Using Topical Sirolimus 2% for Patients With Epidermolysis Bullous Simplex (EBS) Study

Study Overview
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Brief Summary
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Epidermolysis bullosa (EB) simplex is a rare orphan disease caused by a mutation in DNA leading to abnormal dominant keratins in the skin. Patients with EB simplex develop lifelong painful thick soles on their feet, and current standard of care is supportive. This pilot study will target the dominant mutant keratin proteins in the skin to ameliorate the severity of EB simplex. The purpose is to improve the function of EB simplex feet with an application of topical sirolimus, 2%. The investigators plan on inhibiting the mTOR pathway to down regulate the translation of defective keratin proteins and work through anti proliferative pathways.

Detailed Description
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The proposed 40 week pilot study being conducted is a prospective, double-blind, randomized, placebo-controlled crossover study. Participants will be assigned to treat both feet with either topical sirolimus, 2% cream daily or placebo (vehicle-control) for 12 weeks, followed by a 4 week washout period, then re-treatment to both feet will occur by the cross-over intervention. These studies will exploit the naturally occurring transcriptional regulation of keratin sequences, the known gene aberration causing EB simplex, and assess the potential for mTOR pathway inhibition in treatment of the patient's plantar lesions. The objective of this study is to assess (1) the safety of topical rapamycin for plantar lesions for the treatment of EB simplex, and 2) test if topical rapamycin to improves the clinical severity of lesional skin, including pain and itch, in subjects with EB simplex at the end of treatment versus baseline and compared to an intrasubject placebo treated control. Wound size measurement, quality of life evaluation will be assessed using epidermolysis bullosa (QOLEB), and EB disease activity and Scarring Index (EBDASI). With the results of this pilot study, physicians would be able to transition from supportive care (the current state of the art for EB simplex) to targeted molecular therapeutics, leading to improved mobility and quality of life for patients with EB simplex.

Official Title
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A Prospective, Double-Blind, Cross-Over, Pilot Study to Assess Safety and Efficacy of Topical Sirolimus 2% in the Treatment of Plantar Blistering in Patients With Epidermolysis Bullous Simplex (EBS)

Conditions
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Epidermolysis Bullosa Simplex, Epidermolysis Bullosa Simplex Kobner, Weber-Cockayne Syndrome

Intervention / Treatment
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* Drug: Sirolimus, 2%
* Drug: Vehicle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must: Be capable of understanding the purpose and risks of the study and sign a written Informed Consent Form (ICF); Legally authorized representative of subjects willing and able to give consent for children 4-18 yo. Be male or female with a diagnosis of EBS Minimum EBDASI feet activity score of 2/10 Age - 4 years or older Ability to complete 12 study visits within a 40-week period, each for approximately 30-60 minutes. Anticipated life expectancy ≥52 weeks. Males and females of childbearing potential should be using an effective means of contraception. Laboratory values within the range of normal for the participating institution unless the PI feels they are not clinically relevant Be able to comply with all study requirements Exclusion Criteria: Allergy to sirolimus or components of the vehicle ointment Pregnancy, breast feeding Prior history of liver disease Serious known concurrent medical illness or infection, which could potentially present a safety risk and/or prevent compliance with the requirements of the treatment program. Known immunodeficiency virus or syndrome including those with: Acquired Immunodeficiency Syndrome (AIDS) Human Immunodeficiency Virus (HIV) Hepatitis B Prior history of grafting surgeries or other surgeries in the dermatologic treatment area History of significant condition in the dermatologic treatment area such as trauma, which could impair evaluation for the treatment of EBS or non-healing chronic wound. Use of other investigational drugs within 30 days of the screening visit and/or has not recovered from any side effects of prior investigational drugs or procedure in the affected area (e.g., a biopsy). Use of acitretin within the last 1 month Use of Roaccutane within last 3 months Botox injections to the feet within the last 6 months. Participant is planning extra physical activities within the next 3 months. Amputated foot

Ages Eligible for Study
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Minimum Age: 4 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus, then Placebo<br>Participants will receive Sirolimus, 2% topical ointment for 12 weeks followed by placebo to match sirolimus for 12 weeks. | Drug: Sirolimus, 2%<br> <br> Drug: Vehicle<br> <br> * Other names: Placebo;|
| Placebo Comparator: Placebo, then Sirolimus<br>Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks. | Drug: Sirolimus, 2%<br> <br> Drug: Vehicle<br> <br> * Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Foot Health Status Questionnaire, Foot Function Domain Score | Foot function was assessed utilizing the validated Foot Health Status Questionnaire (FHSQ). Low Score (0) means severely limited in performing a broad range of physical activities. High Score (100) means can perform all desired physical activities. Data are reported per intervention. | Week 0 and week 12 of the respective treatment period | 
| Foot Health Status Questionnaire, Physical Activity Domain Score | Physical Activity was assessed utilizing the validated Foot Health Status Questionnaire (FHSQ). Low Score (0) means severely limited in performing a broad range of physical activities. High Score (100) means can perform all desired physical activities. Data are reported per intervention. | Week 0 and week 12 of the respective treatment period | 
| Trough Concentration of Sirolimus | Trough measurements were taken prior to topical sirolimus administration at the week 12 study visit. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Steps Per Day Assessed by FitBit® / Pedometer | Average number of steps walked per day from baseline to the end of each treatment. | 12 weeks | 
| Child Dermatological Quality of Life Questionnaire Score | Quality of Life-Epidermolysis Bullosa (QOLEB) Questionnaire specifically designed for people with EB. The QOLEB can be used to identify everyday life occurrences negatively affected by EB. It assesses change in quality of life over time, an important measure when assessing the success of new treatments for EB. Scores from 0 to 51, with higher scores indicate greater impact of EB on quality of life. Data are reported per intervention. | Week 0 and week 12 of the respective treatment period | 
| Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale Score | The EBDASI is a validated scoring system that objectively quantifies the severity of EB affecting the entire body. It has been designed to evaluate the response to new therapies for the treatment of EB. Scores range from 0 (absent of EB) to 10 (entire area involved). Data are reported per intervention. | Week 0 and week 12 of the respective treatment period | 
| 5-D Pruritus Scale Score | The 5-D Pruritus Scale is a 1-page, 5-question tool used in clinical trials to assess 5 dimensions of background itch: degree, duration, direction, disability, and distribution. Each question corresponds to 1 of the 5 dimensions of itch; participants were to rate their symptoms over the preceding 2-week period on a 1 to 5 scale, with 5 being the most affected. After the summation of individual score, the total score ranges from 5 (least affected) to 25 (most affected). Data are reported per intervention. | Week 0 and week 12 of the respective treatment period | 
| Plantar Defect Size Using 3D Photography | Plantar defect size measurements using 3D photography (% change in total defect area). | Baseline, week 12 | 
| Foot Plantar Pressure Measurements | Foot plantar pressure measurements before and after treatment using the Podotech Elftman Foot Scanner. | Baseline, week 12 | 
| Change in mTOR Pathway Inhibition | Molecular biology study of skin biopsies assayed for mTOR pathway inhibition (e.g. determination of phosphoprotein inhibition included ribosomal protein S6, S6 kinase and/or eIF-4E binding protein). | Baseline, week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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epidermolysis bullosa simplex