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

Primary Purpose

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

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sirolimus, 2%
Vehicle
Sponsored by
Stanford University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Epidermolysis Bullosa Simplex focused on measuring epidermolysis bullosa simplex

Eligibility Criteria

4 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Stanford University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Sirolimus, then Placebo

Placebo, then Sirolimus

Arm Description

Participants will receive Sirolimus, 2% topical ointment for 12 weeks followed by placebo to match sirolimus for 12 weeks.

Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks.

Outcomes

Primary Outcome Measures

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.
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.
Trough Concentration of Sirolimus
Trough measurements were taken prior to topical sirolimus administration at the week 12 study visit.

Secondary Outcome Measures

Average Steps Per Day Assessed by FitBit® / Pedometer
Average number of steps walked per day from baseline to the end of each treatment.
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.
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.
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.
Plantar Defect Size Using 3D Photography
Plantar defect size measurements using 3D photography (% change in total defect area).
Foot Plantar Pressure Measurements
Foot plantar pressure measurements before and after treatment using the Podotech Elftman Foot Scanner.
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).

Full Information

First Posted
June 15, 2016
Last Updated
February 25, 2022
Sponsor
Stanford University
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1. Study Identification

Unique Protocol Identification Number
NCT02960997
Brief Title
Using Topical Sirolimus 2% for Patients With Epidermolysis Bullous Simplex (EBS) Study
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
May 2016 (undefined)
Primary Completion Date
December 14, 2018 (Actual)
Study Completion Date
December 1, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Stanford University

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Epidermolysis Bullosa Simplex, Epidermolysis Bullosa Simplex Kobner, Weber-Cockayne Syndrome
Keywords
epidermolysis bullosa simplex

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
8 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sirolimus, then Placebo
Arm Type
Experimental
Arm Description
Participants will receive Sirolimus, 2% topical ointment for 12 weeks followed by placebo to match sirolimus for 12 weeks.
Arm Title
Placebo, then Sirolimus
Arm Type
Placebo Comparator
Arm Description
Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Sirolimus, 2%
Intervention Type
Drug
Intervention Name(s)
Vehicle
Other Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Foot Health Status Questionnaire, Foot Function Domain Score
Description
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.
Time Frame
Week 0 and week 12 of the respective treatment period
Title
Foot Health Status Questionnaire, Physical Activity Domain Score
Description
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.
Time Frame
Week 0 and week 12 of the respective treatment period
Title
Trough Concentration of Sirolimus
Description
Trough measurements were taken prior to topical sirolimus administration at the week 12 study visit.
Time Frame
Week 12
Secondary Outcome Measure Information:
Title
Average Steps Per Day Assessed by FitBit® / Pedometer
Description
Average number of steps walked per day from baseline to the end of each treatment.
Time Frame
12 weeks
Title
Child Dermatological Quality of Life Questionnaire Score
Description
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.
Time Frame
Week 0 and week 12 of the respective treatment period
Title
Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale Score
Description
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.
Time Frame
Week 0 and week 12 of the respective treatment period
Title
5-D Pruritus Scale Score
Description
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.
Time Frame
Week 0 and week 12 of the respective treatment period
Title
Plantar Defect Size Using 3D Photography
Description
Plantar defect size measurements using 3D photography (% change in total defect area).
Time Frame
Baseline, week 12
Title
Foot Plantar Pressure Measurements
Description
Foot plantar pressure measurements before and after treatment using the Podotech Elftman Foot Scanner.
Time Frame
Baseline, week 12
Title
Change in mTOR Pathway Inhibition
Description
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).
Time Frame
Baseline, week 12

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joyce M Teng, MD, PhD
Organizational Affiliation
Stanford School of Medicine
Official's Role
Study Chair
Facility Information:
Facility Name
Stanford University
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
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Citation
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Using Topical Sirolimus 2% for Patients With Epidermolysis Bullous Simplex (EBS) Study

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