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Effetto della metformina sul comportamento e sul cervello nei bambini trattati per un tumore al cervello (Met Med Can)

21 settembre 2026 aggiornato da: Donald Mabbott

Studio di fase III randomizzato in doppio cieco controllato con placebo sulla metformina per il recupero cognitivo e la crescita della sostanza bianca nei pazienti pediatrici con medulloblastoma

The efficacy of treatment with metformin for promoting cognitive recovery and brain growth in children/adolescents treated for a brain tumour 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 21 years and 11 months who have completed treatment for a brain tumour, 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?

Panoramica dello studio

Stato

Reclutamento

Condizioni

Intervento / Trattamento

Descrizione dettagliata

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 brain tumours 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 paediatric medulloblastoma and other brain tumour survivors. If we find that metformin promotes cognitive improvement and brain growth in paediatric survivors of medulloblastoma and other paediatric brain tumours treated with cranial radiation, 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 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 a brain tumour at Post-Intervention (Week 17) compared to Baseline. 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. 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. 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. 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 and executive functioning, compared to 16 weeks of treatment with placebo at Post-Intervention (Week 17) compared to Baseline. Tests of attention and executive functioning 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 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.
  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.

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 21 years and 11 months - will be recruited from up to 20 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. 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.

Tipo di studio

Interventistico

Iscrizione (Stimato)

140

Fase

  • Fase 3

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Contatto studio

Luoghi di studio

  • Australia
    • New South Wales
      • New Lambton Heights, New South Wales, Australia, 2305
      • Westmead, New South Wales, Australia, 2145
        • Ritirato
        • Children's Hospital in Westmead
    • North Adelaide
      • Adelaide, North Adelaide, Australia, SA 5006
        • Reclutamento
        • Women and Childen's Hospital
        • Contatto:
          • Jordan Hansford, Ph.D.
    • Victoria
      • Clayton, Victoria, Australia, 3168
      • Parkville, Victoria, Australia, 3052
        • Reclutamento
        • Royal Children's Hospital
        • Contatto:
    • Western Australia
      • Nedlands, Western Australia, Australia, 6009
  • Canada
    • Alberta
    • British Columbia
      • Vancouver, British Columbia, Canada, V6H 3V4
        • Reclutamento
        • Children's & Women's Health Centre of British Columbia
        • Contatto:
        • Contatto:
          • Alecia Lim
          • Numero di telefono: 5262 604-875-2345
          • Email: CRA@cw.bc.ca
    • Manitoba
      • Winnipeg, Manitoba, Canada, R3E 0V9
    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3K 6R8
        • Reclutamento
        • Izaak Walton Killam (IWK) Health Centre
        • Contatto:
        • Contatto:
          • Jennifer Curran
          • Numero di telefono: 902-470-8048
    • Ontario
      • Hamilton, Ontario, Canada, L8S 4K1
        • Reclutamento
        • Hamilton Health Sciences - McMaster Children's Hospital
        • Contatto:
      • London, Ontario, Canada, N6A 5W9
        • Reclutamento
        • Children's Hospital, London Health Sciences Centre
        • Contatto:
      • Ottawa, Ontario, Canada, K1H 8L1
        • Reclutamento
        • Children's Hospital of Eastern Ontario
        • Contatto:
      • Toronto, Ontario, Canada, M5G 1X8
    • Quebec
    • Saskatchewan

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

Da 7 anni a 21 anni (Bambino, Adulto)

Accetta volontari sani

No

Sessi ammissibili allo studio

Tutto

Descrizione

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:

      1. medulloblastoma

        OR

      2. ependymoma

        OR

      3. craniopharyngioma

        OR

      4. germ cell tumours

        OR

    • Primary therapy for any other brain tumour treated with cranial radiation - at the discretion of the Study PI

    OR

    • Cranial radiation for relapsed ependymoma

  2. Age 7 years to 21 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. Standard score of less than 60 for full scale IQ on the Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II) (or other Wechsler Scale of Intelligence for English speaking participants) or pro-rated IQ score on the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) or Wechsler Adult Intelligence Scale (WAIS-IV) for French speaking participants at Screening visit
  2. Have a known hypersensitivity to metformin hydrochloride
  3. Have unstable and/or insulin-dependent (Type 1) diabetes
  4. Have a history of hypoglycemia after 2 years of age
  5. 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
  6. Have a history of renal disease or renal dysfunction pre-existing to the diagnosis of Medulloblastoma
  7. Have a history of congestive heart failure requiring pharmacologic treatment (including the use of diuretics) within two years prior to study entry
  8. Currently taking part in a cognitive rehabilitation intervention study
  9. Treatment or planned treatment involving diuretics
  10. 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)
  11. 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.
  12. Pernicious anemia (according to results of the Screening visit blood draw)
  13. Current use of metformin hydrochloride
  14. 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
  15. Are receiving palliative care

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Terapia di supporto
  • Assegnazione: Randomizzato
  • Modello interventistico: Assegnazione parallela
  • Mascheramento: Quadruplicare

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Sperimentale: 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).
Droga: Metformin hydrochloride (HCl) 500mg tablet

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.

Altri nomi:
  • Glucofago
Comparatore placebo: 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).
Droga: Placebo

Matching white round tablet containing excipients only. The placebo tablets will match the active drug as closely as possible in terms of appearance.

Altri nomi:
  • Controllo

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
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
Lasso di tempo: 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)
Change from Week 1 (Baseline) NIH Toolbox List Sort Working Working Memory Test at Week 17 (Post-Intervention) to Assess Working Memory
Lasso di tempo: 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)
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
Lasso di tempo: 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:

  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)

Misure di risultato secondarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Diffusion Kurtosis Imaging (DKI) to Assess White Matter Growth within the Corpus Callosum
Lasso di tempo: 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.

This secondary outcome measure (MRI scan) was made optional to participants enrolled after April 2024.
Week 1 (Baseline), Week 17 (Post-Intervention)

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

Donald Mabbott

Investigatori

  • Cattedra di studio: Donald Mabbott, Ph.D., The Hospital for Sick Children
  • Investigatore principale: Eric Bouffet, M.D., The Hospital for Sick Children

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio (Effettivo)

1 luglio 2022

Completamento primario (Stimato)

30 novembre 2027

Completamento dello studio (Stimato)

30 novembre 2027

Date di iscrizione allo studio

Primo inviato

12 gennaio 2022

Primo inviato che soddisfa i criteri di controllo qualità

28 gennaio 2022

Primo Inserito (Effettivo)

9 febbraio 2022

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Effettivo)

24 settembre 2026

Ultimo aggiornamento inviato che soddisfa i criteri QC

21 settembre 2026

Ultimo verificato

1 settembre 2026

Maggiori informazioni

Termini relativi a questo studio

Parole chiave

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • 1000073107

Piano per i dati dei singoli partecipanti (IPD)

Hai intenzione di condividere i dati dei singoli partecipanti (IPD)?

NO

Informazioni su farmaci e dispositivi, documenti di studio

Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti

No

Studia un dispositivo regolamentato dalla FDA degli Stati Uniti

No

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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