Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED) - DCC

项目摘要/摘要 淋巴管肌瘤病(LAM)是一种女性低度转移性肿瘤，由活化引起 导致肺囊性破坏的mTOR途径突变。良性的出现、突变 具有平滑肌样LAM细胞的浸润性肺组织来自未知来源，并执行 导致囊肿形成、复发性气胸、乳糜性胸腔积液的基质重塑方案 和进行性呼吸衰竭。在过去的十年中，LAM取得了巨大的进步，包括 丰富了对疾病发病机制的分子认识，制定了诊断和预后 生物标记物，以及治疗方法的发现。随机对照的罕见肺病联合体 (RLDC)西罗莫司(MILES)试验的多中心国际LAM疗效(赞助商-FXM，IND 71,340) 证明西罗莫司抑制mTOR是一种有效的稳肺LAM抑制疗法。 肺功能异常妇女的功能、功能表现和生活质量。因以下原因而产生的副作用 西罗莫司在里程中很常见，尽管西罗莫司组和安慰剂组的SAE是平衡的。这个 当西罗莫司在试验的第二年被搁置时，其益处减弱。尽管 主要资格标准是1秒用力呼气量(FEV1)≤70%，登记的英里数患者 有更严重的呼吸损伤，大约一半的肺功能剩余(平均)，限制了 对轻度疾病研究结果的概括性。对毒性的恐惧和终身治疗使大多数临床医生和 患者等到肺功能异常后再开始西罗莫司治疗以稳定肺功能 肺部受损。这种方法是次优的，也是不充分的。多中心介入治疗LAM早期病 试验(MILD)是第三阶段，随机、安慰剂对照试验，以确定早期、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可安全预防疾病 进步。60名FEV1正常的患者(FEV1和GT；70%)将被纳入并随机服用1毫克/天 西罗莫司或安慰剂，随访2年，每4个月检测一次肺功能。初级阶段 终点将是两组之间(安慰剂与西罗莫司)FEV1变化率(升)的差异。 次要终点将包括两组之间在不良事件、用力肺活量、肺 用超极化气体评估容量、弥散能力、血清血管内皮生长因子-D和早期气流阻塞 核磁共振检查。这项研究将使用为RLDC创建的基础设施，使用罕见的肺部疾病 目前正在跟踪1300多名美国LAM患者并进行试验试验。这个 LAM基金会将成为不可或缺的合作伙伴，并将在研究招募和患者参与方面提供帮助。数据 将由南佛罗里达大学数据管理和协调中心管理。成功 完成这些目标将确定小剂量西罗莫司在肺功能正常的患者中的安全性和有效性 功能，并确定西罗莫司是否可以用于防止疾病进展到有症状的阶段。

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.