Reuse of ZD4054 for patients with symptomatic PAD

描述(申请人提供)：外周动脉疾病(PAD)是动脉粥样硬化的主要并发症，仅在美国就有800万人受到影响。间歇性跛行(IC)，定义为腿部疼痛，走路后休息即可缓解，是 PAD最常见的临床表现。随着PAD的流行与年龄增长、糖尿病和吸烟相关，PAD的患者数量和医疗费用将会增加。我们的应用将测试Zibotentan(ZD4054)的“再使用”，它是一种口服活性的A型内皮素拮抗剂，用于IC患者。这项研究将寻求证实该药物的安全性 在间歇性跛行(卢瑟福II或III级)患者中服用10毫克ZD4054的耐受性，同时通过对比增强磁共振成像、功能跑步机性能和生活质量指标评估ZD4054改变小腿肌肉灌注的能力。这项研究将是一项1：1的随机、双盲、安慰剂对照试验，对象为44名间歇性跛行的受试者，随机根据小腿肌肉灌注进行分层。我们将使用磁共振成像来量化随着时间的推移流向缺血肢体的血流的变化，并将药物与安慰剂进行比较。根据ZD4054先前的经验和已知的耐受性，调查团队使用机械上适当的终点措施的经验是NIH资助的其他项目的一部分，我们将直接进行这项第二阶段试验。这项研究的主要终点将是 绝对灌注指标为小腿肌肉从基线到随访，12周后给予10 mg剂量或安慰剂。其他结果指标将包括：a)PAD患者对10毫克ZD4054与安慰剂的耐受性；b)免于意外的严重不良事件；c)10毫克ZD4054组与安慰剂组之间的高峰步行时间从基线到12周的变化；d)在10毫克ZD4054组和安慰剂组之间的ABI从基线到12周的变化；以及d)生活质量测量在10毫克ZD4054组和安慰剂组之间的变化。

DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) is a major complication of atherosclerosis that affects >8 million people in the United States alone. Intermittent claudication (IC), defined as leg pain with walking that is relieved with rest, is the most frequent clinical manifestation of PAD. The number of patients with, and the health care costs of, PAD will increase as the prevalence of PAD is associated with advancing age, diabetes, and smoking. Our application will test the "reuse" of zibotentan (ZD4054), an orally active, endothelin type A antagonist in patients with IC. The study will seek to confirm the safety and tolerability of 10mg of ZD4054 in patients with intermittent claudication (Rutherford II or III and, in parallel, establish the capacity of ZD4054 to change calf muscle perfusion, as assessed by contrast-enhanced magnetic resonance imaging, functional treadmill performance, and quality of life indicators. The study will be a 1:1 randomized, double-blind, placebo-controlled trial of 44 subjects with intermittent claudication with randomization stratified based on the entr calf muscle perfusion. We will use magnetic resonance imaging to quantify changes in blood flow to the ischemic limb over time and compare drug to placebo. Based on the prior experience and the known tolerability of ZD4054, the experience of the investigative team with a mechanistically appropriate end-point measure that is part of other NIH funded projects, we will be proceed directly to this Phase II trial. The primary endpoint of the study will be the change in absolute perfusion in the index calf muscle from baseline to follow-up, after 12 weeks on the 10 mg dose or placebo. Additional outcome measures will be: a) ability of patients with PAD to tolerate 10 mg dose of ZD4054 vs. placebo; b) freedom from unexpected serious adverse events; c) change in peak walking time from baseline to 12 weeks between 10 mg of ZD4054 and placebo groups; d) change in ABI from baseline to 12 weeks between 10 mg of ZD4054 and placebo groups, and; d) change in quality of life measure between 10 mg of ZD4054 and placebo groups.