PHASE III TRIAL FO SIROLIMUS IN LYMPHANGIOLEIOMYLMATOSIS

描述(由申请人提供)： LAM是一种罕见的致命肺部疾病，只影响女性，由结节性硬化症基因突变引起。编码产物Tuberin或Hamartin的功能缺陷导致Akt通路信号失控，Akt通路控制细胞的生长、运动和存活。肺内有大量的平滑肌细胞，很可能来自遥远的地方，通过一种未知的机制促进肺泡壁的破坏和囊肿的形成。LAM患者还可能发生淋巴管通过轴向淋巴结扩散。 西罗莫司是Akt信号的一种特异性抑制剂，与tuberin/hamartin复合体作用于该通路中的同一点。来自结节性硬化症(TSC)动物模型的临床前证据表明，西罗莫司可以缩小肾脏肿瘤和肝脏肿瘤，辛辛那提对11名LAM患者的初步研究表明，西罗莫司可以缩小LAM患者的肾肿瘤和改善肺功能。 迈尔斯(多中心国际淋巴管肌瘤病疗效和安全性)试验将测试西罗莫斯(雷帕霉素)在LAM患者中的安全性和有效性。240名患者将以双盲方式随机分为安慰剂组或西罗莫司组，治疗一年，停药或安慰剂再治疗一年。主要结果将是在12个月内一秒用力呼气量(FEV1)斜率的变化。这项分析将基于“意向治疗”的设计。当100名患者达到一年的时间点时，将进行中期分析。评估反应持久性的最终分析将在24个月后进行。次要结果指标将包括用力肺活量、残气量、弥散能力、6分钟步行、基于容量CT的囊腔体积百分比、全原因死亡率以及基于问卷的呼吸困难、疲劳和抑郁评估。 LAM基金会将协助患者招募和教育。这项试验将使用罕见肺病联合会提供的基础设施进行，该联合会是由美国国立卫生研究院支持的12个机构组成的网络，在LAM、肺泡蛋白沉着症、α1抗胰蛋白酶缺乏症和儿童间质性肺部疾病方面进行合作试验和研究。患者的安全将由NIH数据安全监测委员会(DSMB)进行监测。Miles试验被设计为一项关键研究，以确定西罗莫司是否有效地稳定或改善LAM患者的肺功能。

DESCRIPTION (provided by applicant): LAM is a rare, fatal lung disease that affects only women, caused by mutations in tuberous sclerosis genes. Functional deficiencies of the encoded products, tuberin or hamartin, result in dysregulated signaling through the Akt pathway which controls cell growth, movement and survival. The lung becomes infiltrated with smooth muscle cells, most likely from a remote source, which promote destruction of alveolar walls and cyst formation through an unknown mechanism. Patients with LAM may also develop lymphangitic spread through axial lymph nodes. Sirolimus is a specific inhibitor of Akt signaling that acts at the same point in the pathway as the tuberin/hamartin complex. Preclinical evidence from tuberous sclerosis (TSC) animal models reveals that sirolimus shrinks kidney tumors and hepatic tumors, and a pilot study of 11 patients with LAM in Cincinnati suggested that sirolimus can shrink renal tumors and improve lung function in patients with LAM. The MILES (Multicenter International Lymphangioleiomyomatosis Efficacy and Safety) trial will test the safety and efficacy of sirolimus (Rapamycin) in patients with LAM. Two hundred and forty patients will be randomized to placebo or sirolimus groups in a double-blind fashion, treated for one year and followed off of drug or placebo for one additional year. The primary outcome will be change in forced expiratory volume in one second (FEV1) slope over twelve months. The analysis will be based on an 'intention to treat' design. Interim analyses will occur when 100 patients reach the one year point. The final analysis to assess the durability of response will occur at 24 months. Secondary outcome measures will include forced vital capacity, residual volume, diffusing capacity, six minute walk, cyst volume percent based on volumetric CT, all-cause mortality and questionnaire-based assessments of dyspnea, fatigue and depression. The LAM Foundation will assist with patient recruitment and education. The trial will be conducted using the infrastructure provided by the Rare Lung Disease Consortium, an NIH supported network of 12 institutions which perform cooperative trials and studies in LAM, pulmonary alveolar proteinosis, alpha one antitrypsin deficiency and pediatric interstitial lung disease. Patient safety will be monitored by an NIH Data Safety Monitoring Board (DSMB). The MILES trial is designed as a pivotal study to determine if sirolimus is effective in stabilizing or improving lung function in patients with LAM.