A Safety and Feasibility Trial Protocol of Metformin in Infants after Perinatal Brain Injury
Bibliographic record
Abstract
ABSTRACT Introduction Infants 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 Analysis In 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 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 (DSMB) composed of individuals with the appropriate expertise, including external neonatologists and pharmacologists. Registration This study has been registered at www.clinicaltrials.gov under NCT06429007 . WHAT IS ALREADY KNOWN ON THIS TOPIC Hypoxic-ischemic encephalopathy (HIE) is a major cause of newborn death and neurodevelopmental morbidity. Therapeutic hypothermia reduces the risk of death or disability in infants with HIE, but nonetheless, a large proportion of infants experience long term sequelae. Metformin 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. WHAT THIS STUDY HOPES TO ADD To investigate whether the administration of metformin in infants with a history of HIE is safe and feasible. To investigate the pharmacokinetics of metformin in infants. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY The 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.031 | 0.031 |
| Meta-epidemiology (narrow) | 0.004 | 0.002 |
| Meta-epidemiology (broad) | 0.004 | 0.003 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.002 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.005 | 0.005 |
| Insufficient payload (model declined to judge) | 0.026 | 0.006 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".