Ischemic Stroke
Conditions
Keywords
Ischemic stroke, treatment, recovery, donepezil, Aricept
Brief summary
This study involves treating patients that have suffered an acute ischemic stroke with the medication donepezil (Aricept ®). The hypothesis is that taking donepezil (FDA-approved for the treatment of Alzheimer's Disease) for the first 90 days following a stroke enhances recovery.
Detailed description
We hypothesize that donepezil (5 mg per day, titrated up to 10 mg per day as tolerated) will enhance recovery following stroke by improving attention, learning and memory thereby enhancing rehabilitation. The null hypothesis is that the probability of a favorable outcome among post-stroke donepezil users is equal to that observed among similar participants in an existing National Institutes of Neurological Disorders and Stroke (NINDS) resource, the Phase III clinical trial of Tissue Plasminogen Activator (tPA) for acute ischemic stroke. The NINDS tPA stroke trial has been used as historical control data in pilot trials of reperfusion and neuroprotection. The MASTER trial will be a multicenter, single-arm NINDS Recominant tPA trial-controlled, modified 2-stage adaptive clinical trial set in 2 tertiary care hospitals in the United States. Participants will be men and women with acute (\< 24 hours of onset of symptoms) ischemic stroke. A favorable outcome will be defined as National Institutes of Health Stroke Scale (NIHSS) values of 0 or 1 at 90 days post-stroke.
Interventions
DRUGDonepezil
Study participants will be treated with donepezil orally at an initial dose of 5 mg daily for the first 4 weeks, then increased at their 30-day visit by 5 mg to a maximum dose of 10 mg daily, if tolerated. If the participant does not tolerate the 10 mg dose, they will remain on 5 mg through the course of the study.
Sponsors
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Definite or probable acute ischemic cerebrovascular syndrome (AICS), as defined by Kidwell et al (Stroke. 2003;34:2995-8). * Experimental treatment started within 24 hours of onset of symptoms. * Age ≥ 18 years. * Ability and willingness to return for follow-up visits. * Willingness of an available informant who knows the patient well to participate in informant-based questionnaires for the duration of the follow-up period. * Living in independent or semi-independent living situation before the stroke. * Fluent in English before the stroke. * Provides written informed consent. * Near visual acuity of at least 20/200 in at least one eye. * Auditory acuity of at least having the ability to detect finger rubbing in at least one ear.
Exclusion criteria
* Parkinson's disease or restless leg syndrome. * Partial or generalized seizures. * No acute decompensated heart failure * Routinely requiring daytime supplemental oxygen before the stroke; study participants on continuous positive air pressure (CPAP) for obstructive sleep apnea remain eligible. * Gastrointestinal or genitourinary surgery within 1 month of screening. * Gastrointestinal bleeding. * Syncope or symptomatic bradycardia. * Creatinine ≥ 3.5 mg/dL or requiring dialysis. * Peptic ulcer disease. * Asthma. * Tracheostomy or endotracheal intubation. * Taking donepezil or other acetylcholinesterase inhibitor at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With National Institutes of Health Stroke Scale (NIHSS) Score = 0 or 1 at Day 90 | 90 days post-stroke | The National Institutes of Health Stroke Scale (NIHSS) is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent's ability to answer questions and perform activities. Ratings for each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items. The range of scores is from 0 (normal) to 42 (profound effect of stroke on patient). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean National Institutes of Health Stroke Scale (NIHSS) Score at 90 Days Post-stroke | baseline, 90 days post-stroke | The National Institutes of Health Stroke Scale (NIHSS) is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent's ability to answer questions and perform activities. Ratings for each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items. The range of scores is from 0 (normal) to 42 (profound effect of stroke on patient). |
| Change in Mean Barthel Index of Activities of Daily Living Score at 90 Days Post-stroke | baseline, 90 days post-stroke | The Barthel Index of Activities of Daily Living (ADLs) measures functional disability by quantifying patient performance in 10 activities of daily life. These activities can be grouped according to self-care (feeding, grooming, bathing, dressing, bowel and bladder care, and toilet use) and mobility (ambulation, transfers, and stair climbing). 5-point increments are used in scoring, with a maximal score of 100 indicating that a patient is fully independent in physical functioning, and a lowest score of 0 representing a totally dependent bed-ridden state. |
| Change in Mean Score on Mini Mental State Exam at 90 Days Post-stroke | baseline, 90 days post-stroke | The mini-mental state examination (MMSE) is a 30-point questionnaire test that is used to screen for cognitive impairment. The questionnaire samples functions including arithmetic, memory and orientation to time and place. Scores range from 0 to 30. Any score greater than or equal to 25 points is effectively normal (intact). Below this, scores can indicate severe (≤9 points), moderate (10-20 points) or mild (21-24 points) cognitive impairment. |
| Change in Time to Complete Neuropsychological Trail Making Tests A and B at 90 Days Post-stroke | baseline, 90 days post-stroke | The Trail-making test consists of two parts in which the subject is instructed to connect a set of 25 dots as fast as possible while still maintaining accuracy. It can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning. There are two parts to the test: A, in which the targets are all numbers (1,2,3, etc.)and the test taker needs to connect them in sequential order, and B, in which the subject alternates between numbers and letters (1, A, 2, B, etc.). |
Countries
United States
Participant flow
Recruitment details
Enrollment extended from November 2008 through April 2010. The study was conducted at the Mayo Clinic sites in Jacksonville, FL and Rochester, MN.
Participants by arm
| Arm | Count |
|---|---|
| Donepezil Participants received treatment with donepezil within 24 hours after the onset of ischemic stroke symptoms. Participants received donepezil 5 mg/day for 30 days, followed by an increase to 10 mg/day for 60 days. | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 3 |
| Overall Study | Lost to Follow-up | 2 |
Baseline characteristics
| Characteristic | Donepezil |
|---|---|
| Age, Continuous | 66 years |
| Body Mass Index | 27.1 kg/m^2 |
| Number of Participants with Previous Ischemic Stroke No previous ischemic stroke | 28 participants |
| Number of Participants with Previous Ischemic Stroke Previous ischemic stroke | 5 participants |
| Participant Scores on National Institutes of Health Stroke Scale Mild (<6) | 16 participants |
| Participant Scores on National Institutes of Health Stroke Scale Moderate (6-13) | 12 participants |
| Participant Scores on National Institutes of Health Stroke Scale Severe (>13) | 5 participants |
| Region of Enrollment United States | 33 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 33 / 33 |
| serious Total, serious adverse events | 10 / 33 |
Outcome results
Primary
Percent of Participants With National Institutes of Health Stroke Scale (NIHSS) Score = 0 or 1 at Day 90
The National Institutes of Health Stroke Scale (NIHSS) is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent's ability to answer questions and perform activities. Ratings for each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items. The range of scores is from 0 (normal) to 42 (profound effect of stroke on patient).
Time frame: 90 days post-stroke
Population: Intention-to-treat analysis, all treated participants (n=33). Unobserved because of death (n=3) or loss to follow up (N=2) treated as nonresponse.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Donepezil | Percent of Participants With National Institutes of Health Stroke Scale (NIHSS) Score = 0 or 1 at Day 90 | Stroke severity (NIHSS) mild (<6) (n=11/16) | 69 percentage of participants |
| Donepezil | Percent of Participants With National Institutes of Health Stroke Scale (NIHSS) Score = 0 or 1 at Day 90 | Stroke severity (NIHSS) moderate (6-13) (n=4/12) | 33 percentage of participants |
| Donepezil | Percent of Participants With National Institutes of Health Stroke Scale (NIHSS) Score = 0 or 1 at Day 90 | Stroke severity (NIHSS) severe (>13) (n=0/5) | 0 percentage of participants |
| Donepezil | Percent of Participants With National Institutes of Health Stroke Scale (NIHSS) Score = 0 or 1 at Day 90 | Overall (n=15/33) | 45 percentage of participants |
Secondary
Change in Mean Barthel Index of Activities of Daily Living Score at 90 Days Post-stroke
The Barthel Index of Activities of Daily Living (ADLs) measures functional disability by quantifying patient performance in 10 activities of daily life. These activities can be grouped according to self-care (feeding, grooming, bathing, dressing, bowel and bladder care, and toilet use) and mobility (ambulation, transfers, and stair climbing). 5-point increments are used in scoring, with a maximal score of 100 indicating that a patient is fully independent in physical functioning, and a lowest score of 0 representing a totally dependent bed-ridden state.
Time frame: baseline, 90 days post-stroke
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Change in Mean Barthel Index of Activities of Daily Living Score at 90 Days Post-stroke | 21.4 units on a scale | Standard Error 5.2 |
Comparison: The statistical significance of the change was assessed by the P value associated with estimated regression coefficient (beta coefficient or slope).p-value: <0.001Regression, Linear
Secondary
Change in Mean National Institutes of Health Stroke Scale (NIHSS) Score at 90 Days Post-stroke
The National Institutes of Health Stroke Scale (NIHSS) is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent's ability to answer questions and perform activities. Ratings for each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items. The range of scores is from 0 (normal) to 42 (profound effect of stroke on patient).
Time frame: baseline, 90 days post-stroke
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Change in Mean National Institutes of Health Stroke Scale (NIHSS) Score at 90 Days Post-stroke | -2.8 units on a scale | Standard Error 0.8 |
Comparison: The statistical significance of the change was assessed by the P value associated with estimated regression coefficient (beta coefficient or slope).p-value: <0.001Regression, Linear
Secondary
Change in Mean Score on Mini Mental State Exam at 90 Days Post-stroke
The mini-mental state examination (MMSE) is a 30-point questionnaire test that is used to screen for cognitive impairment. The questionnaire samples functions including arithmetic, memory and orientation to time and place. Scores range from 0 to 30. Any score greater than or equal to 25 points is effectively normal (intact). Below this, scores can indicate severe (≤9 points), moderate (10-20 points) or mild (21-24 points) cognitive impairment.
Time frame: baseline, 90 days post-stroke
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Change in Mean Score on Mini Mental State Exam at 90 Days Post-stroke | 4.4 units on a scale | Standard Error 1.2 |
Comparison: The statistical significance of the change was assessed by the P value associated with estimated regression coefficient (beta coefficient or slope).p-value: <0.001Regression, Linear
Secondary
Change in Time to Complete Neuropsychological Trail Making Tests A and B at 90 Days Post-stroke
The Trail-making test consists of two parts in which the subject is instructed to connect a set of 25 dots as fast as possible while still maintaining accuracy. It can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning. There are two parts to the test: A, in which the targets are all numbers (1,2,3, etc.)and the test taker needs to connect them in sequential order, and B, in which the subject alternates between numbers and letters (1, A, 2, B, etc.).
Time frame: baseline, 90 days post-stroke
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Donepezil | Change in Time to Complete Neuropsychological Trail Making Tests A and B at 90 Days Post-stroke | Trail Making Test A | -43.4 seconds | Standard Error 9.2 |
| Donepezil | Change in Time to Complete Neuropsychological Trail Making Tests A and B at 90 Days Post-stroke | Trail Making Test B | -67.3 seconds | Standard Error 13.3 |