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: 9127803
• 负责人: Mary McGrae McDermott
• 金额: $ 74.85万
• 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/9127803
• 关键词: Adenosine Monophosphate; Angiotensin Receptor; Atrophic; Biological; Biopsy; Cell Count; Control Groups; Exercise; Exercise Therapy; FOXO3A gene; Fibrosis; Functional disorder; Gastrocnemius Muscle; Gene Expression; Health; 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; Placebos; Protein Kinase; Quality of life; Questionnaires; Randomized; Randomized Controlled Clinical Trials; 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; repaired; satellite cell; telmisartan; treadmill

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）患者的行走相关性缺血-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患者的功能损害和活动能力丧失有关。然而，很少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，增加氧气消耗，提高运动表现。同样在小鼠中，ARBs减少肌肉损伤后的纤维化，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患者缺血性再灌注相关的小腿肌肉损伤。为了支持我们的假设，一项小规模的人体试验表明，替米沙坦改善了PAD患者在跑步机上行走的表现。TELEX试验的主要目的是明确确定a)与安慰剂相比，单独替米沙坦是否能改善PAD患者的行走性能；b)联合替米沙坦加监督运动是否比单独替米沙坦和单独监督运动更能改善行走性能。为了实现我们的目标，我们将对240名PAD参与者进行随机对照临床试验（2 × 2因子设计），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+监督运动疗法；D组：安慰剂+“不运动”的对照组。我们的主要结果是基线和6个月随访期间6分钟步行表现的变化。我们的次要目的是测量跑步机步行表现的变化，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）。在探索性目的中，我们将获得小腿肌肉活检来描述这些疗法改善功能的生物学途径。除了确定替米沙坦有和没有运动的治疗益处外，TELEX试验将