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Gentamicin for Junctional Epidermolysis Bullosa

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ClinicalTrials.gov Identifier: NCT03526159
Recruitment Status : Recruiting
First Posted : May 16, 2018
Last Update Posted : April 7, 2020
Information provided by (Responsible Party):
David Woodley, University of Southern California

Brief Summary:
Herlitz junctional epidermolysis bullosa (H-JEB), an incurable, fatal, inherited skin disease, is caused by loss-of-function mutations in the LAMA3, LAMB3 or LAMC2 genes, resulting in loss of laminin 332 and poor epidermal-dermal adherence. Eighty percent of H-JEB patients have LAMB3 mutations and about 95% of these are nonsense mutations. The investigators recently demonstrated that gentamicin readily induced nonsense mutation readthrough and produced full-length laminin beta3 in several nonsense mutations tested. Importantly, the gentamicin-induced laminin beta3 restored laminin 332 assembly, secretion, and deposition into the dermal-epidermal junction (DEJ). Newly induced laminin 332 reversed abnormal H-JEB cellular phenotypes. Herein, the investigators propose the first clinical trial of gentamicin (by topical and intravenous administration) in JEB patients with nonsense mutations. The milestones will include restored laminin 332 and hemidesmosomes at the DEJ, improved wound closure, and the absence of significant gentamicin side effects.

Condition or disease Intervention/treatment Phase
Junctional Epidermolysis Bullosa Drug: Gentamicin Sulfate Phase 1 Phase 2

Detailed Description:

Three subjects (adults and children of any age) will receive topical gentamicin to be applied to select skin sites.

Three subjects (adults and children of any age) will receive intravenous (IV) gentamicin infusions.

Patients will be assessed for Primary and Secondary endpoints during follow up visits.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of the Restoration of Functional Laminin 332 in JEB Patients With Nonsense Mutations After Topical and Intravenous Gentamicin Treatment
Actual Study Start Date : June 1, 2018
Estimated Primary Completion Date : July 30, 2020
Estimated Study Completion Date : August 31, 2020

Arm Intervention/treatment
Experimental: Gentamicin Sulfate

IV Arm:

7.5 mg/kg gentamicin once daily for 14 days.

Topical Arm:

0.5% gentamicin ointment applied twice daily for 14 days to selected skin sites.

Drug: Gentamicin Sulfate
Gentamicin (formulated as gentamicin sulfate) is a well-known, well-characterized antibiotic that has been used for four decades as a treatment against gram negative bacteria. It, like other aminoglycoside antibiotics, has the well documented added potential to facilitate readthrough of premature termination codons in eukaryotic cells and organisms.
Other Name: Gentamicin

Primary Outcome Measures :
  1. Increased laminin beta 3 / laminin 332 expression as assessed by immunofluorescence. [ Time Frame: 3 months ]
    New or increased staining of the target protein, laminin 332, in sections of skin biopsies obtained during follow-up visits in comparison with baseline biopsies. Five micron cryosections will be probed with three different antibodies against laminin 332. Patient samples along with normal control samples will be compared. Mean fluorescence intensity will be calculated for each sample and antibody using ImageJ software. Percent expression relative to normal human skin (set to 100%) will be calculated for each patient sample. Any statistically significant increase in (p value < 0.05) over baseline will be considered improvement.

  2. Incidence of Treatment-Emergent Adverse Events [ Time Frame: 3 months ]
    The total number of adverse events and serious adverse events will be recorded and enumerated for each study participant. Gentamicin in high doses is associated with ototoxicity and nephrotoxicity. Audiometry and creatinine clearance tests will be performed throughout the study to monitor for the emergence of any treatment-related adverse events. In addition, as this treatment may result in the production of a protein that is hasn't been present in the patient's system, commercial ELISA tests will be performed on serum samples to test for the emergence of circulating anti-laminin 332 antibodies. Adverse events include a decline of >15 dB on pure tone audiometry at 2 consecutive frequencies, creatinine clearance <60ml/min, presence of antibodies to laminin 332, and for IV gentamicin recipients, serum gentamicin peak levels above 40 ug/ml and trough levels above 2 ug/ml.

  3. Generation of new hemidesmosomes as assessed by electron microscopy. [ Time Frame: 3 months ]
    Any new hemidesmosomes detected by electron microscopy in post-treatment skin biopsies will be enumerated and compared to baseline.

Secondary Outcome Measures :
  1. Improved wound closure. [ Time Frame: 3 months ]
    Participants in the Topical arm will treat and monitor specific test sites, along with untreated control sites, selected during their baseline visits. Photographs will be used to assess the size of open erosions. Wound areas (treated and untreated) (cm2) will be measured using computer-assisted planimetry of digital photographs taken throughout the study.

  2. Reduction in blistering [ Time Frame: 3 months ]
    Participants in the Topical arm will treat and monitor specific test sites, along with untreated control sites, selected during their baseline visits. Photographs and patient diaries will be used to assess the number of blisters that appear at the test sites as well as whether the wound had closed during treatment.

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

Inclusion Criteria:

1. JEB patients with nonsense mutations in the LAMB3 gene in either one or two alleles.

Exclusion Criteria:

  1. JEB patients who do not have nonsense mutations in the LAMB3 gene in either allele.
  2. Pre-existing known auditory impairment.
  3. Pre-existing known renal impairment.
  4. Pre-existing known allergies to aminoglycosides or sulfate compounds.
  5. Pregnancy.

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): NCT03526159

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Contact: Mei Chen, Ph.D. 3238650621 chenm@usc.edu
Contact: David Woodley, M.D. 3238650956 dwoodley@usc.edu

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United States, California
University of Southern California Recruiting
Los Angeles, California, United States, 90033
Contact: David Woodley, MD    323-865-0956    dwoodley@usc.edu   
Contact: Mei Chen, Ph.D    323-865-0621    chenm@usc.edu   
Sponsors and Collaborators
University of Southern California
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: David Woodley, Professor, University of Southern California
ClinicalTrials.gov Identifier: NCT03526159    
Other Study ID Numbers: HS-18-00290
First Posted: May 16, 2018    Key Record Dates
Last Update Posted: April 7, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by David Woodley, University of Southern California:
Laminin 332
Laminin beta 3
Additional relevant MeSH terms:
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Epidermolysis Bullosa
Epidermolysis Bullosa, Junctional
Skin Abnormalities
Congenital Abnormalities
Skin Diseases, Genetic
Genetic Diseases, Inborn
Skin Diseases
Skin Diseases, Vesiculobullous
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action