Efficacy and Safety of Topical Rapamycin in Patients With Facial Angiofibromas Secondary to Tuberous Sclerosis Complex: The TREATMENT Randomized Clinical Trial

Abstract

Importance: Facial angiofibromas occur in approximately 75% of individuals with tuberous sclerosis complex (TSC), causing substantial morbidity and disfigurement. Current therapies are partially effective, uncomfortable, produce scarring, and need repeating to treat recurrence.

Objective: To evaluate the efficacy and safety of topical rapamycin for TSC-related facial angiofibromas.

Design, setting, and participants: This prospective, multicenter, randomized, double-blind, vehicle-controlled trial with 6 monthly clinic visits enrolled 179 patients with TSC-related facial angiofibromas not treated within 6 months from May 2012 to March 2014 in 9 clinical sites in the United States and 1 in Australia.

Interventions: Patients were randomized (1:1:1) to topical formulation containing 0.3 g per 30 g (1%) rapamycin, 0.03 g per 30 g (0.1%) rapamycin, or vehicle alone. Participants applied 1.0 mL to designated areas daily at bedtime.

Main outcomes and measures: Angiofibroma Grading Scale (AGS) change from baseline scored from photographs by independent masked dermatologists. Safety analyses included adverse events (AEs) and serum rapamycin levels.

Results: All 179 patients randomized (99 [55.3%] female) comprised the primary analysis population (59 in the 1% rapamycin group, 63 in the 0.1% rapamycin group, and 57 in the vehicle-only group). The mean age was 20.5 years (range 3-61 years). Clinically meaningful and statistically significant improvement in facial angiofibromas was observed for both 1% and 0.1% rapamycin relative to the vehicle-only control group, and for 1% vs 0.1% rapamycin, with most of the improvement realized within the first month. At 6 months, AGS mean improvement for 1% rapamycin was 16.7 points compared with 11.0 for 0.1% rapamycin and 2.1 points for vehicle only (P < .001 for 1% and 0.1% vs vehicle only). Compared with baseline, end-of-treatment photos were rated "better" for 81.8% of patients in the 1% rapamycin group, compared with 65.5% for those in the 0.1% rapamycin group and 25.5% for those in the vehicle-only group (P < .001, all 3 pairwise comparisons). Topical rapamycin was generally well-tolerated, with no measurable systemic absorption. Apparent drug-related adverse effects were limited to 10% or less incidence of application site discomfort and/or pain, pruritus, erythema, and irritation. Nearly all AEs were mild, with no drug-related moderate, severe, or serious events.

Conclusions and relevance: Topical rapamycin appears effective and safe for treatment of TSC-related facial angiofibromas. In this trial, the preferred dose was 1% once daily. Future studies are needed to evaluate prophylactic, early, and long-term use of topical rapamycin, durability of response, and combination therapy with oral mammalian target of rapamycin (mTOR) inhibitors.

Trial registration: ClinicalTrials.gov Identifier: NCT01526356.

Figure 1.. The TREATMENT Trial CONSORT Diagram

AGS indicates angiofibroma grading scale; TSC, tuberous sclerosis complex. ^aApplication site rash, mild, probably related to study drug. ^bPhlebitis superficial, moderate, not related to study drug. ^cAll patients excluded on the basis of lacking either baseline or at least 1 postbaseline evaluable photograph.

Figure 2.. AGS Change From Baseline by Treatment Group

Restricted maximum likelihood-based repeated measures linear model. AGS indicates angiofibroma grading scale; LS, least square.

Figure 3.. Baseline to End-of-Study Paired Photographs Comparison

Cochran-Mantel-Haenszel test.

Figure 4.. Patient Photographs

Frontal photographs taken at baseline (A-C) and paired with end of trial photographs (D-F) for 3 patients in the 1% rapamycin treatment group.