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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sirolimus, then Placebo | Experimental | Participants will receive Sirolimus, 2% topical ointment for 12 weeks followed by placebo to match sirolimus for 12 weeks. |
|
| Placebo, then Sirolimus | Placebo Comparator | Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sirolimus, 2% | Drug |
| ||
| Vehicle |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Week 0 and week 12 of the respective treatment period |
| 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. | Week 0 and week 12 of the respective treatment period |
| Trough Concentration of Sirolimus | Trough measurements were taken prior to topical sirolimus administration at the week 12 study visit. | Week 12 |
| Measure | Description | Time Frame |
|---|---|---|
| Average Steps Per Day Assessed by FitBit® / Pedometer | Average number of steps walked per day from baseline to the end of each treatment. | 12 weeks |
| Child Dermatological Quality of Life Questionnaire Score |
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Inclusion Criteria:
Subjects must:
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:
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
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| Name | Affiliation | Role |
|---|---|---|
| Joyce M Teng, MD, PhD | Stanford School of Medicine | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford University | Palo Alto | California | 94304 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24690439 | Background | Fine JD, Bruckner-Tuderman L, Eady RA, Bauer EA, Bauer JW, Has C, Heagerty A, Hintner H, Hovnanian A, Jonkman MF, Leigh I, Marinkovich MP, Martinez AE, McGrath JA, Mellerio JE, Moss C, Murrell DF, Shimizu H, Uitto J, Woodley D, Zambruno G. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol. 2014 Jun;70(6):1103-26. doi: 10.1016/j.jaad.2014.01.903. Epub 2014 Mar 29. | |
| 14987264 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Sirolimus, Then Placebo | Participants will receive Sirolimus, 2% topical ointment for 12 weeks followed by placebo to match sirolimus for 12 weeks. |
| FG001 | Placebo, Then Sirolimus | Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention, 12 Weeks |
| |||||||||||||
| Washout Period, 4 Weeks |
| |||||||||||||
| Second Treatment, 12 Weeks |
| |||||||||||||
| Follow-up Period, 4 Weeks |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Sirolimus, Then Placebo | Participants will receive Sirolimus, 2% topical ointment for 12 weeks followed by placebo to match sirolimus for 12 weeks. |
| BG001 | Placebo, Then Sirolimus |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Deviation | score on a scale | Week 0 and week 12 of the respective treatment period |
|
32 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sirolimus | Sirolimus, 2% topical ointment for 12 weeks | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Allergic Reaction to antiobiotic (sulfamethoxole) | Immune system disorders | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Joyce Teng, MD, PhD | Stanford University | (650) 724-9627 | jteng3@stanford.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 7, 2017 | Dec 11, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D016110 | Epidermolysis Bullosa Simplex |
| ID | Term |
|---|---|
| D004820 | Epidermolysis Bullosa |
| D012868 | Skin Abnormalities |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| ID | Term |
|---|---|
| D020123 | Sirolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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| Drug |
|
|
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.
| Week 0 and week 12 of the respective treatment period |
| 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. | Week 0 and week 12 of the respective treatment period |
| 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. | Week 0 and week 12 of the respective treatment period |
| Plantar Defect Size Using 3D Photography | Plantar defect size measurements using 3D photography (% change in total defect area). | Baseline, week 12 |
| Foot Plantar Pressure Measurements | Foot plantar pressure measurements before and after treatment using the Podotech Elftman Foot Scanner. | Baseline, week 12 |
| 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). | Baseline, week 12 |
| Background |
| Fine JD, Johnson LB, Weiner M, Suchindran C. Assessment of mobility, activities and pain in different subtypes of epidermolysis bullosa. Clin Exp Dermatol. 2004 Mar;29(2):122-7. doi: 10.1111/j.1365-2230.2004.01428.x. |
| 15495218 | Background | Lane EB, McLean WH. Keratins and skin disorders. J Pathol. 2004 Nov;204(4):355-66. doi: 10.1002/path.1643. |
| 11840159 | Background | Castedo M, Ferri KF, Kroemer G. Mammalian target of rapamycin (mTOR): pro- and anti-apoptotic. Cell Death Differ. 2002 Feb;9(2):99-100. doi: 10.1038/sj.cdd.4400978. No abstract available. |
| 11821896 | Background | Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002 Feb;8(2):128-35. doi: 10.1038/nm0202-128. |
| 25769191 | Background | Fogel AL, Hill S, Teng JM. Advances in the therapeutic use of mammalian target of rapamycin (mTOR) inhibitors in dermatology. J Am Acad Dermatol. 2015 May;72(5):879-89. doi: 10.1016/j.jaad.2015.01.014. Epub 2015 Mar 11. |
| 11416184 | Background | Raught B, Gingras AC, Sonenberg N. The target of rapamycin (TOR) proteins. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7037-44. doi: 10.1073/pnas.121145898. |
| 19699613 | Background | Hickerson RP, Leake D, Pho LN, Leachman SA, Kaspar RL. Rapamycin selectively inhibits expression of an inducible keratin (K6a) in human keratinocytes and improves symptoms in pachyonychia congenita patients. J Dermatol Sci. 2009 Nov;56(2):82-8. doi: 10.1016/j.jdermsci.2009.07.008. Epub 2009 Aug 21. |
| 22588747 | Background | Riskowski JL, Hagedorn TJ, Hannan MT. Measures of foot function, foot health, and foot pain: American Academy of Orthopedic Surgeons Lower Limb Outcomes Assessment: Foot and Ankle Module (AAOS-FAM), Bristol Foot Score (BFS), Revised Foot Function Index (FFI-R), Foot Health Status Questionnaire (FHSQ), Manchester Foot Pain and Disability Index (MFPDI), Podiatric Health Questionnaire (PHQ), and Rowan Foot Pain Assessment (ROFPAQ). Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11(0 11):S229-39. doi: 10.1002/acr.20554. No abstract available. |
| 24355263 | Background | Loh CC, Kim J, Su JC, Daniel BS, Venugopal SS, Rhodes LM, Intong LR, Law MG, Murrell DF. Development, reliability, and validity of a novel Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI). J Am Acad Dermatol. 2014 Jan;70(1):89-97.e1-13. doi: 10.1016/j.jaad.2013.09.041. |
| 24075228 | Background | Venugopal SS, Yan W, Frew JW, Cohn HI, Rhodes LM, Tran K, Melbourne W, Nelson JA, Sturm M, Fogarty J, Marinkovich MP, Igawa S, Ishida-Yamamoto A, Murrell DF. A phase II randomized vehicle-controlled trial of intradermal allogeneic fibroblasts for recessive dystrophic epidermolysis bullosa. J Am Acad Dermatol. 2013 Dec;69(6):898-908.e7. doi: 10.1016/j.jaad.2013.08.014. Epub 2013 Sep 24. |
| 19681875 | Background | Frew JW, Martin LK, Nijsten T, Murrell DF. Quality of life evaluation in epidermolysis bullosa (EB) through the development of the QOLEB questionnaire: an EB-specific quality of life instrument. Br J Dermatol. 2009 Dec;161(6):1323-30. doi: 10.1111/j.1365-2133.2009.09347.x. Epub 2009 Jun 11. |
| 19995367 | Background | Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus. Br J Dermatol. 2010 Mar;162(3):587-93. doi: 10.1111/j.1365-2133.2009.09586.x. Epub 2009 Dec 1. |
| 25789630 | Background | Storm FA, Heller BW, Mazza C. Step detection and activity recognition accuracy of seven physical activity monitors. PLoS One. 2015 Mar 19;10(3):e0118723. doi: 10.1371/journal.pone.0118723. eCollection 2015. |
| NOT COMPLETED |
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| NOT COMPLETED |
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| NOT COMPLETED |
|
Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks.
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Foot Health Status Questionnaire, Foot Function | 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 according to randomization group. | Mean | Standard Deviation | score on a scale |
|
| Foot Health Status Questionnaire, Physical Activity | 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 according to randomization group. | Mean | Standard Deviation | score on a scale |
|
| Child Dermatological Quality of Life Questionnaire | Quality of Life-Epidermolysis Bullosa (QOLEB) scores range from 0 to 51; higher scores indicate greater impact of EB on quality of life. Data are reported according to randomization group. | Mean | Standard Deviation | score on a scale |
|
| Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale | Scores range from 0 (absent of EB) to 10 (entire area involved). Data are reported according to randomization group. | Mean | Standard Deviation | score on a scale |
|
| 5-D Pruritus Score | Total score ranges from 5 (least affected) to 25 (most affected). Data are reported according to randomization group. | Mean | Standard Deviation | score on a scale |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| 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. | Posted | Mean | Standard Deviation | score on a scale | Week 0 and week 12 of the respective treatment period |
|
|
|
| Primary | Trough Concentration of Sirolimus | Trough measurements were taken prior to topical sirolimus administration at the week 12 study visit. | Trough concentration of sirolimus was collected during Sirolimus treatment only, so the Placebo group is not presented in this outcome measure. | Posted | Mean | Standard Deviation | ng/mL | Week 12 |
|
|
|
| Secondary | Average Steps Per Day Assessed by FitBit® / Pedometer | Average number of steps walked per day from baseline to the end of each treatment. | 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. | Posted | Mean | Standard Deviation | steps | 12 weeks |
|
|
|
| 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. | Posted | Mean | Standard Deviation | score on a scale | Week 0 and week 12 of the respective treatment period |
|
|
|
| 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. | Posted | Mean | Standard Deviation | score on a scale | Week 0 and week 12 of the respective treatment period |
|
|
|
| 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. | Posted | Mean | Standard Deviation | score on a scale | Week 0 and week 12 of the respective treatment period |
|
|
|
| Secondary | Plantar Defect Size Using 3D Photography | Plantar defect size measurements using 3D photography (% change in total defect area). | Data were not collected for this outcome measure. | Posted | Baseline, week 12 |
|
|
| Secondary | Foot Plantar Pressure Measurements | Foot plantar pressure measurements before and after treatment using the Podotech Elftman Foot Scanner. | Data were not collected for this outcome measure. | Posted | Baseline, week 12 |
|
|
| 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). | Data were not collected for this outcome measure | Posted | Baseline, week 12 |
|
|
| 8 |
| 0 |
| 8 |
| 8 |
| 8 |
| EG001 | Placebo | Placebo to match sirolimus for 12 weeks | 0 | 8 | 0 | 8 | 8 | 8 |
| Burning sensation on feet | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Common cold | Infections and infestations | Systematic Assessment |
|
| Cough | General disorders | Systematic Assessment |
|
| Ear infection | Infections and infestations | Systematic Assessment | 1 event occurred during the follow-up period |
|
| Feet pain | General disorders | Systematic Assessment |
|
| Food poisioning | Injury, poisoning and procedural complications | Systematic Assessment |
|
| High fever | Infections and infestations | Systematic Assessment |
|
| Increased foot pain | General disorders | Systematic Assessment |
|
| Leg infected lesion | Infections and infestations | Systematic Assessment |
|
| Loose stool | Gastrointestinal disorders | Systematic Assessment |
|
| Painful urination | Renal and urinary disorders | Systematic Assessment |
|
| Right and left leg abrasion | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Right footstaph infection | Infections and infestations | Systematic Assessment |
|
| Right thigh abrasion | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Seasonal allergies | Immune system disorders | Systematic Assessment |
|
| Sinusitis | Infections and infestations | Systematic Assessment |
|
| Upset stomach | Gastrointestinal disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
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| D012873 | Skin Diseases, Genetic |
| D030342 | Genetic Diseases, Inborn |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D012872 | Skin Diseases, Vesiculobullous |