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.

外周动脉疾病（PAD）是一种慢性全身炎症和动脉粥样硬化状态， 导致外周动脉变窄或闭塞，最常累及腿部。 20% 的老年人，尤其是退伍军人中，由于吸烟率高达 90%。 的 PAD 患者患有间歇性跛行 (IC)，定义为活动时可重复出现的肌肉疼痛 患有 IC 的人患心血管 (CV) 的风险增加。 随着步行速度和距离、功能独立性的逐渐下降，发病率和死亡率 健康相关的生活质量 (HRQoL) 通过吸烟进行医学优化治疗 IC 人群。 戒烟、阿司匹林和他汀类药物治疗以及运动对 IC 的治疗效果甚微。 有监督的运动疗法确实可以改善步行距离和功能状态，但并不容易实现， 依从性低，且效果不持久，最终，手术血运重建是唯一有效的方法。 这种疗法可以长期可靠地改善 IC 症状，但具有侵入性且昂贵。 二甲双胍是一种廉价、安全、有效的治疗 2 型糖尿病 (DM2) 的药物。 可以抵消活性氧、全身炎症、DNA 损伤和 在临床前研究中，线粒体功能障碍导致与年龄相关的细胞和器官功能障碍。 二甲双胍还刺激血管生成并减少动脉粥样硬化钙化。 表明可以降低 DM2 患者的 CV 特异性发病率和死亡率，与血糖控制无关。 我们追求二甲双胍可能是治疗有症状的 PAD 的有效方法。 二甲双胍有益于间歇性跛行的下肢 (MOBILE IC) 评估效果的试验 二甲双胍对功能状态、PAD 进展、全身和血管炎症、中性粒细胞胞外的影响 患有 PAD 症状的非 DM2 退伍军人中的陷阱、外泌体和 microRNA 以及线粒体功能。 试验是一项四盲、3 期、单一机构、随机对照试验，由 退伍军人的意见基于以患者为中心的结果，共有 200 名男性和女性退伍军人。 在 VA 匹兹堡 (VAPHS) 血管诊所接受评估的有症状 PAD 将按最大程度进行分层 6 分钟步行测试 (6MWT) 的步行距离 (MWD) 和随机 1:1 至 6 个月的 1000 毫克 每日二甲双胍缓释剂或安慰剂该试验有 80% 的效力来确定对主要结局的影响。 6 个月时 6MWT 的 MWD 次要结果包括对整体功能的验证评估。 一般和疾病特异性 HRQoL、亚临床和临床 PAD 进展（踝肱指数、脉搏 体积记录和 EndoPAT 的内皮功能）、全身炎症标志物的变化和 外周血单核细胞的线粒体效率和健康状况所有功能和临床。 结果将在基线、研究药物暴露 6 个月以及治疗后 6 个月时进行测量 停止研究药物时将在基线、3 点和 6 点评估炎症和线粒体变化。 药物暴露月数，以及停药后 6 个月的连续变量，包括主要变量。 结果，将使用具有固定治疗分配的线性混合效应模型分析进行分析， 每个次要结果最好概括为“到达时间”。 将使用 Kaplan-Meier 分析、对数秩检验和 Cox 比例风险来报告事件结果或 精细灰色模型估计治疗组之间的差异。 比较将使用意向治疗方法，显着性将在 0.05 的 𝛼 水平上确定 MOBILE IC 试验的成功将支持二甲双胍作为一种有效、安全和可靠的药物。 治疗 PAD 的廉价疗法也可能对并发的心血管疾病和衰老疾病产生影响。