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.

Conflict of interest statement

Conflict of Interest Disclosures: Drs Koenig, Samuels, and Slopis report grants and personal fees from Novartis Pharmaceutical. Dr Samuels reports personal fees from MedStudy, Inc. Drs Koenig, Hebert, and Northrup report a provisional patent pending. No other disclosures are reported.

Figures

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.