Anti-inflammatory Therapy with Low Dose Methotrexate for Reduction of PAD

描述（由申请方提供）：目前下肢外周动脉疾病（PAD）患者的治疗选择有限，重点是适当调整心血管风险因素，以预防这些高风险患者的冠状动脉或脑血管事件。不幸的是，关于肢体相关结局，迄今为止，没有令人信服的药物治疗显示可以预防无症状个体和有症状患者的临床明显疾病，存在太少的医学选择来改善跛行，改善身体功能，或预防局部进展为肢体威胁性疾病。这项辅助研究提案将扩展目前在心血管炎症减少试验（CIRT）中测试的动脉粥样硬化血栓形成的炎症假设，以涵盖下肢外周动脉粥样硬化，这是一种经常与冠状动脉疾病共存的疾病，并具有许多先前的风险因素，包括2型糖尿病（T2 D），代谢综合征（MetS）和亚临床炎症。CIRT是NHLBI资助的多中心临床试验（U 01 HL 101422和U 01 HL 101389），将7，000例既往心肌梗死（MI）和T2 D和/或MetS受试者随机分配至低剂量甲氨蝶呤组（LDM;目标剂量15 - 20 mg/周）加常规治疗或安慰剂加常规治疗，随访2 - 4年（平均3年）。参与者将从美国和加拿大的大约350至400个临床研究中心招募。主要终点为非致死性MI、卒中和心血管死亡。虽然PAD是试验的第三终点，但用于诊断和监测疾病的终点裁定和踝臂指数（ABI）测量目前未得到试验的资助。我们建议在随机、双盲、安慰剂对照的环境中评价LDM是否将1）减少PAD进展（通过ABI变化评估），2）延缓功能下降（通过基于心率和基于体能的身体功能指标的变化测量并与ABI变化相关），3）减少PAD事件的发生，包括确诊的间歇性跛行、严重肢体缺血，下肢血运重建、截肢或新发ABI < 0.9。总之，我们认为CIRT母试验的研究基础设施提供了一个独特且极具成本效益的机会，可以及时回答有关抗炎治疗预防和治疗下肢PAD的潜在益处的重要问题。我们寻求资金来支持终点验证，并为CIRT招募中心提供多普勒ABI设备，以确定ABI，从而有效地将PAD提升到试验的裁定终点，现在纳入PAD研究界广泛接受的诊断模式。为了达到足够大的样本量以满足我们的科学目标，母研究的自然扩展必须与2013年4月开始的整体CIRT招募同时进行。

DESCRIPTION (provided by applicant): Current treatment options for patients with lower extremity peripheral artery disease (PAD) are limited with appropriately heavy emphasis placed on cardiovascular risk factor modification to prevent coronary or cerebrovascular events in these high-risk patients. Unfortunately, with regard to limb-related outcomes, to date, no pharmacologic therapy has convincingly been shown to prevent clinically overt disease in asymptomatic individuals and among symptomatic patients, too few medical options exist to ameliorate claudication, improve physical function, or prevent local progression to limb threatening disease. This ancillary study proposal will extend the inflammatory hypothesis of atherothrombosis currently being tested in the Cardiovascular Inflammation Reduction Trial (CIRT) to encompass lower extremity peripheral atherosclerosis, a disease which frequently co-exists with coronary disease and shares many antecedent risk factors including type 2 diabetes (T2D), metabolic syndrome (MetS) and subclinical inflammation. CIRT is an NHLBI funded multicenter clinical trial (U01 HL101422 and U01 HL101389) that will randomly allocate 7,000 subjects with prior myocardial infarction (MI) and either T2D and/or MetS to low dose methotrexate (LDM; target dose 15 to 20 mg per week) plus usual care or placebo plus usual care over a follow-up period of 2 to 4 years (average 3 years). Participants will be recruited from roughly 350 to 400 clinical sites in the United States and Canada. The primary endpoint is nonfatal MI, stroke, and cardiovascular death. While PAD is a tertiary endpoint of the trial, endpoint adjudication and ankle-brachial index (ABI) measurement for diagnosis and monitoring of disease are currently not funded by the trial. We propose to evaluate in a randomized, double-blind, placebo-controlled setting whether LDM will 1) reduce PAD progression as assessed by change in ABI, 2) retard functional decline as measured by change in both questionnaire-based and performance- based physical function measures and correlated with change in ABI, and 3) reduce the occurrence of PAD events including confirmed intermittent claudication, critical limb ischemia, lower extremity revascularization, amputation, or new occurrence of ABI < 0.9. In summary, we believe that the research infrastructure of the parent CIRT trial offers a unique and extremely cost-effective opportunity to answer important and timely questions about the potential benefits of anti-inflammatory therapy for the prevention and treatment of lower extremity PAD. We seek funds to support endpoint validation and to provide CIRT recruiting sites with Doppler ABI equipment for ascertainment of the ABI thus effectively elevating PAD to an adjudicated endpoint of the trial and now incorporating a diagnostic modality widely acceptable to the PAD research community. In order to achieve a sufficiently large sample size to address our scientific goals, this natural extension of the parent study must be undertaken in parallel with overall CIRT recruitment which began in April 2013.