TELmisartan plus EXercise to improve functioning in PAD: The TELEX Trial

描述(申请人提供)：外周动脉疾病(PAD)患者与步行相关的缺血-再灌注与小腿骨骼肌纤维萎缩和线粒体功能受损有关。这些小腿肌肉异常与PAD患者的功能损害和行动能力丧失有关。然而，几乎没有医学疗法可以改善PAD患者的活动能力或预防其残疾。最近的证据表明，血管紧张素受体阻滞剂(ARB)替米沙坦可以逆转PAD中存在的骨骼肌异常。在正常小鼠中，替米沙坦增加了I型骨骼肌纤维的数量，改善了线粒体功能，增加了氧气消耗，并提高了运动能力。同样，在小鼠中，ARB可减少肌肉损伤后的纤维化，并增强肌肉损伤后依赖卫星细胞的肌肉再生。我们推测，这些对小鼠骨骼肌的有利作用可能会修复PAD患者所观察到的与缺血再灌注相关的小腿肌肉损伤。为了支持我们的假设，在人体上进行的一项小型试点试验表明，替米沙坦改善了患有PAD的人的跑步机行走能力。电传试验的主要目的是确定a)与安慰剂相比，替米沙坦单独使用是否能改善PAD患者的行走能力；b)替米沙坦加监督锻炼的组合是否分别比单独使用替米沙坦和监督锻炼更能改善行走能力。为了达到我们的目标，我们将对240名PAD参与者进行随机对照临床试验(2×2析因设计)，随机分为四组：A组：替米沙坦+监督运动疗法；B组：替米沙坦+“不运动”对照组；C组：安慰剂+监督运动疗法；以及D组：安慰剂+“不运动”对照组。我们的主要结果是6分钟步行能力在基线和6个月随访期间的变化。我们的次要目标将衡量跑步机行走能力、患者报告的行走能力(通过行走障碍问卷衡量)和生活质量(通过简明36身体功能评分衡量)的变化。在探索性目标中，我们将获得小腿肌肉活组织检查，以描绘这些疗法改善功能的生物途径。除了确定运动前后替米沙坦的治疗益处外，电传试验还将 确定与改善PAD患者的功能表现相关的生物学途径。

DESCRIPTION (provided by applicant): Walking-related ischemia-reperfusion in people with peripheral artery disease (PAD) is associated with calf skeletal muscle fiber atrophy and impaired mitochondrial function. These calf muscle abnormalities are associated with functional impairment and mobility loss in people with PAD. Yet few medical therapies exist to improve mobility or prevent disability in PAD patients. Recent evidence suggests that the angiotensin receptor blocker (ARB) telmisartan may reverse the skeletal muscle abnormalities present in PAD. In normal mice, telmisartan increases the quantity of Type I skeletal muscle fibers, improves mitochondrial function, increases oxygen consumption, and enhances exercise performance. Also in mice, ARBs reduce fibrosis after muscle injury and enhance satellite cell-dependent muscle regeneration after muscle injury. We hypothesize that these favorable effects on skeletal muscle in mice may repair the ischemia-reperfusion related calf muscle injury observed in patients with PAD. In support of our hypothesis, a small pilot trial in humans showed that telmisartan improved treadmill walking performance in people with PAD. The primary aims of the TELEX Trial are to definitively establish a) whether telmisartan alone improves walking performance in people with PAD compared to placebo and b) whether the combination of telmisartan plus supervised exercise improves walking performance more than telmisartan alone and supervised exercise alone, respectively. To achieve our aims, we will conduct a randomized controlled clinical trial (2 x 2 factorial design) of 240 PAD participants randomized to one of four arms: Group A: telmisartan + supervised exercise therapy; Group B: telmisartan + a "no exercise" control group; Group C: placebo + supervised exercise therapy; and Group D: placebo + a "no exercise" control group. Our primary outcome is change in six-minute walk performance between baseline and 6-month follow-up. Our secondary aims will measure change in treadmill walking performance, patient-reported walking performance (measured by the Walking Impairment Questionnaire), and quality of life (measured by the Short Form-36 Physical Functioning score). In exploratory aims, we will obtain calf muscle biopsies to delineate biologic pathways by which these therapies improve functioning. In addition to establishing the therapeutic benefit of telmisartan with and without exercise, the TELEX Trial will identify biological pathways associated with improved functional performance in people with PAD.