Intravenous Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Recessive Dystrophic Epidermolysis Bullosa Clinical Trial

Official title:

Restoration of Full-Length Type VII Collagen in RDEB Patients With Nonsense Mutations After Intravenous Gentamicin Treatment

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03392909
• Other study ID #: HS-17-00995
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: July 5, 2018
• Est. completion date: December 1, 2023

Study information

• Verified date: November 2022
• Source: University of Southern California
• Contact: David T Woodley, MD
• Phone: 626-533-6028
• Email: dwoodley[@]usc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable, devastating, inherited skin disease caused by mutations in the COL7A1 gene that encodes for type VII collagen (C7), the major component of anchoring fibrils (AFs), structures that mediate epidermal-dermal adherence. Thirty percent of RDEB patients have nonsense mutations. The investigators recently demonstrated in 5 such patients that intradermal and topical gentamicin induced "read-through" of their nonsense mutations and created robust and sustained new C7 and AFs at the dermal-epidermal junction (DEJ) of their skin and also stimulated wound closure and reduced new blister formation. No untoward side effects occurred. Herein, the investigators propose evaluating the safety and efficacy of intravenous gentamicin in these patients. In theory, this intravenous administration has the possibility of treating simultaneously all of the patients' skin wounds. The milestones will be increased C7 and AFs in the patients' DEJ, improved EB Disease Activity Scores, and absence of gentamicin side effects.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 9
• Est. completion date: December 1, 2023
• Est. primary completion date: December 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 7 Years and older

Eligibility

Inclusion Criteria:

• Provision of signed and dated informed consent form

• Stated willingness to comply with all study procedures and availability for the duration of the study

• Male or female, aged 7 and up can participate in the 14 day IV gentamicin trial. Male or female, aged 18 and up can participate in the 3 month IV gentamicin trial.

• Been diagnosed with recessive dystrophic epidermolysis bullosa (RDEB) and with a nonsense mutation in the COL7A1 gene.

• Immunofluorescence evaluation of skin biopsies reveals absence or decreased intensity of C7 expression at their DEJ (dermal epidermal junction) compared with normal human skin biopsies.

• Cultured fibroblasts from patient skin synthesize and secrete full-length, 290kDa C7 alpha chains in the presence of supplemented gentamicin (400 µg/ml in culture).

• Ability to sit or lie down for over 30 minutes for IV infusions. For those in the 3 month trial, to be willing to continue treatment at home under the supervision of licensed and trained infusion nurses.

Exclusion Criteria:

• Recent exposure to gentamicin within the past 6 weeks.

• Pre-existing known auditory impairment.

• Pre-existing known renal impairment.

• Pre-existing known allergies to aminoglycosides or sulfate compounds.

• Pregnancy or lactation

• Current use of medications with known ototoxicity or nephrotoxicity.

• Current enrollment in another experimental clinical trial involving systemic treatment with C7 or C7 producing products for the treatment of RDEB.

Related Conditions & MeSH terms

• Epidermolysis Bullosa
• Epidermolysis Bullosa Dystrophica
• Recessive Dystrophic Epidermolysis Bullosa

Intervention

Drug:
• Gentamicin
Short-term intravenous gentamicin therapy should have the advantage of treating all of the patient's multiple skin wounds simultaneously. Six patients (three adults and 3 children) will receive intravenous gentamicin (7.5 mgs/kg) daily for 14 days and then stopped. Three adult patients will receive intravenous gentamicin (7.5mg/kg) biweekly for three months and then stopped.

Locations

Country	Name	City	State
United States	University of Southern California	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
University of Southern California

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Full-length type VII collagen expression	Increased expression of full-length type VII collagen as assessed by immunofluorescence	6 months
Primary	Generation of anchoring fibrils	Generation of new anchoring fibrils as assessed by immuno-electron microscopy	6 months
Primary	Absence of gentamicin side effects	Absence of gentamicin side effects, especially the detection of any ototoxicity or nephrotoxicity	6 months
Secondary	Improved Disease Activity scores	Improved epidermolysis bullosa Disease Activity scores	6 months
Secondary	Improved Quality of Life score	Improved Quality of Life score	6 months