Phase II Trial of Sildenafil in Newborns with Persistent Pulmonary Hyptertension

描述（由申请人提供）：新生儿持续性肺动脉高压（PPHN）与显著的发病率和死亡率相关。目前的管理策略包括机械通气和吸入一氧化氮治疗（iNO）。iNO治疗已被证明是一种安全有效的治疗足月新生儿PPHN的方法，然而，在随机对照试验中，约40%的新生儿仍然需要体外膜肺氧合（ECMO）治疗，因为INO治疗未能持续改善氧合。有研究性辅助治疗可能导致选择性肺血管舒张和/或增强对吸入NO的反应，如5型特异性磷酸二酯酶抑制剂西地那非。虽然西地那非的肠内给药已被报道在新生儿PPHN，危重患者的可变吸收限制了其应用。我们最近完成了一项在PPHN婴儿中使用静脉注射西地那非（IVS）的剂量反应/PK研究，证明其耐受性良好，并与氧合显著改善相关。我们假设，IVS将急性降低肺动脉压，改善近足月新生儿PPHN的氧合，从而减少对INO和/或ECMO抢救治疗的需求。为了验证这一假设，我们设计了一项随机、对照、盲法试验，在5个临床试验点对50名患有PPHN的近足月新生儿进行静脉注射西地那非治疗。本试验旨在提供事件发生率估计值（包括死亡率、ECMO利用率以及肺动脉高压和气体交换的急性变化），这将指导该人群中IVS的大型、多中心、随机对照试验的把握度分析。具体目标#1）确定IVS治疗期间肺动脉压和气体交换的生理结局指标的急性变化。具体目标2：确定对照组和IVS治疗组之间治疗失败（即需要INO/ECMO）的发生率。作为对RFA的回应，临床试验将通过在科罗拉多大学和西北大学进行的2项辅助实验室研究进行补充。相关性：作为对RFA的回应，我们提议将这项II期临床治疗试验作为影响新生儿的严重肺部疾病的一种新型干预措施。我们正在针对生理变量（以及治疗失败结局指标）生成事件发生率，以提供这种疗法的概念证明，我们认为这种疗法具有很大的潜力来修改当前的治疗策略。(End摘要）

DESCRIPTION (provided by applicant): Persistent pulmonary hypertension of the newborn (PPHN) is associated with significant morbidity and mortality. Current management strategies include mechanical ventilation and inhaled nitric oxide therapy (iNO). iNO therapy has proven to be a safe and effective treatment for term newborns with PPHN, however, in randomized, controlled trials, approximately 40% of newborns still required treatment with extracorporeal membrane oxygenation (ECMO) because of the failure of INO therapy to cause sustained improvement in oxygenation. There are investigational adjuvant therapies that have the potential to cause selective pulmonary vasodilation and/or enhance the response to inhaled NO, such as the type 5 specific phosphodiesterase inhibitor sildenafil. Although enteral administration of sildenafil has been reported in newborns with PPHN, variable absorption in critically ill patients limits its application. We have recently completed a dose response/PK study using intravenous sildenafil (IVS) in infants with PPHN demonstrating that it is well tolerated and associated with marked improvements in oxygenation. We hypothesize that IVS will acutely reduce pulmonary artery pressure and improve oxygenation in near-term and term newborns with PPHN, thus reducing the need for rescue therapy with INO and/or ECMO. To test this hypothesis, we have designed a randomized, controlled, masked trial of IV sildenafil treatment In 50 near-term and term newborns with PPHN to be conducted at 5 clinical sites. This trial is designed to provide estimates for event rates (including mortality, ECMO utilization, and acute changes in pulmonary hypertension and gas exchange) that will guide power analysis for a larger, multicenter, randomized controlled trial of IVS in this population Specific Aim #1) To determine the acute changes in the physiological outcome measures of pulmonary artery pressure and gas exchange during treatment with IVS. Specific Aim#2: To determine the incidence of treatment failure (i.e. need for INO/ECMO) between the control and IVS treatment groups. In response to the RFA, the clinical trial will be augmented by 2 ancillary laboratory studies to be conducted at the University of Colorado and Northwestern University. RELEVANCE: In response to the RFA, we are proposing this phase II clinical therapeutic trial as a novel intervention for a severe lung disease affecting newborns. We are targeting physiological variables (as well as a treatment failure outcome measure) to generate event rates to provide proof of concept for this therapy that we believe has high potential for modifying current treatment strategies. (End of Abstract)