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：
10688294
负责人：
ERIK ALLEN JENSEN
金额：
$ 30.8万
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/10688294
关键词：
Acceleration Acute Renal Failure with Renal Papillary Necrosis Admission activity Adult Adverse effects Affect Aminoglycosides Antibiotics Audiology Bacteria Benchmarking Benefits and Risks Biological Blood Bronchopulmonary Dysplasia Cardiopulmonary Caring Cause of Death Cessation of life Child Childhood Chronic Clinical Data Cognition Consent Cystic Fibrosis Dangerousness Data Disease Dose Drug Kinetics Drug usage Eligibility Determination Enrollment Enterobacter Epithelium Escherichia coli FDA approved Health Health Care Costs Home Hour Hypoxemia Infant Infection Inhalation Invaded Investigation Klebsiella pneumoniae Label Link Liquid substance Lower Respiratory Tract Infection Lower respiratory tract structure Lung 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 Penetration Pharmaceutical Preparations Pharmacotherapy Phase Philadelphia Population Pregnancy Premature Birth Premature Infant Procedures Pseudomonas aeruginosa Pseudomonas aeruginosa infection Pulmonary Inflammation Research Respiratory Failure Respiratory Mechanics Respiratory Tract Infections Risk Factors Rod Safety Sample Size Serious Adverse Event Serum Site Tobramycin Trachea Ventilator Work arm aspirate biomedical referral center children with cystic fibrosis cohort cost cytokine design disability drug efficacy endotracheal evidence base extreme prematurity 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 prospective pulmonary function randomized placebo controlled trial respiratory respiratory health respiratory morbidity respiratory pathogen screening therapy duration timeline

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.

项目摘要/摘要支气管肺发育不良（BPD）或慢性肺早产疾病是最具破坏性的早产的并发症。它影响了一半的生存极端婴儿，与终身有关健康和认知缺陷，并带有巨大的社会伯恩和成本。令人惊讶的是，没有毒品证明可以改善BPD婴儿的疗法。我们的研究旨在解决这一护理差距。数据的抽象支持下呼吸道病理微生物侵袭之间的因果关系慢性肺部疾病中的呼吸健康问题（LRT）和担心。我们的工作以及其他人都表明致病革兰氏阴性杆（GNR）的存在在呼吸机的肺中非常非常依赖 BPD的早产儿是显着且持久呼吸道发病率的独立危险因素。全身施用的抗生素不能充分渗透肺上皮衬里液体这些细菌。相比之下，吸入的抗生素直接将药物直接输送到感染部位，提供更安全和更有效的选择。吸入毒素是具有潜在抗GNR活性的氨基糖苷，现在是一个囊性纤维化中的基准治疗，铜绿假单胞菌感染肺部（一种常见的GNR） BPD中的病原体加速实质肺损伤，促进肺功能下降，并有助于早期死亡率。新兴数据还显示了其他儿科和成人慢性遗传毒素的好处呼吸系统疾病困扰着难以治疗的呼吸道病原体。这些数据提供了强大的遗传毒素的生物合理性将使拥有的BPD受益于非常早产的婴儿从LRT培养的致病GNR生物。但是，掺入布拉米霉素仅获得FDA批准在6岁以上的患者中使用。在大龄儿童中使用的典型剂量和持续时间是适合婴儿是不确定的。严格地描述了在BPD的非常早产的婴儿中遗传毒素的风险和好处，我们必须首先确定在这个独特人群中投资良好的剂量。获得这些基本数据，我们建议进行3+3个接受者的，上升剂量的遗传性毒素的试验在呼吸机依赖性的非常早产的BPD中，他们的病原性GNR细菌从 LRT。该试验将调查多达4种不同剂量的遗传毒素：78mg，150mg，216mg和300mg （FDA批准的剂量），每个剂量每12个小时每12小时进行14天。这项研究将确定初步的剂量耐受性，药代动力学和探索性效率数据需要设计和进行首先，对BPD的非常早产的婴儿进行了安慰剂对照，随机试验。总的来说，我们提出的对遗传毒素的研究被毒死，以识别第一种药物疗法改善研究疾病下的长期结局。