Topical Rapamycin and Calcitriol for Angiofibroma of Tuberous Sclerosis

Study Overview
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Brief Summary
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The aim of the study is to determine the effect and safety of topical rapamycin or calcitriol and their combination for the treatment of TSC-associated facial angiofibroma. Methods: A total of 52 TSC patients including 20 male and 32 female subjects were recruited, and 50 of them completed the period 1 study. In period 1, topical rapamycin (0.1%) or calcitriol (3 mcg/g) single-agent therapy versus their combination were applied twice a day by a left-right randomized, split-face comparison for 12 weeks. The primary end point was the reduction of facial angiofibroma severity index (FASI) for the grade of erythema, papule size, elevation and extension of the lesions at week 12. In period 2, the patients entered an open-label study and were reassigned to use the more effective ointment on both cheeks for another 12 weeks (week 13-24). A follow-up FASI analysis for recurrence after drug discontinuance for 12 weeks was also performed (week 36). The secondary end point was the reduction of Visual Analysis Score (VAS) evaluated by the subjects themselves at week 12.

Detailed Description
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Background: Tuberous sclerosis complex (TSC)-associated facial angiofibroma is psychologically debilitating to both patients and their family members. The pathogenesis of TSC stems from TSC1 or TSC2 mutations, leading to the defect in mechanistic target of rapamycin (mTOR) inhibition. Rapamycin is an mTOR inhibitor and is effective for TSC facial angiofibroma through topical administration. Calcitriol, a vitamin D3 analogue, has been shown to lessen skin fibrosis in scleroderma and may be therapeutically beneficial to angiofibromas. Objectives: The aim of the study is to determine the effect and safety of topical rapamycin or calcitriol and their combination for the treatment of TSC-associated facial angiofibroma. Methods: A total of 52 TSC patients including 20 male and 32 female subjects were recruited, and 50 of them completed the period 1 study. In period 1, topical rapamycin (0.1%) or calcitriol (3 mcg/g) single-agent therapy versus their combination were applied twice a day by a left-right randomized, split-face comparison for 12 weeks. The primary end point was the reduction of facial angiofibroma severity index (FASI) for the grade of erythema, papule size, elevation and extension of the lesions at week 12. In period 2, the patients entered an open-label study and were reassigned to use the more effective ointment on both cheeks for another 12 weeks (week 13-24). A follow-up FASI analysis for recurrence after drug discontinuance for 12 weeks was also performed (week 36). The secondary end point was the reduction of Visual Analysis Score (VAS) evaluated by the subjects themselves at week 12.

Official Title
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Study of Combination Therapy With Topical Rapamycin and Calcitriol for Cutaneous Lesions of Tuberous Sclerosis: A Double-blind Randomized Controlled Trial

Conditions
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Facial Angiofibroma

Intervention / Treatment
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* Drug: Rapamycin
* Drug: Calcitriol
* Drug: Rapamycin-calcitriol combination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have been diagnosed or highly suspected as having TSC. Subjects must be aged 7 to 70 years at Screening, and can be either sex. Subjects must have symmetric facial angiofibromas. Exclusion Criteria: Pregnancy or with a plan to be pregnant. Subjects who cannot comply the treatment protocol. Subjects with kidney or liver/ biliary dysfunction. Subjects with hypercalcaemia and patients known to suffer from abnormal calcium metabolism. Subjects on systemic treatment of calcium deficiency. Subjects known to be hypersensitive to rapamycin or calcitriol.

Ages Eligible for Study
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Minimum Age: 7 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rapamycin<br>Rapamycin(0.1%) | Drug: Rapamycin<br>* topical rapamycin (0.1%) or calcitriol (3 mcg/g) single-agent therapy versus their combination were applied twice a day by a left-right randomized, split-face comparison for 12 weeks. In period 2, the patients entered an open-label study and were reassigned to use the more effective ointment on both cheeks for another 12 weeks (week 13-24).<br>* Other names: Sirolimus;|
| Experimental: Calcitriol<br>Calcitriol(3mcg/g) | Drug: Calcitriol<br>* topical rapamycin (0.1%) or calcitriol (3 mcg/g) single-agent therapy versus their combination were applied twice a day by a left-right randomized, split-face comparison for 12 weeks. In period 2, the patients entered an open-label study and were reassigned to use the more effective ointment on both cheeks for another 12 weeks (week 13-24).<br>* Other names: Rocaltrol;|
| Experimental: Rapamycin-calcitriol combination<br>Rapamycin(0.1%) with Calcitriol(3mcg/g) | Drug: Rapamycin-calcitriol combination<br>* topical rapamycin (0.1%) or calcitriol (3 mcg/g) single-agent therapy versus their combination were applied twice a day by a left-right randomized, split-face comparison for 12 weeks. In period 2, the patients entered an open-label study and were reassigned to use the more effective ointment on both cheeks for another 12 weeks (week 13-24).<br>* Other names: Sirolimus-Rocaltrol combination;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| facial angioﬁbroma severity index (FASI) | the reduction of facial angioﬁbroma severity index (FASI) for the grade of erythema, papule size, elevation and extension of the lesions at week 12 | at week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberous sclerosis complex, facial angiofibroma, rapamycin, calcitriol