COCOA flavanols to improve walking performance in PAD: the COCOA-PAD II Trial

可可黄烷醇可改善 PAD 的步行表现：COCOA-PAD II 试验

基本信息

批准号：
10685352
负责人：
Mary McGrae McDermott
金额：
$ 58.37万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685352
关键词：
3-nitrotyrosine Affect Biopsy Blood capillaries Cacao Plant Cell Nucleus Chronic Disease Clinical Clinical Trials Cocoa Powder Disabled Persons Double-Blind Method Elderly Flavanol Funding Impairment Injury Intervention Intervention Studies Ischemia Isolated limb perfusion Lower Extremity Magnetic Resonance Imaging Measures Mediating Mediation Mitochondria Muscle Muscle Mitochondria NOS3 gene Nitric Oxide Outcome Oxidative Stress Oxygen Consumption Participant Performance Perfusion Peripheral arterial disease Persons Phase Phosphorylation Physical activity Pilot Projects Placebos Plasma Population Property Published Comment Randomized Reperfusion Therapy Skeletal Muscle Spirometry Therapeutic Trees Walking actigraphy brachial artery consumption measures density disability follow-up functional decline functional disability human old age (65+)improved improved mobility meter mitochondrial dysfunction pre-clinical preclinical study prevent randomized trial randomized, clinical trials response treadmill

项目摘要

ABSTRACT Lower extremity peripheral artery disease (PAD) affects 10-15% of people age ≥65 in the U.S. and will be increasingly common as the U.S. population lives longer with chronic disease. People with PAD have greater walking impairment and faster functional decline than those without PAD. Yet few therapies have been identified that improve walking impairment or prevent functional decline in people with PAD. In people with PAD, ischemia-reperfusion of calf muscle during walking activity causes pathophysiologic changes in calf skeletal muscle, including increased oxidative stress, myofiber injury, and reduced mitochondrial activity. These calf muscle abnormalities are associated with functional impairment and functional decline in PAD. Cocoa flavanols, from the seeds of theobroma cacao, the “cocoa” tree, have therapeutic properties that may improve calf muscle perfusion and reverse the calf muscle abnormalities in PAD. Pre-clinical evidence shows that cocoa flavanols increase nitric oxide (NO), capillary density, and limb perfusion and also reduce oxidative stress and improve mitochondrial activity in skeletal muscle. Consistent with this pre-clinical evidence, in our NIA-funded pilot clinical trial of 44 participants with PAD, cocoa flavanols significantly improved 6-minute walk distance by 42.6 meters at six-month follow-up, compared to placebo (P=0.005). Therefore, we now propose a Phase III double-blinded, multi-centered randomized trial in 190 participants with PAD, to definitively determine whether 6-months of cocoa flavanols significantly improves 6- minute walk distance at six-month follow-up, compared to placebo. In this revised application (original score: 36, percentile: 17), we will also assess the effects of cocoa flavanols on measures of nitric oxide (measured by brachial artery flow-mediated dilation, calf muscle endothelial nitric oxide synthase (eNOS) and calf muscle phosphorylated eNOS), calf muscle perfusion, whole body oxygen consumption, physical activity, maximal treadmill walking distance, and additional calf muscle biopsy measures at six-month follow-up. In response to reviewer comments, new analyses are proposed to delineate mechanisms and assess persistence of the cocoa flavanols effect on improved walking performance in PAD. If results from our pilot study of cocoa flavanols are confirmed in a definitive Phase III randomized trial, this inexpensive, safe, accessible, and well- tolerated therapy has the potential to meaningfully improve mobility in the large and growing number of older people disabled by PAD.

抽象的在美国，10-15% 的 65 岁以上人群患有下肢外周动脉疾病 (PAD)，并且随着美国人口的寿命延长，患有 PAD 的人患病率也越来越高。与没有 PAD 的患者相比，行走障碍和功能衰退更快，但目前很少有治疗方法。确定可以改善 PAD 患者的行走障碍或预防功能衰退。在 PAD 患者中，步行活动期间小腿肌肉的缺血再灌注会导致病理生理学改变小腿骨骼肌的变化，包括氧化应激增加、肌纤维损伤和减少这些小腿肌肉异常与功能障碍和线粒体活性有关。来自可可树（“可可”树）种子的可可黄烷醇的功能下降。可以改善小腿肌肉治疗灌注并逆转小腿肌肉异常的特性 PAD 临床前证据表明可可黄烷醇可增加一氧化氮 (NO)、毛细血管密度和肢体功能。灌注还可以减少氧化应激并改善骨骼肌中的线粒体活性。有了这些临床前证据，我们在 NIA 资助的试点临床试验中对 44 名患有 PAD 的参与者进行了可可黄烷醇的研究与安慰剂相比，在六个月的随访中，6 分钟步行距离显着改善了 42.6 米 (P=0.005) 因此，我们现在提出一项 190 人的 III 期双盲、多中心随机试验。患有 PAD 的参与者，以确定 6 个月的可可黄烷醇是否能显着改善 6- 与安慰剂相比，六个月随访时的分钟步行距离（原始分数： 36，百分位：17），我们还将评估可可黄烷醇对一氧化氮测量的影响（通过测量肱动脉血流介导的扩张、小腿肌肉内皮一氧化氮合酶 (eNOS) 和小腿肌肉小腿肌肉灌注、全身耗氧量、体力活动、最大跑步机步行距离，以及六个月随访时额外的小腿肌肉活检测量。审稿人提出意见，提出新的分析来描述机制并评估其持续性可可黄烷醇对改善 PAD 步行表现的影响来自我们对可可的初步研究。黄烷醇在一项明确的 III 期随机试验中得到证实，这种廉价、安全、易获得且效果良好的物质耐受治疗有可能显着改善大量且不断增加的老年人的活动能力因 PAD 致残的人。