R01AG068458

Cocoa Flavanols to Improve Walking Performance in PAD: The Cocoa-PAD II Trial - 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.

Northwestern University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Chicago, Illinois 606114550 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the total obligations have increased 375% from $708,737 to $3,367,372.