Gentamicin for RDEB

NCT03012191 | Completed Phase 1 Results FDA Drug

• 1 other identifier: HS-16-00788
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief 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 investigators also propose optimizing the concentration and manner of delivery of topical gentamicin. The unambiguous milestones will be increased C7 and AFs in the patients' DEJ, improved EB Disease Activity Scores, and absence of significant gentamicin side effects.

Conditions

Recessive Dystrophic Epidermolysis Bullosa

Outcome Measures

Primary Outcomes (3)

• Increased Expression 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. 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.

  6 months

• Number of Participants With New or Increased Numbers of 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).

  6 months

• Number of Participants With Absence of Gentamicin Side Effects Especially the Detection of Any Ototoxicity or Nephrotoxicity

  Prolonged exposure to systemic gentamicin is associated with ototoxicity and nephrotoxicity. Specific tests (creatinine clearance and gold-tone audiometry) are performed throughout the study in order to detect any drug-specific adverse events as a result of systemic exposure to gentamicin. Additionally, we test patient skin and serum throughout the study to look for increase of autoantibodies to C7. Since some of these patients may have never had C7 expressed in their bodies, gentamicin-induced C7 may cause in auto-immune response.

  6 months

Secondary Outcomes (1)

• Improved EBDASI Scores

  6 months

Study Arms (1)

Gentamicin

EXPERIMENTAL

Topical gentamicin; Topical gentamicin with microneedle roller assistance; IV gentamicin. While the intervention is the same drug, the topical gentamicin is compounded into a 0.5% ointment and the IV gentamicin is prepared to 7.5 mg/kg body weight and administered over a 30 minutes.

Drug: Gentamicin Sulfate

Interventions

Gentamicin Sulfate DRUG

Participants will be divided into three cohorts: topical gentamicin; Topical gentamicin with microneedle roller assistance; IV gentamicin. While the intervention is the same drug, the topical gentamicin is compounded into a 0.5% ointment and the IV gentamicin is prepared to 7.5 mg/kg body weight and administered over a 30 minutes.

Also known as: Gentamicin, Garamycin

Gentamicin

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

Study Sites (1)

University of Southern California

Los Angeles, California, 90033, United States

Location

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

Limitations and Caveats

Small number of subjects analyzed due to rarity of the disease and experimental plan.

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: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 4, 2017
• First Posted: January 6, 2017
• Study Start: February 2, 2017
• Primary Completion: May 5, 2018
• Study Completion: August 31, 2018
• Last Updated: July 23, 2019
• Results First Posted: July 23, 2019

Record last verified: 2019-07

Locations

US (1)