Metformin for Brain Repair in Children With Cranial-Spinal Radiation for Medulloblastoma

We conducted a pilot randomized, double-blind, placebo-controlled trial with crossover in survivors of pediatric brain tumors with primary endpoints of safety and feasibility and secondary endpoints of cognitive and magnetic resonance imaging (MRI) measures. Twenty-four participants were enrolled and randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either a group AB (AB) or group BA (BA) sequence. At the point of crossover, there was a 10-week washout period in which neither group received any treatment. During the first week of each treatment cycle, a daily dose of 500 mg/m2 of metformin or placebo was administered orally. The dose was increased to 1000mg/m2 daily beginning in the second week and continuing for the remainder of the 12-week cycle.

Test procedures (Clinical & current medications reviews, Blood draws, and MRI and Cognitive testing) were performed at 4 times points during the study: 1. at study entry (Baseline 1), 2. after 12 weeks of treatment (Outcome 1), 3. after a 10-week washout period at 22 weeks (Baseline 2), and 4. At the end of the trial at 34 weeks (Outcome 2).

Inclusion criteria

Survivors will be included if they:

• Have been treated with cranial or cranial-spinal radiation,
• Are between 5 and 21 years of age at time of consent, and
• Either declare English as their native language or have had at least two years of schooling in English at the time of their baseline assessment.
• Have been diagnosed with a brain tumour requiring treatment with cranial or cranial-spinal radiation at least 2 years ago, is not receiving active treatment and no more than 15 years may have elapsed between treatment with cranial-spinal radiation and time of the trial. Survivors with a shunt will be included in the trial, but will need to be identified prior to study enrollment to discuss any specific considerations for imaging.
• Meet criteria for adequate organ function requirements:

• Adequate renal function defined as: Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70ml/min/1.73 m2 or serum creatinine based on age/gender as follows:

Maximum Serum Creatinine Level (mg/dL)

5 to < 10 years: Male = 1; Female = 1

10 to < 13 years: Male = 1.2; Female = 1.2

13 to < 16 years: Male = 1.5; Female = 1.4

≥ 16 years: Male = 1.7; Female = 1.4

• Adequate liver function defined as:

Total bilirubin < 1.5 x upper limit of normal (ULN) for age, and,

serum glutamate oxaloacetate transaminase (SGOT) (AST) or serum glutamate pyruvate transaminase (SGPT) (ALT) < 3 x upper limit of normal (ULN) for age.

• Females of childbearing potential must have a negative pregnancy test result and must agree to use a medically acceptable method of contraception throughout the entire study period and for 30 days after the last dose of study drug.
• Informed consent will be obtained from the participants and/or their legal guardians by study team members authorized to consent for this study.

Exclusion criteria

Survivors will be excluded if they

• Are receiving palliative care.
• Are unable to participate in neuro-imaging without sedation as this is the primary outcome measure for the trial.
• Are unable to swallow tablets.
• Are unstable and/or insulin-dependent (Type 1) diabetic patients.
• Have acute or chronic metabolic acidosis and/or lactic acidosis.
• Any female patient or partner who has reached menarche and male patients who are not willing to use an effective method of contraception.
• Patient who is pregnant or lactating and does not agree to stop breastfeeding while receiving trial treatment.
• Have a history of renal disease or renal dysfunction e.g., as suggested by elevated serum creatinine levels (see 5.a. Inclusion criteria) or abnormal creatinine clearance.
• Have a history of congestive heart failure requiring pharmacologic treatment.
• Have a known hypersensitivity to metformin hydrochloride.