- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05230758
Effect of Metformin on Behaviour and the Brain in Children Treated for a Brain Tumour (Met Med Can)
Phase III Randomized Double-blind Placebo-controlled Trial of Metformin for Cognitive Recovery and White Matter Growth in Paediatric Medulloblastoma Patients
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
A critical barrier to improving the quality of life of children/adolescents living with cancer is that our curative therapies, which include a combination of surgery, chemotherapy and radiation, have toxic effects on healthy tissue, resulting in long-term problems. This is evident for children and adolescents who survive medulloblastoma - a brain tumour requiring aggressive therapy: they experience brain injury and cognitive impairment. There are few therapies for restoring cognitive function and promoting brain growth in survivors; however new work in regenerative medicine offers a possible alternative. The drug metformin promotes brain growth in animal models by activating neural stem cells. In a pilot trial with 24 participants, we found that metformin was safe and tolerable for use in children/adolescents treated with cranial radiation for a brain tumour and may improve cognition and promote white matter growth. In this multi-site clinical trial, we will test the efficacy of treatment with metformin for brain repair and cognitive recovery in medulloblastoma survivors. If we find that metformin promotes cognitive improvement and brain growth in paediatric survivors of medulloblastoma, this may offer a viable therapeutic approach that may improve quality of life of these cancer patients and provide a model for treatment of late effects in other paediatric cancers.
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 (intelligence quotient (IQ) testing will also be conducted at Screening), 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 medulloblastoma at Post-Intervention (Week 17) compared to Baseline (Week 1). 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 (Week 1). 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.
- 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 (Week 1). White matter growth will be assessed using diffusion MRI metrics of myelin and fiber structure.
- 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 (Week 1). Structural MRI measures of hippocampal volume will be explored.
- We hypothesize that 16 weeks of treatment with metformin will result in superior performance on measures of attention, executive functioning, and intelligence compared to 16 weeks of treatment with placebo at Post-Intervention (Week 17) compared to Baseline (Week 1). Tests of attention, executive functioning, and intelligence will be used.
- We hypothesize that all outcome measures will continue in the predicted direction at 24 weeks (6 Month Follow-Up, Week 41) compared to Baseline (Week 1)/ screening (Day 0) following completion of 16 weeks of metformin compared to 16 weeks of placebo.
- 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 (Week 1).
- 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 (Week 1).
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 17 years and 11 months - will be recruited from up to 19 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. Results from IQ testing will be examined to explore the effects metformin versus placebo controlling for Screening visit outcome measurements. 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.
Study Type
Enrollment (Estimated)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Cynthia de Medeiros, M.Sc.
- Phone Number: 307396 416-813-7396
- Email: cynthia.demedeiros@sickkids.ca
Study Locations
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New South Wales
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New Lambton Heights, New South Wales, Australia, 2305
- Recruiting
- John Hunter Children's Hospital
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Contact:
- Frank Alvaro, MMBS
- Phone Number: +612 4985 5612
- Email: frank.alvaro@health.nsw.gov.au
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Westmead, New South Wales, Australia, 2145
- Withdrawn
- Children's Hospital in Westmead
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Victoria
-
Clayton, Victoria, Australia, 3168
- Recruiting
- Monash Children's Hospital
-
Contact:
- Peter Downie, MBBS
- Phone Number: +613 8572 3456
- Email: Peter.Downie@monashhealth.org
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Parkville, Victoria, Australia, 3052
- Recruiting
- Royal Children's Hospital
-
Contact:
- Molly Williams, MBBS
- Phone Number: +613 9345 9184
- Email: molly.wiliams@rch.org.au
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West Australia
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Nedlands, West Australia, Australia, 6009
- Not yet recruiting
- Perth Children's Hospital
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Contact:
- Santosh Valvi, MBBS
- Phone Number: +618 6456 3612
- Email: santosh.valvi@health.wa.gov.au
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-
-
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Alberta
-
Calgary, Alberta, Canada, T3B 6A8
- Recruiting
- Alberta Children's Hospital
-
Contact:
- Sherry Qian
- Phone Number: 403-955-7263
- Email: Sherry.Qian@AlbertaHealthServices.ca
-
Contact:
- Lucie Lafay-Cousin, MD
- Phone Number: 403-955-2554
- Email: lucie.lafay-cousin@albertahealthservices.ca
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Edmonton, Alberta, Canada, T6G 1C9
- Recruiting
- Stollery Children's Hospital
-
Contact:
- Beverly Wilson, MD
- Phone Number: 780-407-8798
- Email: bev.wilson@albertahealthservices.ca
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British Columbia
-
Vancouver, British Columbia, Canada, V6H 3V4
- Recruiting
- Children's & Women's Health Centre of British Columbia
-
Contact:
- Juliette Hukin, MD
- Phone Number: 604-875-2406
- Email: jhukin@cw.bc.ca
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Manitoba
-
Winnipeg, Manitoba, Canada, R3E 0V9
- Recruiting
- Cancer Care Manitoba
-
Contact:
- Magimairajan I Vanan, MD
- Phone Number: 204-787-4724
- Email: mivanan@cancercare.mb.ca
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Contact:
- Clinical Trial Unit CTU
- Phone Number: 204-787-4156
- Email: ctu_web@cancercare.mb.ca
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-
Nova Scotia
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Halifax, Nova Scotia, Canada, B3K 6R8
- Recruiting
- Izaak Walton Killam (IWK) Health Centre
-
Contact:
- Craig Erker, MD
- Phone Number: 902-470-3743
- Email: craig.erker@iwk.nshealth.ca
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Ontario
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Hamilton, Ontario, Canada, L8S 4K1
- Recruiting
- Hamilton Health Sciences - McMaster Children's Hospital
-
Contact:
- Adam Fleming, MD
- Phone Number: 76720 905-521-2100
- Email: afleming@mcmaster.ca
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London, Ontario, Canada, N6A 5W9
- Recruiting
- Children's Hospital, London Health Sciences Centre
-
Contact:
- Shayna Zelcer, MD
- Phone Number: 52678 519-685-8500
- Email: Shayna.Zelcer@lhsc.on.ca
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Ottawa, Ontario, Canada, K1H 8L1
- Recruiting
- Children's Hospital of Eastern Ontario
-
Contact:
- Donna Johnston, MD
- Phone Number: 2210 613-737-7600
- Email: djohnston@cheo.on.ca
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Toronto, Ontario, Canada, M5G 1X8
- Recruiting
- The Hospital for Sick Children
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Contact:
- Vijay Ramaswamy, MD
- Phone Number: 208221 416-813-7654
- Email: vijay.ramaswamy@sickkids.ca
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Contact:
- Cynthia de Mederios, MSc
- Phone Number: 307396 416-813-7396
- Email: cynthia.demedeiros@sickkids.ca
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Quebec
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Montréal, Quebec, Canada, H4A 3J1
- Recruiting
- Montreal Children's Hospital
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Contact:
- Geneviève Legault, MD
- Phone Number: 514-412-4445
- Email: genevieve.legault4@mcgill.ca
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Montréal, Quebec, Canada, H3T 1C5
- Recruiting
- CHU Sainte-Justine
-
Contact:
- Sébastien Perreault, MD
- Phone Number: 5019 514-345-4931
- Email: s.perreault@umontreal.ca
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Quebec City, Quebec, Canada, G1V 4G2
- Recruiting
- CHU de Québec - Université Laval
-
Contact:
- Valérie Larouche, MD
- Phone Number: 40121 418-525-4444
- Email: valerie.larouche.med@ssss.gouv.qc.ca
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Sherbrooke, Quebec, Canada, J1G 2E8
- Not yet recruiting
- CHU de Sherbrooke
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Contact:
- Stéphanie Vairy, MD
- Phone Number: 7-3068 819-346-1110
- Email: Stephanie.Vairy@USherbrooke.ca
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-
Saskatchewan
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Saskatoon, Saskatchewan, Canada, S7N 0W8
- Not yet recruiting
- Saskatchewan Health Authority
-
Contact:
- Kathleen Felton, MD
- Phone Number: 306-655-2733
- Email: Kathleen.Felton@saskhealthauthority.ca
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
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
- Age 7 years to 17 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
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)
- 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:
- Unable to participate in MRI without sedation
- Standard score of less than 60 for full scale IQ on the Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II) (for English speaking participants) or pro-rated IQ score on the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) (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
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Supportive Care
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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 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.
Other Names:
|
Placebo Comparator: 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).
|
Matching white round tablet containing excipients only.
The placebo tablets will match the active drug as closely as possible in terms of appearance.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
Time Frame: Week 1 (Baseline), Week 17 (Post-Intervention)
|
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)
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Change from Week 1 (Baseline) NIH Toolbox List Sort Working Working Memory Test at Week 17 (Post-Intervention) to Assess Working Memory
Time Frame: Week 1 (Baseline), Week 17 (Post-Intervention)
|
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)
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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
Time Frame: Week 1 (Baseline), Week 17 (Post-Intervention)
|
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:
|
Week 1 (Baseline), Week 17 (Post-Intervention)
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Diffusion Kurtosis Imaging (DKI) to Assess White Matter Growth within the Corpus Callosum
Time Frame: Week 1 (Baseline), Week 17 (Post-Intervention)
|
To examine the effectiveness of 16 weeks of treatment with metformin versus 16 weeks of placebo for promoting white matter growth within the corpus callosum as measured by DKI including axonal water fraction (AWF), a metric sensitive to myelin.
|
Week 1 (Baseline), Week 17 (Post-Intervention)
|
Collaborators and Investigators
Sponsor
Investigators
- Study Chair: Donald Mabbott, Ph.D., The Hospital for Sick Children
- Principal Investigator: Eric Bouffet, M.D., The Hospital for Sick Children
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms, Glandular and Epithelial
- Glioma
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Neuroectodermal Tumors, Primitive
- Medulloblastoma
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Metformin
Other Study ID Numbers
- 1000073107
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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