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    Clinical Trial Results:
    MULTICENTRE, OPEN-LABEL, UNCONTROLLED, PIVOTAL CLINICAL TRIAL TO CONFIRM THE EFFICACY AND SAFETY OF AUTOLOGOUS FIBRINCULTURED EPIDERMAL GRAFTS CONTAINING EPIDERMAL STEM CELLS GENETICALLY MODIFIED FOR RESTORATION OF EPIDERMIS IN PATIENTS WITH JUNCTIONAL EPIDERMOLYSIS BULLOSA (HOLOGENE 5)

    Summary
    EudraCT number
    		 2018-000261-36
    Trial protocol
    		 FR   IT  
    Global end of trial date
    12 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Apr 2026
    First version publication date
    17 Apr 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HTA-HG5-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Holostem s.r.l.
    Sponsor organisation address
    via Glauco Gottardi 100, Modena, Italy, 41125
    Public contact
    Fania Ferrari, Holostem s.r.l., +39 059.2058064, f.ferrari.consultant@holostem.com
    Scientific contact
    Dr Roana Hasanaj , Holostem s.r.l., +39 344.2795064 , r.hasanaj.consultant@holostem.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-003137-PIP01-21
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Mar 2026
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Mar 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Hologene 5 at 12 months follow-up as percentage of success based on the following assessments: • clinical performance as % of re-epithelisation in the absence of blisters measured by Investigator through imitoWound imaging application; • functional evaluation based on laboratory analyses and mechanical assessment; • Patient Reported Outcome (PRO) based on participants’ improvement perception on the transplanted areas.
    Protection of trial subjects
    After Hologene 5 transplantation, the participants received post-transplantation treatments with antibiotics, corticosteroids, immunosuppressants and/or immune-modulator agents, either systemic or topical, if considered appropriate by the Investigator, in consultation with the Sponsor Medical Expert, based on specific laboratory results and the participant’s tolerability. All medications administered during and after the transplantation procedure and during the immobilisation (if any) were reported in the eCRF. Permitted Concomitant Medications • Systemic and topical preservative-free corticosteroids, in case of persistent skin inflammation, based on Investigator’s judgment, after completion of the by-protocol post- transplantation treatment period; • Systemic and topical antibiotic treatment to be administered after biopsy and based on investigator’s judgment; • Immunosuppressants and/or immune-modulator agents, either systemic or topical are allowed; • Gastroprotective treatment with proton-pump inhibitors (i.e. omeprazole); • Additional topical or systemic treatments for skin disorders and any other therapy not interfering with the study evaluation parameters in the Investigator’s judgment. All topical concomitant treatments have to be administered in a preservative-free preparation (e.g. Benzalkonium chloride, as well as other quaternary ammonium compounds, is cytotoxic), according to local pharmacopeia.
    Background therapy
    		 See above
    Evidence for comparator
    		 No comparator was used.
    Actual start date of recruitment
    15 Jul 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 2
    Worldwide total number of subjects
    2
    EEA total number of subjects
    2
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was finally approved in Italy on 30 May 2022 and the study was initiated in one clinical site. The first participant was enrolled on 15 July 2022. The last participant concluded the study on 12 March 2024. The study was finally approved in France on 21 July 2022, but it never initiated in the planned clinical site.

    Pre-assignment
    Screening details
    		  Signature of the informed consent/assent;  Inclusion/exclusion criteria verification;  AEs check and collection start after informed consent/assent;  Participant’s demographic data;  Medical history, including previous/concomitant diseases and/or medications;  Verification of the certified molecular diagnosis with identified mutations.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Study treatment arm
    Arm description
    		 Hologene 5 was an autologous cultured epidermal graft containing epidermal stem cells genetically modified with gamma-retroviral (RV) vector carrying LAMB3 cDNA. Eligible participants underwent a skin biopsy from the undamaged skin (area with no frequent blisters). After receipt of the specimen at the Sponsor’s manufacturing facility, epidermal cells were isolated, cultivated, transduced, frozen and used, after thawing. The study treatment included one or more applications of Hologene 5 through a dedicated surgical preparation of the wound bed. For each application, one or more grafts for each equivalent skin surface (144 cm2) was transplanted according to the area width and to the number of wounds to be treated. The size/area of epidermal graft was adapted to the surface of affected area to treat. Each graft contained from 20.000.000 to 30.000.000 viable autologous human epidermal cells, of which at least 50% of clonogenic cells were transduced.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hologene 5
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Matrix for implantation matrix
    Routes of administration
    Implantation
    Dosage and administration details
    The participant was treated with different grafts of Hologene 5. Each batch of product contained up to 15 grafts of Hologene 5 to cover the selected skin surface. Each batch preparation of study product was intended as a single treatment. In case of failure of the first treatment or in order to treat new lesions, the treatment could be repeated according to the Investigator’s assessment, in consultation with the Sponsor Medical Expert.. Study treatment was applied by an appropriately qualified surgeon in hospital under standard sterile operating room conditions. Both the biopsy and the surgery for study product application were planned in advance with the Sponsor in order to permit the manufacturer to receive and process the biopsy and prepare the grafts.

    Number of subjects in period 1
    		Study treatment arm
    Started
    2
    Completed
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 2 2
    Age categorical
    Male and female patients between 6-month and 65-year old were planned to be enrolled. Participant 1 was a 31-year old Caucasian man. Participant 2 was a 12-year old Mulatto boy.
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 1 1
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 2 2

    End points

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    End points reporting groups
    Reporting group title
    Study treatment arm
    Reporting group description
    		 Hologene 5 was an autologous cultured epidermal graft containing epidermal stem cells genetically modified with gamma-retroviral (RV) vector carrying LAMB3 cDNA. Eligible participants underwent a skin biopsy from the undamaged skin (area with no frequent blisters). After receipt of the specimen at the Sponsor’s manufacturing facility, epidermal cells were isolated, cultivated, transduced, frozen and used, after thawing. The study treatment included one or more applications of Hologene 5 through a dedicated surgical preparation of the wound bed. For each application, one or more grafts for each equivalent skin surface (144 cm2) was transplanted according to the area width and to the number of wounds to be treated. The size/area of epidermal graft was adapted to the surface of affected area to treat. Each graft contained from 20.000.000 to 30.000.000 viable autologous human epidermal cells, of which at least 50% of clonogenic cells were transduced.

    Primary: Percentage of transplantation scored as success at the 12-month follow-up based on the definition of success using the 2-step rule

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    End point title
    		 Percentage of transplantation scored as success at the 12-month follow-up based on the definition of success using the 2-step rule [1]
    End point description
    End point type
    Primary
    End point timeframe
    12-month follow-up
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed. The study was interrupted prematurely and only descriptive results were presented. No statistical analysis was performed. The study was interrupted prematurely and only descriptive results were presented.
    End point values
    		 Study treatment arm
    Number of subjects analysed
    0 [2]
    Units: 100
    Notes
    [2] - The primary endpoint could not be evaluated in any subject.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    12-month follow-up
    Adverse event reporting additional description
    AEs were assessed throughout the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    28.0
    Reporting groups
    Reporting group title
    Safety set
    Reporting group description
    		 all enrolled participants undergoing the skin biopsy

    Serious adverse events
    		 Safety set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No serious adverse events were reported during the study. No frequency of non-serious adverse events was calculated for this study. Just a listing of adverse events was presented. No statistical evaluation performed.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Feb 2024
    Final Version 5.0 (Appendix 16.1.1) was issued to implement the major change in the Sponsor’s and IMP manufacturer’s denomination from Holostem Terapie Avanzate s.r.l. to Holostem s.r.l. This protocol version was also harmonised towards CTR 536/2014.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Mar 2024
    LSLV was 12MAR24. Afterwards, no other patients were enrolled in the study and the premature study termination was officially notified on 22NOV24, which was considered the date of study closure. The study was prematurely terminated due to changes in the product development clinical program. Furthermore, the Sponsor considered the option of closing prematurely the study due to the fact that only one clinical site was opened and that the recruitment of eligible patients had become more and more difficult.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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