Effect of Metformin on Behaviour and the Brain in Children Treated for a Brain Tumour
NCT ID: NCT05230758
Last Updated: 2026-01-22
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE3
140 participants
INTERVENTIONAL
2022-07-01
2027-11-30
Brief Summary
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Detailed Description
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This study is designed to test the efficacy of metformin in a 16-week multi-centre, phase III, double-blind, randomized placebo-controlled superiority trial with two parallel conditions (metformin versus placebo). Participants will be randomly assigned to one of the two treatments where they will either complete a 16-week cycle of metformin or a 16-week cycle of placebo. Participants will be randomized using Research Electronic Data Capture (REDCap) to ensure allocation concealment. The randomization code will not be released until the participant has been recruited, consented and passed screening. Outcome assessments will be conducted at Baseline immediately following the completion of week 16 treatment (Post-Intervention, Week 17), and 24 weeks following completion of the intervention (6 Month Follow-Up, Week 41).
The primary endpoint is cognitive function in children/adolescent survivors of a brain tumour at Post-Intervention (Week 17) compared to Baseline. We hypothesize that 16 weeks of treatment with metformin will be associated with better cognitive outcomes than 16 weeks of treatment with placebo. Cognitive outcomes will be measured using tests of working memory, declarative memory, and processing speed.
The key secondary outcome will be diffusion MRI within the corpus callosum at Post-Intervention (Week 17) compared to Baseline. We hypothesize that 16 weeks of treatment with metformin will be associated with increased white matter growth in the corpus callosum compared to 16 weeks of treatment with placebo. Increased white matter growth will be measured using diffusion MRI metrics.
Exploratory outcomes have been selected to investigate broader metformin-induced changes in the brain and cognition.
1. We hypothesize that 16 weeks of treatment with metformin will promote global white matter growth in the brain more so than 16 weeks of treatment with placebo at Post-Intervention (Week 17) compared to Baseline. White matter growth will be assessed using diffusion MRI metrics of myelin and fiber structure.
2. We hypothesize that 16 weeks of treatment with metformin will result in greater increases in hippocampal volume compared to that 16 weeks of treatment with placebo at Post-Intervention (Week 17) compared to Baseline. Structural MRI measures of hippocampal volume will be explored.
3. We hypothesize that 16 weeks of treatment with metformin will result in superior performance on measures of attention and executive functioning, compared to 16 weeks of treatment with placebo at Post-Intervention (Week 17) compared to Baseline. Tests of attention and executive functioning will be used.
4. We hypothesize that all outcome measures will continue in the predicted direction at 24 weeks (6 Month Follow-Up, Week 41) compared to Baseline following completion of 16 weeks of metformin compared to 16 weeks of placebo.
5. We also hypothesize that 16 weeks of treatment with metformin will yield better outcomes in females compared to males for all measures and that these findings will persist at 24 weeks (6 Month Follow-Up, Week 41) following the intervention compared to Baseline.
6. We hypothesize that 16 weeks of treatment with metformin will result in improved ratings of global health as reported by the parent/guardian at Post-Intervention (Week 17) compared to Baseline.
Metformin is a well-studied medication with a broad clinical experience in children including polycystic ovarian syndrome, diabetes, and obesity. The youngest age of use is 2 years old. The proposed dose and the schedule of administration of metformin is based on safety and toxicity data obtained from our pilot trial and previous use in paediatric populations. One hundred and twenty (120) English speaking and twenty (20) French speaking participants - aged 7 years to 21 years and 11 months - will be recruited from up to 20 sites across Canada and Australia.
Analysis of covariance (ANCOVA) will be used to examine the effects metformin versus placebo for each outcome in English speaking participants, controlling for Baseline outcome measurements. For French speaking participants, IQ testing will be completed, but not Cognitive testing as French-Canadian translations are not available. By focusing on a disease that requires some of the most aggressive therapy used in modern protocols, and by targeting the patients most vulnerable to the harmful effects of treatment we hope to provide a model of intervention that can then be applied to other cancers and actively promote brain health and cognitive recovery.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
SUPPORTIVE_CARE
QUADRUPLE
Study Groups
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Metformin
Oral metformin will be administered approximately 500mg/m2/day for 1 week and increased to 1000mg/m2/day for 15 weeks. Doses will be rounded to increments of half tablets (250mg, 500mg, 750mg and 1000mg).
Metformin hydrochloride (HCl) 500mg tablet
Metformin HCl 500mg tablets contain 500mg of active pharmaceutical ingredient (API) and are white, round, biconvex, film-coated tablets, with a score line on one face and debossed with "HMR" on the other. Each tablet contains the non-medicinal ingredients magnesium stearate and povidone. Tablet coating is comprised of hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide.
Placebo
Oral placebo will be administered approximately 500mg/m2/day for 1 week and increased to 1000mg/m2/day for 15 weeks. Doses will be rounded to increments of half tablets (250mg, 500mg, 750mg and 1000mg).
Placebo
Matching white round tablet containing excipients only. The placebo tablets will match the active drug as closely as possible in terms of appearance.
Interventions
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Metformin hydrochloride (HCl) 500mg tablet
Metformin HCl 500mg tablets contain 500mg of active pharmaceutical ingredient (API) and are white, round, biconvex, film-coated tablets, with a score line on one face and debossed with "HMR" on the other. Each tablet contains the non-medicinal ingredients magnesium stearate and povidone. Tablet coating is comprised of hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide.
Placebo
Matching white round tablet containing excipients only. The placebo tablets will match the active drug as closely as possible in terms of appearance.
Other Intervention Names
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Eligibility Criteria
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Inclusion 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
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
7 Years
21 Years
ALL
No
Sponsors
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Donald Mabbott
OTHER
Responsible Party
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Donald Mabbott
Psychologist
Principal Investigators
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Donald Mabbott, Ph.D.
Role: STUDY_CHAIR
The Hospital for Sick Children
Eric Bouffet, M.D.
Role: PRINCIPAL_INVESTIGATOR
The Hospital for Sick Children
Locations
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John Hunter Children's Hospital
New Lambton Heights, New South Wales, Australia
Children's Hospital in Westmead
Westmead, New South Wales, Australia
Women and Childen's Hospital
Adelaide, North Adelaide, Australia
Monash Children's Hospital
Clayton, Victoria, Australia
Royal Children's Hospital
Parkville, Victoria, Australia
Perth Children's Hospital
Nedlands, Western Australia, Australia
Alberta Children's Hospital
Calgary, Alberta, Canada
Stollery Children's Hospital
Edmonton, Alberta, Canada
Children's & Women's Health Centre of British Columbia
Vancouver, British Columbia, Canada
Cancer Care Manitoba
Winnipeg, Manitoba, Canada
Izaak Walton Killam (IWK) Health Centre
Halifax, Nova Scotia, Canada
Hamilton Health Sciences - McMaster Children's Hospital
Hamilton, Ontario, Canada
Children's Hospital, London Health Sciences Centre
London, Ontario, Canada
Children's Hospital of Eastern Ontario
Ottawa, Ontario, Canada
The Hospital for Sick Children
Toronto, Ontario, Canada
CHU Sainte-Justine
Montreal, Quebec, Canada
Montreal Children's Hospital
Montreal, Quebec, Canada
CHU de Québec - Université Laval
Québec, Quebec, Canada
CHU de Sherbrooke
Sherbrooke, Quebec, Canada
Saskatchewan Health Authority
Saskatoon, Saskatchewan, Canada
Countries
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Central Contacts
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Facility Contacts
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Jordan Hansford, Ph.D.
Role: primary
Other Identifiers
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1000073107
Identifier Type: -
Identifier Source: org_study_id
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