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    Summary
    EudraCT Number:2015-000168-32
    Sponsor's Protocol Code Number:NL51705.000.15
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2015-07-09
    Trial 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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2015-000168-32
    A.3Full title of the trial
    Mesenchymal stem cells for Angiogenesis and Neovascularization in digital Ulcers of Systemic sclerosis
    Mesenchymale stamcellen voor angiogenese en neovascularisatie bij digitale ulcera van patiënten met systemische sclerose
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Mesenchymal stem cells as treatment for non healing wounds on the fingers in patients with systemic sclerosis
    Mesenchymale stamcellen als behandeling voor wondjes aan de vingers die niet genezen bij patiënten met systemische sclerose
    A.3.2Name or abbreviated title of the trial where available
    MANUS Trial
    MANUS onderzoek
    A.4.1Sponsor's protocol code numberNL51705.000.15
    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.1.3.4CountryNetherlands
    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 supportZonMW
    B.4.2CountryNetherlands
    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 pointPrincipal investigator
    B.5.3 Address:
    B.5.3.1Street AddressHeidelberglaan 100
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3584CX
    B.5.3.4CountryNetherlands
    B.5.6E-mailm.c.verhaar@umcutrecht.nl
    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 stem cells
    D.3.2Product code 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 IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEX VIVO CULTURED HUMAN MESENCHYMAL STEM CELLS
    D.3.9.3Other descriptive nameEX VIVO CULTURED HUMAN MESENCHYMAL STEM CELLS
    D.3.9.4EV Substance CodeSUB27304
    D.3.10 Strength
    D.3.10.1Concentration unit CFU/ml colony forming unit(s)/millilitre
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number50000000
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    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 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 placeboSuspension and solvent for suspension for injection
    D.8.4Route of administration of the placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    systemic sclerosis
    systemische sclerose
    E.1.1.1Medical condition in easily understood language
    scleroderma
    scleroderma
    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 18.0
    E.1.2Level PT
    E.1.2Classification code 10042953
    E.1.2Term Systemic sclerosis
    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
    Determining the safety and efficacy of intramuscularly administered mesenchymal stem cells for the treatment of digital ucers in systemic sclerosis.
    Het vaststellen van de veiligheid en werkzaamheid van intramusculaire toediening van mesenchymale stamcellen ter behandeling van digitale ulcera bij systemische sclerose.
    E.2.2Secondary objectives of the trial
    To assess the accuracy of various parameters related to inflammation, endothelial activation and angiogenesis to predict therapeutic efficacy and/or serve as biomarkers
    Beoordelen of diverse parameters gerelateerd aan inflammatie, endotheelactivatie en angiogenese verband houden met het therapeutische effect en mogelijk als biomarkers kunnen dienen.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age >18 years
    - Established diagnosis of SSc according to criteria of the American College of Rheumatology (2013)
    - At least one active digital ulcer (painful area, >2 mm in diameter with visible depth and loss of dermis) refractory to intravenous prostacyclins
    ------------‘Refractory to prostacyclins’ is defined as
     -Worsening of ulcer(s) at 1 month after prostacyclins iv
     -No improvement of ulcer(s) at 2 months after prostacyclins iv, as judged by the referring physician
     -Recurrence of exactly the same ulcer(s) (same location) at 3 months after prostacyclins iv
    - Written informed consent
    - ouder dan 18 jaar
    - diagnose systemische sclerose in overeenstemming met de criteria van de American College of Rheumatology (2013)
    minimaal 1 actief digitaal ulcus (pijnlijk, groter dan 2mm, met zichtbare diepte en verlies van dermis) en niet reageert intraveneuze prostacyclines
    ------------------ 'niet reageren' wordt gedefiniëerd als
    - Verslechtering van het ulcus 1 mnd na toediening prostacyclines
    - Geen verbetering van het ulcus 2 mnd na toediening prostacyclines, beoordeeld door de verwijzend specialist
    - Terugkeren van hetzelfde ulcus (zelfde locatie) 3 mnd na toediening
    - Informed consent
    E.4Principal exclusion criteria
    - Ulcer with underlying calcinosis (ruled out by X-ray prior to referral)
    -History of neoplasm or malignancy in the past 10 years
    - Pregnancy or unwillingness to use adequate contraception during study
    - Serious known concomitant disease with life expectancy <1 year
    - Uncontrolled hypertension
    - Uncontrolled acute or chronic infection
    - Follow-up impossible.


    Ulcus ten gevolge van onderliggende calcinose (uitgesloten door röntgenfoto vóór verwijzing)
    Maligniteit in de voorgeschiedenis
    Zwangerschap of niet bereid anticonceptie te gebruiken gedurende de studie
    Ernstige comorbiditeit met een levensverwachting <1 jaar
    Ongereguleerde hypertensie
    Ongereguleerde acute of chronische infectie
    Follow-up niet mogelijk
    E.5 End points
    E.5.1Primary end point(s)
    Number of serious adverse events
    Aantal ernstige ongewenste voorvallen/bijwerkingen
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 weeks
    12 weken
    E.5.2Secondary end point(s)
    Safety:
    - treatment related toxicity as assessed with the WHO parameters

    Efficacy:
    -ulcer count, ulcer area
    -ulcer VAS
    -quality of life as determined with the S-HAQ, SF-36, EQ5D, CHFS
    -capillaroscopy semi-quantitative score
    - change in biomarkers
    Veiligheid:
    - Toxiciteit tgv de behandeling (WHO parameters)

    Effectiviteit:
    - aantal en oppervlakte van de wondjes
    - VAS mbt de wondjes
    - kwaliteit van leven zoals blijkt uit de S-HAQ, SF-36 en EQ5D, CHFS
    - capillaroscopie semi-quantitative score
    - verandering in biomarkers
    E.5.2.1Timepoint(s) of evaluation of this end point
    12 weeks
    12 weken
    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.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 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.8.2.4Number of treatment arms in the trial2
    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
    Treatment-related mortality within 7 days after administration
    Behandelingsgerelateerde mortaliteit binnen 7 dagen na toediening
    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 months
    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: 20
    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 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 state20
    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)
    None
    Geen
    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 Decision2015-06-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-13
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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