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

基本信息

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
项目类别：
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

项目摘要

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）：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有关。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，很少有药物疗法可以改善外周动脉疾病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 I 型骨骼肌纤维的数量，改善线粒体功能，增加耗氧量，并增强运动表现。同样在小鼠中，ARB 可以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 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，一项针对人类的小型试点试验表明，替米沙坦改善了 PAD 患者在跑步机上的行走表现。 TELEX 试验的主要目的是明确 a) 与安慰剂相比，单独使用替米沙坦是否能改善 PAD 患者的步行表现；b) 替米沙坦加监督运动的组合是否比单独使用替米沙坦和单独监督运动更能改善步行表现。为了实现我们的目标，我们将对 240 名 PAD 参与者进行一项随机对照临床试验（2 x 2 析因设计），这些参与者被随机分配到四个组之一：A 组：替米沙坦 + 监督运动疗法；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； D组：安慰剂+“无运动”对照组。我们的主要结果是基线和 6 个月随访期间六分钟步行表现的变化。我们的次要目标是衡量跑步机步行表现、患者报告的步行表现（通过步行障碍问卷测量）和生活质量（通过 Short Form-36 身体功能评分测量）的变化。在探索性目标中，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。除了确定替米沙坦在运动和不运动情况下的治疗效果外，TELEX 试验还将确定与 PAD 患者功能表现改善相关的生物学途径。