Neuromodulation to Improve Respiratory Function in Cervical Spinal Cord Injury

Study Overview
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Brief Summary
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This is a phase 1 study of safety and feasibility of cervical spinal cord stimulator implantation in cervical SCI subjects who are ventilator dependent. The Investigators will be focusing on the safety and feasibility of this approach. Participants may qualify for the study if they are male or female 18-75 years old, are at least 1 year after original injury, have injury at C2 to C7 level, and dependent on mechanical ventilation to help them breathe. Additionally, they need to be able to attend up to twice weekly testing sessions for up to 21 months.

Detailed Description
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There are five main phases to this study. The first phase is baseline testing, second phase is temporary implant, third phase is post-temporary implant mapping/treatment, fourth phase is permanent implant, and fifth phase is post-permanent implant treatment. During each of the three phases, subjects will have twice weekly laboratory testing sessions and daily home training sessions. As this is a feasibility study, the phases are designed to select for subjects that will be most responsive and will benefit from this strategy. Phase 1. Baseline testing/training (up to 6 months, UCLA Semel Institute for Neuroscience and Human Behavior), the purpose of which is to ensure that each subject begins with the full benefits achievable by standard rehabilitative respiratory therapy and has stable baseline of function before they begin epidural stimulation. 15 subjects will undergo this phase. Maximum inspiratory and expiratory pressure, resting spontaneous respiratory activity, and respiratory muscle EMG will be measured during this phase. Subjects on ventilator assist mode (unless or until they can sustain adequate respiration on their own) will be monitored via pneumotachometer for respiratory frequency changes. Additionally, subjects will undergo motor and sensory testing. The subjects must show stable respiratory function before implantation, therefore if a subject is showing small improvements at 3 months the subject will continue training until they have reached their maximal effect from training (up to 6 months). Subjects that show stable baseline at 3 months will proceed to Phase 2. If a subject's health worsens, including non-respiratory functioning, subject will be assessed by appropriate physician and testing will be held until subject's health has improved and maintains stable for at least 2 months. Phase 2. Temporary Implant (1 day, 24 hours overnight stay, UCLA Medical Center, Santa Monica). Subjects will undergo temporary stimulator implant surgery. During surgery, intraoperative mapping with the implant will be performed to demonstrate effective stimulation areas. Up to 12 subjects with evidence of response to baseline testing will undergo this phase from the pool of 12 subjects in Phase 1 above. Response to respiratory training will be based on maximal respiratory effort, respiratory abilities at rest, and respiratory muscle EMG. Subjects will be monitored overnight following surgery as a pre-cautionary measure. Phase 3. Post-temporary implant mapping/treatment (up to 10 days, UCLA Semel Institute for Neuroscience and Human Behavior) Respiratory ability will be assessed. Respiratory rehabilitation regimen with the stimulator will be used to re-enable respiratory function. Subjects will be tested daily, up to 10 non-consecutive sessions in the clinic. Each session will last up to 2 hours. Subject will have the temporary implant for a minimum of 1 week and maximum of 2 weeks. Maximal respiratory effort and resting respiratory abilities will be evaluated as well as post-implant PROMs will be assessed. Once optimal parameters have been identified, electrode configuration(s) that allow subjects to manipulate their respiratory pattern will be used. Subjects will be allowed to use stimulator at home (daily, with identified parameters) with respiratory training in addition to twice weekly testing. Home use will involve turning on the stimulator, breathing with the ventilator. The same 12 subjects from Phase 2 will undergo this phase. Phase 4. Permanent implant (1 day, 24 hours overnight stay, UCLA Medical Center, Santa Monica). Subjects will undergo stimulator implant surgery. During surgery, implantation of electrodes will be performed. The ideal placement location will be based on previous temporary trial location. Up to 10 subjects with most connectivity and evidence of response to baseline testing will undergo this phase from the pool of 12 subjects in Phase 3 above. Response to respiratory training will be assessed. Subjects will be monitored overnight following surgery as a pre-cautionary measure. Phase 5. Post-permanent implant mapping/treatment (up to 12 months, UCLA Semel Institute for Neuroscience and Human Behavior) in which the electrode configuration(s) that activate respiratory muscles will be used. Respiratory rehabilitation regimen with the stimulator will be used to re-enable respiratory function. 10 subjects will be tested up to twice weekly in the clinic for up to 2 hours per session. Respiratory response to stimulation will be assessed. Once optimal parameters have been identified, electrode configuration(s) that allow subjects to manipulate their respiratory pattern will be used. Subjects will be allowed to use stimulator at home (daily, with identified parameters) with respiratory training in addition to twice weekly testing. The same 10 subjects from Phase 4 will undergo this phase. Timeline. The study is a safety and feasibility trial. This is a single arm implantation of permanent electrode to assess safety and early efficacy of cervical spinal epidural stimulation to improve respiratory function. It is conducted over a period of up to 6 months or 21 months in 1, 2, or 3 periods, respectively (Fig. 3): Phase 1. Baseline training (up to 6 months), Phase 2. Temporary Trial Implant (1 day), Phase 3. Post-temporary trial implant treatment (up to 10 days), Phase 4. Permanent Implant (1 day, with up to 2 months for surgical recovery), Phase 5. Post-permanent implant treatment (up to 12 months). Therefore, 15 subjects will be involved for up to 6 months, while 12 subjects will be involved for up to 7 months, and 10 subjects involved for up to 21 months (18 months of testing with up to 2 months recovery). Home Use. To ensure safety, the ventilator will provide support for the patient during home use with stimulator turned on, just as it does when epidural stimulation is not on. The patient will not be completely disconnected to the ventilator unless independence from the ventilator is achieved through a gradual and very closely supervised weaning process in which the patient will demonstrate stable O2 saturation and adequate minute ventilation through the stages of weaning. Weaning (and evidence of improved respiratory muscle function) will consist of gradually reducing the level of support delivered by the ventilator while requiring that as weaning occurs, the patient maintains stable minute ventilation on his own. To ensure safety, these weaning maneuvers will be conducted only with respiratory therapist being present, and an AMBU bag with supplemental O2 will be available. Additionally, for safety, the caregiver will obtain heart rate, blood pressure, temperature at 15 min intervals and O2 saturation continuously, or when there is a change in the ventilator setting. Additionally this will be performed only when the subject is fully conscious, awake, and following commands.

Official Title
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Neuromodulation to Improve Respiratory Function in Cervical Spinal Cord Injury

Conditions
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Spinal Cord Injuries

Intervention / Treatment
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* Device: Epidural stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female Age 18-75. Diagnosed with cervical spinal cord injury (SCI). At least 1 year from initial spinal cord injury. Severe respiratory function compromise. Able to attend weekly testing sessions for up to 21 months. Have intact chest/lung, upper and lower extremity anatomy. The neuromuscular connections between the spinal cord and its effector muscles (respiratory and extremity) are required to be intact. Have intact cognitive ability, able to follow commands/voice concerns, and give consent. Exclusion Criteria: History of severe autonomic dysreflexia. Phrenic nerve or diaphragm pacer. Phrenic nerve paralysis. Musculoskeletal dysfunction, unhealed fracture, pressure ulcer, active infection. Clinically significant depression or ongoing drug abuse. Received lung surgery within one year prior to study enrollment or active intrinsic lung disease (COPD, acute or chronic lung infection, asthma, emphysema, cystic fibrosis, etc).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Epidural Stimulation for Respiratory Function<br>Self-controlled longitudinal safety and feasibility of stimulation and respiratory training. | Device: Epidural stimulation<br>* Epidural electrical stimulation implant weekly sessions for 21 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v4 | International Standards for Neurological Classification of Spinal Cord Injury/American Spinal Injury Association (ISNCSCI/ASIA)- Neurological motor and sensory function given a score A-E: Timeframe: completed at the beginning and end of the phases. | 2.5 years | 
| Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v4 | Resting Spontaneous Respiratory Activity (measured in Breathes per Minute), Maximal Inspiratory Pressure (measured in cmH2O) and Spinal Cord Independence Measure (a score from 0-100) questionnaire: Timeframe: assessed weekly through the duration of the study. Data will be analyzed to compare each individual's function to their own at the beginning of the study, during the baseline period. | 2.5 years | 
| Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v4 | Blood Pressure (mm/Hg): Timeframe: completed at the beginning and end of each testing session. | 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluating Pulmonary Function Throughout the Duration of the Study; 20% increase in minute ventilation. | Tidal Volume = mL Timeframe: assessed weekly through the duration of the study. | 2.5 years | 
| Evaluating Pulmonary Function Throughout the Duration of the Study; 20% increase in minute ventilation. | Maximal Expiratory Pressure = cmH2O Timeframe: assessed weekly through the duration of the study. | 2.5 years | 
| Evaluating Pulmonary Function Throughout the Duration of the Study; 20% | Functional Residual Capacity = mL/kg Timeframe: assessed weekly through the duration of the study. | 2.5 years | 
| Evaluating Pulmonary Function Throughout the Duration of the Study; 20% | Peak Expiratory Flow Rate = mL/min Timeframe: assessed weekly through the duration of the study. | 2.5 years | 
| Evaluating Pulmonary Function Throughout the Duration of the Study; 20% | Minute Volume (measured in L/min): Timeframe: assessed weekly through the duration of the study. Data for all of the assessments mentioned above will be analyzed to compare each individual's function to their own at the beginning of the study, during the baseline period.Electromyography (EMG): Respiratory muscle activity will be assessed with common practice EMG recording and functional measurements. Timeframe: assessed weekly through the duration of the study. | 2.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuromodulation, Respiratory SCI, Implant