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

NCT05230758 | Recruiting Phase 3 DMC

• 1 other identifier: 1000073107
• Study Type: interventional
• Target: 140
• Locations: 2 countries
• Sites: 20

Brief Summary

The efficacy of treatment with metformin for promoting cognitive recovery and brain growth in children/adolescents treated for a brain tumour will be investigated in a multi-site Phase III randomized double-blind placebo-controlled parallel arm superiority trial. Specifically, in children/adolescents aged 7 years to 21 years and 11 months who have completed treatment for a brain tumour, is oral administration of metformin for 16 weeks associated with greater improvement of cognitive function and brain growth compared to placebo administered for 16 weeks?

Conditions

Medulloblastoma, Childhood; Cognitive Impairment

Keywords

Metformin; Paediatric brain tumour; Memory; Cognitive late effects

Outcome Measures

Primary Outcomes (3)

• Change from Week 1 (Baseline) Children's Auditory Verbal Learning Test-2 (CAVLT-2)/Rey Auditory Verbal Learning Test (RAVLT) Immediate Recall at Week 17 (Post-Intervention) to Assess Declarative Memory

  To examine the effectiveness of 16 weeks of treatment with metformin versus 16 weeks of placebo for improving cognition, as measured by CAVLT-2/RAVLT which is a test of auditory verbal learning and memory.

  Week 1 (Baseline), Week 17 (Post-Intervention)

• Change from Week 1 (Baseline) NIH Toolbox List Sort Working Working Memory Test at Week 17 (Post-Intervention) to Assess Working Memory

  To examine the effectiveness of 16 weeks of treatment with metformin versus 16 weeks of placebo for improving cognition, as measured by List Sorting Working Memory Test (LSWMT) in which participants will be required to recall and place in sequence stimuli that are presented visually and verbally.

  Week 1 (Baseline), Week 17 (Post-Intervention)

• Change from Week 1 (Baseline) Cambridge Neuropsychological Test Automated Battery (CANTAB) Mean Reaction Time for Correct Trials across the RVP, RTI, MTS, and DMS Subtests at Week 17 (Post-Intervention) to Assess Processing Speed

  To examine the effectiveness of 16 weeks of treatment with metformin versus 16 weeks of placebo for improving cognition, as measured by mean reaction time for correct trials across subtests of the CANTAB: 1. Rapid Visual Information Processing (RVP) 2. Reaction Time (RTI) 3. Match to Sample Visual Search (MTS) 4. Delayed Matching to Sample (DMS) Each subtest provides an outcome measure of response latency, which will be averaged across all correct trials for each subtest to provide an overall measure of processing speed.

  Week 1 (Baseline), Week 17 (Post-Intervention)

Secondary Outcomes (1)

• Diffusion Kurtosis Imaging (DKI) to Assess White Matter Growth within the Corpus Callosum

  Week 1 (Baseline), Week 17 (Post-Intervention)

Study Arms (2)

Metformin

EXPERIMENTAL

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).

Drug: Metformin hydrochloride (HCl) 500mg tablet

Placebo

PLACEBO COMPARATOR

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).

Drug: Placebo

Interventions

Metformin hydrochloride (HCl) 500mg tablet DRUG

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.

Also known as: Glucophage

Metformin

Placebo DRUG

Matching white round tablet containing excipients only. The placebo tablets will match the active drug as closely as possible in terms of appearance.

Also known as: Control

Placebo

Eligibility Criteria

• Age: 7 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• No less than 3 weeks after completion of:
• Primary therapy for:
• medulloblastoma
• ependymoma
• craniopharyngioma
• germ cell tumours
• Primary therapy for any other brain tumour treated with cranial radiation - at the discretion of the Study PI
• Cranial radiation for relapsed ependymoma
• Age 7 years to 21 years and 11 months at the time of enrollment
• 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
• Able to swallow tablets either whole, crushed or via a feeding tube and be willing to adhere to the study intervention regimen
• Meet criteria for normal organ function requirements as described below:
• 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

You may not qualify if:

• Participants who meet any of the following criteria will not be eligible to take part in the trial:
• 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
• Have a known hypersensitivity to metformin hydrochloride
• Have unstable and/or insulin-dependent (Type 1) diabetes
• Have a history of hypoglycemia after 2 years of age
• 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
• Have a history of renal disease or renal dysfunction pre-existing to the diagnosis of Medulloblastoma
• Have a history of congestive heart failure requiring pharmacologic treatment (including the use of diuretics) within two years prior to study entry
• Currently taking part in a cognitive rehabilitation intervention study
• Treatment or planned treatment involving diuretics
• 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)
• 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.
• Pernicious anemia (according to results of the Screening visit blood draw)
• Current use of metformin hydrochloride
• 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

Sponsors & Collaborators

• Donald Mabbott: lead

Study Sites (20)

John Hunter Children's Hospital

New Lambton Heights, New South Wales, 2305, Australia

RECRUITING

Children's Hospital in Westmead

Westmead, New South Wales, 2145, Australia

WITHDRAWN

Women and Childen's Hospital

Adelaide, North Adelaide, SA 5006, Australia

RECRUITING

Monash Children's Hospital

Clayton, Victoria, 3168, Australia

RECRUITING

Royal Children's Hospital

Parkville, Victoria, 3052, Australia

RECRUITING

Perth Children's Hospital

Nedlands, Western Australia, 6009, Australia

RECRUITING

Alberta Children's Hospital

Calgary, Alberta, T3B 6A8, Canada

RECRUITING

Stollery Children's Hospital

Edmonton, Alberta, T6G 2B7, Canada

RECRUITING

Children's & Women's Health Centre of British Columbia

Vancouver, British Columbia, V6H 3V4, Canada

RECRUITING

Cancer Care Manitoba

Winnipeg, Manitoba, R3E 0V9, Canada

RECRUITING

Izaak Walton Killam (IWK) Health Centre

Halifax, Nova Scotia, B3K 6R8, Canada

RECRUITING

Hamilton Health Sciences - McMaster Children's Hospital

Hamilton, Ontario, L8S 4K1, Canada

RECRUITING

Children's Hospital, London Health Sciences Centre

London, Ontario, N6A 5W9, Canada

RECRUITING

Children's Hospital of Eastern Ontario

Ottawa, Ontario, K1H 8L1, Canada

RECRUITING

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

RECRUITING

CHU Sainte-Justine

Montreal, Quebec, H3T 1C5, Canada

RECRUITING

Montreal Children's Hospital

Montreal, Quebec, H4A 3J1, Canada

RECRUITING

CHU de Québec - Université Laval

Québec, Quebec, G1V 4G2, Canada

RECRUITING

CHU de Sherbrooke

Sherbrooke, Quebec, J1G 2E8, Canada

RECRUITING

Saskatchewan Health Authority

Saskatoon, Saskatchewan, S7N 0W8, Canada

RECRUITING

MeSH Terms

Conditions

Medulloblastoma; Cognitive Dysfunction

Interventions

Metformin; Tablets

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors, Primitive; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Dosage Forms; Pharmaceutical Preparations

Study Officials

• Donald Mabbott, Ph.D.

  The Hospital for Sick Children

  STUDY CHAIR

• Eric Bouffet, M.D.

  The Hospital for Sick Children

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lauren Cole, PhD

CONTACT

416-813-7396; lauren.cole@sickkids.ca

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: We are implementing a double-blind procedure to ensure that neither participants nor members of the research team have knowledge of the randomized treatment group to prevent bias in reporting, outcome assessment and analysis.
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Psychologist

Model Details: We elect to employ a parallel arm superiority trial. As there is no standard of care equivalent for the intervention being investigated (i.e. metformin for improved cognition and white matter growth), a placebo is being used to prevent any potential response bias.

Study Record Dates

• First Submitted: January 12, 2022
• First Posted: February 9, 2022
• Study Start: July 1, 2022
• Primary Completion (Estimated): November 30, 2027
• Study Completion (Estimated): November 30, 2027
• Last Updated: May 1, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

AU (6); CA (14)