Autoantibody-Targeted Therapy for Acute Exacerbations of Idiopathic Pulmonary Fibrosis

自身抗体靶向治疗特发性肺纤维化急性加重

基本信息

批准号：
10231147
负责人：
Gerard J Criner
金额：
$ 70.07万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231147
关键词：
Activities of Daily Living Acute Adverse event Ancillary Study Antibodies Autoantibodies Autoimmune Avidity B-Lymphocytes Biological Assay Biological Markers Cardiopulmonary Catheters Cessation of life Clinical Clinical Trials Confidence Intervals Control Groups Critical Illness Data Disease Dyspnea Elderly Enzyme-Linked Immunosorbent Assay Frequencies Functional disorder Future Glucocorticoids Home Hospitals Hypoxemia IgG autoantibodies Immune Immune system Immunofluorescence Immunologic Immunoprecipitation Indirect Fluorescent Antibody Technique Infection Informed Consent Intravenous Immunoglobulins Investigation Investigational Therapies Lead Lung Lung diseases Lytic Measures Mediating Medical Medical center Metabolic Modality Monoclonal Antibodies Odds Ratio Oxygen Pathologic Patients Pharmaceutical Preparations Phase Plasma Plasmapheresis Production Proteomics Pulmonary Gas Exchange Randomized Refractory Regimen Relapse Research Resistance Respiratory Failure Specimen Steroids Syndrome Testing Time Toxic effect Walking arm autoimmune pathogenesis comparative comparative efficacy disorder control experimental arm foot hazard hemodynamics idiopathic pulmonary fibrosis improved innovation knowledge of results pilot trial precision medicine primary endpoint prospective response rituximab secondary endpoint standard care supplemental oxygen targeted treatment tool translational study treatment as usual treatment duration treatment effect treatment response

项目摘要

Some patients with idiopathic pulmonary fibrosis (IPF), a progressive fibroproliferative lung disease of older adults, develop sudden acute exacerbations (AE-IPF) that can result in respiratory failure and death within days. Steroids are standard treatment for AE-IPF, although these and all other medical therapies tried to date have been ineffectual. Findings of our research group, as well as others, show that numerous immune abnormalities that are identical to conventional autoantibody-mediated syndromes are also common in IPF patients, especially among those who are having or will soon have acute exacerbations. An autoimmune pathogenesis could also explain the refractoriness of AE-IPF to current therapy, since many conventional autoantibody-mediated lung diseases are also resistant to treatment with steroids and other nonspecific agents. However, regimens that specifically reduce preexisting autoantibodies, deplete autoantibody-producing B-cells, and/or inhibit B-cell autoantibody production are more often beneficial for these syndromes. We have conducted a proof-of-concept pilot trial in which seriously-ill AE-IPF patients were treated with therapeutic plasma exchange (TPE) to very rapidly reduce circulating autoantibodies, plus rituximab to deplete autoantibody-producing B-cells, plus intravenous immunoglobulin (IVIG) to further inhibit auto- antibody production. In comparisons to a historical control group, these autoantibody reduction therapies resulted in unprecedented clinical responses in most AE-IPF patients. Accordingly, we hypothesize: AUTOANTIBODY REDUCTION IS BENEFICIAL FOR AE-IPF PATIENTS. We propose here a randomized Phase IIb clinical trial to test this hypothesis by comparing efficacy of TPE plus rituximab plus IVIG vs. treatment as usual (TAU) for AE-IPF patients. After providing informed consent, subjects hospitalized for AE-IPF at five participating medical centers will be randomized (2:1) to either the experimental arm or TAU, respectively. The primary endpoint of this trial is six-month survival. Secondary endpoints include changes in requirements for supplemental oxygen and six-minute walk distances, as well as adverse events rates. We anticipate this innovative experimental treatment will result in improved survival, lesser oxygen requirements, greater functional capacities, and an acceptable toxicity profile. Additional translational studies will examine the potential clinical use of autoantibody assays in AE- IPF patients. Results of this investigation could substantially alter treatment approaches, and save the lives of future patients who have this rapidly progressive and too-often lethal lung disease.

一些患有特发性肺纤维化（IPF）的患者，这是一种进行性纤维增生性肺部疾病老年人出现突然急性加重 (AE-IPF)，可能导致呼吸衰竭和死亡几天之内。类固醇是 AE-IPF 的标准治疗方法，尽管这些疗法和所有其他药物疗法都已尝试过迄今为止都没有效果。我们的研究小组以及其他研究小组的研究结果表明，许多与传统自身抗体介导的综合征相同的免疫异常也很常见 IPF 患者，尤其是那些正在或即将出现急性加重的患者。自身免疫发病机制也可以解释 AE-IPF 对当前治疗的难治性，因为许多传统的自身抗体介导的肺部疾病也对类固醇治疗有抵抗力，其他非特异性药物。然而，专门减少先前存在的自身抗体的治疗方案会耗尽产生自身抗体的 B 细胞和/或抑制 B 细胞自身抗体的产生通常更有益于这些综合症。我们进行了一项概念验证试点试验，其中重病 AE-IPF 患者接受了治疗性血浆置换 (TPE) 可快速减少循环自身抗体，加上利妥昔单抗耗尽产生自身抗体的 B 细胞，加上静脉注射免疫球蛋白 (IVIG) 以进一步抑制自身抗体抗体的产生。与历史对照组相比，这些自身抗体减少疗法在大多数 AE-IPF 患者中产生了前所未有的临床反应。因此，我们假设：自身抗体减少对 AE-IPF 患者有益。我们在此提出一项随机 IIb 期临床试验，通过比较以下药物的功效来检验这一假设：对于 AE-IPF 患者，TPE 加利妥昔单抗加 IVIG 与常规治疗 (TAU) 比较。提供知情后经同意，在五个参与医疗中心因 AE-IPF 住院的受试者将被随机 (2:1) 分配至分别为实验组或 TAU。该试验的主要终点是六个月的生存率。次要终点包括补充氧气和六分钟步行需求的变化距离以及不良事件发生率。我们预计这种创新的实验治疗将会产生提高生存率、减少氧气需求、提高功能能力以及可接受的毒性轮廓。其他转化研究将检验自身抗体检测在 AE 中的潜在临床应用特发性肺纤维化患者。这项调查的结果可能会大大改变治疗方法，并挽救未来的生命患有这种快速进展且往往致命的肺部疾病的患者。