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Metformiinin vaikutus aivokasvaimen vuoksi hoidettujen lasten käyttäytymiseen ja aivoihin (Met Med Can)

maanantai 21. syyskuuta 2026 päivittänyt: Donald Mabbott

Vaiheen III satunnaistettu kaksoissokko lumelääkekontrolloitu koe metformiinilla kognitiivisen toipumisen ja valkoisen aineen kasvun parantamiseksi medulloblastoomapotilaiden lapsilla

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?

Tutkimuksen yleiskatsaus

Tila

Rekrytointi

Ehdot

Interventio / Hoito

Yksityiskohtainen kuvaus

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.

Opintotyyppi

Interventio

Ilmoittautuminen (Arvioitu)

140

Vaihe

  • Vaihe 3

Yhteystiedot ja paikat

Tässä osiossa on tutkimuksen suorittajien yhteystiedot ja tiedot siitä, missä tämä tutkimus suoritetaan.

Opiskeluyhteys

Opiskelupaikat

  • Australia
    • New South Wales
      • New Lambton Heights, New South Wales, Australia, 2305
        • Rekrytointi
        • John Hunter Children's Hospital
        • Ottaa yhteyttä:
      • Westmead, New South Wales, Australia, 2145
        • Peruutettu
        • Children's Hospital in Westmead
    • North Adelaide
      • Adelaide, North Adelaide, Australia, SA 5006
        • Rekrytointi
        • Women and Childen's Hospital
        • Ottaa yhteyttä:
          • Jordan Hansford, Ph.D.
    • Victoria
      • Clayton, Victoria, Australia, 3168
        • Rekrytointi
        • Monash Children's Hospital
        • Ottaa yhteyttä:
      • Parkville, Victoria, Australia, 3052
        • Rekrytointi
        • Royal Children's Hospital
        • Ottaa yhteyttä:
    • Western Australia
      • Nedlands, Western Australia, Australia, 6009
        • Rekrytointi
        • Perth Children's Hospital
        • Ottaa yhteyttä:
  • Kanada
    • Alberta
    • British Columbia
      • Vancouver, British Columbia, Kanada, V6H 3V4
        • Rekrytointi
        • Children's & Women's Health Centre of British Columbia
        • Ottaa yhteyttä:
        • Ottaa yhteyttä:
          • Alecia Lim
          • Puhelinnumero: 5262 604-875-2345
          • Sähköposti: CRA@cw.bc.ca
    • Manitoba
      • Winnipeg, Manitoba, Kanada, R3E 0V9
        • Rekrytointi
        • Cancer Care Manitoba
        • Ottaa yhteyttä:
        • Ottaa yhteyttä:
    • Nova Scotia
      • Halifax, Nova Scotia, Kanada, B3K 6R8
        • Rekrytointi
        • Izaak Walton Killam (IWK) Health Centre
        • Ottaa yhteyttä:
        • Ottaa yhteyttä:
          • Jennifer Curran
          • Puhelinnumero: 902-470-8048
    • Ontario
      • Hamilton, Ontario, Kanada, L8S 4K1
        • Rekrytointi
        • Hamilton Health Sciences - McMaster Children's Hospital
        • Ottaa yhteyttä:
      • London, Ontario, Kanada, N6A 5W9
        • Rekrytointi
        • Children's Hospital, London Health Sciences Centre
        • Ottaa yhteyttä:
      • Ottawa, Ontario, Kanada, K1H 8L1
        • Rekrytointi
        • Children's Hospital of Eastern Ontario
        • Ottaa yhteyttä:
      • Toronto, Ontario, Kanada, M5G 1X8
    • Quebec
      • Montreal, Quebec, Kanada, H3T 1C5
        • Rekrytointi
        • CHU Sainte-Justine
        • Ottaa yhteyttä:
      • Montreal, Quebec, Kanada, H4A 3J1
        • Rekrytointi
        • Montreal Children's Hospital
        • Ottaa yhteyttä:
      • Québec, Quebec, Kanada, G1V 4G2
      • Sherbrooke, Quebec, Kanada, J1G 2E8
    • Saskatchewan

Osallistumiskriteerit

Tutkijat etsivät ihmisiä, jotka sopivat tiettyyn kuvaukseen, jota kutsutaan kelpoisuuskriteereiksi. Joitakin esimerkkejä näistä kriteereistä ovat henkilön yleinen terveydentila tai aiemmat hoidot.

Kelpoisuusvaatimukset

Opintokelpoiset iät

7 vuotta - 21 vuotta (Lapsi, Aikuinen)

Hyväksyy terveitä vapaaehtoisia

Ei

Sukupuolet, jotka voivat opiskella

Kaikki

Kuvaus

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

Opintosuunnitelma

Tässä osiossa on tietoja tutkimussuunnitelmasta, mukaan lukien kuinka tutkimus on suunniteltu ja mitä tutkimuksella mitataan.

Miten tutkimus on suunniteltu?

Suunnittelun yksityiskohdat

  • Ensisijainen käyttötarkoitus: Tukevaa hoitoa
  • Jako: Satunnaistettu
  • Inventiomalli: Rinnakkaistehtävä
  • Naamiointi: Nelinkertaistaa

Aseet ja interventiot

Osallistujaryhmä / Arm
Interventio / Hoito
Kokeellinen: 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).
Lääke: 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.

Muut nimet:
  • Glucophage
Placebo Comparator: 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).
Lääke: Placebo

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

Muut nimet:
  • Ohjaus

Mitä tutkimuksessa mitataan?

Ensisijaiset tulostoimenpiteet

Tulosmittaus
Toimenpiteen kuvaus
Aikaikkuna
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
Aikaikkuna: 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
Aikaikkuna: 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
Aikaikkuna: 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)

Toissijaiset tulostoimenpiteet

Tulosmittaus
Toimenpiteen kuvaus
Aikaikkuna
Diffusion Kurtosis Imaging (DKI) to Assess White Matter Growth within the Corpus Callosum
Aikaikkuna: 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)

Yhteistyökumppanit ja tutkijat

Täältä löydät tähän tutkimukseen osallistuvat ihmiset ja organisaatiot.

Sponsori

Donald Mabbott

Tutkijat

  • Opintojen puheenjohtaja: Donald Mabbott, Ph.D., The Hospital for Sick Children
  • Päätutkija: Eric Bouffet, M.D., The Hospital for Sick Children

Opintojen ennätyspäivät

Nämä päivämäärät seuraavat ClinicalTrials.gov-sivustolle lähetettyjen tutkimustietueiden ja yhteenvetojen edistymistä. National Library of Medicine (NLM) tarkistaa tutkimustiedot ja raportoidut tulokset varmistaakseen, että ne täyttävät tietyt laadunvalvontastandardit, ennen kuin ne julkaistaan ​​julkisella verkkosivustolla.

Opi tärkeimmät päivämäärät

Opiskelun aloitus (Todellinen)

Perjantai 1. heinäkuuta 2022

Ensisijainen valmistuminen (Arvioitu)

Tiistai 30. marraskuuta 2027

Opintojen valmistuminen (Arvioitu)

Tiistai 30. marraskuuta 2027

Opintoihin ilmoittautumispäivät

Ensimmäinen lähetetty

Keskiviikko 12. tammikuuta 2022

Ensimmäinen toimitettu, joka täytti QC-kriteerit

Perjantai 28. tammikuuta 2022

Ensimmäinen Lähetetty (Todellinen)

Keskiviikko 9. helmikuuta 2022

Tutkimustietojen päivitykset

Viimeisin päivitys julkaistu (Todellinen)

Torstai 24. syyskuuta 2026

Viimeisin lähetetty päivitys, joka täytti QC-kriteerit

Maanantai 21. syyskuuta 2026

Viimeksi vahvistettu

Tiistai 1. syyskuuta 2026

Lisää tietoa

Tähän tutkimukseen liittyvät termit

Avainsanat

Muita asiaankuuluvia MeSH-ehtoja

Muut tutkimustunnusnumerot

  • 1000073107

Yksittäisten osallistujien tietojen suunnitelma (IPD)

Aiotko jakaa yksittäisten osallistujien tietoja (IPD)?

EI

Lääke- ja laitetiedot, tutkimusasiakirjat

Tutkii yhdysvaltalaista FDA sääntelemää lääkevalmistetta

Ei

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Ei

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