Optimizing IV Gentamicin in JEB

NCT04140786 | Unknown Phase 1 FDA Drug

• 1 other identifier: HS-19-00760
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Junctional Epidermolysis Bullosa

Keywords

Nonsense mutation

Outcome Measures

Primary Outcomes (4)

• Laminin 332 Expression in Skin

  Expression of laminin 332 as assessed by immunofluorescence of patient skin sections as a percentage of normal skin.

  3 months

• Safety (Ototoxicity)

  Testing for any gentamicin-associated auditory impairment as assessed by pure-tone audiometry assessments.

  3 months

• Safety (Nephrotoxicity)

  Testing for any gentamicin-associated renal impairment as assessed by calculated creatinine clearance.

  3 months

• Safety (Autoimmune Response)

  Testing for the presence of auto antibodies to newly formed laminin 332 in response to gentamicin as assessed by specific ELISA.

  3 months

Secondary Outcomes (2)

• Wound Healing

  3 months

• Epidermolysis Bullosa Disease and Activity and Scarring Index (EBDASI)

  3 months

Study Arms (2)

Daily IV Gentamicin

EXPERIMENTAL

Once daily (for 24 days) IV infusions of 10 mg/kg gentamicin delivered over a 30-60 minute period.

Drug: Gentamicin Sulfate, Injectable

Biweekly IV Gentamicin

EXPERIMENTAL

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

Interventions

Gentamicin Sulfate, Injectable DRUG

10mg/kg prepared from commercially available stock (typically Kabi Pharmaceuticals) by licensed pharmacists.

Also known as: Gentamicin, Garamycin

Biweekly IV Gentamicin; Daily IV Gentamicin

Eligibility Criteria

• Age: 30 Days+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Southern California: lead

Study Sites (1)

University of Southern California

Los Angeles, California, 90033, United States

RECRUITING

Related Publications (1)

• Mosallaei D, Hao M, Antaya RJ, Levian B, Kwong A, Cogan J, Hamilton C, Schwieger-Briel A, Tan C, Tang X, Woodley DT, Chen M. Molecular and Clinical Outcomes After Intravenous Gentamicin Treatment for Patients With Junctional Epidermolysis Bullosa Caused by Nonsense Variants. JAMA Dermatol. 2022 Apr 1;158(4):366-374. doi: 10.1001/jamadermatol.2021.5992.

  PMID: 35234826 DERIVED

MeSH Terms

Conditions

Epidermolysis Bullosa, Junctional

Interventions

Gentamicins; Injections

Condition Hierarchy (Ancestors)

Epidermolysis Bullosa; Skin Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Vesiculobullous

Intervention Hierarchy (Ancestors)

Aminoglycosides; Glycosides; Carbohydrates; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Mei Chen, PhD

  University of Southern California

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David T Woodley, MD

CONTACT

(323) 442 0084; dwoodley@med.usc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Dermatology, Keck School of Medicine

Study Record Dates

• First Submitted: October 23, 2019
• First Posted: October 28, 2019
• Study Start: October 31, 2019
• Primary Completion: November 1, 2023
• Study Completion: November 1, 2023
• Last Updated: November 3, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)