Injections of Botulinic Toxin in Plantar Lesions of Localized Epidermolysis Bullosa Simplex (EBTox)

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.

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).

Study Overview

• Status: Recruiting
• Conditions: Epidermolysis Bullosa Simplex
• Intervention / Treatment: Drug: Botulinic toxin; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Juliette Mazereeuw-Hautier, MD; Phone Number: 33 5 67 77 81 41; Email: mazereeuw-hautier.j@chu-toulouse.fr
• Study Contact Backup: Name: Isabelle DREYFUS, PharmD; Phone Number: 33 5 67 77 81 10; Email: dreyfus.i@chu-toulouse.fr

Study Locations

• France
  • Bordeaux, France, 33000
    • Recruiting
    • University Hospital Bordeaux
    • Contact: Olivier COGREL, MD
  • Nice, France, 06000
    • Recruiting
    • University Hospital NICE
    • Contact: Christine CHIAVERINI, MD
  • Paris, France, 75000
    • Recruiting
    • Saint-Louis Hospital - APHP
    • Contact: Emmanuel Bourrat, MD
  • Toulouse, France, 31059
    • Recruiting
    • Hôpital Larrey - CHU Toulouse
    • Contact: Juliette Mazereeuw-Hautier, Pr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Botulinic toxin; Injections of botulinic toxin (Dysport®, Allergan) 200 UI	Drug: Botulinic toxin; 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; Other Names: Dysport® (experimental drug)
Placebo Comparator: Placebo; Injections of physiological serum	Drug: Placebo; 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; Other Names: physiological serum

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Juliette Mazereeuw-Hautier, MD, University Hospital, Toulouse

Publications and helpful links

General Publications

• Fine JD, Bruckner-Tuderman L, Eady RA, Bauer EA, Bauer JW, Has C, Heagerty A, Hintner H, Hovnanian A, Jonkman MF, Leigh I, Marinkovich MP, Martinez AE, McGrath JA, Mellerio JE, Moss C, Murrell DF, Shimizu H, Uitto J, Woodley D, Zambruno G. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol. 2014 Jun;70(6):1103-26. doi: 10.1016/j.jaad.2014.01.903. Epub 2014 Mar 29.
• Sprecher E. Epidermolysis bullosa simplex. Dermatol Clin. 2010 Jan;28(1):23-32. doi: 10.1016/j.det.2009.10.003.
• Langan SM, Williams HC. A systematic review of randomized controlled trials of treatments for inherited forms of epidermolysis bullosa. Clin Exp Dermatol. 2009 Jan;34(1):20-5. doi: 10.1111/j.1365-2230.2008.02789.x. Epub 2008 Sep 25.
• Abitbol RJ, Zhou LH. Treatment of epidermolysis bullosa simplex, Weber-Cockayne type, with botulinum toxin type A. Arch Dermatol. 2009 Jan;145(1):13-5. doi: 10.1001/archdermatol.2008.546. No abstract available.
• Schwieger-Briel A, Chakkittakandiyil A, Lara-Corrales I, Aujla N, Lane AT, Lucky AW, Bruckner AL, Pope E. Instrument for scoring clinical outcome of research for epidermolysis bullosa: a consensus-generated clinical research tool. Pediatr Dermatol. 2015 Jan-Feb;32(1):41-52. doi: 10.1111/pde.12317. Epub 2014 Mar 20.

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2018
• Primary Completion (Estimated): September 1, 2023
• Study Completion (Estimated): December 1, 2023

Study Registration Dates

• First Submitted: February 6, 2018
• First Submitted That Met QC Criteria: February 26, 2018
• First Posted (Actual): March 5, 2018

Study Record Updates

• Last Update Posted (Actual): August 23, 2023
• Last Update Submitted That Met QC Criteria: August 22, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Dermatology; epidermolysis bullosa simplex; Rare skin diseases; botulinic toxin; blisters
• Additional Relevant MeSH Terms: Skin Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Skin Diseases, Genetic; Skin Diseases, Vesiculobullous; Skin Abnormalities; Epidermolysis Bullosa; Epidermolysis Bullosa Simplex; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; abobotulinumtoxinA
• Other Study ID Numbers: RC31/16/8917; 2017-002332-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No