Rituximab Therapy in Patients with IPF

IPF 患者的利妥昔单抗治疗

基本信息

批准号：
8561444
负责人：
STEVEN R DUNCAN
金额：
$ 67.36万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-16 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8561444
关键词：
Adopted Adrenal Cortex Hormones Adverse event Aftercare Antibodies Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity B cell differentiation B-Lymphocytes Biological Assay Cell Maturation Cell Survival Characteristics Chemokine (C-C Motif) Ligand 4 Clinical Clinical Trials Critical Illness Data Diagnosis Disease Disease Progression Dose Double-Blind Method Drug Kinetics Elderly Enrollment Future Glucocorticoids Hamman-Rich syndrome Health Heat-Shock Proteins 70 Human Immune system Immunoglobulin G Immunoglobulins Indirect Fluorescent Antibody Technique Inflammatory Interleukin-8 Investigation Investigational Therapies Kinetics Lead Lung Lung diseases Lymphocyte MS4A1 gene Malignant Neoplasms Measures Mediating Medical Medical center Modality Monitor Monoclonal Antibodies Monoclonal Antibody CD20 Mus Outcome Measure Pathogenesis Pathologic Processes Patients Pharmaceutical Preparations Pharmacodynamics Phase II Clinical Trials Pilot Projects Placebo Control Placebos Plasma Play Population Process Production Randomized Refractory Refractory Disease Regimen Research Resistance Respiratory physiology Role Safety Steroids Syndrome Testing Time Toxic effect Vital capacity abstracting arm belimumab clinical efficacy design effective therapy improved monocyte novel outcome forecast pilot trial rituximab secondary outcome treatment effect treatment trial trial comparing

项目摘要

DESCRIPTION (provided by applicant): The cause(s) of idiopathic pulmonary fibrosis (IPF) remain unknown, as well as the factors that result in the progression of this disease. No established medical treatments have yet been shown to benefit patients with this disease, and IPF continues to have a worse prognosis than many common malignancies. Recent findings of our research group, as well as others, show that autoantibodies are associated with IPF progression. Results of an early ongoing pilot study further indicate that specific treatments aimed at reducing pre-existing autoantibodies and/or minimizing their future production improve lung function among very ill IPF patients who are having disease exacerbations. We hypothesize that antibody-mediated autoimmunity can play an important role in IPF progression. The presence of autoimmunity could explain the refractoriness of this disease to current therapy, since many autoantibody lung diseases are resistant to treatment with corticosteroids. However, focused treatments targeted at autoantibodies or the lymphocytes that produce these immunoglobulins often have greater efficacy for these diseases than steroids or other nonspecific therapies. Accordingly, we propose here a multicenter, randomized, double-blind, placebo-controlled Phase II clinical trial to explore the efficacy and safety of rituximab (anti-CD20 monoclonal antibody) vs. placebo, among patients with IPF. Fifty-eight (58) ambulatory IPF subjects at four participating U.S. medical centers will be randomized (1:1) to either the experimental arm (rituximab) or placebo. The primary end-point is a global assessment of circulating autoantibodies. Secondary end-points are measures of a specific autoantibody that is associated with clinical progression (anti-heat shock protein 70), as well as a measure of lung function (forced vital capacity), and adverse event rates. We anticipate the novel experimental treatment will show targeted efficacy for reduction of autoantibodies, a favorable safety profile, and possibly stabilization of lung function. Results of these investigations will establish the efficacy and pharmacokinetics of rituximab treatment in IPF patients. Ultimately these studies could challenge current paradigms of IPF pathogenesis, and substantially alter treatment approaches to patients afflicted with this morbid, refractory disease.

描述（由申请人提供）：特发性肺纤维化（IPF）的原因尚不清楚，以及导致该疾病进展的因素。尚未证明既定的医疗治疗可以使这种疾病的患者受益，并且IPF的预后比许多常见的恶性肿瘤更糟糕。我们的研究小组以及其他人的最新发现表明自身抗体与IPF进展有关。一项正在进行的试点研究的结果进一步表明，旨在减少先前存在的自身抗体和/或最小化其未来产量的特定治疗方法可以改善患有疾病恶化的IPF患者的肺功能。我们假设抗体介导的自身免疫可以在IPF进展中发挥重要作用。自身免疫的存在可以解释这种疾病对当前疗法的耐火性，因为许多自身抗体肺部疾病对用皮质类固醇的治疗有抵抗力。但是，针对自身抗体或产生这些免疫球蛋白的淋巴细胞的聚焦治疗通常比类固醇或其他非特异性疗法具有更大的功效。因此，我们在这里提出了一个多中心，随机，双盲，安慰剂对照的II期临床试验，以探索IPF患者中利妥昔单抗（抗CD20单克隆抗体）与安慰剂的功效和安全性。在美国四个参与的医疗中心的58名（58）室外IPF受试者将被随机分配给实验组（利妥昔单抗）或安慰剂。主要终点是对循环自身抗体的全球评估。次要终点是与临床进展有关（抗热休克蛋白70）以及肺功能（强制生命力）和不良事件率的特定自身抗体的度量。我们预计，新型实验治疗将显示出降低自身抗体，有利的安全性以及可能稳定肺功能的靶向疗效。这些研究的结果将确定利妥昔单抗治疗对IPF患者的功效和药代动力学。最终，这些研究可能会挑战IPF发病机理的当前范式，并为患有这种病态的难治性疾病患者的治疗方法实质上改变了治疗方法。