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

• 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
• 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

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.

项目总结/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 早产的并发症。它影响了一半存活的极早产儿，与终身 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， 治疗显示，改善与BPD婴儿的结果。我们的研究旨在解决这一护理差距。 大量的数据支持下呼吸道的病理性微生物侵袭与 慢性肺病患者的呼吸道（LRT）和呼吸系统健康恶化。我们和其他人的工作表明， 呼吸机依赖性肺内存在致病性革兰氏阴性杆菌（GNR）， BPD早产儿是显著和持久呼吸系统疾病的独立危险因素。 全身给药的抗生素不能充分穿透肺上皮衬里液， 这些细菌。相比之下，吸入抗生素将药物直接递送到感染部位，提供了更安全和更有效的治疗方法。 更有效的替代品。吸入性妥布霉素是一种具有强效抗GNR活性的氨基糖苷类药物， 囊性纤维化的基准治疗，其中肺部感染铜绿假单胞菌（常见的GNR BPD中的病原体）加速实质性肺损伤，促进肺功能下降，并有助于 早期死亡率新的数据也显示吸入妥布霉素对其他儿童和成人慢性 呼吸道疾病由难以治疗的呼吸道病原体所困扰。这些数据提供了强有力的 吸入妥布霉素的生物相容性将使患有BPD的极早产儿受益， 从LRT培养的致病GNR微生物。然而，吸入妥布霉素仅被FDA批准用于 用于6岁及以上患者。年龄较大儿童的典型剂量和治疗持续时间是否 是否适合婴儿是不确定的。 为了严格描述吸入妥布霉素治疗极早产儿BPD的风险和益处，我们 必须首先确定在这一独特人群中进行研究的良好耐受剂量。获得这些 必要的数据，我们建议进行一项3+3患者间，剂量递增的吸入妥布霉素1期试验 在呼吸机依赖性极早产BPD婴儿中， 轻轨。本试验将研究多达4种不同剂量的吸入妥布霉素：78 mg、150 mg、216 mg和300 mg (FDA批准的剂量），每12小时给药一次，持续长达14天。这项研究将建立 设计和进行研究所需的初步剂量耐受性、药代动力学和探索性疗效数据。 第一次，安慰剂对照，随机试验，这种有前途的药物治疗极早产儿BPD。 总的来说，我们提出的吸入妥布霉素的研究准备确定第一个药物治疗， 改善了这种研究不足的疾病的长期结局。