Efficacy and safety of topical rapamycin in patients with facial angiofibromas secondary to tuberous sclerosis complex the TREATMENT randomized clinical trial

TREATMENT Trial Collaborators

Research output: Contribution to journalArticle

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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 1.0mL 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 agewas 20.5 years (range 3-61 years). Clinically meaningful and statistically significant improvement in facial angiofibromaswas 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% rapamycinwas 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 photoswere 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 rapamycinwas generallywell-tolerated, with no measurable systemic absorption. Apparent drug-related adverse effectswere limited to 10% or less incidence of application site discomfort and/or pain, pruritus, erythema, and irritation. Nearly all AEswere 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.

Original languageEnglish (US)
Pages (from-to)773-780
Number of pages8
JournalJAMA Dermatology
Volume154
Issue number7
DOIs
StatePublished - Jul 1 2018

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Angiofibroma
Tuberous Sclerosis
Sirolimus
Randomized Controlled Trials
Safety
Therapeutics
Erythema
Pruritus
Ambulatory Care

All Science Journal Classification (ASJC) codes

  • Dermatology

Cite this

Efficacy and safety of topical rapamycin in patients with facial angiofibromas secondary to tuberous sclerosis complex the TREATMENT randomized clinical trial. / TREATMENT Trial Collaborators.

In: JAMA Dermatology, Vol. 154, No. 7, 01.07.2018, p. 773-780.

Research output: Contribution to journalArticle

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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 1.0mL 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 agewas 20.5 years (range 3-61 years). Clinically meaningful and statistically significant improvement in facial angiofibromaswas 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{\%} rapamycinwas 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 photoswere 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 rapamycinwas generallywell-tolerated, with no measurable systemic absorption. Apparent drug-related adverse effectswere limited to 10{\%} or less incidence of application site discomfort and/or pain, pruritus, erythema, and irritation. Nearly all AEswere 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.",
author = "{TREATMENT Trial Collaborators} and Koenig, {Mary Kay} and Bell, {Cynthia S.} and Hebert, {Adelaide A.} and Joan Roberson and Samuels, {Joshua A.} and Slopis, {John M.} and Patti Tate and Hope Northrup and Michael Frost and Bebin, {E. Martina} and Sparagana, {Steven P.} and Thiele, {Elizabeth A.} and Darcy Krueger and Gipson, {Tanjala T.} and Wu, {Joyce Y.} and Rachel Kuperman and Carrie Krupitsky and Tanjala Gipson",
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TY - JOUR

T1 - Efficacy and safety of topical rapamycin in patients with facial angiofibromas secondary to tuberous sclerosis complex the TREATMENT randomized clinical trial

AU - TREATMENT Trial Collaborators

AU - Koenig, Mary Kay

AU - Bell, Cynthia S.

AU - Hebert, Adelaide A.

AU - Roberson, Joan

AU - Samuels, Joshua A.

AU - Slopis, John M.

AU - Tate, Patti

AU - Northrup, Hope

AU - Frost, Michael

AU - Bebin, E. Martina

AU - Sparagana, Steven P.

AU - Thiele, Elizabeth A.

AU - Krueger, Darcy

AU - Gipson, Tanjala T.

AU - Wu, Joyce Y.

AU - Kuperman, Rachel

AU - Krupitsky, Carrie

AU - Gipson, Tanjala

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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 1.0mL 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 agewas 20.5 years (range 3-61 years). Clinically meaningful and statistically significant improvement in facial angiofibromaswas 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% rapamycinwas 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 photoswere 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 rapamycinwas generallywell-tolerated, with no measurable systemic absorption. Apparent drug-related adverse effectswere limited to 10% or less incidence of application site discomfort and/or pain, pruritus, erythema, and irritation. Nearly all AEswere 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.

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 1.0mL 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 agewas 20.5 years (range 3-61 years). Clinically meaningful and statistically significant improvement in facial angiofibromaswas 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% rapamycinwas 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 photoswere 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 rapamycinwas generallywell-tolerated, with no measurable systemic absorption. Apparent drug-related adverse effectswere limited to 10% or less incidence of application site discomfort and/or pain, pruritus, erythema, and irritation. Nearly all AEswere 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.

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