Effect of Metformin on Behaviour and the Brain in Children Treated for a Brain Tumour

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. No less than 3 weeks after completion of:

   * Primary therapy for:

     1. medulloblastoma

        OR
     2. ependymoma

        OR
     3. craniopharyngioma

        OR
     4. germ cell tumours

        OR
   * Primary therapy for any other brain tumour treated with cranial radiation - at the discretion of the Study PI

   OR
   * Cranial radiation for relapsed ependymoma
2. Age 7 years to 21 years and 11 months at the time of enrollment
3. Either declare English (or French in accepting sites) as their native language or have had at least two years of schooling in English (or French in accepting sites) at the time of consent
4. Able to swallow tablets either whole, crushed or via a feeding tube and be willing to adhere to the study intervention regimen
5. Meet criteria for normal organ function requirements as described below:

   1. Normal renal function defined as: Estimated glomerular filtration rate (eGFR) \> 75ml/min/1.73m²

      * eGFR is calculated using the Schwartz formula: eGFR (mL/min/1.73m²) = (0.41 × height in cm) / creatinine in mg/dL
   2. Normal liver function defined as:

      * Serum glutamic-oxaloacetic transaminase (SGOT) (AST) ≤2.5 x institutional upper limit of normal (ULN) for age and gender
      * Serum glutamic pyruvic transaminase (SGPT) (ALT) ≤2.5 x institutional ULN for age and gender
      * Total bilirubin \<1.5x institutional ULN for age and gender (patients with documented Gilbert's Disease may be enrolled with Sponsor approval and total bilirubin ≤2.0 x institutional ULN)
6. Informed consent (and assent, where applicable) will be obtained from the participants and/or their legal guardian(s) by study team members delegated to consent for this study

Exclusion Criteria:

Participants who meet any of the following criteria will not be eligible to take part in the trial:

1. Standard score of less than 60 for full scale IQ on the Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II) (or other Wechsler Scale of Intelligence for English speaking participants) or pro-rated IQ score on the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) or Wechsler Adult Intelligence Scale (WAIS-IV) for French speaking participants at Screening visit
2. Have a known hypersensitivity to metformin hydrochloride
3. Have unstable and/or insulin-dependent (Type 1) diabetes
4. Have a history of hypoglycemia after 2 years of age
5. Have been diagnosed with acute or chronic metabolic acidosis and/or lactic acidosis or if bicarbonate (Total CO2) is less than 22 mmol/L at the Screening visit
6. Have a history of renal disease or renal dysfunction pre-existing to the diagnosis of Medulloblastoma
7. Have a history of congestive heart failure requiring pharmacologic treatment (including the use of diuretics) within two years prior to study entry
8. Currently taking part in a cognitive rehabilitation intervention study
9. Treatment or planned treatment involving diuretics
10. Current or planned treatment with cationic drugs excreted by the kidneys (e.g. amiloride, cimetidine, digoxin, morphine, nifedipine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin)
11. Current or planned treatment with concomitant medications with potential unacceptable interaction with metformin including, lamotrigine, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, glycopyrrolate, and carbonic anhydrase inhibitors, or at the discretion of the Site PI or delegate for medications with potential interactions such as sertraline, lansoprazole and omeprazole.
12. Pernicious anemia (according to results of the Screening visit blood draw)
13. Current use of metformin hydrochloride
14. Any condition or diagnosis, that could in the opinion of the Site 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
15. Are receiving palliative care