A Safety and Feasibility Trial Protocol of Metformin in Infants after Perinatal Brain Injury

IntroductionInfants with hypoxic-ischemic encephalopathy (HIE) are at high risk for neurodevelopmental impairment, despite current standards of care. Adjunctive treatments to promote brain repair are needed. The antidiabetic drug metformin has recently been recognized as a neurorestorative agent, but, to date, has not been used in infants. Herein, we describe a clinical trial with the aim of demonstrating the safety and feasibility of metformin use to improve neurodevelopmental outcomes in infants with HIE. Methods and AnalysisIn collaboration with patient and family stakeholders, we designed a pragmatic clinical trial to assess the safety and feasibility of metformin administration in infants. To determine appropriate dosing of metformin, we performed Physiologically Based Pharmaco-Kinetic (PBPK) modeling 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 modeling and target drug exposure, we determined an optimal target dose of 25 mg/kg/day. Trial participants will complete baseline bloodwork and then receive 6 weeks of daily metformin at 50% of the target dose (12.5mg/kg). At a mid-study visit, repeat laboratory testing will be done, followed by an additional 6 weeks of metformin at target dosing of 25mg/kg. The final study visit will include repeat labs following therapy at target dosing. Pharmacokinetics of metformin will be evaluated with bloodwork collected at study visits, as well as an optional at-home monitoring sub-study. 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 DisseminationApproval of the Boston Childrens Hospital Research Ethics Committee will be obtained prior to study initiation. Trial oversight will be under the direction of a Data Safety Monitoring Board (DSMB) composed of individuals with the appropriate expertise, including external neonatologists and pharmacologists. RegistrationThis study has been registered at www.clinicaltrials.gov under NCT06429007. WHAT IS ALREADY KNOWN ON THIS TOPICO_LIHypoxic-ischemic encephalopathy (HIE) is a major cause of newborn death and neurodevelopmental morbidity. C_LIO_LITherapeutic hypothermia reduces the risk of death or disability in infants with HIE, but nonetheless, a large proportion of infants experience long term sequelae. C_LIO_LIMetformin is an anti-diabetic drug that has shown promise to promote recovery after brain injury, but it has not been widely used in infants or young children. C_LI WHAT THIS STUDY HOPES TO ADDO_LITo investigate whether the administration of metformin in infants with a history of HIE is safe and feasible. C_LIO_LITo investigate the pharmacokinetics of metformin in infants. C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICYO_LIThe results of this trial will serve as the foundation for future clinical trials to study the efficacy of metformin in improving neurodevelopmental outcomes in children with HIE. C_LI