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

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.