The COCOA-PAD II Trial

Peripheral Artery Disease Clinical Trial

— COCOA-PAD II  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04794530
• Other study ID #: STU00213897
• Secondary ID: R01AG068458-01A1
• Status: Recruiting
• Phase: Phase 3
• Start date: November 19, 2021
• Est. completion date: December 31, 2026

Study information

• Verified date: April 2024
• Source: Northwestern University
• Contact: Mary McDermott, MD
• Phone: 312-503-6419
• Email: mdm608[@]northwestern.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 190
• Est. completion date: December 31, 2026
• Est. primary completion date: May 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 55 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Peripheral Arterial Disease
• Peripheral Artery Disease

Intervention

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
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.

Locations

Country	Name	City	State
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	University of Minnesota	Minneapolis	Minnesota

Sponsors (4)

Lead Sponsor	Collaborator
Northwestern University	National Institute on Aging (NIA), University of Chicago, University of Minnesota

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Six-month change in plasma abundance of cocoa flavanols	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	Baseline to six-month follow-up
Other	Association of calf perfusion with baseline gut microbial diversity with response to cocoa flavanols	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.	Baseline to six-month follow-up
Other	Association of six-minute walk distance with baseline gut microbial diversity with response to cocoa flavanols	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.	Baseline to six-month follow-up
Other	Six-month change in gut microbial diversity	The trial will determine whether cocoa flavanols, compared to placebo, favorably alter gut microbial diversity at six-month follow-up.	Baseline to six-month follow-up
Other	Six-month change in gut microbial composition	The trial will determine whether cocoa flavanols, compared to placebo, favorably alter gut microbial composition at six-month follow-up.	Baseline to six-month follow-up
Other	Association of six-minute walk distance with six-month change in gut microbial composition	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.	Baseline to six-month follow-up
Other	Association of calf perfusion with six-month change in gut microbial composition	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.	Baseline to six-month follow-up
Other	Association of metabolomic profiles with improved six-minute walk distance.	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.	Baseline to six-month follow-up
Other	Association of metabolomic profiles with improved calf perfusion	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.	Baseline to six-month follow-up
Other	Association of metabolomic profiles with six-minute walk distance	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.	Baseline to six-month follow-up
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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