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

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Brain Tumor Treated With Cranial or Cranial-Spinal Radiation

Intervention / Treatment
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* Drug: Metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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 | 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) | 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 | 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) | Baseline 1 (Week 1), Outcome 1 (Week 13), Baseline 2 (Week 23), and Outcome 2 (Week 35) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paediatrics, Medulloblastoma, Metformin