Cocoa to Improve Walking Performance in Peripheral Artery Disease

Therapeutic properties that target pathophysiologic impairments in PAD. These therapeutic
properties include improved skeletal muscle mitochondrial function, increased skeletal muscle
capillary density, and favorable changes in skeletal muscle levels of myostatin and
follistatin that increase muscle mass and strength. Cocoa also protects against
ischemia-reperfusion injury, improves endothelial function, and reduces oxidative stress. In
summary, epicatechin-rich cocoa targets and reverses several pathophysiologic processes that
are common in PAD and that are associated with functional impairment and functional decline
in PAD. However, the effect of chronic daily cocoa consumption on functional decline has not
been studied in older people with PAD.

The COCOA-PAD trial is a pilot study of 44 PAD participants age 60 and older: a double-blind,
randomized controlled pilot clinical trial to provide preliminary data to address the
hypothesis that chronic daily epicatechin-rich cocoa improves lower extremity functioning in
older people with PAD by improving mitochondrial oxidative metabolism, increasing calf muscle
capillary density, promoting calf skeletal muscle mitochondrial biogenesis, and improving
endothelial function.

In the primary aim, the investigators will determine whether PAD participants randomized to
an epicatechin-rich cocoa beverage have greater increases or smaller declines in six-minute
walk performance at 6-month follow-up, compared to those randomized to an identical appearing
placebo drink with comparable caloric composition. In the secondary aims, the investigators
will determine whether PAD participants randomized to cocoa have improved treadmill walking
performance, improved brachial artery flow-mediated dilation, favorable changes in calf
muscle biopsy measures of mitochondrial function, mitochondrial biogenesis, follistatin,
myostatin, and capillary density, increased calf skeletal muscle regeneration and reduced
oxidative stress, and increased MRI-measured calf muscle perfusion. Outcome measures will be
carefully timed relative to the last intervention dose to distinguish between the acute vs.
chronic effects of cocoa-epicatechin.

If the hypotheses are correct, results will be used to design a large, definitive randomized
controlled trial of epicatechin-rich cocoa to improve lower extremity functioning and prevent
mobility loss in the large and growing number of older people who are disabled by PAD.

Inclusion Criteria:

1. All participants will be age 60 and older.

2. All participants will have PAD. PAD will be defined as follows. First, an ABI < 0.90
at baseline is an inclusion criterion for PAD. Second, potential participants with an
ABI > 0.90 who have vascular lab evidence of PAD or angiographic evidence of PAD will
be eligible.

Exclusion Criteria:

1. Above- or below-knee amputation.

2. Critical limb ischemia.

3. Wheelchair-bound or requiring a cane or walker to ambulate.

4. Walking is limited by a symptom other than PAD.

5. Baseline six-minute walk value of <500 feet or >1,600 feet

6. Lower extremity revascularization, major orthopedic surgery, cardiovascular event, or
coronary revascularization in the previous three months.

7. Planned revascularization or major surgery during the next six months.

8. Major medical illness including renal disease requiring dialysis, lung disease
requiring oxygen, Parkinson's disease, a life-threatening illness with life expectancy
less than six 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.]

9. Mini-Mental Status Examination (MMSE) score < 23 or dementia.

10. Unwilling to attend three visits in one week for final outcome measures.

11. Allergy to chocolate.

12. Unwilling or unable to consume products manufactured on the same equipment that
processes peanuts, tree nuts, egg, wheat, soy, and milk.

13. Use of cocoa-containing dietary supplements.

14. Unwilling to give up major dietary sources of epicatechin during the study.

15. Symptoms of heart failure or angina that limit walking activity more than ischemic leg
symptoms, increase in angina, or angia at rest (i.e. unstable angina).

16. 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.]

17. Non-English speaking, a visual impairment that limits walking ability.

18. 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.