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

Neuromodulation Using Vagus Nerve Stimulation Following Ischemic Stroke as Therapeutic Adjunct 2

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Ischemic Stroke; Large Vessel Occlusion
• Intervention / Treatment: Device: transcutaneous auricular vagal nerve stimulation; Device: Sham transcutaneous vagal nerve stimulation

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 65
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Angela Birke, MS; Phone Number: (314) 362-5291; Email: birkea@wustl.edu
• Study Contact Backup: Name: Osvaldo Laurido-Soto, MD; Phone Number: 314-273-3294; Email: ojlaurido-soto@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Barnes-Jewish Hospital
      • Principal Investigator: Osvaldo J Laurido-Soto, MD
      • Contact: Angela Birke, MS; Phone Number: (314) 362-5291; Email: birkea@wustl.edu
      • Contact: Osvaldo J Laurido-Soto, MD; Email: ojlaurido-soto@wustl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment - Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator; 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.	Device: transcutaneous auricular vagal nerve stimulation; Stimulus of the auricular branch of the vagal nerve with the transcutaneous auricular vagal nerve stimulation.
Sham Comparator: Control - No Stimulation Transcutaneous Auricular Vagal Nerve Stimulator; 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.	Device: Sham transcutaneous vagal nerve stimulation; Patients assigned to the controls arm will have no electricity applied to the Auricular Branch of the Vagus Nerve.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain Derived Tau	The primary endpoints of the study will include changes in the levels of brain injury biomarkers measured at onset and every 1.5 days till day 7, or discharge (whichever occurs first), this includes: Brain Derived Tau (BD-tau). The investigators will measure BD-tau in aliquots from the plasma with mononuclear antibodies that recognizes a protein of 48 to 68 kilodalton specific to BD-tau. A functional assay will be measured in picogram/milliliter. Will utilize a high sensitivity assays to minimize floor effects.	7 days
Neurofilament light chain	The primary endpoints of the study will include changes in the levels of brain injury biomarkers measured at onset and every 1.5 days till day 7, or discharge (whichever occurs first), this includes: Neurofilament light chain (NfL). The investigators will measure NfL in aliquots from the plasma with mononuclear antibodies that recognizes a protein of 68-70 kilodalton specific to NfL. A functional assay will be measured in picogram/milliliter. Will utilize a high sensitivity assays to minimize floor effects.	7 days
Interleukin - 1b - Changes and Differences in the Levels	The primary endpoints of the study will include changes in the levels of inflammatory markers measured at onset and every 1.5 days till day 7, or discharge (whichever occurs first), this includes: Interleukin (IL) -1b. The investigators will measure IL-1b in aliquots from the plasma with mononuclear antibodies that recognizes a protein of 17-31 kilodalton specific to IL-1b. A functional assay will be measured in picogram/milliliter. Will utilize a high sensitivity assays to minimize floor effects.	7 days
Interleukin - 6 - Changes and Differences in the Levels	The primary endpoints of the study will include changes in the levels of inflammatory markers measured at onset and every 1.5 days till day 7, or discharge (whichever occurs first), this includes: Interleukin (IL) - 6. The investigators will measure IL-6 in aliquots from the plasma with mononuclear antibodies that recognizes a protein of 26 kilodalton specific to IL-6. A functional assay will be measured in picogram/milliliter. Will utilize a high sensitivity assays to minimize floor effects.	7 days
Tumor Necrosis Factor Alpha - Changes and Differences in the Levels	The primary endpoints of the study will include changes in the levels of inflammatory markers measured at onset and every 1.5 days till day 7, or discharge (whichever occurs first), this includes: Tumor necrosis factor alpha (TNF-a). The investigators will measure IL-1b in aliquots from the plasma with mononuclear antibodies that recognizes a protein of 17 kilodalton specific to TNF-a. A functional assay will be measured in picogram/milliliter. Will utilize a high sensitivity assays to minimize floor effects.	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in NIH Stroke Scale (NIHSS)	This is a clinical secondary exploratory endpoints. The NIH Stroke Scale (NIHSS) is a clinical tool used to assess stroke severity, the score ranges from 0 up to 42 (higher is more severe). It will be assessed daily by the investigators and at time of discharge. The investigators will assess differences in NIHSS dependent of the intervention arm.	7 days
Modified Ranking Scale (mRS)	This is a clinical secondary exploratory endpoints. The Modified Ranking Scale (mRS) is a clinical tool used to assess functional status after suffering a stroke. It ranges from 0 up to 6. It will be assessed at day 90 over the phone. The investigators will assess differences in mRS dependent of the intervention arm. 0 = no symptoms at all; = No significant disability despite symptoms; able to carry out all usual duties and activities; = Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance.; = Moderate disability; requiring some help, but able to walk without assistance.; = Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; = Severe disability; bedridden, incontinent and requiring constant nursing care and attention.; = Dead	90 days

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Publications and helpful links

General Publications

• Laurido-Soto OJ, Tan G, Nielsen SS, Huguenard AL, Donovan KM, Xu I, Giles J, Dhar R, Adeoye O, Lee JM, Leuthardt E. Transcutaneous Auricular Vagus Nerve Stimulation Reduces Inflammatory Biomarkers after Large Vessel Occlusion Stroke: Results of a Prospective Randomized Open-Label Blinded Endpoint Trial. Transl Stroke Res. 2025 Dec 22;17(1):7. doi: 10.1007/s12975-025-01405-6.

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2026
• Primary Completion (Estimated): November 29, 2027
• Study Completion (Estimated): February 29, 2028

Study Registration Dates

• First Submitted: February 4, 2026
• First Submitted That Met QC Criteria: February 4, 2026
• First Posted (Actual): February 12, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: cytokines; Acute ischemic stroke; large vessel occlusion; brain injury biomarkers; vagus nerve stimulator
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: 202601166

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified patient level data may be shared upon reasonable requested and approval by the institutions Human Research Protection Office
• IPD Sharing Time Frame: Once the trial is finished and publish. Estimated March 2028
• IPD Sharing Access Criteria: De-identified patient level data may be shared upon reasonable requested and approval by the institutions Human Research Protection Office

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes