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Memantine Hydrochloride and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Reducing Neurocognitive Decline in Patients With Brain Metastases

Sponsor
NRG Oncology (Other)
Overall Status
Completed
CT.gov ID
NCT02360215
Collaborator
National Cancer Institute (NCI) (NIH)
518
Enrollment
220
Locations
2
Arms
49.8
Actual Duration (Months)
2.4
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This randomized phase III trial compares memantine hydrochloride and whole-brain radiotherapy with or without hippocampal avoidance in reducing neurocognitive decline in patients with cancer that has spread from the primary site (place where it started) to the brain. Whole brain radiotherapy (WBRT) is the most common treatment for brain metastasis. Unfortunately, the majority of patients with brain metastases experience cognitive (such as learning and memory) deterioration after WBRT. Memantine hydrochloride may enhance cognitive function by binding to and inhibiting channels of receptors located in the central nervous system. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Using radiation techniques, such as intensity modulated radiotherapy to avoid the hippocampal region during WBRT, may reduce the radiation dose to the hippocampus and help limit the radiation-induced cognitive decline. It is not yet known whether giving memantine hydrochloride and WBRT with or without hippocampal avoidance works better in reducing neurocognitive decline in patients with brain metastases.

Condition or Disease Intervention/Treatment Phase
  • Radiation: Whole brain radiation therapy with hippocampal avoidance
  • Drug: Memantine
  • Radiation: Whole brain radiation therapy
 Phase 3

Detailed Description

PRIMARY OBJECTIVES:
  1. Determine whether the addition of whole-brain radiotherapy with hippocampal avoidance (HA-WBRT) increases time to neurocognitive failure at months 2, 4, 6, and 12 as measured by neurocognitive decline on a battery of tests: the Hopkins Verbal Learning Test-Revised (HVLT-R) for Total Recall, Delayed Recall, and Delayed Recognition, Controlled Oral Word Association (COWA), and the Trail Making Test (TMT) Parts A and B.
SECONDARY OBJECTIVES:

  1. Determine whether the addition of HA-WBRT preserves neurocognitive function at months 2, 4, 6, and 12 as separately measured by each test, the HVLT-R for Total Recall, Delayed Recall, and Delayed Recognition; COWA; and TMT Parts A and B.

  2. Evaluate the potential benefit of HA-WBRT in symptom burden, as measured by the M. D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT).

  3. Assessment of quality adjusted survival and cost analysis using the five-level version of the EuroQol five-dimensional (EQ-5D-5L).

  4. Compare cumulative incidence of progression and overall survival after WBRT versus HA-WBRT.

  5. Compare adverse events between the treatment arms according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 criteria.

TERTIARY OBJECTIVES:

  1. Collect serum, plasma, and imaging studies for future translational research analyses.

  2. Evaluate magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry at baseline and 6 months as potential predictors of neurocognitive decline and differential benefit from HA-WBRT as compared to WBRT.

  3. Association of symptom burden and anxiety/depression with neurocognitive function.

  4. Evaluate the potential correlation between the prognostic scoring systems Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) and the diagnosis-specific graded prognostic assessment (DS-GPA) and neurocognitive function at baseline and overtime.

After completion of study treatment, patients are followed up at 12 months.

Study Design

Study Type:
Interventional
Actual Enrollment :
518 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Supportive Care
Official Title:
A Randomized Phase III Trial of Memantine and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Patients With Brain Metastases
Actual Study Start Date :
Jul 1, 2015
Actual Primary Completion Date :
Apr 30, 2018
Actual Study Completion Date :
Aug 26, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: WBRT + Memantine

Whole brain radiation therapy (WBRT) and memantine

Drug: Memantine
Given PO daily during and after radiation therapy for a total of 24 weeks. Week 1: 5 mg in the AM, none in the PM; Week 2: 5 mg in the AM, 5 mg in the PM; Week 3: 10 mg in the AM, 5 mg in the PM; Weeks 4-24: 10 mg in the AM, 10 mg in the PM. Should start the same day as radiation therapy, at latest before the fourth radiation treatment.
Other Names:
  • Ebixia
  • Memantine Hydrochloride
  • Namenda

    • Radiation: Whole brain radiation therapy
    Whole brain radiation therapy (WBRT) 30 Gy in 10 fractions once per day, 5 days per week for approximately 2 weeks
    Other Names:
  • WBRT
  • whole-brain radiation therapy
  • whole-brain radiotherapy

    		•
    Experimental: HA-WBRT/IMRT+ Memantine

    Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) using intensity modulated radiation therapy (IMRT) and memantine

    Radiation: Whole brain radiation therapy with hippocampal avoidance
    Intensity modulated radiation therapy (IMRT) 30 Gy in 10 fractions once per day, 5 days per week for approximately two week; starting within 21 calendar days after randomization.
    Other Names:
  • IMRT
  • Intensity Modulated RT
  • INTENSITY-MODULATED RADIATION THERAPY
  • Intensity-Modulated Radiotherapy
  • Whole-brain radiation therapy
  • WBRT
  • whole-brain radiotherapy
  • HA-WBRT

    • Drug: Memantine
    Given PO daily during and after radiation therapy for a total of 24 weeks. Week 1: 5 mg in the AM, none in the PM; Week 2: 5 mg in the AM, 5 mg in the PM; Week 3: 10 mg in the AM, 5 mg in the PM; Weeks 4-24: 10 mg in the AM, 10 mg in the PM. Should start the same day as radiation therapy, at latest before the fourth radiation treatment.
    Other Names:
  • Ebixia
  • Memantine Hydrochloride
  • Namenda

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Time to Neurocognitive Failure [From randomization to last follow-up. Maximum follow-up was 15.6 months.]

      Neurocognitive failure is defined as the first failure, defined as a neurocognitive decline using the reliable change index (RCI) on at least one of the following assessments or parts of : Hopkins Verbal Learning Test - Revised (HVLT-R), Trail Making Test (TMT), or Controlled Oral Word Association (COWA). The HVLT-R has 3 parts that were analyzed separately for decline: Total Recall, Delayed Recall, and Delayed Recognition. The TMT has 2 parts that were analyzed separately: Part A and Part B. Neurocognitive failure rate is estimated using the cumulative incidence method. Analysis was planned to occur after 233 events were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided.Analysis was planned to occur after 233 events were reported.

    Secondary Outcome Measures

    1. Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) [Baseline, 2, 4, 6, and 12 months]

      The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.

    2. Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) [Baseline, 2, 4, 6, and 12 months]

      The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.

    3. Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) [Baseline, 2, 4, 6, and 12 months]

      The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized by expressing the deviation from the mean score of the group in units of standard deviation. Change is calculated as baseline score subtracted from post-baseline score.

    4. Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) [Baseline, 2, 4, 6, and 12 months]

      The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order; in the second part (Part B), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete each maze. The range for Part A is 0 to 180 (3 minutes) and for Part B is 0 to 300 (5 minutes). Lower scores indicate better functioning. Scores are standardized, adjusting for age, education, gender as needed, so that mean is 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.

    5. Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) [Baseline, 2, 4, 6, and 12 months]

      The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order; in the second part (Part B), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete each maze. The range for Part A is 0 to 180 (3 minutes) and for Part B is 0 to 300 (5 minutes). A lower score indicates better functioning. Scores are standardized by expressing the deviation from the mean score of the group in units of standard deviation. Change is calculated as baseline score subtracted from post-baseline score.

    6. Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) [Baseline, 2, 4, 6, and 12 months]

      The COWA is a verbal fluency test that measures spontaneous production of words belonging to the same category or beginning with some designated letter. Patients are given 1 minute to name as many words as possible beginning with the designated letter. The procedure is then repeated for the remaining two letters. Two alternate forms of the COWA are employed to minimize practice effects. The score is the sum of the correct responses with a range of 0 to infinity. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean is 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.

    7. Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] [Baseline, 2, 4, 6, and 12 months]

      Clinical Trial Battery Composite score is the arithmetic mean of the HVLT-R (Free Recall, Delayed Recall, Delayed Recognition), TMTA, TMTB, and COWA scores, all of which are standardized, adjusting for age, education, and gender as necessary, such that mean is 0 and standard deviation is 1. A participant must have at least 5 of the 6 scores. A higher composite score indicates better neurocognitive function.Change is calculated as baseline score subtracted from post-baseline score.

    8. Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score [Baseline, 2, 4, 6, and 12 months]

      The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score (Symptom Severity) is the average of the subscale items, given that a specified minimum numbers of items were completed.

    9. Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score [Baseline, 2, 4, 6, and 12 months]

      The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score (Interference) is the average of the subscale items, given that a specified minimum numbers of items were completed.

    10. Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score [Baseline, 2, 4, 6, and 12 months]

      The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score (Cognitive Factor) is the average of the subscale items, given that a specified minimum numbers of items were completed.

    11. Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score [Baseline, 2, 4, 6, and 12 months]

      The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score (Neurologic Factor) is the average of the subscale items, given that a specified minimum numbers of items were completed.

    12. Change in EQ-5D-5L Index Score at 2 Months [Baseline and 2 months]

      The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.

    13. Change in EQ-5D-5L Index Score at 4 Months [Baseline and 4 months]

      The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.

    14. Change in EQ-5D-5L Index Score at 6 Months [Baseline and 6 months]

      The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.

    15. Change in EQ-5D-5L Index Score at 12 Months [Baseline and 12 months]

      The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.

    16. Change in EQ-5D-5L VAS Score at 2 Months [Baseline and 2 months]

      The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.

    17. Change in EQ-5D-5L VAS Score at 4 Months [Baseline and 4 months]

      The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.

    18. Change in EQ-5D-5L VAS Score at 6 Months [Baseline and 6 months]

      The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.

    19. Change in EQ-5D-5L VAS Score at 12 Months [Baseline and 12 months]

      The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.

    20. Intracranial Progression-Free Survival [From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months.]

      Intracranial progression-free survival time is defined as time from registration/randomization to the date of progression in the brain or death from any cause. Intracranial progression-free survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Analysis was planned to occur after 233 primary endpoint events (neurocognitive failure) were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided.

    21. Overall Survival [From randomization to last follow-up. Maximum follow-up was 15.6 months.]

      Overall survival time is defined as time from registration/randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Analysis was planned to occur after 233 primary endpoint events (neurocognitive failure) were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided.

    22. Number of Patients With a Grade 3+ Adverse Event (AE) Regardless of Relationship to Treatment [From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months.]

      . Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.

    Other Outcome Measures

    1. Anxiety/Depression Measured Using the EQ-5D-5L [Up to 12 months]

      An exploratory analysis, beginning with correlation coefficients, will be used to assess the association of symptom burden and anxiety/depression with neurocognitive function at each time point. The symptom burden items of interest are the "distressed (upset)", "sad", and "mood" items. From the EQ-5D-5L, the depression/anxiety item will be of interest.

    2. Effect of Radiation Therapy Oncology Group (RTOG) RPA and the Diagnosis-specific Graded Prognostic Assessment (DSGPA) on Neurocognitive Function [Up to 12 months]

      Neurocognitive function, as measured by the HVLT-R, COWA, and TMT, will be correlated with both the RTOG RPA and the DS-GPA classification systems. Baseline neurocognitive function for each test will be compared between both RPA classes using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.

    3. Effect of White Matter Injury and Hippocampal Volume on Neurocognitive Function [Up to 12 months]

      Evaluated through MRI scans using physician-contoured and auto-contoured scores. Concordance rates will be assessed using Kappa statistics. The auto-contoured scores will be used for the remaining analyses due to the number of physicians reviewing the scans. White matter injury is measured by FLAIR volume change and is a continuous variable. Hippocampal volume is measured as a continuous variable also and both will be covariates considered in the Cox proportional hazards model to assess the impact on time to neurocognitive failure and the longitudinal modeling of neurocognitive function.

    4. MDASI-BT Mood Variables [Up to 12 months]

      The relationship between EQ-5D-5L and MDASI-BT mood variables and neurocognitive function will be assessed.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • PRIOR TO STEP 1 REGISTRATION:

    • Brain metastases outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced magnetic resonance imaging (MRI) performed =< 21 days prior to Step 1 registration; an allowed exception, regarding ability to image brain metastases, would be that patients who had undergone radiosurgery or surgical resection and are planning adjuvant WBRT do not have to have visible disease but do need a pre-surgery MRI or computed tomography (CT) scan demonstrating brain metastases; however, the brain metastases could not have been within 5 mm of either hippocampus

    • Patients must have a gadolinium contrast-enhanced three-dimensional spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) axial MRI scan with standard axial and coronal gadolinium contrast-enhanced T1-weighted sequence and axial T2/FLAIR sequence acquisitions; to yield acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, MP-RAGE, or TFE axial MRI scan should use the smallest possible axial slice thickness not exceeding 1.5 mm; the associated coronal and sagittal contrast-enhanced T1 sequences can be up to 2.5 mm in slice thickness; this MRI must be obtained =< 21 days prior to step 1 registration; the vendor specific MRI protocols are available for download from the Alzheimer's Disease Neuroimaging Initiative (ADNI)

    • Patients must provide study-specific informed consent prior to registration

    • PRIOR TO STEP 2 REGISTRATION:

    • The following baseline neurocognitive assessments must be completed prior to Step 2 registration: HVLT-R, TMT, and COWA;

    • Pathologically (histologically or cytologically) proven diagnosis of solid tumor malignancy within 5 years prior to Step 2 registration

    • History and physical examination within 28 days prior to Step 2 registration

    • Karnofsky performance status of >= 70 within 28 days prior to Step 2 registration

    • Serum creatinine =< 3 mg/dL (265 umol/L) and creatinine clearance >= 30 ml/min

    • Blood urea nitrogen (BUN) within institutional upper limit of normal (e.g. < 20 mg/dL)

    • Total bilirubin =< 2.5 mg/dL (43 umol/L)

    • Patients may have had prior therapy for brain metastasis, including radiosurgery and surgical resection; patients must have completed prior therapy by at least 14 days prior to Step 2 for surgical resection and 7 days for radiosurgery

    • Negative serum pregnancy test (in women of childbearing potential) =< 14 days prior to Step 2; women of childbearing potential and men who are sexually active must practice adequate contraception while on study

    • Patients who are primary English or French speakers are eligible

    Exclusion Criteria:

    • Prior external beam radiation therapy to the brain or whole brain radiation therapy

    • Planned cytotoxic chemotherapy during the WBRT only; patients may have had prior chemotherapy

    • Radiographic evidence of hydrocephalus or other architectural distortion of the ventricular system, including placement of external ventricular drain or ventriculoperitoneal shunt

    • Severe, active co-morbidity defined as follows:

    • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months

    • Transmural myocardial infarction within the last 6 months

    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration

    • Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of registration

    • Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease

    • Renal tubular acidosis or metabolic acidosis

    • Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4 count < 200 cells/microliter; note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to registration; Note also that HIV testing is not required for eligibility for this protocol

    • Pregnant or lactating women, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception

    • Prior allergic reaction to memantine (memantine hydrochloride)

    • Current alcohol or drug abuse (may exacerbate lethargy/dizziness with memantine)

    • Intractable seizures while on adequate anticonvulsant therapy-more than 1 seizure per month for the past 2 months

    • Patients with definitive leptomeningeal metastases

    • Patients with brain metastases from primary germ cell tumors, small cell carcinoma, unknown primary, or lymphoma

    • Contraindication to magnetic resonance (MR) imaging such as implanted metal devices or foreign bodies

    • Contraindication to gadolinium contrast administration during MR imaging, such as allergy or insufficient renal function

    • Current use of (other N-methyl D-aspartate [NMDA] antagonists) amantadine, ketamine, or dextromethorphan

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Lewis and Faye Manderson Cancer Center Tuscaloosa Alabama United States 35401
    2 Banner MD Anderson Cancer Center Gilbert Arizona United States 85234
    3 Banner University Medical Center - Tucson Tucson Arizona United States 85719
    4 Providence Saint Joseph Medical Center/Disney Family Cancer Center Burbank California United States 91505
    5 Mercy San Juan Medical Center Carmichael California United States 95608
    6 City of Hope Comprehensive Cancer Center Duarte California United States 91010
    7 UC San Diego Moores Cancer Center La Jolla California United States 92093
    8 Kaiser Permanente Los Angeles Medical Center Los Angeles California United States 90027
    9 Los Angeles County-USC Medical Center Los Angeles California United States 90033
    10 USC / Norris Comprehensive Cancer Center Los Angeles California United States 90033
    11 Kaiser Permanente Oakland-Broadway Oakland California United States 94611
    12 Stanford Cancer Institute Palo Alto Palo Alto California United States 94304
    13 Kaiser Permanente-Rancho Cordova Cancer Center Rancho Cordova California United States 95670
    14 Rohnert Park Cancer Center Rohnert Park California United States 94928
    15 Sutter Cancer Centers Radiation Oncology Services-Roseville Roseville California United States 95661
    16 The Permanente Medical Group-Roseville Radiation Oncology Roseville California United States 95678
    17 Mercy Cancer Center - Sacramento Sacramento California United States 95816
    18 Sutter Medical Center Sacramento Sacramento California United States 95816
    19 University of California San Diego San Diego California United States 92103
    20 California Pacific Medical Center-Pacific Campus San Francisco California United States 94115
    21 Stanford Cancer Center South Bay San Jose California United States 95124
    22 Kaiser Permanente Medical Center - Santa Clara Santa Clara California United States 95051
    23 Kaiser Permanente Cancer Treatment Center South San Francisco California United States 94080
    24 Sutter Solano Medical Center/Cancer Center Vallejo California United States 94589
    25 Rocky Mountain Cancer Centers-Boulder Boulder Colorado United States 80304
    26 Penrose-Saint Francis Healthcare Colorado Springs Colorado United States 80907
    27 UCHealth Memorial Hospital Central Colorado Springs Colorado United States 80909
    28 Swedish Medical Center Englewood Colorado United States 80113
    29 Saint Vincent's Medical Center Bridgeport Connecticut United States 06606
    30 Helen F Graham Cancer Center Newark Delaware United States 19713
    31 Christiana Care Health System-Christiana Hospital Newark Delaware United States 19718
    32 Boca Raton Regional Hospital Boca Raton Florida United States 33486
    33 UM Sylvester Comprehensive Cancer Center at Coral Gables Coral Gables Florida United States 33146
    34 UM Sylvester Comprehensive Cancer Center at Deerfield Beach Deerfield Beach Florida United States 33442
    35 University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida United States 33136
    36 UF Cancer Center at Orlando Health Orlando Florida United States 32806
    37 Cleveland Clinic-Weston Weston Florida United States 33331
    38 Grady Health System Atlanta Georgia United States 30303
    39 Emory University Hospital Midtown Atlanta Georgia United States 30308
    40 Piedmont Hospital Atlanta Georgia United States 30309
    41 Emory University Hospital/Winship Cancer Institute Atlanta Georgia United States 30322
    42 Emory Saint Joseph's Hospital Atlanta Georgia United States 30342
    43 Memorial Health University Medical Center Savannah Georgia United States 31404
    44 Lewis Cancer and Research Pavilion at Saint Joseph's/Candler Savannah Georgia United States 31405
    45 Saint Alphonsus Cancer Care Center-Boise Boise Idaho United States 83706
    46 Saint Luke's Mountain States Tumor Institute Boise Idaho United States 83712
    47 Saint Luke's Mountain States Tumor Institute - Meridian Meridian Idaho United States 83642
    48 Saint Luke's Mountain States Tumor Institute - Nampa Nampa Idaho United States 83686
    49 Saint Luke's Mountain States Tumor Institute-Twin Falls Twin Falls Idaho United States 83301
    50 SIH Cancer Institute Carterville Illinois United States 62918
    51 Northwestern University Chicago Illinois United States 60611
    52 John H Stroger Jr Hospital of Cook County Chicago Illinois United States 60612
    53 University of Chicago Comprehensive Cancer Center Chicago Illinois United States 60637
    54 Decatur Memorial Hospital Decatur Illinois United States 62526
    55 Crossroads Cancer Center Effingham Illinois United States 62401
    56 Northwestern Medicine Cancer Center Delnor Geneva Illinois United States 60134
    57 Edward Hines Jr VA Hospital Hines Illinois United States 60141
    58 Condell Memorial Hospital Libertyville Illinois United States 60048
    59 Loyola University Medical Center Maywood Illinois United States 60153
    60 Methodist Medical Center of Illinois Peoria Illinois United States 61636
    61 OSF Saint Francis Medical Center Peoria Illinois United States 61637
    62 Memorial Medical Center Springfield Illinois United States 62781
    63 Carle Cancer Center Urbana Illinois United States 61801
    64 Northwestern Medicine Cancer Center Warrenville Warrenville Illinois United States 60555
    65 Parkview Hospital Randallia Fort Wayne Indiana United States 46805
    66 Community Cancer Center East Indianapolis Indiana United States 46219
    67 Community Cancer Center South Indianapolis Indiana United States 46227
    68 Community Cancer Center North Indianapolis Indiana United States 46256
    69 Saint Luke's Hospital Cedar Rapids Iowa United States 52402
    70 University of Kansas Cancer Center Kansas City Kansas United States 66160
    71 Lawrence Memorial Hospital Lawrence Kansas United States 66044
    72 University of Kansas Cancer Center-Overland Park Overland Park Kansas United States 66210
    73 Ascension Via Christi Hospitals Wichita Wichita Kansas United States 67214
    74 Wesley Medical Center Wichita Kansas United States 67214
    75 University of Kentucky/Markey Cancer Center Lexington Kentucky United States 40536
    76 Tulane University Health Sciences Center New Orleans Louisiana United States 70112
    77 University of Maryland/Greenebaum Cancer Center Baltimore Maryland United States 21201
    78 MedStar Union Memorial Hospital Baltimore Maryland United States 21218
    79 UM Upper Chesapeake Medical Center Bel Air Maryland United States 21014
    80 Central Maryland Radiation Oncology in Howard County Columbia Maryland United States 21044
    81 UM Baltimore Washington Medical Center/Tate Cancer Center Glen Burnie Maryland United States 21061
    82 UM Saint Joseph Medical Center Towson Maryland United States 21204
    83 Tufts Medical Center Boston Massachusetts United States 02111
    84 Lahey Hospital and Medical Center Burlington Massachusetts United States 01805
    85 Lowell General Hospital Lowell Massachusetts United States 01854
    86 Saint Joseph Mercy Hospital Ann Arbor Michigan United States 48106
    87 McLaren Cancer Institute-Bay City Bay City Michigan United States 48706
    88 Henry Ford Cancer Institute-Downriver Brownstown Michigan United States 48183
    89 Saint Joseph Mercy Chelsea Chelsea Michigan United States 48118
    90 21st Century Oncology MHP - Clarkston Clarkston Michigan United States 48346
    91 McLaren Cancer Institute-Clarkston Clarkston Michigan United States 48346
    92 Henry Ford Macomb Hospital-Clinton Township Clinton Township Michigan United States 48038
    93 Wayne State University/Karmanos Cancer Institute Detroit Michigan United States 48201
    94 Henry Ford Hospital Detroit Michigan United States 48202
    95 21st Century Oncology MHP - Farmington Farmington Hills Michigan United States 48334
    96 Genesys Hurley Cancer Institute Flint Michigan United States 48503
    97 McLaren Cancer Institute-Flint Flint Michigan United States 48532
    98 Spectrum Health at Butterworth Campus Grand Rapids Michigan United States 49503
    99 West Michigan Cancer Center Kalamazoo Michigan United States 49007
    100 McLaren Cancer Institute-Lapeer Region Lapeer Michigan United States 48446
    101 Saint Mary Mercy Hospital Livonia Michigan United States 48154
    102 McLaren Cancer Institute-Macomb Mount Clemens Michigan United States 48043
    103 McLaren Cancer Institute-Central Michigan Mount Pleasant Michigan United States 48858
    104 Mercy Health Mercy Campus Muskegon Michigan United States 49444
    105 McLaren Cancer Institute-Owosso Owosso Michigan United States 48867
    106 McLaren Cancer Institute-Northern Michigan Petoskey Michigan United States 49770
    107 Saint Joseph Mercy Oakland Pontiac Michigan United States 48341
    108 McLaren-Port Huron Port Huron Michigan United States 48060
    109 Lakeland Medical Center Saint Joseph Saint Joseph Michigan United States 49085
    110 21st Century Oncology MHP - Troy Troy Michigan United States 48098
    111 Henry Ford West Bloomfield Hospital West Bloomfield Michigan United States 48322
    112 Mayo Clinic Health System in Albert Lea Albert Lea Minnesota United States 56007
    113 Unity Hospital Fridley Minnesota United States 55432
    114 Mayo Clinic Health Systems-Mankato Mankato Minnesota United States 56001
    115 Abbott-Northwestern Hospital Minneapolis Minnesota United States 55407
    116 Mayo Clinic Radiation Therapy-Northfield Northfield Minnesota United States 55057
    117 Mayo Clinic Rochester Minnesota United States 55905
    118 Park Nicollet Clinic - Saint Louis Park Saint Louis Park Minnesota United States 55416
    119 Saint Francis Medical Center Cape Girardeau Missouri United States 63703
    120 Siteman Cancer Center at West County Hospital Creve Coeur Missouri United States 63141
    121 North Kansas City Hospital Kansas City Missouri United States 64116
    122 Washington University School of Medicine Saint Louis Missouri United States 63110
    123 Siteman Cancer Center-South County Saint Louis Missouri United States 63129
    124 Missouri Baptist Medical Center Saint Louis Missouri United States 63131
    125 Mercy Hospital Saint Louis Saint Louis Missouri United States 63141
    126 Siteman Cancer Center at Saint Peters Hospital Saint Peters Missouri United States 63376
    127 CoxHealth South Hospital Springfield Missouri United States 65807
    128 Billings Clinic Cancer Center Billings Montana United States 59101
    129 Benefis Healthcare- Sletten Cancer Institute Great Falls Montana United States 59405
    130 Community Medical Hospital Missoula Montana United States 59804
    131 University of Nebraska Medical Center Omaha Nebraska United States 68198
    132 Renown Regional Medical Center Reno Nevada United States 89502
    133 Wentworth-Douglass Hospital Dover New Hampshire United States 03820
    134 Dartmouth Hitchcock Medical Center Lebanon New Hampshire United States 03756
    135 Montefiore Medical Center - Moses Campus Bronx New York United States 10467
    136 New York-Presbyterian/Brooklyn Methodist Hospital Brooklyn New York United States 11215
    137 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    138 University of Rochester Rochester New York United States 14642
    139 UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina United States 27599
    140 NHRMC Radiation Oncology - 16th Street Wilmington North Carolina United States 28401
    141 Sanford Bismarck Medical Center Bismarck North Dakota United States 58501
    142 Sanford Roger Maris Cancer Center Fargo North Dakota United States 58122
    143 Summa Akron City Hospital/Cooper Cancer Center Akron Ohio United States 44304
    144 Cleveland Clinic Akron General Akron Ohio United States 44307
    145 Case Western Reserve University Cleveland Ohio United States 44106
    146 Cleveland Clinic Cancer Center/Fairview Hospital Cleveland Ohio United States 44111
    147 Cleveland Clinic Foundation Cleveland Ohio United States 44195
    148 Ohio State University Comprehensive Cancer Center Columbus Ohio United States 43210
    149 Cleveland Clinic Cancer Center Independence Independence Ohio United States 44131
    150 UH Seidman Cancer Center at Southwest General Hospital Middleburg Heights Ohio United States 44130
    151 University Hospitals Parma Medical Center Parma Ohio United States 44129
    152 Cleveland Clinic Cancer Center Strongsville Strongsville Ohio United States 44136
    153 UHHS-Westlake Medical Center Westlake Ohio United States 44145
    154 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    155 Legacy Mount Hood Medical Center Gresham Oregon United States 97030
    156 Legacy Good Samaritan Hospital and Medical Center Portland Oregon United States 97210
    157 Abington Memorial Hospital Abington Pennsylvania United States 19001
    158 Crozer-Keystone Regional Cancer Center at Broomall Broomall Pennsylvania United States 19008
    159 Bryn Mawr Hospital Bryn Mawr Pennsylvania United States 19010
    160 Christiana Care Health System-Concord Health Center Chadds Ford Pennsylvania United States 19317
    161 Geisinger Medical Center Danville Pennsylvania United States 17822
    162 Northeast Radiation Oncology Center Dunmore Pennsylvania United States 18512
    163 Crozer Regional Cancer Center at Brinton Lake Glen Mills Pennsylvania United States 19342
    164 Riddle Memorial Hospital Media Pennsylvania United States 19063
    165 Thomas Jefferson University Hospital Philadelphia Pennsylvania United States 19107
    166 Fox Chase Cancer Center Philadelphia Pennsylvania United States 19111
    167 Aria Health-Torresdale Campus Philadelphia Pennsylvania United States 19114
    168 Temple University Hospital Philadelphia Pennsylvania United States 19140
    169 Reading Hospital West Reading Pennsylvania United States 19611
    170 Geisinger Wyoming Valley/Henry Cancer Center Wilkes-Barre Pennsylvania United States 18711
    171 Lankenau Medical Center Wynnewood Pennsylvania United States 19096
    172 Greenville Health System Cancer Institute-Faris Greenville South Carolina United States 29605
    173 Greenville Health System Cancer Institute-Eastside Greenville South Carolina United States 29615
    174 Self Regional Healthcare Greenwood South Carolina United States 29646
    175 The Radiation Oncology Center-Hilton Head/Bluffton Hilton Head Island South Carolina United States 29926
    176 Greenville Health System Cancer Institute-Spartanburg Spartanburg South Carolina United States 29307
    177 Sanford USD Medical Center - Sioux Falls Sioux Falls South Dakota United States 57117-5134
    178 Vanderbilt University/Ingram Cancer Center Nashville Tennessee United States 37232
    179 University of Texas Medical Branch Galveston Texas United States 77555-0565
    180 M D Anderson Cancer Center Houston Texas United States 77030
    181 UTMB Cancer Center at Victory Lakes League City Texas United States 77573
    182 Ogden Regional Medical Center Ogden Utah United States 84405
    183 Huntsman Cancer Institute/University of Utah Salt Lake City Utah United States 84112
    184 Norris Cotton Cancer Center-North Saint Johnsbury Vermont United States 05819
    185 Virginia Commonwealth University/Massey Cancer Center Richmond Virginia United States 23298
    186 Virginia Mason Medical Center Seattle Washington United States 98101
    187 North Star Lodge Cancer Center at Yakima Valley Memorial Hospital Yakima Washington United States 98902
    188 West Virginia University Healthcare Morgantown West Virginia United States 26506
    189 Wheeling Hospital/Schiffler Cancer Center Wheeling West Virginia United States 26003
    190 Langlade Hospital and Cancer Center Antigo Wisconsin United States 54409
    191 Mayo Clinic Health System-Eau Claire Clinic Eau Claire Wisconsin United States 54701
    192 Aurora Cancer Care-Grafton Grafton Wisconsin United States 53024
    193 Aurora BayCare Medical Center Green Bay Wisconsin United States 54311
    194 UW Cancer Center Johnson Creek Johnson Creek Wisconsin United States 53038
    195 Aurora Cancer Care-Kenosha South Kenosha Wisconsin United States 53142
    196 Gundersen Lutheran Medical Center La Crosse Wisconsin United States 54601
    197 Mayo Clinic Health System-Franciscan Healthcare La Crosse Wisconsin United States 54601
    198 University of Wisconsin Hospital and Clinics Madison Wisconsin United States 53792
    199 Community Memorial Hospital Menomonee Falls Wisconsin United States 53051
    200 Ascension Columbia Saint Mary's Water Tower Medical Commons Milwaukee Wisconsin United States 53211
    201 Aurora Saint Luke's Medical Center Milwaukee Wisconsin United States 53215
    202 Medical College of Wisconsin Milwaukee Wisconsin United States 53226
    203 Aurora Sinai Medical Center Milwaukee Wisconsin United States 53233
    204 Zablocki Veterans Administration Medical Center Milwaukee Wisconsin United States 53295
    205 Vince Lombardi Cancer Clinic - Oshkosh Oshkosh Wisconsin United States 54904
    206 Marshfield Clinic Stevens Point Center Stevens Point Wisconsin United States 54482
    207 Aurora Medical Center in Summit Summit Wisconsin United States 53066
    208 Vince Lombardi Cancer Clinic-Two Rivers Two Rivers Wisconsin United States 54241
    209 Aspirus Regional Cancer Center Wausau Wisconsin United States 54401
    210 Aurora West Allis Medical Center West Allis Wisconsin United States 53227
    211 Diagnostic and Treatment Center Weston Wisconsin United States 54476
    212 Aspirus UW Cancer Center Wisconsin Rapids Wisconsin United States 54494
    213 CHUM - Hopital Notre-Dame Montreal Quebec Canada H2L 4M1
    214 McGill University Department of Oncology Montreal Quebec Canada H2W 1S6
    215 CHUM - Centre Hospitalier de l'Universite de Montreal Montreal Quebec Canada H2X 3E4
    216 The Research Institute of the McGill University Health Centre (MUHC) Montreal Quebec Canada H3H 2R9
    217 CHU de Quebec-L'Hotel-Dieu de Quebec (HDQ) Quebec City Quebec Canada G1R 2J6
    218 Centre Hospitalier Universitaire de Sherbrooke-Fleurimont Sherbrooke Quebec Canada J1H 5N4
    219 Allan Blair Cancer Centre Regina Saskatchewan Canada S4T 7T1
    220 Saskatoon Cancer Centre Saskatoon Saskatchewan Canada S7N 4H4

    Sponsors and Collaborators

    • NRG Oncology
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Paul Brown, NRG Oncology

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    NRG Oncology
    ClinicalTrials.gov Identifier:
    NCT02360215
    Other Study ID Numbers:
    • NRG-CC001
    • NCI-2015-00030
    • NRG-CC001
    • NRG-CC001
    • NRG-CC001
    • UG1CA189867
    First Posted:
    Feb 10, 2015
    Last Update Posted:
    Jun 2, 2021
    Last Verified:
    Feb 1, 2020
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Neoplasms
    Brain Neoplasms
    Memantine

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Registered patients who completed required baseline neurocognitive assessments were randomized. Of 561 registered patients, 518 were randomized.
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Period Title: Overall Study
    STARTED 257 261
    All Randomized Participants 257 261
    Started Protocol Treatment 232 223
    MDASI-BT Symptom Score 249 251
    MDASI-BT Intererence Score 248 251
    MDASI-BT Cognitive Factor Score 249 251
    MDASI-BT Neurologic Factor Score 249 251
    HVLT-R Total Recall 256 259
    HVLT-R Delayed Recall 256 259
    HVLT-R Recognition 255 259
    Trail Making Test (TMT) Part A 256 260
    TMT Part B 250 257
    Controlled Oral Word Association (COWA) 257 261
    Clinical Trial Battery Composite Score 255 259
    EQ-5D-5L Index at 2 Months 142 125
    EQ-5D-5L Index at 4 Months 110 96
    EQ-5D-5L Index at 6 Months 79 70
    EQ-5D-5L Index at 12 Months 56 45
    EQ-5D-5L VAS at 2 Months 139 123
    EQ-5D-5L VAS at 4 Months 104 193
    EQ-5D-5L VAS at 6 Months 76 69
    EQ-5D-5L VAS at 12 Months 57 48
    COMPLETED 257 261
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine Total
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine Total of all reporting groups
    Overall Participants 257 261 518
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    61
    62
    61.5
    Sex: Female, Male (Count of Participants)
    Female
    149
    58%
    150
    57.5%
    299
    57.7%
    Male
    108
    42%
    111
    42.5%
    219
    42.3%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    5
    1.9%
    9
    3.4%
    14
    2.7%
    Not Hispanic or Latino
    231
    89.9%
    229
    87.7%
    460
    88.8%
    Unknown or Not Reported
    21
    8.2%
    23
    8.8%
    44
    8.5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    0.4%
    2
    0.8%
    3
    0.6%
    Asian
    4
    1.6%
    3
    1.1%
    7
    1.4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    23
    8.9%
    29
    11.1%
    52
    10%
    White
    206
    80.2%
    205
    78.5%
    411
    79.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    23
    8.9%
    22
    8.4%
    45
    8.7%
    Primary tumor (Count of Participants)
    Bone
    1
    0.4%
    1
    0.4%
    2
    0.4%
    Breast
    45
    17.5%
    51
    19.5%
    96
    18.5%
    Colon
    6
    2.3%
    4
    1.5%
    10
    1.9%
    Esophagus
    7
    2.7%
    6
    2.3%
    13
    2.5%
    Gastroesophageal Junction
    1
    0.4%
    1
    0.4%
    2
    0.4%
    Kidney
    8
    3.1%
    5
    1.9%
    13
    2.5%
    Lung
    151
    58.8%
    156
    59.8%
    307
    59.3%
    Ovary
    3
    1.2%
    3
    1.1%
    6
    1.2%
    Skin
    7
    2.7%
    15
    5.7%
    22
    4.2%
    Analcanal
    2
    0.8%
    1
    0.4%
    3
    0.6%
    Pancreas
    1
    0.4%
    1
    0.4%
    2
    0.4%
    Other
    25
    9.7%
    17
    6.5%
    42
    8.1%
    Karnofsky Performance Status (Count of Participants)
    70
    53
    20.6%
    48
    18.4%
    101
    19.5%
    80
    75
    29.2%
    81
    31%
    156
    30.1%
    90
    95
    37%
    85
    32.6%
    180
    34.7%
    100
    34
    13.2%
    47
    18%
    81
    15.6%
    Neurologic Function Status (Count of Participants)
    No neurologic symptoms, FA without assistance
    119
    46.3%
    113
    43.3%
    232
    44.8%
    Minor neurologic symptoms, FA without assistance
    86
    33.5%
    92
    35.2%
    178
    34.4%
    Moderate NS, FA but requires assistance
    27
    10.5%
    24
    9.2%
    51
    9.8%
    Moderate NS, less than FA and requires assistance
    15
    5.8%
    18
    6.9%
    33
    6.4%
    Unknown
    9
    3.5%
    13
    5%
    22
    4.2%
    Not Reported
    1
    0.4%
    1
    0.4%
    2
    0.4%
    Recursive Partitioning Analysis (RPA) Class (Count of Participants)
    Class I
    38
    14.8%
    33
    12.6%
    71
    13.7%
    Class II
    219
    85.2%
    228
    87.4%
    447
    86.3%
    Prior Radiosurgery (Count of Participants)
    No
    197
    76.7%
    200
    76.6%
    397
    76.6%
    Yes
    60
    23.3%
    61
    23.4%
    121
    23.4%
    Prior Surgical Resection (Count of Participants)
    No
    189
    73.5%
    198
    75.9%
    387
    74.7%
    Yes
    68
    26.5%
    63
    24.1%
    131
    25.3%
    Metastases (Count of Participants)
    Brain
    98
    38.1%
    98
    37.5%
    196
    37.8%
    Brain and Other Sites
    159
    61.9%
    163
    62.5%
    322
    62.2%
    Education (Count of Participants)
    No formal education
    1
    0.4%
    1
    0.4%
    2
    0.4%
    Grade school
    9
    3.5%
    5
    1.9%
    14
    2.7%
    Not high education graduate
    15
    5.8%
    22
    8.4%
    37
    7.1%
    High school graduate (including equivalency)
    86
    33.5%
    85
    32.6%
    171
    33%
    Some college or associate degree
    68
    26.5%
    71
    27.2%
    139
    26.8%
    Bachelor's Degree
    43
    16.7%
    38
    14.6%
    81
    15.6%
    Master's Degree
    17
    6.6%
    22
    8.4%
    39
    7.5%
    Doctoral degree or professional degree
    5
    1.9%
    8
    3.1%
    13
    2.5%
    Not reported
    13
    5.1%
    9
    3.4%
    22
    4.2%

    Outcome Measures

    1. Primary Outcome
    Title Time to Neurocognitive Failure
    Description Neurocognitive failure is defined as the first failure, defined as a neurocognitive decline using the reliable change index (RCI) on at least one of the following assessments or parts of : Hopkins Verbal Learning Test - Revised (HVLT-R), Trail Making Test (TMT), or Controlled Oral Word Association (COWA). The HVLT-R has 3 parts that were analyzed separately for decline: Total Recall, Delayed Recall, and Delayed Recognition. The TMT has 2 parts that were analyzed separately: Part A and Part B. Neurocognitive failure rate is estimated using the cumulative incidence method. Analysis was planned to occur after 233 events were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided.Analysis was planned to occur after 233 events were reported.
    Time Frame From randomization to last follow-up. Maximum follow-up was 15.6 months.

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 257 261
    Number (95% Confidence Interval) [percentage of participants]
    68.2
    26.5%
    59.3
    22.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments Null hypothesis: the addition of HA-WBRT as compared to WBRT will increase time to neurocognitive failure from 53.8% in the WBRT arm to 42.8% in the HA-WBRT arm at 6 months. Treating death as a competing risk and using a Gray's test with two-sided α=0.05 to test for statistically significant difference in the distribution of neurocognitive failure times, it was calculated that 230 events over both arms would provide 90% statistical power.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.029
    Comments
    Method Gray's test
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.76
    Confidence Interval (2-Sided) 95%
    0.59 to 0.96
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline)
    Description The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.
    Time Frame Baseline, 2, 4, 6, and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with standardized score at baseline
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 149 129
    2 months
    -0.63
    (1.25)
    -0.47
    (1.21)
    4 months
    -0.68
    (1.29)
    -0.36
    (1.16)
    6 months
    -0.34
    (1.33)
    -0.06
    (1.14)
    12 months
    -0.55
    (1.52)
    -0.34
    (1.34)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with HVLT-R Symptom Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0586
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with HVLT-R Symptom Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Age (>61 year vs. <= 61 years) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0048
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with HVLT-R Symptom Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline Total Recall is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    3. Secondary Outcome
    Title Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline)
    Description The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.
    Time Frame Baseline, 2, 4, 6, and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with standardized score at baseline
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 256 259
    2 months
    -0.75
    (1.51)
    -0.73
    (1.53)
    4 months
    -0.88
    (1.61)
    -0.68
    (1.44)
    6 months
    -0.54
    (1.55)
    -0.30
    (1.31)
    12 months
    -0.89
    (1.65)
    -0.87
    (1.71)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with HVLT-R Delayed Recall Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2656
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with HVLT-R Delayed Recall Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Age (> 61 years vs. <= 61 years) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0067
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with HVLT-R Delayed Recall Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline Delayed Recall is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    4. Secondary Outcome
    Title Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline)
    Description The HVLT-R assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials (Total Recall), recalling the 12 targets after a 20-minute delay (Delayed Recall), and then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are derived for total recall (sum of the number of targets correctly recalled), delayed recall (sum of the number of targets correctly recalled), and a delayed recognition discrimination index (sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified). The range of scores for total recall is 0 to 36, for delayed recall is 0 to 12, and -12 to 12 for recognition. A higher score indicates better functioning. Scores are standardized by expressing the deviation from the mean score of the group in units of standard deviation. Change is calculated as baseline score subtracted from post-baseline score.
    Time Frame Baseline, 2, 4, 6, and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline data
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 256 259
    2 months
    -0.69
    (1.90)
    -0.70
    (1.88)
    4 months
    -0.11
    (1.98)
    -0.12
    (1.41)
    6 months
    -0.55
    (1.83)
    -0.06
    (1.40)
    12 months
    -0.48
    (2.12)
    -0.30
    (1.65)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with HVLT-R Delayed Recognition Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0993
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with HVLT-R Delayed Recognition Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Age (> 61 years vs. <= 61 years) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with HVLT-R Delayed Recognition Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline Delayed Recognition is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    5. Secondary Outcome
    Title Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline)
    Description The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order; in the second part (Part B), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete each maze. The range for Part A is 0 to 180 (3 minutes) and for Part B is 0 to 300 (5 minutes). Lower scores indicate better functioning. Scores are standardized, adjusting for age, education, gender as needed, so that mean is 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.
    Time Frame Baseline, 2, 4, 6, and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with standardized score at baseline
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 256 260
    2 months
    -1.42
    (6.27)
    -1.31
    (5.47)
    4 months
    -0.28
    (2.42)
    0.03
    (2.80)
    6 months
    -2.09
    (13.02)
    0.17
    (2.19)
    12 months
    -1.28
    (5.10)
    -0.70
    (3.10)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with TMT Part A (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5988
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with TMT Part A (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Age (> 61 years vs. <= 61 years) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0005
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with TMT Part A (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline TMT Part A is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method McNemar
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    6. Secondary Outcome
    Title Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline)
    Description The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order; in the second part (Part B), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete each maze. The range for Part A is 0 to 180 (3 minutes) and for Part B is 0 to 300 (5 minutes). A lower score indicates better functioning. Scores are standardized by expressing the deviation from the mean score of the group in units of standard deviation. Change is calculated as baseline score subtracted from post-baseline score.
    Time Frame Baseline, 2, 4, 6, and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline data
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 250 257
    2 months
    -2.86
    (16.60)
    -2.27
    (9.91)
    4 months
    -3.38
    (17.88)
    -0.89
    (6.14)
    6 months
    -0.47
    (7.78)
    -1.06
    (6.55)
    12 months
    -2.49
    (8.18)
    -1.44
    (6.59)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with TMT Part B (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9226
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with TMT Part B (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Age (> 61 years vs. <= 61 years) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0024
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with TMT Part B (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline TMT Part B is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Regression, Cox
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    7. Secondary Outcome
    Title Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline)
    Description The COWA is a verbal fluency test that measures spontaneous production of words belonging to the same category or beginning with some designated letter. Patients are given 1 minute to name as many words as possible beginning with the designated letter. The procedure is then repeated for the remaining two letters. Two alternate forms of the COWA are employed to minimize practice effects. The score is the sum of the correct responses with a range of 0 to infinity. A higher score indicates better functioning. Scores are standardized, adjusting for age, education, and gender as necessary, such that mean is 0 and standard deviation is 1. Change is calculated as baseline score subtracted from post-baseline score.
    Time Frame Baseline, 2, 4, 6, and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with standardized score at baseline
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 257 261
    2 months
    -0.28
    (0.96)
    -0.29
    (1.04)
    4 months
    -0.06
    (0.98)
    -0.08
    (0.99)
    6 months
    -0.15
    (0.87)
    -0.11
    (1.04)
    12 months
    -0.44
    (1.71)
    -0.21
    (1.65)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with COWA (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline COWA is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with COWA (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9749
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with COWA (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Age (> 61 years vs. <= 61 years) is reported here. is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    8. Secondary Outcome
    Title Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline]
    Description Clinical Trial Battery Composite score is the arithmetic mean of the HVLT-R (Free Recall, Delayed Recall, Delayed Recognition), TMTA, TMTB, and COWA scores, all of which are standardized, adjusting for age, education, and gender as necessary, such that mean is 0 and standard deviation is 1. A participant must have at least 5 of the 6 scores. A higher composite score indicates better neurocognitive function.Change is calculated as baseline score subtracted from post-baseline score.
    Time Frame Baseline, 2, 4, 6, and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with standardized score at baseline
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 255 259
    2 months
    -1.09
    (3.45)
    -0.87
    (2.35)
    4 months
    -0.81
    (3.22)
    -0.27
    (1.66)
    6 months
    -0.44
    (1.71)
    -0.21
    (1.65)
    12 months
    -0.98
    (2.51)
    -0.61
    (2.00)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with the neurocognitive composite score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2552
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with the neurocognitive composite score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Age (> 61 years vs. <= 61 years) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with the neurocognitive composite score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline composite score is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    9. Secondary Outcome
    Title Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score
    Description The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score (Symptom Severity) is the average of the subscale items, given that a specified minimum numbers of items were completed.
    Time Frame Baseline, 2, 4, 6, and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline data
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 249 251
    2 months
    0.48
    (1.39)
    0.61
    (1.62)
    4 months
    0.29
    (1.50)
    0.36
    (1.46)
    6 months
    0.24
    (1.49)
    -0.09
    (1.34)
    12 months
    0.53
    (1.69)
    0.09
    (1.47)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with MDASI-BT Symptom Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.57
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with MDASI-BT Symptom Severity score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline symptom severity is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A two-sample t-test with a 2-sided type I error of 0.05 provides >90% statistical power to detect a medium effect size of 0.5 for a comparison of the change from baseline to 6 months from the start of treatment. The comparison at six months was tested within a mixed effects model with covariates age, RPA class, prior radiosurgery, prior surgical resection, baseline score, treatment arm, and time was used.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.083
    Comments
    Method Mixed Models Analysis
    Comments
    10. Secondary Outcome
    Title Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score
    Description The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score (Interference) is the average of the subscale items, given that a specified minimum numbers of items were completed.
    Time Frame Baseline, 2, 4, 6, and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline data
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 248 251
    2 months
    0.84
    (2.45)
    1.09
    (2.79)
    4 months
    0.35
    (2.57)
    0.51
    (2.60)
    6 months
    0.57
    (2.61)
    0.01
    (2.72)
    12 months
    0.64
    (2.86)
    0.14
    (3.00)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with MDASI-BT Interference Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9118
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with MDASI-BT Interference Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline interference score is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    11. Secondary Outcome
    Title Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score
    Description The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score (Cognitive Factor) is the average of the subscale items, given that a specified minimum numbers of items were completed.
    Time Frame Baseline, 2, 4, 6, and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline data
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 249 251
    2 months
    0.45
    (1.81)
    0.50
    (1.95)
    4 months
    0.52
    (1.64)
    0.32
    (1.78)
    6 months
    0.57
    (2.61)
    0.01
    (2.72)
    12 months
    1.04
    (2.33)
    0.50
    (1.69)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with MDASI-BT Cognitive Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1964
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with MDASI-BT Cognitive Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline cognitive factor score is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with MDASI-BT Cognitive Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Prior radiotherapy (yes vs. no) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0032
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    12. Secondary Outcome
    Title Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score
    Description The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score (Neurologic Factor) is the average of the subscale items, given that a specified minimum numbers of items were completed.
    Time Frame Baseline, 2, 4, 6, and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline data
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 249 251
    2 months
    0.17
    (1.91)
    0.28
    (2.31)
    4 months
    0.13
    (2.06)
    0.24
    (1.97)
    6 months
    0.23
    (1.89)
    0.15
    (2.11)
    12 months
    0.60
    (2.20)
    0.40
    (2.53)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with MDASI-BT Neurologic Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Treatment Arm (WBRT+Memantine vs. HA-WBRT Memantine) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8877
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with MDASI-BT Neurologic Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Baseline neurologic factor is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments A mixed effects model was run with MDASI-BT Neurologic Factor Score (baseline, 2, 4, 6, and 12 months) as the outcome of interest. Age, RPA class, prior radiosurgery, prior surgical resection were the covariates considered in each model along with interaction terms treatment*time, time*time, time*time*time and remained if p<0.05. Baseline score, treatment arm, and time were forced into the model. Age (> 61 years vs. <= 61 years) is reported here.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0078
    Comments
    Method Mixed Models Analysis
    Comments Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)
    13. Secondary Outcome
    Title Change in EQ-5D-5L Index Score at 2 Months
    Description The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.
    Time Frame Baseline and 2 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline and 2-month scores
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 142 125
    Mean (Standard Deviation) [score on a scale]
    -0.04
    (0.17)
    -0.05
    (0.16)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.86
    Comments Significance level = 0.05
    Method t-test, 2 sided
    Comments
    14. Secondary Outcome
    Title Change in EQ-5D-5L Index Score at 4 Months
    Description The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.
    Time Frame Baseline and 4 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline and 4-month scores
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 110 96
    Mean (Standard Deviation) [score on a scale]
    -0.03
    (0.17)
    -0.03
    (0.16)
    15. Secondary Outcome
    Title Change in EQ-5D-5L Index Score at 6 Months
    Description The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.
    Time Frame Baseline and 6 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline and 4-month scores
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantin
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 79 70
    Mean (Standard Deviation) [score on a scale]
    -0.03
    (0.14)
    -0.03
    (0.17)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.95
    Comments Significance level = 0.05
    Method t-test, 2 sided
    Comments
    16. Secondary Outcome
    Title Change in EQ-5D-5L Index Score at 12 Months
    Description The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The index score is reported here.
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline and 12-month scores
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 56 45
    Mean (Standard Deviation) [score on a scale]
    -0.03
    (0.17)
    -0.01
    (0.14)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.66
    Comments Significance level = 0.05
    Method t-test, 2 sided
    Comments
    17. Secondary Outcome
    Title Change in EQ-5D-5L VAS Score at 2 Months
    Description The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.
    Time Frame Baseline and 2 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline and 2-month scores
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 139 123
    Mean (Standard Deviation) [score on a scale]
    -5.64
    (24.67)
    -1.41
    (25.79)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.18
    Comments Significance level = 0.05
    Method t-test, 2 sided
    Comments
    18. Secondary Outcome
    Title Change in EQ-5D-5L VAS Score at 4 Months
    Description The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.
    Time Frame Baseline and 4 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline and 4-month scores
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 104 93
    Mean (Standard Deviation) [score on a scale]
    -1.35
    (23.14)
    -2.98
    (25.71)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.64
    Comments Significance level = 0.05
    Method t-test, 2 sided
    Comments
    19. Secondary Outcome
    Title Change in EQ-5D-5L VAS Score at 6 Months
    Description The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.
    Time Frame Baseline and 6 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline and 6-month scores
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 76 69
    Mean (Standard Deviation) [score on a scale]
    3.97
    (25.33)
    3.49
    (22.90)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.91
    Comments Significance level = 0.05
    Method t-test, 2 sided
    Comments
    20. Secondary Outcome
    Title Change in EQ-5D-5L VAS Score at 12 Months
    Description The EQ-5D-5L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm scale ranging from 0 for the worst imaginable health state to 100 for best imaginable health state, marked at 10-point intervals. The VAS score is reported here.
    Time Frame Baseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline and 6-month scores
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 57 48
    Mean (Standard Deviation) [score on a scale]
    2.86
    (19.60)
    2.42
    (23.37)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.92
    Comments Significance level = 0.05
    Method t-test, 2 sided
    Comments
    21. Secondary Outcome
    Title Intracranial Progression-Free Survival
    Description Intracranial progression-free survival time is defined as time from registration/randomization to the date of progression in the brain or death from any cause. Intracranial progression-free survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Analysis was planned to occur after 233 primary endpoint events (neurocognitive failure) were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided.
    Time Frame From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months.

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 257 261
    Number (95% Confidence Interval) [percentage of participants]
    43.9
    17.1%
    44.8
    17.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.076
    Comments Two-sided significance level = 0.05
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.20
    Confidence Interval (2-Sided) 95%
    0.98 to 1.47
    Parameter Dispersion Type:
    Value:
    Estimation Comments Reference level = WBRT + Memantine
    22. Secondary Outcome
    Title Overall Survival
    Description Overall survival time is defined as time from registration/randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Analysis was planned to occur after 233 primary endpoint events (neurocognitive failure) were reported. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Six-month rates are provided.
    Time Frame From randomization to last follow-up. Maximum follow-up was 15.6 months.

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 257 261
    Number (95% Confidence Interval) [percentage of participants]
    54.9
    21.4%
    50.6
    19.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.242
    Comments Two-sided significance level = 0.05
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.14
    Confidence Interval (2-Sided) 95%
    0.91 to 1.43
    Parameter Dispersion Type:
    Value:
    Estimation Comments Reference level = WBRT + Memantin
    23. Secondary Outcome
    Title Number of Patients With a Grade 3+ Adverse Event (AE) Regardless of Relationship to Treatment
    Description . Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.
    Time Frame From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months.

    Outcome Measure Data

    Analysis Population Description
    Randomized participants who started protocol treatment
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantine
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    Measure Participants 232 223
    Count of Participants [Participants]
    144
    56%
    131
    50.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection HA-WBRT + Memantine, WBRT + Memantine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.47
    Comments Two-sided p-value = 0.05
    Method Chi-squared
    Comments
    24. Other Pre-specified Outcome
    Title Anxiety/Depression Measured Using the EQ-5D-5L
    Description An exploratory analysis, beginning with correlation coefficients, will be used to assess the association of symptom burden and anxiety/depression with neurocognitive function at each time point. The symptom burden items of interest are the "distressed (upset)", "sad", and "mood" items. From the EQ-5D-5L, the depression/anxiety item will be of interest.
    Time Frame Up to 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    25. Other Pre-specified Outcome
    Title Effect of Radiation Therapy Oncology Group (RTOG) RPA and the Diagnosis-specific Graded Prognostic Assessment (DSGPA) on Neurocognitive Function
    Description Neurocognitive function, as measured by the HVLT-R, COWA, and TMT, will be correlated with both the RTOG RPA and the DS-GPA classification systems. Baseline neurocognitive function for each test will be compared between both RPA classes using either a t-test or Wilcoxon-Mann-Whitney test, depending on the normality of the data.
    Time Frame Up to 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    26. Other Pre-specified Outcome
    Title Effect of White Matter Injury and Hippocampal Volume on Neurocognitive Function
    Description Evaluated through MRI scans using physician-contoured and auto-contoured scores. Concordance rates will be assessed using Kappa statistics. The auto-contoured scores will be used for the remaining analyses due to the number of physicians reviewing the scans. White matter injury is measured by FLAIR volume change and is a continuous variable. Hippocampal volume is measured as a continuous variable also and both will be covariates considered in the Cox proportional hazards model to assess the impact on time to neurocognitive failure and the longitudinal modeling of neurocognitive function.
    Time Frame Up to 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    27. Other Pre-specified Outcome
    Title MDASI-BT Mood Variables
    Description The relationship between EQ-5D-5L and MDASI-BT mood variables and neurocognitive function will be assessed.
    Time Frame Up to 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame From randomization to last follow-up. Maximum follow-up was 15.6 months.
    Adverse Event Reporting Description
    Arm/Group Title HA-WBRT + Memantine WBRT + Memantin
    Arm/Group Description Whole brain radiation therapy (WBRT) and memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
    All Cause Mortality
    HA-WBRT + Memantine WBRT + Memantin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 138/232 (59.5%) 135/223 (60.5%)
    Serious Adverse Events
    HA-WBRT + Memantine WBRT + Memantin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 98/232 (42.2%) 106/222 (47.7%)
    Blood and lymphatic system disorders
    Anemia 3/232 (1.3%) 5/222 (2.3%)
    Febrile neutropenia 0/232 (0%) 1/222 (0.5%)
    Cardiac disorders
    Atrial fibrillation 1/232 (0.4%) 1/222 (0.5%)
    Cardiac disorders - Other 2/232 (0.9%) 0/222 (0%)
    Pericardial effusion 1/232 (0.4%) 1/222 (0.5%)
    Pericardial tamponade 0/232 (0%) 1/222 (0.5%)
    Sinus tachycardia 1/232 (0.4%) 2/222 (0.9%)
    Endocrine disorders
    Cushingoid 0/232 (0%) 1/222 (0.5%)
    Endocrine disorders - Other 2/232 (0.9%) 0/222 (0%)
    Eye disorders
    Blurred vision 1/232 (0.4%) 1/222 (0.5%)
    Gastrointestinal disorders
    Abdominal distension 1/232 (0.4%) 0/222 (0%)
    Abdominal pain 1/232 (0.4%) 3/222 (1.4%)
    Ascites 1/232 (0.4%) 0/222 (0%)
    Bloating 0/232 (0%) 1/222 (0.5%)
    Colitis 0/232 (0%) 2/222 (0.9%)
    Constipation 3/232 (1.3%) 2/222 (0.9%)
    Diarrhea 0/232 (0%) 2/222 (0.9%)
    Dyspepsia 0/232 (0%) 1/222 (0.5%)
    Dysphagia 0/232 (0%) 4/222 (1.8%)
    Enterocolitis 0/232 (0%) 1/222 (0.5%)
    Esophageal hemorrhage 1/232 (0.4%) 0/222 (0%)
    Esophageal obstruction 0/232 (0%) 1/222 (0.5%)
    Esophagitis 0/232 (0%) 1/222 (0.5%)
    Gastrointestinal disorders - Other 1/232 (0.4%) 1/222 (0.5%)
    Gastrointestinal pain 1/232 (0.4%) 0/222 (0%)
    Ileus 1/232 (0.4%) 1/222 (0.5%)
    Lower gastrointestinal hemorrhage 1/232 (0.4%) 1/222 (0.5%)
    Nausea 5/232 (2.2%) 4/222 (1.8%)
    Pancreatic hemorrhage 0/232 (0%) 1/222 (0.5%)
    Pancreatitis 0/232 (0%) 1/222 (0.5%)
    Small intestinal perforation 2/232 (0.9%) 0/222 (0%)
    Upper gastrointestinal hemorrhage 1/232 (0.4%) 0/222 (0%)
    Vomiting 4/232 (1.7%) 5/222 (2.3%)
    General disorders
    Chills 1/232 (0.4%) 0/222 (0%)
    Death NOS 6/232 (2.6%) 9/222 (4.1%)
    Edema limbs 1/232 (0.4%) 1/222 (0.5%)
    Fatigue 1/232 (0.4%) 12/222 (5.4%)
    Fever 2/232 (0.9%) 3/222 (1.4%)
    Flu like symptoms 1/232 (0.4%) 1/222 (0.5%)
    Gait disturbance 1/232 (0.4%) 2/222 (0.9%)
    General disorders and administration site conditions - Other 2/232 (0.9%) 2/222 (0.9%)
    Infusion related reaction 1/232 (0.4%) 0/222 (0%)
    Localized edema 0/232 (0%) 1/222 (0.5%)
    Multi-organ failure 1/232 (0.4%) 1/222 (0.5%)
    Non-cardiac chest pain 0/232 (0%) 1/222 (0.5%)
    Pain 2/232 (0.9%) 4/222 (1.8%)
    Sudden death NOS 1/232 (0.4%) 0/222 (0%)
    Hepatobiliary disorders
    Bile duct stenosis 1/232 (0.4%) 0/222 (0%)
    Gallbladder obstruction 0/232 (0%) 1/222 (0.5%)
    Hepatic failure 0/232 (0%) 1/222 (0.5%)
    Hepatic pain 1/232 (0.4%) 0/222 (0%)
    Hepatobiliary disorders - Other 1/232 (0.4%) 0/222 (0%)
    Immune system disorders
    Allergic reaction 0/232 (0%) 1/222 (0.5%)
    Infections and infestations
    Abdominal infection 1/232 (0.4%) 0/222 (0%)
    Appendicitis 0/232 (0%) 1/222 (0.5%)
    Bone infection 1/232 (0.4%) 1/222 (0.5%)
    Bronchial infection 0/232 (0%) 1/222 (0.5%)
    Catheter related infection 1/232 (0.4%) 1/222 (0.5%)
    Encephalitis infection 1/232 (0.4%) 0/222 (0%)
    Endocarditis infective 1/232 (0.4%) 0/222 (0%)
    Infections and infestations - Other 2/232 (0.9%) 2/222 (0.9%)
    Lung infection 4/232 (1.7%) 7/222 (3.2%)
    Mucosal infection 1/232 (0.4%) 0/222 (0%)
    Peritoneal infection 1/232 (0.4%) 0/222 (0%)
    Sepsis 8/232 (3.4%) 5/222 (2.3%)
    Small intestine infection 1/232 (0.4%) 0/222 (0%)
    Upper respiratory infection 0/232 (0%) 1/222 (0.5%)
    Urinary tract infection 4/232 (1.7%) 4/222 (1.8%)
    Wound infection 1/232 (0.4%) 1/222 (0.5%)
    Injury, poisoning and procedural complications
    Fall 1/232 (0.4%) 4/222 (1.8%)
    Wound dehiscence 0/232 (0%) 1/222 (0.5%)
    Investigations
    Alanine aminotransferase increased 0/232 (0%) 1/222 (0.5%)
    Alkaline phosphatase increased 0/232 (0%) 1/222 (0.5%)
    Aspartate aminotransferase increased 0/232 (0%) 1/222 (0.5%)
    Blood bilirubin increased 0/232 (0%) 1/222 (0.5%)
    Creatinine increased 1/232 (0.4%) 0/222 (0%)
    INR increased 1/232 (0.4%) 1/222 (0.5%)
    Investigations - Other 0/232 (0%) 2/222 (0.9%)
    Neutrophil count decreased 0/232 (0%) 3/222 (1.4%)
    Platelet count decreased 1/232 (0.4%) 2/222 (0.9%)
    Weight loss 0/232 (0%) 2/222 (0.9%)
    White blood cell decreased 0/232 (0%) 2/222 (0.9%)
    Metabolism and nutrition disorders
    Anorexia 1/232 (0.4%) 2/222 (0.9%)
    Dehydration 2/232 (0.9%) 7/222 (3.2%)
    Hypercalcemia 2/232 (0.9%) 2/222 (0.9%)
    Hyperglycemia 3/232 (1.3%) 1/222 (0.5%)
    Hypocalcemia 0/232 (0%) 1/222 (0.5%)
    Hypoglycemia 0/232 (0%) 1/222 (0.5%)
    Hypokalemia 1/232 (0.4%) 2/222 (0.9%)
    Hypomagnesemia 0/232 (0%) 1/222 (0.5%)
    Hyponatremia 4/232 (1.7%) 4/222 (1.8%)
    Metabolism and nutrition disorders - Other 0/232 (0%) 2/222 (0.9%)
    Musculoskeletal and connective tissue disorders
    Back pain 4/232 (1.7%) 3/222 (1.4%)
    Bone pain 0/232 (0%) 1/222 (0.5%)
    Chest wall pain 0/232 (0%) 1/222 (0.5%)
    Generalized muscle weakness 10/232 (4.3%) 7/222 (3.2%)
    Muscle weakness left-sided 1/232 (0.4%) 1/222 (0.5%)
    Muscle weakness lower limb 2/232 (0.9%) 2/222 (0.9%)
    Muscle weakness right-sided 1/232 (0.4%) 1/222 (0.5%)
    Muscle weakness upper limb 0/232 (0%) 1/222 (0.5%)
    Musculoskeletal and connective tissue disorder - Other 2/232 (0.9%) 0/222 (0%)
    Neck pain 1/232 (0.4%) 0/222 (0%)
    Pain in extremity 2/232 (0.9%) 1/222 (0.5%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 13/232 (5.6%) 9/222 (4.1%)
    Tumor pain 2/232 (0.9%) 1/222 (0.5%)
    Nervous system disorders
    Ataxia 0/232 (0%) 1/222 (0.5%)
    Cognitive disturbance 1/232 (0.4%) 2/222 (0.9%)
    Depressed level of consciousness 0/232 (0%) 1/222 (0.5%)
    Dizziness 1/232 (0.4%) 3/222 (1.4%)
    Dysgeusia 0/232 (0%) 1/222 (0.5%)
    Edema cerebral 1/232 (0.4%) 1/222 (0.5%)
    Encephalopathy 2/232 (0.9%) 0/222 (0%)
    Headache 5/232 (2.2%) 6/222 (2.7%)
    Hydrocephalus 0/232 (0%) 1/222 (0.5%)
    Intracranial hemorrhage 1/232 (0.4%) 2/222 (0.9%)
    Ischemia cerebrovascular 0/232 (0%) 1/222 (0.5%)
    Lethargy 1/232 (0.4%) 0/222 (0%)
    Memory impairment 0/232 (0%) 1/222 (0.5%)
    Movements involuntary 0/232 (0%) 1/222 (0.5%)
    Nervous system disorders - Other 5/232 (2.2%) 0/222 (0%)
    Paresthesia 0/232 (0%) 1/222 (0.5%)
    Peripheral motor neuropathy 0/232 (0%) 2/222 (0.9%)
    Peripheral sensory neuropathy 1/232 (0.4%) 1/222 (0.5%)
    Seizure 7/232 (3%) 0/222 (0%)
    Somnolence 0/232 (0%) 1/222 (0.5%)
    Stroke 2/232 (0.9%) 1/222 (0.5%)
    Syncope 1/232 (0.4%) 0/222 (0%)
    Psychiatric disorders
    Confusion 6/232 (2.6%) 7/222 (3.2%)
    Delirium 1/232 (0.4%) 2/222 (0.9%)
    Depression 1/232 (0.4%) 0/222 (0%)
    Hallucinations 1/232 (0.4%) 0/222 (0%)
    Psychiatric disorders - Other 1/232 (0.4%) 1/222 (0.5%)
    Suicidal ideation 2/232 (0.9%) 0/222 (0%)
    Renal and urinary disorders
    Acute kidney injury 2/232 (0.9%) 4/222 (1.8%)
    Chronic kidney disease 1/232 (0.4%) 0/222 (0%)
    Renal and urinary disorders - Other 1/232 (0.4%) 1/222 (0.5%)
    Renal calculi 1/232 (0.4%) 0/222 (0%)
    Urinary incontinence 0/232 (0%) 1/222 (0.5%)
    Urinary retention 2/232 (0.9%) 0/222 (0%)
    Urinary urgency 1/232 (0.4%) 0/222 (0%)
    Respiratory, thoracic and mediastinal disorders
    Aspiration 1/232 (0.4%) 1/222 (0.5%)
    Bronchopulmonary hemorrhage 1/232 (0.4%) 0/222 (0%)
    Cough 0/232 (0%) 1/222 (0.5%)
    Dyspnea 5/232 (2.2%) 9/222 (4.1%)
    Hypoxia 1/232 (0.4%) 3/222 (1.4%)
    Pleural effusion 4/232 (1.7%) 3/222 (1.4%)
    Pleuritic pain 0/232 (0%) 1/222 (0.5%)
    Pneumonitis 1/232 (0.4%) 2/222 (0.9%)
    Pneumothorax 0/232 (0%) 1/222 (0.5%)
    Respiratory failure 1/232 (0.4%) 6/222 (2.7%)
    Skin and subcutaneous tissue disorders
    Alopecia 0/232 (0%) 1/222 (0.5%)
    Skin and subcutaneous tissue disorders - Other 1/232 (0.4%) 0/222 (0%)
    Skin ulceration 0/232 (0%) 1/222 (0.5%)
    Surgical and medical procedures
    Surgical and medical procedures - Other 0/232 (0%) 1/222 (0.5%)
    Vascular disorders
    Hypertension 1/232 (0.4%) 0/222 (0%)
    Hypotension 2/232 (0.9%) 2/222 (0.9%)
    Peripheral ischemia 0/232 (0%) 1/222 (0.5%)
    Superior vena cava syndrome 1/232 (0.4%) 0/222 (0%)
    Thromboembolic event 12/232 (5.2%) 14/222 (6.3%)
    Vascular disorders - Other 0/232 (0%) 1/222 (0.5%)
    Other (Not Including Serious) Adverse Events
    HA-WBRT + Memantine WBRT + Memantin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 214/232 (92.2%) 201/223 (90.1%)
    Blood and lymphatic system disorders
    Anemia 38/232 (16.4%) 43/223 (19.3%)
    Ear and labyrinth disorders
    Hearing impaired 15/232 (6.5%) 16/223 (7.2%)
    Eye disorders
    Blurred vision 31/232 (13.4%) 23/223 (10.3%)
    Gastrointestinal disorders
    Abdominal pain 25/232 (10.8%) 13/223 (5.8%)
    Constipation 60/232 (25.9%) 41/223 (18.4%)
    Diarrhea 34/232 (14.7%) 19/223 (8.5%)
    Dry mouth 21/232 (9.1%) 18/223 (8.1%)
    Dysphagia 13/232 (5.6%) 14/223 (6.3%)
    Nausea 105/232 (45.3%) 89/223 (39.9%)
    Vomiting 43/232 (18.5%) 34/223 (15.2%)
    General disorders
    Edema limbs 25/232 (10.8%) 18/223 (8.1%)
    Fatigue 157/232 (67.7%) 143/223 (64.1%)
    Gait disturbance 27/232 (11.6%) 22/223 (9.9%)
    Pain 26/232 (11.2%) 28/223 (12.6%)
    Infections and infestations
    Mucosal infection 10/232 (4.3%) 12/223 (5.4%)
    Injury, poisoning and procedural complications
    Dermatitis radiation 18/232 (7.8%) 11/223 (4.9%)
    Fall 15/232 (6.5%) 23/223 (10.3%)
    Investigations
    Alanine aminotransferase increased 11/232 (4.7%) 13/223 (5.8%)
    Alkaline phosphatase increased 10/232 (4.3%) 17/223 (7.6%)
    Aspartate aminotransferase increased 6/232 (2.6%) 12/223 (5.4%)
    Lymphocyte count decreased 22/232 (9.5%) 25/223 (11.2%)
    Platelet count decreased 16/232 (6.9%) 17/223 (7.6%)
    Weight loss 44/232 (19%) 31/223 (13.9%)
    White blood cell decreased 13/232 (5.6%) 20/223 (9%)
    Metabolism and nutrition disorders
    Anorexia 73/232 (31.5%) 69/223 (30.9%)
    Dehydration 13/232 (5.6%) 15/223 (6.7%)
    Hyperglycemia 14/232 (6%) 20/223 (9%)
    Hypoalbuminemia 20/232 (8.6%) 18/223 (8.1%)
    Hypocalcemia 14/232 (6%) 6/223 (2.7%)
    Hypokalemia 21/232 (9.1%) 18/223 (8.1%)
    Hyponatremia 22/232 (9.5%) 17/223 (7.6%)
    Musculoskeletal and connective tissue disorders
    Back pain 28/232 (12.1%) 26/223 (11.7%)
    Generalized muscle weakness 49/232 (21.1%) 42/223 (18.8%)
    Muscle weakness lower limb 11/232 (4.7%) 12/223 (5.4%)
    Pain in extremity 13/232 (5.6%) 6/223 (2.7%)
    Nervous system disorders
    Dizziness 59/232 (25.4%) 51/223 (22.9%)
    Dysgeusia 18/232 (7.8%) 23/223 (10.3%)
    Headache 100/232 (43.1%) 84/223 (37.7%)
    Memory impairment 28/232 (12.1%) 26/223 (11.7%)
    Nervous system disorders - Other 13/232 (5.6%) 7/223 (3.1%)
    Paresthesia 16/232 (6.9%) 13/223 (5.8%)
    Peripheral sensory neuropathy 17/232 (7.3%) 17/223 (7.6%)
    Seizure 16/232 (6.9%) 9/223 (4%)
    Tremor 12/232 (5.2%) 18/223 (8.1%)
    Psychiatric disorders
    Anxiety 23/232 (9.9%) 17/223 (7.6%)
    Confusion 26/232 (11.2%) 26/223 (11.7%)
    Depression 25/232 (10.8%) 17/223 (7.6%)
    Insomnia 32/232 (13.8%) 26/223 (11.7%)
    Respiratory, thoracic and mediastinal disorders
    Cough 45/232 (19.4%) 38/223 (17%)
    Dyspnea 50/232 (21.6%) 50/223 (22.4%)
    Skin and subcutaneous tissue disorders
    Alopecia 70/232 (30.2%) 54/223 (24.2%)
    Pruritus 13/232 (5.6%) 6/223 (2.7%)
    Vascular disorders
    Hypertension 13/232 (5.6%) 17/223 (7.6%)
    Hypotension 10/232 (4.3%) 12/223 (5.4%)
    Thromboembolic event 13/232 (5.6%) 8/223 (3.6%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Must obtain prior Sponsor approval.

    Results Point of Contact

    Name/Title Wendy Seiferheld
    Organization NRG Oncology
    Phone 215-574-3208
    Email seiferheldw@nrgoncology.org
    Responsible Party:
    NRG Oncology
    ClinicalTrials.gov Identifier:
    NCT02360215
    Other Study ID Numbers:
    • NRG-CC001
    • NCI-2015-00030
    • NRG-CC001
    • NRG-CC001
    • NRG-CC001
    • UG1CA189867
    First Posted:
    Feb 10, 2015
    Last Update Posted:
    Jun 2, 2021
    Last Verified:
    Feb 1, 2020