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.

多中心介入淋巴结肌瘤病早期疾病试验（MILED试验） 项目摘要 淋巴血管肌瘤（LAM）是女性的低度转移肿瘤，由激活驱动 MTOR途径中导致肺部囊性破坏的突变。良性出现，突变 轴承平滑肌样的LAM细胞，浸润肺部由未知来源引起并执行A 矩阵重塑的程序，导致囊肿形成，复发性气胸，cy胸膜积液和 进行性呼吸衰竭。在过去的十年中，林的林取得了巨大进展，包括 丰富的分子理解疾病发病机理，诊断和预后生物标志物的发展， 以及发现治疗的发现。随机控制的罕见肺部疾病财团（RLDC）多中心 Sirolimus（Miles）试验的国际LAM功效（赞助商 - FXM，IND 71,340）证明了MTOR 用西罗莫司抑制是一种有效的LAM抑制疗法，稳定肺功能，功能 肺部功能异常的女性的表现和生活质量。西罗莫司引起的副作用是 尽管SAE在西罗莫司和安慰剂组中保持平衡，但在英里中很常见。有益的影响 在审判的第二年举行该药物时，西罗莫司（Sirolimus）逐渐减弱。虽然主要资格标准 在1秒（FEV1）≤70％的强迫呼气量中，招募的英里患者更为先进 呼吸障碍，剩余的肺功能剩余约一半（平均）限制了 温和疾病的发现。担心毒性和寿命长期治疗导致大多数临床医生和患者等到肺 在启动西罗莫司治疗以稳定受损的肺部之前，功能变得异常。这种方法是 次优和不足。多中心介入的LAM早期疾病试验（MILED）是III期， 随机，安慰剂对照试验，以确定早期，长期（2年），低剂量（1 mg/天）Sirolimus是否是否 保存完好的肺功能患者的治疗将安全防止疾病进展。六十位患者 有正常的FEV1（FEV1> 70％）将被录入并随机分配至1 mg/天Sirolimus或安慰剂，然后随后 每4个月进行肺功能测试2年。主要终点将是组间 （安慰剂与西罗莫司）FEV1的变化率差异（以升为单位）。次要终点将包括 在不良事件的群体差异之间，强迫生命力，肺部体积，扩散能力，串行 VEGF-D和使用高极化气体MRI评估的VEGF-D和早期的气流异议。该研究将进行 使用为RLDC创建的基础设施，使用罕见的肺疾病诊所网络，该网络目前是 在1200多名美国LAM患者并进行了越野试验之后。林基金会将是不可或缺的 合作伙伴，将协助研究招聘和患者参与。数据将由大学管理 南佛罗里达州的数据管理和协调中心。这些目标的成功完成将定义 低剂量西罗洛木斯在正常肺功能患者中的安全性和效率，并确定西罗莫司是否可以 用于防止疾病发展到有症状的阶段。