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    Summary
    EudraCT Number:2015-004592-74
    Sponsor's Protocol Code Number:HOLOGENE7(HTA-HG7-01)
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-01-19
    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 ConcernedAustria - BASG
    A.2EudraCT number2015-004592-74
    A.3Full title of the trial
    PROSPECTIVE, OPEN LABEL, UNCONTROLLED CLINICAL TRIAL TO ASSESS THE SAFETY AND EFFICACY OF AUTOLOGOUS CULTURED EPIDERMAL GRAFTS CONTAINING EPIDERMAL STEM CELLS GENETICALLY MODIFIED WITH A GAMMA-RETROVIRAL (RV) VECTOR CARRYING COL7A1 cDNA FOR RESTORATION OF EPIDERMIS IN PATIENTS WITH RECESSIVE DYSTROPHIC EPIDERMOLYSIS BULLOSA.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Gene Therapy for patients with Recessive Dystrophic Epidermolysis Bullosa (RDEB).
    A.3.2Name or abbreviated title of the trial where available
    HOLOGENE7
    A.4.1Sponsor's protocol code numberHOLOGENE7(HTA-HG7-01)
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02984085
    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 SponsorHolostem Terapie Avanzate s.r.l.
    B.1.3.4CountryItaly
    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 supportHolostem Terapie Avanzate s.r.l.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHolostem Terapie Avanzate s.r.l.
    B.5.2Functional name of contact pointClinical Trial Coordinator
    B.5.3 Address:
    B.5.3.1Street Addressvia Glauco Gottardi 100
    B.5.3.2Town/ cityModena
    B.5.3.3Post code41125
    B.5.3.4CountryItaly
    B.5.6E-mailg.dileo@holostem.com
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/15/1466
    D.3 Description of the IMP
    D.3.1Product nameHOLOGENE7
    D.3.2Product code HOLOGENE7
    D.3.4Pharmaceutical form Living tissue equivalent
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraepidermal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTransduced keratinocytes suspension, containing epidermal stem cells genetically corrected with a COL7A1-encoding retroviral vector
    D.3.9.2Current sponsor codeHologene7 DS
    D.3.9.3Other descriptive nameTransduced keratinocytes suspension, containing epidermal stem cells genetically corrected with a COL7A1-encoding retroviral vector, obtained from secondary culture of ex vivo expanded autologous human keratinocytes.
    D.3.10 Strength
    D.3.10.1Concentration unit % percent
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number50 to 100
    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 No
    D.3.11.3.2Gene therapy medical product Yes
    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
    RDEB is characterized by generalized skin blistering, erosions, crusts, atrophic scarring, onychodystrophy and loss of nails, mutilating pseudosyndactyly of hands and feet, as well as oral cavity lesions, esophageal strictures and eye and genitourinary tract lesions, all of which can also lead to anemia, iron deficiency and growth delay. Aggressive metastasizing squamous cell carcinomas are a common complication of RDEB, which reduce patients’ average life expectancy to less than 40 years.
    E.1.1.1Medical condition in easily understood language
    RDEB is genetic skin disease characterized by generalized blistering. Local healing shall be achieved with transplants made from genetically corrected stem cells from the patients.
    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
    To investigate the safety of HOLOGENE 7 up to three months after the first treatment in patients with Epidermolysis Bullosa due to autosomal recessive mutations in the gene encoding for collagen VII (COL7A1).
    E.2.2Secondary objectives of the trial
    •To evaluate the efficacy of one or more treatments with HOLOGENE 7 at three months and one year follow up
    •Percentage of re-epithelialization during follow up;
    •Clinical and mechanical skin stability on the transplanted areas follow up
    •Restoration of type VII collagen expression in regenerated epidermis;
    •Restoration of anchoring fibrils in grafted skin;
    •Potential immune reactions against the transgene;
    •Quality of life evaluated by QOLEB, EBDASI, PGA;
    •Long-term safety.
    •Safety after one or more treatments with HOLOGENE 7.
    •To evaluate the clinical safety profile of treatment with HOLOGENE 7, including biopsy, HOLOGENE 7 transplantation procedure and post-transplantation treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Signed and dated informed consent prior to any study-related procedures. Informed consent will also include the possibility of additional transplantations and of the rolling over to the long-term extension period;
    2.Adult male and female patients (≥18 years old and < 55);
    Paediatric patients aged 6 to 17 years will be also enrolled.
    3.RDEB molecular characterization by mutation analysis;
    4.NC1 or NC2 antibody immunofluorescence or staining positive in Western Blot;
    5.Presence of chronic (persistent or recurrent for more than 3 months) large wounds (>10 cm2) and/or persistent or recurrent erosions;
    6.A cooperative attitude to follow up the study procedures (Caregivers in case of minors).
    E.4Principal exclusion criteria
    1.Known or suspected intolerances against anaesthesia;
    2.Bad general condition (ECOG index >1)
    3.Unresectable or metastasizing SCCs;
    4.Antibodies to type VII collagen associated antigens demonstrated on indirect immunofluorescence;
    5.Clinical and/or laboratory signs of acute systemic infections at the time of screening. Patient can be re-screened after appropriate treatment;
    6.Severe systemic diseases (i.e. uncompensated diabetes);
    7.Female subjects: pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS they are willing to use one or more reliable methods of contraception with a Pearl index ≤1. Reliable contraception should be maintained throughout the study.
    A pregnancy test in urine will be performed at screening in all women of childbearing potential, and repeated before biopsy treatment and at all visits. Any postmenopausal women (physiologic menopause defined as “12 consecutive months of amenorrhea”) or women permanently sterilized (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy) will not be require to undergo pregnancy test.
    Parental control will be applied for the pediatric population when needed.
    8.Allergy, sensitivity or intolerance to drugs or excipients (hypersensitivity to any of the excipients listed in Investigator’s brochure or in this protocol):
    - Transport medium (Dulbecco’s Modified Eagles Medium supplemented with L-glutamine)
    - Fibrin support
    - Betaisodona
    9.Contraindications to the local or systemic antibiotics and/ or corticosteroids foreseen by the protocol;
    10.Contraindications to undergo extensive surgical procedures;
    11.Clinically significant or unstable concurrent disease or other clinical contraindications to stem cell transplantation based upon investigator’s judgment or other concomitant medical conditions affecting grafting procedure;
    12.Patients (or parents in case of paediatric subject) unlikely to comply with the study protocol or unable to understand the nature and scope of the study or the possible benefits or unwanted effects of the study procedures and treatments.
    13.Participation in another clinical trial where investigational drug was received less than 6 months prior to screening visit.
    E.5 End points
    E.5.1Primary end point(s)
    To investigate the safety of HOLOGENE 7 up to three months after the first treatment in patients with Epidermolysis Bullosa due to autosomal recessive mutations in the gene encoding for collagen VII (COL7A1).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Three months
    E.5.2Secondary end point(s)
    To evaluate the efficacy of one or more treatments with HOLOGENE 7 at three months and one year follow up.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Three months and one year.
    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 No
    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) Yes
    E.7.1.1First administration to humans Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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
    The end of the trial is defined as the last visit of the last patient after the last treatment if any.
    But at the end of the study, all consenting patients will be required to enter the safety and efficacy long-term follow-up period.
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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.1.1.5.1Number of subjects for this age range: 3
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 3
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 6
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 12
    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)
    Patients are followed up once a year by their responsible center once a year.
    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 Decision2016-04-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-01
    P. End of Trial
    P.End of Trial StatusOngoing
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