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

描述（由申请人提供）：外周动脉疾病（PAD）患者的步行相关缺血-再灌注与小腿骨骼肌纤维萎缩和线粒体功能受损相关。这些小腿肌肉异常与PAD患者的功能障碍和活动能力丧失有关。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）替米沙坦可能逆转PAD中存在的骨骼肌异常。在正常小鼠中，替米沙坦增加I型骨骼肌纤维的数量，改善线粒体功能，增加耗氧量，并增强运动能力。同样在小鼠中，ARB减少肌肉损伤后的纤维化，并增强肌肉损伤后卫星细胞依赖性肌肉再生。我们假设这些对小鼠骨骼肌的有利作用可能修复PAD患者中观察到的缺血-再灌注相关的小腿肌肉损伤。为了支持我们的假设，一项小型的人体初步试验表明，替米沙坦改善了PAD患者的踏车行走能力。 TELEX试验的主要目的是明确确定a）与安慰剂相比，替米沙坦单药治疗是否可改善PAD患者的步行能力，和B）替米沙坦联合监督运动治疗是否分别比替米沙坦单药治疗和监督运动单药治疗更能改善步行能力。为了实现我们的目标，我们将对240名PAD受试者进行随机对照临床试验（2 x 2析因设计），随机分为四组：A组：替米沙坦+监督运动治疗; B组：替米沙坦+“无运动”对照组; C组：安慰剂+监督运动治疗; D组：安慰剂+“无运动”对照组。我们的主要结果是基线和6个月随访之间6分钟步行能力的变化。我们的次要目标是测量跑步机行走能力、患者报告的行走能力（通过行走障碍问卷测量）和生活质量（通过简表-36身体功能评分测量）的变化。在探索性目的中，我们将获得小腿肌肉活检，以描绘这些疗法改善功能的生物学途径。除了确定运动和不运动时替米沙坦的治疗获益外，TELEX试验还将 确定与PAD患者功能改善相关的生物学途径。

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.