Topical Sirolimus Ointment for Cutaneous Angiofibromas in Subjects With Tuberous Sclerosis Complex

Phase 2 Multi Center Prospective Rand. Double Blind Placebo Cont. Parallel Design Study to Evaluate Safety & Efficacy of Topical Sirolimus for Cutaneous Angiofibromas in Subjects W/ Tuberous Sclerosis Complex Followed by Opt. Open Label

The objective of this study is to evaluate the safety and efficacy of sirolimus (0.2% and 0.4% formulations) and its vehicle when applied topically once daily for 12 weeks for the treatment of cutaneous angiofibromas in pediatric subjects with tuberous sclerosis complex (TSC).

Study Overview

• Status: Terminated
• Conditions: Tuberous Sclerosis; Angiofibroma of Face
• Intervention / Treatment: Drug: Sirolimus 0.2%; Drug: Sirolimus 0.4%; Drug: Placebo ointment

Detailed Description

This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study designed to assess the safety and efficacy of topically-applied sirolimus for the treatment of cutaneous angiofibromas in pediatric subjects with TSC. Approximately 45 subjects will be enrolled at investigational sites in the United States (US) and China, though other countries may be added in the future. Approximately 45 subjects who meet the study entry criteria will randomly be assigned in a 1:1:1 ratio to receive 1 of 3 treatments: sirolimus 0.2% ointment, sirolimus 0.4% ointment, or placebo ointment. The randomization is stratified by site. Subjects, or a parent/guardian, will apply the study medication topically to the cutaneous angiofibromas on the face once daily at night before going to bed for 12 weeks. Subjects who complete the double-blind phase of the study, with an overall compliance rate >80% as determined by the dosing diary, will be offered entry into an open-label period for an additional 12 weeks.

The maximum study duration for each subject will be approximately 30 weeks and includes a screening period of up to 4 weeks, a blinded treatment period of 12 weeks, optional open-label period of 12 weeks, and a follow-up period of 2 weeks.

An interim analysis will be performed when all subjects have completed the double-blind phase (Visit 5 - Week 12). The data will be unblinded to assess for efficacy and results reported.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai, China, 201102
    • Children's Hospital of Fudan University
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • Translational Genomics Research
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital of Los Angeles, Division of Neurology
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Clinical Research Organization, Children's Hospital Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Children's Healthcare of Atlanta
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • LeBonheur Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Generally healthy males or non-pregnant females aged 2 to 21 years, inclusive, at the time of screening.
2. Diagnosis of TSC with visible facial angiofibromas of at least grade 3 up to grade 5, inclusive, based on the IGA.
3. Subjects with 3 or more isolated, measurable lesions of facial angiofibroma, with color grading score ≥2 for each of the 3 lesions.

4. Females of childbearing potential must have a negative urine pregnancy test (or a negative serum pregnancy test if a urine pregnancy test cannot be obtained) (For China, different pregnancy test would be followed) and if sexually active or become sexually active during the study, must agree to use an effective form of birth control for the duration of the study. Females using oral contraceptives must also use a barrier method of contraception during the study. Sexually active male subjects and/or their female partners should also use appropriate contraception.

   Effective contraception is defined as follows:

   • Oral/implant/injectable/transdermal/estrogenic vaginal ring contraceptives, intrauterine device, condom with spermicide, diaphragm with spermicide.
   • Abstinence or partner's vasectomy are acceptable if the female agrees to implement one of the other acceptable methods of birth control if her partner changes.
5. The subject and/or their parent or guardian must be willing and able to provide written informed consent/assent.
6. Willing and able to comply with all trial requirements.
7. Subject or parent/guardian must be able to complete the subject self-assessment survey and subject diary in English or another language into which the documents have been officially translated.

8. Subjects should be in good general health based on the subject's medical history, physical exam, and impression of the study doctor.

   Exclusion Criteria:

9. Has any chronic or acute medical condition, that in the opinion of the investigator, may pose a risk to the safety of the subject during the trial period, or may interfere with the assessment of safety or efficacy in this trial.
10. Has received oral therapy or topical therapy of an mTOR inhibitor (sirolimus, temsirolimus, or everolimus) within 1 month of Baseline or other dermatological treatment to facial angiofibromas within 1 month of baseline. (Sunscreen is expected to be used in this patient population and is not considered treatment.)
11. Is currently receiving any form of immunosuppression therapy or has previously experienced significant immune dysfunction.
12. Has a history of sensitivity to any component of the investigational product.
13. Is pregnant, plans to become pregnant during the course of the study, or is breastfeeding.
14. Has other dermatologic conditions, pigmentation, scarring, pigmented lesions or sunburn in the treatment area that would preclude or prevent adequate assessment of changes to their facial angiofibromas.
15. Has facial hair (e.g., beard, sideburns, mustache) that could interfere with study assessments.
16. Has had laser surgery or cryotherapy to facial angiofibromas within 6 months preceding study entry.
17. Requires the use of any concomitant medication that, in the investigator's opinion, has the potential to cause an adverse effect when given with the investigational product or will interfere with the interpretation of the study results (see Section 16.1 Appendix 1 for Potential Drug Interactions).
18. Has participated in another clinical trial or received an investigational product within 3 months prior to screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sirolimus 0.2%; Sirolimus 0.2% ointment applied topically hs x 12 weeks	Drug: Sirolimus 0.2%; Ointment for topical administration hs x 12 weeks; Other Names: Rapamune; rapamycin; mTOR inhibitor
Active Comparator: Sirolimus 0.4%; Sirolimus 0.4% ointment applied topically hs x 12 weeks	Drug: Sirolimus 0.4%; Ointment for topical administration hs x 12 weeks; Other Names: Rapamune; rapamycin; mTOR inhibitor
Placebo Comparator: Placebo; Placebo ointment applied topically hs x 12 weeks	Drug: Placebo ointment; Placebo ointment comparator for topical administration hs x 12 weeks; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage of Participants Achieved at Least 2-grade Improvement	The Investigator's Global Assessment (IGA) was recorded on a 5-point scale, 0 (minimum) to 5 (maximum) [0 = Clear skin with no signs of erythema and no disease related lesions, 1 = Slight redness with few disease related lesions, 2 = Greater than Grade 1; definite redness with scattered, some disease related lesions, 3 = Greater than Grade 2; marked redness, concentrated, many disease related lesions, 4 = Greater than Grade 3; very bright redness, confluent, highly concentrated disease related lesions, 5= Greater than Grade 4; fiery redness, very extensive disease related lesions covering very large area of the face]. A higher score indicates a more severe, worse outcome.	Double-blind phase and Open-label phase Weeks 4 and 12
The Change in Baseline in Investigator's Global Assessment (IGA) by Visit	The Investigator's Global Assessment (IGA) was recorded on a 5-point scale, 0 (minimum) to 5 (maximum) [0 = Clear skin with no signs of erythema and no disease related lesions, 1 = Slight redness with few disease related lesions, 2 = Greater than Grade 1; definite redness with scattered, some disease related lesions, 3 = Greater than Grade 2; marked redness, concentrated, many disease related lesions, 4 = Greater than Grade 3; very bright redness, confluent, highly concentrated disease related lesions, 5= Greater than Grade 4; fiery redness, very extensive disease related lesions covering very large area of the face]. A higher score indicates a more severe, worse outcome. Negative values indicate improvement (0 = no change, -1 = 1-point improvement, -2 = 2-point improvement)	Double-blind phase and Open-label phase Weeks 4 and 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage of Subjects With at Least 30% Improvement in the Facial Angiofibromas Severity Index (FASI) Score.	The Facial Angiofibromas Severity Index (FASI) is derived from the measurements of erythema, average size, and lesion extension. The FASI score is the sum of scores of Erythema, Size, and Extension. Erythema was recorded on a 4-point grade scale from 0 (minimum) to 4 (maximum) [0 = clear skin with no signs of erythema, 1 = almost clear; slight redness, 3= moderate erythema; marked redness, 4= severe erythema; very bright redness]. Size was recorded on a 4-point grade scale from 0 (minimum) to 4 (maximum) [0 = no lesions, 1= few lesions, average size </= 2mm, 2 = scattered, some lesions, average lesion size >2-to </= 5 mm, 3 = concentrated, many lesions, average lesion size > 5mmg to </= 10mm, 4 = confluent, highly concentrated lesions]. Extension was recorded on a grade scale of 0 (minimum), 2, and 3 (maximum) [0 = no lesions, 2 = </= 50% of the cheek surface, 3 = >50% of the cheek surface]. A higher score for Erythema, Size, and Extension means a more severe, worse outcome.	Double-blind phase Weeks 4 and 12 and Open-label phase Week 12
Facial Angifibromas Severity Index (FASI) Score	The Facial Angiofibromas Severity Index (FASI) is derived from the measurements of erythema, average size, and lesion extension. The FASI score is the sum of scores of Erythema, Size, and Extension. Erythema was recorded on a 4-point grade scale from 0 (minimum) to 4 (maximum) [0 = clear skin with no signs of erythema, 1 = almost clear; slight redness, 3= moderate erythema; marked redness, 4= severe erythema; very bright redness]. Size was recorded on a 4-point grade scale from 0 (minimum) to 4 (maximum) [0 = no lesions, 1= few lesions, average size </= 2mm, 2 = scattered, some lesions, average lesion size >2-to </= 5 mm, 3 = concentrated, many lesions, average lesion size > 5mmg to </= 10mm, 4 = confluent, highly concentrated lesions]. Extension was recorded on a grade scale of 0 (minimum), 2, and 3 (maximum) [0 = no lesions, 2 = </= 50% of the cheek surface, 3 = >50% of the cheek surface]. A higher score for Erythema, Size, and Extension means a more severe, worse outcome.	Baseline, Double blind phase weeks 4 and 12 and Open-label week 12
The Percentage of Subjects Achieved at Least 2-grade Improvement in Categorical Lesion Counts by Visit	Lesion counts are measured based on categories 0 to 4 [0 = no lesion, 1 = <25 lesions, 2 = 25 to 50 lesions, 3 = 51 to 75 lesions, 4 = > 75 lesions]	Double blind phase Weeks 4 and 12 and Open-label phase Week 12
Change From Baseline in Lesion Counts	Lesion counts are measured based on categories 0 to 4 (0 = no lesion, 1 = <25 lesions, 2 = 25 to 50 lesions, 3 = 51 to 75 lesions, 4 = > 75 lesions) Negative values indicate improvement (0 = no change, -1 = 1-point improvement, -2 = 2-point improvement)	Double blind phase weeks 4 and 12 and open-label phase week 12
The Percentage of Subjects Achieved at Least 2-grade Improvement in Lesion Elevation.	The degree of lesion elevation is assessed on categories 0 to 4 (0 = no elevation over normal skin, 1 = possible but difficult to ascertain whether there is slight elevation above normal skin, 2 = slight but definite elevation, 3 = moderate elevation, 4 = marked elevation).	Double blind phase weeks 4 and 12 and open-label phase week 12
The Change From Baseline in Lesion Elevation	The degree of lesion elevation is assessed on categories 0 to 4 (0 = no elevation over normal skin, 1 = possible but difficult to ascertain whether there is slight elevation above normal skin, 2 = slight but definite elevation, 3 = moderate elevation, 4 = marked elevation) Negative values indicate improvement (0 = no change, -1 = 1-point improvement, -2 = 2-point improvement) One participant with baseline elevation grade of 1 improved to grade 0 at week 4. This participant is counted as improvement in lesion elevation. This participant was back to grade 1 at week 12 and open-label week 12.	Double blind phase weeks 4 and 12 and open-label phase week 12
The Percentage of Subjects Achieved at Least 2-grade Improvement in the Subject Self-assessment Survey	Subject self- assessment survey was based on categories 0 to 4 (0 = no redness and no disease related lesions, 1 = very mild redness with few very small bumps, 2 = mild redness with many small and medium sized bumps, 3 = moderate redness with many small and medium sized bumps, 4 = severe redness with numerous small, medium, and large sized bumps)	Double blind phase weeks 4 and 12 and open-label phase weeks 4 and 12
Change From Baseline in Self-Assessment	Subject self- assessment survey was based on categories 0 to 4 (0 = no redness and no disease related lesions, 1 = very mild redness with few very small bumps, 2 = mild redness with many small and medium sized bumps, 3 = moderate redness with many small and medium sized bumps, 4 = severe redness with numerous small, medium, and large sized bumps) Negative values indicate improvement (0 = no change, -1 = 1-point improvement, -2 = 2-point improvement)	Double blind phase weeks 4 and 12 and open label phase weeks 4 and 12

Collaborators and Investigators

• Sponsor: Aucta Pharmaceuticals, Inc
• Investigators: Study Director: Shoufeng Li, Ph.D, Aucta Pharmaceuticals, Inc

Publications and helpful links

General Publications

• Koenig MK, Hebert AA, Roberson J, Samuels J, Slopis J, Woerner A, Northrup H. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. Drugs R D. 2012 Sep 1;12(3):121-6. doi: 10.2165/11634580-000000000-00000.
• Wheless JW, Almoazen H. A novel topical rapamycin cream for the treatment of facial angiofibromas in tuberous sclerosis complex. J Child Neurol. 2013 Jul;28(7):933-6. doi: 10.1177/0883073813488664. Epub 2013 May 16.
• Wataya-Kaneda M, Tanaka M, Nakamura A, Matsumoto S, Katayama I. A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis complex (TSC): a pilot study of nine Japanese patients with TSC of different disease severity. Br J Dermatol. 2011 Oct;165(4):912-6. doi: 10.1111/j.1365-2133.2011.10471.x.
• Tanaka M, Wataya-Kaneda M, Nakamura A, Matsumoto S, Katayama I. First left-right comparative study of topical rapamycin vs. vehicle for facial angiofibromas in patients with tuberous sclerosis complex. Br J Dermatol. 2013 Dec;169(6):1314-8. doi: 10.1111/bjd.12567.
• Rapamune (sirolimus) complete prescribing information. Wyeth Pharmaceuticals Inc. October 2009

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2017
• Primary Completion (Actual): March 24, 2023
• Study Completion (Actual): March 24, 2023

Study Registration Dates

• First Submitted: December 1, 2017
• First Submitted That Met QC Criteria: December 1, 2017
• First Posted (Actual): December 6, 2017

Study Record Updates

• Last Update Posted (Actual): December 1, 2025
• Last Update Submitted That Met QC Criteria: November 17, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: skin; facial; erythema; papules; lesions; rash; face; fibroma; bumps; redness; blood vessel; cheeks
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Neoplasms; Disease Attributes; Genetic Diseases, Inborn; Neoplasms by Histologic Type; Skin Manifestations; Neurodegenerative Diseases; Skin Diseases; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Hamartoma; Neoplasms, Multiple Primary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neoplasms, Fibrous Tissue; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Signs and Symptoms; Tuberous Sclerosis; Facies; Fibroma; Erythema; Exanthema; Organic Chemicals; Macrolides; Lactones; Sirolimus
• Other Study ID Numbers: AUCTA-UAP006-PH2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No