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

摘要 下肢外周动脉疾病（PAD）影响美国10-15%的年龄≥65岁的人群， 随着美国人口患慢性病的寿命延长，这种情况越来越普遍。有PAD的人 步行障碍和更快的功能下降比没有PAD。然而，很少有治疗方法 改善PAD患者的行走障碍或预防功能下降。 在PAD患者中，步行活动期间小腿肌肉的缺血-再灌注引起病理生理学改变， 小牛骨骼肌的变化，包括氧化应激增加、肌纤维损伤和 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的种子， 可以改善小腿肌肉灌注和逆转小腿肌肉异常的治疗特性， 垫.临床前证据表明，可可黄烷醇增加一氧化氮（NO），毛细血管密度，肢体 灌注，还减少氧化应激并改善骨骼肌中的线粒体活性。一致 有了这些临床前证据，在我们由美国国立卫生研究院资助的44名PAD参与者的试点临床试验中，可可黄烷醇 与安慰剂相比，6个月随访时，6分钟步行距离显著改善42.6米 （P=0.005）。因此，我们现在提出一项III期双盲、多中心随机试验， PAD参与者，以明确确定6个月的可可黄烷醇是否显著改善6- 与安慰剂相比，6个月随访时的分钟步行距离。在这份修订后的申请中（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（通过 肱动脉血流介导的舒张功能，腓肠肌内皮型一氧化氮合酶（eNOS）和腓肠肌 磷酸化eNOS），小腿肌肉灌注，全身耗氧量，体力活动，最大 在6个月随访时进行跑步机步行距离和额外的小腿肌肉活检测量。响应于 评论员的意见，提出了新的分析，以描述机制和评估持久性的 可可黄烷醇对改善PAD患者的行走性能的作用。如果我们对可可的初步研究结果 黄烷醇在一项确定性的III期随机试验中得到了证实，这种廉价、安全、容易获得且 耐受性治疗有可能有意义地改善大量和越来越多的老年人的流动性， 因PAD致残的人。

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.