Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED) - DCC

项目概要/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、乳糜性胸腔积液的基质重塑程序 和进行性呼吸衰竭在过去的十年里，LAM取得了巨大的进步，包括 对疾病发病机制的丰富分子理解，诊断和预后的发展 生物标志物，以及治疗方法的发现。随机对照罕见肺病联盟 （RLDC）西罗莫司的多中心国际LAM疗效（MILES）试验（申办者-FXM，IND 71，340） 证明用西罗莫司抑制mTOR是LAM的有效抑制疗法，稳定肺 肺功能异常女性的功能、功能表现和生活质量。副作用由于 西罗莫司在MILES中很常见，尽管西罗莫司和安慰剂组的SAE分布均衡。的 西罗莫司的有益作用在试验的第二年就减弱了。虽然 主要合格标准为1秒用力呼气量（FEV 1）≤ 70%，入组MILES患者 有更严重的呼吸障碍，大约一半的肺功能仍然存在（平均），限制了 研究结果对轻度疾病的普遍性。对毒性和终身治疗的恐惧导致大多数临床医生和 患者应等到肺功能异常后再开始西罗莫司治疗，以稳定 肺部受损这种方法是次优和不充分的。多中心介入治疗LAM早期疾病 试验（MILED）是一项III期、随机、安慰剂对照试验，旨在确定早期、长期（2年）、低剂量 （1毫克/天）西罗莫司治疗肺功能保存良好的患者将安全地预防疾病 进展将招募60名FEV 1正常（FEV 1>70%）的患者，并随机分配至1 mg/天组 西罗莫司或安慰剂，并随访2年，每4个月进行一次肺功能检查。主 终点为FEV 1（以升为单位）变化率的组间（安慰剂vs.西罗莫司）差异。 次要终点将包括不良事件、用力肺活量、肺功能和心功能的组间差异。 使用超极化气体评估容积、弥散能力、血清VEGF-D和早期气流阻塞 核磁共振本研究将使用为RLDC创建的基础设施进行，使用罕见肺部疾病 Clinic Network目前正在跟踪1300多名美国LAM患者并进行TRAIL试验。的 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 将由南佛罗里达大学数据管理和协调中心管理。成功 这些目标的完成将确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， 功能，并确定西罗莫司是否可用于预防疾病进展到症状阶段。

Project summary/abstract 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 lifelong 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 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 1300 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.