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）-CCC

• 批准号: 9520409
• 负责人: Francis Xavier McCormack
• 金额: $ 87.03万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9520409
• 关键词: Address; Adverse effects; 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; International; Intervention; Investments; Japan; Knowledge; Lead; Life; Lung; Lung diseases; Lymphangioleiomyomatosis; Magnetic Resonance Imaging; Measures; Molecular; Mutation; Neoplasm Metastasis; Neoplasms; Obstruction; 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; Research Infrastructure; Respiratory Failure; Respiratory physiology; 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; 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; randomized placebo controlled trial; rate of change; recruit; respiratory; secondary endpoint; targeted treatment

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.

多中心介入性淋巴管平滑肌瘤病早期疾病试验（MILED 试验） 项目概要 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 通路突变导致肺囊性破坏。良性外观，突变 具有类似平滑肌的 LAM 细胞浸润肺部，其来源未知，并执行 基质重塑程序导致囊肿形成、复发性气胸、乳糜性胸腔积液和 进行性呼吸衰竭。过去十年，LAM 取得了巨大进步，其中包括 对疾病发病机制的丰富分子了解，开发诊断和预后生物标志物， 以及治疗方法的发现。随机对照罕见肺病联盟 (RLDC) 多中心 西罗莫司 (MILES) 的国际 LAM 功效试验（申办方-FXM，IND 71,340）证明 mTOR 西罗莫司抑制是 LAM 的有效抑制疗法，可稳定肺功能、功能 肺功能异常女性的表现和生活质量。西罗莫司引起的副作用是 尽管 SAE 在西罗莫司组和安慰剂组中是平衡的，但在 MILES 中很常见。的有益效果 当药物在试验的第二年进行时，西罗莫司的作用逐渐减弱。虽然主要资格标准 1 秒用力呼气量 (FEV1) ≤ 70%，入组的 MILES 患者病情较晚期 呼吸障碍，肺功能仅剩一半（平均），限制了该方法的普遍性 结果为轻度疾病。对毒性和终生治疗的恐惧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部之前，功能出现异常。这种方法是 次优且不充分。多中心介入 LAM 早期疾病试验 (MILED) 是一项 III 期临床试验， 随机、安慰剂对照试验，以确定是否可以早期、长期（2 年）、低剂量（1 毫克/天）西罗莫司 对肺功能保存良好的患者进行治疗将安全地防止疾病进展。六十名患者 FEV1 正常（FEV1>70%）的患者将被纳入并随机接受 1 毫克/天西罗莫司或安慰剂，然后进行随访 持续 2 年，每 4 个月进行一次肺功能检测。主要终点将是组间 （安慰剂与西罗莫司）FEV1 变化率的差异（以升为单位）。次要终点将包括 不良事件、用力肺活量、肺容量、弥散能力、血清的组间差异 使用超极化气体 MRI 评估 VEGF-D 和早期气流阻塞。该研究将进行 使用为 RLDC 创建的基础设施，使用目前正在使用的罕见肺病诊所网络 跟踪超过 1200 名美国 LAM 患者并进行 TRAIL 试验。 LAM 基金会将成为一个不可分割的组成部分 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 南佛罗里达州数据管理和协调中心。成功完成这些目标将定义 低剂量西罗莫司对肺功能正常患者的安全性和有效性，并确定西罗莫司是否可以 用于预防疾病进展至症状阶段。