Clinical trial NCT04794530: The COCOA-PAD II Trial
Official title: COCOA Flavanols to Improve Walking Performance in PAD: the COCOA-PAD II Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Peripheral Artery Disease
Keywords: cocoa flavanols
Lead sponsor: Northwestern University
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: University of Minnesota
name: University of Chicago
First posted: 2021-03-12
Enrollment: 190
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Six-month change in six-minute walk distance
timeFrame: Baseline to six-month follow-up
Secondary outcomes:
measure: Six-month change in gastrocnemius muscle perfusion (measured by magnetic resonance imaging (MRI))
timeFrame: Baseline to six-month follow-up
measure: Six-month change in brachial artery flow-mediated dilation (FMD)
timeFrame: Baseline to six-month follow-up
measure: Six-month change in Actigraph-measured physical activity
timeFrame: Baseline to six-month follow-up
measure: Six-month change in calf muscle endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS
timeFrame: Baseline to six-month follow-up
measure: Six-month change in calf muscle characteristics (measured by calf muscle biopsy)
timeFrame: Baseline to six-month follow-up
measure: Six minute walk at two and four week follow-up after intervention completion.
timeFrame: Six-month follow-up to 2- and 4-weeks post follow-up
Other outcomes:
measure: Six-month change in plasma abundance of cocoa flavanols
timeFrame: Baseline to six-month follow-up
measure: Association of calf perfusion with baseline gut microbial diversity with response to cocoa flavanols
timeFrame: Baseline to six-month follow-up
measure: Association of six-minute walk distance with baseline gut microbial diversity with response to cocoa flavanols
timeFrame: Baseline to six-month follow-up
measure: Six-month change in gut microbial diversity
timeFrame: Baseline to six-month follow-up
measure: Six-month change in gut microbial composition
timeFrame: Baseline to six-month follow-up
measure: Association of six-minute walk distance with six-month change in gut microbial composition
timeFrame: Baseline to six-month follow-up
measure: Association of calf perfusion with six-month change in gut microbial composition
timeFrame: Baseline to six-month follow-up
measure: Association of metabolomic profiles with improved six-minute walk distance.
timeFrame: Baseline to six-month follow-up
measure: Association of metabolomic profiles with improved calf perfusion
timeFrame: Baseline to six-month follow-up
measure: Association of metabolomic profiles with six-minute walk distance
timeFrame: Baseline to six-month follow-up
Locations:
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
Study officials:
affiliation: Northwestern University
name: Mary McDermott, MD
role: PRINCIPAL_INVESTIGATOR
References: