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

• Published in: JAMA dermatology (Chicago, Ill.) Vol. 154; no. 7; p. 773
• Main Authors: Koenig, Mary Kay, Bell, Cynthia S, Hebert, Adelaide A, Roberson, Joan, Samuels, Joshua A, Slopis, John M, Tate, Patti, Northrup, Hope
• Format: Journal Article
• Language: English
• Published: United States 01.07.2018
• Subjects: Administration, Cutaneous; Adolescent; Adult; Angiofibroma - drug therapy; Angiofibroma - etiology; Child; Child, Preschool; Double-Blind Method; Facial Neoplasms - drug therapy; Facial Neoplasms - etiology; Female; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - therapeutic use; Male; Middle Aged; Prospective Studies; Quality of Life; Severity of Illness Index; Sirolimus - adverse effects; Sirolimus - therapeutic use; Skin Neoplasms - drug therapy; Skin Neoplasms - etiology; Time Factors; Tuberous Sclerosis - complications; Young Adult
• ISSN: 2168-6084
• DOI: 10.1001/jamadermatol.2018.0464

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. To evaluate the efficacy and safety of topical rapamycin for TSC-related facial angiofibromas. 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. 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. Angiofibroma Grading Scale (AGS) change from baseline scored from photographs by independent masked dermatologists. Safety analyses included adverse events (AEs) and serum rapamycin levels. 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. 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. ClinicalTrials.gov Identifier: NCT01526356.