Rituximab Therapy in Patients with IPF

IPF 患者的利妥昔单抗治疗

• 批准号: 8890196
• 负责人: STEVEN R DUNCAN
• 金额: $ 67.36万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-12 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890196
• 关键词: Adopted; Adrenal Cortex Hormones; Adverse event; Aftercare; Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell differentiation; B-Lymphocytes; Biological Assay; CCL4 gene; Cell Maturation; Cell Survival; Characteristics; 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; targeted therapy trials; treatment effect; trial comparing

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（由申请方提供）：特发性肺纤维化（IPF）的病因以及导致该疾病进展的因素仍未知。尚未有确定的药物治疗显示对患有这种疾病的患者有益，IPF的预后仍然比许多常见的恶性肿瘤更差。我们研究小组的最新发现以及其他研究结果表明，自身抗体与IPF进展相关。一项正在进行的早期初步研究的结果进一步表明，旨在减少既存自身抗体和/或最大限度地减少其未来产生的特定治疗可改善疾病加重的重度IPF患者的肺功能。我们假设抗体介导的自身免疫在IPF进展中起重要作用。自身免疫的存在可以解释这种疾病对目前治疗的难治性，因为许多自身抗体肺病对皮质类固醇治疗有抵抗力。然而，针对自身抗体或产生这些免疫球蛋白的淋巴细胞的集中治疗通常比类固醇或其他非特异性治疗对这些疾病具有更大的疗效。 因此，我们在此提出了一项多中心、随机、双盲、安慰剂对照的II期临床试验，以探索利妥昔单抗（抗CD 20单克隆抗体）与安慰剂相比在IPF患者中的疗效和安全性。来自4家参与研究的美国医学中心的58例非卧床IPF受试者将随机（1：1）分配至试验组（利妥昔单抗）或安慰剂组。主要终点是对循环自身抗体的总体评估。次要终点是与临床进展相关的特异性自身抗体（抗热休克蛋白70）的测量，以及肺功能（用力肺活量）和不良事件发生率的测量。我们预计新的实验性治疗将显示出减少自身抗体的靶向疗效，有利的安全性特征，以及可能的肺功能稳定。 这些研究的结果将确定利妥昔单抗治疗IPF患者的疗效和药代动力学。最终，这些研究可能会挑战目前IPF发病机制的范式，并大大改变患有这种病态难治性疾病的患者的治疗方法。