Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia

西地那非在患有严重支气管肺发育不良的早产儿中的安全性

基本信息

批准号：
10017313
负责人：
Christoph Hornik
金额：
$ 36.29万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017313
关键词：
Address Adult Adverse event Affect Area Award Biological Markers Blood Vessels Bronchopulmonary Dysplasia Budgets Cardiac Catheterization Procedures Cardiopulmonary Childhood Clinical Clinical Trials Cohort Studies Complication Data Development Diagnosis Disease Dose Double-Blind Method Drug Kinetics Echocardiography Ensure Environment Event FDA approved Failure Functional disorder Funding Gestational Age Goals Hypotension Image Incidence Infant Interdisciplinary Study Knowledge Label Lead Life Logistic Regressions Lung Manuscripts Metabolic Pathway Methods Modeling Morbidity - disease rate NIH Grants and Contracts National Institute of Child Health and Human Development Neonatal Outcome Parents Participant Pharmaceutical Preparations Pharmacodynamics Phase Phase II/III Trial Placebos Population Pregnancy Premature Infant Prevention Prevention trial Probability Public Health Pulmonary Hypertension Randomized Recording of previous events Research Research Design Retinopathy of Prematurity Risk Safety Sample Size Secure Site Surrogate Endpoint Survivors Therapeutic Time Toxic effect Translating Vasodilator Agents Vulnerable Populations Work base clinical research site design drug disposition efficacy trial evidence base experience improved improved outcome innovation interest mortality multidisciplinary off-label drug off-label use open label organ growth pediatric cardiologist pharmacokinetics and pharmacodynamics placebo group population health pre-clinical premature premature lungs preservation prevent primary outcome randomized placebo controlled trial recruit response retention rate safety assessment safety study secondary outcome sildenafil skills success treatment duration

项目摘要

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.

肺动脉高压是支气管肺发育不良（BPD）的致命并发症，是最常见的疾病早产儿肺部疾病。高达 40% 患有肺动脉高压和 BPD 的早产儿会死亡，幸存者则遭受长期的疾病折磨。尽管有这些灾难性的后果，但没有药物被贴上标签或预防该人群肺动脉高压的证据。西地那非是一种强效药物 FDA批准用于治疗成人肺动脉高压的肺血管扩张剂。临床前 BPD 模型表明对肺和血管发育有有益影响，这可能会预防肺疾病高血压。现实世界的证据表明，新生儿科医生越来越多地在早产儿中使用西地那非尽管缺乏有关剂量、安全性和暴露-反应关系的数据，但仍对婴儿进行了研究。由博士领导。劳恩，一个新生儿学家和试验师，以及儿科心脏病学家和临床药理学家 Hornik 博士，我们的多方专家机构和多学科团队致力于开发用于预防和治疗的药物婴儿心肺疾病，这是一个紧迫且未满足的公共卫生需求领域。为了满足这个需求，我们提出一项适应性、随机、安慰剂对照、双盲、剂量递增、4 项预防试验 120 名妊娠 <29 周的早产儿接受研究药物周数（西地那非：安慰剂 3:1 随机分组）根据 IND（IND#112,374，持有者 Laughon），严重 BPD 在 30 个临床中心存在肺动脉高压风险。与 PAR-18-683 的目标一致，拟议的试验将提供必要的剂量、安全性和设计关键的 II/III 期试验所需的初步疗效数据，并将药物推向标签对于这个指示。利用与 NICHD 资助的儿科试验网络和 NCATS 的合作伙伴关系资助试验创新网络，我们将转化多项研究设计和操作创新，而不是常规用于婴儿试验，包括适应性持续重新评估方法、风险调整终点、家长参与工作室和基于现场的临床优化进入早期研究的框架在监管监督下进行。这些创新将在 R61 授予阶段实施。我们的团队拥有开展拟议项目所需的专业知识、接触参与者的机会以及必要的环境研究。特别是，我们已经完成了一项初步的开放标签药代动力学研究，以确定安全性本研究的起始剂量，并进行了一项队列研究来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，从而避免与对这一弱势群体进行侵入性心导管检查。这项前期工作，结合我们团队在按时按预算完成早期婴儿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了证据。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Safety of sildenafil in premature infants with severe bronchopulmonary dysplasia (SILDI-SAFE): a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety study.

西地那非在患有严重支气管肺发育不良的早产儿中的安全性（SILDI-SAFE）：一项多中心、随机、安慰剂对照、序贯剂量递增、双盲安全性研究。

DOI：
发表时间：
2020
期刊：
影响因子：
2.4
作者：
Schneider, Simone;Bailey, Mary;Spears, Tracy;Esther Jr, Charles R;Laughon, Matthew M;Hornik, Christoph P;Jackson, Wesley
通讯作者：
Jackson, Wesley