Efficacy and safety of sirolimus in lymphangioleiomyomatosis.
Efficacy and safety of sirolimus in lymphangioleiomyomatosis.
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DOI：
10.1056/nejmoa1100391
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发表时间：
2011-04-28
期刊：
影响因子：
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通讯作者：
MILES Trial Group
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作者：
McCormack FX;Inoue Y;Moss J;Singer LG;Strange C;Nakata K;Barker AF;Chapman JT;Brantly ML;Stocks JM;Brown KK;Lynch JP 3rd;Goldberg HJ;Young LR;Kinder BW;Downey GP;Sullivan EJ;Colby TV;McKay RT;Cohen MM;Korbee L;Taveira-DaSilva AM;Lee HS;Krischer JP;Trapnell BC;National Institutes of Health Rare Lung Diseases Consortium;MILES Trial Group
淋巴管平滑肌瘤病 (LAM) 是一种女性进行性囊性肺病；它与哺乳动物雷帕霉素靶点 (mTOR) 信号传导的不当激活有关，该信号调节细胞生长和淋巴管生成。西罗莫司（也称为雷帕霉素）可抑制 mTOR，并在涉及 LAM 患者的 1-2 期试验中显示出前景。我们对 89 名患有中度肺损伤的 LAM 患者进行了西罗莫司的两阶段试验，对西罗莫司与安慰剂进行了为期 12 个月的随机、双盲比较，随后进行了 12 个月的观察期。主要终点是各组之间 1 秒用力呼气量 (FEV1) 变化率（斜率）的差异。在治疗期间，安慰剂组（43名患者）的FEV1斜率为每月-12±2ml，西罗莫司组（46名患者）为每月1±2ml（P<0.001）。治疗期间 FEV1 平均变化的组间绝对差异为 153 ml，约为入组时平均 FEV1 的 11%。与安慰剂组相比，西罗莫司组在用力肺活量、功能残气量、血清血管内皮生长因子 D (VEGF-D) 以及生活质量和功能表现方面从基线到 12 个月都有改善。在此间隔内，6 分钟步行距离或肺一氧化碳弥散能力的变化没有显着组间差异。停用西罗莫司后，西罗莫司组的肺功能又恢复下降，与安慰剂组的情况相似。西罗莫司的不良事件更常见，但严重不良事件的发生频率在各组之间没有显着差异。在 LAM 患者中，西罗莫司可稳定肺功能，降低血清 VEGF-D 水平，并与症状减轻和生活质量改善相关。西罗莫司治疗可能对某些 LAM 患者有效。 （由美国国立卫生研究院和其他机构资助；MILES ClinicalTrials.gov 编号，NCT00414648。）
Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1–2 trials involving patients with LAM. We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment — a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV1). During the treatment period, the FEV1 slope was −12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV1 during the treatment period was 153 ml, or approximately 11% of the mean FEV1 at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups. In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.)