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

Study Overview
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Brief Summary
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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).

Detailed Description
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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).

Official Title
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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

Conditions
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Facial Angiofibroma, Tuberous Sclerosis

Intervention / Treatment
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* Drug: rapamycin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged ≥ 6 years and ≤ 65 years on the day informed consent is obtained Patients diagnosed with TSC based on the clinical diagnostic criteria of International Tuberous Sclerosis Complex Consensus Conference 2012 and presenting visible facial angiofibroma An FA severity score of 2 or 3 on the IGA scale Patients or their legal representatives capable of understanding the explanation of the clinical trial and who give written informed consent for participation Patients or their legal representatives able to maintain patient diaries following the instructions of the investigator or sub-investigator Exclusion Criteria: Patients who cannot carry out the treatment plan or follow-up assessment Patients with serious skin lesions such as erosions or ulcers Patients with known hypersensitivity to any component of the study product Patients who have received rapamycin/sirolimus, everolimus, or temsirolimus within 3 months of enrolment Patients who received laser therapy or surgical therapy within 6 months prior to trial enrolment Patients who participated in any other clinical trial within 3 months prior to the day of enrolment Patients judged unsuitable for this clinical trial by the investigator or sub-investigator Pregnant or lactating females Sexually active females of childbearing potential not using adequate contraception and sexually active males not using adequate contraception Patients with immune dysfunction or receiving any form of immunosuppression Patients with severe FA, with a score of 4 on the IGA scale Patients with an FA severity score of less than 2 on the IGA scale

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.5% Rapamycin cream, topical<br>Rapamycin cream topical, 0.5% w/w, applied once daily before bed on affected area for 26 weeks | Drug: rapamycin<br>* Apply to the affected area once a day, approximately half an hour before retiring for bed in the evening, for 26 weeks<br>* Other names: sirolimus;|
| Experimental: 1.0% Rapamycin cream, topical<br>Rapamycin cream topical, 0.5% w/w, applied once daily before bed on affected area for 26 weeks | Drug: rapamycin<br>* Apply to the affected area once a day, approximately half an hour before retiring for bed in the evening, for 26 weeks<br>* Other names: sirolimus;|
| Placebo Comparator: Placebo<br>Placebo cream topical, applied once daily before bed on affected area for 26 weeks | Drug: placebo<br>* Apply to the affected area once a day, approximately half an hour before retiring for bed in the evening, for 26 weeks<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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) | 
| 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 |