The COCOA-PAD II Trial

Study Overview
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Brief Summary
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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.

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

Conditions
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Peripheral Artery Disease

Intervention / Treatment
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* Drug: cocoa flavanols
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 55 and older Presence of peripheral artery disease (PAD). PAD will be defined as either an ABI <= 0.90 at baseline or vascular lab evidence of PAD or angiographic evidence of PAD. 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 at a frequency of once weekly or more 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

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: cocoa flavanols<br> | Drug: cocoa flavanols<br>* 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.<br>|
| Placebo Comparator: placebo<br> | Drug: placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-month change in six-minute walk distance | Change in six-minute walk distance at six-month follow-up will be compared between those randomized to cocoa flavanols vs. those randomized to placebo. | Baseline to six-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-month change in gastrocnemius muscle perfusion (measured by magnetic resonance imaging (MRI)) | Change in gastrocnemius muscle perfusion (measured by MRI) at six-month follow-up will be compared between those randomized to cocoa flavanols vs. those randomized to placebo. | Baseline to six-month follow-up | 
| Six-month change in brachial artery flow-mediated dilation (FMD) | Change in brachial artery flow-mediated dilation (FMD) at six-month follow-up will be compared between those randomized to cocoa flavanols vs. those randomized to placebo. | Baseline to six-month follow-up | 
| Six-month change in Actigraph-measured physical activity | Change in Actigraph-measured physical activity at six-month follow-up will be compared between those randomized to cocoa flavanols vs. those randomized to placebo. | Baseline to six-month follow-up | 
| Six-month change in calf muscle endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS | Change in calf muscle biopsy measures of eNOS and phosphorylated eNOS at six-month follow-up will be compared between those randomized to cocoa flavanols vs. those randomized to placebo. | Baseline to six-month follow-up | 
| Six-month change in calf muscle characteristics (measured by calf muscle biopsy) | Change in calf muscle characteristics (measured by calf muscle biopsy) at six-month follow-up will be compared between those randomized to cocoa flavanols vs. those randomized to placebo. | Baseline to six-month follow-up | 
| Six minute walk at two and four week follow-up after intervention completion. | The trial will determine whether cocoa flavanols, compared to placebo, have a persistent effect on improved six-minute walk distance at two weeks and four weeks after the study intervention is completed | Six-month follow-up to 2- and 4-weeks post follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cocoa flavanols