Phase 2 Study of Digitoxin for the Treatment of Cystic Fibrosis

洋地黄毒素治疗囊性纤维化的 2 期研究

• 批准号: 8747904
• 负责人: Pamela L. Zeitlin
• 金额: $ 28.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-11-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8747904
• 关键词: Phase; Study; Digitoxin; Treatment; Cystic

Cystic Fibrosis (CF) is one of the most common, life limiting autosomal recessive genetic disease in the U.S., with a prevalence of about 30.000 total patients. Cystic Fibrosis has no cure and incurs a huge lifetime financial burden. At least one person with CF dies each day. The average annual cost of CF care per individual with private healthcare insurance in 2006 was $48,098, more than 22 times the cost of an individual without CF. Mortality in CF patients is mostly due to progressive respiratory failure from irreversible obstructive lung disease. The lung is destroyed by infection and complicated by an intrinsically pro-inflammatory NFKB- mediated neutrophil-dominated state in the airway. Airways are infiltrated with increased numbers of neutrophils that are attracted by Il-8. The major source of IL-8 in the CF airway is the airway epithelium, and the resulting high levels of IL-8 attract a large influx of neutrophils and other inflammatory cells. The CF epithelial cells also secrete high levels of other proinflammatory cytokines, but they are in less abundance. IL-8 hypersecretion in the CF lung is due to a dysfunctional TNFa/NF¿B signaling pathway. For that reason an attractive pharmaceutical strategy has been to find a drug that would suppress that part of the pathway involved in IL-8 expression, but not other parts required for physiological responses to infection. This project was devised when low concentrations of the drug digitoxin were discovered to suppress IL-8 hypersecretion by CF lung epithelial cells. The mechanism of digitoxin action is to suppress the TNFa/NF¿B signaling pathway. Digitoxin specifically blocks the interaction between the TNF Receptor and the adaptor protein TRADD. This site of interaction is known as the initiator for assembly of a set of three other adaptor proteins, the "inflammasome" which leads downstream to IL-8 expression. The oral bioavailability of digitoxin is approximately 100%, and therefore we hypothesize that digitoxin will safely suppress IL-8 dependent lung inflammation in cystic fibrosis patients. The purpose of this proposal is to complete the third and final cohort of CF patients to test this hypothesis and select the minimum safe and effective dose. Primary Objective: To measure the effects of digitoxin on IL-8 and neutrophil counts in induced sputum in stable CF patients. The study is a randomized, double blind, placebo-controlled, repeat dosing trial evaluating the effects of 28 days of digitoxin on IL-8 and neutrophil concentrations in induced sputum in CF subjects with mild to moderate cystic fibrosis lung disease. Three groups of 8 subjects each will be given either 0.05 mg or 0.10 mg digitoxin or a placebo. Twenty-four total patients are planned for the study. Secondary Objective 1: To measure the pharmacokinetics of digitoxin in serum in stable CF patients. The length of study participation for each subject is 70 days, and is defined as Screening Days (week ); -4 to day -2) Treatment Days (Day 1-28); and Recovery Days (Day 28-42). Serum (pharmacokinetics) is collected at intervals for analysis. Secondary Objective 2: To measure safety indices, including ECG changes and sputum microbiology, in stable CF patients. Secondary Objective 3: To measure the effect of digitoxin on gene expression in nasal epithelial cells of stable CF patients. Nasal epithelial cells are collected on Day 0 prior to study drug dosing and on day 28 after last study dose. Secondary Objective 4: To measure quality of life scores using the CFQ-R.

囊性纤维化 (CF) 是美国最常见的限制生命的常染色体隐性遗传病之一， 囊性纤维化的患病率约为 30,000 名患者，且无法治愈，并且会导致患者一生漫长。 每天至少有 1 名 CF 患者死亡 平均每年的 CF 护理费用。 2006年拥有私人医疗保险的个人费用为48,098美元，是个人费用的22倍多 没有 CF 的患者的死亡主要是由于不可逆阻塞引起的进行性呼吸衰竭。 肺部疾病因感染而被破坏，并因本质上促炎的 NFKB-而变得复杂。 气道中介导的中性粒细胞主导状态。 被 IL-8 吸引的中性粒细胞 CF 气道中 IL-8 的主要来源是气道上皮，并且 由此产生的高水平 IL-8 会吸引大量中性粒细胞和其他炎症细胞涌入 CF。 上皮细胞还分泌高水平的其他促炎细胞因子，但其含量较少。 CF 肺中的分泌过多是由于 TNFa/NF 功能失调所致？因此 B 信号通路。 有吸引力的药物策略是找到一种能够抑制该通路部分的药物 参与 IL-8 表达，但不涉及感染生理反应所需的其他部分。 当发现低浓度的洋地黄毒苷药物可通过抑制 IL-8 分泌过多时，设计了 CF 肺上皮细胞。洋地黄毒苷的作用机制是抑制 TNFa/NF¿ B信号通路。 洋地黄毒素特异性阻断 TNF 受体和接头蛋白 TRADD 之间的相互作用。 相互作用位点被称为组装一组其他三种接头蛋白的起始子， 导致 IL-8 表达下游的“炎症体” 洋地黄毒苷的口服生物利用度为 大约 100%，因此我们能够安全地抑制 IL-8 依赖性肺 该提案的目的是完成第三个也是最后一个队列。 CF患者检验这一假设并选择最小安全有效剂量主要目的： 测量洋地黄毒苷对稳定 CF 患者诱导痰中 IL-8 和中性粒细胞计数的影响。 该研究是一项随机、双盲、安慰剂对照、重复给药试验，评估 28 种药物的效果 洋地黄毒苷对轻度至中度 CF 受试者诱导痰中 IL-8 和中性粒细胞浓度影响的天数 囊性纤维化肺疾病。三组，每组 8 名受试者，将给予 0.05 毫克或 0.10 毫克洋地黄毒苷。 或安慰剂计划总共有 24 名患者参与该研究。 次要目标 1：测定稳定期 CF 患者血清中洋地黄毒苷的药代动力学。 每个受试者的研究参与时间为 70 天，定义为筛选天数（周）； 第-2天）治疗天（第1-28天）；和恢复天（第28-42天）收集血清（药代动力学）。 分析的间隔。 次要目标2：测量安全指标，包括心电图变化和痰微生物学， 稳定的 CF 患者。 次要目标 3：测量洋地黄毒苷对鼻上皮细胞基因表达的影响 在研究药物给药前第 0 天和第 28 天收集稳定 CF 患者的鼻上皮细胞。 最后一次研究剂量后。 次要目标 4：使用 CFQ-R 衡量生活质量评分。