Phase I/II ex vivo gene therapy clinical trial for RDEB using autologous skin equivalent grafts genetically corrected with a COL7A1-encoding SIN retroviral vector

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut National De La Sante Et De La Recherche Medicale

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

29 Jan 2025 → ongoing

Decision date (initial)

2025-01-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Cure EB

External identifiers

EU CT number

2024-518368-10-00

EudraCT number

2016-002790-35

ClinicalTrials.gov

NCT04186650

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety

The primary objective of this phase I/II clinical trial is to evaluate the safety of grafting SIN RV-mediated COL7A1 gene-modified autologous SE in adults with RDEB at M1, M2, M3, M6, M12 after grafting. This evaluation will be continued during a reglementary 5-year follow up at M18, M24, M30, M36, M42, M48, M54, and M60.

Secondary objectives 2

1. 1) To assess the efficacy of SIN RV-mediated COL7A1 gene-modified autologous SE in adults with RDEB at W2, M1, M3, M6, M12, M24, M36, M48 and M60 after grafting
2. 2)To evaluate the immune response against the recombinant C7 at M1, M3, M12, M18, M24, M30, M36, M42, M48, M54, and M60 after grafting

Conditions and MedDRA coding

Recessive dystrophic epidermolysis bullosa (RDEB)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 1.≥ 18 year-old
2. 2.Clinical and molecular diagnosis of RDEB with confirmed bi-allelic COL7A1 mutations
3. 3.Significantly reduced staining of C7 on skin biopsy, measured by immunofluorescence microscopy (IF)
4. 4.A reduced number of or morphologically abnormal anchoring fibrils confirmed by TEM
5. 5.Presence of non-collagenous-1 domain (NC-1) of C7 on skin biopsy, measured by immunofluorescence microscopy (IF) and/or Western blot analysis
6. 6.Presence of ≥100cm2 of blistered and/or erosive skin areas including chronic wounds suitable for skin grafting
7. 7.Ability to undergo anaesthesia for grafting procedures
8. 8.Subjects aged ≥ 18years, willing and able to give informed consent

Exclusion criteria 9

1. 1.Recipients of other investigational medicinal products within 6 months prior to enrolment into this study
2. 2.Past medical history of biopsy proven skin malignancy
3. 3.Immunotherapy including oral corticosteroids (Prednisolone >1mg/kg) for more than one week (intranasal and topical preparations are permitted) or chemotherapy within 60 days of enrolment into this study
4. 4.Known allergy to any of the constituents of the investigational medicinal product (IMP) including Penicillin
5. 5.Subjects with BOTH: •positive serum antibodies to C7 confirmed by ELISA and •positive IIF with binding to the base of salt split skin and/or •positive Western blot
6. 6.Positive results for HIV, Hepatitis BsAg, Hepatitis BcAb, Hepatitis C IgG, HTLV1&2 or Syphilis serology
7. 7.Clinically significant medical, psychological or laboratory abnormalities limiting the ability of the subject to travel to the trial site(s) and to undergo grafting and follow-up procedures, as determined by the Investigator
8. 8.Absence of adequate social support
9. 9.Subjects who are pregnant, breast-feeding or of child-bearing potential who are neither abstinent nor practicing an acceptable means of contraception when this is in line with the usual and preferred lifestyle of the subject, as determined by the Investigator, for the duration of the trial

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Adverse events (AEs), Serious Adverse Events (SAEs), Adverse Reactions (ARs) and Serious Adverse Reactions (SARs) at each visit over a 12-months period after grafting and at each visit during a long term follow-up period of 5 years in total.

Secondary endpoints 3

1. Skin biopsy analysis of grafted skin at, M3, M6, M12, M24, M36, M48 and M60 after grafting compared to baseline for: a)C7 protein expression by immunofluorescence microscopy (IF) b)Morphology of anchoring fibrils (Wetzels et al.) at the dermal-epidermal junction (DEJ) by transmission electron microscopy (TEM)
2. Serum analysis at M1, M6, M12, M18, M24, M30, M36, M42, M48, M54 and M60 after grafting compared to baseline for: a)Detection of anti-C7 antibodies by enzyme-linked immunosorbent assay (ELISA) (against the entire C7 molecule) indirect immunofluorescence (IIF) and/or Western blot (WB) b)Detection of T-cell responses to the full length C7 by enzyme-linked immunosorbent spot (ELISPOT) assay
3. Clinical assessment at M1, M2, M3, M6, M12, M18, M24, M30, M36, M42, M48, M54 and M60 after grafting compared to baseline for: a)The scar quality measured by the Vancouver Scar Scale (VSS) b)Changes in blister numbers over the grafted skin c)Changes in the clinical appearance of grafted skin through clinical photographs at each visit d)Changes in pruritus measured by the Leuven Itch Scale (LIS) e)Changes in Quality of Life Score measured by the QOLEB

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut National De La Sante Et De La Recherche Medicale

Sponsor organisation

Institut National De La Sante Et De La Recherche Medicale

Address

101 Rue De Tolbiac

City

Paris Cedex 13

Postcode

75654

Country

France

Scientific contact point

Organisation

Institut National De La Sante Et De La Recherche Medicale

Contact name

Alain Hovnanian

Public contact point

Organisation

Institut National De La Sante Et De La Recherche Medicale

Contact name

Gabrielle DEROCLE

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications