Deep Brain Stimulation for the Treatment of Traumatic Brain Injury

Study Overview
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Brief Summary
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This study involves the treatment of cognitive impairment secondary to moderate to severe brain injury using central thalamic deep brain stimulation. Although all patients will receive stimulation continuously through a surgically implanted pacemaker-like device, half of the patients will have the device deactivated during a blinded assessment phase. The device will be reactivated following this assessment and patients will have the option to continue stimulation in an open-label continuation.

Detailed Description
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This preliminary safety study evaluates the use of the Medtronic Activa PC+S system and Medtronic Nexus-E system for central thalamic deep brain stimulation (CT-DBS) in the treatment of cognitive impairment secondary to traumatic brain injury (TBI). It involves a neurosurgical procedure in which electrodes are implanted in the brain, connected to an implanted pacemaker-like device in the chest. The proposed study, if successful, will provide supporting evidence for the development of a novel therapeutic approach utilizing CT-DBS to improve these enduring cognitive impairments arising in persons with multi-focal structural brain injuries. This research will address the critical gap of the lack of any available treatments. CT-DBS targets well-defined neuronal populations within the central thalamus that have known anatomical and physiological specializations, which not only provide a key role in arousal regulation during cognitively-mediated behaviors, but also exhibit a particular vulnerability to dysfunction in the setting of multi-focal, non-selective brain injuries. Our proposed study aims to support development of CT-DBS as a novel therapeutic avenue for accessing cognitive reserve in patients with acquired brain injuries. In the proposed feasibility study of 6 subjects at a single investigational site, we will test the safety of CT-DBS in the severe traumatic brain injury (STBI) population with GOSE 6-7 level recovery and collect data to establish the translation of preclinical studies into human application of CT-DBS.

Official Title
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CT-DBS for Traumatic Brain Injury Using the Medtronic Activa PC+S System

Conditions
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TBI (Traumatic Brain Injury)

Intervention / Treatment
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* Device: Deep brain stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of moderate to severe TBI based on worst GCS score within first 48 hours of injury (acceptable GCS range = 3-12) Age 22-60 At least 24 months from date of onset Fluent in English and able to independently provide consent Rating of upper moderate disability to lower good recovery on the Glasgow Outcome Scale-Extended (GOSE) at time of enrollment (acceptable GOSE range 5-7) Failure to return to pre-injury level of vocational or educational function Either receiving no CNS stimulants or other medications known to affect cognitive function, or on stable doses of these medications for the last three months Exclusion Criteria: History of major developmental, neurologic, psychiatric or substance use disorder with evidence of disability prior to onset of TBI Major medical co-morbidities including: end stage renal failure, severe heart failure, coagulopathy, severe respiratory problems, severe liver failure, uncontrolled hypertension or other significant medical co morbidities Have had a documented seizure within 3 months of study screening (subjects may re-screen if seizure free after initial screen failure) Malignancy with < 5 years life expectancy Untreated / uncontrolled (severe at the time of enrollment) depression or other psychiatric disorder Women of childbearing age who do not regularly use an accepted contraceptive method Inability to stop anticoagulation therapy or platelet anti-aggregation therapy before, during and after surgery Previous DBS or other brain implants Previous ablative intracranial surgery Implantable hardware not compatible with MRI Condition requiring diathermy after DBS implantation Hardware, lesions or other factors limiting placement of electrodes in optimal target location in the judgment of the operating surgeon Concurrent enrollment in any other clinical trial Any condition or finding that, in the judgment of the PI, significantly increases risk or significantly reduces the likelihood of benefit from DBS

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Subjects will be treated with deep brain stimulation throughout the study, with the exception of a brief, 21 day blinded withdrawal phase that will be undertaken to assess for any possible therapeutic effect. | Device: Deep brain stimulation<br>* Delivery of continuous, low-voltage electrical pulses to deep portions of the brain via an implantable pacemaker-like device.<br>* Other names: Central Thalamic DBS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Trail Making Test Part B Time to Completion | The Trail Making Test is a measure of attention, speed and mental flexibility. It also tests spatial organization, visual pursuits, recall, and recognition. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part A tests visual scanning, numeric sequencing, and visuomotor speed. Part B is similar except the person must alternate between numbers and letters and is believed to be more difficult and takes longer to complete. Part B tests cognitive demands including visual motor and visual spatial abilities and mental flexibility. Both sections are timed and the score represents the amount of time required to complete the task. Lower scores (shorter times) correspond to a better outcome. | Pre-surgery baseline to treatment phase end (up to 197 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Trail Making Test Part A Time to Completion | The Trail Making Test is a measure of attention, speed and mental flexibility. It also tests spatial organization, visual pursuits, recall, and recognition. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part A tests visual scanning, numeric sequencing, and visuomotor speed. Part B is similar except the person must alternate between numbers and letters and is believed to be more difficult and takes longer to complete. Part B tests cognitive demands including visual motor and visual spatial abilities and mental flexibility. Both sections are timed and the score represents the amount of time required to complete the task. Lower scores (shorter times) correspond to a better outcome. | Pre-surgery baseline to treatment phase end (up to 197 days) | 
| Percent Change in Traumatic Brain Injury Quality of Life - Executive Function Short Form (TBI-QOL) Scale Score | The TBI-QOL was developed as a comprehensive patient-reported outcomes (PRO) measurement system specifically for individuals with TBI. It consists of 20 independent calibrated item banks and 2 uncalibrated scales that measure physical, emotional, cognitive, and social aspects of health-related quality of life. We will administer the short form (6-10 questions each) of the TBI-QOL Fatigue, Attention/Concentration, and Executive Function subscales. Executive Function score range: 10-50, higher scores correspond to better executive function. | Pre-surgery baseline to treatment phase end (up to 197 days) | 
| Percent Change Traumatic Brain Injury Quality of Life - Attention/Concentration Short Form Scale Score | The TBI-QOL was developed as a comprehensive patient-reported outcomes (PRO) measurement system specifically for individuals with TBI. It consists of 20 independent calibrated item banks and 2 uncalibrated scales that measure physical, emotional, cognitive, and social aspects of health-related quality of life. We will administer the short form (6-10 questions each) of the TBI-QOL Fatigue, Attention/Concentration, and Executive Function subscales. Attention/Concentration score range: 6-30, higher scores correspond to better attention and concentration. | Pre-surgery baseline to treatment phase end (up to 197 days) | 
| Percent Change in Traumatic Brain Injury Quality of Life - Fatigue Short Form Scale Score | The TBI-QOL was developed as a comprehensive patient-reported outcomes (PRO) measurement system specifically for individuals with TBI. It consists of 20 independent calibrated item banks and 2 uncalibrated scales that measure physical, emotional, cognitive, and social aspects of health-related quality of life. We will administer the short form (6-10 questions each) of the TBI-QOL Fatigue, Attention/Concentration, and Executive Function subscales. Fatigue score range: 10-50, lower scores correspond to less fatigue. | Pre-surgery baseline to treatment phase end (up to 197 days) | 
| Percent Change in Rivermead Post-Concussion Symptom Questionnaire Scale Score | The Rivermead PCS Questionnaire (RPQ) was originally developed as a measure of severity of symptoms following mild TBI. It consists of 16 post-concussion symptoms including headaches, dizziness, nausea/vomiting, noise sensitivity, sleep disturbance, fatigue, irritability, feeling depressed/tearful, feeling frustrated/ impatient, forgetfulness, poor concentration, taking longer to think, blurred vision, light sensitivity, double vision and restlessness. In the original version of the RPQ, participants are asked to rate the degree (on a scale of 0 to 4) to which a particular symptom has been absent or a mild, moderate or severe problem over the previous 24 hours compared with premorbid levels. Score range: 0-64, lower scores correspond to fewer symptoms | Pre-surgery baseline to treatment phase end (up to 197 days) | 
| Percent Change in Ruff 2 and 7 Automatic Detection Speed Score | The Ruff 2 & 7 Test was developed to measure two aspects of visual attention: sustained attention (ability to maintain consistent performance level over time) and selective attention (ability to select relevant stimuli while ignoring distractors). The test consists of a series of 20 trials of a visual search and cancellation task. The respondent detects and marks through all occurrences of the two target digits: 2 and 7. In the 10 Automatic Detection trials, the target digits are embedded among alphabetical letters that serve as distractors. In the 10 Controlled Search trials, the target digits are embedded among other numbers that serve as distractors. Correct hits and errors are counted for each trial and serve as the basis for scoring the test. Speed scores reflect the total number of correctly identified targets (hits). Score range: 0 to 300, with higher numbers representing more correctly identified targets within the allotted time (5 minutes) | Pre-surgery baseline to treatment phase end (up to 197 days) | 
| Percent Change in Ruff 2 and 7 Automatic Detection Accuracy Score | The Ruff 2 & 7 Test was developed to measure two aspects of visual attention: sustained attention (ability to maintain consistent performance level over time) and selective attention (ability to select relevant stimuli while ignoring distractors). The test consists of a series of 20 trials of a visual search and cancellation task. The respondent detects and marks through all occurrences of the two target digits: 2 and 7. In the 10 Automatic Detection trials, the target digits are embedded among alphabetical letters that serve as distractors. In the 10 Controlled Search trials, the target digits are embedded among other numbers that serve as distractors. Correct hits and errors are counted for each trial and serve as the basis for scoring the test. Accuracy scores evaluate the number of targets identified in relation to the number of possible targets (n=300), expressed as a percentage. Higher scores represent higher accuracy of target identification. | Pre-surgery baseline to treatment phase end (up to 197 days) | 
| Percent Change in Ruff 2 and 7 Controlled Search Speed Score | The Ruff 2 & 7 Test was developed to measure two aspects of visual attention: sustained attention (ability to maintain consistent performance level over time) and selective attention (ability to select relevant stimuli while ignoring distractors). The test consists of a series of 20 trials of a visual search and cancellation task. The respondent detects and marks through all occurrences of the two target digits: 2 and 7. In the 10 Automatic Detection trials, the target digits are embedded among alphabetical letters that serve as distractors. In the 10 Controlled Search trials, the target digits are embedded among other numbers that serve as distractors. Correct hits and errors are counted for each trial and serve as the basis for scoring the test. Speed scores reflect the total number of correctly identified targets (hits). Score range: 0 to 300, with higher numbers representing more correctly identified targets within the allotted time (5 minutes) | Pre-surgery baseline to treatment phase end (up to 197 days) | 
| Percent Change in Ruff 2 and 7 Controlled Search Accuracy Score | The Ruff 2 & 7 Test was developed to measure two aspects of visual attention: sustained attention (ability to maintain consistent performance level over time) and selective attention (ability to select relevant stimuli while ignoring distractors). The test consists of a series of 20 trials of a visual search and cancellation task. The respondent detects and marks through all occurrences of the two target digits: 2 and 7. In the 10 Automatic Detection trials, the target digits are embedded among alphabetical letters that serve as distractors. In the 10 Controlled Search trials, the target digits are embedded among other numbers that serve as distractors. Correct hits and errors are counted for each trial and serve as the basis for scoring the test. Accuracy scores evaluate the number of targets identified in relation to the number of possible targets (n=300), expressed as a percentage. Higher scores represent higher accuracy of target identification. | Pre-surgery baseline to treatment phase end (up to 197 days) | 
| Percent Change in Patient Health Questionnaire - 9 Scale Score. | The Participant Health Questionnaire 9 is a standardized assessment instrument designed to screen, diagnose, monitor, and measure the severity of depression. Score range: 0 to 27, lower scores correspond to better health outcomes. | Pre-surgery baseline to treatment phase end (up to 197 days) | 
| Number of Participants With ≥1 Point Increase in Glasgow Outcome Scale - Extended Scale Score | The Glasgow Outcome Scale Extended (GOS-E) is a measure of disability and handicap intended for use following head injury. The GOS-E subdivides the upper three categories of the original Glasgow Outcome Scale (GOS), severe disability, moderate disability and good recovery, into an eight-category scale: 1 = dead, 2 = vegetative state, 3 = lower severe disability, 4 = upper severe disability, 5 = lower moderate disability, 6 = upper moderate disability, 7 = lower good recovery, and 8 = upper good recovery to provide more detailed assessment of the functional effects of the injury. A structured interview has been developed to standardize assignment of an outcome category (Wilson et al. 1998). Increase of 1 point on this scale represents a meaningful change in health outcome. | Pre-surgery baseline to treatment phase end (up to 197 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Deep brain stimulation, DBS, Central thalamus, TBI, Traumatic brain injury