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

Phase 2

Completed

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

Interventions: Drug: Sirolimus, 2%
Drug: Vehicle

Registration Number: NCT02960997

Lead Sponsor: Stanford University

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 8

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sirolimus, then Placebo	Vehicle	Participants will receive Sirolimus, 2% topical ointment for 12 weeks followed by placebo to match sirolimus for 12 weeks.
Placebo, then Sirolimus	Sirolimus, 2%	Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks.
Placebo, then Sirolimus	Vehicle	Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks.
Sirolimus, then Placebo	Sirolimus, 2%	Participants will receive Sirolimus, 2% topical ointment for 12 weeks followed by placebo to match sirolimus for 12 weeks.

Primary Outcome Measures

Name	Time	Method
Foot Health Status Questionnaire, Physical Activity Domain Score	Week 0 and week 12 of the respective treatment period	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.
Trough Concentration of Sirolimus	Week 12	Trough measurements were taken prior to topical sirolimus administration at the week 12 study visit.
Foot Health Status Questionnaire, Foot Function Domain Score	Week 0 and week 12 of the respective treatment period	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.

Secondary Outcome Measures

Name	Time	Method
Child Dermatological Quality of Life Questionnaire Score	Week 0 and week 12 of the respective treatment period	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.
Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale Score	Week 0 and week 12 of the respective treatment period	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.
Average Steps Per Day Assessed by FitBit® / Pedometer	12 weeks	Average number of steps walked per day from baseline to the end of each treatment.
Foot Plantar Pressure Measurements	Baseline, week 12	Foot plantar pressure measurements before and after treatment using the Podotech Elftman Foot Scanner.
5-D Pruritus Scale Score	Week 0 and week 12 of the respective treatment period	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.
Plantar Defect Size Using 3D Photography	Baseline, week 12	Plantar defect size measurements using 3D photography (% change in total defect area).
Change in mTOR Pathway Inhibition	Baseline, week 12	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).