Memantine for Prevention of Cognitive Decline in Patients With Breast Cancer

Study Overview
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Brief Summary
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Purpose: To conduct a one-arm phase II trial to: (1) compare changes in pre- to post-chemotherapy cognitive function in a cohort of patients with breast cancer receiving memantine to historical controls; (2) examine how depression, anxiety, fatigue, baseline Intelligence Quotient (IQ), and cognitive effort relate to objective and self-reported cognitive function; and (3) estimate the feasibility of conducting a clinical trial of memantine for attenuating cognitive decline in patients with breast cancer during chemotherapy. Participants: Adult patients with stage I-III breast cancer scheduled for adjuvant or neoadjuvant chemotherapy. Procedures (methods): Cognitive assessments will be performed within one week of initiating and four weeks after completion of chemotherapy. Patients will receive memantine 10 mg twice daily between the pre- and post-chemotherapy study assessments. Cognitive function will be assessed objectively using a computerized cognitive test (Delayed Matching to Sample (DMS) test) and a standard neuropsychological battery. To assess subjective cognitive function, the Patient Reported Outcome Measurement Information System (PROMIS) Cognitive Function measure will be used. Depression, anxiety, fatigue, menopausal status, and sleep will be assessed as covariates.

Detailed Description
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This is a one-arm phase II interventional study in patients with breast cancer to investigate whether memantine can prevent cognitive decline during chemotherapy. The investigators will recruit 56 participants referred to the University of North Carolina (UNC) Breast Center and affiliated outpatient clinics for initiation of adjuvant or neoadjuvant chemotherapy, perform a cognitive assessment within one week of initiating and four weeks after completion of chemotherapy, and treat with memantine 10 mg twice daily between the pre- and post-chemotherapy study assessments (estimated duration: 12-26 weeks, depending on the chemotherapy regimen). Cognitive function will be assessed objectively using a computerized cognitive assessment (Delayed Matching to Sample (DMS) test) and a standard neuropsychological battery. To assess subjective cognitive function, the Patient Reported Outcome Measurement Information System (PROMIS) Cognitive Function measure will be used. Depression, anxiety, fatigue, menopausal status, and sleep are comorbidities known to affect cognitive function, and therefore will be assessed as covariates pre- and post-chemotherapy. Depression, anxiety, health-related quality of life (HRQOL) and functional status will be evaluated as secondary outcomes. The feasibility of the investigator's study by monitoring recruitment, retention, and adherence to memantine will be assessed.

Official Title
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Memantine for Prevention of Cognitive Decline During Adjuvant or Neoadjuvant Chemotherapy in Patients With Breast Cancer

Conditions
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Cognitive Decline, Chemo-brain

Intervention / Treatment
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* Drug: Memantine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide informed consent At least 18 years of age Able to speak English Diagnosed with breast cancer, Stages I-III Scheduled for adjuvant or neoadjuvant chemotherapy Exclusion Criteria: A history of adverse reaction to memantine Another cancer diagnosis with an estimated survival of less than five years Previous chemotherapy exposure Severe cognitive impairment, defined as Blessed Orientation Memory Concentration Test (BOMC) ≥ 11. Pregnancy, confirmed by a negative pregnancy test within 30 days of study enrollment, or breastfeeding Current alcohol or drug abuse

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Memantine<br>Subjects receive memantin | Drug: Memantine<br>* memantine dose Week 1: 5 mg dose once daily Week 2: 5 mg dose twice daily Week 3: 5 mg each morning/10 mg each evening Week 4 through the end of Chemotherapy: 10 mg dose twice daily Total duration: 12 - 26 weeks (depending on chemotherapy regimen)<br>* Other names: Namenda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Visual Working Memory - Delayed Matching to Sample Test | The Delayed Matching to Sample Test (DMS) is a computerized cognitive assessment of visual working memory. The DMS will be administered using Cambridge Neuropsychological Test Automated Battery (CANTAB) eclipse software (Cambridge Cognition, Cambridge, UK). The participant is shown an image with four patterns and asked to match patterns simultaneously or after delay. The investigators will use the percent correct (0 to 100, higher is better) at the 12-second delay on the DMS test for the primary analysis. | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Verbal Memory - Hopkins Verbal Learning Test-Revised | The Hopkins Verbal Learning Test-Revised (HVLT-R) is an objective measure of verbal learning and memory. The examiner reads a list of 12 nouns to the participant, who repeats as many words as remembered. Approximately 20-25 minutes later, participants are asked to recall as many words as possible. Then, the examiner reads a list of 24 words, including the 12 words from the original list, and the participant is asked to determine which words were and were not on the original list. These tasks result in three subscales: total recall (range: 0-36; higher is better), delayed recall (range: 0-12; higher is better), and the Recognition Discrimination Index (range: 0-12; higher is better). | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Change in Processing Speed and Executive Function - Trail Making Test | The Trail Making Test (TMT) is an objective measure of processing speed (part A) and executive function (part B). In part A, the participant is given a diagram of 25 circles, labeled 1 - 25, and asked to connect the circles in ascending order. In part B, the diagram of 25 circles includes some with numbers (1-13) and some with letters (A-L), and the participant is asked to connect the circles alternating between numbers and letters. Performance is measured in the number of seconds required to complete each task (lower is better). | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Change in Processing Speed - Rapid Visual Processing (RVP) | The Rapid Visual Processing test (RVP) is a computerized cognitive assessment of processing speed and sustained attention. The RVP will be administered using Cambridge Neuropsychological Test Automated Battery (CANTAB) eclipse software (Cambridge Cognition, Cambridge, UK). The participant is shown a series of pseudo-random digits from 2 to 9 and asked to recognize target digit sequences by pressing a button on the screen as quickly as possible. The investigators will measure total correct responses (higher is better). This test was added at the start of the COVID-19 pandemic as a substitute for the Trail Making Test. | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Change in Executive Function - One Touch Stockings (OTS) of Cambridge | The One Touch Stockings (OTS) of Cambridge is a computerized cognitive assessment of executive function. The OTS will be administered using Cambridge Neuropsychological Test Automated Battery (CANTAB) eclipse software (Cambridge Cognition, Cambridge, UK). The participant is shown two displays with three colored balls presented as stacks suspended from a beam and a row of numbered boxes along the bottom of the screen. The participant is asked to work out in their head how many moves are required to match the two displays. The investigators will measure mean number of choices to the correct response (lower is better). | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Change in Attention and Working Memory - Digit Span | The Digit Span is an objective measure of attention and working memory. The participant is asked to recite sequences of numbers in forward, backwards, and sequential order. The score for each sequence type is the number of correct responses (higher is better). | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Change in Verbal Fluency - Controlled Oral Word Association Test | The Controlled Oral Word Association Test (COWA) is an objective measure of verbal fluency. The participant is asked to name as many words as possible, excluding proper nouns, in one minute. This is repeated for a total for three different letters. The score is the total number of different words produced between all three letters (higher is better). | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Change in Semantic Fluency - Animal Naming Test | The Animal Naming Test (ANT) is an objective measure of semantic fluency. The participant is asked to name as many animals as possible in one minute. The score is the number of unique animals stated (higher is better). | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Change in Self-reported Cognitive Function - PROMIS Cognitive Function | The National Institute of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) contains a cognitive function bank. The PROMIS Cognitive Function 8a short form will be used. Scores for all PROMIS measures are reported on the T-score metric in which the mean=50 and standard deviation (SD) = 10 are centered on the general population means. Higher scores represent greater degrees of cognitive complaints. | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Change in Depressive Symptoms - PROMIS Depression | The National Institute of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) contains a depression bank. The PROMIS Depression 8a short form will be used. Scores for all PROMIS measures are reported on the T-score metric in which the mean=50 and standard deviation (SD) = 10 are centered on the general population means. Higher scores represent greater degrees of depression. We evaluated the proportion of patients with at least moderately severe symptoms (T-score ≥ 65) at baseline and follow-up. | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Change in Anxiety Symptoms - PROMIS Emotional Distress-Anxiety | The National Institute of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) contains an anxiety bank. The PROMIS Emotional Distress-Anxiety - Short Form 6a will be used. Scores for all PROMIS measures are reported on the T-score metric in which the mean=50 and standard deviation (SD) = 10 are centered on the general population means. Higher scores represent greater degrees of anxiety. We evaluated the proportion of patients with at least moderately severe symptoms (T-score ≥ 65) at baseline and follow-up. | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy. | 
| Change in Karnofsky Performance Status | The number of subjects with Karnofsky Performance Status equal to or more than 80, at baseline and 4 weeks after chemotherapy were compared. The Patient-reported Karnofsky Performance Status (KPS) provides a self-characterization of functional status, ranging from severe/requiring continuous nursing care to normal/no complaints/no symptoms of the disease. Scores range from 30 to 100. Higher scores indicate better function. | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Change in Quality of Life - Functional Assessment of Cancer Therapy-General | The Functional Assessment of Cancer Therapy-General (FACT-G) is a 27-item patient-administered assessment of general quality-of-life measures in cancer patients. It has been validated in the literature and permits the measurement of a number of symptoms including nausea, pain, and insomnia. Responses to each item are on a 5-point Likert scale. The FACT-G total score (range: 0-108; higher is better) will be assessed. | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Proportion of Invited Participants Who Enroll - Recruitment | Feasibility will be based on recruitment success as measured by the proportion of invited participants who enroll. | Baseline (pre-chemotherapy) over the duration of the accrual period | 
| Proportion of Enrolled Participants Who do Not Meet the Primary Outcome Measure - Attrition | Feasibility will be based on retention success as measured by the proportion of enrolled participants who are not eligible for analysis of the primary outcome. | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Proportion of Scheduled Drug Doses Taken - Adherence | Feasibility will be based on adherence success as measured by the proportion of self-reported doses of memantine taken. | From baseline (pre-chemotherapy) to 4 weeks post-chemotherapy | 
| Number of Adverse Events - Safety | Safety is based on the number of all adverse events (AE) associated with memantine. The following most common side effects of memantine were explicitly solicited: headache, dizziness, confusion, constipation, diarrhea, and fatigue. AE was assessed and graded according to the NCI Common Terminology Criteria. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. | From baseline to 4 weeks after chemotherapy (up to 30 weeks) |