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

替米沙坦加锻炼改善 PAD 功能：TELEX 试验

• 批准号: 8798370
• 负责人: Mary McGrae McDermott
• 金额: $ 79.67万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-17 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8798370
• 关键词: Adenosine Monophosphate; Angiotensin Receptor; Atrophic; Biological; Biopsy; Cell Count; Control Groups; Exercise; FOXO3A gene; Fibrosis; Functional disorder; Gastrocnemius Muscle; Gene Expression; Human; Impairment; Individual; Injury; Ischemia; Lower Extremity; Measures; Medical; Mitochondria; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Oral; Oxygen Consumption; PPAR delta; Participant; Pathway interactions; Patients; Performance; Peripheral arterial disease; Peroxisome Proliferator-Activated Receptors; Peroxisome Proliferators; Physical Function; Physical therapy exercises; Placebos; Protein Kinase; Quality of life; Questionnaires; Randomized; Randomized Controlled Clinical Trials; Relative (related person); Reperfusion Therapy; Reporting; Skeletal Muscle; Slow-Twitch Muscle Fibers; Therapeutic; Walking; Work; arm; base; delta opioid receptor; design; disability; effective therapy; follow-up; functional decline; functional disability; improved; improved functioning; improved mobility; muscle regeneration; pilot trial; prevent; primary outcome; public health relevance; repaired; satellite cell; telmisartan

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.

描述（由申请人提供）：具有外周动脉疾病（PAD）的与步行有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患者的功能障碍和活动性损失有关。然而，很少有医疗疗法可以改善帕德患者的流动性或防止残疾。 最近的证据表明，血管紧张素受体阻滞剂（ARB）端子可能会扭转PAD中存在的骨骼肌异常。在正常的小鼠中，telmisartan增加了I型骨骼肌纤维的数量，改善了线粒体功能，增加氧气消耗并提高运动性能。同样在小鼠中，ARB会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会修复与PAD患者观察到的缺血 - 再灌注相关的小腿肌肉损伤。为了支持我们的假设，在人类中进行了一项小型试点试验表明，Telmisartan改善了PAD患者的跑步机步行。 电传试验的主要目的是确定建立a）与安慰剂和b）与安慰剂和b）telmisartan Plus Plus监督运动的组合相比，单独使用PAD的步行表现是否能改善步行绩效比单独的telmisartan和单独的锻炼能力更大。为了实现我们的目标，我们将对240个PAD参与者进行随机对照临床试验（2 x 2阶乘设计），随机分配给四个臂之一：A组：Telmisartan +监督运动疗法； B组：Telmisartan + A“无运动”对照组； C组：安慰剂 +监督运动疗法；和D组：安慰剂 +一个“无运动”对照组。我们的主要结果是在基线和6个月的随访之间进行六分钟步行性能的变化。我们的次要目标将衡量跑步机步行性能的变化，患者报告的步行表现（通过步行障碍问卷来衡量）和生活质量（以短表格36的身体功能分数来衡量）。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。除了通过有没有锻炼的情况下，除了建立Telmisartan的治疗益处外，电传试验还将 确定与PAD患者的功能性能改善相关的生物学途径。