Reuse of ZD4054 for patients with symptomatic PAD

对有症状的 PAD 患者重复使用 ZD4054

基本信息

批准号：
8599139
负责人：
BRIAN H ANNEX
金额：
$ 58.77万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-18 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8599139
关键词：
Activities of Daily Living Adverse effects Affect American Angiotensin-Converting Enzyme Inhibitors Ankle Arteries Atherosclerosis Benign Blood Platelets Blood Pressure Blood flow Clinical Clinical Oncology Clinical Research Complication Data Deterioration Diabetes Mellitus Disease model Dose Edema Elderly Endothelin Endothelin Receptor Endothelin Receptor Antagonist Endothelin-1 Exercise Freedom Functional Magnetic Resonance Imaging Functional disorder Funding Goals Headache Health Care Costs Image Individual Intermittent Claudication Ischemia Lasers Leg Limb structure Lower Extremity Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of ovary Measures Medical Muscle Non-Small-Cell Lung Carcinoma Oral Administration Outcome Measure Pain in lower limb Patients Perception Performance Perfusion Perfusion Weighted MRI Peripheral arterial disease Pharmaceutical Preparations Phase Phase II Clinical Trials Placebos Plasma Prevalence Quality of life Randomized Regimen Rest Risk Safety Sample Size Serious Adverse Event Smoking Solid Symptoms Testing Therapeutic Time Tissues United States United States National Institutes of Health Walking Withholding Treatment base bosentan castration resistant prostate cancer cost effective disability disorder control double-blind placebo controlled trial experience follow-up healthy volunteer improved indexing oncology oncology program patient population phase 2 study pre-clinical preclinical study primary outcome public health relevance receptor secondary outcome smoking cessation

项目摘要

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.

描述（由申请人提供）：外周动脉疾病 (PAD) 是动脉粥样硬化的主要并发症，仅在美国就影响超过 800 万人。间歇性跛行（IC），定义为行走时腿部疼痛，休息后可缓解，是 PAD 最常见的临床表现。由于 PAD 的患病率与年龄增长、糖尿病和吸烟有关，因此 PAD 患者的数量和医疗费用将会增加。我们的应用将测试 zibotentan (ZD4054) 的“重复使用”，zibotentan (ZD4054) 是一种口服活性 A 型内皮素拮抗剂，用于 IC 患者。该研究将寻求确认安全性间歇性跛行患者（卢瑟福 II 或 III）中 10 毫克 ZD4054 的耐受性，同时建立 ZD4054 改变小腿肌肉灌注的能力，通过对比增强磁共振成像、功能性跑步机性能和生活质量进行评估该研究将是一项 1:1 随机、双盲、安慰剂对照试验，对 44 名患有间歇性跛行的受试者进行随机分层。我们将使用磁共振成像来量化缺血肢体的血流量随时间的变化，并根据先前的经验和 ZD4054 的已知耐受性（研究团队的经验）对药物与安慰剂进行比较。适当的终点测量是其他 NIH 资助项目的一部分，我们将直接进行第二阶段试验，该研究的主要终点将是变化。使用 10 mg 剂量或安慰剂 12 周后，指数小腿肌肉从基线到随访的绝对灌注。其他结果指标包括： a) PAD 患者与安慰剂相比耐受 10 mg 剂量 ZD4054 的能力； b) 免受意外严重不良事件的影响； c) 10 mg ZD4054 组和安慰剂组之间峰值步行时间从基线到 12 周的变化； d) 10 mg ZD4054 组和安慰剂组之间 ABI 从基线到 12 周的变化； d) 10 mg ZD4054 组和安慰剂组之间生活质量的变化。