Targeted Plasticity Therapy for Upper Limb Rehabilitation in Spinal Cord Injuries

Study Overview
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Brief Summary
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Texas Biomedical Device Center at UT Dallas has developed an innovative strategy to enhance recovery of motor and sensory function after neurological injury termed targeted plasticity therapy (TPT). This technique uses brief pulses of vagus nerve stimulation to engage pro-plasticity neuromodulatory circuits during rehabilitation exercises. Recovery is associated with neural plasticity in spared motor networks in the brain and spinal cord. Moreover, an early feasibility study and an independent, double-blind, placebo-controlled study in chronic stroke participants indicate that VNS is safe in participants with upper limb deficits, and yields a clinically-significant three-fold increase in neural connections during rehabilitation exercises. Given the track record of safety and potential for VNS to enhance recovery of upper limb motor function in spinal cord injured individuals, the purpose of this double blind randomized placebo controlled optional open-label extension study is to assess the safety of using a new device to deliver vagus nerve stimulation to reduce symptom severity in participants with SCI. Additionally, the study will assess the prospective benefit of the system and garner an initial estimate of efficacy for a subsequent trial. Participants may undergo additional sessions of training with VNS.

Official Title
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Targeted Plasticity Therapy for Upper Limb Rehabilitation in Spinal Cord Injuries

Conditions
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Spinal Cord Injuries, Upper Extremity Paresis

Intervention / Treatment
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* Device: Active Vagus Nerve Stimulation
* Device: Placebo Vagus Nerve Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria In order to be eligible to participate in this study, an individual must meet all of the following criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Adult, aged 18-64 In good general health as evidenced by medical history and diagnosed with first time cervical spinal cord injury resulting in an ASIA grade B, C, or D, and level 1 or better motor function as described by the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). SCI caused by trauma that occurred ≥ 12 months prior to enrollment Meets all clinical criteria for the surgical VNS implantation as determined by the PI, surgeon, and anesthesiologist Must demonstrate some residual upper limb and hand movement in either arm Appropriate candidate for VNS implantation Willing and able to comply with the study protocol Exclusion Criteria An individual who meets any of the following criteria will be excluded from participation in this study: Spinal cord injuries by sharp objects, firearms, and non-traumatic or congenital causes, even if at different levels of the spinal cord Any evidence of recurrent laryngeal nerve injury (Evident during required laryngoscopy for all participants with Prior right-sided anterior cervical surgery- done prior to randomization) Excessive scar tissue marking implantation unsafe (evident at surgery) Concomitant clinically significant brain injuries Prior injury to vagus nerve Prior or current treatment with vagus nerve stimulation Participant receiving any therapy (medication or otherwise) that would interfere with VNS Pregnancy or lactation Clinical complications that hinder or contraindicate the surgical procedure Psychiatric disorders, psychosocial, and/or cognitive impairment that would interfere with study participation, as assessed by medical evaluation Abusive use of alcohol and/or illegal substances use Participation in other interventional clinical trial Participants with known immunodeficiency including participants who are receiving or have received chronic corticosteroids, immunosuppressants, immunostimulating agents or radiation therapy within 6 months Significant comorbidities or conditions associated with high risk for surgical or anesthetic survival (e.g. renal failure, peripheral vascular disease, unstable cardiac disease, poorly controlled diabetes, immunosuppression, etc.). Active neoplastic disease. Participants with significant local circulatory problems, (e.g. thrombophlebitis and lymphedema). Participants with any medical condition or other circumstances that might interfere with their ability to return for follow-up visits in the judgment of the Investigator, including systemic illness, neuromuscular, neurosensory, or musculoskeletal deficiency that would render the participant unable to perform appropriate postoperative rehabilitation. Any condition which, in the judgment of the Investigator, would preclude adequate evaluation of device's safety and performance. Aphasia and other cognitive deficits that make understanding the potential risks and benefits of the study impossible for participant. Inability to personally provide informed consent. A recent history of syncope A recent history of dysphagia Currently require, or are likely to require diathermy Significant respiratory issues that would interfere with participation Non-English speaking Patients who are acutely suicidal and/or have been admitted for a suicide attempt Incarceration or legal detention

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Device Feasibility
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Double blind, randomized placebo controlled, optional open-label extension design
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immediate Start Vagus Nerve Stimulation group<br>The Immediate Start VNS group will receive rehabilitation and active stimulation for 18 in-office sessions over the course of approximately 6 weeks during phase 1. For phase 2, all subjects will be provided the option to participate in an open-label extension consisting of an additional 18 sessions of in-office rehabilitation with active VNS over the course of approximately 6 weeks. Participants that elect to continue in the open-label extension will be assessed approximately 1 week after the conclusion of the additional 18 sessions of therapy. | Device: Active Vagus Nerve Stimulation<br>* Stimulation of the vagus nerve that is paired with upper extremity rehabilitation. VNS stimulation as described in the current study consists of 0.5 s trains of 0.8 mA 100 µs biphasic pulses delivered at 30 Hz. Stimulation trains are delivered only during rehabilitation.<br>* Other names: paired VNS;|
| Placebo Comparator: Delayed Start Vagus Nerve Stimulation group<br>The Delayed Start VNS group will receive equivalent rehabilitation with placebo stimulation for 18 in-office sessions over the course of approximately 6 weeks during phase 1. For phase 2, all subjects will be provided the option to participate in an open-label extension consisting of an additional 18 sessions of in-office rehabilitation with active VNS over the course of approximately 6 weeks. Participants that elect to continue in the open-label extension will be assessed approximately 1 week after the conclusion of the additional 18 sessions of therapy. | Device: Placebo Vagus Nerve Stimulation<br>* During Phase 1 of the study, the placebo group will receive a minimal amount of stimulation that fails to sufficiently activate the nerve, unknown to the participant and therapists. All participants will receive active stimulation during the Phase 2 open-label portion of the study.<br>* Other names: control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events [Device Safety] | Review of adverse events reported throughout the trial will be used to inform the potential risks associated with the ReStore system and provide a better understanding of risk/benefit analysis. | From Week 1 through study follow-up, approximately two years from the date of implant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Restore System Feasibility during Rehabilitation | If stimulation delivery is successful during the active portion of therapy sessions then the system is feasible to use. The primary endpoint will be: greater than 50% of the valid attempts to stimulate are successful per the ReStore system log. | Weeks 7-12, Weeks 14-19 | 
| Quantitative Force and Range of Motion Assessment | This is a physical assessment of upper limb changes in force/torque as a result of VNS paired rehabilitation. The primary endpoints will be: 10% increase in finger pinch and flexion force following active VNS, 10% increase in wrist flexion and extension force following active VNS, and 10% increase in wrist pronation and supination force following active VNS. This will serve as an efficacy measurement to use as basis for estimate of sample size for a pivotal trial. | Week 1, 6, 13, 20 | 
| Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) | Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) is a measure used for spinal cord injury patients. The measure includes five subsets of questions designed to quantitatively measure clinical upper limb impairment (Kalsi-Ryan et al., 2012). The primary endpoint will be: >4 point shift in GRASSP assessment following active VNS. This will serve as an efficacy measurement to use as basis for estimate of sample size for a pivotal trial. | Week 1, 6, 13, 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vagus Nerve Stimulation (VNS), Rehabilitation, Targeted Plasticity Therapy