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    Summary
    EudraCT Number:2022-001780-27
    Sponsor's Protocol Code Number:HTA-HG5-04
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2022-08-10
    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 ConcernedGermany - PEI
    A.2EudraCT number2022-001780-27
    A.3Full title of the trial
    OPEN-LABEL, UNCONTROLLED, CLINICAL TRIAL TO EVALUATE THE SAFETY AND EFFICACY OF AUTOLOGOUS FIBRIN-CULTURED EPIDERMAL GRAFTS CONTAINING EPIDERMAL STEM CELLS GENETICALLY MODIFIED FOR RESTORATION OF EPIDERMIS IN PATIENTS WITH JUNCTIONAL EPIDERMOLYSIS BULLOSA
    OFFENE, UNKONTROLLIERTE KLINISCHE STUDIE ZUR BEWERTUNG DER SICHERHEIT UND WIRKSAMKEIT VON AUTOLOGEN FIBRINKULTURIERTEN EPIDERMALEN TRANSPLANTATEN MIT GENETISCH VERÄNDERTEN EPIDERMALEN STAMMZELLEN ZUR WIEDERHERSTELLUNG DER EPIDERMIS BEI PATIENTEN MIT EPIDERMOLYSIS BULLOSA JUNKTIONALIS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Gene Therapy for patient with Junctional Epidermolysis Bullosa
    Gentherapie für Patienten mit Epidermolysis bullosa.
    A.3.2Name or abbreviated title of the trial where available
    Hologene 5
    A.4.1Sponsor's protocol code numberHTA-HG5-04
    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 organisationCROSS Research SA
    B.5.2Functional name of contact pointPatrick Santoro
    B.5.3 Address:
    B.5.3.1Street AddressVia FA Giorgioli 14
    B.5.3.2Town/ cityArzo
    B.5.3.3Post code6864
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+41916300510
    B.5.5Fax number+41916300511
    B.5.6E-mailpatrick.Santoro@croalliance.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/3/15/1465
    D.3 Description of the IMP
    D.3.1Product nameHologene 5
    D.3.4Pharmaceutical form Living tissue equivalent
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPCutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot Yet Assigned
    D.3.9.1CAS number Not Assigned
    D.3.9.2Current sponsor codeHologene 5 DS
    D.3.9.3Other descriptive nameEx-vivo-expanded autologous human keratinocytes containing epidermal stem cells transduced with a LAMB3-encoding retroviral vector
    D.3.9.4EV Substance CodeSUB194480
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number20000000 to 30000000
    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 Yes
    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
    Inherited Epidermolysis Bullosa (EB) is a group of rare, devastating genetic disorders characterized by structural and mechanical fragility of skin and mucosal membranes, impairing the patient’s quality of life. Generalized JEB is a chronic, life-threatening condition caused by mutations in genes– encoding different chains of laminin 332. All of these mutations hamper hemidesmosome formation, causing blisters. The most frequent, and perhaps most severe, JEB is due to mutations in LAMB3.
    E.1.1.1Medical condition in easily understood language
    Gene Therapy for patient with Junctional Epidermolysis Bullosa
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10014989
    E.1.2Term Epidermolysis bullosa
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective is to evaluate the safety of Hologene-5 and the procedures associated with the administration of the IMP (infections, lack of engraftment, transplant rejection, immunoreactions etc.) and the patient’s safety measured by occurrence of AEs, TEAEs, AESIs, SAEs at any time during the study.
    E.2.2Secondary objectives of the trial
    To evaluate Hologene-5 efficacy as clinical and functional restoration of skin integrity.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed and dated informed consent prior to any study-related procedures. For pediatric patients
    parental consent must be obtained;
    2. Male and female patients from 1 y.o.;
    3. Clinical and molecular diagnosis of LAMB3-dependent Junctional Epidermolysis Bullosa (by
    NGS or Sanger sequencing and/or immunofluorescence);
    4. Detectable residual expression of laminin 332 (and its beta3 chain) by immunofluorescence
    and/or Western Blot analysis;
    5. Presence of blisters or wounds (persistent or recurrent for more than 3 months). Persistence for
    more than 1 month should be considered for minors of 1 year of age;
    6. Patients’ compliance with the study schedule and procedures and willingness to accomplish all
    the required follow up visits.
    E.4Principal exclusion criteria
    1. Contraindications to undergo surgical procedures (i.e. known or suspected hypersensitivity to
    local or general anaesthesia);
    2. Bad general condition (ECOG index >1);
    3. Presence of any skin cancers in the area(s) qualified for Hologene-5 treatment;
    4. Evidence of systemic infections. Patient can be -rescreened after appropriate treatment and recovering;
    5. Female subjects: Pregnant or lactating women and all women with physiologically capable of
    becoming pregnant (i.e. women of childbearing potential [WOCBP]) unless they are willing
    to use highly effective birth control reliable methods such as:
    a. Placement of an intrauterine device (IUD) or intrauterine releasing system (IUS);
    b. Oral, intravaginal, transdermal combined estrogen and progestogen containing hormonal contraception or oral, injectable, implantable progestogen only hormonal contraception;
    c. Bilateral tubal occlusion;
    d. Partner vasectomy (provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success);
    e. Sexual abstinence defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.
    Women of non-childbearing potential defined as physiologically incapable of becoming pregnant: premenarchal, post-menopausal (defined as no menses for 12 months without an alternative medical cause) or permanently sterile (hysterectomy, bilateral salpingectomy and bilateral oophorectomy) are eligible. If indicated, as per Investigator’s request, postmenopausal status may be confirmed by follicle-stimulating hormone levels (according to local laboratory ranges) in women not using hormonal contraception or hormonal replacement therapy;
    A pregnancy test will be performed at screening in all women of childbearing potential and repeated before biopsy treatment and at all visits. A pregnancy test will not be required for postmenopausal women (physiologic menopause defined as “12 consecutive months of amenorrhea”) or women permanently sterilized (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy).
    Contraception has to be maintained until the end of study visit (6 months after the last graft).
    Parental control will be applied for the pediatric population when needed;
    6. Known allergy to any of the constituents of the product or study medication excipients or
    other material required by study protocol (as per Investigator’s Brochure)
    7. Presence of i) systemic diseases, ii) clinically significant or unstable concurrent disease, iii) other concomitant medical conditions, iv) other clinical contraindications to stem cell transplantation, which based on Investigator’s judgment, in consultation with the Sponsor Medical Expert may affect the participation in the study;
    8. Inability to understand the study and to cooperate with the scope of the study (in case of
    children this is required for caregivers);
    9. Previous treatments or participation in clinical trials envisaging the use of cells (including
    bone marrow transplantation, BMT) and/or both in vivo or ex vivo gene therapy products.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoints
    • Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), Adverse Events
    of Special Interest (AESI), and Adverse Drug Reaction (ADRs);
    • Vital signs and laboratory results.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1, 3, and 6 months
    E.5.2Secondary end point(s)
    Secondary Endpoints
    • Transplantation efficacy at 1-, 3- and 6-months follow-up measured as change in % of reepithelization through imitoWound imaging application by the Investigator;
    • Transplantation efficacy at 3, 6 months follow-up measured as evidence of molecular
    correction (LAMB3 expression) based on immunofluorescence and/or in situ hybridization
    and/or PCR;
    • Transplantation efficacy at 6 months follow-up measured by mechanical stress test (strip test);
    • Transplantation efficacy at 1, 3 and 6 months follow-up measured as change versus baseline
    by Investigator judgment based on clinical inspection.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1, 3, and 6 months
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase I/II
    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 Yes
    E.8.1.7.1Other trial design description
    multicentric, prospective, open label, uncontrolled, interventional
    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.8.2.4Number of treatment arms in the trial1
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months10
    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: 4
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 1
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 1
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 1
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 state4
    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
    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 Decision2023-03-29
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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