Ignite Creation Date:
2024-05-06 @ 1:51 PM
Last Modification Date:
2024-10-26 @ 1:21 PM
Study NCT ID:
NCT04140786
Status:
RECRUITING
Last Update Posted:
2022-11-03
First Post:
2019-10-23
Brief Title:
Optimizing IV Gentamicin in JEB
Sponsor:
University of Southern California
Organization:
University of Southern California
Study Overview
Official Title:
Optimization of Intravenous Gentamicin Treatment to Restore Functional Laminin 332 in JEB Patients With Nonsense Mutations
Status:
RECRUITING
Status Verified Date:
2022-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 mutations
A Short Term Daily IV Gentamicin Study Three patients of any age with JEB caused by nonsense mutations in the LAMA3 and LAMB3 genes will receive intravenous gentamicin 10 mgskg 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 mutations in the LAMA3 and LAMB3 genes will receive intravenous gentamicin 10 mgskg 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 adultschildren 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 A3laminin B3laminin 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
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 mutations
A Short Term Daily IV Gentamicin Study Three patients of any age with JEB caused by nonsense mutations in the LAMA3 and LAMB3 genes will receive intravenous gentamicin 10 mgskg 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 mutations in the LAMA3 and LAMB3 genes will receive intravenous gentamicin 10 mgskg 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 adultschildren 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 A3laminin B3laminin 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None