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    Summary
    EudraCT Number:2012-000605-72
    Sponsor's Protocol Code Number:CB+MSCforEB
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-08-12
    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 number2012-000605-72
    A.3Full title of the trial
    Unrelated cord blood transplantation after reduced toxicity conditioning with mesenchymal stromal cell co-infusion in patients with severe epidermolysis bullosa
    Allogene stamcel transplantatie middels navelstreng bloed na verminderd toxiciteit conditionering met mesenchymale stromale cel co-infusie voor ernstige vormen van epidermolysis bullosa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Stem cell transplantation with cord blood and mesenchymal stem cells after reduced intensity conditioning for severe forms of the blistering disease epidermolysis bullosa
    Stamcel transplantation middels navelstreng bloed met mesenchymale stamcellen na verminderd toxische chemotherapie als behandeling voor het ernstige blaarziekte epidermolysis bullosa
    A.3.2Name or abbreviated title of the trial where available
    CB+MSCforEB
    A.4.1Sponsor's protocol code numberCB+MSCforEB
    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 SponsorUniversitair Medisch Centrum 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 supportStichting Vlinderkind
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportZeldzame Ziekten Fonds
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitair Medische Centrum Utrecht
    B.5.2Functional name of contact pointDr. J.J.Boelens
    B.5.3 Address:
    B.5.3.1Street AddressLundlaan 6
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3503 AB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31887554003
    B.5.5Fax number31887555350
    B.5.6E-mailj.j.boelens@umcutrecht.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 nameTC-MSC
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation Yes
    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.3.9.2Current sponsor codeTC-MSC
    D.3.10 Strength
    D.3.10.1Concentration unit thousand organisms/ml thousand organisms/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1000 to 2000
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Busilvex
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) 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 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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Fludarabine
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameFLudarabine
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) 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 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.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 THYMOGLOBULINE
    D.2.1.1.2Name of the Marketing Authorisation holderGENZYME EUROPE B.V
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameThymoglobuline
    D.3.4Pharmaceutical form Powder and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) 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 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
    The source population consists of patients referred to or within the UMC Groningen because they have diagnosed clinically and genetically severe generalized RDEB.
    E.1.1.1Medical condition in easily understood language
    Epidermolysis Bullosa is a genetic skin disease characterized by blistering and chronic wounds of the skin and mucous membranes.
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1) To investigate the safety of unrelated cord blood transplantation with additional mesenchymal stromal cell co-infusion, preceeded by reduced toxicity conditioning in patients with severe generalized dystrophic epidermolysis bullosa.

    2) To assess clinical improvement of skin with regards to wound healing and blister formation. To study the biology of engraftment of hematopoietic & non-hematopoietic stem cells in skin on a molecular basis with a variety of laboratory techniques. Focus will be on expression of C7 and anchoring fibrils at the dermal-epidermal junction for RDEB-sev-gen before and after transplantation.
    E.2.2Secondary objectives of the trial
    1) Sustained full cord blood donor chimerism.
    2) Toxicity: acute-GvHD, chronic-GvHD prevention with standard chemotherapy prophylaxis
    3) To investigate whether infusion of a single cord blood unit with additional mesenchymal stromal cell co-infusion preceded by the standard “reduced toxicity” conditioning regimen (UMC Utrecht protocol for non malignant disease) will ameliorate the blistering phenotype clinically seen in patients with severe generalized recessive dystrophic epidermolysis bullosa (RDEB-sev-gen).

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Diagnosed recessive dystrophic EB, severe generalized type (complete loss of functional type VII collagen by immunofluorescence microscopy and confirmed by molecular analysis).
    2) having a single matching (≥ 5/6) umbilical CB unit available with sufficient cell count total NC count > 3 * E7/kg
    3) Lansky / Karnofsky > 40
    4) Age <18 *( *= Karnofs364 days)
    5) Signed Informed Consent
    6) Approval by International Expert Advisory Panel (Annex 7) & UMCU kernteam-HCT
    E.4Principal exclusion criteria
    1) Creatinine clearance < 40 ml/min
    2) Cardiac dysfunction (SF < 30%) (Ejection fraction < 45%), unstable angina, or unstable cardiac arrhythmias
    3) Pulmonary function test (for those who can do: age dependent) VC, FEV1 and/ or DOC< 50%
    4) Subjects with medical history of evidence of malignancy, including cutaneous squamous cell carcinoma
    5) Patients with positive auto-antibodies to type VII collagen Determined with blood sample and salt split skin test (Immunodermatology lab UMCG)
    6) Allergy to any of the known constituents found in the investigational products (reduced toxicity chemotherapy drugs, CB and MSC)
    7) HIV seropositive infection
    E.5 End points
    E.5.1Primary end point(s)
    Safety:
    The primary efficacy in this Phase II trial will be based on the safety of the administration of the IMPs in this disease population measured according to Transplantation related mortality (Death associated with the procedure: <40%) at day+100
    Biology:
    • Clinical improvement of wound healing and shorter time to blister formation
    • Punch biopsies: Assessment of protein expression at the dermal-epidermal junction using immunofluorescence (Antigen mapping): Collagen VII deposition at various time points (prior to transplantation, D60, 180, 240, 365, and 730) 6 times during course of the trial, 2 biopsies each time
    • Quantitative analysis of the donor cells dermal chimerism (Days: see above, same biopsy is used). Fluorescence in-situ hybridization (FISH)
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary efficacy in this Phase II trial will be based on the safety of the administration of the 3 IMPs (reduced intensity conditioning, cord blood transplantation and mesenchymal stromal cells) in this disease population measured according to Non-Relapse mortality (Death associated with the procedure). This will be measured at the classical TRM endpoint for allogeneic stem cell transplantation at day+100.
    Biology:
    Clinical improvement of wound healing and shorter time to blister formation
    Assessment of protein expression at the dermal-epidermal junction: Collagen VII deposition at the DEJ at various time points (D60, 180, 240, 365 and 730)
    Quantitative analysis of the donor cells dermal chimerism (Days: see above)
    E.5.2Secondary end point(s)
    • Disease specific outcomes: Clinical blister assessment: Suction Blister Time (Electronic Diversities. U.S.A) & Skin Rub Test (Kiritsi et al, 2013 personal communication)
    • Acute GVHD (Grade II-IV: Gluckberg Criteria)
    • Engraftment: Neutrophils > 500K/uL for 3 consecutive days and Platelet (day 180 > 50 K) engraftment.
    • Loss of CB chimerism (<25%) at 6 mths post HSCT
    • Event Free Survival (>6 mths follow up). Event defined as: death, graft-failure (<25% total donor chimerism) or relapse.
    • Overall Survival
    • Chronic GVHD: limited and extensive (Shulman Criteria)
    • VOD (Seattle Criteria)
    • Mucositis ≥ CTC grade 3
    • ISCOREB: Disease specific severity score and quality of life assessment
    • Antibody formation (Col7) Blood sample during routine control is used
    E.5.2.1Timepoint(s) of evaluation of this end point
    Protein expression/skin chimerism assessment: (prior to transplantation, D60, D180, D240, D365, and D730)
    Quality of Life/Disease Specific Severity Score: (prior to transplantation, D60, D180, D240, D365 and D730)
    Clinical Blister testing (Suction & Rub Test): Prior to transplantation, D180, D365 and D730)
    Phenotype improvement: (prior to transplantation, D0, D30, D60, D120, D180, D240, D365, and D730)
    Hematologic assessment will be done during admission and by regular control visits
    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 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 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 concerned2
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    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 Yes
    F.1.1Number of subjects for this age range: 2
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 2
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 2
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 2
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 2
    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 No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state11
    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)
    Subjects participating in the trial will continue under the care of the Centre for Blistering Diseases in UMC Groningen, the Netherlands. Should they have complications pertaining to the allogeneic stem cell transplantation itself they will be seen at UMC Utrecht.
    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 Decision2013-03-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-02-06
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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