Topical Gentamicin Nonsense Suppression Therapy of EB

Study Overview
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Brief Summary
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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 overall duration of part A in this study is planned to be 18 weeks per patients and consists of a 6 weeks treatment period followed by a 12 week follow up period. Each patient will attend 3 study visits: at week 0, week 6 and week 18. All patients will be included within a time period of 12 months. The overall duration of part B will be up to 8 weeks per patients of which 4-7 weeks are spent to prepare fibroblasts obtained from skin biopsies. Then 5 days of in vitro intervention and subsequent analysis follows. Altogether, the duration of the GENTELBULL study will be 78 weeks or less.

Official Title
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TOPICAL GENTAMICIN TREATMENT OF PATIENTS WITH EPIDERMOLYSIS BULLOSA DUE TO NONSENSE MUTATIONS

Conditions
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Epidermolysis Bullosa

Intervention / Treatment
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* Drug: Gentamicin Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient has EB caused by nonsense mutation 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. 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. Women of childbearing potential must use a highly effective contraception method Exclusion Criteria: Known contact allergy against gentamicin sulfate or other ingredients in the ointment Known intolerance to gentamicin sulfate of any sort Moderate or severely reduced kidney function (eGFR <45) Use other experimental therapy against EB Receiving systemic aminoglycosides during the last 3 months The patient uses muscle relaxant drug(s)
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Each patient serve as its own control, study treatment is given to one half of the body, the other half receives regular wound treatment. Which side to be treated is determined with randomization.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br>Each patient serves as its own control: one half is treated with the study treatment in addition to standard wound therapy, the other half receives standard wound therapy only. | Drug: Gentamicin Sulfate<br>* Topical gentamicin ointment on wounds once daily for 6 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wound size reduction | 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 independent of the other participants | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Healed skin robustness | 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 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 | 18 weeks | 
| Systemic gentamicin levels | Trough levels gentamicin in serum day 1 and week 6. If detectable day 1, levels will be monitored more frequently | 6 weeks | 
| Protein restoration by gentamicin | Immune histochemistry analysis of skin biopsy obtained from healed treated wound area at week 6 and 18 compared to skin biopsy from non-treated non-affected skin obtained at baseline (negative control) and non-affected skin from one healthy control (positive control) | 6 weeks |