3 months prior to MSC infusion and the number of adverse events 3 months after MSC infusion.
    Totaal aantal bijwerkingen in de 3 maanden voorafgaand aan MSC infusie en het aantal bijwerkingen 3 maanden na MSC infusie.
    E.5.1.1Timepoint(s) of evaluation of this end point
    52 weeks after the (first) MSC injection
    52 weken na de (eerste) MSC injectie
    E.5.2Secondary end point(s)
    The ACR Pediatric 30 criteria should be met.
    The ACR Pedi 30 criteria are defined as improvement of ≥ 30% in at least 3 of 6 core response variables used to assess disease activity with no more than 1 variable worsening by ≥ 30%.

    Clinical outcomes:
    Clinical visits (at least 7 times in the first year 0-51 wks): -13, 0, 4, 8, 12, 16, 26, 39, 52 weeks
    The visits will encompass complete medical history and monitoring for side effects. Furthermore complete physical examination including total joint count. Validated health and functionality related questionnaires (see below) will be provided to the parents/patients. Global assessments by the parents/patients measured with a 10-cm VAS.
    Most widely used questionnaire for JIA is the Childhood Health Assessment Questionnaire (C-HAQ 30+8).
    In children with JIA, a functional measure focused to assess the function of individual joint groups, the Juvenile Arthritis Functionality Scale (JAFS), detects with greater precision the functional impact of arthritis in specific body areas than does a standard questionnaire based on the assessment of activities of daily living (the C-HAQ).
    Normal evaluation of JIA includes: articular index of tender joints, evaluation of the joint range of motion (EPM-ROM scale) 44 and will contain an evaluation of all joints as described previously. In short the joints will be assessed as being normal, warm, painful/tender, tender on passive motion, limited in motion. The degrees of passive motion will be noted for all limited joints. Global assessments by the physician measured with a 10-cm visual analogue scale (VAS).
    A weighted joint score improves the information provided by joint counts on the severity of arthritis and its impact on patients' well-being since a small finger joint of the non-dominant hand does not have the same impact as a knee that's is involved.
    ACR Pedi 30, 50, 70 and 90-scores are most frequently used for clinical trials. A composite disease activity score for JIA, the Juvenile Arthritis Disease Activity Score (JADAS), has the advantage of the measurement of actual disease activity and the comparison of one patient's absolute response with that of another patient's since it quantifies the absolute level of disease activity by providing one summary number on a continuous scale. All the above will be evaluated since all these parameters are complementary.
    Lastly the proposed preliminary definition of minimal disease activity in polyarticular JIA, the proposed preliminary definition of inactive disease in polyarticular JIA and the cut-off values for various disease states for the JADAS scores will be evaluated.

    Radiological outcomes:
    Magnetic Resonance Imaging (MRI 3x): MRI will be performed before MSC-infusion (wk0), 8 weeks (wk8) and 1 year after MSC infusion (wk52)
    The most active (highest burden in pain/swelling/limitation) large peripheral joint will be imaged; if only small joints of hands or feet are involved a whole hand or foot will be imaged. No data on treatment will be provided to the radiologist.
    Synovial enhancement, bone edema, cartilage loss, and bone erosion will all be scored as absent, mild, moderate and severe in both joints. Overall, there is fair (grade B) strength of evidence that MRI is an accurate diagnostic method for evaluating synovium and cartilage and for assessing clinical responsiveness to treatment in peripheral joints in JIA. In the case of knees the JAMRIS score can be used.

    Laboratory outcomes:
    Venapuncture (at least 7x in the first year): at every clinical visit -13, 0, 4, 8, 12, 16, 26, 39, 52 weeks.
    The blood for erythrocyte sedimentation rate (ESR), C-reactive protein level (CRP), complete blood count, leucocyte differentiation, ASAT, ALAT, LDH, BUN, Creatinine, total IgG, Rheumatoid factor, anti-CCP. Furthermore lymphocyte subpopulations will be analyzed using our FACS Canto machine and by their cytokine production measured by Luminex as previously described by our own group: (effector and regulatory subpopulations: including CD19+, CD4+, CD8+lymphocytes and Th1-, Th2-, Th17-, FoxP3-Treg, IL10+-Treg phenotype).
    Detailed B cell activation markers: within the CD19 positive B-cell we will look for CD38+, CD86+, CD10+ , CD27+, sIgM, sIgD, sIgG en sIgA. With these markers we can assess the proportion of naïve, mature and memory cells.
    Serumcytokines will also be examined by Luminex (including IL1, IL6, IL12, IL17, IL23, TNFα, IFNγ, IL4, IL10).
    Myeloid related proteins will be measured.
    At last we will investigate the in vitro suppression by MSC and by T-regs of the proliferation of the stimulated PBMC. Supernatant of stimulated PBMC’s will be examined by Luminex.
    ACR Ped 30 criteria moeten gehaald worden.

    Klinische resultaten:
    De meest gebruikte vragenlijst voor JIA is de Childhood Health Assessment Questionnaire (C-HAQ). Bij kinderen met JIA, is de Juvenile Arthritis Functionality Scale (JAFS) ontwikkeld, die detecteert met een grotere nauwkeurigheid de functionele gevolgen van artritis in specifieke delen van het lichaam dan een standaard vragenlijst zoals de C-HAQ. Normale evaluatie van JIA omvat: gewrichtsindex van gevoelige gewrichten, evaluatie van de bewegingsbeperkingen (EPM-ROM schaal). Een gewogen gewrichtsscore verbetert de informatie doordat verschillende gewrichten een andere impact hebben op patiënten-welzijn aangezien een ontstoken kleine vinger gewricht van de niet-dominante hand heeft niet dezelfde problemen geeft als een ontstoken enkel.
    ACR Pedi 30, 50, 70 en 90 scores worden het meest gebruikt voor klinische trials. Een samengestelde ziekte-activiteitsscore voor JIA de Juvenile Arthritis Disease Activity Score (JADAS), heeft het voordeel dat de meting van de actuele ziekteactiviteit en de vergelijking van de absolute respons van een patient kan worden vergeleken met de respons van een andere patiënt aangezien het het absolute niveau van ziekte-activiteit kwantificeert met een samengesteld getal op een continue schaal.
    Al het bovenstaande zal worden geëvalueerd, omdat al deze parameters complementair zijn. Ten slotte zal de voorgestelde voorlopige definitie van minimale ziekte-activiteit in polyarticulaire JIA en de voorgestelde voorlopige definitie van inactieve ziekte in polyarticulaire JIA worden geëvalueerd.

    Radiologische resultaten:
    MRi van aangedaan gewricht waarbij de radioloog niet word ingelicht over stadium van behandeling.
    Synoviale aankleuring, bot oedeem, verlies van kraakbeen en bot erosie zullen allemaal worden gescoord als afwezig, mild, matig en ernstig in beide gewrichten. Over het geheel genomen is er redelijke (graad B) mate van bewijs dat een MRI een nauwkeurige diagnostische methode is voor het evalueren van synovium en kraakbeen en voor de beoordeling van de klinische respons op de behandeling van de perifere gewrichten bij JIA.

    Laboratorium uitkomsten:
    BSE en CRP.
    Lymfocyten subpopulaties (effector en regulerende subpopulaties), cytokines in het serum en van supernatant van gestimuleerde PBMC's (onderzocht met Luminex). Ook de in vitro onderdrukking door MSC van de proliferatie van gestimuleerde PBMCs. Verder zijn we geïnteresseerd in de responsiviteit van effector-T-cellen op regulatoire T-cel gemedieerde onderdrukking, omdat we hebben gemerkt dat bij JIA de effector-T-cellen niet meer reageren op Treg-gemedieerde onderdrukking. De MSC behandeling zou een "reset" kunnen induceren van de effectorcellen zodat zij nu wel effectief worden onderdrukt door gebruikelijke T-regs. MRP-eiwitten in het serum worden bepaald.
    E.5.2.1Timepoint(s) of evaluation of this end point
    52 weeks after the (first) MSC injection
    52 weken na de (eerste) MSC injectie
    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 Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E. trial type description
    In the specific patientpopulation : safety (primary), frequency and hint of effectiveness (secondary
    Bij beoogde patientenpopulatie: veiligheid (primair), frequentie en hint v effectiviteit (secundair
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    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 No
    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 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
    This is a pilot study powered for 6 study subjects.
    Stopping rules: progression of arthritis after MSC infusion in >50% of patients. Any treatment related mortality within 7 days of MSC injection in the first series of 6 patients. Occurrence of malignancies.
    Dit betreft een pilot studie van 6 participanten.
    De pilotstudie wordt gestaakt als er progressie van de artritis optreedt in >50% van de patienten na de MSC injectie.Er wordt ook gestaakt indien er enige behandelingsgerelateerde mortaliteit is binnen 7 dagen na de MSC-injectie bij de eerste 6 patienten. Tevens wordt er gestopt indien er een maligniteit optreedt bij 1 van de patienten.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 6
    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) Yes
    F. of subjects for this age range: 3
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 3
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 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 Yes
    F. of subjects incapable of giving consent
    Minors could be included in this study.
    Minderjarigen mogen meedoen aan deze studie
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    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)
    At least 36 weeks after the last MSC injection patients will be followed by outpatient clinical visits, blood monitoring and an extra MRI of most active joint. If the patient is not yet transitioned to adult rheumatology care the follow-up will be longer with routine visits at our department.
    Minstens 36 weken na de laatste MSC injectie zal de patient poliklinisch vervolgd worden inclusief bloedonderzoek en een extra MRI van het meest aangedane gewricht. Als de patient niet in transitie overgaat naar de volwassen reumatologie dan zal de patient routinematig worden teruggezien op onze polikliniek.
    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 Decision2013-09-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-30
    P. End of Trial
    P.End of Trial StatusOngoing
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