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Intravenous Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB)

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ClinicalTrials.gov Identifier: NCT03392909
Recruitment Status : Not yet recruiting
First Posted : January 8, 2018
Last Update Posted : June 13, 2018
Sponsor:
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 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.

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 9 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Restoration of Full-Length Type VII Collagen in RDEB Patients With Nonsense Mutations After Intravenous Gentamicin Treatment
Estimated Study Start Date : July 2018
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : July 2020


Arm Intervention/treatment
Experimental: Intravenous Gentamicin
Intravenous gentamicin (7.5 mgs/kg) daily for for either 14 days and then stopped or twice weekly for three months and then stopped.
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.
Other Name: Gentamicin Sulfate




Primary Outcome Measures :
  1. Full-length type VII collagen expression [ Time Frame: 6 months ]
    Increased expression of full-length type VII collagen as assessed by immunofluorescence

  2. Generation of anchoring fibrils [ Time Frame: 6 months ]
    Generation of new anchoring fibrils as assessed by immuno-electron microscopy

  3. Absence of gentamicin side effects [ Time Frame: 6 months ]
    Absence of gentamicin side effects, especially the detection of any ototoxicity or nephrotoxicity


Secondary Outcome Measures :
  1. Improved Disease Activity scores [ Time Frame: 6 months ]
    Improved epidermolysis bullosa Disease Activity scores

  2. Improved Quality of Life score [ Time Frame: 6 months ]
    Improved Quality of Life score



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Ages Eligible for Study:   7 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT03392909


Contacts
Contact: David Woodley, MD 323-865-0956 dwoodley@usc.edu
Contact: Mei Chen, Ph.D 323-865-0621 chenm@usc.edu

Locations
United States, California
University of Southern California Not yet 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
Investigators
Principal Investigator: David Woodley, MD Professor, University of Southern California
Principal Investigator: Mei Chen, Ph.D Professor, University of Southern California

Responsible Party: David Woodley, Professor, University of Southern California
ClinicalTrials.gov Identifier: NCT03392909     History of Changes
Other Study ID Numbers: HS-17-00995
First Posted: January 8, 2018    Key Record Dates
Last Update Posted: June 13, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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:
Nonsense Mutations

Additional relevant MeSH terms:
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
Gentamicins
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action