Safety Study of Gene-modified Autologous Fibroblasts in Recessive Dystrophic Epidermolysis Bullosa

• ClinicalTrials.gov Identifier: NCT02493816
• Recruitment Status: Completed
• First Posted: July 10, 2015
• Last Update Posted: September 24, 2019
• Sponsor: King's College London
• Collaborator: University College, London
• Information provided by (Responsible Party): King's College London

Study Description

Brief Summary:

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of blistering skin disease caused by mutations in COL7A1 gene. This study aims to assess the safety of intradermal injections of gene-modified autologous fibroblasts in 5-10 adults with RDEB.

Condition or disease	Intervention/treatment	Phase
Recessive Dystrophic Epidermolysis Bullosa	Drug: Gene-modified autologous fibroblasts	Phase 1

Detailed Description:

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of blistering skin disease caused by mutations in COL7A1 gene. This study aims to assess the safety of intradermal injections of gene-modified autologous fibroblasts in 5-10 adults with RDEB.

This is an open-label single-centre phase I study with primary objective to evaluate the adverse and serious adverse events over 12 months' follow-up period. Secondary objectives include (1) analysis of type VII collagen (C7) expression and morphology of anchoring fibrils in the injected areas of the skin; (2) analysis of immune response to newly expressed C7.

Each study participant will receive three intradermal injections of COL7A1 gene-modified autologous fibroblasts on Day 0 only. Each subject will undergo an initial screening including a physical examination and assessment of disease severity. Blood analyses and skin biopsies will be performed at various time points as per the monitoring schedule over 12 months.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Study of Lentiviral-mediated COL7A1 Gene-modified Autologous Fibroblasts in Adults With Recessive Dystrophic Epidermolysis Bullosa.
• Actual Study Start Date: September 2015
• Actual Primary Completion Date: March 2018
• Actual Study Completion Date: March 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Gene-modified autologous fibroblasts; 3 intradermal injections of COL7A1 gene-modified autologous fibroblasts will be administered on day 0 only.	Drug: Gene-modified autologous fibroblasts; 3 intradermal injections of COL7A1 gene-modified autologous fibroblasts will be administered on day 0 only.; Other Name: COL7A1 gene-modified autologous fibroblasts

Outcome Measures

Primary Outcome Measures :

1. Adverse events (AEs), Serious Adverse Events (SAEs), Adverse Reactions (ARs) and Serious Adverse Reactions (SARs) at each visit over 12 months' follow up period. [ Time Frame: 12 months ]

Secondary Outcome Measures :

1. Type VII collagen protein expression, measured by direct immunofluorescence, in the treated and untreated skin [ Time Frame: Week 2, Month 3 and Month 12 ]
2. Morphology of anchoring fibrils, measured by transmission electron microscopy, in the treated and untreated skin [ Time Frame: Week 2, Month 3 and Month 12 ]
3. Vector copy number, measured by q-PCR, in the treated and untreated skin [ Time Frame: Week 2, Month 3 and Month 12 ]
4. Anti-type VII collagen antibodies measured by ELISA and indirect immunofluorescence [ Time Frame: Week 2, Month 1, Month 3, Month 6 and Month 12 ]
5. T-cell responses to full length type VII collagen measured by ELISPOT [ Time Frame: Week 2, Month 1, Month 3, Month 6 and Month 12 ]

Eligibility Criteria

• Ages Eligible for Study: 17 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Clinical and genetic diagnosis of RDEB with confirmed bi-allelic COL7A1 mutations.
2. A reduced number or morphologically abnormal anchoring fibrils confirmed by TEM.
3. At least 5x8cm of intact skin on the trunk and/or extremities that is suitable for cell injections.
4. Able to undergo local anaesthesia.
5. Subjects aged ≥ 17 years and able to give informed consent prior to the first study intervention.

Exclusion Criteria:

1. Subjects who received other investigational medicinal products within 6 months prior to enrolment into this study.
2. Past medical history of biopsy proven skin malignancy.
3. Subjects who have received 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. Known allergy to any of the constituents of the investigational medicinal product (IMP).

5. Subjects with BOTH:

   • positive serum antibodies to C7 confirmed by ELISA and
   • positive IIF with binding to the base of salt split skin.
6. Subjects who are pregnant or of child-bearing potential who are neither abstinent nor practising 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 12 months after the cell injections.
7. Subjects with positive results for HIV, Hepatitis B, Hepatitis C, HTLV or Syphilis.

Contacts and Locations

Locations

United Kingdom

Guy's and St Thomas' NHS Foundation Trust

London, United Kingdom, SE1 9RT

Sponsors and Collaborators

King's College London

University College, London

Investigators

• Principal Investigator: John A McGrath, FRCP; King's College London

  Study Documents (Full-Text)

Documents provided by King's College London:

Study Protocol  [PDF] March 1, 2016

Statistical Analysis Plan  [PDF] November 28, 2016

More Information

Publications of Results:

Lwin SM, Syed F, Di WL, Kadiyirire T, Liu L, Guy A, Petrova A, Abdul-Wahab A, Reid F, Phillips R, Elstad M, Georgiadis C, Aristodemou S, Lovell PA, McMillan JR, Mee J, Miskinyte S, Titeux M, Ozoemena L, Pramanik R, Serrano S, Rowles R, Maurin C, Orrin E, Martinez-Queipo M, Rashidghamat E, Tziotzios C, Onoufriadis A, Chen M, Chan L, Farzaneh F, Del Rio M, Tolar J, Bauer JW, Larcher F, Antoniou MN, Hovnanian A, Thrasher AJ, Mellerio JE, Qasim W, McGrath JA. Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa. JCI Insight. 2019 Jun 6;4(11). pii: 126243. doi: 10.1172/jci.insight.126243. eCollection 2019 Jun 6.

Other Publications:

Wong T, Gammon L, Liu L, Mellerio JE, Dopping-Hepenstal PJ, Pacy J, Elia G, Jeffery R, Leigh IM, Navsaria H, McGrath JA. Potential of fibroblast cell therapy for recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 2008 Sep;128(9):2179-89. doi: 10.1038/jid.2008.78. Epub 2008 Apr 3.

• Responsible Party: King's College London
• ClinicalTrials.gov Identifier: NCT02493816
• Other Study ID Numbers: LENTICOL-F
• First Posted: July 10, 2015
• Last Update Posted: September 24, 2019
• Last Verified: August 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Skin Abnormalities; Congenital Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases; Skin Diseases, Vesiculobullous; Collagen Diseases; Connective Tissue Diseases