HIE, Hypoxic-Ischemic Encephalopathy, Infant Development, Neurodevelopment
Conditions
Keywords
HIE, metformin, Hypoxic-Ischemic Encephalopathy, Pharmacokinetic modeling, Neonates, Brain Injury
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.
Interventions
DRUGMetformin
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.
Sponsors
Boston Children's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 6 Months
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety profile of kidney function | 12 weeks | A renal function panel (chem 10 with renal function) will be performed prior to the initiation of therapy and at all subsequent study visits. |
| Safety profile of liver function | 12 weeks | A liver function test (LFT) will be performed prior to the initiation of therapy and at all subsequent study visits. |
| Recruitment feasibility | 12 weeks | To assess feasibility, the number of eligible patients will be compared to the number of patients who consent to participate in the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Validity of neonatal model of metformin pharmacokinetics | 12 weeks | Plasma metformin levels will be analyzed by investigators with whole blood obtained at study visits. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBrian Kalish, MD
Boston Children's Hospital
Outcome results
None listed