Phase 2 Study of rhCC10 to Prevent Neonatal Bronchopulmonary Dysplasia

rhCC10 预防新生儿支气管肺发育不良的 2 期研究

• 批准号: 8925691
• 负责人: Jonathan M. Davis
• 金额: $ 40万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925691
• 关键词: Phase; Study; rhCC10; Prevent; Neonatal

DESCRIPTION (provided by applicant): Recombinant human CC10 protein (rhCC10) is a novel therapeutic agent used to prevent the development of chronic respiratory morbidity (CRM; repeated respiratory infections, asthma, re-hospitalizations) in preterm infants. Native CC10 protein is a natural anti-inflammatory and immunomodulatory factor produced by Clara Cells in the lung and is the most abundant protein in respiratory mucosa. Animal data demonstrate that a single intratracheal dose of rhCC10 protein administered shortly after birth reduces lung inflammation, promotes normal lung development, preserves lung architecture, improves pulmonary function, suppresses the response to endotoxin and enhances resistance to pulmonary infections. In preterm infants who die or develop lung inflammation and subsequent bronchopulmonary dysplasia (BPD), both the concentration and activity of CC10 protein are significantly reduced indicating that CC10 protein is essential for preventing lung injury and promoting normal lung development. In a small Phase 1 study, recombinant human CC10 protein significantly decreased several indices of pulmonary inflammation in the lungs of premature infants who were at risk of developing BPD and associated chronic respiratory morbidity. The drug appeared to be safe, well-tolerated, and reduced risk of re-hospitalization due to respiratory illness for 9-10 months after a single intratracheal dose at the time of birth (0 of 11 recombinant human CC10 protein-treated infants versus 3 of 6 placebo treated). This supports the protective role of recombinant human CC10 protein against damage from hyperoxia, mechanical ventilation, inflammation, and infection in the immature lung. A more normal airway epithelium will produce significantly more endogenous CC10 protein, with both factors contributing to enhanced resistance to infections, less asthma, and improved long-term respiratory outcome. The applicant proposes to conduct a Phase 2 clinical trial to evaluate rhCC10 protein in extremely premature infants (<29 weeks gestation) for the prevention of BPD and chronic respiratory morbidity (CRM). This will be a randomized, double-blind, placebo-controlled dose escalation study in 88 premature infants. A single intratracheal dose of study drug (rhCC10 protein or placebo) will be administered to preterm infants receiving surfactant and mechanical ventilation for treatment of respiratory distress syndrome. Infants will be followed to evaluate safety, pharmacokinetics, and short and long term efficacy of this approach. Safety will be evaluated through serious adverse event (SAE) and adverse event monitoring and by Bayley neurodevelopmental assessments at 18 months corrected gestational age (CGA). Efficacy measurements will include the primary combined endpoint of alive without evidence of CRM at 12 months CGA comparing recombinant human CC10 protein treated to placebo controls. This will be defined by parental diaries and pulmonary questionnaires.

描述（由申请人提供）： 重组人CC10蛋白（RHCC10）是一种新型的治疗剂，用于防止早产儿中慢性呼吸发病率（CRM；重复的呼吸道感染，哮喘，再生气化）。 天然CC10蛋白是肺中克拉拉细胞产生的天然抗炎和免疫调节因子，是呼吸粘膜中最丰富的蛋白质。 动物数据表明，出生后不久服用的单一气管内剂量的RHCC10蛋白会减少肺部炎症，促进正常的肺发育，保留肺建筑，改善肺功能，抑制对内毒素的反应并增强对肺部感染的抵抗力。 在死亡或发展肺部炎症的早产儿中，随后的支气管肺发育不良（BPD），CC10蛋白的浓度和活性都大大减少，这表明CC10蛋白对于预防肺损伤和促进正常肺发育至关重要。 在一项小期研究中，重组人CC10蛋白显着降低了有可能患有BPD及其相关慢性呼吸道发病率的早产儿的肺部炎症指标。 该药物似乎是安全，耐受性的，并且在出生时单次气管内剂量后9-10个月引起的重新住院风险降低了（11个重组人CC10蛋白质治疗的婴儿，与6个安慰剂治疗中的3个）。 这支持重组人CC10蛋白免受未成熟肺中高氧，机械通气，炎症和感染的损害的保护作用。 更正常的气道上皮将产生更多的内源性CC10蛋白，这两种因素都促进了对感染，哮喘较少和改善长期呼吸系统预后的耐药性。 申请人提议进行2期临床试验，以评估极早的婴儿（妊娠<29周）的RHCC10蛋白，以预防BPD和慢性呼吸发病率（CRM）。 这将是一项在88个早产婴儿中进行的随机，双盲，安慰剂控制的剂量升级研究。 将对接受表面活性剂和机械通气的早产儿进行研究药物（RHCC10蛋白或安慰剂）的单一运动剂量（RHCC10蛋白或安慰剂），以治疗呼吸遇险综合征。 将遵循婴儿，以评估这种方法的安全性，药代动力学以及短期和长期疗效。 安全将通过严重的不良事件（SAE）和不良事件监测以及18个月校正妊娠年龄（CGA）的Bayley神经发育评估进行评估。 功效测量将包括活着的主要终点，而没有CRM在12个月时CGA的证据，并比较了接受治疗的安慰剂对照的重组人CC10蛋白。 这将由父母日记和肺问卷定义。