Trial of Late SURFactant (TOLSURF) to Prevent BPD - Clinical Coord Ctr

描述（由申请人提供）： 支气管肺发育不良（BPD）是极低出生体重儿（ELBW <1000 g且妊娠<30周）长期肺功能障碍的主要原因，且费用昂贵。BPD的发病机制是多因素的，具有遗传成分，并且涉及肺损伤和继发于在欠发达、未成熟的肺中用氧气和机械通气治疗的炎症。吸入一氧化氮（iNO）治疗ELBW婴儿可增加无BPD的存活率，改善1岁内的肺部结局，具有成本效益，且与短期或长期不良反应无关。然而，50%接受iNO治疗的婴儿仍然会出现BPD。极低出生体重婴儿在发育上缺乏肺表面活性物质，出生时接受替代表面活性物质治疗。我们观察到通气婴儿呼吸状态的恶化与功能障碍的表面活性物质和表面活性蛋白B和C含量低有关，并提出这些事件通过增加继发于更多氧气暴露和呼吸机诱导的体积创伤的肺部炎症和损伤而促进BPD的发展。INO治疗可短暂改善表面活性物质功能，接受治疗的婴儿表面活性物质功能正常与预后改善相关。我们认为，iNO和晚期表面活性物质的组合将相互作用，以促进肺泡发育和减少持续的肺损伤，分别。我们假设，在7-14日龄接受iNO治疗并需要机械通气的婴儿中给予晚期剂量的表面活性剂是安全的，并将增加经后36周（PMA）时无BPD的存活率。目的1：在一项多中心随机、盲法、对照试验中，评估晚期剂量表面活性剂对接受iNO通气的ELBW婴儿BPD发生率和严重程度的影响。要证明36周PMA时无BPD的主要生存结局从50%增加到62.5%，需要500名婴儿具有80%的把握度和0.05的双侧α，允许进行一次中期分析，7%的多胎分娩，并因有效或无效而停止。次要结局包括40周（足月）时停止呼吸支持，通气和住院时间，以及1岁和2岁时的肺部发病率和神经发育结局。目的2评估晚期表面活性物质治疗对表面活性物质状态和肺部炎症生物标志物的影响。表面活性剂是从一系列气管吸出物样品中分离出来的，以确定体外表面活性剂特性与呼吸状态、表面活性剂治疗和结果的关系。气管吸出物细胞因子的测定将检查联合治疗的安全性和潜在的抗炎作用。将建立一个DNA储存库，用于未来分析与BPD相关的多态性和对治疗的反应。本申请描述了本试验的临床协调中心。支气管肺发育不良（BPD）是发生在早产儿中的慢性肺部疾病，与长期和昂贵的住院治疗、长期肺部疾病、神经发育异常和死亡率相关，患病率估计为30，000例/这项临床试验由经验丰富的研究人员利用已建立的试验网络进行，将确定一种新的预防早产儿BPD的治疗方法。这项研究有可能减少慢性婴儿肺病和哮喘，这是公共卫生的重要领域，降低护理成本，并改善早产儿的长期结局。

DESCRIPTION (provided by applicant): Bronchopulmonary dysplasia (BPD) is a major and costly cause of long-term pulmonary disability in extremely low birth weight (ELBW <1000 g and <30 weeks gestation) infants. The pathogensis of BPD is multi-factorial, has a genetic component, and involves lung injury and inflammation secondary to treatment with oxygen and mechanical ventilation in an underdeveloped, immature lung. Inhaled Nitric Oxide (iNO) therapy in ELBW infants increases survival without BPD, improves pulmonary outcome through 1 year of age, is cost effective, and is not associated with short- or long-term adverse effects. However 50% of iNO-treated infants still develop BPD. ELBW infants are developmentally deficient in pulmonary surfactant and receive replacement surfactant treatment at birth. We observed that deteriorations in respiratory status in ventilated infants are associated with dysfunctional surfactant and low content of surfactant proteins B and C, and propose that these episodes contribute to development of BPD by increasing lung inflammation and injury secondary to greater exposure to oxygen and ventilator-induced volutrauma. INO therapy transiently improves surfactant function, and normal surfactant function in treated infants is associated with improved outcome. We propose that the combination of iNO and late surfactant will interact to promote alveolar development and reduce continuing lung injury, respectively. We hypothesize that late doses of surfactant administered to infants receiving iNO and requiring mechanical ventilation at 7-14 d of age is safe and will increase survival without BPD at 36 wk post menstrual age (PMA). Aim 1 assesses the effect of late doses of surfactant on the occurrence and severity of BPD in ventilated ELBW infants who are receiving iNO in a multi-center randomized, blinded, controlled trial. Demonstrating an increase from 50 to 62.5% in the primary outcome of survival without BPD at 36 wk PMA requires 500 infants to have 80% power and a two-sided alpha of 0.05, allowing for one interim analysis, 7% multiple births, and stopping for either efficacy or futility. Secondary outcomes include discharge off respiratory support at 40 wk (term), duration of ventilation and hospitalization, and pulmonary morbidity and neurodevelopmental outcome at 1 and 2 years of age. Aim 2 assesses effects of late surfactant treatment on surfactant status and lung inflammatory biomarkers. Surfactant is isolated from serial tracheal aspirate samples to determine the association of in vitro surfactant properties with respiratory status, surfactant treatment, and outcome. Assays of tracheal aspirate cytokines will examine safety and potential anti- inflammatory effects of combined treatment. A DNA repository will be established for future analysis of polymorphisms associated with BPD and response to treatment. This application describes the Clinical Coordinating Center for the trial. Project Narrative Bronchopulmonary Dysplasia (BPD) is the chronic lung disease that occurs in premature infants and is associated with prolonged and costly hospitalization, long-term lung diseases, and neurodevelopmental abnormalities and mortality, with a prevalence estimated at 30,000 cases/year in the U.S. This clinical trial by experienced investigators utilizing an established trial network will determine the safety and efficacy of a new therapeutic approach for prevention of BPD in premature infants. This research has potential to decrease chronic infant lung disease and asthma, important areas of public health, reduce cost of care, and improve long-term outcome for premature infants.