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 Contact: Name: Rosa West; Phone Number: 732-652-9225; Email: rosa.west@auctapharma.com
• Study Contact Backup: Name: Wilson Chang; Phone Number: 732-640-6030; Email: wilson.chang@auctapharma.com

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
• Genders Eligible for Study: All

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: Arm 1; 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: Arm 2; 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: Arm 3; 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 proportion of subjects with a clinical response of treatment success.	At least a 2-grade improvement on the Week 12 Investigator Global Assessment (IGA) of the facial skin lesions assessed by the investigator.	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of subjects with at least 30% improvement at Week 12 as compared to Baseline in the Facial Angiofibromas Severity Index (FASI) score.	Based on lesion erythema, size, and extension	Week 12
The time to reach at least 30% improvement from Baseline in the Facial Angiofibromas Severity Index (FASI) score	Based on lesion erythema, size, and extension	Week 12
The proportion of subjects with at least 2-grade improvement as compared to Baseline in categorical lesion counts	Based on number of lesions	Week 12
The proportion of subjects with at least 2-grade improvement as compared to Baseline in lesion elevation score	Based on elevation over normal skin	Week 12
The proportion of subjects with at least 2-grade improvement as compared to Baseline in the subject self-assessment survey	Based on redness and disease-related lesions	Week 12
The proportion of subjects with an investigator assessed IGA score of clear or almost clear with at least a 2-grade improvement on the Week 12 IGA of the facial skin lesions	Based on IGA score	Week 12
Overall response of angiofibroma assessed by the investigator at Week 12 as compared to baseline based on Modified Nobel Scoring System	Based on target and non-target lesions. Minimum value of -2 and maximum value of 4 with higher score indicating better outcome.	Week 12
Overall response of angiofibroma assessed by the IRC at Week 12 compared to baseline based on Modified Nobel Scoring System	Based on target and non-target lesions Minimum value of -2 and maximum value of 4 with higher score indicating better outcome.	Week 12
The proportion of subjects with at least Moderate Improvement on Modified Nobel Scoring System assessed by the investigator at Week 12	Based on target and non-target lesions	Week 12
The proportion of subjects with at least Moderate Improvement on Modified Nobel Scoring System assessed by the IRC at Week 12	Based on target and non-target lesions	Week 12
The proportion of subjects with at least a 2-grade improvement on the Week 12 Investigator Global Assessment (IGA) of the facial skin lesions assessed by the IRC	Based on IGA Score	Week 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): March 30, 2023
• Last Update Submitted That Met QC Criteria: March 28, 2023
• Last Verified: March 1, 2023

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: Pathologic Processes; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Neoplasms, Vascular Tissue; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Hamartoma; Neoplasms, Multiple Primary; Sclerosis; Tuberous Sclerosis; Angiofibroma; 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: 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