Safety of Sildenafil in Premature Infants at Risk of Bronchopulmonary Dysplasia

项目摘要 患有支气管肺发育不良(BPD)的早产儿通常死亡，幸存者患有终生疾病。 BPD是最常见的早产儿发病率，在美国每年影响约17,000名婴儿。因为 BPD的后果是灾难性的，新生儿医生经常在没有证实疗效的情况下使用药物。 尝试预防BPD。西地那非是美国食品和药物管理局批准的5型磷酸二酯酶的有效抑制剂 以及美国药品监督管理局(FDA)对成人肺动脉高压的治疗。临床前 模型显示西地那非抑制导致肺损伤(和BPD)的炎性介质。 促进肺血管发育。早产儿合并BPD相关性肺损伤病例报告 对于高血压患者，西地那非通过降低需氧量和平均气道压来改善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。我们将表演一场 随机、对照、序贯剂量递增、双盲II期试验 在多达30个临床地点对120名患有BPD的高危早产儿进行调查。我们会在安全后增加剂量 对每40名参与者进行回顾。长期目标是通过发展治疗方法来促进公共健康 预防早产儿BPD。短期目标是：1)确定西地那非的安全性 BPD高危早产儿；2)确定接受以下治疗的早产儿BPD风险变化 西地那非和3)在BPD高危早产儿中测定西地那非的PK。该提案将是 由Laughon博士领导，他是一位在流行病学和临床药理学方面训练有素的新生儿专家。Dr。 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的领先地位；以及在以下方面的成功历史 时间和预算上的NIH项目。北卡罗来纳大学的研究环境和杜克大学的DCRI提供了 富有成效的、合作的和合作的氛围，以实现上述研究和培训目标。 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 关键的III期疗效试验的安全性、初步有效性和PK数据，如果成功，将 提供证据证明在联邦监管监督下进行的唯一预防BPD的治疗 早产儿。

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.