Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia

肺动脉高压是最常见的支气管肺发育不良(Bpd)的致命并发症。 早产儿肺部发病率。高达40%的早产儿患有肺动脉高压和BPD 死亡，幸存者遭受长期的疾病折磨。尽管有这些灾难性的后果，但没有任何药物被贴上标签 或基于证据来预防这一人群中的肺动脉高压。西地那非是一种强效的 FDA批准的肺血管扩张剂，用于治疗成人肺动脉高压。临床前 BPD模型显示了对肺和血管发育的有益影响，这可能会阻止肺 高血压。现实世界的证据表明，新生儿科医生越来越多地使用西地那非治疗早产儿 尽管缺乏关于剂量、安全性和暴露-反应关系的数据。在劳恩博士的带领下，一个 新生儿专家和试验专家，以及霍尼克医生，一位儿科心脏病专家和临床药理学家，我们的多- 机构和多学科团队致力于开发预防和治疗糖尿病的药物。 婴儿的心肺疾病，这是一个迫切和未得到满足的公共卫生需求领域。为了满足这一需求，我们 提出一项适应性、随机化、安慰剂对照、双盲、剂量递增、预防试验 120例妊娠29周的早产儿的研究药物(西地那非：安慰剂3：1随机) 在IND(IND#112,374，持有者Laughon)的30个临床站点中，重度BPD存在肺动脉高压的风险。 与PAR-18-683的目标一致，拟议的试验将提供必要的剂量、安全性和 初步疗效数据需要设计一项关键的II/III期试验，并将药物推向标签 为了这一迹象。利用与NICHD资助的儿科试验网络和NCATS的伙伴关系 资助的试验创新网络，我们将把几项研究设计和操作创新翻译为 常规用于婴儿试验，包括适应性持续重新评估方法、风险调整的终点、 将家长参与工作室和基于现场的临床优化纳入早期研究框架 在监管监督下进行。这些创新将在R61颁奖阶段实施。 我们的团队拥有实施计划所需的专业知识、与参与者接触的权限和环境 研究。特别是，我们已经完成了初步的开放标签药代动力学研究，以确定安全 这项研究的起始剂量，并进行了一项队列研究，以验证基于超声心动图的评分作为 早产儿肺动脉高压的替代终点，从而避免与 在这一脆弱人群中进行有创性心导管置入术。这项前期工作，结合 我们的团队在按时和按预算完成婴儿早期临床试验方面拥有无与伦比的经验，将 确保拟议研究的成功，并通过以下方式直接改善早产儿的公共健康 为预防早产儿肺动脉高压的唯一治疗方法提供证据。

Pulmonary hypertension is a deadly complication of bronchopulmonary dysplasia (BPD), the most common pulmonary morbidity of prematurity. Up to 40% of premature infants with pulmonary hypertension and BPD will die, and survivors suffer long-term morbidities. Despite these catastrophic consequences, no drugs are labeled or evidence based for the prevention of pulmonary hypertension in this population. Sildenafil is a potent pulmonary vasodilator approved by the FDA for the treatment of pulmonary hypertension in adults. Preclinical BPD models suggest a beneficial effect on lung and vascular development, which may prevent pulmonary hypertension. Real world evidence shows that neonatologists are increasingly using sildenafil in premature infants despite lack of data on dosing, safety, and the exposure-response relationship. Led by Drs. Laughon, a neonatologist and trialist, and Dr. Hornik, a pediatric cardiologist and clinical pharmacologist, our multi- institutional and multidisciplinary team is dedicated to developing drugs for the prevention and treatment of cardiopulmonary morbidities in infants, an area of urgent and unmet public health need. To meet this need, we propose an adaptive, randomized, placebo controlled, double-blind, dose-escalation, prevention trial of 4 weeks of study drug (sildenafil: placebo 3:1 randomization) in 120 premature infants <29 weeks gestation with severe BPD at risk for pulmonary hypertension at 30 clinical sites under IND (IND#112,374, holder Laughon). Consistent with the goals of PAR-18-683, the proposed trial will provide the necessary dosing, safety, and preliminary efficacy data needed to design a pivotal phase II/III trial, and move the drug forward toward labeling for this indication. Leveraging partnerships with the NICHD funded Pediatric Trials Network, and the NCATS funded Trial Innovation Network, we will translate several study design and operational innovations not routinely utilized in infant trials including adaptive continual reassessment methods, risk-adjusted endpoints, parent-engagement studios, and site based clinical optimization into the framework of an early phase study conducted under regulatory oversight. These innovations will be implemented during the R61 award phase. Our team has the expertise, access to participants, and environment necessary to conduct the proposed research. In particular, we have completed a preliminary open-label pharmacokinetic study to identify safe starting doses for this study, and conducted a cohort study to validate an echocardiogram based score as a surrogate endpoint for pulmonary hypertension in premature infants, thereby avoiding the risks associated with invasive cardiac catheterization in this vulnerable population. This preliminary work, combined with the unparalleled experience of our team to complete early phase infant clinical trials on time and on budget, will ensure the success of the proposed study, and directly improve the public health of premature infants by providing evidence for the only therapeutic to prevent pulmonary hypertension in premature infants.