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Gentamicin for RDEB

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ClinicalTrials.gov Identifier: NCT03012191
Recruitment Status : Completed
First Posted : January 6, 2017
Results First Posted : July 23, 2019
Last Update Posted : July 23, 2019
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 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.

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

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa Patients With Nonsense Mutations
Actual Study Start Date : February 2, 2017
Actual Primary Completion Date : May 5, 2018
Actual Study Completion Date : August 31, 2018


Arm Intervention/treatment
Experimental: Gentamicin
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
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.
Other Name: Gentamicin, Garamycin




Primary Outcome Measures :
  1. Increased Expression of Full-length Type VII Collagen as Assessed by Immunofluorescence [ Time Frame: 6 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. 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 New or Increased Numbers of Anchoring Fibrils as Assessed by Immuno-electron Microscopy [ Time Frame: 6 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).

  3. Number of Participants With Absence of Gentamicin Side Effects Especially the Detection of Any Ototoxicity or Nephrotoxicity [ Time Frame: 6 months ]
    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.


Secondary Outcome Measures :
  1. Improved EBDASI Scores [ Time Frame: 6 months ]
    EBDASI - Epidermolysis Bullosa Disease Activity and Scarring Index Scale - Minimum (0) to Maximum (506) A lower score indicates a better outcome (less disease activity and/or damage) A clinical tool for evaluating the disease activity and damage associated with bullous patients. To be administered by a licensed dermatologist.



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

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): NCT03012191


Locations
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United States, California
University of Southern California
Los Angeles, California, United States, 90033
Sponsors and Collaborators
University of Southern California
Investigators
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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] March 2, 2017
Statistical Analysis Plan  [PDF] March 2, 2017


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Responsible Party: David Woodley, Professor, University of Southern California
ClinicalTrials.gov Identifier: NCT03012191     History of Changes
Other Study ID Numbers: HS-16-00788
First Posted: January 6, 2017    Key Record Dates
Results First Posted: July 23, 2019
Last Update Posted: July 23, 2019
Last Verified: July 2019

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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
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
Gentamicins
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action