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)是一种慢性全身炎症和动脉粥样硬化的状态 导致周围动脉狭窄或闭塞，最常见的是累及腿部。衬垫影响向上 到20%的老年人，由于吸烟率高，在退伍军人中尤其普遍。近90% 患有PAD的患者患有间歇性跛行(IC)，定义为伴有活动的重复性肌肉疼痛 由于血液流量减少，休息后会得到缓解。患有IC的人患心血管疾病(CV)的风险增加 发病率和死亡率随着步行速度和距离的进行性下降、功能独立性和 健康相关生活质量(HRQOL)。吸烟对IC生物的医学优化治疗 戒烟，阿司匹林和他汀类药物治疗，以及锻炼。IC的药物治疗效果微乎其微。 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， 合规性很低，好处不是持久的。最终，外科血运重建是唯一有效的方法。 可以长期可靠地改善IC症状的治疗，但具有侵入性和昂贵的特点。 二甲双胍是一种治疗2型糖尿病(DM2)的廉价、安全和有效的药物。它有很多 可以对抗活性氧、全身炎症、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， 二甲双胍还可以刺激血管生成，减少动脉粥样硬化的钙化。最后，二甲双胍已经被 结果显示，在不依赖血糖控制的情况下，DM2患者可降低心血管疾病的发病率和死亡率。因此， 我们推测二甲双胍可能是治疗症状性PAD的有效方法。我们开发了 应用间歇性跛行(Mobile IC)试验评价二甲双胍对下肢的疗效 二甲双胍对功能状态、PAD进展、全身和血管炎症、中性粒细胞外的影响 患有症状性PAD的非DM2退伍军人的陷阱、外切体和microRNAs以及线粒体功能。这个 试验是一项四盲、3期、单机构、随机对照试验，由 经验丰富的投入，并以患者为中心的结果为基础。共有200名男性和女性退伍军人 在VA匹兹堡(VAPHS)血管诊所正在评估的症状性PAD将按最大值分层 步行距离(MWD)对6分钟步行试验(6MWT)和随机1：1至6个月的1000 mg 每日服用二甲双胍ER或安慰剂。这项试验有80%的权力确定对主要结果的影响 6个月时6MWT的MWD。次要结果包括对整体功能的验证评估， 一般和疾病特有的HRQOL、亚临床和临床PAD进展(踝臂指数、脉搏 容量记录和血管内皮细胞功能)，全身炎症标志物和 外周血单核细胞的系统线粒体效率与健康。所有功能和临床 结果将在基线、研究药物暴露6个月和研究结束后6个月进行评估。 停用研究用药。炎症和线粒体变化将在基线时进行评估，分别为3和6 药物暴露6个月，停药后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，其中有固定的治疗分配和 基准值的协变量调整。每个次要结果最好概括为- 事件结果将使用Kaplan-Meier分析、对数等级检验和Cox比例风险或 用精细灰色模型估计各治疗组之间的差异。对治疗组的初步分析 比较将使用意向处理方法，显著性将在𝛼水平为0.05时确定 将会被使用。移动IC试验的成功将支持二甲双胍作为一种有效、安全和 对PAD的廉价治疗，可能对并发的心血管疾病和老年性疾病也有影响。