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JAMA Dermatol. 2018 Jul 1;154(7):781-788. doi: 10.1001/jamadermatol.2018.1408.

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

Author information

1
Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
2
Department of Dermatology, JR Tokyo General Hospital, Tokyo, Japan.
3
Department of Dermatology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
4
Department of Dermatology, Medical Hospital, Tokyo Medical and Dental University, Tokyo, Japan.
5
Division of Dermatology, Department of Surgical Subspecialties, National Center for Child Health and Development, Tokyo, Japan.
6
Department of Dermatology, Seirei Hamamatsu General Hospital, Shizuoka, Japan.
7
Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan.
8
Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Hyogo, Japan.
9
Division of Dermatology, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, Tottori University, Tottori, Japan.
10
Nobelpharma Co, Ltd, Tokyo, Japan.

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.

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