NICotinamidE riboside to improve functioning in PAD: The NICE Trial - ABSTRACT Our work and that of others show that people with lower extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, and higher rates of mobility loss than people without PAD. Yet few therapies improve walking impairment or prevent functional decline in people with PAD. In people with PAD, lower extremity ischemia is associated with increased oxidative stress and impaired mitochondrial activity in lower extremity muscle. Nicotine adenine dinucleotide (NAD+) is a coenzyme that is essential for mitochondrial activity. In animals, NAD+ reduces oxidative stress and increases endothelial nitric oxide synthase (eNOS) activity and nitric oxide abundance. In animals, interventions that increase NAD+ abundance improve mitochondrial activity, grip strength, and running endurance. In humans, NAD+ abundance significantly declines with age. Nicotinamide riboside (NR) is a B3 vitamin and precursor to NAD+. In humans, oral ingestion of NR increases intracellular and whole blood abundance of NAD+ in a dose dependent manner. We hypothesize that by increasing NAD+ abundance, NR will improve skeletal muscle mitochondrial activity, reduce oxidative stress, and increase bioavailability of nitric oxide, thereby improving lower extremity perfusion in older people with PAD. Consistent with our hypotheses, our NICE Pilot randomized clinical trial showed that, compared to placebo, NR increased 6-minute walk distance by 17.6 meters and maximal treadmill walking time by 2.1 minutes (i.e. by 28.6%), at 6-month follow-up in people with PAD. In participants with 75% or greater adherence to study pills, NR improved 6-minute walk by 31.0 meters, compared to placebo (P=0.014), an effect size similar to the effects of supervised exercise on 6-minute walk in PAD patients. We now propose a Phase III multi-centered double blinded randomized clinical trial to determine whether NR, compared to placebo, significantly improves 6-minute walk distance at 6-month follow-up in 250 people with PAD. In secondary aims, we will determine whether NR significantly improves calf muscle perfusion (measured by magnetic resonance imaging arterial spin labeling), oxidative stress (measured by plasma oxidized LDL), and mitochondrial activity (measured by oxidative phosphorylation in gastrocnemius muscle biopsies) at 6-month follow-up, compared to placebo. Effects of NAD+ to increase perfusion, reduce oxidative stress, and improve mitochondrial activity directly target the pathophysiologic changes present in PAD. If results from our NICE Pilot Trial are confirmed in this proposed randomized clinical trial, this inexpensive, safe, accessible, and well- tolerated therapy has the potential to meaningfully improve mobility in the large and growing number of older people disabled by PAD.
