Junctional Epidermolysis BullosaPhase 1/2NCT03526159
Gentamicin for Junctional Epidermolysis Bullosa
A Phase 1/2 study testing Gentamicin Sulfate 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, fatal, inherited skin disease, is caused by loss-of-function mutations in the LAMA3, LAMB3 or LAMC2 genes, resulting in loss of laminin 332 and poor epidermal-dermal adherence. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Junctional Epidermolysis Bullosa
- What is being tested?
- Gentamicin Sulfate
- 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
- 1 Jun 2018to 31 Aug 2020
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 1. JEB patients with nonsense mutations in the LAMB3 gene in either one or two alleles.
Who cannot join
- JEB patients who do not have nonsense mutations in the LAMB3 gene in either allele.
- Pre-existing known auditory impairment.
- Pre-existing known renal impairment.
- Pre-existing known allergies to aminoglycosides or sulfate compounds.
- Pregnancy.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of Southern California
Los Angeles, California, 90033
David Woodley, MD, 323-865-0956, dwoodley@usc.edu
Mei Chen, Ph.D, 323-865-0621, chenm@usc.edu
About this study
Official title: A Pilot Study of the Restoration of Functional Laminin 332 in JEB Patients With Nonsense Mutations After Topical and Intravenous Gentamicin Treatment
Herlitz junctional epidermolysis bullosa (H-JEB), an incurable, fatal, inherited skin disease, is caused by loss-of-function mutations in the LAMA3, LAMB3 or LAMC2 genes, resulting in loss of laminin 332 and poor epidermal-dermal adherence. Eighty percent of H-JEB patients have LAMB3 mutations and about 95% of these are nonsense mutations. The investigators recently demonstrated that gentamicin readily induced nonsense mutation readthrough and produced full-length laminin beta3 in several nonsense mutations tested. Importantly, the gentamicin-induced laminin beta3 restored laminin 332 assembly, secretion, and deposition into the dermal-epidermal junction (DEJ). Newly induced laminin 332 reversed abnormal H-JEB cellular phenotypes. Herein, the investigators propose the first clinical trial of gentamicin (by topical and intravenous administration) in JEB patients with nonsense mutations. The milestones will include restored laminin 332 and hemidesmosomes at the DEJ, improved wound closure, and the absence of significant gentamicin side effects.
Read the detailed description
Three subjects (adults and children of any age) will receive topical gentamicin to be applied to select skin sites.
Three subjects (adults and children of any age) will receive intravenous (IV) gentamicin infusions.
Patients will be assessed for Primary and Secondary endpoints during follow up visits.
- Conditions
- Junctional Epidermolysis Bullosa
- Being tested
- Gentamicin Sulfate
- Keywords
- Herlitz, Laminin 332, Laminin beta 3, JEB
- 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 SulfateDrug
Also called Gentamicin
Gentamicin (formulated as gentamicin sulfate) is a well-known, well-characterized antibiotic that has been used for four decades as a treatment against gram negative bacteria. It, like other aminoglycoside antibiotics, has the well documented added potential to facilitate readthrough of premature termination codons in eukaryotic cells and organisms.
| Study group | Role | What they receive |
|---|---|---|
| Gentamicin Sulfate | Experimental | IV Arm:
7.5 mg/kg gentamicin once daily for 14 days.
Topical Arm:
0.5% gentamicin ointment applied twice daily for 14 days to selected skin sites. Receives: Drug: Gentamicin Sulfate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Increased laminin beta 3 / laminin 332 expression as assessed by immunofluorescence.
New or increased staining of the target protein, laminin 332, in sections of skin biopsies obtained during follow-up visits in comparison with baseline biopsies. Five micron cryosections will be probed with three different antibodies against laminin 332. Patient samples along with normal control samples will be compared. Mean fluorescence intensity will be calculated for each sample and antibody using ImageJ software. Percent expression relative to normal human skin (set to 100%) will be calculated for each patient sample. Any statistically significant increase in (p value < 0.05) over baseline will be considered improvement.
Measured: 3 months
Incidence of Treatment-Emergent Adverse Events
The total number of adverse events and serious adverse events will be recorded and enumerated for each study participant. Gentamicin in high doses is associated with ototoxicity and nephrotoxicity. Audiometry and creatinine clearance tests will be performed throughout the study to monitor for the emergence of any treatment-related adverse events. In addition, as this treatment may result in the production of a protein that is hasn't been present in the patient's system, commercial ELISA tests will be performed on serum samples to test for the emergence of circulating anti-laminin 332 antibodies. Adverse events include a decline of >15 dB on pure tone audiometry at 2 consecutive frequencies, creatinine clearance <60ml/min, presence of antibodies to laminin 332, and for IV gentamicin recipients, serum gentamicin peak levels above 40 ug/ml and trough levels above 2 ug/ml.
Measured: 3 months
Generation of new hemidesmosomes as assessed by electron microscopy.
Any new hemidesmosomes detected by electron microscopy in post-treatment skin biopsies will be enumerated and compared to baseline.
Measured: 3 months
Secondary outcomes (2)
Improved wound closure.
Participants in the Topical arm will treat and monitor specific test sites, along with untreated control sites, selected during their baseline visits. Photographs will be used to assess the size of open erosions. Wound areas (treated and untreated) (cm2) will be measured using computer-assisted planimetry of digital photographs taken throughout the study.
Measured: 3 months
Reduction in blistering
Participants in the Topical arm will treat and monitor specific test sites, along with untreated control sites, selected during their baseline visits. Photographs and patient diaries will be used to assess the number of blisters that appear at the test sites as well as whether the wound had closed during treatment.
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 posted16 May 2018
- Study start1 Jun 2018
- Primary completion30 Jul 2020 (estimated)
- Study completion31 Aug 2020 (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
- Not applicable
- 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
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03526159
- Sponsor's protocol ID
- HS-18-00290
- Status last verified
- Apr 2020
- First submitted
- 17 Apr 2018
- Last updated
- 7 Apr 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- 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 7 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study of the Restoration of Functional Laminin 332 in JEB Patients With Nonsense Mutations After Topical and Intravenous Gentamicin Treatment
- ClinicalTrials.gov ID
- NCT03526159
- Acronym / sponsor ID
- HS-18-00290
- Conditions
- Junctional Epidermolysis Bullosa
- Keywords
- Herlitz, Laminin 332, Laminin beta 3, JEB
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 6 participants (estimated)
- Lead sponsor
- University of Southern CaliforniaUniversity, hospital or other
- Study start
- 1 Jun 2018 (actual)
- Primary completion
- 30 Jul 2020 (estimated)
- Study completion
- 31 Aug 2020 (estimated)
- First posted
- 16 May 2018 (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, fatal, inherited skin disease, is caused by loss-of-function mutations in the LAMA3, LAMB3 or LAMC2 genes, resulting in loss of laminin 332 and poor epidermal-dermal adherence. Eighty percent of H-JEB patients have LAMB3 mutations and about 95% of these are nonsense mutations. The investigators recently demonstrated that gentamicin readily induced nonsense mutation readthrough and produced full-length laminin beta3 in several nonsense mutations tested. Importantly, the gentamicin-induced laminin beta3 restored laminin 332 assembly, secretion, and deposition into the dermal-epidermal junction (DEJ). Newly induced laminin 332 reversed abnormal H-JEB cellular phenotypes. Herein, the investigators propose the first clinical trial of gentamicin (by topical and intravenous administration) in JEB patients with nonsense mutations. The milestones will include restored laminin 332 and hemidesmosomes at the DEJ, improved wound closure, and the absence of significant gentamicin side effects.
Detailed description
Three subjects (adults and children of any age) will receive topical gentamicin to be applied to select skin sites.
Three subjects (adults and children of any age) will receive intravenous (IV) gentamicin infusions.
Patients will be assessed for Primary and Secondary endpoints during follow up visits.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Gentamicin Sulfate | Experimental | Drug: Gentamicin SulfateIV Arm: 7.5 mg/kg gentamicin once daily for 14 days. Topical Arm: 0.5% gentamicin ointment applied twice daily for 14 days to selected skin sites. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (1 listed)
- 1. JEB patients with nonsense mutations in the LAMB3 gene in either one or two alleles.
Key exclusion criteria (5 listed)
- JEB patients who do not have nonsense mutations in the LAMB3 gene in either allele.
- Pre-existing known auditory impairment.
- Pre-existing known renal impairment.
- Pre-existing known allergies to aminoglycosides or sulfate compounds.
- Pregnancy.
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 SulfateAlso: GentamicinGentamicin (formulated as gentamicin sulfate) is a well-known, well-characterized antibiotic that has been used for four decades as a treatment against gram negative bacteria. It, like other aminoglycoside antibiotics, has the well documented added potential to facilitate readthrough of premature termination codons in eukaryotic cells and organisms. | Drug | Gentamicin Sulfate |
Primary outcome
Increased laminin beta 3 / laminin 332 expression as assessed by immunofluorescence.
Time frame: 3 months
New or increased staining of the target protein, laminin 332, in sections of skin biopsies obtained during follow-up visits in comparison with baseline biopsies. Five micron cryosections will be probed with three different antibodies against laminin 332. Patient samples along with normal control samples will be compared. Mean fluorescence intensity will be calculated for each sample and antibody using ImageJ software. Percent expression relative to normal human skin (set to 100%) will be calculated for each patient sample. Any statistically significant increase in (p value < 0.05) over baseline will be considered improvement.
Incidence of Treatment-Emergent Adverse Events
Time frame: 3 months
The total number of adverse events and serious adverse events will be recorded and enumerated for each study participant. Gentamicin in high doses is associated with ototoxicity and nephrotoxicity. Audiometry and creatinine clearance tests will be performed throughout the study to monitor for the emergence of any treatment-related adverse events. In addition, as this treatment may result in the production of a protein that is hasn't been present in the patient's system, commercial ELISA tests will be performed on serum samples to test for the emergence of circulating anti-laminin 332 antibodies. Adverse events include a decline of >15 dB on pure tone audiometry at 2 consecutive frequencies, creatinine clearance <60ml/min, presence of antibodies to laminin 332, and for IV gentamicin recipients, serum gentamicin peak levels above 40 ug/ml and trough levels above 2 ug/ml.
Generation of new hemidesmosomes as assessed by electron microscopy.
Time frame: 3 months
Any new hemidesmosomes detected by electron microscopy in post-treatment skin biopsies will be enumerated and compared to baseline.
2 secondary outcomes
Improved wound closure.
Time frame: 3 months
Reduction in blistering
Time frame: 3 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Apr 2020.
- 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.
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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.
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 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 1 inclusion and 5 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: looking for participants now, as of the sponsor's last update on 7 Apr 2020. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Mei Chen, Ph.D. (3238650621, chenm@usc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Increased laminin beta 3 / laminin 332 expression as assessed by immunofluorescence. (time frame: 3 months). The study lists 3 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 NCT03526159, 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 7 Apr 2020.