The COCOA-PAD II Trial

Official title

COCOA Flavanols to Improve Walking Performance in PAD: the COCOA-PAD II Trial

Overview

Among people with peripheral artery disease (PAD) age 55 and older, the investigators will test the hypothesis that PAD participants randomized to cocoa flavanols will have greater improvement or less decline in six-minute walk distance at six-month follow-up, compared to those randomized to placebo. The study will randomize 190 participants with PAD age 55 and older to one of two groups for six months: cocoa flavanols vs placebo. Our primary outcome is change in six-minute walk distance at six-month follow-up. Secondary outcomes are Actigraph-measured physical activity, brachial artery flow-mediated dilation (FMD), gastrocnemius muscle biopsy measures of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS, gastrocnemius muscle perfusion (measured by magnetic resonance imaging (MRI)) and gastrocnemius muscle characteristics (measured by muscle biopsy). To achieve the specific aims, the study will randomize 190 participants age 55 and older with PAD to one of two groups: cocoa flavanols vs placebo. Participants will be followed for six months.

Interventions

• Drug cocoa flavanols
  The cocoa flavanols intervention is manufactured by Mars Inc. Participants randomized to cocoa flavanols will take two capsules daily of cocoa flavanols. The two capsules of cocoa flavanols will contain approximately 500 mg of cocoa flavanols and appoximately 80 mg of (-)-epicatechin.
• Drug placebo
  The placebo intervention will be manufactured by Mars Inc. and will appear identical to the cocoa flavanols intervention. Participants will take two capsules daily of placebo. The placebo will be a cellulose based capsule and will not contain cocoa flavanols or (-)-epicatechin.

Primary outcome measures

• Six-month change in six-minute walk distance [Time frame: Baseline to six-month follow-up]

Secondary outcome measures (6)

• Six-month change in gastrocnemius muscle perfusion (measured by magnetic resonance imaging (MRI)) [Time frame: Baseline to six-month follow-up]
• Six-month change in brachial artery flow-mediated dilation (FMD) [Time frame: Baseline to six-month follow-up]
• Six-month change in Actigraph-measured physical activity [Time frame: Baseline to six-month follow-up]
• Six-month change in calf muscle endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS [Time frame: Baseline to six-month follow-up]
• Six-month change in calf muscle characteristics (measured by calf muscle biopsy) [Time frame: Baseline to six-month follow-up]
• Six minute walk at two and four week follow-up after intervention completion. [Time frame: Six-month follow-up to 2- and 4-weeks post follow-up]

Eligibility criteria

Inclusion criteria

• Age 55 and older
• Presence of peripheral artery disease (PAD). PAD will be defined as either:

• An ABI <= 0.90 at baseline.
• Vascular lab evidence of PAD (such as a toe brachial pressure < 0.70 or an ankle brachial index less than or equal to 0.90), or angiographic evidence of PAD defined as at least 70% stenosis of an artery supplying the lower extremities.
• An ABI of >0.90 and <=1.00 who experience a a 20% or greater drop in ABI in either leg after the heel-rise test will also be included.

Exclusion criteria

• Above- or below-knee amputation
• Critical limb ischemia
• Wheelchair confinement or requiring a walker to ambulate
• Walking is limited by a symptom other than PAD
• Current foot ulcer on bottom of foot
• Failure to successfully complete the one-week study run-in
• Planned major surgery, coronary or leg revascularization during the next eight months
• Major surgery, coronary or leg revascularization or major cardiovascular event in the previous three months
• Major medical illness including lung disease requiring oxygen, Parkinson's disease, a life-threatening illness with life expectancy less than eight months, or cancer requiring treatment in the previous two years. \[NOTE: potential participants may still qualify if they have had treatment for an early stage cancer in the past two years and the prognosis is excellent. Participants who require oxygen only at night may still qualify.\]
• Mini-Mental Status Examination (MMSE) score < 23
• Allergy to the study intervention
• Potential participants who have taken cocoa supplements in previous three months, are unwilling to avoid taking cocoa flavanol supplements, or are consuming dark chocolate regularly (i.e. approximately 1.5 ounces of dark chocolate more than three times per week, or more than 4.5 ounces per week).
• Non-English speaking
• Participation in or completion of a clinical trial in the previous three months. \[NOTE: after completing a stem cell or gene therapy intervention, participants will become eligible after the final study follow-up visit of the stem cell or gene therapy study so long as at least six months have passed since the final intervention administration. After completing a supplement or drug therapy (other than stem cell or gene therapy), participants will be eligible after the final study follow-up visit as long as at least three months have passed since the final intervention of the trial.\]
• Visual impairment that limits walking ability
• Six-minute walk distance of <500 feet or >1600 feet.
• Participation in a supervised treadmill exercise program in previous three months
• Unable to tolerate caffeine
• In addition to the above criteria, investigator discretion will be used to determine if the trial is unsafe or not a good fit for the potential participant

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 3 centers

• Northwestern University — Chicago
• University of Chicago — Chicago
• University of Minnesota — Minneapolis

Publications

• McDermott MM, Cetlin MD, Domanchuk KJ, Xu S, Whipple MO, Polonsky T, Criqui MH, Guralnik JM, Tian L, Zhao L, Ho KJ, Greenland P, Treat-Jacobson D. Community-based recruitment with ankle brachial index testing to identify peripheral artery disease participants for randomized clinical trials. Am Heart J. 2026 Oct;300:107450. doi: 10.1016/j.ahj.2026.107450. Epub 2026 Apr 24. PMID 42035974

Identifiers

NCT: NCT04794530 · STU00213897 · R01AG068458-01A1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗