Epidermolysis bullosa caused by nonsense mutations or splice site mutations
Conditions
Interventions
Trade Name: Infectogenta
Product Name: Gentamicin sulfate 0.1% ointment
Pharmaceutical Form:
Sponsors
Oslo University Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Part A 1. The patient has EB caused by nonsense mutation 2. The patient has a symmetrical distribution of wounds which allows for wounds on one side of the body to serve as control wounds, while study therapy is applied to the other side. 3. The patient (if an adult) or parent(s)/guardian(s) is capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol Part B 1. The patient has EB caused by splice site mutations 2. The patient (if an adult) or parent(s)/guardian(s) is capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Are the trial subjects under 18? yes Number of subjects for this age range: 4 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 4 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Part A 1. Known contact allergy against gentamicin sulfate or other ingredients in the ointment 2. Known intolerance to gentamicin sulfate of any sort 3. Moderate or severely reduced kidney function (eGFR <30) 4. Use other experimental therapy against EB 5. Receiving systemic aminoglycosides during the last 3 months Part B 1. The patient also carries a nonsense mutation that can be the cause of EB
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The overall purpose of this study is to address whether topical gentamicin therapy is an effective and feasible treatment. Specifically, we will investigate the effect of non-intensive treatment (once daily or every other day) on skin protein expression, as well as quantify the effect on wound healing in patients with EB caused by PSC (part A). Furthermore, we will address in vitro whether gentamicin restores protein expression of genes affected by SSM in fibroblasts derived from skin biopsies obtained from patients with EB caused by SSM (part B). If these in vitro experiments yield positive results, the patients donating the cells will be offered to enter part A of this study. The main objective is to investigate whether non-intensive topical gentamicin therapy reduces total wound area after 6 weeks treatment.;Timepoint(s) of evaluation of this end point: Part A: week 6 Part B: after 5 days of in vitro stimulation with gentamici;Secondary Objective: Whether non-intensive topical gentamicin therapy for 6 weeks reduces wound relapse the following 12 weeks. Whether non-intensive topical gentamicin therapy improves the affected protein translation at week 6. And if so, whether expression of the affected protein is maintained 12 weeks after the treatment has ended. Whether the topical gentamicin treatment results in measurable systemic levels of gentamicin Whether gentamicin (500 ug/mL) rescues the affected protein translation in dermal fibroblasts carrying EB-causing splice site mutations in vitro Whether gentamicin increases mRNA expression of the affected protein in dermal fibroblasts in vitro ;Primary end point(s): Part A • Mean of ratios for wound areas (measured in cm2) at week 6 to that of week 0 of gentamicin-treated wounds, compared to the corresponding mean of ratios for standard care-treated wounds. The observed effect is considered significant if p<0.05 (unpaired t-test). Of note, each patient may or may not reach the primary end point indep | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part A • Mean of ratios for single wound areas (measured in cm2) at week 18 to that of week 6 of gentamicin-treated wounds, compared to the corresponding mean of ratios for standard care-treated wounds. The XML File Identifier: H/W4MJ2tgNOBmJBwcafOdWe3MTI= Page 11/20 observed effect is considered significant if p<0.05 (unpaired t-test). Of note, each patient may or may not reach the primary end point independent of the other participants • Immune histochemistry analysis of skin biopsy obtained from healed treated wound area at week 6 and 18 compared to skin biopsy from nontreated non-affected skin obtained at baseline (negative control) and non-affected skin from one healthy control (positive control) • Trough levels gentamicin in serum day 1 and week 6. If detectable day 1, levels will be monitored more frequently (see section 8.3.3) Part B • mRNA expression in treated cells, untreated cells (negative control) and cells from one healthy control (positive control) quantified with polymerase chain reaction (qPCR);Timepoint(s) of evaluation of this end point: Part A Week 6 or 18 as indicated Part B after 5 days of in vitro stimulation with gentamicin | — |
Countries
Norway
Contacts
Public ContactØystein Sandanger
Section of dermatology, Oslo University Hospital
Outcome results
None listed