Stroke
Conditions
Brief summary
A pivotal, prospective, multi-center, randomized, controlled, double-blinded study combining active Nexstim NBS-guided 1Hz rTMS or sham-rTMS targeting the healthy hemisphere with standardized task oriented rehabilitation will be conducted in patients with post-stroke motor impairment. The therapy will be provided for 6 weeks and primary outcome assessed 6 months later.
Interventions
DEVICENBS-guided rTMS
DEVICESham rTMS
PROCEDURETask oriented rehabilitation
Sponsors
Nexstim Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * ≥ 18 years of age * An ischemic or hemorrhagic stroke suffered 3-12 months prior to the study; * no other known brain abnormalities by history; * A one-sided stroke resulting in upper extremity paresis * A Chedoke-McMaster Stroke Assessment arm stage and hand stage of 3-6 for the affected limb
Exclusion criteria
* Implanted metallic parts of implanted electronic devices, including pacemakers, defibrillators, or implant medication pump; * Pregnant or trying to become pregnant; Lack of pregnancy established in females of child-bearing potential by a negative urine pregnancy test at screening. * Active alcohol abuse, illicit drug use or drug abuse or significant mental illness * Patients suffering from depression as measured by a score of \>10 on the Patient Health Questionnaire (PHQ9). For clarity, patients diagnosed with depression which is controlled with stable anti-depressive medication and in whom PHQ9 is \<10 are eligible to participate in the trial. * History of epilepsy, defined as at least two unprovoked seizures occurring greater than 24 hours apart or diagnosis of an epilepsy syndrome, OR a seizure within the last 12 months. * Any condition that would prevent the subject from giving voluntary informed consent; * An implanted brain stimulator; * Any metal in head with the exception of dental work or any ferromagnetic metal elsewhere in the body; * Enrolled or plans to enroll in an interventional trial during this study; * Scalp wounds or infections; * Claustrophobia precluding MRI; * A fixed contraction deformity in the affected limb that would prevent normal dexterity if patient were neurologically intact; * Excessive spasticity as indicated by the Modified Ashworth Spasticity (MAS) Scale \>2/4 in either elbow flexors, wrist flexors or finger flexors of the affected limb;i * previous stroke with residual deficits (TIAs not a reason for exclusion); * premorbid (retrospective) modified Rankin Scale (mRS) score ≥2 of any aetiology; * a concurrent progressive neurologic disorder, acute coronary syndrome, severe heart disease (NYHA Classification \> 3), or other major medical condition, * confirmed or suspected lower-limb fracture preventing mobilization, * patients requiring palliative care * patients planning to undergo any other occupational therapy during the 6 week active treatment period of the trial (see section 5.2 for study schedule) than what is provided in the study * A recent injection of botulinium toxin to the affected upper limb in the last 3 months, or the need of an injection of botulinum toxin anytime during the study period and follow up. * A recent injection of phenol to the affected upper limb in the last 6 months, or the need of an injection of phenol anytime during the study period and follow up. * Ataxia as measured by a score \> 1 on item 7 (limb ataxia) of the NIH stroke scale. * Severe sensory deficits as measured by a score of 2 on item 8 of the NIH stroke scale. * Severe aphasia as measured by a score of \> 2 on item 9 (best language) of the NIH stroke scale. * Severe neglect as measured by a score of 2 on item 11 (extinction and inattention) of the NIH stroke scale. * Patients unable to comprehend or follow verbal commands * Based on PI's or local physician's assessment patient unable to tolerate the trial procedure due to medical condition * A Mini mental status exam (MMSE) \<25.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Upper Extremity Fugl-Meyer Score | Baseline - 6 months post-treatment | Number of Participants with Improvement in Upper Extremity Fugl-Meyer (UEFM) Score at 6 Months Post-treatment equal or exceeding the Minimal Clinically Important Difference (MCID) of 5 points (MCID). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stroke Impact Scale (SIS) | Baseline - 6 months post-treatment | Score used to detect the consequences of stroke on physical functioning and activities of daily living. The SIS-16 is a 16 item survey that inquires about daily tasks performed over the previous 2 weeks. Scale minimum 16, maximum 80. Higher values indicate better function |
| Arm-Research Action Test (ARAT) | Baseline - 6 months post-treatment | Scale minimum 0, maximum 57. Greater values indicate better motor function. |
| Wolf Motor Function Test | Baseline - 6 months post-treatment | Time in seconds to perform test tasks. Shorter time indicates better motor function. |
| Chedoke-McMaster Stroke Assessment (CMSA) | Baseline - 6 months post-treatment | Scale minimum 1, maximum 7. Higher values indicate better motor function of hand. |
| Patient Health Questionnaire (PHQ9) | Baseline - 6 months post-treatment | The possible presence and severity of depression will be assessed using the Patient Health Questionnaire (PHQ9). PHQ9 is a scale with a minimum value 0 and maximum of 27. Higher values indicate more depressed mood |
| Quality of Life Assessment: EuroQol EQ-5D Scale | Baseline - 6 months post-treatment | The EuroQoL EQ-5D is a visual analog scale scale from 0 (minimum) to 100 (maximum) assessing quality of life. Higher values indicate better quality of life. |
| NIH Stroke Scale (NIHSS) | Baseline - 6 months post-treatment | Scale is a measure of neurological functioning, with higher scores reflecting greater deficit (minimum 0,maximum 42) |
Other
| Measure | Time frame | Description |
|---|---|---|
| To Assess Safety of Study Device Use, All Serious Adverse Events Will be Recorded and Compared Between Groups | Baseline - 6 months post-treatment | Serious Adverse Events were recorded and their occurrence was compared between treatment arms |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NBS-rTMS + Task-oriented Rehabilitation NBS-guided rTMS + task-oriented rehabilitation
NBS-guided rTMS
Task oriented rehabilitation | 132 |
| Sham rTMS + Task-oriented Rehabilitation Sham rTMS + task-oriented rehabilitation
Sham rTMS
Task oriented rehabilitation | 67 |
| Total | 199 |
Baseline characteristics
| Characteristic | NBS-rTMS + Task-oriented Rehabilitation | Sham rTMS + Task-oriented Rehabilitation | Total |
|---|---|---|---|
| Age, Continuous | 59.2 years STANDARD_DEVIATION 13.3 | 57.6 years STANDARD_DEVIATION 12.7 | 58.7 years STANDARD_DEVIATION 13.1 |
| Arm Research Action Test | 27.3 units on a scale STANDARD_DEVIATION 16.3 | 30.0 units on a scale STANDARD_DEVIATION 15.8 | 28.2 units on a scale STANDARD_DEVIATION 16.1 |
| Chedoke-McMaster Stroke Assessment Arn | 3.5 units on a scale STANDARD_DEVIATION 0.8 | 3.6 units on a scale STANDARD_DEVIATION 0.9 | 3.5 units on a scale STANDARD_DEVIATION 0.9 |
| Chedoke-McMaster Stroke Assessment Hand | 4.0 units on a scale STANDARD_DEVIATION 0.9 | 4.1 units on a scale STANDARD_DEVIATION 1 | 4.0 units on a scale STANDARD_DEVIATION 0.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 27 Participants | 18 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 105 Participants | 49 Participants | 154 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| EuroQol ED-5Q scale | 68.2 units on a scale STANDARD_DEVIATION 18.4 | 70.4 units on a scale STANDARD_DEVIATION 17.9 | 68.8 units on a scale STANDARD_DEVIATION 18.3 |
| NIH Stroke Scale | 2.7 units on a scale STANDARD_DEVIATION 1.6 | 2.3 units on a scale STANDARD_DEVIATION 1.9 | 2.6 units on a scale STANDARD_DEVIATION 1.8 |
| Patient Health Questionnaire - 9 (PHQ9) | 3.5 units on a scale STANDARD_DEVIATION 2.9 | 3.7 units on a scale STANDARD_DEVIATION 3.2 | 3.6 units on a scale STANDARD_DEVIATION 3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 5 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 35 Participants | 12 Participants | 47 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) White | 83 Participants | 47 Participants | 130 Participants |
| Region of Enrollment United States | 132 participants | 67 participants | 199 participants |
| Sex: Female, Male Female | 44 Participants | 25 Participants | 69 Participants |
| Sex: Female, Male Male | 88 Participants | 42 Participants | 130 Participants |
| Stroke Impact Scale | 63.3 units on a scale STANDARD_DEVIATION 16.9 | 65.3 units on a scale STANDARD_DEVIATION 16 | 64.7 units on a scale STANDARD_DEVIATION 16.8 |
| Upper Extremity Fugl-Meyer | 34.0 units on a scale STANDARD_DEVIATION 12.2 | 35.0 units on a scale STANDARD_DEVIATION 12.5 | 34.3 units on a scale STANDARD_DEVIATION 12.3 |
| Wolf Motor Function Test | 32.1 seconds of time STANDARD_DEVIATION 48.4 | 29.4 seconds of time STANDARD_DEVIATION 46.8 | 31.2 seconds of time STANDARD_DEVIATION 48.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 132 | 0 / 67 |
| other Total, other adverse events | 30 / 132 | 15 / 67 |
| serious Total, serious adverse events | 11 / 132 | 7 / 67 |
Outcome results
Primary
Upper Extremity Fugl-Meyer Score
Number of Participants with Improvement in Upper Extremity Fugl-Meyer (UEFM) Score at 6 Months Post-treatment equal or exceeding the Minimal Clinically Important Difference (MCID) of 5 points (MCID).
Time frame: Baseline - 6 months post-treatment
Population: Intent to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NBS-rTMS + Task-oriented Rehabilitation | Upper Extremity Fugl-Meyer Score | 88 Participants |
| Sham rTMS + Task-oriented Rehabilitation | Upper Extremity Fugl-Meyer Score | 43 Participants |
p-value: 0.76Chi-squared
Secondary
Arm-Research Action Test (ARAT)
Scale minimum 0, maximum 57. Greater values indicate better motor function.
Time frame: Baseline - 6 months post-treatment
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBS-rTMS + Task-oriented Rehabilitation | Arm-Research Action Test (ARAT) | 5.0 units on a scale | Standard Deviation 7.7 |
| Sham rTMS + Task-oriented Rehabilitation | Arm-Research Action Test (ARAT) | 5.0 units on a scale | Standard Deviation 10.9 |
p-value: 0.8t-test, 2 sided
Secondary
Chedoke-McMaster Stroke Assessment (CMSA)
Scale minimum 1, maximum 7. Higher values indicate better motor function of hand.
Time frame: Baseline - 6 months post-treatment
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBS-rTMS + Task-oriented Rehabilitation | Chedoke-McMaster Stroke Assessment (CMSA) | 0.5 units on a scale | Standard Deviation 1 |
| Sham rTMS + Task-oriented Rehabilitation | Chedoke-McMaster Stroke Assessment (CMSA) | 0.5 units on a scale | Standard Deviation 1.1 |
p-value: 0.14t-test, 2 sided
Secondary
NIH Stroke Scale (NIHSS)
Scale is a measure of neurological functioning, with higher scores reflecting greater deficit (minimum 0,maximum 42)
Time frame: Baseline - 6 months post-treatment
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBS-rTMS + Task-oriented Rehabilitation | NIH Stroke Scale (NIHSS) | -0.4 units on a scale | Standard Deviation 1.3 |
| Sham rTMS + Task-oriented Rehabilitation | NIH Stroke Scale (NIHSS) | -0.7 units on a scale | Standard Deviation 1.2 |
p-value: 0.14t-test, 2 sided
Secondary
Patient Health Questionnaire (PHQ9)
The possible presence and severity of depression will be assessed using the Patient Health Questionnaire (PHQ9). PHQ9 is a scale with a minimum value 0 and maximum of 27. Higher values indicate more depressed mood
Time frame: Baseline - 6 months post-treatment
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBS-rTMS + Task-oriented Rehabilitation | Patient Health Questionnaire (PHQ9) | -0.2 units on a scale | Standard Deviation 3.3 |
| Sham rTMS + Task-oriented Rehabilitation | Patient Health Questionnaire (PHQ9) | 0.0 units on a scale | Standard Deviation 4.1 |
p-value: 0.95t-test, 2 sided
Secondary
Quality of Life Assessment: EuroQol EQ-5D Scale
The EuroQoL EQ-5D is a visual analog scale scale from 0 (minimum) to 100 (maximum) assessing quality of life. Higher values indicate better quality of life.
Time frame: Baseline - 6 months post-treatment
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBS-rTMS + Task-oriented Rehabilitation | Quality of Life Assessment: EuroQol EQ-5D Scale | 7.7 units on a scale | Standard Deviation 15.7 |
| Sham rTMS + Task-oriented Rehabilitation | Quality of Life Assessment: EuroQol EQ-5D Scale | 6.9 units on a scale | Standard Deviation 14.7 |
p-value: 0.96t-test, 2 sided
Secondary
Stroke Impact Scale (SIS)
Score used to detect the consequences of stroke on physical functioning and activities of daily living. The SIS-16 is a 16 item survey that inquires about daily tasks performed over the previous 2 weeks. Scale minimum 16, maximum 80. Higher values indicate better function
Time frame: Baseline - 6 months post-treatment
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBS-rTMS + Task-oriented Rehabilitation | Stroke Impact Scale (SIS) | 6.7 units on a scale | Standard Deviation 11.6 |
| Sham rTMS + Task-oriented Rehabilitation | Stroke Impact Scale (SIS) | 8.7 units on a scale | Standard Deviation 14.5 |
Secondary
Wolf Motor Function Test
Time in seconds to perform test tasks. Shorter time indicates better motor function.
Time frame: Baseline - 6 months post-treatment
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBS-rTMS + Task-oriented Rehabilitation | Wolf Motor Function Test | -9.0 seconds of time | Standard Deviation 29.5 |
| Sham rTMS + Task-oriented Rehabilitation | Wolf Motor Function Test | -10.6 seconds of time | Standard Deviation 36.5 |
p-value: 0.55Wilcoxon (Mann-Whitney)
Other Pre-specified
To Assess Safety of Study Device Use, All Serious Adverse Events Will be Recorded and Compared Between Groups
Serious Adverse Events were recorded and their occurrence was compared between treatment arms
Time frame: Baseline - 6 months post-treatment
Population: Intent to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NBS-rTMS + Task-oriented Rehabilitation | To Assess Safety of Study Device Use, All Serious Adverse Events Will be Recorded and Compared Between Groups | 16 number of events |
| Sham rTMS + Task-oriented Rehabilitation | To Assess Safety of Study Device Use, All Serious Adverse Events Will be Recorded and Compared Between Groups | 10 number of events |
p-value: 0.63Chi-squared