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

NCT ID: NCT06429007

Last Updated: 2025-11-25

Basic Information

• Recruitment Status: ENROLLING_BY_INVITATION
• Clinical Phase: PHASE1
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-10-01
• Study Completion Date: 2029-03-01

Brief Summary

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, the investigator describes a clinical trial with the aim of demonstrating the safety and feasibility of metformin use to improve neurodevelopmental outcomes in infants with HIE.

Conditions

Hypoxic-Ischemic Encephalopathy; HIE; Neurodevelopment; Infant Development

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Metformin Intervention

Participants will complete a pre-study visit with baseline bloodwork including a complete blood count (CBC), liver and renal function, basic chemistry, glucose, and lactate. At this visit, parents will be taught how to administer metformin and given a 6-week supply (at 25% \& 50% of the target dose for three weeks each) to minimize potential gastrointestinal upset. Parents will be educated on adverse effects and receive a diary to log dose administration and side effects. They will also be asked to perform at-home glucometer checks twice daily for 3 days post the dose escalation. After six weeks, participants will return for a study visit with repeat labs including assessing the levels of vitamin B12 and plasma metformin for measurement of pharmacokinetics. Parents will then receive a 6-week supply of metformin at the full dose (\~25mg/kg) for 6 weeks. A final study visit will then occur following 12-weeks of metformin therapy, with repeat labs including plasma metformin levels.

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

Metformin will be initiated at 25% of the target dose (4 mg/kg administered twice daily, total daily dose 8 mg/kg) for three weeks. In the absence of adverse effects, metformin dose will be escalated to 50% of the target dose (8 mg/kg administered twice daily for a total daily dose of 16mg/kg) for remaining 3 weeks to minimize potential gastrointestinal upset at higher doses. Parents will be documenting adverse events and performing glucometer checks twice a day for 3 days post dose escalation.

Parents will then receive a 6-week supply of metformin at the target dose (16 mg/kg administered twice daily, total daily dose 32 mg/kg). Adverse events will be documented and glucometer checks will be performed twice a day for 3 days following dose escalation.

Interventions

Metformin

Metformin will be initiated at 25% of the target dose (4 mg/kg administered twice daily, total daily dose 8 mg/kg) for three weeks. In the absence of adverse effects, metformin dose will be escalated to 50% of the target dose (8 mg/kg administered twice daily for a total daily dose of 16mg/kg) for remaining 3 weeks to minimize potential gastrointestinal upset at higher doses. Parents will be documenting adverse events and performing glucometer checks twice a day for 3 days post dose escalation.

Parents will then receive a 6-week supply of metformin at the target dose (16 mg/kg administered twice daily, total daily dose 32 mg/kg). Adverse events will be documented and glucometer checks will be performed twice a day for 3 days following dose escalation.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• <6 months old at time of enrollment, and able to initiate study drug between 3 and 6 months old.
• Born > 35 weeks gestational age with a clinical diagnosis of HIE at birth, who receive therapeutic hypothermia.
• Post-hypothermia brain MRI with evidence of hypoxic-ischemic brain injury, based on the neuroradiology clinical report. Specifically, participants must have had evidence of a lactate peak by magnetic resonance spectroscopy and/or signal abnormalities by conventional (T1 and/or T2) or diffusion-weighted images consistent with hypoxic-ischemic pattern of injury.
• English- or Spanish-speaking families, as the parents/guardians will be responsible for documenting dose administrations and adverse events.

Exclusion Criteria

• Known genetic or chromosomal disorder, and in the presence of congenital or acquired liver or kidney disease that might, in the opinion of the Principal Investigator (PI) or delegate, affect drug metabolism.
• Maternal use of metformin while actively breastfeeding.
• Infant weight below the 10th percentile based on WHO growth charts at the time of study drug initiation.
• Normal post-hypothermia brain MRI, without evidence of ischemic brain injury, based on the neuroradiology clinical report.
• Concomitant use of the following drugs: anti-diabetic drugs (insulin, sulfonylureas), steroids, diuretics (furosemide, chlorothiazide, spironolactone), diazoxide, beta blockers, ACE inhibitors, angiotensin II blockers, calcium channel blockers (including nifedipine), phenytoin, valproic acid, topiramate, cimetidine, corticosteroids, thyroid medications, sympathomimetics, carbonic anhydrase inhibitors, or any antibiotics.
• Any condition or diagnosis, that could in the opinion of the PI or delegate, interfere with the participant's ability to comply with study instructions, might confound the interpretation of the study results, or put the participant at risk.

• Minimum Eligible Age: 3 Months
• Maximum Eligible Age: 6 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boston Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Brian Kalish

Neonatologist, Assistant Professor of Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Brian Kalish, MD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Locations

Boston Children's Hospital

Boston, Massachusetts, United States

Countries

United States

References

Hutchinson AM, Pais R, Endginton AN, Pilon B, MacDonald JM, MacDonald ME, Lewis T, Offringa M, Kalish BT. Safety and feasibility trial protocol of metformin in infants after perinatal brain injury. BMJ Paediatr Open. 2025 Aug 24;9(1):e002784. doi: 10.1136/bmjpo-2024-002784.

Reference Type: DERIVED

PMID: 40850908 (View on PubMed)

Other Identifiers

IRB-P00048370

Identifier Type: -

Identifier Source: org_study_id