Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB) Nonsense Mutation Patients

NCT02698735 | Completed Phase 1 Results

• 1 other identifier: HS-15-00821
• Study Type: interventional
• Target: 5
• Locations: 0 countries
• Sites: N/A

Brief Summary

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable, devastating, inherited skin disease for which there is only supportive care. RDEB is due to mutations in COL7A1 gene that encodes for type VII collagen (C7), the major component of anchoring fibrils (AFs) mediating epidermal-dermal adherence. Approximately 20% of COL7A1 mutations are nonsense mutations leading to premature stop codons and a truncated C7 with diminished function. The investigators demonstrated that aminoglycosides such as gentamicin readily induce premature termination codon (PTC) "read through" and produce biologically functional C7 in 22 reported COL7A1 nonsense mutations. Importantly, aminoglycoside-induced C7 reversed the abnormal RDEB cell phenotype and incorporated into the dermal-epidermal junction. Herein, the investigators propose the first clinical trial of gentamicin (topical and intradermal) in RDEB patients with nonsense mutations that the investigators have fully characterized. The milestones include increased C7 and AFs at the patients' dermal-epidermal junction and absence of significant gentamicin side effects.

Conditions

Recessive Dystrophic Epidermolysis Bullosa

Outcome Measures

Primary Outcomes (2)

• Restoration of Full-length Type VII Collagen as Assessed by Immunofluorescence.

  The expression of type VII collagen at the patients' dermal-epidermal junction was assessed by immunofluorescence (IF) using an antibody specific to type VII collagen. The expression was semi-quantitated using NIH Image J software. The IF expression of type VII collagen was assessed before treatment and at one and three months after treatment for each patient. All treated and untreated sites for all patients were also analyzed to determine statistical significance of treatment versus placebo for topical and intradermal administrations. At each assessment time point, type VII collagen expression was also measured in normal human skin. The expression of type VII collagen was then expressed as a percentage of the type VII collagen expressed in normal human skin.

  3 months

• Number of Participants With Anchoring Fibrils as Assessed by Immuno-electron Microscopy

  The expression of anchoring fibril structures at the patients' dermal-epidermal junction was assessed by immuno-electron microscopy (IEM) using an antibody specific to type VII collagen. The IEM expression of anchoring fibrils was assessed before treatment and at one and three months after treatment. At each assessment time point, anchoring fibrils were compared with normal human skin. Baseline pre-treatment and one and three month post-treatment sites were compared for the presence of anchoring fibrils after gentamicin treatment (or increase if anchoring fibrils were detected at baseline in patients). Comparisons were also made between placebo-treated and gentamicin-treated sites.

  3 months

Study Arms (2)

Gentamicin

EXPERIMENTAL

Gentamicin antibiotic

Drug: Gentamicin

Placebo

PLACEBO COMPARATOR

Vehicle control

Drug: Placebo

Interventions

Gentamicin DRUG

Gentamicin was either formulated into a 0.1% ointment or solutions for injection were purchased directly from suppliers.

Also known as: Gentamicin Sulfate, Garamycin

Gentamicin

Placebo DRUG

There are two placebos used in this study. The ointment vehicle (same as used to formulate gentamicin) and vehicle solution for injection.

Also known as: Vehicle

Placebo

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• (i) RDEB patients with a nonsense mutation in COL7A1 in either one or two alleles (ii) An absence or decrease in C7 expression at their DEJ when compared to that of normal human skin.

You may not qualify if:

• (i) Pre-existing renal or auditory impairment (ii) Allergies to aminoglycosides or sulfate compounds (iii) Pregnancy (iv) Exposure to gentamicin within the past 6 weeks.

Sponsors & Collaborators

• University of Southern California: lead

Related Publications (1)

• Woodley DT, Cogan J, Hou Y, Lyu C, Marinkovich MP, Keene D, Chen M. Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients. J Clin Invest. 2017 Aug 1;127(8):3028-3038. doi: 10.1172/JCI92707. Epub 2017 Jul 10.

  PMID: 28691931 DERIVED

MeSH Terms

Conditions

Epidermolysis Bullosa Dystrophica

Interventions

Gentamicins

Condition Hierarchy (Ancestors)

Epidermolysis Bullosa; Skin Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Collagen Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases; Skin Diseases, Vesiculobullous

Intervention Hierarchy (Ancestors)

Aminoglycosides; Glycosides; Carbohydrates

Results Point of Contact

• Title: Dr. David Woodley
• Organization: University of Southern California Department of Dermatology

dwoodley@med.usc.edu

(323)442-0084

Study Officials

• David Woodley, MD

  University of Southern California Department of Dermatology

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Ointments were formulated by an independent pharmacy and masked before receipt by investigators and delivered to participants as such. Intradermal injections were blinded by clinic staff (unrelated to the study) before injection.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Dermatology

Model Details: Each participant will receive gentamicin ointment, and placebo ointment to treat two separate matched wounds (each ointment used exclusively on one wound) for 14 days as well as receive a intradermal injections of gentamicin and placebo at two intact skin sites (one site for each treatment).

Study Record Dates

• First Submitted: February 19, 2016
• First Posted: March 4, 2016
• Study Start: February 25, 2016
• Primary Completion: March 31, 2017
• Study Completion: June 30, 2017
• Last Updated: October 29, 2019
• Results First Posted: August 14, 2019

Record last verified: 2019-10