Junctional Epidermolysis BullosaPhase 1/2NCT04140786
Optimizing IV Gentamicin in JEB
A Phase 1/2 study testing Gentamicin Sulfate, Injectable in people with Junctional Epidermolysis Bullosa, run by University of Southern California at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 30 days and older
- Conditions the study is for
- Junctional Epidermolysis Bullosa
- What is being tested?
- Gentamicin Sulfate, Injectable
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- 31 Oct 2019to 1 Nov 2023
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 days and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site, 1 recruiting
- Recruiting
University of Southern California
Los Angeles, California, 90033
David Woodley, MD, 323-865-0956, dwoodley@med.usc.edu
Mei Chen, Ph.D, 3238650621, chenm@usc.edu
About this study
Official title: Optimization of Intravenous Gentamicin Treatment to Restore Functional Laminin 332 in JEB Patients With Nonsense Mutations
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.
Read the 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):
- 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.
- 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
- Being tested
- Gentamicin Sulfate, Injectable
- Keywords
- Nonsense mutation
- Medical subject headings
- Epidermolysis Bullosa, Junctional
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gentamicin Sulfate, InjectableDrug
Also called Gentamicin, Garamycin
10mg/kg prepared from commercially available stock (typically Kabi Pharmaceuticals) by licensed pharmacists.
| Study group | Role | What they receive |
|---|---|---|
| Daily IV Gentamicin | Experimental | Once daily (for 24 days) IV infusions of 10 mg/kg gentamicin delivered over a 30-60 minute period. Receives: 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. Receives: Drug: Gentamicin Sulfate, Injectable |
What is being measured
The primary outcome is the main question the study is designed to answer.
Laminin 332 Expression in Skin
Expression of laminin 332 as assessed by immunofluorescence of patient skin sections as a percentage of normal skin.
Measured: 3 months
Safety (Ototoxicity)
Testing for any gentamicin-associated auditory impairment as assessed by pure-tone audiometry assessments.
Measured: 3 months
Safety (Nephrotoxicity)
Testing for any gentamicin-associated renal impairment as assessed by calculated creatinine clearance.
Measured: 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.
Measured: 3 months
Secondary outcomes (2)
Wound Healing
Size of skin wounds selected for monitoring at baseline as assessed by computer assisted planimetry of photographs.
Measured: 3 months
Epidermolysis Bullosa Disease and Activity and Scarring Index (EBDASI)
A disease scoring system designed for patients with epidermolysis bullosa (EB).
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Oct 2019
- Study start31 Oct 2019
- Primary completion1 Nov 2023 (estimated)
- Study completion1 Nov 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Junctional Epidermolysis BullosaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Southern California
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, David Woodley, University of Southern California
- Investigators
- Mei Chen, PhD, Principal investigator, University of Southern California
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04140786
- Sponsor's protocol ID
- HS-19-00760
- Status last verified
- Nov 2022
- First submitted
- 23 Oct 2019
- Last updated
- 3 Nov 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 35234826
Study at a glance
From the registry record, last updated by the sponsor on 3 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimization of Intravenous Gentamicin Treatment to Restore Functional Laminin 332 in JEB Patients With Nonsense Mutations
- ClinicalTrials.gov ID
- NCT04140786
- Acronym / sponsor ID
- HS-19-00760
- Conditions
- Junctional Epidermolysis Bullosa
- Keywords
- Nonsense mutation
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 6 participants (estimated)
- Lead sponsor
- University of Southern CaliforniaUniversity, hospital or other
- Study start
- 31 Oct 2019 (actual)
- Primary completion
- 1 Nov 2023 (estimated)
- Study completion
- 1 Nov 2023 (estimated)
- First posted
- 28 Oct 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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):
- 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.
- 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
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Daily IV Gentamicin | Experimental | Drug: Gentamicin Sulfate, InjectableOnce daily (for 24 days) IV infusions of 10 mg/kg gentamicin delivered over a 30-60 minute period. |
| Biweekly IV Gentamicin | Experimental | Drug: Gentamicin Sulfate, InjectableTwice weekly (for 3 months or 24 total) IV infusions of 10 mg/kg gentamicin delivered over a 30-60 minute period. |
Who may qualify
- Ages
- 30 days and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (6 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Gentamicin Sulfate, InjectableAlso: Gentamicin, Garamycin10mg/kg prepared from commercially available stock (typically Kabi Pharmaceuticals) by licensed pharmacists. | Drug | Biweekly IV Gentamicin, Daily IV Gentamicin |
Primary outcome
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.
Safety (Ototoxicity)
Time frame: 3 months
Testing for any gentamicin-associated auditory impairment as assessed by pure-tone audiometry assessments.
Safety (Nephrotoxicity)
Time frame: 3 months
Testing for any gentamicin-associated renal impairment as assessed by calculated creatinine clearance.
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.
2 secondary outcomes
Wound Healing
Time frame: 3 months
Epidermolysis Bullosa Disease and Activity and Scarring Index (EBDASI)
Time frame: 3 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Nov 2022.
- Derived from this study: PubMed 35234826Mosallaei 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.
- Individual participant dataSharing planned: No
Related trials for Junctional Epidermolysis Bullosa
RecruitingPhase 2
A Phase 2 Study of TCP-25 Gel in Patients With Epidermolysis Bullosa, STEP-study
Epidermolysis Bullosa (EB), Dystrophic Epidermolysis Bullosa
RecruitingPhase 2
A Study to Evaluate ENERGI-F703EB Cream in Epidermolysis Bullosa
Epidermolysis Bullosa (EB), Junctional Epidermolysis Bullosa
RecruitingObservational study
A Study to Assess the Incidence of Skin Cancers in Patients With Epidermolysis Bullosa Receiving Filsuvez
Epidermolysis Bullosa, Dystrophic, Epidermolysis Bullosa, Junctional
Active, not recruitingPhase 1
Pilot Study of ELK-003 Eye Drops for Treating Ocular Manifestations of Epidermolysis Bullosa
Junctional Epidermolysis Bullosa, Epidermolysis Bullosa (EB)
RecruitingPhase 3
A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
Epidermolysis Bullosa, Junctional Epidermolysis Bullosa
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mei Chen, PhD principal investigator
University of Southern California
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Gentamicin Sulfate, Injectable in people with Junctional Epidermolysis Bullosa, run by University of Southern California at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 3 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact David T Woodley, MD ((323) 442 0084, dwoodley@med.usc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Laminin 332 Expression in Skin (time frame: 3 months). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04140786, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Nov 2022.