Phase 1 trial of inhaled tobramycin in very preterm infants with bronchopulmonary dysplasia

吸入妥布霉素治疗支气管肺发育不良极早产儿的 1 期试验

基本信息

批准号：
10301605
负责人：
ERIK ALLEN JENSEN
金额：
$ 26.4万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10301605
关键词：
Acute Renal Failure with Renal Papillary Necrosis Adult Adverse effects Affect Aminoglycosides Antibiotics Aspirate substance Audiology Bacteria Benchmarking Benefits and Risks Biological Blood Bronchopulmonary Dysplasia Cardiopulmonary Caring Cause of Death Cessation of life Child Childhood Chronic Chronic lung disease Clinical Data Cognition Consent Cystic Fibrosis Dangerousness Data Disease Dose Drug Kinetics Drug usage Eligibility Determination Enrollment Enterobacter Epithelial Escherichia coli FDA approved Health Health Care Costs Home Hour Hypoxemia Infant Infection Inhalation Investigation Klebsiella pneumoniae Label Life Link Liquid substance Lower Respiratory Tract Infection Lower respiratory tract structure Lung Lung Inflammation Lung infections Measures Mechanical ventilation Mechanics Neonatal Intensive Care Units Neurodevelopmental Impairment Organism Outcome Outcome Measure Oxygen Therapy Care Parents Participant Pathogenicity Pathologic Patients Pediatric Hospitals Pharmaceutical Preparations Pharmacotherapy Phase Philadelphia Placebos Population Pregnancy Premature Birth Premature Infant Procedures Pseudomonas aeruginosa Pseudomonas aeruginosa infection Research Respiratory Failure Respiratory Mechanics Risk Factors Rod Safety Sample Size Serious Adverse Event Serum Site TimeLine Tobramycin Ventilator Work arm biomedical referral center children with cystic fibrosis cohort cost cytokine design disability drug efficacy endotracheal evidence base feasibility trial hospitalization rates improved improved outcome infant outcome lung injury microbial mortality neurodevelopment novel therapeutics open label pathogen pathogenic bacteria phase I trial placebo controlled trial premature prospective pulmonary function randomized placebo controlled trial randomized trial respiratory respiratory health respiratory morbidity respiratory pathogen screening therapy duration

项目摘要

PROJECT SUMMARY/ABSTRACT Bronchopulmonary dysplasia (BPD), or chronic lung disease of prematurity, is among the most devastating complications of preterm birth. It affects half of surviving extremely preterm infants, is associated with life-long deficits in health and cognition, and carries enormous societal burden and cost. Strikingly, there are no drug therapies shown to improve outcomes for infants with BPD. Our research seeks to resolve this care gap. An abundance of data support a causal link between pathologic microbial invasion of the lower respiratory tract (LRT) and worsening of respiratory health in chronic lung illness. Our work, and others’, has shown that the presence of pathogenic Gram-negative rod (GNR) bacteria in the lungs of ventilator dependent very preterm infants with BPD is an independent risk factor for significant and enduring respiratory morbidity. Systemically administered antibiotics do not adequately penetrate the lung epithelial lining fluid to eradicate these bacteria. In contrast, inhaled antibiotics deliver drug directly to the site of infection, offering a safer and more effective alternative. Inhaled tobramycin, an aminoglycoside with potent anti-GNR activity, is now a benchmark therapy in cystic fibrosis, where lung infection by Pseudomonas aeruginosa (a common GNR pathogen in BPD) accelerates parenchymal lung damage, promotes decline in lung function, and contributes to early mortality. Emerging data also show benefit with inhaled tobramycin in other pediatric and adult chronic respiratory conditions plagued by difficult to treated respiratory pathogens. These data provide strong biological plausibility that inhaled tobramycin will benefit very preterm infants with BPD who have pathogenic GNR organisms cultured from the LRT. However, inhaled tobramycin is only FDA approved for use in patients 6 years and older. Whether the typical dose and duration of therapy used in older children is appropriate for infants is uncertain. To rigorously characterize the risks and benefits of inhaled tobramycin in very preterm infants with BPD, we must first identify a well-tolerated dose for investigation in this unique population. To obtain these essential data, we propose to conduct a 3+3 inter-patient, ascending dose phase 1 trial of inhaled tobramycin in ventilator dependent very preterm infants with BPD who have pathogenic GNR bacteria cultured from the LRT. This trial will investigate up to 4 different doses of inhaled tobramycin: 78mg, 150mg, 216mg, and 300mg (FDA approved dose), each administered every 12 hours for up to 14 days. This study will establish the preliminary dose tolerability, pharmacokinetic, and exploratory efficacy data needed to design and conduct the first, placebo-controlled, randomized trial of this promising drug therapy in very preterm infants with BPD. Collectively, our proposed studies of inhaled tobramycin are poised to identify the first drug therapy that improves long-term outcomes in this under studied disease.

项目概要/摘要支气管肺发育不良 (BPD) 或早产儿慢性肺病是最具破坏性的疾病之一早产并发症影响半数幸存的极早产儿，并与终生相关。健康和认知缺陷，并带来巨大的社会负担和成本。令人惊讶的是，没有药物。我们的研究旨在解决这一护理缺口。大量数据支持下呼吸道病理性微生物入侵之间存在因果关系我们和其他人的工作表明，慢性肺部疾病导致呼吸道健康恶化。依赖呼吸机的患者肺部存在致病性革兰氏阴性杆菌 (GNR) 患有 BPD 的早产儿是显着且持久的呼吸道疾病的独立危险因素。全身施用的抗生素不能充分渗透肺上皮内层液以根除相比之下，吸入抗生素将药物直接输送到感染部位，提供了更安全和更安全的方法。吸入妥布霉素是一种具有有效抗 GNR 活性的氨基糖苷类药物，现已成为一种更有效的替代方案。囊性纤维化的基准治疗，其中铜绿假单胞菌（一种常见的 GNR）肺部感染 BPD 中的病原体）会加速肺实质损伤，促进肺功能下降，并导致新数据还显示吸入妥布霉素对其他儿童和成人慢性病患者有好处。这些数据为受难以治疗的呼吸道病原体困扰的呼吸道疾病提供了强有力的证据。吸入妥布霉素将使患有 BPD 的早产儿受益的生物学合理性从 LRT 中培养的致病性 GNR 微生物然而，吸入妥布霉素仅获得 FDA 批准。 6 岁及以上患者的使用情况。较大儿童使用的典型剂量和治疗持续时间是否为是否适合婴儿尚不确定。为了严格描述吸入妥布霉素对患有 BPD 的早产儿的风险和益处，我们必须首先确定一个耐受良好的剂量，以便在这个独特的人群中进行研究以获得这些剂量。基本数据，我们建议进行吸入妥布霉素的 3+3 患者间、剂量递增的 1 期试验患有 BPD 且依赖呼吸机的早产儿，其体内培养有致病性 GNR 细菌 LRT。该试验将研究多达 4 种不同剂量的吸入妥布霉素：78 毫克、150 毫克、216 毫克和 300 毫克。（FDA 批准的剂量），每 12 小时给药一次，持续长达 14 天。设计和进行试验所需的初步剂量耐受性、药代动力学和探索性疗效数据首先，对患有 BPD 的早产儿进行了安慰剂对照、随机试验，对这种有前景的药物疗法进行了试验。总的来说，我们提出的吸入妥布霉素中毒研究旨在确定第一种药物疗法改善这种正在研究的疾病的长期结果。