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Completed

NCT Number: NCT03743636

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

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.

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Key information

Conditions

Peripheral Artery Disease Arterial Occlusive Diseases Arteriosclerosis Atherosclerosis Cardiovascular Diseases Peripheral Arterial Disease Peripheral Vascular Diseases Vascular Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Northwestern University

Chicago, Illinois, 60611, United States

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Nicotinamide riboside

Drug

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.

Other names: NR, Niagen

Resveratrol

Drug

Participants randomized to the NR + resveratrol arm of the study will receive 125 mg of resveratrol daily for six months.

Placebo

Other

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.

Primary outcomes

  1. Six-minute Walk Distance (NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR alone improves six-minute walk distance at 6-month follow-up, compared to placebo.

  2. Six-minute Walk Distance (NR/Resveratrol vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    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.

Secondary outcomes

  1. Six-minute Walk Distance (NR Alone vs. Placebo)

    Time frame: Baseline to 3-month follow-up

    Among participants with PAD, investigators will determine whether NR alone improves six-minute walk performance at 3-month follow-up, compared to placebo.

  2. Six-minute Walk Distance (NR/Resveratrol vs. Placebo)

    Time frame: Baseline to 3-month follow-up

    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.

  3. Six-minute Walk Distance (NR/Resveratrol vs. NR Alone)

    Time frame: Baseline to 3-month follow-up

    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.

  4. Six-minute Walk Distance (NR/Resveratrol vs. NR Alone)

    Time frame: Baseline to 6-month follow-up

    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.

  5. Maximal Treadmill Walking Time (NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR alone improves maximal treadmill walking time at 6-month follow-up, compared to placebo.

  6. Walking Impairment Questionnaire (WIQ) Distance Score (NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR alone improves the Walking Impairment Questionnaire (WIQ) distance score at 6-month follow-up, compared to placebo.

    The WIQ is a well validated questionnaire that measures patient-reported walking limitations in distance and speed and stair-climbing. They are scored on a 0-100 scale and that 100 indicates the best possible score.

  7. Physical Activity (NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR alone improves physical activity at 6-month follow-up, compared to placebo.

    The physical activity outcome was measured with the ActiGraph, in Activity Units. Higher scores indicate greater activity. The lowest possible score is zero, indicating sedentary time.

  8. Maximal Treadmill Walking Time (NR/Resveratrol vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    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.

  9. Walking Impairment Questionnaire (WIQ) Distance Score (NR/Resveratrol vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR combined with resveratrol improves the Walking Impairment Questionnaire distance score at 6-month follow-up, compared to placebo.

    The WIQ is a well validated questionnaire that measures patient-reported walking limitations in distance and speed and stair-climbing. They are scored on a 0-100 scale and that 100 indicates the best possible score.

  10. Physical Activity (NR/Resveratrol vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR combined with resveratrol improves physical activity at 6-month follow-up, compared to placebo.

    The physical activity outcome was measured with the ActiGraph, in Activity Units. Higher scores indicate greater activity. The lowest possible score is zero, indicating sedentary time.

  11. Maximal Treadmill Walking Time (NR/Resveratrol vs. NR Alone)

    Time frame: Baseline to 6-month follow-up

    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.

  12. Walking Impairment Questionnaire (WIQ) Distance Score (NR/Resveratrol vs. NR Alone)

    Time frame: Baseline to 6-month follow-up

    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.

    The WIQ is a well validated questionnaire that measures patient-reported walking limitations in distance and speed and stair-climbing. They are scored on a 0-100 scale and that 100 indicates the best possible score.

  13. Physical Activity (NR/Resveratrol vs. NR Alone)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR combined with resveratrol improves physical activity at 6-month follow-up, compared to NR alone..

    The physical activity outcome was measured with the ActiGraph, in Activity Units. Higher scores indicate greater activity. The lowest possible score is zero, indicating sedentary time.

  14. Six-minute Walk Distance (NR/Resveratrol or NR Alone vs. Placebo)

    Time frame: Baseline to 3-month follow-up

    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.

    Mixed model for repeated measures is applied to Placebo vs. 2 NR groups combined. The reported results of within group change and between group difference are Least Squares Mean (Standard Error) from the model adjusted for baseline six-minute walk + age + sex + race + resveratrol usage.

  15. Six-minute Walk Distance (NR/Resveratrol or NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    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.

    Mixed model for repeated measures is applied to Placebo vs. 2 NR groups combined. The reported results of within group change and between group difference are Least Squares Mean (Standard Error) from the model adjusted for baseline six-minute walk + age + sex + race + resveratrol usage.

  16. Maximal Treadmill Walking Time (NR/Resveratrol or NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    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.

  17. Walking Impairment Questionnaire (WIQ) Distance Score (NR/Resveratrol or NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    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 Walking Impairment Questionnaire distance score, compared to those randomized to placebo.

    The WIQ is a well validated questionnaire that measures patient-reported walking limitations in distance and speed and stair-climbing. They are scored on a 0-100 scale and that 100 indicates the best possible score.

  18. Physical Activity (NR/Resveratrol or NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    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.

    The physical activity outcome was measured with the ActiGraph, in Activity Units. Higher scores indicate greater activity. The lowest possible score is zero, indicating sedentary time.

    Mixed model for repeated measures is applied to Placebo vs. 2 NR groups combined. The reported results of within group change and between group difference are Least Squares Mean (Standard Error) from the model adjusted for baseline six-minute walk + age + sex + race + resveratrol usage.

  19. NAD+ Abundance in Gastrocnemius Muscle (NR/Resveratrol or NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    The outcome measure is the comparison of 6-month change in gastrocnemius muscle biopsy measures of NAD+ abundance between NR and placebo and between NR + resveratrol and 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. Measurements of NAD+ abundance were completed using High Performance Liquid Chromatography (HPLC) with a Shimadzu LC-20A pump and UV-VIS detector using a Supelco LC-18-Tcolumn, normalized to muscle weight.

  20. Satellite Cell Abundance in Gastrocnemius Muscle (NR/Resveratrol or NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    The outcome measure is the comparison of 6-month changes in gastrocnemius muscle biopsy measures of satellite cell abundance between NR and placebo and between NR + resveratrol and 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. Satellite cell abundance was measured via density (satellite cells/100 fibers) using antibodies against: Pax7, type 1 myosin, and laminin.

  21. Gastrocnemius Muscle Fiber Phenotype(NR/Resveratrol or NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    The outcome measure is the comparison of 6-month changes in gastrocnemius muscle biopsy measures of Percent Type 1 myofibers (%) between NR and placebo and between NR + resveratrol and 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. Measurements of fiber type % were determined on frozen muscle sections using antibodies against: Pax7, type 1 myosin, and laminin.

    Mixed model for repeated measures is applied to Placebo vs. 2 NR groups combined. The reported results of within group change and between group difference are Least Squares Mean (Standard Error) from the model adjusted for baseline six-minute walk + age + sex + race + resveratrol usage.

Other outcomes

  1. Gastrocnemius Muscle Satellite Cell Abundance (NR/Resveratrol vs. Placebo and NR vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Investigators will perform calf muscle biopsies to determine whether among participants with PAD, those randomized to NR + resveratrol and NR alone have increased satellite cell abundance compared to the placebo group. Satellite cell abundance was measured via density (satellite cells/100 fibers) using antibodies against: Pax7, type 1 myosin, and laminin.

  2. NAD+ Abundance in Gastrocnemius Muscle (NR/Resveratrol vs. Placebo and NR vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Investigators will perform calf muscle biopsies to determine whether among participants with PAD, those randomized to NR + resveratrol and NR alone have increased calf muscle NAD+ abundance, compared to the placebo group. Measurements of NAD+ abundance were completed using High Performance Liquid Chromatography (HPLC) with a Shimadzu LC-20A pump and UV-VIS detector using a Supelco LC-18-Tcolumn, normalized to muscle weight.

  3. Muscle Fiber Phenotype in Gastrocnemius Muscle (NR/Resveratrol vs. Placebo and NR vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Investigators will perform calf muscle biopsies to determine whether among participants with PAD, those randomized to NR + resveratrol and NR alone have improved muscle fiber phenotype (Percent Type 1 myofibers (%)), compared to the placebo group. Measurements of fiber type % were determined on frozen muscle sections using antibodies against: Pax7, type 1 myosin, and laminin.

  4. Walking Impairment Questionnaire (WIQ) Speed Score (NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR alone improves the Walking Impairment Questionnaire speed and stair climbing score at 6-month follow-up, compared to placebo.

    The WIQ is a well validated questionnaire that measures patient-reported walking limitations in distance and speed and stair-climbing. They are scored on a 0-100 scale and that 100 indicates the best possible score.

  5. Short-Form Physical Functioning (SF-36) Score (NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR alone improves the Walking Impairment Questionnaire speed and stair climbing scores and the Short-Form Physical Functioning score at 6-month follow-up, compared to placebo.

    The SF-36 measures health status. The score range is 0-100, where 100 is best.

  6. Walking Impairment Questionnaire (WIQ) Stair Climbing Score (NR/Resveratrol vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR combined with resveratrol improves the Walking Impairment Questionnaire speed and stair climbing scores at 6-month follow-up, compared to placebo.

    The WIQ is a well validated questionnaire that measures patient-reported walking limitations in distance and speed and stair-climbing. They are scored on a 0-100 scale and that 100 indicates the best possible score.

  7. Short-Form Physical Functioning (SF-36) Score (NR/Resveratrol vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR combined with resveratrol improves the Short-Form Physical Functioning score at 6-month follow-up, compared to placebo.

    The SF-36 measures health status. The score range is 0-100, where 100 is best.

  8. Walking Impairment Questionnaire (WIQ) Speed Score (NR/Resveratrol vs. NR Alone)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR combined with resveratrol improves the Walking Impairment Questionnaire speed and stair climbing score at 6-month follow-up, compared to NR alone.

    The WIQ is a well validated questionnaire that measures patient-reported walking limitations in distance and speed and stair-climbing. They are scored on a 0-100 scale and that 100 indicates the best possible score.

  9. Short-Form Physical Functioning (SF-36) Score (NR/Resveratrol vs. NR Alone)

    Time frame: Baseline to 6-month follow-up

    Among participants with PAD, investigators will determine whether NR combined with resveratrol improves the Walking Impairment Questionnaire speed and stair climbing scores and the Short-Form Physical Functioning score at 6-month follow-up, compared to NR alone.

    The SF-36 measures health status. The score range is 0-100, where 100 is best.

  10. Walking Impairment Questionnaire (WIQ) Speed Score (NR/Resveratrol or NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    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 the Walking Impairment Questionnaire (WIQ) speed and stair climbing score at 6-month follow-up, compared to placebo.

    The WIQ is a well validated questionnaire that measures patient-reported walking limitations in distance and speed and stair-climbing. They are scored on a 0-100 scale and that 100 indicates the best possible score.

  11. Short-Form Physical Functioning (SF-36) Score (NR/Resveratrol or NR Alone vs. Placebo)

    Time frame: Baseline to 6-month follow-up

    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 the Short-Form Physical Functioning score at 6-month follow-up, compared to placebo.

    The SF-36 measures health status. The score range is 0-100, where 100 is best.

Sponsors and collaborators

Lead sponsor

Northwestern University

Other

Collaborators

  • American Heart Association

Registry information

Official study title

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

Acronym: NICE

Important dates

Study start
2018
Primary completion
2023
Study completion
2023
First posted
Nov 16, 2018
Registry last updated
Jan 14, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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