RESveratrol To Improve Outcomes in oldeR pEople With PAD (the RESTORE Trial)

Eight million men and women in the United States have lower extremity peripheral arterial
disease (PAD). PAD is expected to be increasingly common as the population survives longer
with chronic disease. Patients with PAD have greater functional impairment and faster
functional decline compared to those without PAD. However, currently there are only two FDA
approved medications for improving functional performance in patients with PAD. Furthermore,
these FDA approved medications are only modestly beneficial for improving walking performance
in patients with PAD.

Emerging evidence, including our pilot data, demonstrates that calf skeletal muscle
mitochondria dysfunction contributes to functional impairment in people with PAD.
Resveratrol, a polyphenol and natural supplement, has pharmacological properties that target
specific mitochondrial impairments that are associated with functional impairment in older
people with PAD. Animal models and preliminary human evidence show that resveratrol protects
against ischemia-reperfusion injury, reduces inflammation, and improves endothelial
dysfunction. Ischemia-reperfusion injury, inflammation, and endothelial dysfunction are all
present in people with PAD and contribute to adverse outcomes in PAD.

We now propose a pilot study of 66 PAD participants age 65 and older: a double-blind,
randomized controlled pilot clinical trial to provide preliminary data to address our
hypothesis that resveratrol significantly improves lower extremity functioning in people with
PAD by improving calf skeletal muscle oxidative metabolism, increasing calf skeletal muscle
mitochondrial biogenesis, and improving systemic endothelial function in older people with
PAD.

In our primary specific aims, we will determine 1) whether PAD participants randomized to
resveratrol 500 mgs daily achieve greater increases or have less decline in six-minute walk
performance at 6-month follow-up, compared to those randomized to placebo and 2) whether PAD
participants randomized to resveratrol 125 mgs daily achieve greater increases or have less
decline in six-minute walk performance at 6-month follow-up, compared to those randomized to
placebo. In our secondary aims, we will determine whether PAD participants randomized to
resveratrol have improved treadmill walking performance, increased calf muscle
biopsy-measured mitochondrial function, increased calf muscle biopsy-measured mitochondrial
biogenesis, and improved brachial artery flow-mediated dilation at six-month follow-up,
compared to those randomized to control. For each secondary specific aim, participants
randomized to 500 mgs of resveratrol (N=22) will be compared to those randomized to placebo
(N=20) and participants randomized to 125 mgs of resveratrol (N=22) will be compared to those
randomized to placebo (N=22), respectively. In an exploratory specific aim, we will determine
whether participants randomized to resveratrol 125 mgs (N=22) have greater improvement in
each study outcome compared to those randomized to resveratrol 500 mgs (N=22).

If our hypotheses are correct, results will be used to design a large, definitive randomized
controlled trial of resveratrol therapy to improve lower extremity functioning and prevent
mobility loss in the large and growing number of older people who are disabled by PAD. By
studying two doses of resveratrol, our results will also provide guidance on the most optimal
dose of resveratrol to use in a large definitive trial.

Inclusion Criteria:

- Ankle-brachial index (ABI) < 0.90 at baseline screening (at visit), or, medical
evidence of prior lower extremity revascularization if ABI ≥ 0.90.

- 65 or older

Exclusion Criteria:

- Above/below-knee amputation, critical limb ischemia, wheelchair-bound, or require the
use of a walker or cane

- Other symptom(s) limiting walking ability, other than PAD

- Underwent/experienced lower extremity revascularization, a cardiovascular event, or
coronary artery bypass surgery within 3 months of screening. Underwent major
orthopedic surgery within 6 months of screening. Planning to have revascularization or
major elective surgery within the next 6 months.

- Major medical illness including renal disease that requires dialysis or lung disease
that requires oxygen

- Score of < 23 on Mini-Mental Status Examination at screening or major psychiatric
illness

- Currently participating in a separate clinical trial

- Significant renal or liver dysfunction at baseline

- Does not successfully complete the study run-in period

- Has an extreme baseline 6 minute walk value (< 500 ft or > 1,600 feet )

- Treated for cancer during the last 2 years (unless prognosis is excellent)

- Severe hearing impairment or other communication difficulties (e.g. non-English
speaking) or legally blind

- Diagnosis of Parkinson's disease

- Unable to return to medical center at required visit frequency

- Otherwise poorly suited to intervention (at the discretion of the PI)