Trial Outcomes & Findings for Memantine Hydrochloride and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Reducing Neurocognitive Decline in Patients With Brain Metastases (NCT NCT02360215)

NCT ID: NCT02360215

Last Updated: 2025-04-23

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 518 participants
• Primary outcome timeframe: From randomization to last follow-up. Maximum follow-up was 15.6 months.
• Results posted on: 2025-04-23

Participant Flow

Registered patients who completed required baseline neurocognitive assessments were randomized. Of 561 registered patients, 518 were randomized.

Participant milestones

Measure	WBRT + Memantine Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Overall Study STARTED	257	261
Overall Study All Randomized Participants	257	261
Overall Study Started Protocol Treatment	232	223
Overall Study MDASI-BT Symptom Score	249	251
Overall Study MDASI-BT Intererence Score	248	251
Overall Study MDASI-BT Cognitive Factor Score	249	251
Overall Study MDASI-BT Neurologic Factor Score	249	251
Overall Study HVLT-R Total Recall	256	259
Overall Study HVLT-R Delayed Recall	256	259
Overall Study HVLT-R Recognition	255	259
Overall Study Trail Making Test (TMT) Part A	256	260
Overall Study TMT Part B	250	257
Overall Study Controlled Oral Word Association (COWA)	257	261
Overall Study Clinical Trial Battery Composite Score	255	259
Overall Study EQ-5D-5L Index at 2 Months	142	125
Overall Study EQ-5D-5L Index at 4 Months	110	96
Overall Study EQ-5D-5L Index at 6 Months	79	70
Overall Study EQ-5D-5L Index at 12 Months	56	45
Overall Study EQ-5D-5L VAS at 2 Months	139	123
Overall Study EQ-5D-5L VAS at 4 Months	104	193
Overall Study EQ-5D-5L VAS at 6 Months	76	69
Overall Study EQ-5D-5L VAS at 12 Months	57	48
Overall Study COMPLETED	257	261
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	WBRT + Memantine n=257 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=261 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine	Total n=518 Participants Total of all reporting groups
Age, Continuous	61 years n=5 Participants	62 years n=7 Participants	61.5 years n=5 Participants
Sex: Female, Male Female	149 Participants n=5 Participants	150 Participants n=7 Participants	299 Participants n=5 Participants
Sex: Female, Male Male	108 Participants n=5 Participants	111 Participants n=7 Participants	219 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants	9 Participants n=7 Participants	14 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	231 Participants n=5 Participants	229 Participants n=7 Participants	460 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	21 Participants n=5 Participants	23 Participants n=7 Participants	44 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	23 Participants n=5 Participants	29 Participants n=7 Participants	52 Participants n=5 Participants
Race (NIH/OMB) White	206 Participants n=5 Participants	205 Participants n=7 Participants	411 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	23 Participants n=5 Participants	22 Participants n=7 Participants	45 Participants n=5 Participants
Primary tumor Bone	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Primary tumor Breast	45 Participants n=5 Participants	51 Participants n=7 Participants	96 Participants n=5 Participants
Primary tumor Colon	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants
Primary tumor Esophagus	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Primary tumor Gastroesophageal Junction	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Primary tumor Kidney	8 Participants n=5 Participants	5 Participants n=7 Participants	13 Participants n=5 Participants
Primary tumor Lung	151 Participants n=5 Participants	156 Participants n=7 Participants	307 Participants n=5 Participants
Primary tumor Ovary	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Primary tumor Skin	7 Participants n=5 Participants	15 Participants n=7 Participants	22 Participants n=5 Participants
Primary tumor Analcanal	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Primary tumor Pancreas	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Primary tumor Other	25 Participants n=5 Participants	17 Participants n=7 Participants	42 Participants n=5 Participants
Karnofsky Performance Status 70	53 Participants n=5 Participants	48 Participants n=7 Participants	101 Participants n=5 Participants
Karnofsky Performance Status 80	75 Participants n=5 Participants	81 Participants n=7 Participants	156 Participants n=5 Participants
Karnofsky Performance Status 90	95 Participants n=5 Participants	85 Participants n=7 Participants	180 Participants n=5 Participants
Karnofsky Performance Status 100	34 Participants n=5 Participants	47 Participants n=7 Participants	81 Participants n=5 Participants
Neurologic Function Status No neurologic symptoms, FA without assistance	119 Participants n=5 Participants	113 Participants n=7 Participants	232 Participants n=5 Participants
Neurologic Function Status Minor neurologic symptoms, FA without assistance	86 Participants n=5 Participants	92 Participants n=7 Participants	178 Participants n=5 Participants
Neurologic Function Status Moderate NS, FA but requires assistance	27 Participants n=5 Participants	24 Participants n=7 Participants	51 Participants n=5 Participants
Neurologic Function Status Moderate NS, less than FA and requires assistance	15 Participants n=5 Participants	18 Participants n=7 Participants	33 Participants n=5 Participants
Neurologic Function Status Unknown	9 Participants n=5 Participants	13 Participants n=7 Participants	22 Participants n=5 Participants
Neurologic Function Status Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Recursive Partitioning Analysis (RPA) Class Class I	38 Participants n=5 Participants	33 Participants n=7 Participants	71 Participants n=5 Participants
Recursive Partitioning Analysis (RPA) Class Class II	219 Participants n=5 Participants	228 Participants n=7 Participants	447 Participants n=5 Participants
Prior Radiosurgery No	197 Participants n=5 Participants	200 Participants n=7 Participants	397 Participants n=5 Participants
Prior Radiosurgery Yes	60 Participants n=5 Participants	61 Participants n=7 Participants	121 Participants n=5 Participants
Prior Surgical Resection No	189 Participants n=5 Participants	198 Participants n=7 Participants	387 Participants n=5 Participants
Prior Surgical Resection Yes	68 Participants n=5 Participants	63 Participants n=7 Participants	131 Participants n=5 Participants
Metastases Brain	98 Participants n=5 Participants	98 Participants n=7 Participants	196 Participants n=5 Participants
Metastases Brain and Other Sites	159 Participants n=5 Participants	163 Participants n=7 Participants	322 Participants n=5 Participants
Education No formal education	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Education Grade school	9 Participants n=5 Participants	5 Participants n=7 Participants	14 Participants n=5 Participants
Education Not high education graduate	15 Participants n=5 Participants	22 Participants n=7 Participants	37 Participants n=5 Participants
Education High school graduate (including equivalency)	86 Participants n=5 Participants	85 Participants n=7 Participants	171 Participants n=5 Participants
Education Some college or associate degree	68 Participants n=5 Participants	71 Participants n=7 Participants	139 Participants n=5 Participants
Education Bachelor's Degree	43 Participants n=5 Participants	38 Participants n=7 Participants	81 Participants n=5 Participants
Education Master's Degree	17 Participants n=5 Participants	22 Participants n=7 Participants	39 Participants n=5 Participants
Education Doctoral degree or professional degree	5 Participants n=5 Participants	8 Participants n=7 Participants	13 Participants n=5 Participants
Education Not reported	13 Participants n=5 Participants	9 Participants n=7 Participants	22 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization to last follow-up. Maximum follow-up was 15.6 months.

Population: All randomized participants

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.

Outcome measures

Measure	WBRT + Memantine n=257 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=261 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Time to Neurocognitive Failure	68.2 percentage of participants Interval 61.2 to 74.2	59.3 percentage of participants Interval 51.9 to 66.0

SECONDARY outcome

Timeframe: Baseline, 2, 4, 6, and 12 months

Population: Participants with standardized score at baseline

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.

Outcome measures

Measure	WBRT + Memantine n=149 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=129 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) 2 months	-0.63 units on a scale Standard Deviation 1.25	-0.47 units on a scale Standard Deviation 1.21
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) 4 months	-0.68 units on a scale Standard Deviation 1.29	-0.36 units on a scale Standard Deviation 1.16
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) 6 months	-0.34 units on a scale Standard Deviation 1.33	-0.06 units on a scale Standard Deviation 1.14
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) 12 months	-0.55 units on a scale Standard Deviation 1.52	-0.34 units on a scale Standard Deviation 1.34

SECONDARY outcome

Timeframe: Baseline, 2, 4, 6, and 12 months

Population: Participants with standardized score at baseline

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.

Outcome measures

Measure	WBRT + Memantine n=256 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=259 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) 2 months	-0.75 units on a scale Standard Deviation 1.51	-0.73 units on a scale Standard Deviation 1.53
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) 4 months	-0.88 units on a scale Standard Deviation 1.61	-0.68 units on a scale Standard Deviation 1.44
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) 6 months	-0.54 units on a scale Standard Deviation 1.55	-0.30 units on a scale Standard Deviation 1.31
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) 12 months	-0.89 units on a scale Standard Deviation 1.65	-0.87 units on a scale Standard Deviation 1.71

SECONDARY outcome

Timeframe: Baseline, 2, 4, 6, and 12 months

Population: Participants with baseline data

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.

Outcome measures

Measure	WBRT + Memantine n=256 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=259 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) 2 months	-0.69 units on a scale Standard Deviation 1.90	-0.70 units on a scale Standard Deviation 1.88
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) 4 months	-0.11 units on a scale Standard Deviation 1.98	-0.12 units on a scale Standard Deviation 1.41
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) 6 months	-0.55 units on a scale Standard Deviation 1.83	-0.06 units on a scale Standard Deviation 1.40
Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) 12 months	-0.48 units on a scale Standard Deviation 2.12	-0.30 units on a scale Standard Deviation 1.65

SECONDARY outcome

Timeframe: Baseline, 2, 4, 6, and 12 months

Population: Participants with standardized score at baseline

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.

Outcome measures

Measure	WBRT + Memantine n=256 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=260 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) 2 months	-1.42 units on a scale Standard Deviation 6.27	-1.31 units on a scale Standard Deviation 5.47
Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) 4 months	-0.28 units on a scale Standard Deviation 2.42	0.03 units on a scale Standard Deviation 2.80
Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) 6 months	-2.09 units on a scale Standard Deviation 13.02	0.17 units on a scale Standard Deviation 2.19
Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) 12 months	-1.28 units on a scale Standard Deviation 5.10	-0.70 units on a scale Standard Deviation 3.10

SECONDARY outcome

Timeframe: Baseline, 2, 4, 6, and 12 months

Population: Participants with baseline data

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.

Outcome measures

Measure	WBRT + Memantine n=250 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=257 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) 2 months	-2.86 units on a scale Standard Deviation 16.60	-2.27 units on a scale Standard Deviation 9.91
Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) 4 months	-3.38 units on a scale Standard Deviation 17.88	-0.89 units on a scale Standard Deviation 6.14
Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) 6 months	-0.47 units on a scale Standard Deviation 7.78	-1.06 units on a scale Standard Deviation 6.55
Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) 12 months	-2.49 units on a scale Standard Deviation 8.18	-1.44 units on a scale Standard Deviation 6.59

SECONDARY outcome

Timeframe: Baseline, 2, 4, 6, and 12 months

Population: Participants with standardized score at baseline

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.

Outcome measures

Measure	WBRT + Memantine n=257 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=261 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) 2 months	-0.28 units on a scale Standard Deviation 0.96	-0.29 units on a scale Standard Deviation 1.04
Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) 4 months	-0.06 units on a scale Standard Deviation 0.98	-0.08 units on a scale Standard Deviation 0.99
Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) 6 months	-0.15 units on a scale Standard Deviation 0.87	-0.11 units on a scale Standard Deviation 1.04
Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) 12 months	-0.44 units on a scale Standard Deviation 1.71	-0.21 units on a scale Standard Deviation 1.65

SECONDARY outcome

Timeframe: Baseline, 2, 4, 6, and 12 months

Population: Participants with standardized score at baseline

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.

Outcome measures

Measure	WBRT + Memantine n=255 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=259 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] 2 months	-1.09 units on a scale Standard Deviation 3.45	-0.87 units on a scale Standard Deviation 2.35
Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] 4 months	-0.81 units on a scale Standard Deviation 3.22	-0.27 units on a scale Standard Deviation 1.66
Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] 6 months	-0.44 units on a scale Standard Deviation 1.71	-0.21 units on a scale Standard Deviation 1.65
Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] 12 months	-0.98 units on a scale Standard Deviation 2.51	-0.61 units on a scale Standard Deviation 2.00

SECONDARY outcome

Timeframe: Baseline, 2, 4, 6, and 12 months

Population: Participants with baseline data

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.

Outcome measures

Measure	WBRT + Memantine n=249 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=251 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score 2 months	0.48 score on a scale Standard Deviation 1.39	0.61 score on a scale Standard Deviation 1.62
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score 4 months	0.29 score on a scale Standard Deviation 1.50	0.36 score on a scale Standard Deviation 1.46
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score 6 months	0.24 score on a scale Standard Deviation 1.49	-0.09 score on a scale Standard Deviation 1.34
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score 12 months	0.53 score on a scale Standard Deviation 1.69	0.09 score on a scale Standard Deviation 1.47

SECONDARY outcome

Timeframe: Baseline, 2, 4, 6, and 12 months

Population: Participants with baseline data

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.

Outcome measures

Measure	WBRT + Memantine n=248 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=251 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score 6 months	0.57 score on a scale Standard Deviation 2.61	0.01 score on a scale Standard Deviation 2.72
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score 12 months	0.64 score on a scale Standard Deviation 2.86	0.14 score on a scale Standard Deviation 3.00
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score 2 months	0.84 score on a scale Standard Deviation 2.45	1.09 score on a scale Standard Deviation 2.79
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score 4 months	0.35 score on a scale Standard Deviation 2.57	0.51 score on a scale Standard Deviation 2.60

SECONDARY outcome

Timeframe: Baseline, 2, 4, 6, and 12 months

Population: Participants with baseline data

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.

Outcome measures

Measure	WBRT + Memantine n=249 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=251 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score 2 months	0.45 score on a scale Standard Deviation 1.81	0.50 score on a scale Standard Deviation 1.95
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score 4 months	0.52 score on a scale Standard Deviation 1.64	0.32 score on a scale Standard Deviation 1.78
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score 6 months	0.57 score on a scale Standard Deviation 2.61	0.01 score on a scale Standard Deviation 2.72
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score 12 months	1.04 score on a scale Standard Deviation 2.33	0.50 score on a scale Standard Deviation 1.69

SECONDARY outcome

Timeframe: Baseline, 2, 4, 6, and 12 months

Population: Participants with baseline data

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.

Outcome measures

Measure	WBRT + Memantine n=249 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=251 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score 2 months	0.17 score on a scale Standard Deviation 1.91	0.28 score on a scale Standard Deviation 2.31
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score 4 months	0.13 score on a scale Standard Deviation 2.06	0.24 score on a scale Standard Deviation 1.97
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score 6 months	0.23 score on a scale Standard Deviation 1.89	0.15 score on a scale Standard Deviation 2.11
Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score 12 months	0.60 score on a scale Standard Deviation 2.20	0.40 score on a scale Standard Deviation 2.53

SECONDARY outcome

Timeframe: Baseline and 2 months

Population: Participants with baseline and 2-month scores

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.

Outcome measures

Measure	WBRT + Memantine n=142 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=125 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in EQ-5D-5L Index Score at 2 Months	-0.04 score on a scale Standard Deviation 0.17	-0.05 score on a scale Standard Deviation 0.16

SECONDARY outcome

Timeframe: Baseline and 4 months

Population: Participants with baseline and 4-month scores

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.

Outcome measures

Measure	WBRT + Memantine n=110 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=96 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in EQ-5D-5L Index Score at 4 Months	-0.03 score on a scale Standard Deviation 0.17	-0.03 score on a scale Standard Deviation 0.16

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: Participants with baseline and 4-month scores

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.

Outcome measures

Measure	WBRT + Memantine n=79 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=70 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in EQ-5D-5L Index Score at 6 Months	-0.03 score on a scale Standard Deviation 0.14	-0.03 score on a scale Standard Deviation 0.17

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: Participants with baseline and 12-month scores

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.

Outcome measures

Measure	WBRT + Memantine n=56 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=45 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in EQ-5D-5L Index Score at 12 Months	-0.03 score on a scale Standard Deviation 0.17	-0.01 score on a scale Standard Deviation 0.14

SECONDARY outcome

Timeframe: Baseline and 2 months

Population: Participants with baseline and 2-month scores

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.

Outcome measures

Measure	WBRT + Memantine n=139 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=123 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in EQ-5D-5L VAS Score at 2 Months	-5.64 score on a scale Standard Deviation 24.67	-1.41 score on a scale Standard Deviation 25.79

SECONDARY outcome

Timeframe: Baseline and 4 months

Population: Participants with baseline and 4-month scores

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.

Outcome measures

Measure	WBRT + Memantine n=104 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=93 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in EQ-5D-5L VAS Score at 4 Months	-1.35 score on a scale Standard Deviation 23.14	-2.98 score on a scale Standard Deviation 25.71

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: Participants with baseline and 6-month scores

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.

Outcome measures

Measure	WBRT + Memantine n=76 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=69 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in EQ-5D-5L VAS Score at 6 Months	3.97 score on a scale Standard Deviation 25.33	3.49 score on a scale Standard Deviation 22.90

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: Participants with baseline and 6-month scores

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.

Outcome measures

Measure	WBRT + Memantine n=57 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=48 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Change in EQ-5D-5L VAS Score at 12 Months	2.86 score on a scale Standard Deviation 19.60	2.42 score on a scale Standard Deviation 23.37

SECONDARY outcome

Timeframe: From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months.

Population: All randomized participants

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.

Outcome measures

Measure	WBRT + Memantine n=257 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=261 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Intracranial Progression-Free Survival	43.9 percentage of participants Interval 37.5 to 50.2	44.8 percentage of participants Interval 38.5 to 51.2

SECONDARY outcome

Timeframe: From randomization to last follow-up. Maximum follow-up was 15.6 months.

Population: All randomized participants

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.

Outcome measures

Measure	WBRT + Memantine n=257 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=261 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Overall Survival	54.9 percentage of participants Interval 48.6 to 61.2	50.6 percentage of participants Interval 44.2 to 57.0

SECONDARY outcome

Timeframe: From randomization to last follow-up. Analysis was planned to occur after 233 events were reported. Maximum follow-up was 15.6 months.

Population: Randomized participants who started protocol treatment

. 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.

Outcome measures

Measure	WBRT + Memantine n=232 Participants Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantine n=223 Participants Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Number of Patients With a Grade 3+ Adverse Event (AE) Regardless of Relationship to Treatment	144 Participants	131 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 12 months

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

Outcome measures

Outcome data not reported

Adverse Events

WBRT + Memantine

Serious events: 98 serious events

Other events: 214 other events

Deaths: 138 deaths

HA-WBRT + Memantin

Serious events: 106 serious events

Other events: 201 other events

Deaths: 135 deaths

Serious adverse events

Measure	WBRT + Memantine n=232 participants at risk Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantin n=223 participants at risk Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Cardiac disorders Pericardial tamponade	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Cardiac disorders Sinus tachycardia	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Endocrine disorders Cushingoid	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Endocrine disorders Endocrine disorders - Other	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Eye disorders Blurred vision	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Abdominal distension	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Blood and lymphatic system disorders Anemia	1.3% 3/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	2.2% 5/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Cardiac disorders Atrial fibrillation	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Cardiac disorders Cardiac disorders - Other	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Cardiac disorders Pericardial effusion	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Abdominal pain	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.3% 3/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Ascites	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Bloating	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Colitis	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Constipation	1.3% 3/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Diarrhea	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Dyspepsia	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Dysphagia	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.8% 4/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Enterocolitis	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Esophageal hemorrhage	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Esophageal obstruction	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Esophagitis	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Gastrointestinal disorders - Other	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Gastrointestinal pain	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Ileus	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Lower gastrointestinal hemorrhage	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Nausea	2.2% 5/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.8% 4/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Pancreatic hemorrhage	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Pancreatitis	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Small intestinal perforation	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Upper gastrointestinal hemorrhage	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Vomiting	1.7% 4/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	2.2% 5/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Chills	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Death NOS	2.6% 6/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	4.0% 9/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Edema limbs	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Fatigue	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	5.4% 12/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Fever	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.3% 3/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Flu like symptoms	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Gait disturbance	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders General disorders and administration site conditions - Other	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Infusion related reaction	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Localized edema	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Multi-organ failure	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Non-cardiac chest pain	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Pain	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.8% 4/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Sudden death NOS	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Hepatobiliary disorders Bile duct stenosis	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Hepatobiliary disorders Gallbladder obstruction	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Hepatobiliary disorders Hepatic failure	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Hepatobiliary disorders Hepatic pain	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Hepatobiliary disorders Hepatobiliary disorders - Other	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Immune system disorders Allergic reaction	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Abdominal infection	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Appendicitis	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Bone infection	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Bronchial infection	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Catheter related infection	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Encephalitis infection	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Endocarditis infective	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Infections and infestations - Other	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Lung infection	1.7% 4/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	3.1% 7/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Mucosal infection	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Peritoneal infection	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Sepsis	3.4% 8/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	2.2% 5/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Small intestine infection	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Upper respiratory infection	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Urinary tract infection	1.7% 4/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.8% 4/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Wound infection	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Injury, poisoning and procedural complications Fall	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.8% 4/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Injury, poisoning and procedural complications Wound dehiscence	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Alanine aminotransferase increased	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Alkaline phosphatase increased	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Aspartate aminotransferase increased	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Blood bilirubin increased	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Creatinine increased	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations INR increased	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Investigations - Other	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Neutrophil count decreased	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.3% 3/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Platelet count decreased	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Weight loss	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations White blood cell decreased	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Anorexia	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Dehydration	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	3.1% 7/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Hypercalcemia	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Hyperglycemia	1.3% 3/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Hypocalcemia	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Hypoglycemia	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Hypokalemia	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Hypomagnesemia	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Hyponatremia	1.7% 4/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.8% 4/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Metabolism and nutrition disorders - Other	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Back pain	1.7% 4/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.3% 3/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Chest wall pain	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	4.3% 10/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	3.1% 7/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Muscle weakness left-sided	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Muscle weakness lower limb	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Muscle weakness right-sided	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Muscle weakness upper limb	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Neck pain	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Pain in extremity	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	5.6% 13/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	4.0% 9/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor pain	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Ataxia	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Cognitive disturbance	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Depressed level of consciousness	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Dizziness	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.3% 3/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Dysgeusia	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Edema cerebral	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Encephalopathy	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Headache	2.2% 5/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	2.7% 6/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Hydrocephalus	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Intracranial hemorrhage	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Ischemia cerebrovascular	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Lethargy	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Memory impairment	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Movements involuntary	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Nervous system disorders - Other	2.2% 5/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Paresthesia	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Peripheral motor neuropathy	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Peripheral sensory neuropathy	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Seizure	3.0% 7/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Somnolence	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Stroke	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Syncope	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Psychiatric disorders Confusion	2.6% 6/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	3.1% 7/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Psychiatric disorders Delirium	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Psychiatric disorders Depression	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Psychiatric disorders Hallucinations	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Psychiatric disorders Psychiatric disorders - Other	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Psychiatric disorders Suicidal ideation	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Renal and urinary disorders Acute kidney injury	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.8% 4/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Renal and urinary disorders Chronic kidney disease	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Renal and urinary disorders Renal and urinary disorders - Other	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Renal and urinary disorders Renal calculi	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Renal and urinary disorders Urinary incontinence	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Renal and urinary disorders Urinary retention	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Renal and urinary disorders Urinary urgency	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Aspiration	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Bronchopulmonary hemorrhage	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Dyspnea	2.2% 5/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	4.0% 9/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.3% 3/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.7% 4/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	1.3% 3/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Pleuritic pain	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	2.7% 6/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - Other	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Skin and subcutaneous tissue disorders Skin ulceration	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Surgical and medical procedures Surgical and medical procedures - Other	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Vascular disorders Hypertension	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Vascular disorders Hypotension	0.86% 2/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.90% 2/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Vascular disorders Peripheral ischemia	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Vascular disorders Superior vena cava syndrome	0.43% 1/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.00% 0/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Vascular disorders Thromboembolic event	5.2% 12/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	6.3% 14/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Vascular disorders Vascular disorders - Other	0.00% 0/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	0.45% 1/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.

Other adverse events

Measure	WBRT + Memantine n=232 participants at risk Whole brain radiation therapy (WBRT) and memantine	HA-WBRT + Memantin n=223 participants at risk Whole brain radiation therapy with hippocampal avoidance (HA-WBRT) and memantine
Metabolism and nutrition disorders Hypoalbuminemia	8.6% 20/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	8.1% 18/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Hypocalcemia	6.0% 14/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	2.7% 6/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Hypokalemia	9.1% 21/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	8.1% 18/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Hyponatremia	9.5% 22/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	7.6% 17/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Injury, poisoning and procedural complications Fall	6.5% 15/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	10.3% 23/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Alanine aminotransferase increased	4.7% 11/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	5.8% 13/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Alkaline phosphatase increased	4.3% 10/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	7.6% 17/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Aspartate aminotransferase increased	2.6% 6/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	5.4% 12/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Lymphocyte count decreased	9.5% 22/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	11.2% 25/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Platelet count decreased	6.9% 16/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	7.6% 17/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations Weight loss	19.0% 44/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	13.9% 31/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Investigations White blood cell decreased	5.6% 13/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	9.0% 20/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Anorexia	31.5% 73/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	30.9% 69/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Dehydration	5.6% 13/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	6.7% 15/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Metabolism and nutrition disorders Hyperglycemia	6.0% 14/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	9.0% 20/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Blood and lymphatic system disorders Anemia	16.4% 38/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	19.3% 43/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Ear and labyrinth disorders Hearing impaired	6.5% 15/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	7.2% 16/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Eye disorders Blurred vision	13.4% 31/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	10.3% 23/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Abdominal pain	10.8% 25/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	5.8% 13/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Constipation	25.9% 60/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	18.4% 41/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Diarrhea	14.7% 34/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	8.5% 19/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Dry mouth	9.1% 21/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	8.1% 18/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Dysphagia	5.6% 13/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	6.3% 14/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Nausea	45.3% 105/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	39.9% 89/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Gastrointestinal disorders Vomiting	18.5% 43/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	15.2% 34/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Edema limbs	10.8% 25/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	8.1% 18/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Fatigue	67.7% 157/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	64.1% 143/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Gait disturbance	11.6% 27/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	9.9% 22/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
General disorders Pain	11.2% 26/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	12.6% 28/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Infections and infestations Mucosal infection	4.3% 10/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	5.4% 12/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Injury, poisoning and procedural complications Dermatitis radiation	7.8% 18/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	4.9% 11/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Back pain	12.1% 28/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	11.7% 26/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	21.1% 49/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	18.8% 42/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Muscle weakness lower limb	4.7% 11/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	5.4% 12/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Musculoskeletal and connective tissue disorders Pain in extremity	5.6% 13/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	2.7% 6/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Dizziness	25.4% 59/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	22.9% 51/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Dysgeusia	7.8% 18/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	10.3% 23/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Headache	43.1% 100/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	37.7% 84/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Memory impairment	12.1% 28/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	11.7% 26/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Nervous system disorders - Other	5.6% 13/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	3.1% 7/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Paresthesia	6.9% 16/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	5.8% 13/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Peripheral sensory neuropathy	7.3% 17/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	7.6% 17/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Seizure	6.9% 16/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	4.0% 9/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Nervous system disorders Tremor	5.2% 12/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	8.1% 18/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Psychiatric disorders Anxiety	9.9% 23/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	7.6% 17/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Psychiatric disorders Confusion	11.2% 26/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	11.7% 26/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Psychiatric disorders Depression	10.8% 25/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	7.6% 17/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Psychiatric disorders Insomnia	13.8% 32/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	11.7% 26/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Cough	19.4% 45/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	17.0% 38/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Respiratory, thoracic and mediastinal disorders Dyspnea	21.6% 50/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	22.4% 50/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Skin and subcutaneous tissue disorders Alopecia	30.2% 70/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	24.2% 54/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Skin and subcutaneous tissue disorders Pruritus	5.6% 13/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	2.7% 6/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Vascular disorders Hypertension	5.6% 13/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	7.6% 17/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Vascular disorders Hypotension	4.3% 10/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	5.4% 12/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.
Vascular disorders Thromboembolic event	5.6% 13/232 • From randomization to last follow-up. Maximum follow-up was 15.6 months.	3.6% 8/223 • From randomization to last follow-up. Maximum follow-up was 15.6 months.

Additional Information

Wendy Seiferheld

NRG Oncology

Phone: 215-574-3208

Email: seiferheldw@nrgoncology.org

Results disclosure agreements

• Principal investigator is a sponsor employee Must obtain prior Sponsor approval.
• Publication restrictions are in place

Restriction type: OTHER