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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02960997
Recruitment Status : Completed
First Posted : November 10, 2016
Results First Posted : January 30, 2020
Last Update Posted : March 9, 2022
Sponsor:
Information provided by (Responsible Party):
Joyce Teng, 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.

Condition or disease Intervention/treatment Phase
Epidermolysis Bullosa Simplex Epidermolysis Bullosa Simplex Kobner Weber-Cockayne Syndrome Drug: Sirolimus, 2% Drug: Vehicle Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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 Start Date : May 2016
Actual Primary Completion Date : December 14, 2018
Actual Study Completion Date : December 1, 2021


Arm Intervention/treatment
Experimental: Sirolimus, then Placebo
Participants will receive Sirolimus, 2% topical ointment for 12 weeks followed by placebo to match sirolimus for 12 weeks.
Drug: Sirolimus, 2%
Drug: Vehicle
Other Name: Placebo

Placebo Comparator: Placebo, then Sirolimus
Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks.
Drug: Sirolimus, 2%
Drug: Vehicle
Other Name: Placebo




Primary Outcome Measures :
  1. Foot Health Status Questionnaire, Foot Function Domain Score [ Time Frame: 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.

  2. Foot Health Status Questionnaire, Physical Activity Domain Score [ Time Frame: 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.

  3. Trough Concentration of Sirolimus [ Time Frame: Week 12 ]
    Trough measurements were taken prior to topical sirolimus administration at the week 12 study visit.


Secondary Outcome Measures :
  1. Average Steps Per Day Assessed by FitBit® / Pedometer [ Time Frame: 12 weeks ]
    Average number of steps walked per day from baseline to the end of each treatment.

  2. Child Dermatological Quality of Life Questionnaire Score [ Time Frame: 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.

  3. Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale Score [ Time Frame: 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.

  4. 5-D Pruritus Scale Score [ Time Frame: 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.

  5. Plantar Defect Size Using 3D Photography [ Time Frame: Baseline, week 12 ]
    Plantar defect size measurements using 3D photography (% change in total defect area).

  6. Foot Plantar Pressure Measurements [ Time Frame: Baseline, week 12 ]
    Foot plantar pressure measurements before and after treatment using the Podotech Elftman Foot Scanner.

  7. Change in mTOR Pathway Inhibition [ Time Frame: 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02960997


Locations
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United States, California
Stanford University
Palo Alto, California, United States, 94304
Sponsors and Collaborators
Stanford University
Investigators
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Study Chair: Joyce M Teng, MD, PhD Stanford School of Medicine
  Study Documents (Full-Text)

Documents provided by Joyce Teng, Stanford University:
Publications:

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Responsible Party: Joyce Teng, Director of Pediatric Dermatology, Stanford University
ClinicalTrials.gov Identifier: NCT02960997    
Other Study ID Numbers: 35498
First Posted: November 10, 2016    Key Record Dates
Results First Posted: January 30, 2020
Last Update Posted: March 9, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Joyce Teng, Stanford University:
epidermolysis bullosa simplex
Additional relevant MeSH terms:
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Cockayne Syndrome
Epidermolysis Bullosa
Epidermolysis Bullosa Simplex
Skin Abnormalities
Congenital Abnormalities
Skin Diseases, Genetic
Genetic Diseases, Inborn
Skin Diseases
Skin Diseases, Vesiculobullous
Dwarfism
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Nervous System Diseases
Abnormalities, Multiple
DNA Repair-Deficiency Disorders
Metabolic Diseases
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs