Non-invasive Vagus Nerve Stimulation to Reduce Inflammation and Brain Injury Blood Biomarkers Following an Acute Ischemic Stroke (NUVISTA2)

The Washington University

Status: Enrolling

Conditions: Large Vessel Occlusion; Acute Ischemic Stroke

Treatments: Device: transcutaneous auricular vagal nerve stimulation; Device: Sham transcutaneous vagal nerve stimulation

Study type: Interventional

Funder types: Other

Identifiers

NCT07404852

202601166

Details and patient eligibility

About

This is a randomized open-label, with blinded outcome pilot study to evaluate the effect on inflammatory and brain injury laboratory values and explore clinical outcomes in patients who present with ischemic strokes due to large vessel occlusions and are treated with either current accepted management, or accepted management in addition to transcutaneous auricular vagal nerve stimulation.

Full description

Ischemic stroke is a leading cause of death and long-term disability worldwide. Large vessel occlusion (LVO) accounts for ~38% of acute ischemic strokes (AIS) and is associated with disproportionately poor outcomes: without treatment, 64% of patients are dead or dependent at six months, and even after successful mechanical thrombectomy, nearly half have poor functional recovery. These data highlight a critical unmet need for adjunctive therapies that limit secondary brain injury following reperfusion.

Neuroinflammation is a major contributor to ischemic brain injury and neurologic deterioration after AIS. In experimental models, inhibition of inflammatory pathways reduces infarct size and improves outcomes, and in human AIS, elevations in pro-inflammatory cytokines are associated with worse recovery. However, clinical trials targeting individual inflammatory mediators have failed, suggesting that effective therapy may require coordinated modulation of multiple immune pathways rather than blockade of a single target. Vagus nerve stimulation (VNS) engages an evolutionary conserved neuroimmune reflex that broadly regulates innate and adaptive immune responses. While implantable VNS is not feasible in acute stroke, non-invasive transauricular VNS (taVNS) enables rapid deployment in emergent settings.

The investigators recently completed the Neuromodulation Using Vagus Nerve Stimulation Following Ischemic Stroke as Therapeutic Adjunct (NUVISTA) pilot randomized trial (n=35) in AIS patients with LVO. taVNS was rapidly deployable and safe, significantly attenuated the trajectory of plasma interleukin-6 (IL-6) and other inflammatory mediators, and demonstrated encouraging signals of improved clinical outcomes. These findings support further mechanistic and translational investigation in a well-powered cohort.

The central hypothesis of this proposal is that taVNS engages endogenous neuroimmune reflexes to reprogram peripheral immune responses following LVO AIS, resulting in reduced systemic inflammation, attenuation of neuroaxonal injury, and improved early recovery. The investigators will test this hypothesis in a randomized, sham-controlled clinical study of 65 AIS patients

Patients enrolled in the trial will be randomized to treatment with electrical stimulation to the auricular branch of the vagus nerve (intervention) or no stimulation to the auricular branch (Sham) via an auricular, transcutaneous vagus nerve stimulator. All patients will be fitted with the device, the investigators will attach the ear electrodes to the left ear. Stimulation sessions will occur for 20 minutes twice daily during the inpatient period. Patients will have electricity applied to the different nerves depending on the randomization, they will be treated with stimulation with the following parameters: frequency 20 Hz, pulse width 250 μm, and a fixed intensity of 0.5 milliampere. The amplitude of stimulation may be reduced if a patient complains of discomfort at the site of stimulation. The site of stimulation will be inspected daily before and after treatment to ensure there is no redness or irritation at the site. The investigators will obtain laboratory samples on admission, day 0, and every 1.5 days till day 7 or discharge (whichever occurs first) to assess the patients inflammatory markers.

Enrollment: 65 estimated patients

Sex: All

Ages: 18 to 99 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Adult patients who present with acute ischemic strokes due to large vessel occlusions

Exclusion criteria

• <18 years old
• patients with presumed chronic large vessel occlusions
• NIHSS<6
• pre-morbid modified Rankin score (mRS) >2
• unable to initiate treatment under 24 hours from symptom discovery
• Chronic or acute infection, Recent surgery, active immune disease
• life expectancy <3 months
• patients' undergoing active cancer or immunosuppressive/modulating therapy
• patients with sustained bradycardia on arrival with a heart rate <50 beats per minute.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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65 participants in 2 patient groups

Treatment - Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator

Experimental group

Description:

All patients will be fitted with the device, the investigator will attach an electrode to the left ear. Stimulation sessions will occur for 20 minutes twice daily during the inpatient period, the investigator will stimulate the auricular branch of the vagus nerve. Patients' will be treated with the following parameters: frequency 20 Hz, pulse width 250 μm, and and a fixed intensity of 0.5 milliampere.

Treatment:

Device: transcutaneous auricular vagal nerve stimulation

Control - No Stimulation Transcutaneous Auricular Vagal Nerve Stimulator

Sham Comparator group

Description:

All patients will be fitted with the device, the investigator will attach an electrode to the left ear. Sham stimulation sessions will occur for 20 minutes twice daily during the inpatient period. Patients assigned to the controls arm will have no electricity applied to the auricular branch of the vagus nerve.

Treatment:

Device: Sham transcutaneous vagal nerve stimulation