Sequential Multiple Assessment Randomized Trial of Exercise for PAD: SMART Exercise for PAD Supervised exercise therapy (SET), consisting of treadmill exercise conducted 3 times/week at a center in the presence of healthcare personnel, is first line therapy for people disabled by lower extremity peripheral artery disease (PAD). However, travelling to a center for SET is burdensome. As of 2018, only 1.3% of patients with Medicare and symptomatic PAD had enrolled in SET. Home-based exercise is more accessible and less burdensome than SET. Yet, guidelines recommend SET over home-based exercise for PAD. Clinical trials have identified three characteristics of home-based exercise interventions that are highly effective for people with PAD: 1) incorporation of behavioral change methods; 2) regular contact with a coach, and 3) an exercise intensity that elicits ischemic leg symptoms during exercise. Recently we reported in JAMA that a home-based exercise intervention that included these characteristics significantly and meaningfully improved 6-minute walk in PAD, compared to an attention control group. However, no randomized trials have directly compared SET to a highly effective home-based exercise intervention for people with PAD. In addition, 45% of people with PAD do not meaningfully respond to exercise, defined as failure to improve six-minute walk distance by > 20 meters (a clinically meaningful improvement). This phenomenon occurs for both supervised and home-based exercise. Our Phase II trial showed that nitrate-rich beetroot juice, which increases plasma nitrite, limb perfusion, and exercise intensity, significantly reduced rates of non-response to exercise, compared to placebo, in PAD. Therefore, we will use a Sequential Multiple Assessment Randomized Trial (SMART) to address two major barriers to benefit from exercise for PAD: First, the recommendation for supervised exercise. Second, the lack of treatment for non-response to exercise in PAD. In SMART Exercise for PAD, 250 participants with PAD will be randomized to home-based exercise or SET for 12 weeks (Stage I). At 12-week follow-up, participants will be classified into ‘responders’ (> 20 meter improvement in 6-minute walk) or ‘non-responders’ (< 20 meter improvement in 6-minute walk). In weeks 13- 24 (Stage II), all participants will continue their originally assigned exercise condition (SET or home-based), and non-responders will be re-randomized to either augmentation with beetroot juice or placebo while continuing their original exercise. We will test two primary hypotheses. First, whether our home-based exercise intervention improves 6-minute walk more than SET at 12-week follow-up (Primary Aim #1). Second, whether biologic augmentation of exercise with beetroot juice improves 6-minute walk in PAD patients unresponsive to exercise after 12 weeks (Primary Aim #2). In Secondary and Exploratory Aims, we will identify the optimal exercise strategy to maximize gains in walking distance...