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: 9125662
• 负责人: Jonathan M. Davis
• 金额: $ 39.64万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9125662
• 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) 是一种新型治疗剂，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）的发生。 天然CC10蛋白是肺部Clara细胞产生的天然抗炎和免疫调节因子，是呼吸道粘膜中最丰富的蛋白质。 动物数据表明，出生后不久气管内注射单剂量的 rhCC10 蛋白可减少肺部炎症，促进正常肺部发育，保留肺结构，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。 在死亡或出现肺部炎症以及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着降低，表明CC10蛋白对于预防肺损伤和促进正常肺部发育至关重要。 在一项小型 1 期研究中，重组人 CC10 蛋白显着降低了早产儿肺部炎症的多项指标，这些早产儿有患 BPD 和相关慢性呼吸道疾病的风险。 该药物似乎安全、耐受性良好，并且在出生时气管内单次给药后 9-10 个月内可降低因呼吸系统疾病而再次住院的风险（11 名重组人 CC10 蛋白治疗的婴儿中有 0 名，而 3 名） 6 安慰剂治疗）。 这支持了重组人CC10蛋白对未成熟肺中高氧、机械通气、炎症和感染造成的损伤的保护作用。 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。 申请人提议进行一项2期临床试验，以评估极早产儿（妊娠<29周）中rhCC10蛋白对于预防BPD和慢性呼吸道疾病（CRM）的作用。 这将是一项针对 88 名早产儿的随机、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气管内剂量的研究药物（rhCC10蛋白或安慰剂）。 将跟踪婴儿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) 时的贝利神经发育评估来评估安全性。 功效测量将包括将重组人 CC10 蛋白治疗与安慰剂对照进行比较，在 12 个月 CGA 时没有 CRM 证据的情况下存活的主要综合终点。 这将通过父母日记和肺部问卷来定义。

项目成果

Assessment of a shortened informed consent form for pediatric research: a pilot study.

儿科研究缩短知情同意书的评估：一项试点研究。

• 发表时间: 2018-10
• 影响因子: 3.6
• 作者: Murray, Peter D;Bierer, Barbara E;Hirschfeld, Steven;Klein, Andreas K;Davis, Jonathan M
• 通讯作者: Davis, Jonathan M

The role of recombinant human CC10 in the prevention of chronic pulmonary insufficiency of prematurity.

重组人CC10在预防早产儿慢性肺功能不全中的作用。

• 发表时间: 2019
• 影响因子: 3.6
• 作者: Davis, Jonathan M;Pilon, Aprile L;Shenberger, Jeffrey;Breeze, Janis L;Terrin, Norma;Mazela, Jan;Gulczynska, Ewa;Lauterbach, Ryszard;Parad, Richard
• 通讯作者: Parad, Richard

Evaluation of Club Cell 10-kDa Protein (CC10) Levels in Full-Term Infants.

足月婴儿俱乐部细胞 10-kDa 蛋白 (CC10) 水平的评估。

• 发表时间: 2017
• 影响因子: 2.5
• 作者: Gorji, Nasim;Pilon, Aprile L;Winn, Melissa E;Newsome, Morgan;Davis, Jonathan M
• 通讯作者: Davis, Jonathan M