- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02960997
Using Topical Sirolimus 2% for Patients With Epidermolysis Bullous Simplex (EBS) Study
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 Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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California
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Palo Alto, California, United States, 94304
- Stanford University
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Triple
Arms and Interventions
Participant Group / 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.
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Other Names:
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Placebo Comparator: Placebo, then Sirolimus
Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks.
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Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Foot Health Status Questionnaire, Foot Function Domain Score
Time Frame: Week 0 and week 12 of the respective treatment period
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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.
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Week 0 and week 12 of the respective treatment period
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Foot Health Status Questionnaire, Physical Activity Domain Score
Time Frame: Week 0 and week 12 of the respective treatment period
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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.
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Week 0 and week 12 of the respective treatment period
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Trough Concentration of Sirolimus
Time Frame: Week 12
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Trough measurements were taken prior to topical sirolimus administration at the week 12 study visit.
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Week 12
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Average Steps Per Day Assessed by FitBit® / Pedometer
Time Frame: 12 weeks
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Average number of steps walked per day from baseline to the end of each treatment.
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12 weeks
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Child Dermatological Quality of Life Questionnaire Score
Time Frame: Week 0 and week 12 of the respective treatment period
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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.
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Week 0 and week 12 of the respective treatment period
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Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale Score
Time Frame: Week 0 and week 12 of the respective treatment period
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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.
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Week 0 and week 12 of the respective treatment period
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5-D Pruritus Scale Score
Time Frame: Week 0 and week 12 of the respective treatment period
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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.
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Week 0 and week 12 of the respective treatment period
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Plantar Defect Size Using 3D Photography
Time Frame: Baseline, week 12
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Plantar defect size measurements using 3D photography (% change in total defect area).
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Baseline, week 12
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Foot Plantar Pressure Measurements
Time Frame: Baseline, week 12
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Foot plantar pressure measurements before and after treatment using the Podotech Elftman Foot Scanner.
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Baseline, week 12
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Change in mTOR Pathway Inhibition
Time Frame: Baseline, week 12
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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).
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Baseline, week 12
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Collaborators and Investigators
Sponsor
Investigators
- Study Chair: Joyce M Teng, MD, PhD, Stanford School of Medicine
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
- 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.
- Lane EB, McLean WH. Keratins and skin disorders. J Pathol. 2004 Nov;204(4):355-66. doi: 10.1002/path.1643.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. Erratum In: Br J Dermatol. 2010 Mar;162(3):701.
- 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.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Metabolic Diseases
- Nervous System Diseases
- Skin Diseases
- Congenital Abnormalities
- Genetic Diseases, Inborn
- Musculoskeletal Diseases
- Neurodegenerative Diseases
- Skin Diseases, Genetic
- Bone Diseases
- Heredodegenerative Disorders, Nervous System
- Skin Diseases, Vesiculobullous
- DNA Repair-Deficiency Disorders
- Skin Abnormalities
- Abnormalities, Multiple
- Dwarfism
- Bone Diseases, Developmental
- Epidermolysis Bullosa
- Epidermolysis Bullosa Simplex
- Cockayne Syndrome
- Physiological Effects of Drugs
- Anti-Infective Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antifungal Agents
- Sirolimus
Other Study ID Numbers
- 35498
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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