Translational Studies in Sarcoidosis

结节病的转化研究

• 批准号: 8158024
• 负责人: VINCENT MANGANIELLO
• 金额: $ 0.75万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 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/8158024
• 关键词: Sarcoidosis; translational study; Sarcoidosis; translational study

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 (Prcis): 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). Finally, we will study the utility of exhaled nitric oxide in monitoring disease activity. 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, cell counts, and cytokines; exhaled nitric oxide and carbon monoxide) Imaging (Standard chest x-ray and computerized tomography, and high resolution computerized tomography with semi-quantitative and quantitative scoring) Progress achieved: Since the last continuing review (September 2009) 4 subjects have been enrolled and randomized, bringing the accrual to 41. Three new candidates were recently screened (September and October) and are scheduled for enrollment. We are in the process of scheduling 10 highly eligible candidates for clinical evaluation. Reasons to continue the protocol: Sarcoidosis is a multi-system granulomatous inflammatory disease of unknown etiology. Pulmonary involvement is the most common manifestation. Patients typically experience cough, dyspnea, and fatigue. Disease progression can impair the quality of life and lead to end-stage pulmonary fibrosis and death. 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 a number of 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. Accrual data: Recruitment Parameters n Telephone Screening Questionnaires 913 Clinical Exams/Screens Completed 127 Accepted 44 Enrolled 41 Study Findings to Date: Forty-one subjects have been enrolled, randomized, and started on study agent. Because the study is double-blinded, we cannot compare differences in treatment arms. For the purpose of this report we are defining evaluable subjects, as those participants who have at least 6 months of data. Pulmonary sarcoidosis flares and prednisone usage are secondary endpoints, and thus far, we have observed the following: 18/34 evaluable subjects ( 53%) have flared; 5 of the 18 flared subjects had a second flare event. With each flare, there is a substantial increase in prednisone usage. Total number of subjects enrolled: 41 Total of subjects randomized to study agent: 41 Total number of subjects completed 1 year of study agent: 31 Total of currently active participants: 14 Number of patients still on study agent 6 Number of patients still in the follow-up phase 8 Total number of withdrawals: 4 Subject Accrual Table: 06-H-0072 American Indian or Alaskan Native Asian or Pacific Islander Black, not of Hispanic Origin Hispanic White, not of Hispanic Origin Other or Unknown Total Male 0 0 7 0 9 0 16 Female 0 0 11 1 13 0 25 Total 0 0 18 0 23 0 41 Subjects withdrawn from protocol: 4 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）：Atorvastatin在II期和III期肺结节病中作为疾病改良剂：一项随机，双盲，安慰剂对照试验。在NHLBI临床方案96-H-100的基础下，一些生物测量也将被收集/储存。 PI：Joseph Fontana，工作人员医师，PVMB 协议的目的（PRCIS）： 结节病是一种多系统肉芽肿性炎症性疾病。 肺部受累是最常见的。 患者通常患有疲劳，无力和呼吸困难。 呼吸道肌肉无力可能继发于肉芽肿性炎症，与呼吸困难和生活质量降低有关（QOL）。 这种疾病可以自发地释放或慢性病，并因加剧和恢复而造成慢性。 在某些患者中，它可以发展为肺纤维化和死亡。 肉芽肿性炎症主要是由单核细胞，巨噬细胞和活化的T淋巴细胞的积累来表征，其关键炎症介质的产生增加，TNF-，INF-，IL-2，IL-2和IL-12，Th1偏振剂反应的特征（T-Helper lymphopyphopyte-1）。 皮质类固醇是当前治疗的主要支柱，但它们的长期益处尚不确定。 由于类固醇通常会产生不良的副作用，因此有必要进行识别替代疗法的研究。 有足够的证据可以检验概念证明，即他汀类药物靶向的途径将对结节病具有治疗作用，因为在临床前研究中，他汀类药物钝性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类固醇使用较少和需要较长的类固醇间隔时间，而无类固醇的间隔则需要需要厌食症治疗的肺结节病患者。 主要终点是类固醇比期的持续时间。 次要临床和生理终点旨在分析药物的可能抗炎和有益作用。 由于结节病没有黄金标准结果度量，因此将使用四类次要终点来表征治疗剂对疾病临床过程的影响：成像（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）和功能效应（CPET，PFTS）。 最后，我们将研究呼出的一氧化氮在监测疾病活动中的效用。 基本设计： 18至70岁的受试者患有II期或III期肺结节病，由兼容的临床病史诊断，并由肺，淋巴结或组织活检支持，如果需要泼尼松治疗，将纳入研究。 受试者将随机分配给两组；由于泼尼松在两组中都逐渐变细，因此一组将接受安慰剂，另一组将接受Atorvastatin（80 mg/天）。 该研究药物将进行十二个月，在此期间，将定期评估患者的临床状况和泼尼松的要求。 药丸计数和患者日记将用于确定研究期间的泼尼松使用量。 端点 主要终点是确定阿托伐他汀的给药是否导致需要泼尼松的肺结节病患者的类固醇分配时间更长。 次要端点包括： 临床（总泼尼松使用，缓解和复发率（耀斑），生活质量指标（SF-36，SGRQ），呼吸困难量表（AMA和BDI/TDI）和探索性参数，治疗率指数。 生理（肺功能测试，心肺运动测试和六分钟的步行测试） 免疫学（血清标记：血管血管紧张素转化酶，肿瘤坏死因子Alpha II受体，血清可溶性IL-2受体和C反应蛋白；支气管肺泡灌洗液炎症标记物，细胞计数和细胞因子和细胞因子； 成像（标准的胸部X射线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测） 取得的进步： 自从上次持续审查（2009年9月）以来，4个受试者已被录取和随机分配，使应计入41个。最近筛选了三名新候选人（9月和10月），并计划入学。我们正在安排10位高度合格的候选人进行临床评估。 继续该协议的原因： 结节病是未知病因的多系统肉芽肿性炎症性疾病。 肺部受累是最常见的表现。 患者通常患有咳嗽，呼吸困难和疲劳。 疾病进展会损害生活质量，并导致终末期肺纤维化和死亡。 皮质类固醇是当前治疗的主要支柱，但它们的长期益处尚不确定，并且使用与生活质量的降低有关。 由于类固醇会产生不良的副作用，因此有必要进行识别替代疗法的研究。 虽然有替代疗法可用，但没有FDA批准。 大多数替代疗法不是良性的，并且没有长期数据支持它们在肺结节病中的使用。 考虑到有限的选择，这些选择都不是理想的（即具有轻度副作用/毒性概况的高效药物），患者自负自身，有时完全放弃治疗，以避免类固醇或替代药物的不受欢迎的影响。 需要进行严格的临床试验来确定抗炎药是否可以提供类固醇的益处并改善治疗结果。 由于我们有许多主题，因此他们的数据持续收集对于评估本研究的主要和次要终点很重要。 因此，我们认为按计划继续进行研究是有价值的。 应计数据： 招聘参数n 电话筛选问卷913 临床考试/屏幕完成127 接受44 注册41 迄今为止的研究结果： 已经招募，随机分配了41名受试者，并开始研究代理。 由于这项研究是双盲的，因此我们无法比较治疗组的差异。出于本报告的目的，我们将可评估的主题定义为具有至少6个月数据的参与者。肺结节病和泼尼松的使用是次要终点，到目前为止，我们已经观察到以下内容：18/34可评估的受试者（53％）已经爆发；在18个爆发主题中，有5个发生了第二次耀斑事件。每次耀斑，泼尼松的使用情况都有很大增加。 招募的主题总数：41 随机分配到研究代理的受试者总数：41 完成1年学习代理的受试者总数：31 当前活跃的参与者总共：14 仍在研究代理的患者数量6 仍在后续第8阶段的患者人数 提款总数：4 主题应计表：06-H-0072 美洲印第安人或阿拉斯加原住民亚洲人或太平洋岛民黑人，不是西班牙裔西班牙裔白人，而不是西班牙裔其他或未知的总数 男性0 0 7 0 9 0 16 女性0 0 11 1 13 0 25 总计0 0 18 0 23 0 41 从协议中撤回的主题：4 陈述当前研究的风险/收益分析。 这项研究涉及具有直接利益前景的受试者的最小风险，并且很可能会产生有关该疾病的概括知识。