Translational Studies in Sarcoidosis

结节病的转化研究

基本信息

批准号：
8746566
负责人：
VINCENT MANGANIELLO
金额：
$ 5.49万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8746566
关键词：
Acute Adrenal Cortex Hormones Adverse effects Affect African American Age Alternative Therapies Alveolitis Anti-Inflammatory Agents Anti-inflammatory Benefits and Risks Benign Biological Biological Markers Biopsy Bronchoalveolar Lavage Fluid C-reactive protein Cardiac Cardiopulmonary Categories Cause of Death Cells Cessation of life Characteristics Chest Chronic Cicatrix Clinical Clinical Course of Disease Clinical Protocols Clinical Trials Clinical Trials Design Clostridium perfringens epsilon toxin Collaborations Collection Data Deterioration Diabetes Mellitus Diagnosis Disease Disease remission Doctor of Philosophy Double-Blind Method Dyspnea Enrollment Etiology Exercise stress test FDA approved Fatigue Fibrosis Flare Functional disorder Gold Granuloma Granulomatous Helper-Inducer T-Lymphocyte Hypertension Image Immunologic Tests Incidence Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-12 Interleukin-2 Interstitial Pneumonia Investigation Knowledge Lung Mediating Mediator of activation protein Mononuclear Morbidity - disease rate Muscle Weakness National Heart, Lung, and Blood Institute Organ Osteoporosis Outcome Outcome Measure Participant Pathogenesis Pathway interactions Patients Peptidyl-Dipeptidase A Pharmaceutical Preparations Phase Phenotype Physicians Physiological Placebos Prednisone Process Production Protocols documentation Pulmonary Fibrosis Pulmonary Sarcoidosis Pulmonary function tests Quality of life Quality-of-Life Assessment Race Randomized Recording of previous events Relapse Reporting Research Research Personnel Resolution Respiratory Muscles Respiratory physiology Risk SF-36 Sarcoidosis Secondary to Serious Adverse Event Serum Serum Markers Specimen Staging Steroids Structure System T-Lymphocyte TNF gene Testing Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Index Time Tissues Toxic effect Translational Research Tumor Necrosis Factor-alpha Walking Withdrawal X-Ray Computed Tomography atorvastatin chemokine cytokine design diaries double-blind placebo controlled trial experience follow-up improved inflammatory marker inhibitor/antagonist lymph nodes macrophage minimal risk monocyte novel pill preclinical study receptor response screening sex translational study young adult

项目摘要

Clinical Protocol (NHLBI 06-H-0072): Atorvastatin as a disease-modifying agent in Stage II and Stage III Pulmonary Sarcoidosis: A randomized, double-blinded, placebo-controlled trial. Some Biospecimens will also be collected/stored under the NHLBI Clinical Protocol 96-H-100. PI: Joseph Fontana, Staff Physician, PVMB Purpose of protocol (Precis): Sarcoidosis is a multi-system granulomatous inflammatory disease. Pulmonary involvement is most common. Patients typically experience fatigue, weakness and dyspnea. Respiratory muscle weakness, which may be secondary to granulomatous inflammation, is associated with dyspnea and decreased quality of life (QOL). The disease can remit spontaneously or become chronic, with exacerbations and remissions. In some patients, it can progress to pulmonary fibrosis and death. Granulomatous inflammation is characterized primarily by accumulation of monocytes, macrophages and activated T-lymphocytes, with increased production of key inflammatory mediators, TNF-, INF-, IL-2, and IL-12, characteristic of a Th1-polarized response (T-helper lymphocyte-1 response). Corticosteroids are the current mainstay of treatment, but their long-term benefits are not certain. Because steroids often produce undesirable side effects, investigations to identify alternative therapies are warranted. There is sufficient evidence to test the proof of concept that pathways targeted by statins will have a therapeutic effect in sarcoidosis, since, in pre-clinical studies, statins blunt Th1-mediated inflammatory responses. Objectives: The objective of this protocol is to conduct a randomized, double-blind placebo-controlled, trial which aims to determine if atorvastatin administration results in less steroid use and longer steroid-free intervals in patients with pulmonary sarcoidosis who require prednisone treatment. The primary endpoint is the duration of the steroid-sparing period. Secondary clinical and physiological endpoints are intended to analyze possible anti-inflammatory and beneficial effects of the drugs. Since there is no gold standard outcome measure in sarcoidosis, four categories of secondary endpoints will be used to characterize the effects of the therapeutic agent on the clinical course of the disease: imaging (high resolution chest CT); quality of life assessments (SF-36 and SGRQ), anti-inflammatory effects (biomarkers and relapse rates), and functional effects (CPET, PFTs). Basic Design: Subjects, 18-70 years old, with stage II or III pulmonary sarcoidosis, diagnosed by a compatible clinical history and supported by a lung, lymph node, or tissue biopsy, will be enrolled in the study, if they require prednisone therapy. The subjects will be randomly assigned to two groups; as prednisone is tapered in both groups, one group will receive placebo, and the other, atorvastatin (80 mg/day). The study drug will be administered for twelve months, during which time patients will be periodically evaluated as to their clinical status and prednisone requirements. Pill counts and patient diaries will be used to determine the amount of prednisone use during the study period. Endpoints The primary endpoint is to determine if atorvastatin administration results in longer steroid-sparing intervals in patients with pulmonary sarcoidosis who require prednisone. The secondary endpoints include: Clinical (Total prednisone usage, remission and relapse rates (flares), quality of life indicators (SF-36, SGRQ), dyspnea scales (AMA and BDI/TDI), and an exploratory parameter, the therapeutic index.) Physiologic (Pulmonary function tests, cardiopulmonary exercise tests, and the six-minute walk test) Immunologic (Serum markers: serum angiotensin converting enzyme, tumor necrosis factor alpha II receptor, serum soluble IL-2 receptor, and C-reactive protein; bronchoalveolar lavage fluid inflammatory markers, cellll counts, and cytokines) Imaging (Standard chest x-ray and computerized tomography, and high resolution computerized tomography with semi-quantitative and quantitative scoring) Progress achieved: Fifty three subjects have been enrolled and randomized.Forty four subjects have completed the 1 year treatment phase of the study. Accrual Ceiling: 96 Total number of subjects enrolled: 53 Total of subjects randomized to study agent: 53 Total number of subjects completed 1 year of study agent: 44 Total of currently active participants: 4 Number of patients still on study agent 3 Number of patients still in the follow-up phase 1 Total number of withdrawals: 6 Reasons to continue the protocol: Sarcoidosis is a multi-system granulomatous inflammatory disease of unknown etiology. Corticosteroids are the current mainstay of treatment, but their long-term benefits are not certain, and their use is associated with a decrease in quality of life. Because steroids produce undesirable side effects, investigations to identify alternative therapies are warranted. While alternative therapies are available, none are FDA-approved. Most alternative therapies are not benign, and there are no long-term data supporting their use in pulmonary sarcoidosis. Given the limited options, none of which are ideal, (that is, highly effective agents with mild side-effect/toxicity profiles), patients, at their own risk, sometimes forego treatment altogether, to avoid the untoward effects of steroids or the alternative agents. Rigorous clinical trials are needed to determine whether anti-inflammatory agents can provide steroid-sparing benefits and improve therapeutic outcomes. Because we have active subjects, on-going collection of their data will be important in evaluating the primary and secondary endpoints of this study. We therefore believe that there is merit in continuing the study as planned. Study Findings to Date: An interim analysis was previously performed on the available data from 49 of 50 randomized subjects. The analysis was completed in accordance with protocol; it demonstrated no significant difference between the treatment groups. The study has remained double blinded. There have been no serious adverse events attributable to the study agent. Of the serious adverse events, most were considered to be unrelated or unlikely. Of note, the screening process has enabled the investigational team to clinically phenotype and collect biological specimens on the majority of candidate subjects. As a byproduct, we have approximately seven active translational research collaborations with intramural investigators, including Alan Sher, PhD, Bruno Andrade, MD, Eva Mezey, PhD, Thomas Waldmann, MD, and Stewart Levine, MD. State the current risk/benefit analysis of the study. This research involves greater than minimal risk to subjects with the prospect of direct benefit and is likely to yield generalizeable knowledge about the disease.

临床方案 (NHLBI 06-H-0072)：阿托伐他汀作为 II 期和 III 期肺结节病的疾病缓解剂：一项随机、双盲、安慰剂对照试验。一些生物样本也将根据 NHLBI 临床协议 96-H-100 进行收集/存储。 PI：Joseph Fontana，PVMB 主治医师协议目的（概要）：结节病是一种多系统肉芽肿性炎症性疾病。肺部受累最为常见。患者通常会感到疲劳、虚弱和呼吸困难。呼吸肌无力可能继发于肉芽肿性炎症，与呼吸困难和生活质量 (QOL) 下降有关。该疾病可以自发缓解或转为慢性，并伴有恶化和缓解。在一些患者中，它可能进展为肺纤维化和死亡。肉芽肿性炎症的主要特征是单核细胞、巨噬细胞和活化的 T 淋巴细胞积聚，同时关键炎症介质 TNF-α、INF-α、IL-2 和 IL-12 的产生增加，这是 Th1 极化反应的特征。 T 辅助淋巴细胞-1 反应）。皮质类固醇是目前的主要治疗方法，但其长期益处尚不确定。由于类固醇通常会产生不良副作用，因此有必要进行研究以确定替代疗法。有足够的证据来验证他汀类药物针对的途径对结节病具有治疗作用的概念，因为在临床前研究中，他汀类药物可以减弱 Th1 介导的炎症反应。目标：该方案的目的是进行一项随机、双盲安慰剂对照试验，旨在确定阿托伐他汀给药是否会导致需要泼尼松治疗的肺结节病患者减少类固醇使用并延长无类固醇间隔。主要终点是类固醇保留期的持续时间。次要临床和生理终点旨在分析药物可能的抗炎和有益作用。由于结节病没有金标准结果测量，因此将使用四类次要终点来表征治疗药物对疾病临床病程的影响：影像学（高分辨率胸部 CT）；生活质量评估（SF-36 和 SGRQ）、抗炎作用（生物标志物和复发率）和功能作用（CPET、PFT）。基本设计：年龄为 18-70 岁、患有 II 期或 III 期肺结节病、经相容的临床病史诊断并得到肺、淋巴结或组织活检支持的受试者，如果需要泼尼松治疗，将参加该研究。受试者将被随机分配到两组；由于泼尼松在两组中逐渐减少，一组将接受安慰剂，另一组将接受阿托伐他汀（80 毫克/天）。研究药物将服用十二个月，在此期间将定期评估患者的临床状态和泼尼松需求。药丸计数和患者日记将用于确定研究期间泼尼松的使用量。端点主要终点是确定阿托伐他汀给药是否会导致需要泼尼松的肺结节病患者延长类固醇保留间隔。次要终点包括：临床（泼尼松总使用量、缓解率和复发率（发作）、生活质量指标（SF-36、SGRQ）、呼吸困难量表（AMA 和 BDI/TDI）以及探索性参数（治疗指数）。）生理（肺功能测试、心肺运动测试、六分钟步行测试）免疫学（血清标志物：血清血管紧张素转换酶、肿瘤坏死因子αII受体、血清可溶性IL-2受体、C反应蛋白；支气管肺泡灌洗液炎症标志物、细胞计数、细胞因子）成像（标准胸部 X 光检查和计算机断层扫描，以及具有半定量和定量评分的高分辨率计算机断层扫描）取得的进展：已入组并随机分配了 53 名受试者。44 名受试者已完成该研究的 1 年治疗阶段。累计上限：96 注册科目总数：53 随机分配研究药物的受试者总数：53 代理学习一年完成的科目总数：44 当前活跃参与者总数：4 仍在使用研究药物 3 的患者人数仍处于随访第 1 阶段的患者人数提款总数：6 继续该协议的原因：结节病是一种病因不明的多系统肉芽肿性炎症性疾病。皮质类固醇是目前的主要治疗方法，但其长期益处尚不确定，而且其使用会导致生活质量下降。由于类固醇会产生不良副作用，因此有必要进行研究以确定替代疗法。虽然有替代疗法，但没有一种疗法获得 FDA 批准。大多数替代疗法都不是良性的，并且没有长期数据支持它们在肺结节病中的使用。鉴于选择有限，没有一个是理想的（即具有轻微副作用/毒性的高效药物），患者有时会完全放弃治疗，以避免类固醇或替代药物的不良影响，风险自负代理。需要严格的临床试验来确定抗炎药是否可以提供节省类固醇的益处并改善治疗结果。由于我们有活跃的受试者，因此持续收集他们的数据对于评估本研究的主要和次要终点非常重要。因此，我们认为按计划继续进行研究是有好处的。迄今为止的研究结果：之前对 50 名随机受试者中的 49 名受试者的可用数据进行了中期分析。按照方案完成分析；结果表明治疗组之间没有显着差异。该研究仍然是双盲的。尚无因研究药物引起的严重不良事件。在严重不良事件中，大多数被认为是无关的或不太可能发生。值得注意的是，筛选过程使研究团队能够对大多数候选受试者进行临床表型分析并收集生物样本。作为副产品，我们与校内研究人员开展了大约七项积极的转化研究合作，包括 Alan Sher 博士、Bruno Andrade 医学博士、Eva Mezey 博士、Thomas Waldmann 医学博士和 Stewart Levine 医学博士。说明该研究当前的风险/收益分析。这项研究对受试者的风险大于最小风险，并有望带来直接利益，并可能产生有关该疾病的普遍知识。