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

Phase 3

Completed

• Conditions: Brain Tumor Treated with Cranial or Cranial-Spinal Radiation
• Interventions: Drug: Metformin; Drug: Placebo

• Registration Number: NCT02040376
• Lead Sponsor: The Hospital for Sick Children

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).

Study Timeline

• Study First Submitted: 2014-01-07
• Study First Submitted QC: 2014-01-15
• Study First Posted: 2014-01-20
• Study Start: 2014-06-13
• Primary Completion: 2017-12-15
• Study Completion: 2017-12-15
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-27
• Last Update Posted: 2025-01-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Group B (Crossover Group 2)	Metformin	Subjects assigned to this arm will receive placebo first, followed by a washout period and then metformin.
Group A (Crossover Group 1)	Placebo	Subjects assigned to this arm will receive metformin first, followed by a washout period and then placebo.
Group A (Crossover Group 1)	Metformin	Subjects assigned to this arm will receive metformin first, followed by a washout period and then placebo.
Group B (Crossover Group 2)	Placebo	Subjects assigned to this arm will receive placebo first, followed by a washout period and then metformin.

Primary Outcome Measures

Name	Time	Method
Safety: Frequency of Adverse Events (AE)	Outcome 2 (Week 35)	The frequency of all AEs experienced during metformin and placebo treatment for all participants.
Feasibility: Medication Adherence	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.

Secondary Outcome Measures

Name	Time	Method
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)	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)
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)	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)
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)	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)

Trial Locations

Locations (1)

The Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada