Reuse of ZD4054 for patients with symptomatic PAD

对有症状的 PAD 患者重复使用 ZD4054

• 批准号: 8685367
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-18 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685367
• 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

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），定义为步行时腿部疼痛，休息后缓解， 最常见的PAD临床表现。PAD的患病率与年龄增长、糖尿病和吸烟有关，因此PAD患者的数量和医疗保健费用将增加。我们的申请将测试“重复使用”的zibotentan（ZD 4054），口服活性，内皮素A型拮抗剂在IC患者。这项研究将试图证实安全性 和10 mg ZD 4054在间歇性跛行（Rutherford II或III）患者中的耐受性，同时，通过对比增强磁共振成像、功能性跑步机性能和生活质量指标评估，确定ZD 4054改变小腿肌肉灌注的能力。本研究将是一项在44例间歇性跛行受试者中进行的1：1随机化、双盲、安慰剂对照试验，根据小腿内侧肌肉灌注进行随机化分层。我们将使用磁共振成像来量化缺血肢体血流随时间的变化，并将药物与安慰剂进行比较。根据既往经验和已知的ZD 4054耐受性，以及研究团队在其他NIH资助项目中采用机械适当终点指标的经验，我们将直接进行该II期试验。本研究的主要终点将是 10 mg剂量组或安慰剂组12周后，从基线至随访的指标小腿肌肉的绝对灌注。其他结局指标将是：a）PAD患者耐受10 mg ZD 4054与安慰剂的能力; B）无非预期严重不良事件; c）10 mg ZD 4054与安慰剂组之间峰值步行时间从基线至12周的变化; d）10 mg ZD 4054与安慰剂组之间ABI从基线至12周的变化，以及; d）10 mg ZD 4054组和安慰剂组之间生活质量指标的变化。