Dose-Ranging Efficacy and Safety Study of Topical Rapamycin Cream for Facial Angiofibroma Associated With Tuberous Sclerosis Complex

A Phase 2/3, Multi-Center, Double-Blind, Placebo-Controlled, Randomized, Parallel-Group, Dose-Response Comparison of the Efficacy and Safety of a Topical Rapamycin Cream for the Treatment of Facial Angiofibromas (FA) Associated With Tuberous Sclerosis Complex (TSC) in Patients 6 Years of Age and Over

The study aims to compare the safety and efficacy of two different strengths of Rapamycin cream, topical and placebo over 26 weeks in the treatment of facial angiofibroma (FA) associated with Tuberous Sclerosis Complex (TSC).

Study Overview

• Status: Completed
• Conditions: Tuberous Sclerosis; Facial Angiofibroma
• Intervention / Treatment: Drug: rapamycin; Drug: placebo

Detailed Description

Topical rapamycin has previously been used to treat FA associated with TSC, reducing erythema, papule size, while flattening lesions and improving skin texture. Topical rapamycin has been reported to be well tolerated.

The efficacy and safety of a topical rapamycin cream at two strengths (0.5% and 1.0%) will be assessed during a 26 week double-blind treatment phase with assessments made at clinical visits at baseline, 2, 8, 14, 20 and 26 weeks, and at follow-up (4 weeks after the last dose of study drug).

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Children's Health Queensland
• Czechia
  • Brno, Czechia, 5HG9+4W
    • Fakultní Nemocnice Brno
• Hungary
  • Budapest, Hungary, G39Q+49
    • Bethesda Children's Hospital of the Hungarian Reformed Church
  • Pécs, Hungary, H-7624
    • University of Pecs
• New Zealand
  • Canterbury
    • Christchurch, Canterbury, New Zealand, 8011
      • Canterbury District Health Board
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Center of Serbia
  • Belgrade, Serbia, 11000
    • Clinic of Neurology and Psychiatry for Children and Youth
• Slovakia
  • Bratislava, Slovakia, 83340
    • Narodny Ustav Detskych Chorob
• Spain
  • Madrid, Spain, 28007
    • Clinica Universidad de Navarra
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universidad de Navarra
• Taiwan
  • Taipei, Taiwan
    • National Taiwan University Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • La Jolla, California, United States, 92037
      • University of California San Diego
  • Florida
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Research Institute
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male and female patients aged ≥ 6 years and ≤ 65 years on the day informed consent is obtained
2. Patients diagnosed with TSC based on the clinical diagnostic criteria of International Tuberous Sclerosis Complex Consensus Conference 2012 and presenting visible facial angiofibroma
3. An FA severity score of 2 or 3 on the IGA scale
4. Patients or their legal representatives capable of understanding the explanation of the clinical trial and who give written informed consent for participation
5. Patients or their legal representatives able to maintain patient diaries following the instructions of the investigator or sub-investigator

Exclusion Criteria:

1. Patients who cannot carry out the treatment plan or follow-up assessment
2. Patients with serious skin lesions such as erosions or ulcers
3. Patients with known hypersensitivity to any component of the study product
4. Patients who have received rapamycin/sirolimus, everolimus, or temsirolimus within 3 months of enrolment
5. Patients who received laser therapy or surgical therapy within 6 months prior to trial enrolment
6. Patients who participated in any other clinical trial within 3 months prior to the day of enrolment
7. Patients judged unsuitable for this clinical trial by the investigator or sub-investigator
8. Pregnant or lactating females
9. Sexually active females of childbearing potential not using adequate contraception and sexually active males not using adequate contraception
10. Patients with immune dysfunction or receiving any form of immunosuppression
11. Patients with severe FA, with a score of 4 on the IGA scale
12. Patients with an FA severity score of less than 2 on the IGA scale

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
Experimental: 0.5% Rapamycin cream, topical; Rapamycin cream topical, 0.5% w/w, applied once daily before bed on affected area for 26 weeks	Drug: rapamycin; Apply to the affected area once a day, approximately half an hour before retiring for bed in the evening, for 26 weeks; Other Names: sirolimus
Experimental: 1.0% Rapamycin cream, topical; Rapamycin cream topical, 0.5% w/w, applied once daily before bed on affected area for 26 weeks	Drug: rapamycin; Apply to the affected area once a day, approximately half an hour before retiring for bed in the evening, for 26 weeks; Other Names: sirolimus
Placebo Comparator: Placebo; Placebo cream topical, applied once daily before bed on affected area for 26 weeks	Drug: placebo; Apply to the affected area once a day, approximately half an hour before retiring for bed in the evening, for 26 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Obtaining Successful Treatment	Success on the Investigator Global Assessment (IGA) scale is defined as clear or almost clear with an improvement of at least two grades from baseline. IGA scores range from 0-4: 0=Clear; Almost Clear; Mild; Moderate; Severe	After 26 weeks treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Investigator's Global Assessment	The change in grading on the Investigator's Global Assessment (IGA) scale from baseline. IGA scores range from 0-4: 0=Clear; Almost Clear; Mild; Moderate; Severe	At baseline and after 26 weeks treatment
Change From Baseline in Facial Angiofibroma Severity Index (FASI)	The change in grading on the Facial Angiofibroma Severity Index (FASI) from baseline. FASI grades lesions according to their erythema, size and extent by summing the scores of each category. The final FASI scores range from (mild) 2-9 (severe). Erythema Skin color 0 Light Red 1 Red 2 Dark Red/purple 3 Size None 0 Small (< 5mm) 1 Large (> 5mm) 2 Confluent 3 Extension <50 % cheek surface 2 >50% cheek surface 3	At baseline and after 26 weeks treatment
Subjective (Participant or Parent/Caregiver) Percentage Change Rating Scale	Percentage change in facial angiofibroma since beginning treatment, as assessed by the participant or parent/caregiver. A large value indicates most improvement to facial angiofibroma (minimum=0, maximum=100). This was a single assessment time-point, where the participant or parent/caregiver estimated the percentage change in the facial angiofibroma lesion appearance from their perspective since baseline.	After 26 weeks treatment
Objective (Clinician) Percentage Change Rating Scale	Percentage improvement in facial angiofibroma since beginning treatment, as assessed by the clinician. A large value indicates most improvement to facial angiofibroma (minimum=0, maximum=100). This was a single assessment time-point, where clinicians estimated the percentage change in the facial angiofibroma lesion appearance from their perspective since baseline.	After 26 weeks treatment
Categorical Change in Facial Angiofibroma	Change in facial angiofibroma since beginning treatment on a 5-point scale, as assessed by the participant or parent/caregiver. This was a single assessment time-point, where the participant or parent/caregiver evaluated the change in the facial angiofibroma lesion appearance from their perspective since baseline.	After 26 weeks treatment
Time to Treatment Success	The time elapsed from the first dose to the time of treatment success, according to the Investigator's Global Assessment (IGA) scale. The total time of treatment was 26 weeks, although Covid-19 visit delays led to an extension of up to 2 weeks (28 weeks total) for some patients. Success on the Investigator Global Assessment (IGA) scale is defined as clear or almost clear with an improvement of at least two grades from baseline. IGA scores range from 0-4: 0=Clear; Almost Clear; Mild; Moderate; Severe	From first dose to 26 weeks (± 2 weeks)

Collaborators and Investigators

• Sponsor: Dermatology Specialties Limited Partnership
• Investigators: Study Director: Ioana Stanescu, Dermatology Specialties Limited Partnership

Publications and helpful links

General Publications

• Aitken P, Stanescu I, Boddington L, Mahon C, Fogarasi A, Liao YH, Ivars M, Moreno-Artero E, Trauner D, DeRoos ST, Jancic J, Nikolic M, Balazova P, Price HN, Hadzsiev K, Riney K, Stapleton S, Tollefson MM, Bauer D, Pinkova B, Atkinson H. A novel rapamycin cream formulation improves facial angiofibromas associated with tuberous sclerosis complex: a double-blinded, randomised, placebo-controlled trial. Br J Dermatol. 2023 Jul 18:ljad243. doi: 10.1093/bjd/ljad243. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2019
• Primary Completion (Actual): September 1, 2022
• Study Completion (Actual): September 1, 2022

Study Registration Dates

• First Submitted: January 29, 2019
• First Submitted That Met QC Criteria: January 30, 2019
• First Posted (Actual): February 1, 2019

Study Record Updates

• Last Update Posted (Actual): September 8, 2023
• Last Update Submitted That Met QC Criteria: August 17, 2023
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; 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; Facies; 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: DSLP-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual Participant Data is not planned to be shared with other researchers

Drug and device information, study documents

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