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

晚期 SURFactant (TOLSURF) 预防 BPD 的试验 - Clinical Coord Ctr

• 批准号: 8520379
• 负责人: Roberta Anderson Ballard
• 金额: $ 95.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520379
• 关键词: 1 year old; 2 year old; Adrenal Cortex Hormones; Adsorption; Adverse effects; Age; Air; Alveolar; Alveolus; Anti-Inflammatory Agents; Anti-inflammatory; Area; Aspirate substance; Asthma; Biochemical; Biological Assay; Biological Markers; Birth; Birth Weight; Blinded; Bronchodilator Agents; Bronchopulmonary Dysplasia; Caffeine; Caring; Case Report Form; Chronic; Chronic lung disease; Clinical; Clinical Trials; Combined Modality Therapy; Confidence Intervals; DNA; DNA Repository; Data; Data Coordinating Center; Deterioration; Development; Disease; Disease-Free Survival; Diuretics; Dose; Enrollment; Environmental air flow; Exposure to; Extremely Low Birth Weight Infant; Functional disorder; Funding; Futility; Future; Genetic; Genomics; Glossary; Health Services; Home environment; Hospitalization; In Vitro; Incidence; Infant; Infant Care; Inflammation; Inflammatory; Injury; Interleukins; Late Effects; Lung; Lung Inflammation; Lung diseases; Mass Fragmentography; Measurement; Measures; Mechanical Ventilators; Mechanical ventilation; Messenger RNA; Monitor; Morbidity - disease rate; Multiple Birth Offspring; Necrotizing Enterocolitis; Neonatal; Neonatal Intensive Care Units; Nitric Oxide; Odds Ratio; Outcome; Oxygen; Oxygen Therapy Care; Patent Ductus Arteriosus; Pathogenesis; Periventricular Leukomalacia; Pharmaceutical Preparations; Pharmacodynamics; Phospholipids; Pilot Projects; Placebos; Polymorphism Analysis; Pregnancy; Premature Infant; Prevalence; Prevention; Prevention approach; Property; Proteins; Public Health; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactants; RNA; Randomized; Research; Research Personnel; Resources; Retinopathy of Prematurity; Safety; Sampling; Secondary to; Severities; Side; Single Nucleotide Polymorphism; Surface Tension; TNF gene; Testing; Therapeutic; Toxic effect; Treatment outcome; Tumor Necrosis Factor-alpha; United States; Ventilator; Vitamin A; Volutrauma; adverse outcome; base; control trial; cost; cost effective; cytokine; disability; experience; health care service utilization; high risk; improved; indexing; inhaled nitric oxide; intraventricular hemorrhage; long term hospitalization; lung injury; mortality; nCPAP Ventilation; novel therapeutic intervention; oxygen toxicity; pilot trial; placebo controlled study; postnatal; premature; pressure; prevent; primary outcome; randomized placebo controlled trial; respiratory; respiratory distress syndrome; response; secondary outcome; surfactant

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.

描述(由申请人提供)： 支气管肺发育不良(BPD)是导致极低出生体重(ELBW&lt；1000 g和&lt；30周)婴儿长期肺部残疾的主要和昂贵的原因。BPD的发病是多因素的，有遗传成分，涉及肺损伤和炎症，继发于不发达、未成熟的肺的氧气和机械通气治疗。吸入一氧化氮(INO)治疗极低出生体重(ELBW)婴儿可提高无BPD的存活率，改善1岁以上的肺部结局，具有成本效益，且与短期或长期不良反应无关。然而，接受iNO治疗的婴儿中仍有50%发展为BPD。极低出生体重儿是肺表面活性物质发育缺陷的婴儿，在出生时接受替代表面活性物质治疗。我们观察到，呼吸机婴儿呼吸状态的恶化与肺表面活性物质功能障碍和低表面活性蛋白B和C含量有关，并认为这些事件通过增加肺部炎症和继发于更多的氧气暴露和呼吸机诱导的蜗牛创伤而导致BPD的发生。INO治疗可以暂时改善肺表面活性物质的功能，而接受治疗的婴儿的表面活性物质功能正常与改善预后有关。我们认为，iNO和Late表面活性物质的联合使用将分别促进肺泡发育和减少持续性肺损伤。我们假设，在7-14天接受iNO并需要机械通气的婴儿晚期使用表面活性物质是安全的，并将在36周后月经年龄(PMA)时增加没有BPD的存活率。目的1在一项多中心随机、盲法对照试验中，评估晚期应用肺表面活性物质对接受iNO呼吸机治疗的极低出生体重儿BPD的发生和严重程度的影响。证明在36周PMA时，没有BPD的主要生存结局从50%增加到62.5%，需要500名婴儿拥有80%的能量和0.05的双侧阿尔法，允许一次中期分析，7%的多胞胎，并停止有效或无效。次要结果包括40wk(足月)出院呼吸支持、呼吸机持续时间和住院时间，以及1岁和2岁时的肺部发病率和神经发育结果。目的2评价晚期肺表面活性物质治疗对肺表面活性物质状态和肺炎性标志物的影响。从连续的气管抽吸物样本中分离出表面活性物质，以确定体外表面活性物质的性质与呼吸状态、表面活性物质治疗和结果的关系。气管抽吸物细胞因子的检测将检查联合治疗的安全性和潜在的抗炎效果。将建立DNA储存库，用于未来分析与BPD相关的多态性和治疗反应。本申请描述了试验的临床协调中心。项目简介支气管肺发育不良(BPD)是一种发生在早产儿身上的慢性肺部疾病，与长期昂贵的住院时间、长期的肺部疾病以及神经发育异常和死亡有关，在美国的患病率估计为30,000例/年。这项由经验丰富的研究人员利用已建立的试验网络进行的临床试验将确定预防早产儿BPD的一种新的治疗方法的安全性和有效性。这项研究有可能减少慢性婴儿肺部疾病和哮喘，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。

项目成果

Characteristics of Extremely Low Gestational Age Newborns Undergoing Tracheotomy: A Secondary Analysis of the Trial of Late Surfactant Randomized Clinical Trial.

接受气管切开术的极低胎龄新生儿的特征：晚期表面活性剂随机临床试验的二次分析。

• DOI: 10.1001/jamaoto.2016.2428
• 发表时间: 2017
• 期刊: JAMA otolaryngology-- head & neck surgery
• 作者: Wai,KatherineC;Keller,RobertaL;Lusk,LeslieA;Ballard,RobertaA;Chan,DylanK;TrialofLateSurfactant(TOLSURF)StudyGroup
• 通讯作者: TrialofLateSurfactant(TOLSURF)StudyGroup

Early Cumulative Supplemental Oxygen Predicts Bronchopulmonary Dysplasia in High Risk Extremely Low Gestational Age Newborns.

• DOI: 10.1016/j.jpeds.2016.06.079
• 发表时间: 2016-10
• 期刊: JOURNAL OF PEDIATRICS
• 影响因子: 5.1
• 作者: Wai, Katherine C.;Kohn, Michael A.;Ballard, Roberta A.;Truog, William E.;Black, Dennis M.;Asselin, Jeanette M.;Ballard, Philip L.;Rogers, Elizabeth E.;Keller, Roberta L.
• 通讯作者: Keller, Roberta L.