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

Sponsor
Stanford University (Other)
Overall Status
Completed
CT.gov ID
NCT02960997
Collaborator
(none)
8
Enrollment
1
Location
2
Arms
67
Duration (Months)
0.1
Patients Per Site Per Month

Study Details

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.

Condition or Disease Intervention/Treatment Phase
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.

Study Design

Study Type:
Interventional
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 1, 2016
Actual Primary Completion Date :
Dec 14, 2018
Actual Study Completion Date :
Dec 1, 2021

Arms and Interventions

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 Names:
  • 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 Names:
  • Placebo

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. 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.

    3. Trough Concentration of Sirolimus [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 [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 [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 [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 [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 [Baseline, week 12]

      Plantar defect size measurements using 3D photography (% change in total defect area).

    6. Foot Plantar Pressure Measurements [Baseline, week 12]

      Foot plantar pressure measurements before and after treatment using the Podotech Elftman Foot Scanner.

    7. 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).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    4 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Stanford University Palo Alto California United States 94304

    Sponsors and Collaborators

    • Stanford University

    Investigators

    • Study Chair: Joyce M Teng, MD, PhD, Stanford School of Medicine

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Joyce Teng, Director of Pediatric Dermatology, Stanford University
    ClinicalTrials.gov Identifier:
    NCT02960997
    Other Study ID Numbers:
    • 35498
    First Posted:
    Nov 10, 2016
    Last Update Posted:
    Mar 9, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Joyce Teng, Director of Pediatric Dermatology, Stanford University
    epidermolysis bullosa simplex
    Additional relevant MeSH terms:
    Cockayne Syndrome
    Epidermolysis Bullosa
    Epidermolysis Bullosa Simplex
    Sirolimus

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Sirolimus, Then Placebo Placebo, Then Sirolimus
    Arm/Group 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.
    Period Title: First Intervention, 12 Weeks
    STARTED 4 4
    COMPLETED 4 4
    NOT COMPLETED 0 0
    Period Title: First Intervention, 12 Weeks
    STARTED 4 4
    COMPLETED 4 4
    NOT COMPLETED 0 0
    Period Title: First Intervention, 12 Weeks
    STARTED 4 4
    COMPLETED 4 4
    NOT COMPLETED 0 0
    Period Title: First Intervention, 12 Weeks
    STARTED 4 4
    COMPLETED 4 4
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Sirolimus, Then Placebo Placebo, Then Sirolimus Total
    Arm/Group 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. Total of all reporting groups
    Overall Participants 4 4 8
    Age (Count of Participants)
    <=18 years
    4
    100%
    4
    100%
    8
    100%
    Between 18 and 65 years
    0
    0%
    0
    0%
    0
    0%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    3
    75%
    2
    50%
    5
    62.5%
    Male
    1
    25%
    2
    50%
    3
    37.5%
    Race/Ethnicity, Customized (Count of Participants)
    White
    2
    50%
    1
    25%
    3
    37.5%
    Hispanic
    1
    25%
    3
    75%
    4
    50%
    Black
    1
    25%
    0
    0%
    1
    12.5%
    Region of Enrollment (Count of Participants)
    United States
    4
    100%
    4
    100%
    8
    100%
    Foot Health Status Questionnaire, Foot Function (score on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [score on a scale]
    51.6
    (11.16)
    51.6
    (20.90)
    51.6
    (16.76)
    Foot Health Status Questionnaire, Physical Activity (score on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [score on a scale]
    63.9
    (25.00)
    54.2
    (22.35)
    59.0
    (24.21)
    Child Dermatological Quality of Life Questionnaire (score on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [score on a scale]
    18.0
    (10.17)
    17.3
    (4.60)
    17.6
    (7.90)
    Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale (score on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [score on a scale]
    2.8
    (0.43)
    3.5
    (0.87)
    3.1
    (0.78)
    5-D Pruritus Score (score on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [score on a scale]
    15.0
    (1.87)
    11.0
    (2.35)
    13.0
    (2.92)

    Outcome Measures

    1. Primary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sirolimus Placebo
    Arm/Group Description Sirolimus, 2% topical ointment for 12 weeks Placebo to match sirolimus for 12 weeks
    Measure Participants 8 8
    Week 0
    61.7
    (26.48)
    49.3
    (20.83)
    Week 12
    60.2
    (23.37)
    56.3
    (24.09)
    2. Primary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sirolimus Placebo
    Arm/Group Description Sirolimus, 2% topical ointment for 12 weeks Placebo to match sirolimus for 12 weeks
    Measure Participants 8 8
    Week 0
    69.4
    (24.37)
    54.2
    (21.65)
    Week 12
    70.8
    (20.37)
    61.8
    (24.91)
    3. Primary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    Trough concentration of sirolimus was collected during Sirolimus treatment only, so the Placebo group is not presented in this outcome measure.
    Arm/Group Title Sirolimus
    Arm/Group Description Sirolimus, 2% topical ointment for 12 weeks
    Measure Participants 8
    Mean (Standard Deviation) [ng/mL]
    NA
    (NA)
    4. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    One participant had no Fitbit data during placebo treatment and is excluded from the analysis. Three participants lost their Fitbit devices for week 12 reporting during sirolimus treatment; their data through week 8 are included in the analysis.
    Arm/Group Title Sirolimus Placebo
    Arm/Group Description Sirolimus, 2% topical ointment for 12 weeks Placebo to match sirolimus for 12 weeks
    Measure Participants 8 7
    Mean (Standard Deviation) [steps]
    6624
    (1847)
    7130
    (3025)
    5. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sirolimus Placebo
    Arm/Group Description Sirolimus, 2% topical ointment for 12 weeks Placebo to match sirolimus for 12 weeks
    Measure Participants 8 8
    Week 0
    14.1
    (9.37)
    6.6
    (8.79)
    Week 12
    14.5
    (10.14)
    13.3
    (9.32)
    6. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sirolimus Placebo
    Arm/Group Description Sirolimus, 2% topical ointment for 12 weeks Placebo to match sirolimus for 12 weeks
    Measure Participants 8 8
    Week 0
    2.6
    (1.32)
    3.5
    (1.22)
    Week 12
    2.9
    (1.54)
    2.5
    (1.41)
    7. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sirolimus Placebo
    Arm/Group Description Sirolimus, 2% topical ointment for 12 weeks Placebo to match sirolimus for 12 weeks
    Measure Participants 8 8
    Week 0
    12.8
    (3.03)
    11.5
    (1.87)
    Week 12
    12.5
    (3.46)
    11.8
    (3.80)
    8. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    Data were not collected for this outcome measure.
    Arm/Group Title Sirolimus Placebo
    Arm/Group Description Sirolimus, 2% topical ointment for 12 weeks Placebo to match sirolimus for 12 weeks
    Measure Participants 0 0
    9. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    Data were not collected for this outcome measure.
    Arm/Group Title Sirolimus Placebo
    Arm/Group Description Sirolimus, 2% topical ointment for 12 weeks Placebo to match sirolimus for 12 weeks
    Measure Participants 0 0
    10. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    Data were not collected for this outcome measure
    Arm/Group Title Sirolimus Placebo
    Arm/Group Description Sirolimus, 2% topical ointment for 12 weeks Placebo to match sirolimus for 12 weeks
    Measure Participants 0 0

    Adverse Events

    Time Frame 32 weeks
    Adverse Event Reporting Description
    Arm/Group Title Sirolimus Placebo
    Arm/Group Description Sirolimus, 2% topical ointment for 12 weeks Placebo to match sirolimus for 12 weeks
    All Cause Mortality
    Sirolimus Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/8 (0%) 0/8 (0%)
    Serious Adverse Events
    Sirolimus Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/8 (0%) 0/8 (0%)
    Other (Not Including Serious) Adverse Events
    Sirolimus Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/8 (100%) 8/8 (100%)
    Gastrointestinal disorders
    Loose stool 0/8 (0%) 1/8 (12.5%)
    Upset stomach 0/8 (0%) 1/8 (12.5%)
    Vomiting 0/8 (0%) 1/8 (12.5%)
    General disorders
    Cough 0/8 (0%) 2/8 (25%)
    Feet pain 1/8 (12.5%) 1/8 (12.5%)
    Increased foot pain 0/8 (0%) 2/8 (25%)
    Immune system disorders
    Allergic Reaction to antiobiotic (sulfamethoxole) 0/8 (0%) 1/8 (12.5%)
    Seasonal allergies 1/8 (12.5%) 0/8 (0%)
    Infections and infestations
    Common cold 0/8 (0%) 3/8 (37.5%)
    Ear infection 2/8 (25%) 0/8 (0%)
    High fever 1/8 (12.5%) 0/8 (0%)
    Leg infected lesion 1/8 (12.5%) 0/8 (0%)
    Right footstaph infection 0/8 (0%) 1/8 (12.5%)
    Sinusitis 0/8 (0%) 1/8 (12.5%)
    Injury, poisoning and procedural complications
    Food poisioning 0/8 (0%) 1/8 (12.5%)
    Right and left leg abrasion 0/8 (0%) 1/8 (12.5%)
    Right thigh abrasion 0/8 (0%) 1/8 (12.5%)
    Renal and urinary disorders
    Painful urination 1/8 (12.5%) 0/8 (0%)
    Skin and subcutaneous tissue disorders
    Burning sensation on feet 1/8 (12.5%) 0/8 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Joyce Teng, MD, PhD
    Organization Stanford University
    Phone (650) 724-9627
    Email jteng3@stanford.edu
    Responsible Party:
    Joyce Teng, Director of Pediatric Dermatology, Stanford University
    ClinicalTrials.gov Identifier:
    NCT02960997
    Other Study ID Numbers:
    • 35498
    First Posted:
    Nov 10, 2016
    Last Update Posted:
    Mar 9, 2022
    Last Verified:
    Feb 1, 2022