Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED) - DCC

多中心介入性淋巴管平滑肌瘤病早期疾病试验 (MILED) - DCC

基本信息

批准号：
10249943
负责人：
JEFFREY P KRISCHER
金额：
$ 29.14万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10249943
关键词：
Address Adverse event Aromatase Inhibitors Benign Biological Markers Cells Cessation of life Charge Chronic Chronic Myeloid Leukemia Clinic Clinical Communities Cyst Data Data Coordinating Center Department of Defense Development Diffuse Disease Disease Progression Dose Eligibility Determination Enrollment FDA approved FRAP1 gene Florida Foundations Fright Gases Genes Gleevec Goals Growth Growth Factor Impairment Information Dissemination Infrastructure International Intervention Investments Japan Knowledge Lead Lung Lung diseases Lymphangiogenesis Lymphangioleiomyomatosis Magnetic Resonance Imaging Measures Molecular Mutation Neoplasm Metastasis Neoplasms Pathogenesis Pathway interactions Patient Participation Patients Performance Pharmaceutical Preparations Phase Placebos Pleural effusion disorder Pneumothorax Prognostic Marker Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary function tests Quality of life Randomized Recurrence Respiratory Failure Safety Serum Severities Signal Transduction Sirolimus Site Smooth Muscle Smooth Muscle Myocytes Source Time Toxic effect Tuberous Sclerosis Universities Vascular Endothelial Growth Factor D Vital capacity Woman advanced disease airway obstruction biomarker discovery data management diagnostic biomarker disability improved lung injury lung preservation lung volume mTOR Inhibitor mTOR inhibition middle age mortality neoplastic placebo group prevent primary endpoint programs pulmonary function pulmonary function decline randomized placebo controlled trial rate of change recruit respiratory secondary endpoint side effect targeted treatment

项目摘要

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.

项目概要/摘要淋巴管平滑肌瘤病 (LAM) 是一种女性低度转移性肿瘤，由激活性肿瘤驱动 mTOR 通路中的突变会导致肺部囊性破坏，这种突变看起来是良性的。具有类似平滑肌的 LAM 细胞浸润肺部，其来源未知，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程序过去十年，LAM 取得了巨大进展，包括：对疾病发病机制、诊断和预后的发展有丰富的分子了解生物标志物，以及随机对照罕见肺病联盟的发现。 (RLDC) 西罗莫司 (MILES) 多中心国际 LAM 疗效试验（主办方 - FXM，IND 71,340）证明用西罗莫司抑制 mTOR 是一种有效的 LAM 抑制疗法，可稳定肺部因肺功能异常而引起的副作用的女性的功能、功能表现和生活质量。尽管西罗莫司组和安慰剂组的 SAE 是平衡的，但西罗莫司在 MILES 中很常见。在试验的第二年，西罗莫司的有益效果减弱了。主要资格标准是 1 秒用力呼气量 (FEV1) ≤ 70%，纳入 MILES 患者患有更严重的呼吸障碍，肺功能仅剩一半（平均），限制了对毒性和终身治疗的恐惧导致了研究结果对轻度疾病的普遍性。患者应等到肺功能出现异常后再开始西罗莫司治疗以稳定病情这种方法是次优且不充分的。试验 (MILED) 是 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可安全预防疾病 60 名 FEV1 正常（FEV1>70%）的患者将被纳入并随机接受 1 mg/天。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测。终点是组间（安慰剂与西罗莫司）FEV1 变化率的差异（以升为单位）。次要终点包括不良事件、用力肺活量、肺功能的组间差异。使用超极化气体评估体积、扩散能力、血清 VEGF-D 和早期气流阻塞该研究将使用为 RLDC 创建的基础设施和罕见肺病进行。 Clinic Network 目前正在追踪 1300 多名美国 LAM 患者并进行 TRAIL 试验。 LAM 基金会将成为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。这些目标的完成将确定低剂量西罗莫司在正常肺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至症状阶段。