Craniopharyngioma, Ependymoma, Germ Cell Tumor, Glioma of Brain
Conditions
Keywords
Pediatric oncology, Brain tumor, Low grade glioma, Cognitive late effects, Radiation therapy, Neuroprotection, Memantine
Brief summary
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
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.
Interventions
DRUGMemantine
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.
OTHERPlacebo
A placebo that appears exactly like the study drug, memantine, will be given in a manner identical to the study drug.
OTHERCognitive Assessment
Cognitive and neurologic examinations will be conducted to assess cognitive, social, quality of life, and neurological outcomes associated with memantine at baseline prior to medication start, 6 weeks (end of radiation therapy), 12 weeks (discontinuation of study medication or placebo), and one year post radiation therapy.
Sponsors
St. Jude Children's Research Hospital
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized, double-blind, placebo-controlled trial design.
Eligibility
Sex/Gender
ALL
Age
6 Years to 21 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Approached Participants Who Consent to Study Participation | Once, prior to enrollment | 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. |
| Percent of Participants Who Complete All 12 Weeks of Memantine/Placebo Therapy | At completion of memantine/placebo therapy (12 weeks) | 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. |
| Percent of Participants Who Complete at Least 3 of 4 Cognitive Assessments | At end of study (up to one year after study enrollment) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Neurobehavioral Outcome | At baseline (prior to start of therapy) compared at end of radiation therapy (6 weeks later) | 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. Cogstate Identification Reaction Time z-score (Identification RT Z) is an estimate of attention choice speed, with a mean of 0 and lower scores indicating faster (better) performance. |
| Frequency of Memantine or Placebo Side Effects (All Groups) | From start of memantine/placebo therapy through end of therapy (up to 12 weeks later) | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORHeather M. Conklin, PhD
St. Jude Children's Research Hospital
Participant flow
Recruitment details
From 11/1/17 to 6/22/22,103 potential patients were identified; 45 found ineligible upon review/physician consult. Seventeen families declined participation and 41 patients were consented/screened. There were 7 screen failures (eg, high liver enzymes, abnormal EKG, seizures). Thirty-four patients were randomized, 4 withdrew from study after randomization (pill swallowing, rash, preexisting cardiac issue, initiated new stimulant). Results are reported for 30 patients completing the trial.
Pre-assignment details
41 patients were consent/screened for eligibility, with 7 not qualifying for the medication trial. The 34 randomized are dileneated below.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 11.93 years STANDARD_DEVIATION 2.87 |
| Memantine (Intervention) or Placebo (Control) | 14 Participants |
| Race/Ethnicity, Customized Race/Ethnicity, Customized black | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity, Customized Other | 5 Participants |
| Race/Ethnicity, Customized Race/Ethnicity, Customized white | 12 Participants |
| Region of Enrollment United States Hispanic | 2 Participants |
| Region of Enrollment United States Non-Hispanic | 28 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 14 | 0 / 16 | 0 / 14 |
| other Total, other adverse events | 8 / 16 | 12 / 14 | 14 / 16 | 13 / 14 |
| serious Total, serious adverse events | 0 / 16 | 0 / 14 | 0 / 16 | 1 / 14 |
Outcome results
None listed