Safety of Sildenafil in Premature Infants at Risk of Bronchopulmonary Dysplasia

西地那非对有支气管肺发育不良风险的早产儿的安全性

• 批准号: 9755384
• 负责人: Matthew Laughon
• 金额: $ 49.89万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-05 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755384
• 关键词: Safety; Sildenafil; Premature; Infants; Risk

Project Summary Premature infants with bronchopulmonary dysplasia (BPD) often die and survivors have life-long morbidities. BPD is the most common morbidity of prematurity, and affects ~17,000 infants per year in the US. Because the consequences of BPD are catastrophic, neonatologists frequently use drugs without proven efficacy in an attempt to prevent BPD. Sildenafil is a potent inhibitor of type 5 phosphodiesterase approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary arterial hypertension in adults. Preclinical models demonstrate that sildenafil suppresses inflammatory mediators that contribute to lung injury (and BPD) and improve lung vascular development. In case reports in premature infants with BPD-associated pulmonary hypertension, sildenafil improves BPD severity by decreasing oxygen requirement and mean airway pressure. These findings suggest that sildenafil likely is an effective therapy to prevent BPD. We will perform a randomized, controlled, sequential dose escalating, double-masked phase II trial of 4 weeks of sildenafil in up to 120 premature infants at high risk for BPD at up to 30 clinical sites. We will increase dose after a safety review of each 40 participants. The long-term goal is to advance public health by developing therapeutics to prevent BPD in premature infants. The short-term goals are to 1) Determine the safety of sildenafil in premature infants at high risk for BPD; 2) Determine the change in risk of BPD in premature infants receiving sildenafil and 3) Determine the PK of sildenafil in premature infants at high risk for BPD. The proposal will be led by Dr. Laughon, a neonatologist with strong training in epidemiology and clinical pharmacology. Dr. Laughon has led multicenter clinical pharmacology trials in premature infants. The team assembled is uniquely qualified, and strengths include extensive clinical research experience; internationally recognized thought leadership in neonatal and pediatric cardiology quantitative methods; and a successful history of productive on time and on budget NIH projects. The research environment at UNC and the DCRI at Duke provide a productive, collegial, and collaborative atmosphere in which to pursue the above research and training goals. At the conclusion of this proposal, the research team will submit these data to the FDA and provide critical safety, preliminary effectiveness, and PK data for the pivotal phase III efficacy trial which, if successful, will provide evidence for the only therapeutic conducted under federal regulatory oversight to prevent BPD in premature infants.

项目概要 患有支气管肺发育不良 (BPD) 的早产儿经常死亡，幸存者则终生患病。 BPD 是最常见的早产儿疾病，在美国每年影响约 17,000 名婴儿。因为 BPD 的后果是灾难性的，新生儿科医生经常使用未经证实有效的药物来治疗 尝试预防 BPD。西地那非是美国食品和药物管理局批准的5型磷酸二酯酶的强效抑制剂 和药物管理局（FDA）用于治疗成人肺动脉高压。临床前 模型表明西地那非可抑制导致肺损伤（和 BPD）的炎症介质 并改善肺血管发育。早产儿患有 BPD 相关肺部疾病的病例报告 西地那非通过降低需氧量和平均气道压力来改善 BPD 的严重程度。 这些发现表明西地那非可能是预防 BPD 的有效疗法。我们将执行一个 为期 4 周的西地那非随机、对照、序贯剂量递增、双盲 II 期试验 在多达 30 个临床中心对 120 名 BPD 高风险早产儿进行了研究。安全后我们会增加剂量 每 40 名参与者进行审查。长期目标是通过开发治疗方法来促进公共卫生 预防早产儿 BPD。短期目标是 1) 确定西地那非的安全性 早产儿是 BPD 的高危人群； 2) 确定早产儿 BPD 风险的变化 西地那非；3) 确定西地那非在 BPD 高风险早产儿中的 PK。该提案将是 由在流行病学和临床药理学方面受过严格训练的新生儿学家 Laughon 博士领导。博士。 劳恩领导了早产儿的多中心临床药理学试验。组建的团队是独一无二的 合格，优势包括丰富的临床研究经验；国际公认的思想 在新生儿和儿科心脏病学定量方法方面处于领先地位；以及富有成效的成功历史 NIH 项目的时间和预算。北卡罗来纳大学 (UNC) 和杜克大学 DCRI 的研究环境提供了 实现上述研究和培训目标的富有成效、学院和协作的氛围。 在该提案结束时，研究小组将向 FDA 提交这些数据并提供关键的 关键 III 期疗效试验的安全性、初步有效性和 PK 数据，如果成功，将 为在联邦监管监督下进行的唯一治疗方法提供证据，以预防 BPD 早产儿。