Pivotal Study of VNS During Rehab After Stroke (VNS-REHAB) (VNS-REHAB)

A Pivotal Randomized Study Assessing Vagus Nerve Stimulation (VNS) During Rehabilitation for Improved Upper Limb Motor Function After Stroke (VNS-REHAB)

This is a pivotal phase study of up to 120 subjects and 15 clinical sites. All subjects are implanted with the Vivistim System® and then randomized to either study treatment or active-control treatment. The randomization will be stratified by age (<30, >30) and baseline FMA UE (20 to <35; >35 to 50). Study treatment is vagus nerve stimulation (VNS) delivered during rehabilitation. Active control treatment is rehabilitation (standard-of-care treatment) with only a minimal amount of VNS at the start of each session intended to support blinding.

This study has three distinct stages: Stage I, an acute blinded stage, Stage II, an unblinded stage through one year of standard VNS, and Stage III, an unblinded stage for yearly follow-up after one year of VNS. The Control group crosses over to VNS treatment at Stage II. For Stage I, subjects have: consent and evaluation (screening), one pre-implant evaluation, surgical implant of the device system and randomization into one of the treatment arms, one baseline evaluation after device implant surgery but before initiation of treatment, 6 weeks of treatment (standard-of-care rehabilitation + standard VNS or standard-of-care rehabilitation + active control VNS), and then post-acute therapy evaluations at 1, 30 and 90 days after the 6 weeks of treatment. Between Day 1 (V5) and Day 30 (V6) post-acute therapy, both groups will receive in-home, self-directed rehabilitation (30 minutes of daily rehabilitation as assigned by the therapist) with either in-home activated VNS (VNS group) or no VNS (Control group). This means that the control subjects will not have the in-home activated VNS until they complete the second 6-week session of in-clinic rehabilitation with follow-up assessments as described below in Stage II. At this point (Day 30) subjects start scheduling for their continuing long-term follow-up. Between Day 30 and Day 90 post-acute therapy, both groups continue in-home, self-directed rehabilitation (30 minutes of daily rehabilitation as assigned by the therapist). The VNS group continues to receive in-home VNS with magnet use; the Control group continues to use the magnet but does not receive any VNS. The Day 90 post-acute therapy visit is V7; it is the first quarterly visit (3 months after study therapy) for the VNS group and is the re-baseline visit (visit just prior to the initiation of standard VNS therapy) for the Control group. Stage II: VNS subjects will continue to have quarterly assessments through the end of the first year (6m, 9m, 12m). Subjects in the control group will crossover for a second 6-week in-clinic rehabilitation period where they will now receive rehabilitation with standard VNS. Control subjects will then have the three post therapy assessments (1, 30 and 90 days after therapy ends); in-home VNS initiated by a magnet swipe starts at the Post-1 visit (LT1). Thereafter, control subjects will follow the same schedule as VNS subjects for the remainder of the study (6m, 9m, 12m follow-ups, plus yearly visits thereafter). Subjects in both groups will receive "booster" in-clinic rehabilitation plus VNS therapy sessions one month prior to their 6- and 12-month assessment visits. These sessions occur on three days over a one-week period (typically Mon, Wed, Fri). Stage III: • After one year of standard VNS therapy (~13.5 months after implant for VNS group subjects and ~18 months after implant for Control group subjects), subjects who wish to keep their device for further use will have annual follow-up assessments until commercial approval.

Double blind, randomized, parallel study with partial crossover (control subjects crossover to treatment after randomized portion)

Participants, therapists (care providers), investigators, and outcomes assessors do not know which group (VNS or control VNS) the patients are randomized. Only one person at the site - the programmer who programs the device settings - knows which group the subject is randomized into.

Active control treatment is rehabilitation (standard-of-care treatment) with only a minimal amount of VNS at the start of each session intended to support blinding.

The Fugl-Meyer Assessment, Upper Limb (FMA-UE) was analyzed for difference in average change at 1-day after 6-weeks of therapy compared to baseline (Difference in average change in FM-A from baseline [V4] to one day after therapy [V5]). The upper extremity portion of the Fugl-Meyer Assessment (FMA-UE) was collected at each visit. The FMA-UE is a common scale used to measure motor impairment after a stroke. The range is 0 (more impairment) to 66 (no impairment).

The Fugl-Meyer Assessment, Upper Limb (FMA-UE) was analyzed for change in average score at 90-days after 6-weeks of therapy (change in average FMA-UE from baseline [V4] to 90 days after therapy [V7]). The upper extremity portion of the Fugl-Meyer Assessment (FMA-UE) was collected at each visit. The FMA-UE is a common scale used to measure motor impairment after a stroke. The range is 0 (more impairment) to 66 (no impairment).

The Fugl-Meyer Assessment, Upper Limb (FMA-UE) Response is the percent of patients with a 6 point or greater improvement on the (FMA-UE). The percent of patients with the 6-point change is calculated at 90-days after 6-weeks of therapy compared to baseline (V4). The upper extremity portion of the Fugl-Meyer Assessment (FMA-UE) was collected at each visit. The FMA-UE is a common scale used to measure motor impairment after a stroke. The range is 0 (more impairment) to 66 (no impairment).

The Wolf Motor Function Test (WMFT) is an assessment scale of upper extremity functional level after stroke. The functional assessment range is an average of 15 sub-items with a range from 0 to 5, with 0 (meaning did not attempt) to 5 (meaning normal). WMFT 90-day - is a measure of the functional assessment change from baseline to 90 days after 6-weeks of therapy.

Inclusion Criteria: History of unilateral supratentorial ischemic stroke that occurred at least 9 months but not more than ten 10 years prior to enrollment. Age >22 years and <80 years. FMA-UE score of 20 to 50 (inclusive of 20 and 50). Ability to communicate, understand, and give appropriate consent. Subjects should be able to follow two-step commands. Right- or left-sided weakness of upper extremity. Active wrist flexion/extension; active abduction/extension of thumb and at least two additional digits. Exclusion Criteria: History of hemorrhagic stroke Presence of ongoing dysphagia or aspiration difficulties. Subject receiving medication that may significantly interfere with the actions of VNS on neurotransmitter systems at study entry. A list of excluded medications will be provided to Investigators. Prior injury to vagus nerve, either bilateral or unilateral (e.g., injury during carotid endarterectomy). Severe or worse depression (Beck Depression Scale > 29) (Beck et al., 1961) Unfavorable candidacy for device implant surgery (e.g., history of adverse reactions to anesthetics, poor surgical candidate in surgeon's opinion, etc.) Current use of any other stimulation device, such as a pacemaker or other neurostimulator; current use of any other investigational device or drug. Medical or mental instability (diagnosis of personality disorder, psychosis, or substance abuse) that would prevent subject from meeting protocol timeline. Pregnancy or plans to become pregnant or to breastfeed during the study period. Current requirement, or likely future requirement, of diathermy during the study duration. Active rehabilitation within 4 weeks prior to consent. Botox injections or any other non-study active rehabilitation of the upper extremity within 4 weeks prior to therapy through the post-30 day visit (Visit 6). Severe spasticity of the upper limb (Modified Ashworth ≥3) (Bohannon and Smith, 1987). Significant sensory loss. Sensory loss will be measured using the Upper Extremity sensory section of the Fugl Meyer Assessment of Physical Performance. The assessment addresses light touch (2 items) and proprioception (4 items).The highest points attained is 12; subjects with scores less than 6 will be excluded from the study.

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