A Study to See if Memantine Protects the Brain During Radiation Therapy Treatment for a Brain Tumor
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| ClinicalTrials.gov Identifier: NCT04939597 |
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Recruitment Status :
Recruiting
First Posted : June 25, 2021
Last Update Posted : March 20, 2023
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| Condition or disease | Intervention/treatment | Phase |
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| Brain Neoplasm Recurrent Brain Neoplasm | Procedure: Cognitive Assessment Drug: Memantine Hydrochloride Drug: Placebo Administration | Phase 3 |
PRIMARY OBJECTIVE:
I. To determine the efficacy, as measured by the slope of change of the Cogstate composite Z score from baseline to 12 months, of oral memantine hydrochloride (memantine) administered for a period of 6 months, when compared to placebo, in children ages 4-18 receiving cranial or craniospinal radiotherapy for primary central nervous system tumors.
EXPLORATORY OBJECTIVES:
I. To determine if memantine is associated with improved cognitive function as measured for participants in the optional Children's Oncology Group (COG) Standardized Battery at 12 months.
II. To determine if memantine is associated with change in cognitive function version (vs.) placebo as measured by Cogstate composite score at end of radiation therapy (RT), 3 and 6 months.
III. To determine if memantine is associated with differences in cognitive function vs. placebo as measured by Cogstate composite score at 30 and 60 months for participants in the optional COG Standardized Battery.
IV. To correlate early cognitive changes (end of RT, 3, 6, 12 months Cogstate composite score) with late cognitive function (30 and 60 months Cogstate composite score).
V. To correlate COG Standardized Battery scores to Cogstate composite scores at 12, 30, and 60 months.
VI. To estimate the 36-month disease-free and overall survival (of primary brain tumor) after memantine treatment compared to placebo.
VII. To correlate changes in quantitative volumetric magnetic resonance imaging (MRI) measurements of critical brain regions with cognitive function over time.
VIII. To evaluate impact of memantine versus placebo on molecular biomarkers associated with cognitive decline after radiotherapy.
IX. To determine whether oral memantine, when compared to placebo, is associated with reduction in the incidence of decline of composite Cogstate score at 12 months in children ages 4-18 receiving cranial radiotherapy for primary central nervous system tumors.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive memantine hydrochloride orally (PO) twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 30, and 60 months.
ARM II: Patients receive placebo PO BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 30, and 60 months.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 162 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 3 Randomized, Placebo-Controlled Trial Evaluating Memantine for Neurocognitive Protection in Children Undergoing Cranial Radiotherapy as Part of Treatment for Primary Central Nervous System Tumors |
| Actual Study Start Date : | November 15, 2021 |
| Estimated Primary Completion Date : | September 30, 2027 |
| Estimated Study Completion Date : | September 30, 2027 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm I (memantine hydrochloride)
Patients receive memantine hydrochloride PO BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 30, and 60 months.
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Procedure: Cognitive Assessment
Complete cognitive testing Drug: Memantine Hydrochloride Given PO
Other Names:
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Placebo Comparator: Arm II (placebo)
Patients receive placebo PO BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 30, and 60 months.
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Procedure: Cognitive Assessment
Complete cognitive testing Drug: Placebo Administration Given PO |
- The slope of the Cogstate composite Z score (an average of detection Z scores, Identification Z scores, and one-back Z scores calculated using cogstate age-based normative data) [ Time Frame: Up-to 12 months post baseline ]The slope of the Cogstate composite Z score (an average of detection Z scores, Identification Z scores, and one-back Z scores calculated using cogstate age-based normative data) We will estimate the difference in mean Cogstate composite Z score slopes (reflecting change in Cogstate composite Z scores from baseline to 12 months post baseline taking into account measurements at those time points as well as end of radiation therapy and 3 and 6-months post baseline) between the treatment and control arms using a generalized estimating equation model with compound symmetry correlation structure and will provide a point estimate and corresponding 95% confidence interval. Up-to 12 months post baseline.
- Intelligence quotient score (assessed by age-appropriate Wechsler Intelligence Scale) [ Time Frame: At 12-months post baseline ]We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
- Processing speed score (assessed by processing speed/attention subtests of age-appropriate Wechsler Intelligence Scale) [ Time Frame: At 12-months post baseline ]We will estimate the difference in mean standard scores and will provide a point estimate and corresponding 95% confidence interval.
- Verbal memory score (assessed by Children's Memory Scale [CMS] Stories subtest, or the Wechsler Memory Scale - Fourth Edition [WMS-IV] Logical Memory I and II subtests, depending on age) [ Time Frame: At 12-months post baseline ]We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
- Visual memory score (assessed by CMS or WMS-IV Faces subtest scores, Immediate and Delayed, depending on age) [ Time Frame: At 12-months post baseline ]We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
- Working memory score (assessed by Digit Span subtests of age-appropriate Wechsler Intelligence Scales) [ Time Frame: At 12-months post baseline ]We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
- Verbal score (assessed by the California Verbal Learning Test - Children's Version [CVLT-C] or 2nd Edition [CVLT-II] based on age, using the List A Trials 1-5 Total T-score) [ Time Frame: At 12-months post baseline ]We will estimate the difference in mean standard scores and will provide a point estimate and corresponding 95% confidence interval.
- Visual learning score (assessed by CMS Dot Locations subtest or WMS-IV Symbol Span subtest, depending on age) [ Time Frame: At 12-months post baseline ]We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
- Executive functioning score (assessed by the Cognitive Regulation Index of the Brief Rating Inventory of Executive Function) [ Time Frame: At 12-months post baseline ]We will estimate the difference in mean standard scores across treatment arms and will provide a point estimate and corresponding 95% confidence interval.
- Disease-free survival [ Time Frame: Up-to 36 months post baseline ]We will estimate the hazard ratio comparing time-to-relapse of primary brain tumor or death due to any cause in the memantine relative to placebo arm and will provide a point estimate and corresponding 95% confidence interval.
- Overall survival [ Time Frame: Up-to 36 months post baseline ]We will estimate the hazard ratio comparing time-to- death due to any cause in the memantine relative to placebo arm and will provide a point estimate and corresponding 95% confidence interval.
- Quantitative volumetric magnetic resonance imaging (MRI) measurements of critical brain regions (hippocampus, frontal cortex) [ Time Frame: At 12-months post baseline ]We will estimate a correlation coefficient between changes in quantitative volumetric MRI measurements for the three regions of interest and changes in Cogstate composite Z scores (from baseline to 12 months post baseline).
- Number of patients who consented to biobanking [ Time Frame: Up-to 12 months post baseline ]The number of patients who agree to be in the biobanking part of the study future research.
- Composite cognitive score decline (0.5 standard deviation or more decline in Cogstate composite score relative to baseline) [ Time Frame: At 12-months post baseline ]We will estimate the proportion of patients who experience composite cognitive score decline in the memantine and placebo arms and will provide corresponding 95% confidence intervals.
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| Ages Eligible for Study: | 4 Years to 17 Years (Child) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- >= 4 and < 18 years at time of study entry
- Patients must weigh 15 kg or greater at time of study entry
- Newly diagnosed or recurrent primary brain tumors that have not received prior cranial radiotherapy
- Planned focal, cranial or craniospinal radiation treatment for a primary brain tumor
- The patient must have receptive and expressive language skills in English, French or Spanish since the neurocognitive function and quality of life (QOL) assessment instruments are available in these languages only
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Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
- Age: 4 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 male; 0.8 female
- Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 male; 1 female
- Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 male; 1.2 female
- Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 male; 1.4 female
- Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 male; 1.4 female
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
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Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
- Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
- The patient must be able to undergo magnetic resonance imaging
- All patients and/or their parents or legal guardians must sign a written informed consent
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion Criteria:
- Life expectancy of less than 18 months
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Pre-existing conditions:
- Any contraindication or allergy to memantine
- Intractable seizures while on adequate anticonvulsant therapy, defined as more than one seizure per month for the past 2 months or since initiating anticonvulsant therapy
- Co-morbid systemic illnesses, psychiatric conditions, social situations, or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or would limit compliance with the study requirements
- Patients with a motor, visual, or auditory condition that precludes computerized neurocognitive assessments are not eligible to participate
- Patients with any medical condition or taking medications that lead to alterations of urine pH towards the alkaline condition (e.g., renal tubular acidosis, carbonic anhydrase inhibitors, sodium bicarbonate)
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Personal history of prior cranial or craniospinal radiotherapy is not allowed
- Note: Prior anti-cancer therapy including surgery, chemotherapy, targeted agents are allowed as per standard of care clinical treatment guidelines
- Female patients who are pregnant are excluded since fetal toxicities and teratogenic effects have been noted for the study drug. A pregnancy test is required for female patients of childbearing potential
- Lactating females who plan to breastfeed their infants
- Sexually active patients of reproductive potential who do not agree to use an effective contraceptive method for the duration of their study participation
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04939597
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| Principal Investigator: | Nadia N Laack | Children's Oncology Group |
| Responsible Party: | Children's Oncology Group |
| ClinicalTrials.gov Identifier: | NCT04939597 |
| Other Study ID Numbers: |
ACCL2031 NCI-2020-07502 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) ACCL2031 ( Other Identifier: Children's Oncology Group ) COG-ACCL2031 ( Other Identifier: DCP ) ACCL2031 ( Other Identifier: CTEP ) U01CA246568 ( U.S. NIH Grant/Contract ) U24CA196173 ( U.S. NIH Grant/Contract ) UG1CA189955 ( U.S. NIH Grant/Contract ) |
| First Posted: | June 25, 2021 Key Record Dates |
| Last Update Posted: | March 20, 2023 |
| Last Verified: | March 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Neoplasms Brain Neoplasms Central Nervous System Neoplasms Nervous System Neoplasms Neoplasms by Site Brain Diseases Central Nervous System Diseases Nervous System Diseases Memantine |
Antiparkinson Agents Anti-Dyskinesia Agents Dopamine Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs Excitatory Amino Acid Antagonists Excitatory Amino Acid Agents |