Clinical trial NCT05230758: Effect of Metformin on Behaviour and the Brain in Children Treated for a Brain Tumour
Official title: Phase III Randomized Double-blind Placebo-controlled Trial of Metformin for Cognitive Recovery and White Matter Growth in Paediatric Medulloblastoma Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Medulloblastoma, Childhood
Cognitive Impairment
Keywords: Metformin
Paediatric brain tumour
Memory
Cognitive late effects
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
First posted: 2022-02-09
Enrollment: 140
Sex: ALL
Minimum age (years): 7
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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?

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.

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: 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 20 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, for those patients who do not opt out of the optional MRI part of the study
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 pre-existing to the diagnosis of Medulloblastoma
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

Primary outcomes:
measure: 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
timeFrame: Week 1 (Baseline), Week 17 (Post-Intervention)
measure: Change from Week 1 (Baseline) NIH Toolbox List Sort Working Working Memory Test at Week 17 (Post-Intervention) to Assess Working Memory
timeFrame: Week 1 (Baseline), Week 17 (Post-Intervention)
measure: 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
timeFrame: Week 1 (Baseline), Week 17 (Post-Intervention)
Secondary outcomes:
measure: Diffusion Kurtosis Imaging (DKI) to Assess White Matter Growth within the Corpus Callosum
timeFrame: Week 1 (Baseline), Week 17 (Post-Intervention)
Other outcomes:
Locations:
city: New Lambton Heights
country: Australia
facility: John Hunter Children's Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Children's Hospital in Westmead
state: New South Wales
city: Clayton
country: Australia
facility: Monash Children's Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Perth Children's Hospital
state: West Australia
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Children's & Women's Health Centre of British Columbia
state: British Columbia
city: Winnipeg
country: Canada
facility: Cancer Care Manitoba
state: Manitoba
city: Halifax
country: Canada
facility: Izaak Walton Killam (IWK) Health Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences - McMaster Children's Hospital
state: Ontario
city: London
country: Canada
facility: Children's Hospital, London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Montréal
country: Canada
facility: CHU Sainte-Justine
state: Quebec
city: Montréal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Quebec City
country: Canada
facility: CHU de Québec - Université Laval
state: Quebec
city: Sherbrooke
country: Canada
facility: CHU de Sherbrooke
state: Quebec
city: Saskatoon
country: Canada
facility: Saskatchewan Health Authority
state: Saskatchewan
Study officials:
affiliation: The Hospital for Sick Children
name: Donald Mabbott, Ph.D.
role: STUDY_CHAIR
affiliation: The Hospital for Sick Children
name: Eric Bouffet, M.D.
role: PRINCIPAL_INVESTIGATOR
References: