Cognitive Impairment Clinical Trial
— Met Med CanOfficial title:
Phase III Randomized Double-blind Placebo-controlled Trial of Metformin for Cognitive Recovery and White Matter Growth in Paediatric Medulloblastoma Patients
The efficacy of treatment with metformin for promoting cognitive recovery and brain growth in children/adolescents treated for medulloblastoma 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 17 years and 11 months who have completed treatment for medulloblastoma, 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?
Status | Recruiting |
Enrollment | 140 |
Est. completion date | June 30, 2027 |
Est. primary completion date | June 30, 2027 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 7 Years to 17 Years |
Eligibility | 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 medulloblastoma 2. Age 7 years to 17 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. Unable to participate in MRI without sedation 2. 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 3. Have a known hypersensitivity to metformin hydrochloride 4. Have unstable and/or insulin-dependent (Type 1) diabetes 5. Have a history of hypoglycemia after 2 years of age 6. 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 7. Have a history of renal disease or renal dysfunction 8. Have a history of congestive heart failure requiring pharmacologic treatment (including the use of diuretics) within two years prior to study entry 9. Currently taking part in a cognitive rehabilitation intervention study 10. Treatment or planned treatment involving diuretics 11. 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) 12. 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. 13. Pernicious anemia (according to results of the Screening visit blood draw) 14. Current use of metformin hydrochloride 15. 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 |
Country | Name | City | State |
---|---|---|---|
Australia | Monash Children's Hospital | Clayton | Victoria |
Australia | Perth Children's Hospital | Nedlands | West Australia |
Australia | John Hunter Children's Hospital | New Lambton Heights | New South Wales |
Australia | Royal Children's Hospital | Parkville | Victoria |
Australia | Children's Hospital in Westmead | Westmead | New South Wales |
Canada | Alberta Children's Hospital | Calgary | Alberta |
Canada | Stollery Children's Hospital | Edmonton | Alberta |
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 | CHU Sainte-Justine | Montréal | Quebec |
Canada | Montreal Children's Hospital | Montréal | Quebec |
Canada | Children's Hospital of Eastern Ontario | Ottawa | Ontario |
Canada | CHU de Québec - Université Laval | Quebec City | Quebec |
Canada | Saskatchewan Health Authority | Saskatoon | Saskatchewan |
Canada | CHU de Sherbrooke | Sherbrooke | Quebec |
Canada | The Hospital for Sick Children | Toronto | Ontario |
Canada | Children's & Women's Health Centre of British Columbia | Vancouver | British Columbia |
Canada | Cancer Care Manitoba | Winnipeg | Manitoba |
Lead Sponsor | Collaborator |
---|---|
Donald Mabbott |
Australia, Canada,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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) | |
Primary | 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) | |
Primary | 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:
Rapid Visual Information Processing (RVP) Reaction Time (RTI) Match to Sample Visual Search (MTS) 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 | Diffusion Kurtosis Imaging (DKI) to Assess White Matter Growth within the Corpus Callosum | 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) |
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