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

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ClinicalTrials.gov Identifier: NCT02698735
Recruitment Status : Completed
First Posted : March 4, 2016
Results First Posted : August 14, 2019
Last Update Posted : October 29, 2019
Information provided by (Responsible Party):
David Woodley, University of Southern California

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.

Condition or disease Intervention/treatment Phase
Recessive Dystrophic Epidermolysis Bullosa Drug: Gentamicin Drug: Placebo Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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).
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Treatment
Actual Study Start Date : February 25, 2016
Actual Primary Completion Date : March 31, 2017
Actual Study Completion Date : June 30, 2017

Arm Intervention/treatment
Experimental: Gentamicin
Gentamicin antibiotic
Drug: Gentamicin
Gentamicin was either formulated into a 0.1% ointment or solutions for injection were purchased directly from suppliers.
Other Name: Gentamicin Sulfate, Garamycin

Placebo Comparator: Placebo
Vehicle control
Drug: Placebo
There are two placebos used in this study. The ointment vehicle (same as used to formulate gentamicin) and vehicle solution for injection.
Other Name: Vehicle

Primary Outcome Measures :
  1. Restoration of Full-length Type VII Collagen as Assessed by Immunofluorescence. [ Time Frame: 3 months ]
    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.

  2. Number of Participants With Anchoring Fibrils as Assessed by Immuno-electron Microscopy [ Time Frame: 3 months ]
    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.

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

(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.

Exclusion Criteria:

(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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02698735

Sponsors and Collaborators
University of Southern California
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Principal Investigator: David Woodley, MD University of Southern California Department of Dermatology
  Study Documents (Full-Text)

Documents provided by David Woodley, University of Southern California:
Study Protocol  [PDF] February 9, 2016
Statistical Analysis Plan  [PDF] February 9, 2016

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: David Woodley, Professor of Dermatology, University of Southern California
ClinicalTrials.gov Identifier: NCT02698735    
Other Study ID Numbers: HS-15-00821
First Posted: March 4, 2016    Key Record Dates
Results First Posted: August 14, 2019
Last Update Posted: October 29, 2019
Last Verified: October 2019
Additional relevant MeSH terms:
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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
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action