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）：下肢外周动脉疾病（PAD）患者的当前治疗选择受到限制，重点是对心血管危险因素的改性，以防止这些高风险患者在这些高危患者中进行冠状动脉或脑血管事件。不幸的是，关于与肢体相关的结局，迄今为止，尚未有令人信服的药物治疗可防止无症状的个体和有症状的患者的临床明显疾病，因此存在很少的医疗选择，无法改善laud虫，改善身体机能或防止局部进展到威胁肢体疾病。这项辅助研究建议将扩大目前在心血管炎症减少试验中正在测试的动脉粥样硬化的炎症假说（CIRT），以涵盖下肢外围性动脉粥样硬化，这种疾病经常与冠状动脉疾病共存，并与2型糖尿病（包括2型糖尿病）（包括2型糖尿病）（T22D）（t2d d2d）（Metscys and Absbersys）共存。 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年（平均3年）。参与者将在美国和加拿大的大约350至400个临床场所招募。主要终点是非致命的MI，中风和心血管死亡。虽然PAD是试验的第三端终点，但目前尚未通过该试验资助终点裁决和用于诊断和监测疾病的脚踝 - 桥梁指数（ABI）测量。 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,截肢或ABI <0.9的新事件。总而言之，我们认为，父母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，可以回答有关抗炎疗法对预防和治疗下肢垫的潜在益处的重要和及时的问题。我们寻求资金来支持端点验证，并为CIRT招聘站点提供多普勒ABI设备来确定ABI，从而有效地将PAD提升到试验的裁决端点，现在纳入PAD研究社区可以广泛接受的诊断方式。为了实现足够大的样本量以解决我们的科学目标，必须与2013年4月始于2013年4月开始的整体CIRT招募进行这种自然扩展。