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

NCT ID: NCT02040376

Last Updated: 2025-07-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-06-13
• Study Completion Date: 2017-12-15

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.

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).

Conditions

Brain Tumor Treated With Cranial or Cranial-Spinal Radiation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Group A (Crossover Group 1)

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

Group Type: EXPERIMENTAL

Metformin

Intervention Type: 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.

Placebo

Intervention Type: 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 B (Crossover Group 2)

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

Group Type: EXPERIMENTAL

Metformin

Intervention Type: 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.

Placebo

Intervention Type: 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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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.

9. Have a history of congestive heart failure requiring pharmacologic treatment.

10. Have a known hypersensitivity to metformin hydrochloride.

Exclusion Criteria

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.

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Hospital for Sick Children

OTHER

Sponsor Role: lead

Responsible Party

Donald Mabbott

Psychologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Donald Mabbott, PhD

Role: PRINCIPAL_INVESTIGATOR

The Hospital for Sick Children

Locations

The Hospital for Sick Children

Toronto, Ontario, Canada

Countries

Canada

References

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.

Reference Type: BACKGROUND

PMID: 32719487 (View on PubMed)

Other Identifiers

1000039383

Identifier Type: -

Identifier Source: org_study_id