Azithromycin To Prevent BPD In Ureaplasma-Infected Preterms

阿奇霉素可预防解脲支原体感染的早产儿 BPD

基本信息

批准号：
9262594
负责人：
MICHAEL L TERRIN
金额：
$ 67.9万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-10 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262594
关键词：
Address Age Alveolar Antibiotic Therapy Antibiotics Azithromycin Body Weight Bronchopulmonary Dysplasia Cessation of life Child Childhood Chronic Clinical Clinical Management Clinical Research Clinical Trials Comorbidity Coughing Data Development Disease Dose Double-Blind Method Drug Kinetics Drug Labeling Duct (organ) structure Emergency Situation Enrollment Ensure Environmental air flow Epithelial Erythromycin Exhibits Exposure to Fetal Lung Future Genital system Goals Guidelines Hospitalization In Vitro Incidence Inclusion Bodies Infant Infection Inflammation Inflammatory Response Injury Intravenous Lead Liquid substance Lung Lung Inflammation Lung diseases Mediating Meta-Analysis Microbiology Mission Modeling Morbidity - disease rate Mus Mycoplasma National Institute of Child Health and Human Development Neonatal Neurodevelopmental Impairment Outcome Oxygen Perinatal Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Physicians Physiological Placebo Control Placebos Plasma Population Pre-Par Pregnancy Premature Infant Property Public Health Randomized Recurrence Regimen Reporting Research Research Design Respiratory System Respiratory tract structure Risk Risk Factors Safety Serious Adverse Event Sheep Steroids Supplementation Survival Rate Therapeutic Ureaplasma Ureaplasma Infections Visit Wheezing antimicrobial chemokine design disability double-blind placebo controlled trial efficacy trial evidence based guidelines follow-up high risk immunoregulation improved infant outcome inflammatory marker lung development lung injury macrophage mortality neonate neurodevelopment neutrophil nonhuman primate pathogen postnatal pre-clinical premature pressure prevent primary outcome programs research clinical testing respiratory risk benefit ratio secondary outcome therapeutic candidate therapy development

项目摘要

PROJECT SUMMARY: Meta-analyses of clinical studies over the past 30 years have confirmed Ureaplasma respiratory colonization as an independent risk factor for bronchopulmonary dysplasia (BPD). This application addresses the fundamental problem that there is currently insufficient data concerning the benefit/risk ratio of antibiotic therapy to recommend treatment guidelines to prevent BPD and long-term adverse pulmonary outcomes in preterm infants at-risk or with confirmed Ureaplasma infection. Our long- term objective is to develop therapies to eradicate Ureaplasma from the respiratory tract of preterm infants and prevent or ameliorate Ureaplasma-mediated lung injury. The azalide antibiotic azithromcyin (AZM) has antimicrobial and immunomodulatory properties that make it an ideal therapeutic candidate to prevent Ureaplasma-mediated lung injury. We conducted PK/PD studies characterizing the population PK, safety, tolerability, and biologic effects of a single dose of 10 and 20 mg/kg IV AZM and multiple dose 20 mg/kg x 3d in 24-28 wk gestation neonates who are at highest risk for Ureaplasma respiratory tract colonization and BPD. A 2-compartment model with all parameters allometrically scaled on body weight best described the PK of AZM in preterm neonates. Compared to the single dose groups, the 20 mg/kg multi-dose effectively eradicated Ureaplasma in all subjects who were colonized pre-dose. The multi-dose regimen appeared safe, with no deaths or serious adverse events attributed to the drug. Our objectives in this application are to determine the safety and microbiological efficacy of a short course of IV AZM to eradicate respiratory tract Ureaplasma infection and its' potential to improve short-term (BPD) and long-term pulmonary and neurodevelopmental outcomes in preterm neonates. The central hypothesis is that AZM therapy will reduce pulmonary morbidity in Ureaplasma-infected preterm infants by accelerating pathogen clearance and/or down-regulating the pulmonary inflammatory response. We have completed 80% planned enrollment in the current multicenter, randomized, double-blind, placebo-controlled Phase IIb clinical trial of 20 mg/kg x3d IV AZM. The specific aims of this renewal application will extend outcomes up to 24 months adjusted age and will address the next steps preparatory to Phase III safety and efficacy trials of AZM in the preterm population. The specific aims of this proposal are: 1) to determine the safety and microbiological efficacy of IV AZM to eradicate respiratory tract Ureaplasma infection in preterm neonates; 2) to analyze the potential of AZM to reduce BPD and improve long-term pulmonary outcomes; and 3) to assess the impact of AZM on the risk for neurodevelopmental impairment at 22-26 months adjusted age. The proposed research is significant because it will lead directly to decisions concerning future Phase III safety and efficacy trials of AZM in the preterm population and to evidence-based recommendations concerning the clinical evaluation and management of perinatally-acquired Ureaplasma respiratory colonization in the preterm population.

项目摘要：过去 30 年临床研究的荟萃分析证实解脲支原体呼吸道定植是支气管肺发育不良（BPD）的独立危险因素。该申请解决了目前有关该问题的数据不足的根本问题。抗生素治疗的效益/风险比，以推荐预防 BPD 和长期治疗的指南有风险或确诊解脲支原体感染的早产儿出现不良肺部结局。我们的长期短期目标是开发根除早产儿呼吸道解脲支原体的疗法预防或改善解脲支原体介导的肺损伤。氮杂内酯类抗生素阿奇霉素（AZM）具有抗菌和免疫调节特性使其成为预防疾病的理想治疗候选药物解脲支原体介导的肺损伤。我们进行了 PK/PD 研究，描述了人群 PK、安全性、单剂量 10 和 20 mg/kg IV AZM 和多剂量 20 mg/kg x 的耐受性和生物效应妊娠 24-28 周内 3 天的新生儿，解脲支原体呼吸道定植风险最高，并且边缘性人格障碍。所有参数均根据体重进行异速生长的 2 室模型最能描述 AZM 在早产儿中的 PK。与单剂量组相比，20mg/kg多剂量组有效根除所有给药前定植的受试者中的解脲支原体。多剂量方案出现安全，没有因该药物引起的死亡或严重不良事件。我们在此应用程序中的目标是确定短期静脉注射 AZM 根除呼吸道疾病的安全性和微生物学功效道解脲支原体感染及其改善短期 (BPD) 和长期肺部和早产儿的神经发育结果。中心假设是 AZM 治疗会减少通过加速病原体清除和/或减少解脲支原体感染的早产儿的肺部发病率下调肺部炎症反应。我们已经完成了计划招生的80% 目前正在进行 20 mg/kg x3d IV 的多中心、随机、双盲、安慰剂对照 IIb 期临床试验 AZM。此续签申请的具体目标是将调整后的年龄延长至 24 个月，并且将解决 AZM 早产儿 III 期安全性和有效性试验的后续步骤人口。该提案的具体目标是：1）确定以下物质的安全性和微生物功效： IV AZM 根除早产儿呼吸道解脲支原体感染； 2）分析潜力 AZM 可减少 BPD 并改善长期肺部结局； 3) 评估 AZM 对 22-26 个月调整年龄时神经发育障碍的风险。拟议的研究是意义重大，因为它将直接导致有关未来 III 期安全性和有效性试验的决定早产人群中的 AZM 以及有关临床评估的循证建议以及早产儿人群围产期获得性解脲支原体呼吸道定植的管理。