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Optimizing IV Gentamicin in JEB

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ClinicalTrials.gov Identifier: NCT04140786
Recruitment Status : Recruiting
First Posted : October 28, 2019
Last Update Posted : November 3, 2022
Sponsor:
Information provided by (Responsible Party):
David Woodley, University of Southern California

Study Description
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Brief Summary:
Herlitz junctional epidermolysis bullosa (H-JEB), an incurable and fatal inherited skin disease, is caused by loss-of-function mutations in LAMA3, LAMB3 and LAMC2. These mutations result in diminished laminin 332 and epidermal-dermal adherence. 85% of JEB patients have nonsense mutations in LAMA3, LAMB3, or LAMC2, suggesting that H-JEB is a prime therapeutic target for nonsense suppression therapy. The investigators recently demonstrated in three patients that topical gentamicin created new and stable laminin 332 at the dermal-epidermal junction (DEJ), and also improved wound closure and skin quality. Furthermore, these preliminary studies showed that intravenous gentamicin also induced laminin 332 and transiently improved patients' clinical outcomes. No untoward side effects occurred. The investigators propose to optimize the intravenous gentamicin regimen including dosage and infusion schedules to enhance the therapeutic outcome. The milestones will be an increase of laminin 332 in the patients' DEJ, improvement in EB Disease Activity Scores, and no gentamicin-associated side effects.

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

Detailed Description:

RATIONALE:

Herlitz junctional epidermolysis bullosa (H-JEB), an incurable and fatal inherited skin disease, is caused by loss-of-function mutations in LAMA3, LAMB3 and LAMC2. These mutations result in diminished laminin 332 and epidermal-dermal adherence. 85% of JEB patients have nonsense mutations in LAMA3, LAMB3, or LAMC2, suggesting that H-JEB is a prime therapeutic target for nonsense suppression therapy. The investigators recently demonstrated in three patients that topical gentamicin created new and stable laminin 332 at the dermal-epidermal junction (DEJ), and also improved wound closure and skin quality. Furthermore, these preliminary studies showed that intravenous gentamicin also induced laminin 332 and transiently improved patients' clinical outcomes. No untoward side effects occurred. The investigators propose to optimize the intravenous gentamicin regimen including dosage and infusion schedules to enhance the therapeutic outcome.

INTERVENTION:

There will be two study designs on JEB patients with nonsense mutation(s):

A. Short Term Daily IV Gentamicin Study: Three patients of any age with JEB caused by nonsense mutation(s) in the LAMA3 and LAMB3 genes will receive intravenous gentamicin (10 mgs/kg) daily for 24 days and then stop. Prior to treatment and at 1 month and 3 months post treatment, selected skin test sites will have skin biopsies and the specimens evaluated for the expression of laminin 332 at the dermal-epidermal junction by direct immunofluorescent staining of the skin. Safety parameters such as physical exam, review of systems, laboratory tests, audiometry, and renal function at the same time periods.

B. Long Term Biweekly IV Gentamicin Study: Three patients of any age with JEB caused by nonsense mutation(s) in the LAMA3 and LAMB3 genes will receive intravenous gentamicin (10 mgs/kg) twice weekly for 3 months (24 total infusions) and then stop. Before and after evaluations will be performed and will be the same as those in the short term intravenous study outlined above.

STUDY POPULATION:

3 adults/children for who have JEB due to nonsense mutations in the LAMA3 or LAMB3 gene for each intervention arm.

STUDY ENDPOINTS OR OUTCOMES Analysis of safety parameters, wound healing, and generation of new laminin 332 at the dermal-epidermal junction of the skin by direct immunofluorescent stain.

FOLLOW-UP Participants will be followed out to 90 days post treatment

STATISTICS Without treatment, these JEB patients have little or no laminin A3/laminin B3/laminin 332 at their dermal-epidermal junction. The expression of any newly generated laminin 332 will be measure against normal human skin (100%) by NIH Image J software.

PLANS FOR ANALYSIS Safety parameters are outlined above and will be examined at baseline and after each patient visit. Efficacy parameters outlined above will be measured at baseline and at post treatment days 30 and 90.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Optimization of Intravenous Gentamicin Treatment to Restore Functional Laminin 332 in JEB Patients With Nonsense Mutations
Actual Study Start Date : October 31, 2019
Estimated Primary Completion Date : November 1, 2023
Estimated Study Completion Date : November 1, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Daily IV Gentamicin
Once daily (for 24 days) IV infusions of 10 mg/kg gentamicin delivered over a 30-60 minute period.
 Drug: Gentamicin Sulfate, Injectable
10mg/kg prepared from commercially available stock (typically Kabi Pharmaceuticals) by licensed pharmacists.
Other Name: Gentamicin, Garamycin
Experimental: Biweekly IV Gentamicin
Twice weekly (for 3 months or 24 total) IV infusions of 10 mg/kg gentamicin delivered over a 30-60 minute period.
 Drug: Gentamicin Sulfate, Injectable
10mg/kg prepared from commercially available stock (typically Kabi Pharmaceuticals) by licensed pharmacists.
Other Name: Gentamicin, Garamycin


Outcome Measures
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Primary Outcome Measures :
  1. Laminin 332 Expression in Skin [ Time Frame: 3 months ]
    Expression of laminin 332 as assessed by immunofluorescence of patient skin sections as a percentage of normal skin.

  2. Safety (Ototoxicity) [ Time Frame: 3 months ]
    Testing for any gentamicin-associated auditory impairment as assessed by pure-tone audiometry assessments.

  3. Safety (Nephrotoxicity) [ Time Frame: 3 months ]
    Testing for any gentamicin-associated renal impairment as assessed by calculated creatinine clearance.

  4. Safety (Autoimmune Response) [ Time Frame: 3 months ]
    Testing for the presence of auto antibodies to newly formed laminin 332 in response to gentamicin as assessed by specific ELISA.


Secondary Outcome Measures :
  1. Wound Healing [ Time Frame: 3 months ]
    Size of skin wounds selected for monitoring at baseline as assessed by computer assisted planimetry of photographs.

  2. Epidermolysis Bullosa Disease and Activity and Scarring Index (EBDASI) [ Time Frame: 3 months ]
    A disease scoring system designed for patients with epidermolysis bullosa (EB).


Eligibility Criteria
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Ages Eligible for Study:   30 Days and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • JEB patients with nonsense mutations in LAMB3 or LAMA3 in either one or two alleles
  • Immunofluorescence (IF) analysis showing absence or decreased laminin 332 expression at their DEJ compared with normal skin.

Exclusion Criteria:

  • Pre-existing known auditory impairment.
  • Pre-existing known renal impairment.
  • Pre-existing known allergies to aminoglycosides or sulfate compounds.
  • Pregnancy.
  • Recent exposure to systemic gentamicin within the past 6 weeks.
  • Current use of any medications with known potential ototoxicity or nephrotoxicity.
Contacts and Locations
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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): NCT04140786


Contacts
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Contact: David T Woodley, MD (323) 442 0084 dwoodley@med.usc.edu

Locations
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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@med.usc.edu   
Contact: Mei Chen, Ph.D    3238650621    chenm@usc.edu   
Sponsors and Collaborators
University of Southern California
Investigators
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Principal Investigator: Mei Chen, PhD University of Southern California
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: David Woodley, Professor of Dermatology, Keck School of Medicine, University of Southern California
ClinicalTrials.gov Identifier: NCT04140786    
Other Study ID Numbers: HS-19-00760
First Posted: October 28, 2019    Key Record Dates
Last Update Posted: November 3, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
Nonsense mutation
Additional relevant MeSH terms:
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Epidermolysis Bullosa
Epidermolysis Bullosa, Junctional
Gentamicins
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