Stroke
Conditions
Keywords
stroke, hemiparesis, randomized controlled trial, d-cycloserine, distributed practice, constraint induced movement therapy
Brief summary
Each year 730,000 Americans experience a stroke. Forty percent are left with significant paralysis of one arm. Certain types of physical therapy, for example constraint induced movement therapy (CIMT), have been shown to be effective in improving arm function. However, for most subjects, improvement is modest. In this trial, we test two approaches that may increase the amount of improvement achieved: 1) distributing treatment over a greater amount of time; and 2) adding a drug, d-cycloserine, which theoretically enhances the molecular mechanisms of learning.
Detailed description
Each year, 730,000 Americans experience a stroke. Forty percent are left with persistent impairment of upper extremity function. Although scientifically vetted rehabilitation therapies for this impairment are starting to emerge, current treatment is generally unsatisfactory. Therapies that seek to engage neuroplastic mechanisms constitute one approach to this problem. A good example is constraint induced movement therapy (CIMT), a treatment that seeks, through extensive functional task practice, to overcome an acquired intentional predisposition to use the spared arm (learned non-use), and to improve motor function in the affected arm. CIMT has been tested in a host of trials, most recently a multicenter randomized controlled trial (RCT) - the EXCITE trial. These trials have generally demonstrated that on average, the treatment shows efficacy, and the results from the RCT indicate that it is more efficacious than standard therapies. However, problems with CIMT can be readily identified that pose research challenges: 1) on average, efficacy is limited; 2) only a fraction of subjects show substantial benefit. We propose to address these two problems in a pilot RCT of 20 subjects that will test two modifications of standard CIMT: 1) addition of a drug, d-cycloserine, that may enhance neuroplasticity by potentiating NMDA-glutamate receptor-mediated learning mechanisms; 2) delivery of a fixed amount of CIMT over a greater number of days, which according to learning research, may enhance long-term retention of gains. All subjects in this trial will receive CIMT. Subjects will be randomized to one of 4 groups: A. CIMT + d-cycloserine, more condensed treatment B. CIMT + d-cycloserine, less condensed treatment C. CIMT + placebo, more condensed treatment D. CIMT + placebo, less condensed treatment The primary outcome measure will be performance on the Wolf Motor Function Test (time) 3 months after completion of treatment.
Interventions
BEHAVIORALD-cycloserine + condensed treatment
Subjects will receive CIMT 6 hours/day, 5 days a week, for 2 weeks, in conjunction with d-cycloserine 50 mg PO administered before each treatment session
DRUGPlacebo + distributed treatment
Subjects will receive CIMT 2 hours/day, 3 days a week, for 10 weeks, in conjunction with placebo administered before each treatment session
BEHAVIORALPlacebo + condensed treatment
Subjects will receive CIMT 6 hours/day, 5 days a week, for 2 weeks, in conjunction with placebo administered before each treatment session
DRUGD-cycloserine + distributed treatment
Subjects will receive CIMT 2 hours/day, 3 days a week, for 10 weeks, in conjunction with d-cycloserine 50 mg PO administered before each treatment session
Sponsors
US Department of Veterans Affairs
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age 21-80, * of either sex, * diverse ethnic background, * s/p a single unilateral hemispheric stroke 6 or more months prior, * who meet upper extremity functional criteria for participation in constraint induced movement therapy.
Exclusion criteria
* History of more than minor head trauma, * subarachnoid hemorrhage, * dementia or other neurodegenerative disease, * multiple sclerosis, * lobar intracerebral hemorrhage, * epilepsy, * drug or alcohol abuse, * serious medical illness, * serum creatinine \>1.5, * schizophrenia, * major refractory depression, * insufficient cardiopulmonary function to participate in low-intensity, * sustained upper extremity exercise, * severe visual impairment, * pregnancy, * inability to understand the potential risks and benefits of the study, * personally provide informed consent, and * understand and cooperate with treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Wolf Motor Function Test (Time) | 3 months after completion of treatment | The Wolf Motor Function Test (time) score is the average time in seconds taken to perform each of 15 functional tasks ranging in difficulty from putting one's forearm on a table to stacking checkers. Participants are given 120 seconds to perform a task and if they fail, they are scored 120 for that task. Score range on the WMFT-T is 0-120, lower scores being better. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited between 1/5/10 and 6/3/11. Recruitment sites included: 1) The VA Rehabilitation Research and Development Brain Rehabilitation Research Center of Excellence at the Malcom Randall VA Medical Center, Gainesville, Florida; and outpatient clinics of the Brooks Rehabilitation Hospital, Jacksonville, Florida.
Pre-assignment details
All potential participants who met inclusion and exclusion criteria for the study and who provided informed consent were promptly randomized and entered into the study.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 D-cycloserine + distributed treatment
D-cycloserine + distributed treatment : Subjects will receive CIMT 2 hours/day, 3 days a week, for 10 weeks, in conjunction with d-cycloserine 50 mg PO administered before each treatment session | 6 |
| Arm 2 D-cycloserine + condensed treatment
D-cycloserine + condensed treatment : Subjects will receive CIMT 6 hours/day, 5 days a week, for 2 weeks, in conjunction with d-cycloserine 50 mg PO administered before each treatment session | 6 |
| Arm 3 Placebo + distributed treatment
Placebo + distributed treatment : Subjects will receive CIMT 2 hours/day, 3 days a week, for 10 weeks, in conjunction with placebo administered before each treatment session | 6 |
| Arm 4 Placebo + condensed treatment
Placebo + condensed treatment : Subjects will receive CIMT 6 hours/day, 5 days a week, for 2 weeks, in conjunction with placebo administered before each treatment session | 6 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Arm 2 | Arm 3 | Arm 1 | Arm 4 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 4 Participants | 4 Participants | 4 Participants | 18 Participants |
| Age, Continuous | 57.83 years STANDARD_DEVIATION 4.4 | 56.50 years STANDARD_DEVIATION 12.31 | 60.33 years STANDARD_DEVIATION 6.71 | 58.17 years STANDARD_DEVIATION 11.63 | 58.2 years STANDARD_DEVIATION 8.9 |
| Region of Enrollment United States | 6 participants | 6 participants | 6 participants | 6 participants | 24 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 3 Participants | 2 Participants | 12 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 3 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 6 | 0 / 6 | 1 / 6 | 1 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 1 / 6 | 0 / 6 |
Outcome results
Primary
Wolf Motor Function Test (Time)
The Wolf Motor Function Test (time) score is the average time in seconds taken to perform each of 15 functional tasks ranging in difficulty from putting one's forearm on a table to stacking checkers. Participants are given 120 seconds to perform a task and if they fail, they are scored 120 for that task. Score range on the WMFT-T is 0-120, lower scores being better.
Time frame: 3 months after completion of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Wolf Motor Function Test (Time) | 10.21 units on a scale | Standard Deviation 14.26 |
| Arm 2 | Wolf Motor Function Test (Time) | 29.69 units on a scale | Standard Deviation 39.06 |
| Arm 3 | Wolf Motor Function Test (Time) | 19.09 units on a scale | Standard Deviation 32.55 |
| Arm 4 | Wolf Motor Function Test (Time) | 26.05 units on a scale | Standard Deviation 31.03 |
Comparison: A general linear model was employed. The independent variables were baseline WMFT score, treatment (condensed vs distributed), treatment (d-cycloserine vs placebo), and treatment interaction effect. The dependent measure was WMFT score at 3 months post treatment.p-value: <0.05Regression, Linear