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

July 11, 2025 updated by: Donald Mabbott, The Hospital for Sick Children

Placebo Controlled Double Blind Crossover Trial of Metformin for Brain Repair in Children With Cranial-Spinal Radiation for Medulloblastoma

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

We conducted a pilot randomized, double-blind, placebo-controlled trial with crossover in survivors of pediatric brain tumors with primary endpoints of safety and feasibility and secondary endpoints of cognitive and magnetic resonance imaging (MRI) measures. Twenty-four participants were enrolled and randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either a group AB (AB) or group BA (BA) sequence. At the point of crossover, there was a 10-week washout period in which neither group received any treatment. During the first week of each treatment cycle, a daily dose of 500 mg/m2 of metformin or placebo was administered orally. The dose was increased to 1000mg/m2 daily beginning in the second week and continuing for the remainder of the 12-week cycle.

Test procedures (Clinical & current medications reviews, Blood draws, and MRI and Cognitive testing) were performed at 4 times points during the study: 1. at study entry (Baseline 1), 2. after 12 weeks of treatment (Outcome 1), 3. after a 10-week washout period at 22 weeks (Baseline 2), and 4. At the end of the trial at 34 weeks (Outcome 2).

Study Type

Interventional

Enrollment (Actual)

24

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 1X8
        • The Hospital for Sick Children

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

5 years to 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

Inclusion criteria: Survivors will be included if they:

  1. Have been treated with cranial or cranial-spinal radiation,
  2. Are between 5 and 21 years of age at time of consent, and
  3. 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.
  4. 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.

  5. Meet criteria for adequate organ function requirements:

    1. 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)

      5 to < 10 years: Male = 1; Female = 1

      10 to < 13 years: Male = 1.2; Female = 1.2

      13 to < 16 years: Male = 1.5; Female = 1.4

      ≥ 16 years: Male = 1.7; Female = 1.4

    2. 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.

  6. 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.
  7. Informed consent will be obtained from the participants and/or their legal guardians by study team members authorized to consent for this study.

Exclusion criteria: Survivors will be excluded if they

  1. Are receiving palliative care.
  2. Are unable to participate in neuro-imaging without sedation as this is the primary outcome measure for the trial.
  3. Are unable to swallow tablets.
  4. Are unstable and/or insulin-dependent (Type 1) diabetic patients.
  5. Have acute or chronic metabolic acidosis and/or lactic acidosis.
  6. Any female patient or partner who has reached menarche and male patients who are not willing to use an effective method of contraception.
  7. Patient who is pregnant or lactating and does not agree to stop breastfeeding while receiving trial treatment.
  8. Have a history of renal disease or renal dysfunction e.g., as suggested by elevated serum creatinine levels (see 5.a. Inclusion criteria) or abnormal creatinine clearance.
  9. Have a history of congestive heart failure requiring pharmacologic treatment.
  10. Have a known hypersensitivity to metformin hydrochloride.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Group A (Crossover Group 1)
Subjects assigned to this arm will receive metformin first, followed by a washout period and then placebo.
Drug: Metformin
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.
Drug: Placebo
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.
Experimental: Group B (Crossover Group 2)
Subjects assigned to this arm will receive placebo first, followed by a washout period and then metformin.
Drug: Metformin
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.
Drug: Placebo
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Feasibility: Medication Adherence
Time Frame: Outcome 2 (Week 35)

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)
Time Frame: Outcome 2 (Week 35)
The frequency of all AEs experienced during metformin and placebo treatment for all participants.
Outcome 2 (Week 35)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cognitive Testing: Declarative Memory - Change in Children's Auditory Verbal Learning Test -2 (CAVLT-2)
Time Frame: Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35)

For Arm AB:

  1. Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 1 (Week 13, post 12-week intervention)
  2. Change in Immediate Recall test from Baseline 2 (Week 23, post 10-week washout) at Outcome 2 (Week 35, post 2nd 12-week intervention)
  3. Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 2 (Week 35, post 2nd 12-week intervention)

For Arm BA:

  1. Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 1 (Week 13)
  2. Change in Immediate Recall test from Baseline 2 (Week 23) at Outcome 2 (Week 35)
  3. Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 2 (Week 35)
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
Time Frame: Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), Outcome 2 (Week 35)

For Arm AB:

  1. Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 1 (Week 13)
  2. Change in List Sort Working Memory Test from Baseline 2 (Week 23) at Outcome 2 (Week 35)
  3. Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 2 (Week 35)

For Arm BA:

  1. Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 1 (Week 13)
  2. Change in List Sort Working Memory Test from Baseline 2 (Week 23) at Outcome 2 (Week 35)
  3. Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 2 (Week 35)
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
Time Frame: Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35)

Change in Mean Reaction Time (MRT) across the following CANTAB subtests:

  1. Rapid Visual Information Processing (RVP)
  2. Reaction Time (RT)
  3. Match to Sample Visual Search (MTS)
  4. Delayed Matching in 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.

For Arm AB:

  1. Change in MRT from Baseline 1 (Week 1) at Outcome 1 (Week 13)
  2. Change in MRT from Baseline 2 (Week 23) at Outcome 2 (Week 35)
  3. Change in MRT from Baseline 1 (Week 1) at Outcome 2 (Week 35)

For Arm BA:

  1. Change in MRT from Baseline 1 (Week 1) at Outcome 1 (Week 13)
  2. Change in MRT from Baseline 2 (Week 23) at Outcome 2 (Week 35)
  3. Change in MRT from Baseline 1 (Week 1) at Outcome 2 (Week 35)
Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neuroimaging: MRI Measures of White Matter Growth within the Corpus Callosum
Time Frame: Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35)
Change in Axonal Water Fraction (AWF)- Diffusion Kurtosis Imaging (DKI) metric sensitive to myelin
Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35)
Neuroimaging: MRI Measures of Hippocampal Volume
Time Frame: Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35
Change in Hippocampal Volume, as measured by Cerebral Blood Flow (CBF)
Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Hospital for Sick Children

Investigators

  • Principal Investigator: Donald Mabbott, PhD, The Hospital for Sick Children

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 13, 2014

Primary Completion (Actual)

December 15, 2017

Study Completion (Actual)

December 15, 2017

Study Registration Dates

First Submitted

January 7, 2014

First Submitted That Met QC Criteria

January 15, 2014

First Posted (Estimated)

January 20, 2014

Study Record Updates

Last Update Posted (Actual)

July 16, 2025

Last Update Submitted That Met QC Criteria

July 11, 2025

Last Verified

July 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1000039383

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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