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

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.

Inclusion Criteria:

1. History of unilateral supratentorial ischemic stroke that occurred at least 9 months
but not more than ten 10 years prior to enrollment.

2. Age >22 years and <80 years.

3. FMA-UE score of 20 to 50 (inclusive of 20 and 50).

4. Ability to communicate, understand, and give appropriate consent. Subjects should be
able to follow two-step commands.

5. Right- or left-sided weakness of upper extremity.

6. Active wrist flexion/extension; active abduction/extension of thumb and at least two
additional digits.

Exclusion Criteria:

1. History of hemorrhagic stroke

2. Presence of ongoing dysphagia or aspiration difficulties.

3. 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.

4. Prior injury to vagus nerve, either bilateral or unilateral (e.g., injury during
carotid endarterectomy).

5. Severe or worse depression (Beck Depression Scale > 29) (Beck et al., 1961)

6. Unfavorable candidacy for device implant surgery (e.g., history of adverse reactions
to anesthetics, poor surgical candidate in surgeon's opinion, etc.)

7. Current use of any other stimulation device, such as a pacemaker or other
neurostimulator; current use of any other investigational device or drug.

8. Medical or mental instability (diagnosis of personality disorder, psychosis, or
substance abuse) that would prevent subject from meeting protocol timeline.

9. Pregnancy or plans to become pregnant or to breastfeed during the study period.

10. Current requirement, or likely future requirement, of diathermy during the study
duration.

11. Active rehabilitation within 4 weeks prior to consent.

12. 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).

13. Severe spasticity of the upper limb (Modified Ashworth ≥3) (Bohannon and Smith, 1987).

14. 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.