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Effect of Metformin on Behaviour and the Brain in Children Treated for a Brain Tumour
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?.
Study details:
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. 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 (Week 1).
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 (Week 1).
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, 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. 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 (Week 1)/ screening (Day 0) 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 (Week 1). 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 (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.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
Exclusion criteria
Eligibility
Age eligible for study : 7 and older
Healthy volunteers accepted : No
Gender eligible for study: All
Things to know
Study dates
Study start: 2022-07-01
Primary completion: 2027-06-30
Study completion finish: 2027-06-30
Study type
SUPPORTIVE_CARE
Phase
PHASE3
Trial ID
NCT05230758
Intervention or treatment
DRUG: Metformin hydrochloride (HCl) 500mg tablet
DRUG: Placebo
Conditions
- • Cognitive Impairment
- • Medulloblastoma, Childhood
Find a site
Closest Location:
John Hunter Children's Hospital
Research sites nearby
Select from list below to view details:
John Hunter Children's Hospital
New Lambton Heights, New South Wales, Australia
Monash Children's Hospital
Clayton, Victoria, Australia
Royal Children's Hospital
Parkville, Victoria, Australia
Children's Hospital in Westmead
Westmead, New South Wales, Australia
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: Metformin
| DRUG: Metformin hydrochloride (HCl) 500mg tablet
|
PLACEBO_COMPARATOR: Placebo
| DRUG: Placebo
|
What is the study measuring?
Primary outcome
| Primary Outcome Measure | Primary Outcome Description | Primary Outcome 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 | 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 outcome
| Secondary Outcome Measure | Secondary Outcome Description | Secondary Outcome Time Frame |
|---|---|---|
| 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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