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

• 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
• 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

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 下肢外围动脉疾病（PAD）在美国影响10-15％的年龄≥65岁的人，将是 随着美国人口与慢性疾病的寿命更长，越来越普遍。垫子的人有更大的 与没有PAD的人相比，步行障碍和更快的功能下降。然而几乎没有治疗 确定改善行走障碍或防止PAD患者的功能下降。 在有垫的人中，步行活动中小腿肌肉的缺血再灌注会导致病理生理 小腿骨骼肌的变化，包括增加的氧化应激，肌纤维损伤和减少 线粒体活性。这些小腿肌肉异常与功能障碍和 PAD的功能下降。可可黄烷醇，来自obroma caca的种子，“可可”树，有 可以改善小腿肌肉灌注并逆转小腿肌肉异常的治疗特性 软垫。临床前证据表明，可可黄烷醇会增加一氧化氮（NO），毛细管密度和肢体 灌注并减少氧化应激并改善骨骼肌中的线粒体活性。持续的 有了这一临床前证据，在我们的NIA资助的44名参与者的NIA资助的先导临床试验中，可可黄烷醇 与安慰剂相比 （p = 0.005）。因此，我们现在提出了190年的III期双盲，以多为中心的随机试验 使用PAD的参与者明确地确定6个月的可可黄烷醇是否显着改善6-- 与安慰剂相比，步行六个月的随访。在此修订应用程序中（原始分数： 36，百分位数：17），我们还将评估可可黄烷醇对一氧化氮测量的影响（通过 臂动脉流介导的词典，小腿肌肉内皮一氧化氮合酶（ENOS）和小腿肌肉 磷酸化的eNOS），小腿肌肉灌注，全身氧气消耗，体育锻炼，最大 跑步机步行距离，并在六个月的随访中进行额外的小腿肌肉活检。响应 审稿人的评论，提出了新的分析来描述机制并评估持久性 可可黄烷醇对垫子中提高步行性能的影响。如果我们的可可试点研究结果 黄酮醇在一项确定的III期随机试验中得到了证实，该试验廉价，安全，可及 耐受疗法有可能改善较大较大数量的较大数量的迁移率 人们被垫子残疾。