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

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.