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

小剂量甲氨蝶呤抗炎治疗可减少 PAD

• 批准号: 8738800
• 负责人: Aruna Das Pradhan
• 金额: $ 44.23万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738800
• 关键词: Address; Affect; Amputation; Ancillary Study; Angiotensin-Converting Enzyme Inhibitors; Ankle; Anti-Inflammatory Agents; Anti-inflammatory; Arginine; Atherosclerosis; Blood Pressure; Blood Vessels; Canada; Cardiovascular system; Cerebrovascular Disorders; Cessation of life; Chelation Therapy; Cilostazol; Classification; Clinical; Clinical Trials; Communities; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Data; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Disease Progression; Dose; Double-Blind Method; Dyslipidemias; Elderly; Epidemiologic Studies; Equipment; Evaluation; Event; FDA approved; Funding; Future; Gangrene; Ginkgo biloba; Glycosylated hemoglobin A; Goals; Hypertension; Impairment; Individual; Inflammation; Inflammatory; Intermittent Claudication; Ischemia; Levocarnitine; Limb structure; Lipids; Lower Extremity; Measurement; Measures; Medical; Metabolic syndrome; Methotrexate; Modality; Modification; Monitor; Myocardial Infarction; National Heart, Lung, and Blood Institute; Non-Insulin-Dependent Diabetes Mellitus; Oral; Outcome; Pain; Parents; Participant; Patients; Pentoxifylline; Performance; Peripheral; Peripheral arterial disease; Pharmaceutical Preparations; Physical Function; Placebo Control; Placebos; Population; Population Study; Prevalence; Prevention therapy; Questionnaires; Randomized; Recruitment Activity; Relative (related person); Research; Research Design; Research Infrastructure; Rest; Risk; Risk Factors; Role; SF-36; Safety; Sample Size; Site; Smoking; Speed; Stroke; Symptoms; Testing; Ulcer; United States; Validation; Vasodilator Agents; Walking; Withholding Treatment; Woman; abstracting; adjudicate; adjudication; atherothrombosis; base; blood pressure regulation; cardiovascular risk factor; cerebrovascular; claudication; clinical research site; cost; cost effective; disorder prevention; follow-up; functional decline; high risk; improved; indexing; men; mortality; novel; prevent; public health relevance; smoking cessation; therapeutic angiogenesis; treatment as usual

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.

描述（由申请人提供）：当前下肢外周动脉疾病（PAD）患者的治疗选择有限，适当强调心血管危险因素的改变，以预防这些高危患者发生冠状动脉或脑血管事件。不幸的是，就肢体相关结果而言，迄今为止，尚无药物治疗被令人信服地证明可以预防无症状个体和有症状患者的临床明显疾病，能够改善跛行、改善身体功能或预防局部进展的医疗选择太少威胁肢体的疾病。这项辅助研究提案将扩展目前正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说，以涵盖下肢外周动脉粥样硬化，这种疾病经常与冠心病共存，并具有许多先行危险因素，包括 2 型糖尿病（T2D）、代谢综合征（MetS）和亚临床炎症。 CIRT 是一项 NHLBI 资助的多中心临床试验（U01 HL101422 和 U01 HL101389），将随机分配 7,000 名既往患有心肌梗塞 (MI) 且患有 T2D 和/或 MetS 的受试者接受低剂量甲氨蝶呤 (LDM；目标剂量为每周 15 至 20 毫克) ) 加常规治疗或安慰剂加常规治疗 2 至 4 年的随访期（平均3年）。参与者将从美国和加拿大约 350 至 400 个临床中心招募。主要终点是非致命性心肌梗死、中风和心血管死亡。虽然 PAD 是该试验的第三个终点，但该试验目前并未资助用于诊断和监测疾病的终点判定和踝臂指数 (ABI) 测量。我们建议在随机、双盲、安慰剂对照的环境中评估 LDM 是否会 1）减少 PAD 进展（通过 ABI 的变化评估），2）延缓功能衰退（通过基于问卷和基于表现的身体变化来衡量）功能测量并与 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、截肢或新发生 ABI < 0.9。总之，我们相信母公司 CIRT 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，可以回答有关抗炎治疗对于预防和治疗下肢 PAD 的潜在益处的重要而及时的问题。我们寻求资金来支持终点验证，并为 CIRT 招募站点提供多普勒 ABI 设备来确定 ABI，从而有效地将 PAD 提升到试验的判定终点，并且现在纳入了 PAD 研究界广泛接受的诊断方式。为了获得足够大的样本量来实现我们的科学目标，母研究的这种自然延伸必须与 2013 年 4 月开始的 CIRT 整体招募同时进行。