Injections of Botulinic Toxin in Plantar Lesions of Localized Epidermolysis Bullosa Simplex

Study Overview
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Brief Summary
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The investigators hypothesize that palmar injections of botulinic toxin, via an inhibition of the sudation, would limit the occurrence of blisters in localized epidermolysis bullosa simplex (LEBS).

Detailed Description
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Epidermolysis bullosa is a group of rare genetic diseases characterized by the occurrence of blisters and erosions due to skin fragility. There are 4 different subgroups, based on the location of the skin cleavage area. The most frequent subgroup is the simplex form, consisting predominantly of the localized form (localized epidermolysis bullosa simplex: LEBS). The incidence of LEBS was estimated at between 1/318.000 and 1/35.000. The disease starts early in infancy by the occurrence of blisters and erosions located on soles, secondary to frictions during the walk. The phenomenon is worsened by heat and sudation. LEBS is due to mutations in keratin genes. Life expectancy in LEBS is normal but the quality of life is significantly impaired due to permanent skin pain and limitation of everyday activities (walking, sports). There is no effective or curative treatment. Patients must limit the frictions, protect the skin and use plasters in case of skin lesions. Botulinic toxin has an agreement for the treatment of axillary hyperhidrosis and has been shown to be also effective on palms and soles. The efficacy of botulinic toxin in plantar lesions of LEBS has been reported in the literature (one case report and a short retrospective series of 6 patients) but there is no proper study.

Official Title
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Evaluation of the Efficacy of Injections of Botulinic Toxin in Plantar Lesions of Patients Suffering From Localized Epidermolysis Bullosa Simplex : Double Blind Randomized Controlled Study.

Conditions
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Epidermolysis Bullosa Simplex

Intervention / Treatment
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* Drug: Botulinic toxin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of LEBS based on clinical symptoms and in some cases histological or molecular findings Palmar skin lesions: blisters and/or : erosions, edematous and erythematous lesions, crusts. 3 lesions per foot, as a minimum Similar clinical severity of skin lesions on both feet Patient with social security Written consent of the patient Patient able to understand the study's questionnaires Exclusion Criteria: Patients with only one leg and a different number of toes on each foot. Known hypersensitivity to botulinic toxin or its excipients Current treatment with aminosides Myasthenia Swallowing difficulties Respiratory disorders Past medical history of dysphagia or pneumopathy of inhalation Known allergy or contraindications to lidocaine, prilocaine, paracetamol or nitrous oxide Pregnancy (positive pregnancy test (β-HCG) for women of childbearing age, performed within the 2 days prior to the study. Breastfeeding. Contraception during 6 months from inclusion Mental or physical or judicial incapacity to fill the questionnaires Guardianship patients Skin infection on the soles at the time of the inclusion Skin lesions located on the soles, not related to LEBS (ie. post traumatic wound, wart) Patient suffering from dishydrosis Botulinic toxin injections in the previous 6 months Inclusion in another study in the previous 2 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Each subject is his own witness, receiving the 2 treatments : left foot vs. right foot
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Botulinic toxin<br>Injections of botulinic toxin (Dysport®, Allergan) 200 UI | Drug: Botulinic toxin<br>* Clinical photographs of the soles Standardized anesthesia protocol (lidocaine, prilocaine on soles, cryo-spray, oral administration of paracetamol and only if necessary oxycodone and hydroxyzine). Cleaning and antiseptic on the soles Injections of botulinic toxin (200 UI) on right or left foot<br>* Other names: Dysport® (experimental drug);|
| Placebo Comparator: Placebo<br>Injections of physiological serum | Drug: Placebo<br>* Clinical photographs of the soles Standardized anesthesia protocol (lidocaine, prilocaine on soles, cryo-spray, oral administration of paracetamol and only if necessary oxycodone and hydroxyzine). Cleaning and antiseptic on the soles Injections of physiological serum (200 UI) on right or left foot<br>* Other names: physiological serum;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global clinical improvement on each foot assessed by a blinded centralized independent reviewer using photographs, at M3 vs.baseline: IGA score (Improvement Global Assessment) assessed for each foot | IGA score is a 5-point scale (range from 0 to 4): 0=no improvement or worsening / 1=minimal improvement / 2=moderate improvement / 3=significant improvement / 4=total disappearance | at baseline vs month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global clinical improvement on each foot assessed by a blinded centralized independent reviewer using photographs: IGA score (Improvement Global Assessment) for each foot | IGA score is a 5-point scale (range from 0 to 4): 0=no improvement or worsening / 1=minimal improvement / 2=moderate improvement / 3=significant improvement / 4=total disappearance | at baseline vs month 6 | 
| Global clinical improvement on each foot assessed by the investigator: IGA score (Improvement Global Assessment) assessed for each foot. | IGA score is a 5-point scale (range from 0 to 4): 0=no improvement or worsening / 1=minimal improvement / 2=moderate improvement / 3=significant improvement / 4=total disappearance | at month1, month 3 and month 6 respectively vs baseline | 
| Efficacy assessment concerning the number of plantar lesions clinically observed by the investigator | on each foot (erythematous and edematous areas, blisters, skin erosion, crusts) | at baseline, month 1, month 3 and month 6 | 
| Efficacy assessment on each foot of the affected plantar skin surface (blisters, erosions, erythematous and edematous areas, crusts) | calculation of this affected surface by delimiting its contours on a standardized photography using Image J software = computerized assessment by a blinded centralized independent reviewer. | at baseline, month 1, month 3 and month 6 | 
| Efficacy assessment by the patient himself, for each foot | Global improvement assessed with a 5-point score (0=no improvement or worsening / 1=minimal improvement / 2=moderate improvement / 3=significant improvement / 4=total disappearance) | at month 1, month 3, month 6 and month 9 | 
| Plantar pain assessment by the patient himself, for each foot | Plantar pain assessment , using a 0 to 10 pain EVA scale. To perform the assessment, patient is requested to be standing on one foot (assessment of pain felt for this foot using EVA scale) then, standing on the other foot (assessment of pain felt for this other foot using EVA scale). | at baseline, month 1, month 3 and month 6 | 
| Immediate tolerance during injection : | Assessment performed by the patient of the pain felt during the act for each foot, using a 0 to 10 pain EVA scale (patient interview). Assessment performed by the investigator of local adverse events (for each foot) or general adverse events, during the injections | Day 0 | 
| Mid-term and long-term tolerance | Assessment performed by the patient of local adverse events (for each foot) or general adverse events reported in the home patient's diary between the protocol visits (collected at month 1, month 3, month 6 and month 9). • Assessment performed by investigator of local adverse events (for each foot) or general adverse events, at D0 (at the end of/after the injections), M3 and M6. | Day 0, month 1, month 3 and month 6 and month 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dermatology, Rare skin diseases, epidermolysis bullosa simplex, botulinic toxin, blisters