Central Radiologist Review in Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia

Central Radiologist Review Information
Study Description
The primary objective of this multi-center, randomized, dose-escalating, placebo-controlled study was to describe the safety of furosemide in premature infants at risk of bronchopulmonary dysplasia (BPD). The secondary objectives were to evaluate the preliminary effectiveness and pharmacokinetics of furosemide. The rates of adverse events (AEs), serious adverse events (SAEs) and related SAEs were similar by cohort among furosemide treated participants. Among most safety events of special interest (death, failed hearing test, nephrocalcinosis/nephrolithiasis), there were no significant differences seen between furosemide versus placebo treated participants. The lack of difference between furosemide and placebo group for failed hearing test and nephrocalcinosis/nephrolithiasis is consistent with recent manuscripts comparing infants exposed to furosemide versus unexposed and with systematic reviews of the safety of furosemide. However, there were more electrolyte abnormality AEs in the furosemide versus placebo infants. There was no difference in the preliminary effectiveness outcomes of moderate to severe BPD or death or in the change of BPD over time. In the population pharmacokinetics analysis of furosemide in premature neonates and infants, body weight and postnatal age were found to be influential covariates on furosemide clearance. In premature infants at risk for BPD, furosemide increased the risk of electrolyte AEs but did not increase overall risk of AEs, hearing loss, or nephrocalcinosis/nephrolithiasis. The safety population included 80 premature infant participants who were randomized and dosed to either placebo or furosemide.

中心放射医师评审资料
研究概况
这项多中心、随机、剂量递增、安慰剂对照研究的首要目标为：阐明呋塞米在罹患支气管肺发育不良（bronchopulmonary dysplasia, BPD）风险的早产婴儿中的安全性。次要目标为评估呋塞米的初步有效性与药代动力学（pharmacokinetics）特征。
呋塞米治疗组各队列的不良事件（adverse events, AEs）、严重不良事件（serious adverse events, SAEs）及相关严重不良事件发生率均无显著差异。在多数重点关注的安全性事件（死亡、听力筛查未通过、肾钙化/肾结石病）中，呋塞米组与安慰剂组受试者未见显著差异。呋塞米组与安慰剂组在听力筛查未通过、肾钙化/肾结石病方面无差异这一结果，与近期对比暴露与未暴露于呋塞米婴儿的相关研究论文，以及呋塞米安全性系统评价的结论一致。但呋塞米组婴儿的电解质异常不良事件发生率高于安慰剂组。
中度至重度BPD、死亡的初步有效性结局指标，以及BPD随时间的变化情况，两组间均无显著差异。在早产新生儿与婴儿的呋塞米群体药代动力学（population pharmacokinetics）分析中，体重与出生后年龄被证实为影响呋塞米清除率的重要协变量。
针对存在BPD风险的早产婴儿，呋塞米会升高电解质异常不良事件的发生风险，但不会升高整体不良事件、听力损失或肾钙化/肾结石病的发生风险。本研究的安全性分析人群共纳入80名早产婴儿受试者，均被随机分配至安慰剂组或呋塞米给药组。