Niche Trial: Navigated Inhibitory rTMS to Contralesional Hemisphere Trial

Study Overview
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Brief Summary
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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.

Official Title
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Pivotal Phase III, Prospective, Multicenter, Double Blinded, Randomized, Sham Controlled Trial to Determine the Therapeutic Effects of Navigation Guided 1 Hz rTMS Administered to the Contralesional Hemisphere as Adjuvant to Task Oriented Rehabilitation in Patients With Ischemic or Hemorrhagic Stroke

Conditions
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Stroke

Intervention / Treatment
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* Device: NBS-guided rTMS
* Device: Sham rTMS
* Procedure: Task oriented rehabilitation


Participation Criteria
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Eligibility Criteria
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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.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: NBS-rTMS + task-oriented rehabilitation<br>NBS-guided rTMS + task-oriented rehabilitation | Device: NBS-guided rTMS<br> <br> * Other names: Nexstim;Procedure: Task oriented rehabilitation<br> <br> |
| Sham Comparator: Sham rTMS + task-oriented rehabilitation<br>Sham rTMS + task-oriented rehabilitation | Device: Sham rTMS<br> <br> Procedure: Task oriented rehabilitation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline - 6 months post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arm-Research Action Test (ARAT) | Scale minimum 0, maximum 57. Greater values indicate better motor function. | Baseline - 6 months post-treatment | 
| Wolf Motor Function Test | Time in seconds to perform test tasks. Shorter time indicates better motor function. | Baseline - 6 months post-treatment | 
| NIH Stroke Scale (NIHSS) | Scale is a measure of neurological functioning, with higher scores reflecting greater deficit (minimum 0,maximum 42) | Baseline - 6 months post-treatment | 
| Chedoke-McMaster Stroke Assessment (CMSA) | Scale minimum 1, maximum 7. Higher values indicate better motor function of hand. | Baseline - 6 months post-treatment | 
| 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 | Baseline - 6 months post-treatment | 
| 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 | Baseline - 6 months post-treatment | 
| 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. | Baseline - 6 months post-treatment |