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Clinical Trial to Assess Safety and Efficacy of Autologous Cultured Epidermal Grafts Containing Epidermal Stem Cells Genetically Modified in Patients With JEB (HOLOGENE17) (HOLOGENE17)

Primary Purpose

Junctional Epidermolysis Bullosa

Status

Terminated

Phase

Phase 1

Locations

Austria

Study Type

Interventional

Intervention

Transplantation surgery of genetically corrected cultured epidermal autograft (ATMP)

About this trial

This is an interventional treatment trial for Junctional Epidermolysis Bullosa focused on measuring JEB, Stem cells, Gene Therapy

Eligibility Criteria

6 Years - 54 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Signed and dated informed consent prior to any study-related procedures;
Male and female patients between 6 years old to 54 years old;
JEB molecular characterization by mutation analysis;
NC16A antibody immunofluorescence or positive staining in Western Blot analysis with polyclonal antibody produced against a synthetic peptide corresponding to amino acids 131-145 of human COL17A1;
Presence of chronic (persistent or recurrent for more than 3 months) large wounds (>10 cm2) and/or persistent or recurrent erosions;
A cooperative attitude to follow up the study procedures (Caregivers in case of minors).

Exclusion Criteria:

Known or suspected intolerances against anaesthesia;
Bad general condition (ECOG index >1);
Unresectable metastasizing Squamous Cell Carcinomas (SCCs);
Antibodies to type XVII collagen associated antigens demonstrated on indirect immunofluorescence;
Clinical and/or laboratory signs of acute systemic infections at the time of screening. Patient can be re-screened after appropriate treatment;
Severe systemic diseases (i.e. uncompensated diabetes mellitus);
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.
Allergy, sensitivity or intolerance to drugs, excipients or other material (as per Investigator's brochure):
- Transport medium (Dulbecco's Modified Eagles Medium supplemented with L-glutamine)
- Fibrin support
- Povidone iodine
Contraindications to the local or systemic antibiotics and/ or corticosteroids foreseen by the protocol;
Contraindications to undergo extensive surgical procedures;
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;
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;
Participation in another clinical trial where investigational drug was received less than 6 months prior to screening Visit.

Sites / Locations

EB House Austria, Department of Dermatology, Paracelsus Medical University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Genetically corrected cultured epidermal autograft

Arm 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 (Hologene17) 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.

Outcomes

Primary Outcome Measures

Safety events (ADRs and SAEs) related to the study treatment (tolerability)

Number of patients experiencing treatment-related adverse events (TRAEs) - either to the epidermal graft and to the surgical procedures. Adverse events (serious and not serious) and adverse drug reactions (ADRs) will be collected and described

Safety events (ADRs and SAEs) related to the study treatment (tolerability)

Percentage of patients experiencing treatment-related adverse events (TRAEs) - either to the epidermal graft and to the surgical procedures. Adverse events (serious and not serious) and adverse drug reactions (ADRs) will be collected and described

Secondary Outcome Measures

Skin stability in the short term (Treatment efficacy)

The skin stability will be evaluated by means of stripping test and visual inspection of the treated areas

Skin functionality in the short term (Treatment efficacy)

The skin functionality will be evaluated by means of molecular testing on skin punch biopsies taken from the transplanted areas.

Skin stability in the long term (Treatment efficacy)

The skin stability will be evaluated by means of stripping test and visual inspection of the treated areas

Skin functionality in the long term (Treatment efficacy)

The skin functionality will be evaluated by means of molecular testing on skin punch biopsies taken from the transplanted areas.

Full Information

NCT ID

NCT03490331

First Posted

March 18, 2018

Last Updated

February 18, 2022

Sponsor

Holostem Terapie Avanzate s.r.l.

Collaborators

Paracelsus Medical University

1. Study Identification

Unique Protocol Identification Number

NCT03490331

Brief Title

Clinical Trial to Assess Safety and Efficacy of Autologous Cultured Epidermal Grafts Containing Epidermal Stem Cells Genetically Modified in Patients With JEB (HOLOGENE17)

Acronym

HOLOGENE17

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 COL17A1 cDNA for Restoration of Epidermis in Patients With Junctional Epidermolysis Bullosa

Study Type

Interventional

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Terminated

Why Stopped

No patient ongoing (none completed the study). Changes to the viral vector ongoing.

Study Start Date

March 19, 2018 (Actual)

Primary Completion Date

September 11, 2018 (Actual)

Study Completion Date

September 11, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Holostem Terapie Avanzate s.r.l.

Collaborators

Paracelsus Medical University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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 COL17A1 complementary DNA (cDNA) for restoration of the epidermis in patients with junctional 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 17) in patients suffering of junctional epidermolysis bullosa (JEB) with COL17A1 mutation.

Detailed Description

This is a 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 17) will be implanted into the selected area. The specialist surgeon will either use a local or general anaesthetic for the transplant 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Junctional Epidermolysis Bullosa

Keywords

JEB, Stem cells, Gene Therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

1 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Genetically corrected cultured epidermal autograft

Arm Type

Experimental

Arm Description

Intervention Type

Other

Intervention Name(s)

Transplantation surgery of genetically corrected cultured epidermal autograft (ATMP)

Other Intervention Name(s)

Transplantation of Hologene17 study product (ATMP)

Intervention Description

Surgergical procedure for transplantation under anaesthesia of genetically corrected cultured epidermal autograft (Hologene17) on blistering skin areas of JEB patients. By taking some autologous epidermal cells, a new layer of transgenic tissue is grown in the laboratory. This layer of tissue - containing genetically modified stem cells - 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.

Primary Outcome Measure Information:

Title

Safety events (ADRs and SAEs) related to the study treatment (tolerability)

Description

Time Frame

3 months after treatment

Title

Safety events (ADRs and SAEs) related to the study treatment (tolerability)

Description

Time Frame

12 months after treatment

Secondary Outcome Measure Information:

Title

Skin stability in the short term (Treatment efficacy)

Description

The skin stability will be evaluated by means of stripping test and visual inspection of the treated areas

Time Frame

3 months after transplantation

Title

Skin functionality in the short term (Treatment efficacy)

Description

The skin functionality will be evaluated by means of molecular testing on skin punch biopsies taken from the transplanted areas.

Time Frame

3 months after transplantation

Title

Skin stability in the long term (Treatment efficacy)

Description

The skin stability will be evaluated by means of stripping test and visual inspection of the treated areas

Time Frame

12 months after transplantation

Title

Skin functionality in the long term (Treatment efficacy)

Description

The skin functionality will be evaluated by means of molecular testing on skin punch biopsies taken from the transplanted areas.

Time Frame

12 months after transplantation

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Years

Maximum Age & Unit of Time

54 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Signed and dated informed consent prior to any study-related procedures; Male and female patients between 6 years old to 54 years old; JEB molecular characterization by mutation analysis; NC16A antibody immunofluorescence or positive staining in Western Blot analysis with polyclonal antibody produced against a synthetic peptide corresponding to amino acids 131-145 of human COL17A1; Presence of chronic (persistent or recurrent for more than 3 months) large wounds (>10 cm2) and/or persistent or recurrent erosions; A cooperative attitude to follow up the study procedures (Caregivers in case of minors). Exclusion Criteria: Known or suspected intolerances against anaesthesia; Bad general condition (ECOG index >1); Unresectable metastasizing Squamous Cell Carcinomas (SCCs); Antibodies to type XVII collagen associated antigens demonstrated on indirect immunofluorescence; Clinical and/or laboratory signs of acute systemic infections at the time of screening. Patient can be re-screened after appropriate treatment; Severe systemic diseases (i.e. uncompensated diabetes mellitus); 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. Allergy, sensitivity or intolerance to drugs, excipients or other material (as per Investigator's brochure): Transport medium (Dulbecco's Modified Eagles Medium supplemented with L-glutamine) Fibrin support Povidone iodine Contraindications to the local or systemic antibiotics and/ or corticosteroids foreseen by the protocol; Contraindications to undergo extensive surgical procedures; 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; 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; Participation in another clinical trial where investigational drug was received less than 6 months prior to screening Visit.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michele De Luca, MD/Professor

Organizational Affiliation

Holostem Terapie Avanzate s.r.l.

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Johann W. Bauer, MD

Organizational Affiliation

Paracelsus Medical University - EB House

Official's Role

Principal Investigator

Facility Information:

Facility Name

EB House Austria, Department of Dermatology, Paracelsus Medical University

City

Salzburg

ZIP/Postal Code

5020

Country

Austria

12. IPD Sharing Statement

Plan to Share IPD

Links:

URL

https://www.ncbi.nlm.nih.gov/pubmed/17115047

Description

Description Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells.

URL

http://www.ncbi.nlm.nih.gov/pubmed/24511464

Description

Description Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa.

URL

http://www.nature.com/articles/nature24487

Description

Regeneration of the entire human epidermis using transgenic stem cells

URL

http://www.ncbi.nlm.nih.gov/pubmed/27840234

Description

Description Closure of a large chronic wound through transplantation of gene-corrected epidermal stem cells.

Learn more about this trial

Clinical Trial to Assess Safety and Efficacy of Autologous Cultured Epidermal Grafts Containing Epidermal Stem Cells Genetically Modified in Patients With JEB (HOLOGENE17)

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