<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02984085</url>
  </required_header>
  <id_info>
    <org_study_id>HOLOGENE 7</org_study_id>
    <nct_id>NCT02984085</nct_id>
  </id_info>
  <brief_title>Clinical Trial to Assess Safety and Efficacy of Autologous Cultured Epidermal Grafts Containing Epidermal Stem Cells Genetically Modified in Patients With RDEB.</brief_title>
  <acronym>HOLOGENE7</acronym>
  <official_title>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.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Holostem Terapie Avanzate s.r.l.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Paracelsus Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Holostem Terapie Avanzate s.r.l.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Prospective open-label, uncontrolled clinical study to assess the safety and efficacy of&#xD;
      autologous cultured epidermal grafts containing epidermal stem cells genetically modified&#xD;
      with the aid of a gamma-retroviral vector carrying COL7A1 complementary DNA (cDNA) for&#xD;
      restoration of the epidermis in patients with recessive dystrophic epidermolysis bullosa. The&#xD;
      purpose of this study is to demonstrate the safety and efficacy after one or more treatments&#xD;
      with genetically corrected cultured epidermal autograft (Hologene 7) in patients suffering of&#xD;
      recessive dystrophic epidermolysis bullosa (RDEB) with COL7A1 mutation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a monocentric, prospective, open label, uncontrolled clinical trial, phase I/II.&#xD;
&#xD;
      Patients will be screened according to the Study Inclusion and Exclusion criteria and will be&#xD;
      candidate for the treatment if all inclusion and none of the exclusion criteria are met.&#xD;
&#xD;
      After confirmation of eligibility, patients will undergo biopsy for the collection of the&#xD;
      autologous epidermal cells to be used to produce the tissue for the treatment. In case all&#xD;
      criteria are met, the transplantation of the new cultured transgenic epidermis will be&#xD;
      planned according to the procedures and the need of the patient.&#xD;
&#xD;
      The study treatment consists of a surgical intervention for new restored stem cells&#xD;
      implantation.&#xD;
&#xD;
      The surgery will be carried out in 2 stages, the first aims at taking biopsy to isolate&#xD;
      epidermal cells including stem cells. The biopsy will be processed in a laboratory of a&#xD;
      regenerative medicine manufacturing site where they will be corrected, expanded and prepared&#xD;
      as final sheets to be implanted. Therefore, the patient can have his second intervention. In&#xD;
      this second surgery, genetically corrected cultured epidermal autograft (Hologene 7) will be&#xD;
      implanted into the selected area. The specialist surgeon will either use a local or general&#xD;
      anaesthetic for the implant operation. The treated area will be immobilized for some days&#xD;
      after this operation. Antibiotics and anti-inflammatory drugs will be administered (if&#xD;
      necessary) to prevent infections and to minimise swelling.&#xD;
&#xD;
      Three months after the transplantation, primary endpoint will be evaluated by the&#xD;
      Investigator. The study completion will be reached when 1 year (secondary endpoint) of&#xD;
      follow-up after the last transplant in the last patient will be accomplished.&#xD;
&#xD;
      The end of the trial is defined as the last visit of the last patient after the last&#xD;
      treatment if any.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Replaced by new study in progress&#xD;
  </why_stopped>
  <start_date type="Actual">January 30, 2017</start_date>
  <completion_date type="Actual">August 6, 2018</completion_date>
  <primary_completion_date type="Actual">August 6, 2018</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety</measure>
    <time_frame>3-month</time_frame>
    <description>number and percentage of patients experiencing treatment-related adverse events (TRAEs), serious adverse events (SAEs) and serious adverse drug reactions (ADRs) up to 3 months after the first treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy</measure>
    <time_frame>3- and 12-months</time_frame>
    <description>Percentage of patients with clinical success after one or more treatments with study product at 3 and 12 months follow up.&#xD;
Clinically success is reached when both the following conditions are met:&#xD;
o Regeneration of a clinically normal appearing skin with absence of detectable blister.&#xD;
AND&#xD;
o Restoration of type VII collagen expression and restoration of anchoring fibrils in the treated area.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Treatment success</measure>
    <time_frame>12-months</time_frame>
    <description>Percentage of patients defined as &quot;success&quot; by Investigator site according to the same parameters as for the primary and key secondary efficacy assessments 12 months after last treatment;</description>
  </other_outcome>
  <other_outcome>
    <measure>Fibrin re-absorption</measure>
    <time_frame>1- and 4-weeks</time_frame>
    <description>• Complete matrix re-absorption (by visual inspection) one week after the transplantation and clinical success (defined as the primary efficacy assessment) at early assessment time points (1 and 4 weeks after transplantation).</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Recessive Dystrophic Epidermolysis Bullosa</condition>
  <arm_group>
    <arm_group_label>Genetically corrected cultured epidermal autograft</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The surgery will be carried out in 2 stages, the first aims at taking biopsy to isolate epidermal cells including stem cells. The biopsy will be processed in a laboratory of a regenerative medicine manufacturing site where they will be corrected, expanded and prepared as final sheets to be implanted.&#xD;
In the second surgery, genetically corrected cultured epidermal autograft (Hologene 7) will be implanted into the selected area. The specialist surgeon will either use a local or general anaesthetic for the implant operation. The treated area will be immobilized for some days after this operation. Antibiotics and anti-inflammatory drugs will be administered (if necessary) to prevent infections and to minimise swelling.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Genetically corrected cultured epidermal autograft (ATMP)</intervention_name>
    <description>Genetically corrected cultured epidermal autograft (Hologene 7) is intended for transplantation onto surgically prepared blistering skin areas of RDEB patients and permanent regeneration of a healthy, functional and renewing epidermis sustained by the engraftment of transduced epidermal stem cells.&#xD;
By taking some autologous epidermal cells, a new layer of transgenic tissue is grown in the laboratory. This layer of tissue is then implanted by a surgeon into the damaged area. The implantation can be done in one or more areas and repeated in case of failure of the first surgery.</description>
    <arm_group_label>Genetically corrected cultured epidermal autograft</arm_group_label>
    <other_name>Hologene 7 Study product (ATMP)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed and dated informed consent prior to any study-related procedures. Informed&#xD;
             consent will also include the possibility of additional transplantations and of the&#xD;
             rolling over to the long-term extension period;&#xD;
&#xD;
          2. Adult male and female patients (≥18 years old and &lt; 55); Paediatric patients aged 6 to&#xD;
             17 years will be also enrolled.&#xD;
&#xD;
          3. RDEB molecular characterization by mutation analysis;&#xD;
&#xD;
          4. Non-collagenous domain (NC1 or NC2) antibody immunofluorescence or staining positive&#xD;
             in Western Blot;&#xD;
&#xD;
          5. Presence of chronic (persistent for more than 3 months) large wounds (&gt;10 cm2) and/or&#xD;
             erosion;&#xD;
&#xD;
          6. A cooperative attitude to follow up the study procedures (Caregivers in case of&#xD;
             minors).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Known or suspected intolerances against anaesthesia;&#xD;
&#xD;
          2. Bad general condition (ECOG index &gt;1)&#xD;
&#xD;
          3. Unresectable or metastasizing squamous cell carcinoma (SCCs);&#xD;
&#xD;
          4. Antibodies to type VII collagen associated antigens demonstrated on indirect&#xD;
             immunofluorescence;&#xD;
&#xD;
          5. Clinical and/or laboratory signs of acute systemic infections at the time of&#xD;
             screening. Patient can be re-screened after appropriate treatment;&#xD;
&#xD;
          6. Severe systemic diseases (i.e. uncompensated diabetes);&#xD;
&#xD;
          7. Female subjects: pregnant or lactating women and all women physiologically capable of&#xD;
             becoming pregnant (i.e. women of childbearing potential) UNLESS they are willing to&#xD;
             use one or more reliable methods of contraception with a Pearl index ≤1.&#xD;
&#xD;
          8. Allergy, sensitivity or intolerance to drugs or excipients (hypersensitivity to any of&#xD;
             the excipients listed in Investigator's brochure or in this protocol):&#xD;
&#xD;
               -  Transport medium (Dulbecco's Modified Eagles Medium supplemented with&#xD;
                  L-glutamine)&#xD;
&#xD;
               -  Fibrin support&#xD;
&#xD;
               -  Betaisodona&#xD;
&#xD;
          9. Contraindications to the local or systemic antibiotics and/ or corticosteroids&#xD;
             foreseen by the protocol;&#xD;
&#xD;
         10. Contraindications to undergo extensive surgical procedures;&#xD;
&#xD;
         11. Clinically significant or unstable concurrent disease or other clinical&#xD;
             contraindications to stem cell transplantation based upon investigator's judgment or&#xD;
             other concomitant medical conditions affecting grafting procedure;&#xD;
&#xD;
         12. Patients (or parents in case of paediatric subject) unlikely to comply with the study&#xD;
             protocol or unable to understand the nature and scope of the study or the possible&#xD;
             benefits or unwanted effects of the study procedures and treatments.&#xD;
&#xD;
         13. Participation in another clinical trial where investigational drug was received less&#xD;
             than 6 months prior to screening visit.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>54 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michele De Luca, MD/Professor</last_name>
    <role>Study Director</role>
    <affiliation>Holostem Terapie Avanzate s.r.l.</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Johann W. Bauer, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Paracelsus Medical University - EB House</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>EB House Austria, Department of Dermatology, Paracelsus Medical University</name>
      <address>
        <city>Salzburg</city>
        <zip>5020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <link>
    <url>https://www.ncbi.nlm.nih.gov/pubmed/17115047</url>
    <description>Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells.</description>
  </link>
  <link>
    <url>https://www.ncbi.nlm.nih.gov/pubmed/24511464</url>
    <description>Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa.</description>
  </link>
  <link>
    <url>https://www.ncbi.nlm.nih.gov/pubmed/27840234</url>
    <description>Closure of a large chronic wound through transplantation of gene-corrected epidermal stem cells.</description>
  </link>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>December 2, 2016</study_first_submitted>
  <study_first_submitted_qc>December 2, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 6, 2016</study_first_posted>
  <last_update_submitted>February 15, 2022</last_update_submitted>
  <last_update_submitted_qc>February 15, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 16, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>RDEB</keyword>
  <keyword>Stem cells</keyword>
  <keyword>Gene therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epidermolysis Bullosa</mesh_term>
    <mesh_term>Epidermolysis Bullosa Dystrophica</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02984085
org study id: HOLOGENE 7
nct id: NCT02984085
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Prospective open-label, uncontrolled clinical study to assess the safety and efficacy of
      autologous cultured epidermal grafts containing epidermal stem cells genetically modified
      with the aid of a gamma-retroviral vector carrying COL7A1 complementary DNA (cDNA) for
      restoration of the epidermis in patients with recessive dystrophic epidermolysis bullosa. The
      purpose of this study is to demonstrate the safety and efficacy after one or more treatments
      with genetically corrected cultured epidermal autograft (Hologene 7) in patients suffering of
      recessive dystrophic epidermolysis bullosa (RDEB) with COL7A1 mutation.
This is a monocentric, prospective, open label, uncontrolled clinical trial, phase I/II.

      Patients will be screened according to the Study Inclusion and Exclusion criteria and will be
      candidate for the treatment if all inclusion and none of the exclusion criteria are met.

      After confirmation of eligibility, patients will undergo biopsy for the collection of the
      autologous epidermal cells to be used to produce the tissue for the treatment. In case all
      criteria are met, the transplantation of the new cultured transgenic epidermis will be
      planned according to the procedures and the need of the patient.

      The study treatment consists of a surgical intervention for new restored stem cells
      implantation.

      The surgery will be carried out in 2 stages, the first aims at taking biopsy to isolate
      epidermal cells including stem cells. The biopsy will be processed in a laboratory of a
      regenerative medicine manufacturing site where they will be corrected, expanded and prepared
      as final sheets to be implanted. Therefore, the patient can have his second intervention. In
      this second surgery, genetically corrected cultured epidermal autograft (Hologene 7) will be
      implanted into the selected area. The specialist surgeon will either use a local or general
      anaesthetic for the implant operation. The treated area will be immobilized for some days
      after this operation. Antibiotics and anti-inflammatory drugs will be administered (if
      necessary) to prevent infections and to minimise swelling.

      Three months after the transplantation, primary endpoint will be evaluated by the
      Investigator. The study completion will be reached when 1 year (secondary endpoint) of
      follow-up after the last transplant in the last patient will be accomplished.

      The end of the trial is defined as the last visit of the last patient after the last
      treatment if any.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety
time frame: 3-month
description: number and percentage of patients experiencing treatment-related adverse events (TRAEs), serious adverse events (SAEs) and serious adverse drug reactions (ADRs) up to 3 months after the first treatment.
measure: Efficacy
time frame: 3- and 12-months
description: Percentage of patients with clinical success after one or more treatments with study product at 3 and 12 months follow up.
Clinically success is reached when both the following conditions are met:
o Regeneration of a clinically normal appearing skin with absence of detectable blister.
AND
o Restoration of type VII collagen expression and restoration of anchoring fibrils in the treated area.
measure: Treatment success
time frame: 12-months
description: Percentage of patients defined as "success" by Investigator site according to the same parameters as for the primary and key secondary efficacy assessments 12 months after last treatment;
measure: Fibrin re-absorption
time frame: 1- and 4-weeks
description: • Complete matrix re-absorption (by visual inspection) one week after the transplantation and clinical success (defined as the primary efficacy assessment) at early assessment time points (1 and 4 weeks after transplantation).
arm group label: Genetically corrected cultured epidermal autograft
arm group type: Experimental
description: The surgery will be carried out in 2 stages, the first aims at taking biopsy to isolate epidermal cells including stem cells. The biopsy will be processed in a laboratory of a regenerative medicine manufacturing site where they will be corrected, expanded and prepared as final sheets to be implanted.
In the second surgery, genetically corrected cultured epidermal autograft (Hologene 7) will be implanted into the selected area. The specialist surgeon will either use a local or general anaesthetic for the implant operation. The treated area will be immobilized for some days after this operation. Antibiotics and anti-inflammatory drugs will be administered (if necessary) to prevent infections and to minimise swelling.
intervention type: Drug
intervention name: Genetically corrected cultured epidermal autograft (ATMP)
description: Genetically corrected cultured epidermal autograft (Hologene 7) is intended for transplantation onto surgically prepared blistering skin areas of RDEB patients and permanent regeneration of a healthy, functional and renewing epidermis sustained by the engraftment of transduced epidermal stem cells.
By taking some autologous epidermal cells, a new layer of transgenic tissue is grown in the laboratory. This layer of tissue is then implanted by a surgeon into the damaged area. The implantation can be done in one or more areas and repeated in case of failure of the first surgery.
arm group label: Genetically corrected cultured epidermal autograft
other name: Hologene 7 Study product (ATMP)
criteria: 
gender: All
minimum age: 6 Years
maximum age: 54 Years
healthy volunteers: No
last name: Michele De Luca, MD/Professor
role: Study Director
affiliation: Holostem Terapie Avanzate s.r.l.
last name: Johann W. Bauer, MD
role: Principal Investigator
affiliation: Paracelsus Medical University - EB House
facility: 
country: Austria
url: https://www.ncbi.nlm.nih.gov/pubmed/17115047
description: Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells.
url: https://www.ncbi.nlm.nih.gov/pubmed/24511464
description: Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa.
url: https://www.ncbi.nlm.nih.gov/pubmed/27840234
description: Closure of a large chronic wound through transplantation of gene-corrected epidermal stem cells.
responsible party type: Sponsor
mesh term: Epidermolysis Bullosa
mesh term: Epidermolysis Bullosa Dystrophica
sharing ipd: No