Sequential Multiple Assessment Randomized Trial of Exercise for PAD: SMART Exercise for PAD

运动治疗PAD的序贯多重评估随机试验：SMART运动治疗PAD 监督运动疗法（SET），包括在中心进行3次/周的跑步机运动 在医护人员在场的情况下，是下肢外周残疾人的一线治疗 动脉疾病（PAD）。然而，前往中心进行SET是一项繁重的工作。截至2018年，只有1.3%的 有症状的PAD患者参加了SET。在家锻炼更容易获得 而且比SET的负担更小。然而，指南建议SET而不是PAD的家庭锻炼。 临床试验已经确定了家庭运动干预的三个特征， 对PAD患者有效：1）结合行为改变方法; 2）定期与教练接触， 以及3）在运动期间诱发缺血性腿部症状的运动强度。最近我们在JAMA上报道了 一个以家庭为基础的运动干预，包括这些特点显着和有意义的， 与注意力控制组相比，PAD组的6分钟步行改善。然而，没有随机试验 直接将SET与PAD患者的高效家庭运动干预进行了比较。此外，本发明还提供了一种方法， 45%的PAD患者对运动没有有意义的反应，定义为未能改善6分钟步行 距离> 20米（临床上有意义的改善）。这种现象发生在两个监督 在家锻炼。我们的第二阶段试验表明，富含硝酸盐的甜菜根汁， 亚硝酸盐、肢体灌注和运动强度，显著降低了对运动无反应的比率， 与安慰剂相比，在PAD中。因此，我们将使用序贯多重评估随机试验 （SMART）解决PAD从运动中受益的两个主要障碍：第一， 监督练习。第二，缺乏对PAD运动无反应的治疗。 在PAD的SMART锻炼中，250名PAD参与者将被随机分配到家庭锻炼或 SET 12周（第一阶段）。在12周的随访中，参与者将被分类为“反应者”（> 20米）。 6分钟步行改善）或“无反应者”（6分钟步行改善< 20米）。在第13周- 24（第二阶段），所有参与者将继续他们最初分配的锻炼条件（SET或家庭）， 无反应者将被重新随机分配到甜菜根汁或安慰剂组， 继续进行原来的练习。我们将检验两个主要假设。首先，我们的家庭是否 在12周随访时，运动干预比SET更能改善6分钟步行（主要目标#1）。第二、 甜菜根汁生物强化运动是否能改善PAD患者的6分钟步行 12周后对运动无反应（主要目的#2）。在次要和探索性目标中，我们将确定 最佳的运动策略，以最大限度地提高所有PAD患者的步行距离，从而 改善数百万因PAD致残的老年人的行动能力。

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 distances for all patients with PAD, thereby improving mobility in the millions of older people disabled by PAD.