The COCOA-PAD II Trial (COCOA-PAD II)

• ClinicalTrials.gov Identifier: NCT04794530
• Recruitment Status: Recruiting
• First Posted: March 12, 2021
• Last Update Posted: May 24, 2023
• Sponsor: Northwestern University
• Collaborators: National Institute on Aging (NIA); University of Minnesota; University of Chicago
• Information provided by (Responsible Party): Mary McDermott, Northwestern University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Peripheral Artery Disease	Drug: cocoa flavanols; Drug: placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 190 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: COCOA Flavanols to Improve Walking Performance in PAD: the COCOA-PAD II Trial
• Actual Study Start Date: November 19, 2021
• Estimated Primary Completion Date: May 31, 2026
• Estimated Study Completion Date: December 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: cocoa flavanols	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.
Placebo Comparator: placebo	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.

Outcome Measures

Primary Outcome Measures :

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 Outcome Measures :

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 Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 55 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age 55 and older
2. 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:

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 at a frequency of once weekly or more
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

Contacts and Locations

Contacts

Contact: Mary McDermott, MD; 312-503-6419; mdm608@northwestern.edu

Contact: Kathryn Domanchuk, BS; 312-503-6438; k-domanchuk@northwestern.edu

Locations

United States, Illinois

Northwestern University; Recruiting

Chicago, Illinois, United States, 60611

Contact: Mary McDermott, MD 312-503-6419 mdm608@northwestern.edu

University of Chicago; Recruiting

Chicago, Illinois, United States, 60637

Contact: Tamar Polonsky, MD 312-608-0250 tpolonsky@bsd.uchicago.edu

United States, Minnesota

University of Minnesota; Recruiting

Minneapolis, Minnesota, United States, 55455

Contact: Diane Treat-Jacobson, PhD 612-624-7613 treat001@umn.edu

Sponsors and Collaborators

Northwestern University

National Institute on Aging (NIA)

University of Minnesota

University of Chicago

Investigators

• Principal Investigator: Mary McDermott, MD; Northwestern University

More Information

• Responsible Party: Mary McDermott, Jeremiah Stamler Professor of Medicine, Northwestern University
• ClinicalTrials.gov Identifier: NCT04794530
• Other Study ID Numbers: STU00213897; R01AG068458-01A1 ( U.S. NIH Grant/Contract )
• First Posted: March 12, 2021
• Last Update Posted: May 24, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Mary McDermott, Northwestern University:

cocoa flavanols

Additional relevant MeSH terms:

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