Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors

Study Overview
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Brief Summary
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Children with brain tumors who have had radiation therapy are at risk for problems with attention, memory, and problem solving. Such problems may cause difficulty in school and daily life. Memantine, the drug being used for this study, is not yet approved for use in children by the U.S. Food and Drug Administration. However, studies have shown some improvements in memory for patients with dementia, Attention Deficit Hyperactivity Disorder, and autism. Scientists have also used this medication for adult cancer patients receiving radiation therapy with results showing less cognitive declines over time compared to patients taking a placebo (inactive pill). These studies have also shown few side effects. This is a pilot/feasibility study and the first known study involving children with a cancer diagnosis or brain tumor. PRIMARY OBJECTIVES: To estimate the participation rate in a study of memantine used as a neuro-protective agent in children undergoing radiotherapy for localized brain tumors (low grade glioma, craniopharyngioma, ependymoma, or germ cell tumor) To estimate the rate of memantine medication adherence To estimate the rate of completion of cognitive assessments SECONDARY OBJECTIVES: To estimate the effect size of change in neurobehavioral outcomes (cognitive, social, quality of life, neurologic) associated with memantine To evaluate the frequency and nature of memantine side effects as measured by the Systematic Assessment for Treatment Emergent Events (SAFTEE)

Detailed Description
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Participants will be randomized to take part in one of two groups: The Memantine Group will be prescribed memantine at a dosage following FDA-approved adult labeling. A low dose will initially be given beginning at least two weeks (± 7 days) prior to beginning radiation therapy. The dose will increase until participants reach the target dose of 20 mg/day. Memantine will be given for a total of 12 weeks. The Placebo Group will be prescribed identical capsules with no active drug. The placebo drug will be given in the same dose and frequency as described for the Memantine group. Participants will undergo the same evaluations and monitoring throughout the medication phase. Assessments will be done at baseline prior to study start, with follow-up assessments at 6 weeks (end of radiation therapy), and 12 weeks (end of study medication). Psychological testing to measure attention, working memory, problem solving, intelligence and academics will be done for each participant. Caregivers will also complete questionnaires about attention, problem solving, mood and interpersonal interactions. Caregivers will also be asked to complete a questionnaire about the family's general characteristics and medical history. At the time points noted above, blood work, vital signs and echocardiograms will be obtained, and the study neurologist will examine the participant to monitor side effects and neurological functioning. A study nurse will contact the participant once per week during the 12 weeks of medication administration to identify possible medication-related side effects and to check on rate of compliance with taking the medication. A remote app will be installed on the participant's home computer or cell phone to help remind them to take the medication and track success. At one year post medication, psychological and neurological examinations will be repeated.

Official Title
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Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors: A Pilot Study

Conditions
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Glioma of Brain, Craniopharyngioma, Ependymoma, Germ Cell Tumor

Intervention / Treatment
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* Drug: Memantine
* Other: Placebo
* Other: Cognitive Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 6 years to 21 years at time of study enrollment Diagnosis of localized low grade glioma [e.g., pilocytic astrocytoma, optic pathway glioma, ogligodendroglioma, ganglioglioma, pleomorphic xanthoastrocytoma (PXA)], craniopharyngioma, ependymoma, or germ cell tumor Initiating focal cranial radiation therapy (photon or proton) Laboratory tests [transaminases (ALT, AST, ALP), BUN and creatinine not greater than twice normal] and normal ECG Speak, read and understand English sufficiently to complete study assessments Adequate vision and hearing for valid completion of study measures Negative βHCG pregnancy test among females of childbearing age Participant must be able to swallow pills (psychology staff will be available to assist with pill swallowing training if needed) Parent/Legal guardian available and able to speak, read and understand English Exclusion Criteria: Medical disorder that would endanger subject's well-being (e.g., uncorrected hypothyroidism, cardiac arrhythmia, hypertension requiring treatment, sick sinus syndrome, prolonged QTc) History of significant neurological disease including poorly controlled seizures (i.e., > 1 seizure per month; anti-epileptic medications are acceptable), stroke, or head injury with loss of consciousness Psychiatric condition that would preclude or take precedence over study participation (e.g., active psychosis, suicidal ideation) IQ below 70 based on baseline/screening assessment Treatment with psychotropic medication (psychostimulant, antidepressant, anxiolytic, antipsychotic) within the past two weeks, unless being prescribed specifically as an anti-emetic History of substance abuse History of hypersensitivity or reaction to NMDA receptor antagonists History of prior cranial radiation therapy

Ages Eligible for Study
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Minimum Age: 6 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled trial design.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Memantine<br>Beginning at least two weeks prior to radiation therapy, participants receive memantine. Treatment continues for 12 weeks with periodic cognitive assessments and lab work. | Drug: Memantine<br>* Medication dosing will be overseen by one of the study neurologists, with step-wise dose reductions (5 mg intervals) allowable in the case of side effects.<br>* Other names: Namenda®;Other: Cognitive Assessment<br>* Cognitive and neurologic examinations will be conducted to assess cognitive, social, quality of life, and neurological outcomes associated with memantine will be completed at baseline prior to medication start, and at 6 weeks (end of radiation therapy), 12 weeks (discontinuation of study medication or placebo), and one year post radiation therapy.<br>* Other names: Cognitive and neurologic examinations;|
| Placebo Comparator: Placebo<br>Beginning at least two weeks prior to radiation therapy, participants receive a placebo. Treatment and assessment are identical to the memantine group. | Other: Placebo<br>* A placebo that appears exactly like the study drug, memantine, will be given in a manner identical to the study drug.<br>* Other names: Look-alike drug;Other: Cognitive Assessment<br>* Cognitive and neurologic examinations will be conducted to assess cognitive, social, quality of life, and neurological outcomes associated with memantine will be completed at baseline prior to medication start, and at 6 weeks (end of radiation therapy), 12 weeks (discontinuation of study medication or placebo), and one year post radiation therapy.<br>* Other names: Cognitive and neurologic examinations;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of approached participants who consent to study participation | The rates of study participation and related 90% Blyth-Still-Casella intervals, as well as their regular 90% confidence interval, will be estimated. Test of one proportion will be performed against an estimated rate of 60%. The rate will be evaluated for the group as a whole as well as separately for the memantine intervention and placebo-control groups. | Once, prior to enrollment | 
| Percent of participants who complete all 12 weeks of memantine/placebo therapy | The rates of medication adherence and related 90% Blyth-Still-Casella intervals, as well as their regular 90% confidence interval, will be estimated. Test of one proportion will be performed against an estimated rate of 80%. The rate will be evaluated for the group as a whole as well as separately for the memantine intervention and placebo-control groups. | At completion of memantine/placebo therapy (12 weeks) | 
| Percent of participants who complete at least 3 of 4 cognitive assessments | The rates of completion of cognitive assessments and related 90% Blyth-Still-Casella intervals, as well as their regular 90% confidence interval, will be estimated. Test of one proportion will be performed against an estimated rate of 75%. The rate will be evaluated for the group as a whole as well as separately for the memantine intervention and placebo-control groups. | At end of study (up to one year after study enrollment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in neurobehavioral outcome | The effect size (Cohen's d- the standardized difference between two means) of memantine on neurobehavioral outcomes (cognitive, social, quality of life, neurologic) will be estimated by comparing performance at baseline to performance at 6 weeks (end of radiation therapy) using paired difference divided by its estimated standard deviation. In addition, due to the missing data, mixed-effects models will be fitted to investigate the change of outcome from baseline to 6 weeks. | At baseline (prior to start of therapy) compared at end of radiation therapy (6 weeks later) | 
| Change in neurobehavioral outcome | The effect size (Cohen's d- the standardized difference between two means) of memantine on neurobehavioral outcomes (cognitive, social, quality of life, neurologic) will be estimated by comparing performance at baseline to performance at 12 weeks (end of medication trial) using paired difference divided by its estimated standard deviation. In addition, due to the missing data, mixed-effects models will be fitted to investigate the change of outcome from baseline to 12 weeks. | At baseline (prior to start of therapy) compared at end of medication trial (12 weeks later) | 
| Change in neurobehavioral outcome | The effect size (Cohen's d- the standardized difference between two means) of memantine on neurobehavioral outcomes (cognitive, social, quality of life, neurologic) will be estimated by comparing performance at baseline to performance at follow-up (up to 1 year) using paired difference divided by its estimated standard deviation. In addition, due to the missing data, mixed-effects models will be fitted to investigate the change of outcome from baseline to 1 year. | At baseline (prior to start of therapy) compared at follow-up (up to 1 year later) | 
| Frequency of memantine side effects | The frequency and nature of memantine side effects as measured by the SAFTEE will be evaluated qualitatively by calculating the frequency of side effect reporting by severity rating at different time points in the medication trial and comparing these frequencies across the memantine intervention and placebo-control groups. The frequency of side effects will be compared between the intervention and placebo-control groups using at t-test or other appropriate test, depending on the data distribution features of the compared outcome. | From start of memantine/placebo therapy through end of therapy (up to 12 weeks later) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric oncology, Brain tumor, Low grade glioma, Cognitive late effects, Radiation therapy, Neuroprotection, Memantine