PROgenitor Cell Release Plus Exercise To Improve Functional Performance In PAD

描述（由申请人提供）：我们的工作和其他人的工作表明，患有下肢外周动脉疾病（PAD）的男性和女性与没有PAD的男性和女性相比，功能障碍更大，功能下降更快。PAD患者记录的功能障碍与活动能力丧失、死亡率增加和生活质量差相关。 初步证据表明，增加循环中CD 34+细胞水平的干预措施可能会改善PAD的功能表现。然而，三个小的临床试验测试是否粒细胞单核细胞集落刺激因子（GM-CSF）改善PAD的行走性能产生了混合的结果。GM-CSF与PAD患者步行能力改善的相关性尚未明确确定。初步数据还表明，下肢缺血，在步行锻炼过程中诱导，可能会增加循环的CD 34+细胞水平，增强归巢的CD 34+细胞的缺血部位，并增加GM-CSF的能力，以改善PAD的步行性能。我们提出了一项随机对照临床试验（2 × 2析因设计），240名PAD受试者将被随机分配到四个组之一：a）GM-CSF +监督运动治疗; B）GM-CSF治疗+注意力控制组; c）安慰剂+监督运动治疗; d）安慰剂+注意力控制组。 在我们的主要具体目标中，我们将确定与单独使用GM-CSF和单独使用有监督的跑步机运动相比，GM-CSF联合有监督的跑步机运动在12周随访时是否显著改善了6分钟步行能力。我们还将确定与安慰剂相比，单独使用GM-CSF是否在12周随访时显著改善6分钟步行能力。我们将证实，与注意力控制组相比，在12周的随访中，有监督的跑步机运动疗法显著提高了6分钟步行能力。在我们的第二个具体目标中，我们将确定与单独使用GM-CSF和单独使用监督下的运动相比，GM-CSF联合监督下的跑步机运动是否与12周随访时肱动脉血流介导的扩张（FMD）和最大跑步机步行时间的更大增加相关。在我们的探索性目标中，我们将建立6分钟步行能力，最大跑步机步行时间和肱动脉FMD对GM-CSF反应的时间轨迹。我们还将建立祖细胞增加的时间轨迹，以响应有监督的跑步机运动。 除了确定我们的干预措施的治疗益处外，这项研究还有望确定与PAD参与者功能表现改善相关的生物学途径。

DESCRIPTION (provided by applicant): Our work and that of others demonstrates that men and women with lower extremity peripheral arterial disease (PAD) have greater functional impairment and more rapid functional decline compared to those without PAD. The functional impairments documented in patients with PAD are associated with mobility loss, increased mortality, and poor quality of life. Preliminary evidence suggests that interventions to increase circulating levels of CD34+ cells may improve functional performance in PAD. However, three small clinical trials testing whether granulocyte monocyte colony stimulating factor (GM-CSF) improves walking performance in PAD yielded mixed results. The association of GM-CSF with improved walking performance in PAD is not definitively established. Preliminary data also suggest that lower extremity ischemia, induced during walking exercise, may increase circulating CD34+ cell levels, enhance homing of CD34+ cells to ischemic sites, and augment the ability of GM-CSF to improve walking performance in PAD. We propose a randomized controlled clinical trial (2 x 2 factorial design) of 240 participants with PAD who will be randomized to one of four arms: a) GM-CSF + supervised exercise therapy; b) GM-CSF therapy + an attention control group; c) placebo + supervised exercise therapy; and d) placebo + attention control group. In our primary specific aim, we will determine whether GM-CSF combined with supervised treadmill exercise significantly improves six-minute walk performance at 12-week follow-up, compared to GM-CSF alone and supervised exercise alone, respectively. We will also determine whether GM-CSF alone significantly improves six-minute walk performance at 12-week follow-up, compared to placebo. We will confirm that supervised treadmill exercise therapy significantly increases six-minute walk performance at 12-week follow- up, compared to an attention control group. In our secondary specific aim, we will determine whether GM-CSF combined with supervised treadmill exercise is associated with greater increases in brachial artery flow- mediated dilation (FMD) and maximal treadmill walking time at 12-week follow-up, compared to GM-CSF alone and supervised exercise alone, respectively. In our exploratory aim, we will establish the temporal trajectory of changes in six-minute walk performance, maximal treadmill walking time, and brachial artery FMD in response to GM-CSF. We will also establish the temporal trajectory of increases in progenitor cells in response to supervised treadmill exercise. In addition to establishing the therapeutic benefit of our interventions, this study is expected to identify biological pathways associated with improved functional performance in participants with PAD.