Epidermolysis Bullosa Simplex, Epidermolysis Bullosa Simplex Kobner, Weber-Cockayne Syndrome
Conditions
Keywords
epidermolysis bullosa simplex
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.
Interventions
DRUGSirolimus, 2%
DRUGVehicle
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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). |
| Foot Plantar Pressure Measurements | Baseline, week 12 | Foot plantar pressure measurements before and after treatment using the Podotech Elftman Foot Scanner. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus, Then Placebo Participants will receive Sirolimus, 2% topical ointment for 12 weeks followed by placebo to match sirolimus for 12 weeks. | 4 |
| Placebo, Then Sirolimus Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks. | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | Sirolimus, Then Placebo | Placebo, Then Sirolimus | Total |
|---|---|---|---|
| 5-D Pruritus Score | 15.0 score on a scale STANDARD_DEVIATION 1.87 | 11.0 score on a scale STANDARD_DEVIATION 2.35 | 13.0 score on a scale STANDARD_DEVIATION 2.92 |
| Age, Categorical <=18 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Child Dermatological Quality of Life Questionnaire | 18.0 score on a scale STANDARD_DEVIATION 10.17 | 17.3 score on a scale STANDARD_DEVIATION 4.6 | 17.6 score on a scale STANDARD_DEVIATION 7.9 |
| Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale | 2.8 score on a scale STANDARD_DEVIATION 0.43 | 3.5 score on a scale STANDARD_DEVIATION 0.87 | 3.1 score on a scale STANDARD_DEVIATION 0.78 |
| Foot Health Status Questionnaire, Foot Function | 51.6 score on a scale STANDARD_DEVIATION 11.16 | 51.6 score on a scale STANDARD_DEVIATION 20.9 | 51.6 score on a scale STANDARD_DEVIATION 16.76 |
| Foot Health Status Questionnaire, Physical Activity | 63.9 score on a scale STANDARD_DEVIATION 25 | 54.2 score on a scale STANDARD_DEVIATION 22.35 | 59.0 score on a scale STANDARD_DEVIATION 24.21 |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 8 / 8 | 8 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
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.
Time frame: Week 0 and week 12 of the respective treatment period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Foot Health Status Questionnaire, Foot Function Domain Score | Week 0 | 61.7 score on a scale | Standard Deviation 26.48 |
| Sirolimus | Foot Health Status Questionnaire, Foot Function Domain Score | Week 12 | 60.2 score on a scale | Standard Deviation 23.37 |
| Placebo | Foot Health Status Questionnaire, Foot Function Domain Score | Week 0 | 49.3 score on a scale | Standard Deviation 20.83 |
| Placebo | Foot Health Status Questionnaire, Foot Function Domain Score | Week 12 | 56.3 score on a scale | Standard Deviation 24.09 |
Primary
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.
Time frame: Week 0 and week 12 of the respective treatment period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Foot Health Status Questionnaire, Physical Activity Domain Score | Week 0 | 69.4 score on a scale | Standard Deviation 24.37 |
| Sirolimus | Foot Health Status Questionnaire, Physical Activity Domain Score | Week 12 | 70.8 score on a scale | Standard Deviation 20.37 |
| Placebo | Foot Health Status Questionnaire, Physical Activity Domain Score | Week 0 | 54.2 score on a scale | Standard Deviation 21.65 |
| Placebo | Foot Health Status Questionnaire, Physical Activity Domain Score | Week 12 | 61.8 score on a scale | Standard Deviation 24.91 |
Primary
Trough Concentration of Sirolimus
Trough measurements were taken prior to topical sirolimus administration at the week 12 study visit.
Time frame: Week 12
Population: Trough concentration of sirolimus was collected during Sirolimus treatment only, so the Placebo group is not presented in this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sirolimus | Trough Concentration of Sirolimus | NA ng/mL |
Secondary
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.
Time frame: Week 0 and week 12 of the respective treatment period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | 5-D Pruritus Scale Score | Week 0 | 12.8 score on a scale | Standard Deviation 3.03 |
| Sirolimus | 5-D Pruritus Scale Score | Week 12 | 12.5 score on a scale | Standard Deviation 3.46 |
| Placebo | 5-D Pruritus Scale Score | Week 0 | 11.5 score on a scale | Standard Deviation 1.87 |
| Placebo | 5-D Pruritus Scale Score | Week 12 | 11.8 score on a scale | Standard Deviation 3.8 |
Secondary
Average Steps Per Day Assessed by FitBit® / Pedometer
Average number of steps walked per day from baseline to the end of each treatment.
Time frame: 12 weeks
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Average Steps Per Day Assessed by FitBit® / Pedometer | 6624 steps | Standard Deviation 1847 |
| Placebo | Average Steps Per Day Assessed by FitBit® / Pedometer | 7130 steps | Standard Deviation 3025 |
Secondary
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).
Time frame: Baseline, week 12
Population: Data were not collected for this outcome measure
Secondary
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.
Time frame: Week 0 and week 12 of the respective treatment period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Child Dermatological Quality of Life Questionnaire Score | Week 0 | 14.1 score on a scale | Standard Deviation 9.37 |
| Sirolimus | Child Dermatological Quality of Life Questionnaire Score | Week 12 | 14.5 score on a scale | Standard Deviation 10.14 |
| Placebo | Child Dermatological Quality of Life Questionnaire Score | Week 0 | 6.6 score on a scale | Standard Deviation 8.79 |
| Placebo | Child Dermatological Quality of Life Questionnaire Score | Week 12 | 13.3 score on a scale | Standard Deviation 9.32 |
Secondary
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.
Time frame: Week 0 and week 12 of the respective treatment period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale Score | Week 0 | 2.6 score on a scale | Standard Deviation 1.32 |
| Sirolimus | Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale Score | Week 12 | 2.9 score on a scale | Standard Deviation 1.54 |
| Placebo | Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale Score | Week 0 | 3.5 score on a scale | Standard Deviation 1.22 |
| Placebo | Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale Score | Week 12 | 2.5 score on a scale | Standard Deviation 1.41 |
Secondary
Foot Plantar Pressure Measurements
Foot plantar pressure measurements before and after treatment using the Podotech Elftman Foot Scanner.
Time frame: Baseline, week 12
Population: Data were not collected for this outcome measure.
Secondary
Plantar Defect Size Using 3D Photography
Plantar defect size measurements using 3D photography (% change in total defect area).
Time frame: Baseline, week 12
Population: Data were not collected for this outcome measure.