Phase 2 Study of rhCC10 to Prevent Neonatal Bronchopulmonary Dysplasia

描述（由申请人提供）： 重组人CC 10蛋白（rhCC 10）是一种用于预防早产儿慢性呼吸道疾病（CRM;反复呼吸道感染、哮喘、再住院）发展的新型治疗药物。 天然CC 10蛋白是由肺中的Clara细胞产生的天然抗炎和免疫调节因子，并且是呼吸道粘膜中最丰富的蛋白质。 动物数据表明，出生后不久给予rhCC 10蛋白的单次气管内给药可减少肺部炎症，促进正常的肺发育，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。 在死亡或发生肺部炎症和随后的支气管肺发育不良（BPD）的早产儿中，CC 10蛋白的浓度和活性均显著降低，表明CC 10蛋白对于预防肺损伤和促进正常肺发育至关重要。 在一项小型1期研究中，重组人CC 10蛋白显著降低了早产儿肺部炎症的几个指标，这些早产儿有发生BPD和相关慢性呼吸道疾病的风险。 该药物似乎是安全的，耐受性良好，并且在出生时单次静脉内给药后9-10个月内由于呼吸系统疾病而再次住院的风险降低（11例重组人CC 10蛋白治疗的婴儿中的0例与6例安慰剂治疗的婴儿中的3例）。 这支持了重组人CC 10蛋白对未成熟肺中高氧、机械通气、炎症和感染的损伤的保护作用。 一个更正常的气道上皮细胞将产生更多的内源性CC 10蛋白，这两个因素有助于增强对感染的抵抗力，减少哮喘，改善长期呼吸结果。 申请人拟开展一项II期临床试验，以评估rhCC 10蛋白在极早产儿（妊娠<29周）中预防BPD和慢性呼吸道疾病（CRM）的作用。 这是一项在88名早产儿中进行的随机、双盲、安慰剂对照剂量递增研究。 接受表面活性剂和机械通气治疗呼吸窘迫综合征的早产儿将接受单次鼻内给药研究药物（rhCC 10蛋白或安慰剂）。 将对婴儿进行随访，以评估该方法的安全性、药代动力学以及短期和长期疗效。 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神经发育评估来评价安全性。 功效测量将包括主要组合终点，即在12个月CGA时存活而无CRM证据，将重组人CC 10蛋白治疗与安慰剂对照进行比较。 这将通过父母日记和肺部问卷进行定义。

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.