Metformin BenefIts Lower Extremities with Intermittent Claudication (MOBILE_IC)

二甲双胍有益于间歇性跛行的下肢 (MOBILE_IC)

• 批准号: 10257312
• 负责人: Edith Tzeng
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10257312
• 关键词: Address; Adult; Affect; Aging; Amputation; Ankle; Arteries; Aspirin; Atherosclerosis; Attenuated; Blood Vessels; Blood flow; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cell Respiration; Chronic; Cilostazol; Clinic; Clinical; Cross-Over Studies; DNA Damage; Data; Disease; Disease Progression; Dose; Drug Exposure; Effectiveness; Elderly; Endothelium; Event; Exercise; Exercise Test; Exercise Therapy; Exposure to; Female; Functional disorder; Glucose; Goals; Hand Strength; Health; Health system; Impairment; Incidence; Inflammation; Inflammatory; Institution; Intention; Intermittent Claudication; Kidney Diseases; Leg; Link; Lower Extremity; Malignant Neoplasms; Measures; Medical; Metformin; MicroRNAs; Mitochondria; Modeling; Morbidity - disease rate; Myalgia; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Operative Surgical Procedures; Organ; Outcome; Oxidative Stress; Oxygen Consumption; Patient-Focused Outcomes; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Peripheral arterial disease; Pharmaceutical Preparations; Pharmacology; Phase; Physiologic pulse; Placebos; Plasma; Production; Prospective Studies; Quality of life; Questionnaires; Randomized; Randomized Controlled Trials; Reactive Oxygen Species; Recurrence; Reporting; Reproducibility; Rest; Retrospective Studies; Risk; Secondary to; Smoking; Stroke; Supervision; Surveys; Symptoms; Testing; Time; Tobacco; Tobacco use; Vascular Diseases; Vascular blood supply; Veterans; Walking; age related; aged; angiogenesis; atherogenesis; base; blind; blood glucose regulation; blood pressure regulation; calcification; cardiovascular disorder risk; cardiovascular risk factor; comorbidity; comparison group; effective therapy; effectiveness evaluation; exercise program; exosome; experience; extracellular; follow-up; frailty; functional improvement; functional independence; functional status; hazard; health related quality of life; improved; indexing; inflammatory marker; innovation; insight; limb loss; male; mitochondrial dysfunction; mortality; neutrophil; novel; peripheral blood; pleiotropism; preclinical study; prevent; primary outcome; programs; prospective; randomized placebo controlled trial; randomized trial; secondary outcome; smoking cessation; success; symptom treatment; systemic inflammatory response; treatment group; vascular inflammation; walking speed

Peripheral arterial disease (PAD) is a state of chronic systemic inflammation and atherosclerosis that results in the narrowing or occlusion of peripheral arteries, most commonly involving the legs. PAD affects up to 20% of older adults and is especially prevalent among Veterans due to a high rate of smoking. Nearly 90% of those with PAD suffer from intermittent claudication (IC), defined as reproducible muscle pain with activity due to reduced blood flow and is relieved with rest. Those with IC are at increased risk of cardiovascular (CV) morbidity and mortality with progressive decline in walking speeds and distance, functional independence, and health related quality of life (HRQoL). The treatment of IC beings with medical optimization with smoking cessation, aspirin and statin therapy, and exercise. Pharmacological therapies for IC are minimally effective. Supervised exercise therapy does improve walking distance and functional status but is not easily accessible, compliance is low, and the benefits are not durable. Ultimately, surgical revascularization is the only effective therapy that can reliably improve IC symptoms long-term but is invasive and expensive. Metformin is an inexpensive, safe, and effective treatment for Type 2 diabetes (DM2). It has numerous effects that can counteract the reactive oxygen species, systemic inflammation, DNA damage, and mitochondrial dysfunction that contribute to age related cellular and organ dysfunction. In preclinical studies, metformin also stimulates angiogenesis and reduces atherosclerotic calcification. Finally, metformin has been shown to reduce CV specific morbidity and mortality in those with DM2, independent of glucose control. Thus, we hypothesize that metformin may be an effective treatment for symptomatic PAD. We developed the MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC) Trial to evaluate the effect of metformin on functional status, PAD progression, systemic and vascular inflammation, neutrophil extracellular traps, exosomes and microRNAs, and mitochondrial function in nonDM2 Veterans with symptomatic PAD. The trial is a quadruple-blind, phase 3, single institution, randomized controlled trial which was developed with Veteran input and is based on patient centered outcomes. A total of 200 male and female Veterans with symptomatic PAD being evaluated at the VA Pittsburgh (VAPHS) vascular clinic will be stratified by maximum walking distance (MWD) on the 6-minute walk test (6MWT) and randomized 1:1 to 6 months of 1000mg of Metformin ER or placebo daily. This trial has 80% power to determine the effect on the primary outcome of MWD on the 6MWT at 6 months. Secondary outcomes include validated assessments of overall functionality, general and disease specific HRQoL, subclinical and clinical PAD progression (ankle brachial index, pulse volume recordings, and endothelial function by EndoPAT), changes in systemic inflammatory markers and systemic mitochondrial efficiency and health in peripheral blood mononuclear cells. All functional and clinical outcomes will be measured at baseline, at 6 months of study drug exposure, and 6 months following the cessation of study drug. Inflammatory and mitochondrial changes will be evaluated at baseline, at 3 and 6 months of drug exposure, and 6 months following cessation. Continuous variables, including the primary outcome, will be analyzed using linear mixed-effects model analysis with a fixed treatment assignment and covariate adjustment for the baseline value. Each of the secondary outcomes best summarized as time-to- event outcomes will be reported using Kaplan-Meier analysis, log-rank tests, and Cox proportional-hazards or Fine-Gray models to estimate the difference between treatment groups. Primary analyses for treatment group comparisons will use an intention-to-treat approach and significance will be determined at an 𝛼 level of 0.05 will be used. The success of the MOBILE IC Trial would support Metformin as an effective, safe, and inexpensive therapy for PAD that may also have effects on concurrent CV diseases and diseases of aging.

外周动脉疾病（PAD）是一种慢性全身性炎症和动脉粥样硬化的状态， 导致外周动脉变窄或闭塞，最常见的是累及腿部。PAD影响向上 20%的老年人，尤其是退伍军人，由于吸烟率高。近90% 的PAD患者患有间歇性跛行（IC），定义为活动时可再现的肌肉疼痛 由于血流量减少，休息后缓解。IC患者的心血管（CV）风险增加 发病率和死亡率随行走速度和距离、功能独立性的进行性下降，以及 健康相关生活质量（HRQoL）。药物优化结合吸烟治疗IC患者 戒烟、阿司匹林和他汀类药物治疗以及锻炼。IC的药物治疗效果最低。 有监督的运动疗法确实可以改善步行距离和功能状态，但不容易获得， 遵守率低，而且好处不持久。最终，手术血运重建是唯一有效的方法 可以长期可靠地改善IC症状，但侵入性和昂贵的治疗。 二甲双胍是2型糖尿病（DM 2）的廉价，安全和有效的治疗方法。它有许多 可以抵消活性氧、全身炎症、DNA损伤和 线粒体功能障碍导致年龄相关的细胞和器官功能障碍。在临床前研究中， 二甲双胍还刺激血管生成并减少动脉粥样硬化钙化。最后， 显示降低DM 2患者的CV特异性发病率和死亡率，与血糖控制无关。因此，在本发明中， 我们假设二甲双胍可能是症状性PAD的有效治疗。我们开发了 MetfOrmin有益于间歇性跛行的下肢（移动的IC）试验，以评估 二甲双胍对功能状态、PAD进展、全身和血管炎症、中性粒细胞外 陷阱，外泌体和microRNA，和线粒体功能在非DM 2退伍军人与症状性PAD。的 试验是一项四盲、III期、单机构、随机对照试验， 退伍军人输入，并基于以患者为中心的结果。共有200名男女退伍军人， 在VA匹兹堡（VAPHS）血管诊所评价的症状性PAD将按最大值分层 6分钟步行试验（6 MWT）的步行距离（MWD），并以1：1的比例随机分配至1000 mg 美托洛尔或安慰剂每日一次。本试验有80%的把握度确定对主要结局的影响， 6个月时6 MWT的MWD。次要结局包括总体功能的有效评估， 一般和疾病特异性HRQoL、亚临床和临床PAD进展（踝臂指数、脉搏 体积记录和内皮功能（EndoPAT），全身炎症标志物的变化， 外周血单个核细胞中的系统线粒体效率和健康。所有功能和临床 将在基线、研究药物暴露6个月和研究药物暴露后6个月测量结局。 停用研究药物。将在基线、3和6时评价炎症和线粒体变化 药物暴露6个月，以及停药后6个月。连续变量，包括主要变量 将使用固定治疗分配的线性混合效应模型分析， 基线值的协变量调整。每个次要结局最好总结为 将使用Kaplan-Meier分析、对数秩检验和考克斯比例风险报告事件结局，或 Fine-Gray模型用于估计治疗组之间的差异。治疗组的主要分析 比较将使用意向治疗方法，显著性将在0.05的水平上确定 将用于移动的IC试验的成功将支持美托洛尔作为一种有效，安全， PAD的廉价治疗也可能对并发CV疾病和衰老疾病产生影响。