Sirolimus Gel Treatment vs Placebo for Facial Angiofibromas in Patients With Tuberous Sclerosis Complex

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.

Improved health-related quality of life in patients treated with topical sirolimus for facial angiofibroma associated with tuberous sclerosis complex

“…for FA associated with TSC using the Dermatology Life Quality Index (DLQI) and Children's DLQI (CDLQI). They reported that the total scores on the DLQI and CDLQI after 12 weeks of treatment did not differ markedly between the sirolimus gel group and the placebo group 7 . Similar findings were reported in previous studies analyzing the QOL improvement of patients with topical mTOR inhibitors for FA associated with TSC using the DLQI and CDLQI 10,11 .…”

“…The conditions of the patients after three months of treatment with sirolimus gel were classified into three categories according to the criteria shown in Table 1: "improved," "unchanged," and "aggravated." 7 Adverse events were investigated using the CTCAE v5.0-JCOG (National Cancer Institute, Bethesda, MD, USA). This study was approved by the institutional review board of JR Tokyo General Hospital (No.…”

“…Similar findings were reported in previous studies analyzing the QOL improvement of patients with topical mTOR inhibitors for FA associated with TSC using the DLQI and CDLQI 10,11 . The DLQI and CDLQI are often used for QOL assessments in the treatment of skin diseases 7,12,13 . They are simple and comprised of 10 questions evaluating the disease impact on key aspects of patients' lives [12][13][14] .…”

“…Wataya-Kaneda et al reported phase 2 and 3 randomized clinical trials of topical sirolimus treatment with a sirolimus gel formulation in TSC patients and showed significant reductions in the size and color of the FAs associated with TSC 6,7 . In Japan, sirolimus gel was approved for the treatment of TSC skin lesions in 2018.…”

Improved health-related quality of life in patients treated with topical sirolimus for facial angiofibroma associated with tuberous sclerosis complex.

“…Wataya-Kaneda et al reported phase 2 and 3 randomized clinical trials of topical sirolimus treatment with a sirolimus gel formulation in TSC patients and showed signi cant reductions in the size and color of the FAs associated with TSC 6,7 . In Japan, sirolimus gel was approved for the treatment of TSC skin lesions in 2018.…”