Topical Rapamycin and Calcitriol for Angiofibroma of Tuberous Sclerosis
Topical Rapamycin and Calcitriol for Angiofibroma of Tuberous Sclerosis
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.
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.
Inclusion Criteria:

 1. Subjects must have been diagnosed or highly suspected as having TSC.

 2. Subjects must be aged 7 to 70 years at Screening, and can be either sex.

 3. Subjects must have symmetric facial angiofibromas.

 Exclusion Criteria:

 1. Pregnancy or with a plan to be pregnant.

 2. Subjects who cannot comply the treatment protocol.

 3. Subjects with kidney or liver/ biliary dysfunction.

 4. Subjects with hypercalcaemia and patients known to suffer from abnormal calcium
 metabolism.

 5. Subjects on systemic treatment of calcium deficiency.

 6. Subjects known to be hypersensitive to rapamycin or calcitriol.