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: 10426266
• 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/10426266
• 关键词: Address; Adult; Affect; Age Years; Aging; Amputation; Ankle; Arteries; Aspirin; Atherosclerosis; Blood Platelets; 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; Phase; Physiologic pulse; Placebo Control; 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; Surveys; Symptoms; Testing; Time; Tobacco use; Vascular Diseases; Vascular blood supply; Vascularization; Veterans; Walking; age related; aged; angiogenesis; atherogenesis; blind; blood glucose regulation; blood pressure control; 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; pharmacologic; pleiotropism; preclinical study; prevent; primary outcome; programs; prospective; randomized placebo controlled trial; revascularization surgery; secondary outcome; smoking cessation; success; symptom treatment; symptomatic improvement; 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.

周围动脉疾病（PAD）是一种慢性全身注射和动脉粥样硬化状态， 导致周围动脉的狭窄或阻塞，最常见的是腿部。垫子会影响 由于吸烟率高，因此20％的老年人在退伍军人中尤其普遍。近90％ 患有垫子的人患有间歇性lau不平（IC），被定义为可再现的肌肉疼痛 由于血液流量减少，并且休息可以缓解。患有IC的人患心血管（CV）的风险增加 发病率和死亡率随着步行速度和距离，功能独立性的逐步下降和 与健康相关的生活质量（HRQOL）。通过吸烟的医学优化处理IC生物 停止，阿司匹林和他汀类药物疗法以及运动。 IC的药理疗法至少有效。 监督运动疗法确实可以提高步行距离和功能状态，但不容易获得， 合规性很低，好处不持久。最终，手术血运重建是唯一有效的 可以长期可靠地改善IC症状但具有侵入性和昂贵的治疗。 二甲双胍是2型糖尿病（DM2）的廉价，安全且有效的治疗方法。它有很多 可以抵消活性氧，全身注射，DNA损伤和 线粒体功能障碍导致与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降低动脉粥样硬化钙化。最后，二甲双胍一直 证明可以降低DM2患者的CV特异性发病率和死亡率，而与葡萄糖控制无关。那， 我们假设二甲双胍可能是对症状垫的有效治疗方法。我们开发了 二甲双胍通过间歇性克劳（Mobile IC）试验使下肢有益于下肢，以评估 二甲双胍对功能状态，垫进展，全身和血管注射，中性粒细胞外注射 陷阱，外泌体和microRNA，以及有症状垫的NondM2退伍军人中的线粒体功能。这 试验是四倍盲，第3阶段，单一机构，随机对照试验，与 退伍军人输入，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）血管诊所进行评估的有症状垫将按最大分层 步行距离（MWD）在6分钟步行测试（6MWT）和随机1：1至6个月的1000mg 每天二甲双胍或安慰剂。该试验具有80％的功率来确定对主要结果的影响 MWD在6个月时在6MWT上。次要结果包括对总体功能的验证评估， 一般和疾病特异性HRQOL，亚临床和临床垫进展（踝臂指数，脉冲 卷记录和内皮的内皮功能），系统性炎症标记的变化和 外周血单核细胞中的全身线粒体效率和健康。所有功能和临床 结果将在基线，6个月的研究药物暴露时进行测量，以及在 停止研究药物。炎症和线粒体变化将在基线时评估3和6 药物暴露的月份，停止后6个月。连续变量，包括主要变量 结果将使用线性混合效应模型分析，并通过固定的治疗分配和 基线值的协变量调整。每个次要结果最好总结为时间 事件结果将使用Kaplan-Meier分析，对数秩测试和COX比例危害或 细灰模型以估计治疗组之间的差异。治疗组的主要分析 比较将使用意向性治疗方法，并在0.05的水平上确定意义 将使用。移动IC试验的成功将支持二甲双胍作为有效，安全，并且 对PAD的廉价疗法也可能对同时发生的简历疾病和衰老疾病产生影响。