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

Primary Purpose

Brain Tumor Treated With Cranial or Cranial-Spinal Radiation

Status

Completed

Phase

Phase 3

Locations

Canada

Study Type

Interventional

Intervention

Metformin

Placebo

About this trial

This is an interventional treatment trial for Brain Tumor Treated With Cranial or Cranial-Spinal Radiation focused on measuring Paediatrics, Medulloblastoma, Metformin

Eligibility Criteria

5 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria: Survivors will be included if they:

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:
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.
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.
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

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 renal disease or renal dysfunction e.g., as suggested by elevated serum creatinine levels (see 5.a. Inclusion criteria) or abnormal creatinine clearance.
Have a history of congestive heart failure requiring pharmacologic treatment.
Have a known hypersensitivity to metformin hydrochloride.

Sites / Locations

The Hospital for Sick Children

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Group A (Crossover Group 1)

Group B (Crossover Group 2)

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Safety: Frequency of Adverse Events (AE)

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

Secondary Outcome Measures

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

For Arm AB: Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 1 (Week 13, post 12-week intervention) Change in Immediate Recall test from Baseline 2 (Week 23, post 10-week washout) at Outcome 2 (Week 35, post 2nd 12-week intervention) Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 2 (Week 35, post 2nd 12-week intervention) For Arm BA: Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 1 (Week 13) Change in Immediate Recall test from Baseline 2 (Week 23) at Outcome 2 (Week 35) Change in Immediate Recall test from Baseline 1 (Week 1) at Outcome 2 (Week 35)

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

For Arm AB: Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 1 (Week 13) Change in List Sort Working Memory Test from Baseline 2 (Week 23) at Outcome 2 (Week 35) Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 2 (Week 35) For Arm BA: Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 1 (Week 13) Change in List Sort Working Memory Test from Baseline 2 (Week 23) at Outcome 2 (Week 35) Change in List Sort Working Memory Test from Baseline 1 (Week 1) at Outcome 2 (Week 35)

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

Change in Mean Reaction Time (MRT) across the following CANTAB subtests: Rapid Visual Information Processing (RVP) Reaction Time (RT) Match to Sample Visual Search (MTS) 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: Change in MRT from Baseline 1 (Week 1) at Outcome 1 (Week 13) Change in MRT from Baseline 2 (Week 23) at Outcome 2 (Week 35) Change in MRT from Baseline 1 (Week 1) at Outcome 2 (Week 35) For Arm BA: Change in MRT from Baseline 1 (Week 1) at Outcome 1 (Week 13) Change in MRT from Baseline 2 (Week 23) at Outcome 2 (Week 35) Change in MRT from Baseline 1 (Week 1) at Outcome 2 (Week 35)

Full Information

NCT ID

NCT02040376

First Posted

January 7, 2014

Last Updated

September 7, 2022

Sponsor

The Hospital for Sick Children

1. Study Identification

Unique Protocol Identification Number

NCT02040376

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Completed

Study Start Date

June 13, 2014 (Actual)

Primary Completion Date

December 15, 2017 (Actual)

Study Completion Date

December 15, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

The Hospital for Sick Children

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Brain Tumor Treated With Cranial or Cranial-Spinal Radiation

Keywords

Paediatrics, Medulloblastoma, Metformin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group A (Crossover Group 1)

Arm Type

Experimental

Arm Description

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

Arm Title

Group B (Crossover Group 2)

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Metformin

Intervention Description

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

Intervention Name(s)

Placebo

Intervention Description

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.

Primary Outcome Measure Information:

Title

Feasibility: Medication Adherence

Description

Time Frame

Outcome 2 (Week 35)

Title

Safety: Frequency of Adverse Events (AE)

Description

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

Time Frame

Outcome 2 (Week 35)

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Other Pre-specified Outcome Measures:

Title

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

Description

Change in Axonal Water Fraction (AWF)- Diffusion Kurtosis Imaging (DKI) metric sensitive to myelin

Time Frame

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

Title

Neuroimaging: MRI Measures of Hippocampal Volume

Description

Change in Hippocampal Volume, as measured by Cerebral Blood Flow (CBF)

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

5 Years

Maximum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: Survivors will be included if they: 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) 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 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. 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 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 renal disease or renal dysfunction e.g., as suggested by elevated serum creatinine levels (see 5.a. Inclusion criteria) or abnormal creatinine clearance. Have a history of congestive heart failure requiring pharmacologic treatment. Have a known hypersensitivity to metformin hydrochloride.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Donald Mabbott, PhD

Organizational Affiliation

The Hospital for Sick Children

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Hospital for Sick Children

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 1X8

Country

Canada

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

32719487

Citation

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.

Results Reference

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

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