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.

一些特发性肺纤维化（IPF）的患者是一种进行性纤维增生性肺部疾病老年人，会出现突然的急性加重（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，尽管这些和所有其他医疗疗法尝试迄今为止是无效的。我们的研究小组以及其他研究结果表明，许多与常规自身抗体介导的综合征相同的免疫异常也很常见在IPF患者中，特别是在患有或很快会急性加重的患者中。由于许多常规的自身抗体介导的肺疾病也对用类固醇和其他非特异性代理。但是，专门减少先前存在的自身抗体的方案，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对这些综合征。我们已经进行了概念验证试验试验，其中认真对待了AE-IPF患者治疗性等离子体交换（TPE）非常快速地减少循环自身抗体，再加上利妥昔单抗耗尽产生自身抗体的B细胞，加上静脉免疫球蛋白（IVIG），以进一步抑制自身抗体产生。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，导致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。我们在这里提出了一项随机IIB临床试验，以通过比较的功效来检验该假设 TPE Plus Rituximab Plus IVIG与往常一样（TAU）的AE-IPF患者。提供通知后同意，在五个参与医疗中心住院的AE-IPF的受试者将被随机分配（2：1）实验臂或tau分别。该试验的主要终点是六个月的生存期。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率。我们预计这种创新的实验治疗将导致在提高生存率，较小的氧气需求，更大的功能能力和可接受的毒性中轮廓。其他翻译研究将研究AE-自身抗体测定的潜在临床使用 IPF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行性且经常致命性肺部病的患者。