Nicotinamide Riboside With and Without Resveratrol to Improve Functioning in Peripheral Artery Disease

Study Overview
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Brief Summary
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NICE is a randomized clinical trial that will examine the effects of nicotinamide riboside (NR) both with and without resveratrol to test whether, among people with PAD, NR significantly improves walking performance more than placebo and whether NR combined with resveratrol significantly improves walking performance more than placebo. If findings support the hypotheses, results will be used to design a large, definitive randomized clinical. The study will randomize 90 participants with PAD to one of the following three groups: NR + resveratrol, NR + placebo, or placebo + placebo.

Official Title
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Nicotinamide Riboside With and Without Resveratrol to Improve Functioning in Peripheral Artery Disease: The NICE Trial

Conditions
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Peripheral Artery Disease

Intervention / Treatment
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* Drug: Nicotinamide riboside
* Drug: Resveratrol
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All participants will have PAD. PAD will be defined as the following: 1) An ankle-brachial index (ABI) <=0.90 at the baseline study visit or 2) Vascular laboratory evidence or angiographic evidence of PAD. Inclusion based on prior vascular laboratory evidence will be determined by the study principal investigator and includes, for example, a toe brachial index (TBI) < 0.70, Duplex measure showing 70% stenosis or great, a post heel-rise or post-exercise ABI drop of 20% or greater, or ABI values <= 0.90. Angiographic evidence of PAD consists of a stenosis of 70% or greater in a lower extremity artery. Exclusion Criteria: Above- or below-knee amputation. Critical limb ischemia. Wheelchair-bound or requiring a walker to ambulate. Walking is limited by a symptom other than PAD. Current foot ulcer on bottom of foot. End stage renal disease defined as a GFR less than 20 ml/min/1.73 M2. Significant liver impairment defined as two or more hepatic function enzymes >3.0 times the upper limit of normal. [NOTE: participants who meet this criterion may undergo a re-test of hepatic function tests to determine whether initially elevated hepatic enzymes represented a transient or spurious phenomenon.] Failure to successfully complete the 2-week study run-in. Planned lower extremity revascularization, orthopedic surgery, or other major surgery during the next six months. Lower extremity revascularization, orthopedic surgery, cardiovascular event, coronary revascularization, or other major surgery in the previous three months. Participation in supervised treadmill exercise during the previous three months. 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 only use oxygen at night may still qualify.] Mini-Mental Status Examination (MMSE) score <23 or dementia. 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.] Currently taking a dose of 250 mg or more of nicotinamide riboside, vitamin B3, niacin. Currently taking a slow-release form of niacin. Currently taking resveratrol or has taken any these drug(s) in past six months. Participants taking a multi-vitamin will not be excluded if the dose of vitamin B3 is less than 250 mgs. Increase in angina or angina at rest Non-English speaking. Visual impairment that limits walking ability. Women who are pregnant or who are pre-menopausal will not be eligible. 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. Potentially eligible participants will be advised that Medicare coverage for 12 weeks of supervised treadmill exercise is now available. Potential participants who have not participated in supervised treadmill exercise covered by Medicare and who desire to participate will be referred back to their physician for follow-up. These individuals may become eligible six months after they complete supervised treadmill exercise. Vulnerable populations (fetuses, pregnant women, children, prisoners, and institutionalized persons) and adults unable to consent will not be included in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nicotinamide riboside + resveratrol<br>Participants randomized to the NR + resveratrol arm of the study will receive 1,000 mg of NR and 125 mg of resveratrol daily for six months. | Drug: Nicotinamide riboside<br>* Participants randomized to the NR + resveratrol arm or the NR + placebo arm of the study will receive 1,000 mg of NR daily for six months.<br>* Other names: Niagen;Drug: Resveratrol<br>* Participants randomized to the NR + resveratrol arm of the study will receive 125 mg of resveratrol daily for six months.<br>|
| Active Comparator: Nicotinamide riboside + placebo<br>Participants randomized to the NR + placebo arm of the study will receive 1,000 mg of NR and a placebo daily for six months. | Drug: Nicotinamide riboside<br>* Participants randomized to the NR + resveratrol arm or the NR + placebo arm of the study will receive 1,000 mg of NR daily for six months.<br>* Other names: Niagen;Other: Placebo<br>* Participants randomized to the NR + placebo arm of the study will receiving placebo pills that are identical in appearance to resveratrol. Participants randomized to the placebo + placebo arm of the study will receive pills that are identical in appearance to NR and resveratrol. Participants will receive placebo pills daily for six months.<br>|
| Placebo Comparator: Placebo + placebo<br>Participants randomized to the placebo + placebo arm of study will receive placebo pills. | Other: Placebo<br>* Participants randomized to the NR + placebo arm of the study will receiving placebo pills that are identical in appearance to resveratrol. Participants randomized to the placebo + placebo arm of the study will receive pills that are identical in appearance to NR and resveratrol. Participants will receive placebo pills daily for six months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-minute walk distance (NR alone vs. placebo) | Among participants with PAD, investigators will determine whether NR alone improves six-minute walk distance at 6-month follow-up, compared to placebo. | Baseline to 6-month follow-up | 
| Six-minute walk distance (NR/resveratrol vs. placebo) | Among participants with PAD, investigators will determine whether NR combined with resveratrol improves six-minute walk performance at 6-month follow-up, compared to placebo. | Baseline to 6-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-minute walk distance (NR alone vs. placebo) | Among participants with PAD, investigators will determine whether NR alone improves six-minute walk performance at 3-month follow-up, compared to placebo. | Baseline to 3-month follow-up | 
| Six-minute walk distance (NR/resveratrol vs. placebo) | Among participants with PAD, investigators will determine whether NR combined with resveratrol improves six-minute walk performance at 3-month follow-up, compared to placebo. | Baseline to 3-month follow-up | 
| Six-minute walk distance (NR/resveratrol vs. NR alone) | Among participants with PAD, investigators will determine whether NR combined with resveratrol improves six-minute walk performance at 3-month follow-up, compared to NR alone. | Baseline to 3-month follow-up | 
| Six-minute walk distance (NR/resveratrol vs. NR alone) | Among participants with PAD, investigators will determine whether NR combined with resveratrol improves six-minute walk performance at 6-month follow-up, compared to NR alone. | Baseline to 6-month follow-up | 
| Maximal treadmill walking time (NR alone vs. placebo) | Among participants with PAD, investigators will determine whether NR alone improves maximal treadmill walking time at 6-month follow-up, compared to placebo. | Baseline to 6-month follow-up | 
| Walking Impairment Questionnaire (WIQ) distance score (NR alone vs. placebo) | Among participants with PAD, investigators will determine whether NR alone improves the WIQ distance score at 6-month follow-up, compared to placebo. | Baseline to 6-month follow-up | 
| Physical activity (NR alone vs. placebo) | Among participants with PAD, investigators will determine whether NR alone improves physical activity at 6-month follow-up, compared to placebo. | Baseline to 6-month follow-up | 
| Maximal treadmill walking time (NR/resveratrol vs. placebo) | Among participants with PAD, investigators will determine whether NR combined with resveratrol improves maximal treadmill walking time at 6-month follow-up, compared to placebo. | Baseline to 6-month follow-up | 
| Walking Impairment Questionnaire (WIQ) distance score (NR/resveratrol vs. placebo) | Among participants with PAD, investigators will determine whether NR combined with resveratrol improves the WIQ distance score at 6-month follow-up, compared to placebo. | Baseline to 6-month follow-up | 
| Physical activity (NR/Resveratrol vs. placebo) | Among participants with PAD, investigators will determine whether NR combined with resveratrol improves physical activity at 6-month follow-up, compared to placebo. | Baseline to 6-month follow-up | 
| Maximal treadmill walking time (NR/resveratrol vs. NR alone) | Among participants with PAD, investigators will determine whether NR combined with resveratrol improves maximal treadmill walking time at 6-month follow-up, compared to NR alone. | Baseline to 6-month follow-up | 
| Walking Impairment Questionnaire (WIQ) distance score (NR/resveratrol vs. NR alone) | Among participants with PAD, investigators will determine whether NR combined with resveratrol improves the Walking Impairment Questionnaire (WIQ) distance score at 6-month follow-up, compared to NR alone. | Baseline to 6-month follow-up | 
| Physical activity (NR/Resveratrol vs. NR alone) | Among participants with PAD, investigators will determine whether NR combined with resveratrol improves physical activity at 6-month follow-up, compared to NR alone. | Baseline to 6-month follow-up | 
| Six-minute walk distance (NR/Resveratrol or NR alone vs. placebo) | Participants with PAD who received NR alone and those who received NR + resveratrol will be combined into one group and compared to the group receiving placebo, to determine whether NR alone or NR+ resveratrol (combined group)have greater improvement in six-minute walk distance, compared to those randomized to placebo. | Baseline to 3-month follow-up | 
| Six-minute walk distance (NR/Resveratrol or NR alone vs. placebo) | Participants with PAD who received NR alone and those who received NR + resveratrol will be combined into one group and compared to the group receiving placebo, to determine whether NR alone or NR+ resveratrol (combined group)have greater improvement in six-minute walk distance, compared to those randomized to placebo. | Baseline to 6-month follow-up | 
| Maximal treadmill walking time (NR/resveratrol or NR alone vs. placebo) | Participants with PAD who received NR alone and those who received NR + resveratrol will be combined into one group and compared to the group receiving placebo, to determine whether NR alone or NR+ resveratrol (combined group)have greater improvement in maximal treadmill walking time, compared to those randomized to placebo. | Baseline to 6-month follow-up | 
| Walking Impairment Questionnaire (WIQ) distance score (NR/resveratrol or NR alone vs. placebo) | Participants with PAD who received NR alone and those who received NR + resveratrol will be combined into one group and compared to the group receiving placebo, to determine whether NR alone or NR+ resveratrol (combined group)have greater improvement in WIQ distance score, compared to those randomized to placebo. | Baseline to 6-month follow-up | 
| Physical Activity (NR/resveratrol or NR alone vs. placebo) | Participants with PAD who received NR alone and those who received NR + resveratrol will be combined into one group and compared to the group receiving placebo, to determine whether NR alone or NR+ resveratrol (combined group)have greater improvement in physical activity, compared to those randomized to placebo. | Baseline to 6-month follow-up | 
| NAD+ Abundance in gastrocnemius muscle (NR/resveratrol or NR alone vs. placebo) | Participants with PAD who received NR alone and those who received NR + resveratrol will be combined into one group and compared to the group receiving placebo, to determine whether NR alone or NR+ resveratrol (combined group)have greater improvement in NAD+ abundance, compared to those randomized to placebo. | Baseline to 6-month follow-up | 
| Satellite Cell Abundance in gastrocnemius muscle (NR/resveratrol or NR alone vs. placebo) | Participants with PAD who received NR alone and those who received NR + resveratrol will be combined into one group and compared to the group receiving placebo, to determine whether NR alone or NR+ resveratrol (combined group)have greater improvement in satellite cell abundance, compared to those randomized to placebo. | Baseline to 6-month follow-up | 
| Gastrocnemius Muscle Fiber Phenotype(NR/resveratrol or NR alone vs. placebo) | Participants with PAD who received NR alone and those who received NR + resveratrol will be combined into one group and compared to the group receiving placebo, to determine whether NR alone or NR+ resveratrol (combined group)have greater improvement in muscle fiber phenotype, compared to those randomized to placebo. | Baseline to 6-month follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peripheral Artery Disease, PAD, Resveratrol, Nicotinamide riboside (NR), Six-minute walk, Functional performance