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: 10209585
• 负责人: Mary McGrae McDermott
• 金额: $ 70.87万
• 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/10209585
• 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; 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; Phase; Physical activity; Pilot Projects; Placebos; Plasma; Population; Property; Published Comment; Randomized; Randomized Clinical Trials; Reperfusion Therapy; Seeds; Skeletal Muscle; 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; 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 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 随着美国人的寿命延长，患有慢性病的情况越来越普遍。患有 PAD 的人有更大的 与没有 PAD 的患者相比，行走障碍和功能衰退更快。但迄今为止，治疗方法还很少 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 线粒体活性。这些小腿肌肉异常与功能障碍有关 PAD 功能下降。可可黄烷醇，来自可可树（“可可”树）的种子，具有 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，可可黄烷醇可增加一氧化氮 (NO)、毛细血管密度和肢体功能 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年的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。在这个修改后的应用程序中（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 磷酸化 eNOS）、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。作为回应 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 可可黄烷醇可改善 PAD 的步行表现。如果我们对可可的试点研究结果 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。