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，炎症生物标志物hsCRP水平升高的患者血管风险增加，但抑制炎症本身是否会降低血管事件发生率尚不清楚。拟议的心血管炎症减少试验（CIRT）的主要目的是通过评估低剂量甲氨蝶呤（LDM）是否会降低hsCRP持续升高提示风险增加的稳定性心血管疾病患者的复发性心肌梗死、卒中和心血管死亡率，直接检验动脉粥样硬化血栓形成的炎症假说。研究人员建议在7,000名有心肌梗死病史且hsCRP> 2 mg/L和<20 mg/L的男性和女性中进行一项随机、双盲、安慰剂对照、多中心试验。合格的受试者将在3 - 4年内随机分配至常规治疗加安慰剂或常规治疗加LDM（初始剂量为每周10 mg po，4个月后根据安全性和耐受性证据，基于安全性滴定至每周15 mg po）。研究参与者将额外接受每日1 mg口服叶酸。尽管在当代实践环境中被广泛认为是安全的，但通过对所有研究者和协调员进行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沟通，通过将入组限制在没有恶性肿瘤、肝炎、肾功能不全、慢性感染或其他甲氨蝶呤风险因素证据的受试者，通过进行最初的4周活性治疗导入期，旨在随机化前排除对治疗不耐受的个体，并通过使用旨在确保受试者安全性的集中方法每月监测肝功能和血液学指标，允许在保持研究盲态的同时降低剂量，并提供一个有效的方法，以符合成本效益的中央方式处理遵守和后续行动问题。主要试验终点将包括非致死性心肌梗死、非致死性卒中和心血管死亡，并额外监测全因死亡率。次要终点包括糖尿病、静脉血栓形成和房颤，所有这些都有炎症基础。组建的研究团队在大规模随机试验的设计、启动、实施和分析以及LDM的临床使用方面具有丰富的经验。我们的外部流变学顾问都认为LDM的剂量对MI后人群是安全的，LDM对脂质、葡萄糖和血栓形成没有混淆作用，这些作用显著限制了包括羟氯喹在内的其他药物。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症假说的核心问题，因此，如果成功，将开辟心血管治疗的主要新方向。(End摘要）

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)