The COCOA-PAD II Trial

Phase 3

Recruiting

• Conditions: Peripheral Artery Disease
• Interventions: Drug: cocoa flavanols; Drug: placebo

• Registration Number: NCT04794530
• Lead Sponsor: Northwestern University

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-03-07
• Study First Submitted QC: 2021-03-10
• Study First Posted: 2021-03-12
• Study Start: 2021-11-19
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-12
• Last Update Posted: 2025-05-15
• Primary Completion: 2026-05-31
• Study Completion: 2027-01-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 190

Inclusion Criteria

1. Age 55 and older

2. Presence of peripheral artery disease (PAD). PAD will be defined as either:

   1. An ABI <= 0.90 at baseline.
   2. 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.
   3. 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

1. Above- or below-knee amputation
2. Critical limb ischemia
3. Wheelchair confinement or requiring a walker to ambulate
4. Walking is limited by a symptom other than PAD
5. Current foot ulcer on bottom of foot
6. Failure to successfully complete the one-week study run-in
7. Planned major surgery, coronary or leg revascularization during the next eight months
8. Major surgery, coronary or leg revascularization or major cardiovascular event in the previous three months
9. 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.]
10. Mini-Mental Status Examination (MMSE) score < 23
11. Allergy to the study intervention
12. 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).
13. Non-English speaking
14. 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.]
15. Visual impairment that limits walking ability
16. Six-minute walk distance of <500 feet or >1600 feet.
17. Participation in a supervised treadmill exercise program in previous three months
18. Unable to tolerate caffeine
19. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
cocoa flavanols	cocoa flavanols	-
placebo	placebo	-

Primary Outcome Measures

Name	Time	Method
Six-month change in six-minute walk distance	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 Outcome Measures

Name	Time	Method
Six-month change in Actigraph-measured physical activity	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.
Six minute walk at two and four week follow-up after intervention completion.	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
Six-month change in calf muscle endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS	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.
Six-month change in gastrocnemius muscle perfusion (measured by magnetic resonance imaging (MRI))	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.
Six-month change in brachial artery flow-mediated dilation (FMD)	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.
Six-month change in calf muscle characteristics (measured by calf muscle biopsy)	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.

Trial Locations

Locations (3)

University of Chicago; 🇺🇸 Chicago, Illinois, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States