Efficacy and Safety of Topical Sirolimus Therapy for Facial Angiofibromas in the Tuberous Sclerosis Complex : A Randomized Clinical Trial | Congenital Defects | JAMA Dermatology | JAMA Network
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Original Investigation
January 2017

Efficacy and Safety of Topical Sirolimus Therapy for Facial Angiofibromas in the Tuberous Sclerosis Complex : A Randomized Clinical Trial

Author Affiliations
  • 1Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan
  • 2Department of Pharmacy, Osaka University Hospital, Osaka, Japan
  • 3Department of Clinical Epidemiology and Biostatistics, Graduate School of Medicine, Osaka University, Osaka, Japan
JAMA Dermatol. 2017;153(1):39-48. doi:10.1001/jamadermatol.2016.3545
Key Points

Question  What is the optimal concentration of topical sirolimus for the treatment of facial angiofibromas in tuberous sclerosis complex?

Findings  In this randomized clinical trial of 18 children and 18 adults, sirolimus gel at a concentration of 0.2% demonstrated significantly more improvement at the end of treatment compared with placebo, with minimum toxic effects.

Meaning  Topical treatment with a 0.2% concentration of sirolimus gel will be a useful medication for facial angiofibromas in tuberous sclerosis complex.


Importance  Inhibitors of mammalian target of rapamycin complex 1, such as sirolimus, effectively target skin lesions in tuberous sclerosis complex (TSC). However, systemic treatment causes adverse effects, and topical sirolimus has shown promise in the treatment of facial angiofibromas.

Objective  To evaluate the efficacy, safety, and optimal concentration of a topical sirolimus gel vs placebo for treatment of facial angiofibromas in TSC.

Design, Setting, and Participants  A double-blind, placebo-controlled, parallel-group, dose-escalation, phase 2 randomized clinical trial using 3 sirolimus gel concentrations was performed at Osaka University Hospital, Osaka, Japan. Thirty-six patients with TSC and facial angiofibromas, including 18 aged 3 to 18 years (children) and 18 aged 19 to 65 years (adults), were enrolled from December 10, 2013, to July 17, 2014. Analysis was by intention to treat.

Interventions  The adult and child groups were each subdivided into 3 groups (n = 12 each) and randomized to receive sirolimus gel concentrations of 0.05%, 0.1%, or 0.2% or placebo using a web-response system in a 2:1 fashion. The medication was applied to the patient’s lesions twice per day for 12 weeks. Each patient underwent assessment at 2, 4, 8, and 12 weeks during treatment and at 4 weeks after discontinuation of the treatment (16 weeks).

Main Outcomes and Measures  The primary end point, planned before starting data collection, was an improvement factor, represented as a variable composed of tumor size reduction and a lessening of the redness of the 3 target tumors at 12 weeks relative to baseline.

Results  All 36 patients (13 male and 23 female; median age, 40 years; range, 6-47 years) completed the study analyses. The improvement factor was statistically significant in all active treatment groups receiving 0.2% sirolimus (mean [SD], 1.94 [0.68]; P < .001) and not in the adult subgroups receiving 0.1% (mean [SD], 0.88 [0.85]; P = .31) and 0.05% (mean [SD], 1.63 [1.11]; P = .09) concentrations of sirolimus. No significant adverse effects were observed. Mild skin dryness (13 patients [36%]) and irritation (11 patients [31%]) were observed. Low blood levels of sirolimus (<0.25 ng/mL) were detected in adults (1 patient [25%] in the 0.1% adult subgroup and 2 patients [50%] in the 0.2% adult subgroup) and particularly in children (1 patient [25%] in the 0.05% child subgroup, 2 patients [50%] in the 0.1% child subgroup, and 4 patients [100%] in the 0.2% child subgroup).

Conclusions and Relevance  Topical sirolimus gel is safe and effective for facial angiofibromas in TSC. The optimal concentration of sirolimus was 0.2%.

Trial Registration  umin.ac.jp Identifier: UMIN000012420