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NCT Number: NCT04794530

The COCOA-PAD II Trial

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.

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Key information

Conditions

Peripheral Artery Disease Arterial Occlusive Diseases Arteriosclerosis Atherosclerosis Cardiovascular Diseases Peripheral Arterial Disease Peripheral Vascular Diseases Vascular Diseases

Age range

55 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Northwestern University, Chicago, Illinois, United States

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

cocoa flavanols

Drug

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.

Placebo

Drug

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 outcomes

  1. Six-month change in six-minute walk distance

    Time frame: Baseline to six-month follow-up

    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.

Secondary outcomes

  1. Six-month change in gastrocnemius muscle perfusion (measured by magnetic resonance imaging (MRI))

    Time frame: Baseline to six-month follow-up

    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.

  2. Six-month change in brachial artery flow-mediated dilation (FMD)

    Time frame: Baseline to six-month follow-up

    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.

  3. Six-month change in Actigraph-measured physical activity

    Time frame: Baseline to six-month follow-up

    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.

  4. Six-month change in calf muscle endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS

    Time frame: Baseline to six-month follow-up

    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.

  5. Six-month change in calf muscle characteristics (measured by calf muscle biopsy)

    Time frame: Baseline to six-month follow-up

    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.

  6. 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

    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

Other outcomes

  1. Six-month change in plasma abundance of cocoa flavanols

    Time frame: Baseline to six-month follow-up

    The trial will determine whether lower plasma abundance of cocoa flavanols at baseline and whether greater increases in plasma abundance of cocoa flavanols at 6-month follow-up are associated with greater improvement in six-minute walk distance at 6-month follow-up, compared to higher plasma abundance of cocoa flavanols at baseline and compared to smaller increases in plasma cocoa flavanols at 6-month follow-up, respectively

  2. Association of calf perfusion with baseline gut microbial diversity with response to cocoa flavanols

    Time frame: Baseline to six-month follow-up

    The trial will determine whether baseline gut microbial diversity and composition are associated with the degree of response to cocoa flavanols, compared to placebo, measured by greater improvement calf perfusion at 6-month follow-up.

  3. Association of six-minute walk distance with baseline gut microbial diversity with response to cocoa flavanols

    Time frame: Baseline to six-month follow-up

    The trial will determine whether baseline gut microbial diversity and composition are associated with the degree of response to cocoa flavanols, compared to placebo, measured by greater improvement in six-minute walk distance at 6-month follow-up.

  4. Six-month change in gut microbial diversity

    Time frame: Baseline to six-month follow-up

    The trial will determine whether cocoa flavanols, compared to placebo, favorably alter gut microbial diversity at six-month follow-up.

  5. Six-month change in gut microbial composition

    Time frame: Baseline to six-month follow-up

    The trial will determine whether cocoa flavanols, compared to placebo, favorably alter gut microbial composition at six-month follow-up.

  6. Association of six-minute walk distance with six-month change in gut microbial composition

    Time frame: Baseline to six-month follow-up

    The trial will determine whether cocoa flavanol-induced changes in gut microbial composition, compared to placebo, between baseline and 6-month follow-up are associated with greater improvement in six-minute walk distance.

  7. Association of calf perfusion with six-month change in gut microbial composition

    Time frame: Baseline to six-month follow-up

    The trial will determine whether cocoa flavanol-induced changes in gut microbial composition, compared to placebo, between baseline and 6-month follow-up are associated with greater improvement in calf perfusion.

  8. Association of metabolomic profiles with improved six-minute walk distance.

    Time frame: Baseline to six-month follow-up

    The trial will perform microbe-associated metabolomic profiling in blood and stool at six-month follow-up to identify metabolomic profiles that are associated with improved six-minute walk distance at 6-month follow-up.

  9. Association of metabolomic profiles with improved calf perfusion

    Time frame: Baseline to six-month follow-up

    The trial will perform microbe-associated metabolomic profiling in blood and stool at six-month follow-up to identify metabolomic profiles that are associated with improved calf perfusion at 6-month follow-up.

  10. Association of metabolomic profiles with six-minute walk distance

    Time frame: Baseline to six-month follow-up

    The trial will perform microbe-associated metabolomic profiling in blood and stool at six-month follow-up to identify metabolomic profiles that are associated with improved six-minute walk distance at six-month follow-up.

Study contacts

Contact information is provided by the study sponsor or research team.

Kathryn Domanchuk, BS

CONTACT

[email protected]

312-503-6438

Mary McDermott, MD

CONTACT

[email protected]

312-503-6419

Sponsors and collaborators

Lead sponsor

Northwestern University

Other

Collaborators

  • National Institute on Aging (NIA)
  • University of Chicago
  • University of Minnesota

Registry information

Official study title

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

Acronym: COCOA-PAD II

Important dates

Study start
2021
Primary completion
2026
Study completion
2027
First posted
Mar 12, 2021
Registry last updated
May 28, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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