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：
9743827
负责人：
JEFFREY P KRISCHER
金额：
$ 30.14万
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9743827
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 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 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 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 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.

项目摘要/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，cylous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，包括对疾病发病机理的丰富分子理解，诊断和预后的发展生物标志物和治疗的发现。随机控制的罕见肺部疾病财团（RLDC）Sirolimus（Miles）试验的多中心国际LAM功效（赞助商 - FXM，IND 71,340）证明对Sirolimus抑制MTOR是对LAM的有效抑制疗法，稳定肺肺部功能异常的女性的功能，功能性能和生活质量。副作用是由于西罗莫木斯（Sirolimus）在英里处很常见，尽管SAE在Sirolimus和安慰剂组中保持平衡。这在试验的第二年举行该药物时，Sirolimus的有益影响减弱。虽然初级资格标准在1秒（FEV1）≤70％，招募的英里患者中被迫到期量呼吸障碍更高级，剩余的肺功能（平均）限制了一半调查结果对轻度疾病的概括性。害怕毒性和终身治疗导致大多数临床医生和患者等到肺功能变得异常，然后开始西罗里木司治疗才能稳定受损的肺。这种方法是次优的和不足的。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毫克/天）西罗里木斯对保存完好的肺功能的患者治疗将安全预防疾病进展。 60例FEV1（FEV1> 70％）的患者将被招募并随机分为1 mg/天 Sirolimus或安慰剂，随后每4个月进行一次肺功能测试2年。主要端点将是FEV1（以升）变化率的组间（安慰剂与西罗莫司）的差异。次要终点将包括不良事件的群体差异，强迫生命力，肺使用高极化气体评估的体积，扩散能力，血清VEGF-D和早期气流异常 MRI。该研究将使用为RLDC创建的基础设施进行，使用罕见的肺部疾病临床网络，目前正在关注1300多名美国LAM患者并进行越野试验。这 Lam Foundation将是一个不可或缺的合作伙伴，并将协助研究招聘和患者参与。数据将由南佛罗里达大学的数据管理和协调中心管理。成功的这些目的的完成将定义正常肺患者的低剂量西洛里木斯的安全性和效率功能，并确定Sirolimus是否可以用于防止疾病发展到症状阶段。