Dataset Information

Sirolimus Gel Treatment vs Placebo for Facial Angiofibromas in Patients With Tuberous Sclerosis Complex: A Randomized Clinical Trial.

ABSTRACT: Importance:Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment. Objective:To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions. Design, Setting, and Patients:Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC. Interventions:Patients who developed angiofibromas were randomly assigned, in a 1:1 ratio, to receive sirolimus gel, 0.2%, or placebo, each applied topically twice daily for 12 weeks. Main Outcomes and Measures:The primary end point was composite improvement in the size and color of angiofibromas in photographs at week 12 of treatment. It was assessed by an independent review committee comprising 3 blinded dermatologists who categorized patient results into the following 6 categories: "markedly improved," "improved," "slightly improved," "unchanged," "slightly aggravated," and "aggravated." Results:Sixty-two patients (27 pediatric and 35 adult; 34 [55%] female; mean [SD] age, 22.5 [11.9] years) were enrolled and randomly assigned to receive sirolimus gel, 0.2% (30 patients), or placebo (32 patients). The response rates of angiofibromas at weeks 4, 8, and 12 of treatment were 0 each in the placebo group in contrast to 20% (95% CI, 8%-39%; P = .01), 43% (95% CI, 26%-63%; P < .001), and 60% (95% CI, 41%-77%; P < .001), respectively, in the sirolimus group. None of the 31 assessable patients in the placebo group were rated improved or better, and 26 of them (84%) were rated unchanged. In contrast, 5 (17%) and 13 (43%) patients in the sirolimus group were rated markedly improved and improved, respectively. Adverse events were mild to moderate and were observed in 27 (90%) and 22 (69%) patients in the sirolimus and placebo groups, respectively; however, none of the trial participants discontinued treatment. Acute pancreatitis developed as a serious adverse event in 1 patient in the sirolimus group, and the patient recovered soon after hospitalization without discontinuing treatment. Conclusions and Relevance:Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality. Trial Registration:ClinicalTrials.gov Identifier: NCT02635789.

SUBMITTER: Wataya-Kaneda M

PROVIDER: S-EPMC6128500 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Sirolimus Gel Treatment vs Placebo for Facial Angiofibromas in Patients With Tuberous Sclerosis Complex: A Randomized Clinical Trial.

Wataya-Kaneda Mari M Ohno Yuuki Y Fujita Yasuyuki Y Yokozeki Hiroo H Niizeki Hironori H Ogai Masaaki M Fukai Kazuyoshi K Nagai Hiroshi H Yoshida Yuichi Y Hamada Izumi I Hio Taihei T Shimizu Kenji K Murota Hiroyuki H

JAMA dermatology 20180701 7

<h4>Importance</h4>Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment.<h4>Objective</h4>To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with ang ...[more]

PMID: 29800026

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Project description: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.

Project description:BackgroundAngiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling.MethodsWe conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed.ResultsOf the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections.ConclusionsAngiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)

Project description:IntroductionTuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder affecting several organs, including skin. We sought to assess the real-world effectiveness and safety of a topical sirolimus 0.2% gel treatment for TSC-related cutaneous manifestations.MethodsWe conducted an interim analysis of postmarketing surveillance conducted in Japan over 52 weeks. A total of 635 and 630 patients were included in the safety and efficacy analysis sets, respectively. Improvement rate of overall cutaneous manifestations, responder rate of improvement in individual lesions, adverse events (AEs), adverse drug reactions (ADRs), and patient satisfaction level of topical sirolimus 0.2% gel treatment were evaluated along with patient characteristics associated with the improvement rate of cutaneous manifestations or safety.ResultsThe mean age of the patients was 22.9 years and 46.1% were men. At week 52 of treatment, the overall improvement rate was 74.8% and the responder rate was the highest for facial angiofibroma (86.2%). Overall, the incidence rates of AEs and ADRs were 24.6% and 18.4%, respectively. Efficacy was associated with age (< 15, ≥ 15 to < 65, and ≥ 65 years, p = 0.010), duration of use (p < 0.001), and total dosage (p = 0.005). Safety was associated with age (< 15, ≥ 15 to < 65, and ≥ 65 years, p = 0.011) and duration of use (p < 0.001). However, when the broad age group (≥ 15 to < 65) was subcategorized by 10-year intervals, the incidence of ADRs was similar among the age groups with no significant differences. Hepatic or renal impairment or concomitant use of systemic mTOR inhibitors had no effect on the effectiveness or safety. Overall, 53% of patients were "very satisfied" or "satisfied" with the treatment received.ConclusionsTopical sirolimus 0.2% gel is effective in the management of TSC-related cutaneous manifestations and generally well tolerated. Age and duration of usage had a significant association with the effectiveness or safety of topical sirolimus 0.2% gel, whereas total dosage had a significant association with the effectiveness.

Dataset Information

Sirolimus Gel Treatment vs Placebo for Facial Angiofibromas in Patients With Tuberous Sclerosis Complex: A Randomized Clinical Trial.

Publications

Sirolimus Gel Treatment vs Placebo for Facial Angiofibromas in Patients With Tuberous Sclerosis Complex: A Randomized Clinical Trial.

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