Metformin Treatment in Infants After Perinatal Brain Injury

A Phase I Safety and Feasibility of Metformin Treatment in Infants After Perinatal Brain Injury

A phase I study to test the feasibility and safety of treatment with metformin in infants affected by hypoxic ischemic encephalopathy (HIE) or prematurity-related brain injury

Study Overview

• Status: Terminated
• Conditions: Premature Birth; Hypoxic Ischemic Encephalopathy of Newborn
• Intervention / Treatment: Drug: Metformin Hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Rosanna Yankanah, MSc; Phone Number: 202919 416-813-7654; Email: rosanna.yankanah@sickkids.ca
• Study Contact Backup: Name: Brian T Kalish, MD; Phone Number: 301433 416-813-7654; Email: brian.kalish@sickkids.ca

Study Locations

• Canada
  • Ontartio
    • Toronto, Ontartio, Canada, M5G 1X8
      • The Hospital for Sick Children
      • Contact: Brian T Kalish, MD; Phone Number: 301433 416-813-7654; Email: brian.kalish@sickkids.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

HIE Patients:

1. > 35 weeks gestation at time of birth
2. ≤3 months at time of consent
3. Clinical diagnosis of HIE
4. Infant received therapeutic hypothermia for the treatment of HIE
5. Family lives within one hour distance of the Hospital for Sick Children (in order to facilitate home visits)

Preterm Infants:

1. <32 weeks gestation at time of birth
2. 36-44 weeks corrected (postmenstrual) gestational age at time of metformin administration
3. Clinical team anticipates hospitalization at SickKids for at least 1 week after study enrollment

Exclusion Criteria:

1. Have a known genetic or chromosomal disorder.
2. Congenital or acquired liver or kidney disease that might, in the opinion of the Principal Investigator or delegate, affect drug metabolism.
3. History of hypoglycemia in the newborn period requiring glucose infusion rate > 10 mg/kg/min or treatment with glucagon or diazoxide.
4. Any condition or diagnosis, that could in the opinion of the Principal Investigator 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
5. >3 months of age at the time of enrollment (term HIE patients only)
6. Weight <10%ile based on WHO growth charts at time of initiation of study drug (term HIE patients only).
7. Maternal use of metformin while actively breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HIE: 20 mg/kg	Drug: Metformin Hydrochloride; Infants will receive 14 consecutive doses, once daily, of metformin, with two dose cohorts. Arm 1: Five infants with HIE will be enrolled on the first dose cohort of 20 mg/kg. Once complete, another five infants will be enrolled on the second dose cohort of 25 mg/kg. Arm 2: Five preterm infants will be enrolled on the first dose cohort of 15 mg/kg. Once complete, another five preterm infants will be enrolled on the second dose cohort of 20 mg/kg.
Experimental: HIE: 25 mg/kg	Drug: Metformin Hydrochloride; Infants will receive 14 consecutive doses, once daily, of metformin, with two dose cohorts. Arm 1: Five infants with HIE will be enrolled on the first dose cohort of 20 mg/kg. Once complete, another five infants will be enrolled on the second dose cohort of 25 mg/kg. Arm 2: Five preterm infants will be enrolled on the first dose cohort of 15 mg/kg. Once complete, another five preterm infants will be enrolled on the second dose cohort of 20 mg/kg.
Experimental: Preterm: 15 mg/kg	Drug: Metformin Hydrochloride; Infants will receive 14 consecutive doses, once daily, of metformin, with two dose cohorts. Arm 1: Five infants with HIE will be enrolled on the first dose cohort of 20 mg/kg. Once complete, another five infants will be enrolled on the second dose cohort of 25 mg/kg. Arm 2: Five preterm infants will be enrolled on the first dose cohort of 15 mg/kg. Once complete, another five preterm infants will be enrolled on the second dose cohort of 20 mg/kg.
Experimental: Preterm: 20 mg/kg	Drug: Metformin Hydrochloride; Infants will receive 14 consecutive doses, once daily, of metformin, with two dose cohorts. Arm 1: Five infants with HIE will be enrolled on the first dose cohort of 20 mg/kg. Once complete, another five infants will be enrolled on the second dose cohort of 25 mg/kg. Arm 2: Five preterm infants will be enrolled on the first dose cohort of 15 mg/kg. Once complete, another five preterm infants will be enrolled on the second dose cohort of 20 mg/kg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with hypoglycemia (serum glucose <3.3mmol/L)	Number of patients with hyperglycemia (glucose>10mmol/L)	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma metformin levels	Pharmacokinetics analysis	2 weeks
Number of patients who complete study	Feasibility of study intervention administration	2 weeks
Number of patients who complete all study procedures	Feasibility of executing study operations	2 weeks

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Collaborators: University of Alberta; University of Waterloo
• Investigators: Principal Investigator: Brian T Kalish, MD, The Hospital for Sick Children

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2023
• Primary Completion (Actual): February 22, 2024
• Study Completion (Actual): February 22, 2024

Study Registration Dates

• First Submitted: October 18, 2022
• First Submitted That Met QC Criteria: October 18, 2022
• First Posted (Actual): October 21, 2022

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Metformin; Hypoxic Ischemic Encephalopathy; Newborn; Prematurity
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Signs and Symptoms, Respiratory; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Hypoxia; Hypoxia, Brain; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Brain Ischemia; Brain Injuries; Premature Birth; Brain Diseases; Hypoxia-Ischemia, Brain; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 3987

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No