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

NCT02960997 | Completed Phase 2 Results

• 1 other identifier: 35498
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

Conditions

Epidermolysis Bullosa Simplex; Epidermolysis Bullosa Simplex Kobner; Weber-Cockayne Syndrome

Keywords

epidermolysis bullosa simplex

Outcome Measures

Primary Outcomes (3)

• 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

Secondary Outcomes (7)

• Average Steps Per Day Assessed by FitBit® / Pedometer

  12 weeks

• Child Dermatological Quality of Life Questionnaire Score

  Week 0 and week 12 of the respective treatment period

• Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Disease Severity Scale Score

  Week 0 and week 12 of the respective treatment period

• 5-D Pruritus Scale Score

  Week 0 and week 12 of the respective treatment period

• Plantar Defect Size Using 3D Photography

  Baseline, week 12

Study Arms (2)

Sirolimus, then Placebo

EXPERIMENTAL

Participants will receive Sirolimus, 2% topical ointment for 12 weeks followed by placebo to match sirolimus for 12 weeks.

Drug: Sirolimus, 2%; Drug: Vehicle

Placebo, then Sirolimus

PLACEBO COMPARATOR

Participants will receive placebo to match sirolimus for 12 weeks followed by Sirolimus, 2% topical ointment for 12 weeks.

Drug: Sirolimus, 2%; Drug: Vehicle

Interventions

Sirolimus, 2% DRUG

Placebo, then Sirolimus; Sirolimus, then Placebo

Vehicle DRUG

Also known as: Placebo

Placebo, then Sirolimus; Sirolimus, then Placebo

Eligibility Criteria

• Age: 4 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Stanford University: lead

Study Sites (1)

Stanford University

Palo Alto, California, 94304, United States

Location

Related Publications (14)

• 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.

  PMID: 24690439 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.

  PMID: 14987264 BACKGROUND

• Lane EB, McLean WH. Keratins and skin disorders. J Pathol. 2004 Nov;204(4):355-66. doi: 10.1002/path.1643.

  PMID: 15495218 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.

  PMID: 11840159 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.

  PMID: 11821896 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.

  PMID: 25769191 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.

  PMID: 11416184 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.

  PMID: 19699613 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.

  PMID: 22588747 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.

  PMID: 24355263 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.

  PMID: 24075228 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.

  PMID: 19681875 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.

  PMID: 19995367 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.

  PMID: 25789630 BACKGROUND

MeSH Terms

Conditions

Epidermolysis Bullosa Simplex

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Epidermolysis Bullosa; Skin Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Vesiculobullous

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Joyce Teng, MD, PhD
• Organization: Stanford University

jteng3@stanford.edu

(650) 724-9627

Study Officials

• Joyce M Teng, MD, PhD

  Stanford School of Medicine

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Pediatric Dermatology

Study Record Dates

• First Submitted: June 15, 2016
• First Posted: November 10, 2016
• Study Start: May 1, 2016
• Primary Completion: December 14, 2018
• Study Completion: December 1, 2021
• Last Updated: March 9, 2022
• Results First Posted: January 30, 2020

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)