Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED)-CCC

多中心介入性淋巴管平滑肌瘤病早期疾病试验（MILED试验） 项目摘要 淋巴管平滑肌瘤病（LAM）是女性的低度转移性肿瘤， 导致肺囊性破坏的mTOR通路突变。良性的出现，突变 带有平滑肌样LAM细胞的细胞浸润肺部，来源不明， 导致囊肿形成、复发性气胸、乳糜性胸腔积液和 进行性呼吸衰竭在过去的十年里，LAM取得了巨大的进步，其中包括 对疾病发病机制的丰富分子理解，诊断和预后生物标志物的开发， 以及治疗方法的发现随机对照罕见肺病联盟（RLDC）多中心 西罗莫司的国际LAM疗效（MILES）试验（申办者-FXM，IND 71，340）证明mTOR 西罗莫司抑制是一种有效的LAM抑制治疗，稳定肺功能，功能 肺功能异常的女性的性能和生活质量。西罗莫司的副作用是 在MILES中常见，尽管西罗莫司组和安慰剂组中SAE均衡。的有益效果 西罗莫司在试验的第二年开始下降。虽然主要合格标准 1秒用力呼气量（FEV 1）≤ 70%，入组MILES患者的晚期 呼吸障碍，大约一半的肺功能仍然存在（平均），限制了 发现轻微疾病。对毒性的恐惧和终身治疗导致大多数临床医生和患者等到肺 在开始西罗莫司治疗以稳定受损的肺之前，肺功能变得异常。这种方法 次优和不足。多中心介入性LAM早期疾病试验（MILED）是一项III期， 一项随机、安慰剂对照试验，以确定早期、长期（2年）、低剂量（1 mg/天）西罗莫司 对肺功能保存良好的患者的治疗将安全地防止疾病进展。60名患者 将招募具有正常FEV 1（FEV 1>70%）的患者，并随机分配至1 mg/天西罗莫司或安慰剂组，并随访 2年，每4个月进行一次肺功能检查。主要终点为组间 （安慰剂对比西罗莫司）FEV 1（以升计）变化率的差异。次要终点将包括 不良事件、用力肺活量、肺容量、弥散量、血清 VEGF-D和使用超极化气体MRI评估的早期气流阻塞。本研究的开展将 使用为RLDC创建的基础设施，使用罕见肺病诊所网络，该网络目前 跟踪了1200多名美国LAM患者并进行了TRAIL试验。LAM基金会将是一个不可或缺的 合作伙伴，并将协助研究招募和患者参与。数据将由大学管理 南佛罗里达数据管理和协调中心。这些目标的成功实现将决定 低剂量西罗莫司在肺功能正常患者中的安全性和有效性，并确定西罗莫司是否可以 用于预防疾病进展到症状阶段。

Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (The MILED Trial) Project Summary Lymphangioleiomyomatosis (LAM) is low-grade metastasizing neoplasm of women, driven by activating mutations in the mTOR pathway that result in cystic destruction of the lung. The benign appearing, mutation bearing smooth muscle-like LAM cells that infiltrate the lung arise from an unknown source and execute a program of matrix remodeling that leads to cyst formation, recurrent pneumothorax, chylous pleural effusion and progressive respiratory failure. There has been tremendous progress in LAM in the past decade, including a rich molecular understanding of disease pathogenesis, development of a diagnostic and prognostic biomarker, and the discovery of a treatment. The randomized controlled Rare Lung Disease Consortium (RLDC) Multicenter International LAM Efficacy of Sirolimus (MILES) Trial (Sponsor-FXM, IND 71,340) demonstrated that mTOR inhibition with sirolimus is an effective suppressive therapy for LAM, stabilizing lung function, functional performance, and quality of life in women with abnormal lung function. Side effects due to sirolimus were common in MILES, although SAEs were balanced in the sirolimus and placebo groups. The beneficial effects of sirolimus waned when the drug was held in the second year of the trial. Although the primary eligibility criterion was forced expiratory volume in 1 second (FEV1) ≤ 70%, enrolled MILES patients had more advanced respiratory impairment, with about half of lung function remaining (on average), limiting the generalizability of the findings to mild disease. Fear of toxicities and life long therapy lead most clinicians and patients to wait until lung function becomes abnormal before initiating sirolimus therapy to stabilize the damaged lung. This approach is suboptimal and inadequate. The Multicenter Interventional LAM Early Disease Trial (MILED) is a phase III, randomized, placebo-controlled trial to determine if early, long term (2 yr), low dose (1 mg/day) sirolimus treatment of patients with well-preserved lung function will safely prevent disease progression. Sixty patients with normal FEV1 (FEV1>70%) will be enrolled and randomized to 1 mg/day sirolimus or placebo, and followed for 2 years with pulmonary function testing every 4 months. The primary endpoint will be the between-group (placebo vs. sirolimus) difference in the rate of change in FEV1 (in liters). Secondary endpoints will include between group differences in adverse events, forced vital capacity, lung volumes, diffusing capacity, serum VEGF-D, and early airflow obstruction assessed using hyper-polarized gas MRI. The study will be conducted using the infrastructure created for the RLDC, using the Rare Lung Disease Clinic Network, which is currently following over 1200 U.S. LAM patients and conducting the TRAIL trial. The LAM Foundation will be an integral partner and will assist with study recruitment and patient participation. Data will be managed by the University of South Florida Data Management and Coordinating Center. Successful completion of these aims will define the safety and efficacy of low dose sirolimus in patients with normal lung function, and determine if sirolimus can be used to prevent disease progression to symptomatic stages.