Phase 2 Study of rhCC10 to Prevent Neonatal Bronchopulmonary Dysplasia

描述(由申请人提供)： 重组人CC10蛋白(RhCC10)是一种新型的治疗药物，用于预防早产儿慢性呼吸道疾病(CRM；反复呼吸道感染、哮喘、再次住院)的发展。天然CC10蛋白是由肺内Clara细胞产生的一种天然抗炎和免疫调节因子，是呼吸道粘膜中含量最丰富的蛋白质。动物数据表明，出生后不久气管内一次性注射rhCC10蛋白可减少肺部炎症，促进正常肺发育，保护肺结构，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。在死亡或发展为肺部炎症和随后的支气管肺发育不良(BPD)的早产儿中，CC10蛋白的浓度和活性均显著降低，表明CC10蛋白对于预防肺损伤和促进正常肺发育是必不可少的。在一项小规模的第一阶段研究中，重组人CC10蛋白显著降低了早产儿肺部炎症的几个指数，这些早产儿有患BPD和相关的慢性呼吸道疾病的风险。该药物似乎是安全的，耐受性良好，在出生时单次气管内给药后9-10个月内因呼吸道疾病再次住院的风险降低(11名接受重组人CC10蛋白治疗的婴儿中有0名，6名接受安慰剂治疗的婴儿中有3名)。这支持了重组人CC10蛋白对高氧、机械通风、炎症和未成熟肺感染的保护作用。更正常的呼吸道上皮将产生显著更多的内源性CC10蛋白，这两个因素都有助于增强对感染的抵抗力，减少哮喘，并改善长期呼吸结果。申请人建议进行一项第二阶段临床试验，评估极早产儿(妊娠29周)的重组人CC10蛋白，以预防BPD和慢性呼吸道疾病(CRM)。这将是一项对88名早产儿进行的随机、双盲、安慰剂对照剂量递增研究。单次气管内剂量的研究药物(重组人CC10蛋白或安慰剂)将用于接受肺表面活性物质和机械通气治疗呼吸窘迫综合征的早产儿。将对婴儿进行跟踪，以评估该方法的安全性、药代动力学以及短期和长期疗效。安全性将通过严重不良事件(SAE)和不良事件监测以及18个月校正胎龄(CGA)时的Bayley神经发育评估进行评估。疗效测量将包括12个月CGA时没有CRM证据的ALIVE的主要联合终点，将接受治疗的重组人CC10蛋白与安慰剂对照组进行比较。这将通过父母日记和肺部调查问卷来定义。

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.