Safety and feasibility trial protocol of metformin in infants after perinatal brain injury.

IF 2.3 4区 医学 Q2 PEDIATRICS
Anne-Marie Hutchinson, Rosanna Pais, Andrea N Endginton, Betsy Pilon, Jordan M MacDonald, Mallory E MacDonald, Tamorah Lewis, Martin Offringa, Brian Thomas Kalish
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Abstract

Introduction: Infants with hypoxic-ischaemic encephalopathy (HIE) are at a high risk for neurodevelopmental impairment, and adjunctive treatments to promote brain repair are needed. The antidiabetic drug metformin has recently been recognised as a neurorestorative agent, but, to date, has not been used in infants. Herein, we describe a clinical trial of the safety, feasibility and pharmacokinetics of metformin in infants with HIE.  METHODS AND ANALYSIS: In collaboration with patient and family stakeholders, we designed a pragmatic clinical trial. To determine appropriate dosing of metformin, we performed physiologically based pharmacokinetic (PBPK) modelling after scaling a published adult PBPK model of metformin to an infant population of full-term newborns to 3-month-olds. Based on this PBPK modelling and target drug exposure, we determined an optimal target dose of 32 mg/kg/day. Trial participants will complete baseline bloodwork and then receive 3 weeks of metformin at 25% of the target dose, followed by 3 weeks of metformin at 50% of the target dose. At a mid-study (6 week) visit, repeat laboratory testing will be done, followed by an additional 6 weeks of metformin at target dosing. The final study visit will include repeat labs following therapy at target dosing. At-home blood glucose monitoring will be used between study visits. Pharmacokinetics of metformin will be evaluated with bloodwork collected at study visits. The incidence of safety events and feasibility measures will be reported using descriptive statistics. Our infant PBPK model will be validated with study samples and the dose for future trials adjusted based on new knowledge about metformin PK in infants.

Ethics and dissemination: Approval of the Boston Children's Hospital Research Ethics Committee will be obtained prior to study initiation. Trial oversight will be under the direction of a Data Safety Monitoring Board.

Trial registration number: This study has been registered at www.

Clinicaltrials: gov under NCT06429007.

二甲双胍在围产儿脑损伤后应用的安全性和可行性研究方案。
新生儿缺氧缺血性脑病(HIE)是神经发育障碍的高危人群,需要辅助治疗促进脑修复。抗糖尿病药物二甲双胍最近被认为是一种神经恢复剂,但是,迄今为止,还没有在婴儿中使用。在此,我们描述了二甲双胍在新生儿HIE中的安全性、可行性和药代动力学的临床试验。方法与分析:与患者和家属利益相关者合作,我们设计了一项实用的临床试验。为了确定适当的二甲双胍剂量,我们在将已发表的成人二甲双胍PBPK模型扩展到足月新生儿至3个月大的婴儿群体后,进行了基于生理的药代动力学(PBPK)建模。基于PBPK模型和靶药物暴露,我们确定了32 mg/kg/天的最佳靶剂量。试验参与者将完成基线血液检查,然后接受3周的二甲双胍治疗,剂量为目标剂量的25%,然后是3周的二甲双胍治疗,剂量为目标剂量的50%。在研究中期(6周)访问时,将进行重复实验室测试,随后再进行6周的二甲双胍目标剂量治疗。最后的研究访问将包括目标剂量治疗后的重复实验室。在家血糖监测将在研究访问之间使用。二甲双胍的药代动力学将在研究访问时采集血液进行评估。使用描述性统计报告安全事件的发生率和可行性措施。我们的婴儿PBPK模型将通过研究样本进行验证,未来试验的剂量将根据婴儿二甲双胍PK的新知识进行调整。伦理和传播:在研究开始之前,将获得波士顿儿童医院研究伦理委员会的批准。试验监督将在数据安全监测委员会的指导下进行。试验注册号:本研究已在www.Clinicaltrials: gov注册,编号为NCT06429007。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BMJ Paediatrics Open
BMJ Paediatrics Open Medicine-Pediatrics, Perinatology and Child Health
CiteScore
4.10
自引率
3.80%
发文量
124
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