Cardiovascular Inflammation Reduction Trial (CIRT): DCC

描述(由申请人提供)： 虽然炎症是动脉粥样硬化血栓形成的关键因素，而且炎症生物标记物hsCRP水平升高的患者会增加血管风险，但抑制炎症本身是否会降低血管事件的发生率尚不清楚。拟议的心血管炎症减少试验(CIRT)的主要目的是通过评估小剂量甲氨蝶呤(LDM)是否会降低因hsCRP持续升高而风险增加的稳定性心血管疾病患者的再发心肌梗死、中风和心血管死亡的发生率，直接测试动脉粥样硬化血栓形成的炎症假说。研究人员建议对7,000名有心肌梗死史的男性和女性进行一项随机、双盲、安慰剂对照的多中心试验，这些患者的hsCRP&gt；2 mg/L和20 mg/L。符合条件的参与者将在三到四年内被随机分配到常规护理加安慰剂或常规护理加低密度脂多糖(基于安全性和耐受性的证据，起始剂量为每周10毫克，4个月后基于安全性的滴定为每周15毫克)。研究参与者每天还将服用1毫克的口服叶酸。尽管在当代实践环境中被广泛认为是安全的，但通过为所有研究人员和协调员提供强制性的两年一次的教育计划，通过每周与所有研究参与者进行电话交流，通过将登记限制在没有恶性肿瘤、肝炎、肾功能障碍、慢性感染或其他甲氨蝶呤风险因素的人，通过进行初始的为期4周的积极治疗磨合，旨在随机之前消除不耐受治疗的个人，以及通过使用旨在确保参与者安全的集中方法每月监测肝功能和血液学指标，以及通过使用旨在确保参与者安全的集中化方法来每月监测肝功能和血液学指标，并提供一种有效的方法，在成本效益高的基础上集中解决遵约和后续行动问题。主要试验终点将包括非致命性心肌梗死、非致命性中风和心血管死亡，并对所有原因的死亡率进行额外监测。次要终点包括糖尿病、静脉血栓形成和心房颤动，所有这些都有炎症基础。所组建的研究团队在设计、启动、实施和分析大规模随机试验以及LDM的临床应用方面拥有丰富的经验。我们的外部风湿学顾问都认为LDM的剂量对心肌梗死后的人群是安全的，并且LDM对血脂、血糖和血栓的混杂影响不会显著限制其他药物，包括羟氯喹。这项试验的潜在临床影响是广泛的，因为它有足够的力量直接解决动脉粥样硬化血栓形成的炎性假说中的核心问题，因此，如果成功，将为心血管治疗开辟重要的新方向。(摘要结束)

DESCRIPTION (provided by applicant): While inflammation contributes crucially to atherothrombosis and patients with elevated levels of the inflammatory biomarker hsCRP have increased vascular risk, it is unknown whether inhibition of inflammation per se will lower vascular event rates. The primary aim of the proposed Cardiovascular Inflammation Reduction Trial (CIRT) is to directly test the inflammatory hypothesis of atherothrombosis by evaluating whether or not low-dose methotrexate (LDM) will reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among patients with stable cardiovascular disease who are at increased risk indicated by persistent elevations of hsCRP. The investigators propose to conduct a randomized, double-blind, placebo-controlled, multi-center trial among 7,000 men and women with prior myocardial infarction and hsCRP>2mg/L and <20mg/L. Eligible participants will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM (initial dose 10 mg po per week with a safety-based titration to 15 mg po per week after 4 months based on evidence of safety and tolerability). Study participants will additionally receive 1 mg daily oral folate. Although widely considered safe in contemporary practice settings, LDM complications will further be minimized by mandatory bi-annual education programs for all investigators and coordinators, through weekly telephone communication with all study participants, by limiting enrollment to those with no evidence of malignancy, hepatitis, renal dysfunction, chronic infection, or other methotrexate risk factors, by conducting an initial 4-week active-therapy run-in designed to eliminate individuals intolerant to treatment before randomization, and through monthly monitoring of liver function and hematologic indices using a centralized methodology designed to ensure participant safety, allow for dose reductions while maintaining the study blind, and provide an efficient method to address issues of compliance and follow- up on a cost-effective centralized basis. The primary trial endpoint will include non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with additional monitoring for all-cause mortality. Secondary endpoints include diabetes, venous thrombosis, and atrial fibrillation, all of which have an inflammatory basis. The study team assembled has extensive experience in the design, initiation, conduct, and analysis of large-scale randomized trials and in the clinical use of LDM. Our external rheumatology consultants all feel the dose of LDM is safe for this post-MI population and that LDM is free of the confounding effects on lipids, glucose, and thrombosis that significantly limit other agents including hydroxychloroquine. The potential clinical impact of this trial is broad as it has sufficient power to directly address core issues in the inflammatory hypothesis of atherothrombosis, and thus, if successful, will open major new directions for cardiovascular treatment. (End of Abstract)