Combination Therapy in IPF

IPF 的联合治疗

• 批准号: 7413979
• 负责人: Imre Noth
• 金额: $ 19.32万
• 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/7413979
• 关键词: Address; Adrenal Cortex Hormones; Alveolar; Apoptosis; Arachidonate 5-Lipoxygenase; Attenuated; Biological Preservation; Cessation of life; Chronic; Clinical Trials; Combined Modality Therapy; Cyclic AMP; Cytotoxic agent; Data; Disease; Disease Progression; Distal; Double-Blind Method; End Point; Epithelial Cells; Etiology; Exercise Tolerance; Extracellular Matrix; Fibroblasts; Fibrosis; Gases; Growth Factor; Hamman-Rich syndrome; In Vitro; Inflammation; Interferon Type II; Interferons; Interstitial Lung Diseases; Lovastatin; Lung; Morbidity - disease rate; Myofibroblast; Oxidoreductase; Oxygen; Patients; Pirfenidone; Placebo Control; Placebos; Platelet-Derived Growth Factor; Production; Proteins; Pulmonary Fibrosis; Randomized; Rate; Respiratory physiology; Safety; Testing; Therapeutic Agents; Time; Transforming Growth Factor beta; Translating; Vital capacity; Walking; abstracting; cell injury; clinical effect; cohort; cytokine; improved; in vivo Model; inhibitor/antagonist; interstitial; mortality; novel strategies; novel therapeutics; prevent; repaired

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）是一种致命的疾病，目前的治疗方法已经失败。 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）激活/存活可能会减缓纤维化的进展并提高存活率。 来自体外研究、肺纤维化体内模型和先前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物可能会减轻纤维化。 吡非尼酮和干扰素-γ (IFN-?) 可能下调 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) 下调成纤维细胞生成的细胞外基质 生产。 我们假设这些药物有可能提高 IPF 患者的生存率并减缓疾病进展。 为了解决这个问题，我们提出以下具体目标： 具体目标 1：确定通过吡非尼酮和 IFN-γ-1b 联合治疗下调远端气道生长因子的产生是否可以改善 IPF 患者两年以上的生存率。 我们假设这两种药物的组合将比单独使用吡非尼酮药物更大程度地降低死亡率并减缓疾病进展。 为了测试这一点，我们将在一大群 IPF 患者中进行一项多中心、随机、双盲、安慰剂对照、分层、平行组的为期两年的研究，比较吡非尼酮和 IFN?-1b 与单独使用吡非尼酮或安慰剂的临床效果。 具体目标 2：确定洛伐他汀和 MK-0591 联合下调成纤维细胞存活率和基质蛋白产量是否可以改善 IPF 患者两年内的存活率。 我们假设这两种药物的组合将比单独使用任何一种药物更大程度地降低死亡率并减缓疾病进展。 为了测试这一点，我们将在一大群 IPF 患者中进行一项多中心、随机、双盲、安慰剂对照、分层、平行组的为期两年的研究，比较洛伐他汀和 MK-0591 与单独用药或安慰剂的临床效果。 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是否可以降低 IPF 的死亡率并减缓疾病进展，从而减少远端气道的纤维化和后续损伤。 （摘要完）