Combination Therapy in IPF

IPF 的联合治疗

• 批准号: 7060342
• 负责人: Imre Noth
• 金额: $ 19.17万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7060342
• 关键词: clinical research; clinical trials; combination chemotherapy; cooperative study; drug screening /evaluation; human mortality; human subject; human therapy evaluation; idiopathic pulmonary fibrosis; immunotherapy; indoles; interferon gamma; longitudinal human study; lovastatin; nonsteroidal antiinflammatory agent; outcomes research; pathologic process; patient oriented research; respiratory disorder chemotherapy; statistics /biometry

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a fatal disease for which current therapies have failed. Preventing alveolar epithelial cell (AEC) injury and myofibroblast (MF) activation/survival in distal airways may slow progression of fibrosis and enhance survival. Recent evidence from in vitro studies, in vivo models of pulmonary fibrosis, and previous clinical trials indicate that agents that block either growth factor production or fibroblast survival may attenuate fibrosis. Pirfenidone and interferon-gamma (IFN-?) may down-regulate both AEC apoptosis and fibroblast survival, HMGCoA reductase inhibitors (lovastatin) down-regulate fibroblast survival and 5-lipoxygenase activating protein (FLAP) inhibitors (MK-0591) down-regulate fibroblast-generated extracellular matrix production. We hypothesize that these agents have the potential to improve survival and slow disease progression in patients with IPF. To address this, we propose the following specific aims: Specific Aim 1: Determine if down-regulating growth factor production in distal airways via treatment with the combination of pirfenidone and IFN-?-lb improves survival over two years in patients with IPF. We hypothesize that the combination of these two agents will decrease mortality and slow disease progression to a greater extent than pirfenidone agent alone. To test this, we will conduct a multi-center, randomized, double-blind, placebo-controlled, stratified, parallel group two-year study of clinical effect of pirfenidone and IFN?-1b compared with pirfenidone alone or placebo in a large cohort of patients with IPF. Specific Aim 2: Determine if down-regulating fibroblast survival and matrix protein production with the combination of lovastatin and MK-0591 improves survival over two years in patients with IPF. We hypothesize that the combination of these two agents will decrease mortality and slow disease progression to a greater extent than either agent alone. To test this, we will conduct a multi-center, randomized, double-blind, placebo-controlled, stratified, parallel group two-year study of clinical effect of lovastatin and MK-0591 compared with either agent alone or placebo in a large cohort of patients with IPF. These clinical trials will establish whether agents that modulate interactions between AECs and fibroblasts, and thus reduce fibrosis and sequential damage in distal airways, can reduce mortality and slow disease progression in IPF. (End of Abstract)

描述（由申请人提供）： 特发性肺纤维化（IPF）是一种目前治疗失败的致命疾病。 预防远端气道中的肺泡上皮细胞（AEC）损伤和肌成纤维细胞（MF）活化/存活可以减缓纤维化的进展并提高存活率。 来自体外研究、肺纤维化的体内模型和先前的临床试验的最新证据表明，阻断生长因子产生或成纤维细胞存活的药剂可减弱纤维化。 吡非尼酮和干扰素-γ（IFN-？）可下调AEC凋亡和成纤维细胞存活，HMGCoA还原酶抑制剂（洛伐他汀）下调成纤维细胞存活，5-脂氧合酶激活蛋白（FLAP）抑制剂（MK-0591）下调成纤维细胞产生的细胞外基质产生。 我们假设这些药物有可能改善IPF患者的生存率并减缓疾病进展。 为解决这一问题，我们提出以下具体目标： 具体目的1：确定通过吡非尼酮和IFN-γ联合治疗是否下调远端气道中的生长因子产生。Ib改善了患有IPF的患者在两年内的存活率。 我们假设，这两种药物的组合将在更大程度上降低死亡率和减缓疾病进展比吡非尼酮药物单独。 为了验证这一点，我们将进行一项为期2年的多中心、随机、双盲、安慰剂对照、分层、平行组吡非尼酮和IFN？的临床疗效研究。1b在一个大型IPF患者队列中与吡非尼酮单药或安慰剂相比。 具体目标二：确定洛伐他汀和MK-0591联合用药下调成纤维细胞存活和基质蛋白产生是否可改善IPF患者的两年生存率。 我们假设这两种药物的联合使用将比单独使用任何一种药物更大程度地降低死亡率和减缓疾病进展。 为了检验这一点，我们将在一个大型队列中进行一项多中心、随机、双盲、安慰剂对照、分层、平行组两年研究，比较洛伐他汀和MK-0591与单独药物或安慰剂的临床效果。患有IPF的患者。 这些临床试验将确定调节AEC和成纤维细胞之间相互作用的药物，从而减少远端气道的纤维化和继发性损伤，是否可以降低IPF的死亡率和减缓疾病进展。 (End摘要）