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Trial registered on ANZCTR


Registration number
ACTRN12622000045718
Ethics application status
Approved
Date submitted
7/12/2021
Date registered
17/01/2022
Date last updated
3/04/2024
Date data sharing statement initially provided
17/01/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
METMED: Metformin for cognitive and brain recovery in children treated for Medulloblastoma
Scientific title
Phase III randomized double-blind placebo-controlled trial of metformin for cognitive recovery and white matter growth in paediatric medulloblastoma patients
Secondary ID [1] 302877 0
NCT05230758
Secondary ID [2] 306695 0
ANZCHOG2101
Universal Trial Number (UTN)
Trial acronym
METMED
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Medulloblastoma 324553 0
Condition category
Condition code
Cancer 322022 322022 0 0
Children's - Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
For all participants in the treatment group, the intervention is as follows:
Week 1: 500mg/m^2 metformin hydrochloride tablet administered orally once per day
Weeks 2-16: 1000 mg/m^2 metformin hydrochloride tablet administered orally once per day
Doses will be rounded to increments of half tablets (250mg, 500mg, 750mg and 1000mg).
Pill counts will be conducted to calculate percent adherence to therapy based on the number of pills consumed vs. anticipated pill consumption.
Intervention code [1] 322349 0
Treatment: Drugs
Comparator / control treatment
A control group of medulloblastoma patients be administered a placebo tablet of similar appearance to the treatment group. The placebo group will follow the same dosage plan as the study group over the 16 weeks,
The composition of the placebo tablet is as follows:
Tablet Core - Cellulose microcrystalline, povidone, magnesium stearate,

Film Coating - hypromellose, polyethylene glycol, titanium dioxide
Control group
Placebo

Outcomes
Primary outcome [1] 329780 0
To examine whether there are significant improvements in the treatment group's test scores compared to the placebo group in the tests used to assess declarative memory (immediate recall from the Children's Auditory Verbal Learning Test and Rey Auditory Verbal Learning Test (CAVLT-2/RAVLT)
Timepoint [1] 329780 0
Baseline, at the end of 16 weeks treatment (primary endpoint), 6 months post-treatment completion
Primary outcome [2] 329954 0
To examine whether there are significant improvements in the treatment group's test scores compared to the placebo group in the tests used to assess working memory via the List Sorting Working Memory Test
Timepoint [2] 329954 0
Baseline, after 16 weeks treatment (primary endpoint), post 6 months treatment
Primary outcome [3] 329955 0
To examine whether there are significant improvements in the treatment group's test scores compared to the placebo group in the tests used to assess processing speed (mean reaction time for correct trials across the Cambridge Neuropsychological Test Automated Battery tests.
Timepoint [3] 329955 0
Baseline, after 16 weeks treatment (primary endpoint), post-6 months treatment
Secondary outcome [1] 403747 0
To examine the effectiveness of 16 weeks of treatment with metformin versus 16 weeks of placebo in white matter growth within the corpus callosum measured using Diffusion Kurtosis Imaging (DKI).
Timepoint [1] 403747 0
Baseline, at the end of the 16 weeks treatment, 6- months post-treatment completion

Eligibility
Key inclusion criteria
1. No less than 3 weeks after completion of primary therapy for medulloblastoma
2. Medically stable
3. Age 7 years to 17 years and 11 months at the time of enrolment
4. 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
5. Able to swallow tablets either whole, crushed or via a feeding tube and be willing to adhere to the study intervention regimen
6. Meet criteria for normal organ function requirements as described below:
a. 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/dL114,115
b. Normal liver function defined as:
• SGOT (AST) <1.5 institutional upper limit of normal (ULN) for age and gender
• SGPT (ALT) <1.5 institutional ULN for age and gender
• Total bilirubin <1.5 institutional ULN for age and gender
7. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to Screening and agreement to use such a method during study participation
8. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner during study participation
9. 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
Minimum age
84 Months
Maximum age
215 Months
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Unable to participate in MRI without sedation
2. Standard score of less than 60 for full scale IQ on the WASI-II (for English speaking participants) or pro-rated IQ score on the 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. Experienced aspiration pneumonias in the last year requiring hospitalization
7. Have acute or chronic metabolic acidosis and/or lactic acidosis over the lifespan, including a lactate level greater than 5 mmol/L at the Screening visit
8. Have a history of renal disease or renal dysfunction
9. Have a history of congestive heart failure (including the use of diuretics) requiring pharmacologic treatment within a two-year timespan prior to study entry
10. Taking part in a cognitive rehabilitation intervention study
11. Treatment or planned treatment involving diuretics
12. 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)
13. Current or planned treatment with concomitant medications with potential unacceptable interaction with metformin including topiramate, lamotrigine, levetiracetam, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, glycopyrrolate, and carbonic anhydrase inhibitors, or at the discretion of the delegated study physician for medications with potential interactions such as sertraline, lansoprazole and omeprazole.
14. Females who are pregnant, nursing, or planning a pregnancy during the study
15. Pernicious anemia (according to results of the Screening visit blood draw)
16. Current use of metformin hydrochloride
17. Any condition or diagnosis, that could in the opinion of the Principal Investigator 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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be randomized using Research Electronic Data Capture (REDCap) to ensure allocation concealment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to either metformin or placebo with a 1:1 allocation as per a computer generated randomization schedule using permuted 2-4 blocks of random sizes stratified for:
• Site
• Age: median age at Baseline assessment: less than or equal to 12 years 11 months versus greater than or equal to 13 years 0 months
• Biological sex
• Presence of residual complications: i.e., hydrocephalus requiring intervention, severe sensorineural hearing loss (a Chang autotoxicity grade of greater than or equal to 2dB), cranial nerve deficit, mutism, ataxia, dysmetria, dysdiadochokinesia
• Cranial-spinal radiation modality, dose and field: no radiation versus least intense (all proton doses and fields, photon reduced dose tumour bed boost [2400cGy]) versus most intense (photon reduced dose posterior fossa boost [2400cGy], photon standard dose [3600cGy] with tumour bed boost or posterior fossa boost)

The block sizes will not be disclosed. The randomization code will be held and maintained by the Research Support Pharmacy at the Hospital for Sick Children. The randomization code will not be released until the participant has been recruited and consented to the trial and after all Baseline measurements have been completed. Participants and families, as well as the health care and research teams will be blind to treatment assignment unless an emergency situation that requires unblinding occurs.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2023
Actual
7/03/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
120
Accrual to date
5
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA,VIC
Recruitment hospital [1] 21254 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [2] 21255 0
Monash Children’s Hospital - Clayton
Recruitment hospital [3] 21256 0
Perth Children's Hospital - Nedlands
Recruitment hospital [4] 21258 0
John Hunter Children's Hospital - New Lambton
Recruitment postcode(s) [1] 36127 0
3052 - Parkville
Recruitment postcode(s) [2] 36128 0
3168 - Clayton
Recruitment postcode(s) [3] 36129 0
6009 - Nedlands
Recruitment postcode(s) [4] 36131 0
2305 - New Lambton
Recruitment outside Australia
Country [1] 24364 0
New Zealand
State/province [1] 24364 0

Funding & Sponsors
Funding source category [1] 307294 0
Charities/Societies/Foundations
Name [1] 307294 0
Canadian Cancer Society
Country [1] 307294 0
Canada
Funding source category [2] 310300 0
Government body
Name [2] 310300 0
Canadian Institutes of Health Research
Country [2] 310300 0
Canada
Funding source category [3] 310301 0
Government body
Name [3] 310301 0
Australian Government
Country [3] 310301 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The Hospital for Sick Children (SickKids), Canada
Address
555 University Ave,
Toronto, ON M5G 1X8, Canada
Country
Canada
Secondary sponsor category [1] 311418 0
Other Collaborative groups
Name [1] 311418 0
Australian and New Zealand Children's Haematology/Oncology Group -ANZCHOG
Address [1] 311418 0
ANZCHOG
Hudson Institute of Medical Research
Level 6, TRF Building
27-31 Wright St, Clayton,
Victoria 3168
Country [1] 311418 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307391 0
The Royal Children’s Hospital Human Research Ethics Committee
Ethics committee address [1] 307391 0
Ethics committee country [1] 307391 0
Australia
Date submitted for ethics approval [1] 307391 0
03/08/2021
Approval date [1] 307391 0
16/11/2021
Ethics approval number [1] 307391 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 107070 0
Dr Donald Mabbott
Address 107070 0
The Hospital for Sick Children
555 University Ave,
Toronto, ON M5G 1X8, Canada
Country 107070 0
Canada
Phone 107070 0
+14168138875
Fax 107070 0
Email 107070 0
[email protected]
Contact person for public queries
Name 107071 0
Jordan Hansford
Address 107071 0
The Royal Children's Hospital Melbourne
50 Flemington Road
Parkville Victoria 3052 Australia
Country 107071 0
Australia
Phone 107071 0
+61393455522
Fax 107071 0
Email 107071 0
[email protected]
Contact person for scientific queries
Name 107072 0
Jordan Hansford
Address 107072 0
The Royal Children's Hospital Melbourne
50 Flemington Road
Parkville Victoria 3052 Australia
Country 107072 0
Australia
Phone 107072 0
+61393455522
Fax 107072 0
Email 107072 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.