PMID- 29800048 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20220331 IS - 2168-6084 (Electronic) IS - 2168-6068 (Print) IS - 2168-6068 (Linking) VI - 154 IP - 7 DP - 2018 Jul 1 TI - Efficacy and Safety of Topical Rapamycin in Patients With Facial Angiofibromas Secondary to Tuberous Sclerosis Complex: The TREATMENT Randomized Clinical Trial. PG - 773-780 LID - 10.1001/jamadermatol.2018.0464 [doi] AB - 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. FAU - Koenig, Mary Kay AU - Koenig MK AD - Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston. FAU - Bell, Cynthia S AU - Bell CS AD - Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston. FAU - Hebert, Adelaide A AU - Hebert AA AD - Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston. AD - Department of Dermatology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston. FAU - Roberson, Joan AU - Roberson J AD - Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston. FAU - Samuels, Joshua A AU - Samuels JA AD - Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston. FAU - Slopis, John M AU - Slopis JM AD - Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston. AD - Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston. FAU - Tate, Patti AU - Tate P AD - Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston. FAU - Northrup, Hope AU - Northrup H AD - Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston. CN - TREATMENT Trial Collaborators LA - eng SI - ClinicalTrials.gov/NCT01526356 GR - UL1 TR000371/TR/NCATS NIH HHS/United States PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - JAMA Dermatol JT - JAMA dermatology JID - 101589530 RN - 0 (Immunosuppressive Agents) RN - W36ZG6FT64 (Sirolimus) SB - IM CIN - JAMA Dermatol. 2018 Jul 1;154(7):761-762. PMID: 29800103 MH - Administration, Cutaneous MH - Adolescent MH - Adult MH - Angiofibroma/*drug therapy/etiology MH - Child MH - Child, Preschool MH - Double-Blind Method MH - Facial Neoplasms/*drug therapy/etiology MH - Female MH - Humans MH - Immunosuppressive Agents/adverse effects/*therapeutic use MH - Male MH - Middle Aged MH - Prospective Studies MH - Quality of Life MH - Severity of Illness Index MH - Sirolimus/adverse effects/*therapeutic use MH - Skin Neoplasms/*drug therapy/etiology MH - Time Factors MH - Tuberous Sclerosis/*complications MH - Young Adult PMC - PMC6128508 COIS- 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. EDAT- 2018/05/26 06:00 MHDA- 2019/09/17 06:00 PMCR- 2019/05/23 CRDT- 2018/05/26 06:00 PHST- 2018/05/26 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] PHST- 2018/05/26 06:00 [entrez] PHST- 2019/05/23 00:00 [pmc-release] AID - 2682034 [pii] AID - doi180010 [pii] AID - 10.1001/jamadermatol.2018.0464 [doi] PST - ppublish SO - JAMA Dermatol. 2018 Jul 1;154(7):773-780. doi: 10.1001/jamadermatol.2018.0464.