Metformin for Brain Repair in Children With Cranial-Spinal Radiation for Medulloblastoma

NCT02040376 | Completed Phase 3

• 1 other identifier: 1000039383
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

A placebo controlled double blind crossover trial of metformin in 30 children treated with radiation for medulloblastoma - the most common malignant brain tumour. The investigators used tests of thinking and learning and brain imaging techniques to examine whether metformin can enhance cognition or promote brain repair following radiation-induced brain injury.

Conditions

Brain Tumor Treated With Cranial or Cranial-Spinal Radiation

Keywords

Paediatrics; Medulloblastoma; Metformin

Outcome Measures

Primary Outcomes (2)

• Feasibility: Medication Adherence

  Participant's adherence to taking study medication (Metformin or Placebo) as instructed based on dosing nomogram, for the whole study. % Medication adherence = (Number of tablets actually consumed / Number of tablets expected to be consumed)\*100 Number of tablets actually consumed is based on compliance counts conducted at the end of the study.

  Outcome 2 (Week 35)

• Safety: Frequency of Adverse Events (AE)

  The frequency of all AEs experienced during metformin and placebo treatment for all participants.

  Outcome 2 (Week 35)

Secondary Outcomes (3)

• Cognitive Testing: Declarative Memory - Change in Children's Auditory Verbal Learning Test -2 (CAVLT-2)

  Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35)

• Cognitive Testing: Working Memory - Change in List Sort Working Memory Subtest of the NIH Toolbox Cognition Battery

  Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), Outcome 2 (Week 35)

• Cognitive Testing: Processing Speed - Change in Mean Reaction Time across Cambridge Neuropsychological Test Automated Battery (CANTAB) subtests

  Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35)

Other Outcomes (2)

• Neuroimaging: MRI Measures of White Matter Growth within the Corpus Callosum

  Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35)

• Neuroimaging: MRI Measures of Hippocampal Volume

  Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35

Study Arms (2)

Group A (Crossover Group 1)

EXPERIMENTAL

Subjects assigned to this arm will receive metformin first, followed by a washout period and then placebo.

Drug: Metformin; Drug: Placebo

Group B (Crossover Group 2)

EXPERIMENTAL

Subjects assigned to this arm will receive placebo first, followed by a washout period and then metformin.

Drug: Metformin; Drug: Placebo

Interventions

Metformin DRUG

Metformin doses will be 500 mg/m2 po daily given in 2 doses for one week and if there are no concerns increased to 1000 mg/m2 po daily given in 2 doses for the rest of the 12 week trial. The investigators will use the closest dose according to body surface area (250-500-750-1000) BID.

Group A (Crossover Group 1); Group B (Crossover Group 2)

Placebo DRUG

Placebo doses will be 500 mg/m2 po daily given in 2 doses for one week and if there are no concerns increased to 1000 mg/m2 po daily given in 2 doses for the rest of the 12 week trial. The investigators will use the closest dose according to body surface area (250-500-750-1000) BID.

Group A (Crossover Group 1); Group B (Crossover Group 2)

Eligibility Criteria

• Age: 5 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Have been treated with cranial or cranial-spinal radiation,
• Are between 5 and 21 years of age at time of consent, and
• Either declare English as their native language or have had at least two years of schooling in English at the time of their baseline assessment.
• Have been diagnosed with a brain tumour requiring treatment with cranial or cranial-spinal radiation at least 2 years ago, is not receiving active treatment and no more than 15 years may have elapsed between treatment with cranial-spinal radiation and time of the trial. Survivors with a shunt will be included in the trial, but will need to be identified prior to study enrollment to discuss any specific considerations for imaging.
• Meet criteria for adequate organ function requirements:
• Adequate renal function defined as: Creatinine clearance or radioisotope glomerular filtration rate (GFR) \> 70ml/min/1.73 m2 or serum creatinine based on age/gender as follows:
• Maximum Serum Creatinine Level (mg/dL)
• to \< 10 years: Male = 1; Female = 1
• to \< 13 years: Male = 1.2; Female = 1.2
• to \< 16 years: Male = 1.5; Female = 1.4
• ≥ 16 years: Male = 1.7; Female = 1.4
• Adequate liver function defined as:
• Total bilirubin \< 1.5 x upper limit of normal (ULN) for age, and,
• serum glutamate oxaloacetate transaminase (SGOT) (AST) or serum glutamate pyruvate transaminase (SGPT) (ALT) \< 3 x upper limit of normal (ULN) for age.
• Females of childbearing potential must have a negative pregnancy test result and must agree to use a medically acceptable method of contraception throughout the entire study period and for 30 days after the last dose of study drug.

You may not qualify if:

• Are receiving palliative care.
• Are unable to participate in neuro-imaging without sedation as this is the primary outcome measure for the trial.
• Are unable to swallow tablets.
• Are unstable and/or insulin-dependent (Type 1) diabetic patients.
• Have acute or chronic metabolic acidosis and/or lactic acidosis.
• Any female patient or partner who has reached menarche and male patients who are not willing to use an effective method of contraception.
• Patient who is pregnant or lactating and does not agree to stop breastfeeding while receiving trial treatment.
• Have a history of congestive heart failure requiring pharmacologic treatment.
• Have a known hypersensitivity to metformin hydrochloride.

Sponsors & Collaborators

• The Hospital for Sick Children: lead

Study Sites (1)

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (1)

• Ayoub R, Ruddy RM, Cox E, Oyefiade A, Derkach D, Laughlin S, Ades-Aron B, Shirzadi Z, Fieremans E, MacIntosh BJ, de Medeiros CB, Skocic J, Bouffet E, Miller FD, Morshead CM, Mabbott DJ. Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin. Nat Med. 2020 Aug;26(8):1285-1294. doi: 10.1038/s41591-020-0985-2. Epub 2020 Jul 27.

  PMID: 32719487 BACKGROUND

MeSH Terms

Conditions

Medulloblastoma

Interventions

Metformin

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors, Primitive; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Donald Mabbott, PhD

  The Hospital for Sick Children

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Psychologist

Study Record Dates

• First Submitted: January 7, 2014
• First Posted: January 20, 2014
• Study Start: June 13, 2014
• Primary Completion: December 15, 2017
• Study Completion: December 15, 2017
• Last Updated: July 16, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)