Optimizing IV Gentamicin in JEB

NCT ID: NCT04140786

Last Updated: 2022-11-03

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-31
• Study Completion Date: 2023-11-01

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.

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.

Conditions

Junctional Epidermolysis Bullosa

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Daily IV Gentamicin

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

Group Type: EXPERIMENTAL

Gentamicin Sulfate, Injectable

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Gentamicin Sulfate, Injectable

Intervention Type: DRUG

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

Interventions

Gentamicin Sulfate, Injectable

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

Intervention Type: DRUG

Other Intervention Names

Gentamicin, Garamycin

Eligibility 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.

• Minimum Eligible Age: 30 Days
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Southern California

OTHER

Sponsor Role: lead

Responsible Party

David Woodley

Professor of Dermatology, Keck School of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Mei Chen, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Southern California

Locations

University of Southern California

Los Angeles, California, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

David T Woodley, MD

Role: CONTACT

dwoodley@med.usc.edu

(323) 442 0084

Facility Contacts

David Woodley, MD

Role: primary

dwoodley@med.usc.edu

323-865-0956

Mei Chen, Ph.D

Role: backup

chenm@usc.edu

3238650621

References

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.

Reference Type: DERIVED

PMID: 35234826 (View on PubMed)

Other Identifiers

HS-19-00760

Identifier Type: -

Identifier Source: org_study_id