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

• ClinicalTrials.gov Identifier: NCT02246660
• Recruitment Status: Completed
• First Posted: September 23, 2014
• Results First Posted: April 30, 2018
• Last Update Posted: April 30, 2018
• Sponsor: Northwestern University
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Mary McDermott, Northwestern University

Study Description

Brief Summary:

The RESTORE trial will determine whether resveratrol supplementation can improve walking performance in older people with lower extremity peripheral arterial disease (PAD). Resveratrol, a polyphenol and natural supplement, specifically targets several impairments associated with walking difficulty and mobility loss in people with PAD.

Condition or disease	Intervention/treatment	Phase
Peripheral Arterial Disease	Drug: Resveratrol; Drug: Placebo	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 66 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: RESveratrol To Improve Outcomes in oldeR pEople With PAD (the RESTORE Trial)
• Study Start Date: January 2015
• Actual Primary Completion Date: July 2016
• Actual Study Completion Date: September 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Resveratrol - 500 mg/day; The dose of Resveratrol will be 500 mg daily for six months. Resveratrol is taken orally. Resveratrol is a natural plant derivative.	Drug: Resveratrol; The dose of Resveratrol will be 500 mg daily for six months. Resveratrol is taken orally. Resveratrol is a natural plant derivative. OR The dose of Resveratrol will be 125 mg daily for six months. Resveratrol is taken orally. Resveratrol is a natural plant derivative.; Other Name: Polygonum cuspidatum
Active Comparator: Resveratrol - 125 mg/day; The dose of Resveratrol will be 125 mg daily for six months. Resveratrol is taken orally. Resveratrol is a natural plant derivative.	Drug: Resveratrol; The dose of Resveratrol will be 500 mg daily for six months. Resveratrol is taken orally. Resveratrol is a natural plant derivative. OR The dose of Resveratrol will be 125 mg daily for six months. Resveratrol is taken orally. Resveratrol is a natural plant derivative.; Other Name: Polygonum cuspidatum
Placebo Comparator: Placebo; Placebo will be taken orally for 6 months.	Drug: Placebo; Placebo will be taken orally for 6 months.; Other Name: No active study medication

Outcome Measures

Primary Outcome Measures :

1. 6-Minute Walk Distance, Meters [ Time Frame: Baseline and 6 month follow-up ]
   Six month changes in 6-Minute Walk Distance (meters) in response to resveratrol therapy in patients with Peripheral Artery Disease were measured.

Eligibility Criteria

• Ages Eligible for Study: 65 Years and older (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

United States, Illinois

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States, 60611

Sponsors and Collaborators

Northwestern University

National Institute on Aging (NIA)

Investigators

• Principal Investigator: Mary M McDermott, MD; Northwestern University

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gonzalez-Freire M, Moore AZ, Peterson CA, Kosmac K, McDermott MM, Sufit RL, Guralnik JM, Polonsky T, Tian L, Kibbe MR, Criqui MH, Li L, Leeuwenburgh C, Ferrucci L. Associations of Peripheral Artery Disease With Calf Skeletal Muscle Mitochondrial DNA Heteroplasmy. J Am Heart Assoc. 2020 Apr 7;9(7):e015197. doi: 10.1161/JAHA.119.015197. Epub 2020 Mar 21.

McDermott MM, Peterson CA, Sufit R, Ferrucci L, Guralnik JM, Kibbe MR, Polonsky TS, Tian L, Criqui MH, Zhao L, Stein JH, Li L, Leeuwenburgh C. Peripheral artery disease, calf skeletal muscle mitochondrial DNA copy number, and functional performance. Vasc Med. 2018 Aug;23(4):340-348. doi: 10.1177/1358863X18765667. Epub 2018 May 8.

McDermott MM, Leeuwenburgh C, Guralnik JM, Tian L, Sufit R, Zhao L, Criqui MH, Kibbe MR, Stein JH, Lloyd-Jones D, Anton SD, Polonsky TS, Gao Y, de Cabo R, Ferrucci L. Effect of Resveratrol on Walking Performance in Older People With Peripheral Artery Disease: The RESTORE Randomized Clinical Trial. JAMA Cardiol. 2017 Aug 1;2(8):902-907. doi: 10.1001/jamacardio.2017.0538.

• Responsible Party: Mary McDermott, Professor of Medicine, Northwestern University
• ClinicalTrials.gov Identifier: NCT02246660
• Other Study ID Numbers: 1R21AG047510-01 ( U.S. NIH Grant/Contract ); R21AG047510 ( U.S. NIH Grant/Contract )
• First Posted: September 23, 2014
• Results First Posted: April 30, 2018
• Last Update Posted: April 30, 2018
• Last Verified: November 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Mary McDermott, Northwestern University:

Peripheral Artery Disease; Peripheral Arterial Disease; PAD

Additional relevant MeSH terms:

Peripheral Arterial Disease; Peripheral Vascular Diseases; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Resveratrol; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs; Enzyme Inhibitors; Platelet Aggregation Inhibitors