Memantine for Enhanced Stroke Recovery

Study Overview
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Brief Summary
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This will be a randomized double blind placebo-controlled pilot study using a repeated measures design in which participants with acute ischemic stroke and upper extremity weakness are randomized to either drug or placebo

Detailed Description
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This will be a randomized double blind placebo-controlled pilot study using a repeated measures design in which participants with acute ischemic stroke and upper extremity weakness are randomized to either drug or placebo, complete therapy, and complete outcomes assessments at baseline, 4, and 12 weeks post-stroke. Target enrollment will be 10 patients per group and adaptive randomization will be used to assist with equal representation of pre-stroke selective serotonin reuptake inhibitor (SSRI) use and motor severity (Fugl-Meyer score) in each arm. The primary purpose of this pilot study is to measure adverse events, drop-out rates, feasibility of trial conductance, and establishment of effect sizes in each group in order to power a larger efficacy trial at the University of Utah. An intention to treat model will be used during the study.

Official Title
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Pilot Study of Memantine for Enhanced Stroke Recovery

Conditions
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Ischemic Stroke, Upper Extremity Weakness

Intervention / Treatment
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* Drug: Memantine XR
* Drug: Placebo (for memantine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years old Randomization between 3 days-8 weeks days of stroke symptom onset Arm weakness severe enough to warrant inpatient or outpatient occupational therapies Able to voluntarily move affected UE Living independently prior to their stroke Image-confirmed ischemic stroke (MRI or CT) Supratentorial location of stroke Fugl-Meyer Upper Extremity Score of 50 or less and/or Fugl Meyer Lower Extremity Score of 28 or less Ability to swallow pills Exclusion Criteria: subarachnoid hemorrhage, subdural hemorrhage or other cause of symptoms other than ischemic or hemorrhagic stroke Infratentorial location of stroke (brainstem or cerebellum) NIH Stroke Scale >20 at the time of randomization History of dementia that will interfere with rehabilitation Pre or post-stroke use of memantine or amantadine Contraindications to taking memantine XR in pill form History of prior clinical stroke with residual symptoms on the same side as the current symptoms that would interfere with outcomes of this study Documented severe renal impairment (CrCl < 30 ml/min) Blood tests will be performed prior to study procedures that will ensure patients do not have renal impairment if not done as part of clinical care. Moribund or not expected to live 6 months Severe cognitive deficits or pre-morbid function causing inaccurate neurologic assessment or inability to complete the initial assessment Comorbid neurologic disease that would interfere with the results including but not limited to Multiple Sclerosis, neurodegenerative diseases, spinal cord disease, and central nervous system cancer. Documented severe hepatic impairment (Child-Pugh score > 6) or severe hepatic disease (hepatitis) Patients who are pregnant or breast feeding

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo plus standard of care<br>Participants will start taking either memantine or placebo within 24 hours after baseline testing and randomization is completed, but no later than day 8 post-symptom onset. Participants will titrate up on the dose of placebo until taking twice daily. Participants will continue for 90 days with placebo. Continue with standard of care for other treatment of stroke. | Drug: Placebo (for memantine)<br>* Placebo to be capsuled to look identical to active drug (memantine)<br>* Other names: sugar capsule;|
| Active Comparator: Memantine plus standard of care<br>Participants will start taking either memantine or placebo within 24 hours after baseline testing and randomization is completed, but no later than day 8 post-symptom onset. Participants will use a titration schedule starting at 7mg daily for 1 week, increasing by 7mg (1 capsule) per week until at a goal dose of 28mg daily (goal dose) as recommend by the manufacturer. Participants will continue memantine for 90 days. Continue with standard care for stroke. | Drug: Memantine XR<br>* The active drug will be encapsulated by the University of Utah Research Pharmacy to maintain blinding.<br>* Other names: Namenda XR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fugl-Meyer Assessment | Fugl-Meyer Assessment UE and LE scales (FMUE and FMLE). Our primary outcome measures will be the scores on the FMUE and FMLE as they have been shown to have good reliability and validity. These scales measure motor impairment by asking the participant to perform various arm, hand, and leg motions. Items are scored on a 3-point scale with 0 representing no movement, 1 representing the inability to complete the entire item and 2 representing ability to complete the item as asked. Scores range from 0-66 on the FMUE and 0-34 on the FMLE with higher scores indicating better motor control. In addition, the proprioception subscale of the FM will be used to assess status of proprioception in the UE and LE. The hip, knee, ankle, big toe, shoulder, elbow, wrist, and the thumb are moved passively and the participant is asked to indicate in which direction the joint was moved. | 30 days | 
| Fugl-Meyer Assessment | Fugl-Meyer Assessment UE and LE scales (FMUE and FMLE). Our primary outcome measures will be the scores on the FMUE and FMLE as they have been shown to have good reliability and validity. These scales measure motor impairment by asking the participant to perform various arm, hand, and leg motions. Items are scored on a 3-point scale with 0 representing no movement, 1 representing the inability to complete the entire item and 2 representing ability to complete the item as asked. Scores range from 0-66 on the FMUE and 0-34 on the FMLE with higher scores indicating better motor control. In addition, the proprioception subscale of the FM will be used to assess status of proprioception in the UE and LE. The hip, knee, ankle, big toe, shoulder, elbow, wrist, and the thumb are moved passively and the participant is asked to indicate in which direction the joint was moved. | 90 days | 
| Adverse events | Participants will be contacted by the stroke research nurse after weeks 1, 2, 3, and 8 of after randomization by telephone call or inpatient visit (if in the hospital or acute inpatient rehabilitation). Participants will be asked about potential adverse events during each phone call and each clinic visit. All adverse events, serious and minor, will be recorded on an adverse event table. The study investigators will review study records after every 5 participants are enrolled to monitor for patterns of adverse events to evaluate the safety of continuing the study. | up to 30 days | 
| Adverse Events | Participants will be contacted by the stroke research nurse after weeks 1, 2, 3, and 8 of after randomization by telephone call or inpatient visit (if in the hospital or acute inpatient rehabilitation). Participants will be asked about potential adverse events during each phone call and each clinic visit. All adverse events, serious and minor, will be recorded on an adverse event table. The study investigators will review study records after every 5 participants are enrolled to monitor for patterns of adverse events to evaluate the safety of continuing the study. | 30-90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor Activity Log (MAL) | The validity of the MAL has been well established against upper extremity accelerometry. The Motor Activity Log is a self-report measure of how frequently the participant uses his or her paretic hand in 30 common daily activities, such as opening a drawer and shaving or putting on make-up. Participants rate how often they use the paretic UE in these tasks on a 6 point scale from 0 representing no use to 5 representing as much use as before the stroke. The quality of movement scale on the Motor Activity Log asks the participant to rate how well he or she perceives the task is performed with the paretic UE. The ratings are also made on a 6 point scale with 0 representing no use to 5 representing as well as before the stroke. This assessment will only be completed at post-intervention and follow-up as it is invalid assessment in the in-patient setting where participants have few opportunities to engage in the tested items. | 30 days | 
| Motor Activity Log (MAL) | The validity of the MAL has been well established against upper extremity accelerometry. The Motor Activity Log is a self-report measure of how frequently the participant uses his or her paretic hand in 30 common daily activities, such as opening a drawer and shaving or putting on make-up. Participants rate how often they use the paretic UE in these tasks on a 6 point scale from 0 representing no use to 5 representing as much use as before the stroke. The quality of movement scale on the Motor Activity Log asks the participant to rate how well he or she perceives the task is performed with the paretic UE. The ratings are also made on a 6 point scale with 0 representing no use to 5 representing as well as before the stroke. This assessment will only be completed at post-intervention and follow-up as it is invalid assessment in the in-patient setting where participants have few opportunities to engage in the tested items. | 90 days | 
| Ten Meter Walk Test | The 10 meter walk is a measure of typical gait speed. The participant is asked to walk at his/her usual pace for 10 meters along a hallway. Two trials are completed with the best time in seconds to walk the distance recorded. The test is reliable. We will videotape the walk and later use the Riverside Scale for rating quality of locomotion. | 30 days | 
| Ten Meter Walk Test | The 10 meter walk is a measure of typical gait speed. The participant is asked to walk at his/her usual pace for 10 meters along a hallway. Two trials are completed with the best time in seconds to walk the distance recorded. The test is reliable. We will videotape the walk and later use the Riverside Scale for rating quality of locomotion. | 90 days | 
| Stroke Impact Scale (SIS) | The SIS is a self-report measure of functioning after stroke at the body function, activity, and participation levels. Participants rate on a 5 point scale how frequently statements apply to them across 8 domains (strength, communication, emotion, hand use, activities of daily living, mobility, thinking, and social participation). Scores for each domain are tallied and converted to a 100-point scale. Scores across domains are also tallied and converted to a 100-point scale. The SIS has been shown to be reliable and valid. This assessment will only be completed at post-intervention and follow-up as many of the items concern activities that are only encountered in the community. Participants who are new inpatients will not have had the opportunity to engage in these activities. | 30 days | 
| Stroke Impact Scale (SIS) | The SIS is a self-report measure of functioning after stroke at the body function, activity, and participation levels. Participants rate on a 5 point scale how frequently statements apply to them across 8 domains (strength, communication, emotion, hand use, activities of daily living, mobility, thinking, and social participation). Scores for each domain are tallied and converted to a 100-point scale. Scores across domains are also tallied and converted to a 100-point scale. The SIS has been shown to be reliable and valid. This assessment will only be completed at post-intervention and follow-up as many of the items concern activities that are only encountered in the community. Participants who are new inpatients will not have had the opportunity to engage in these activities. | 90 days | 
| Cancellation Tests | These tests measure the presence of unilateral neglect. The letter cancellation task includes 40 target letters (E, R) among 130 non-target letters on an A4-sized landscape sheet (maximum score 40, cutoff point 32). The letters are arranged in five rows, each containing 34 items. The star cancellation task consists of 56 targets (small stars) and 75 non-targets (big stars, words, and letters) randomly spaced on an A4-sized landscape sheet. In these three cancellation tasks, participants are instructed to search and mark all the targets on the stimulus sheet. The total number of targets crossed out on the left and the right of each form will be tallied and the percentage. | 30 Days | 
| Cancellations Tests | These tests measure the presence of unilateral neglect. The letter cancellation task includes 40 target letters (E, R) among 130 non-target letters on an A4-sized landscape sheet (maximum score 40, cutoff point 32). The letters are arranged in five rows, each containing 34 items. The star cancellation task consists of 56 targets (small stars) and 75 non-targets (big stars, words, and letters) randomly spaced on an A4-sized landscape sheet. In these three cancellation tasks, participants are instructed to search and mark all the targets on the stimulus sheet. The total number of targets crossed out on the left and the right of each form will be tallied and the percentage. | 90 Days | 
| Grip Strength Test | Grip strength will be tested using the American Hand Therapy Association recommended protocol. Briefly, the participant will be seated in a straight backed chair with the paretic shoulder in neutral, elbow flexed, forearm half-way between supination and pronation. He or she grasps the Jamar-type dynamometer by the handle and squeezes it as hard as possible for 5 seconds. The tester gives the command Ok, squeeze as hard as you can….harder…..harder…..relax. The test is repeated 2 more times with a 30 second rest in between squeezes. Grip strength will be measured as the average of the 3 trials to the nearest kilogram. | 30 Days | 
| Grip Strength Test | Grip strength will be tested using the American Hand Therapy Association recommended protocol. Briefly, the participant will be seated in a straight backed chair with the paretic shoulder in neutral, elbow flexed, forearm half-way between supination and pronation. He or she grasps the Jamar-type dynamometer by the handle and squeezes it as hard as possible for 5 seconds. The tester gives the command Ok, squeeze as hard as you can….harder…..harder…..relax. The test is repeated 2 more times with a 30 second rest in between squeezes. Grip strength will be measured as the average of the 3 trials to the nearest kilogram. | 90 Days | 
| Montreal Cognitive Assessment (MoCA©) | The MoCA© is recommended by NIH and Canadian Stroke Consortium for Cognitive Assessment after Stroke. It is reliable and valid for the stroke population. | 30 Days | 
| Montreal Cognitive Assessment (MoCA©) | The MoCA© is recommended by NIH and Canadian Stroke Consortium for Cognitive Assessment after Stroke. It is reliable and valid for the stroke population. | 90 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ischemic stroke, memantine, upper extremity weakness, motor recovery