Neuromodulation Using Vagus Nerve Stimulation Following Ischemic Stroke as Therapeutic Adjunct

NCT05390580 | Completed Results FDA Device

• 1 other identifier: 202203086
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This is a randomized open-label, with blinded outcome pilot study to evaluate the effect on inflammatory 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.

Conditions

Acute Ischemic Stroke

Keywords

acute ischemic stroke; cytokines; large vessel occlusion; vagal nerve stimulator

Outcome Measures

Primary Outcomes (5)

• Interleukin - 1b - Changes and Differences in the Levels

  The primary endpoint was change in inflammatory biomarkers from baseline to day 5, with samples obtained every 1.5 days. Interleukin-1β was the main analyte. Repeated measures were analyzed longitudinally using mixed-effects models (FDA guidance), specifying subject as a random effect to account for multiple observations. This approach accommodated irregular timing, missing data, and time-varying covariates. Models included treatment, time since last known normal, and their interaction to test group differences in biomarker trajectories. Time was modeled quadratically for cytokine and WBC outcomes to capture U-shaped temporal patterns. Interaction p-values assessed trajectory differences between taVNS and sham arms.

  5 days

• Interleukin - 6 - Changes and Differences in the Levels

  The primary endpoint was change in inflammatory biomarkers from baseline to day 5, with samples obtained every 1.5 days. Interleukin-6 was the main analyte. Repeated measures were analyzed longitudinally using mixed-effects models (FDA guidance), specifying subject as a random effect to account for multiple observations. This approach accommodated irregular timing, missing data, and time-varying covariates. Models included treatment, time since last known normal, and their interaction to test group differences in biomarker trajectories. Time was modeled quadratically for cytokine and WBC outcomes to capture U-shaped temporal patterns. Interaction p-values assessed trajectory differences between taVNS and sham arms.

  5 days

• Tumor Necrosis Factor Alpha - Changes and Differences in the Levels

  The primary endpoint was change in inflammatory biomarkers from baseline to day 5, with samples obtained every 1.5 days. Tumor necrosis factor was the main analyte. Repeated measures were analyzed longitudinally using mixed-effects models (FDA guidance), specifying subject as a random effect to account for multiple observations. This approach accommodated irregular timing, missing data, and time-varying covariates. Models included treatment, time since last known normal, and their interaction to test group differences in biomarker trajectories. Time was modeled quadratically for cytokine and WBC outcomes to capture U-shaped temporal patterns. Interaction p-values assessed trajectory differences between taVNS and sham arms.

  5 days

• White Blood Cell Total Count - Changes and Differences in the Levels

  The primary endpoint was change in inflammatory biomarkers from baseline to day 5, with samples obtained every 1.5 days. WBC count was the main analyte. Repeated measures were analyzed longitudinally using mixed-effects models (FDA guidance), specifying subject as a random effect to account for multiple observations. This approach accommodated irregular timing, missing data, and time-varying covariates. Models included treatment, time since last known normal, and their interaction to test group differences in biomarker trajectories. Time was modeled quadratically for cytokine and WBC outcomes to capture U-shaped temporal patterns. Interaction p-values assessed trajectory differences between taVNS and sham arms.

  5 days

• Neutrophil to Lymphocyte Ratio - Changes and Differences in the Levels

  The primary endpoint was change in inflammatory biomarkers from baseline to day 5, with samples obtained every 1.5 days. neutrophil to lymphocyte ratio based on blood samples was the main result of interestse. Repeated measures were planned to be analyzed longitudinally using mixed-effects models (FDA guidance), specifying subject as a random effect to account for multiple observations. This approach accommodated irregular timing, missing data, and time-varying covariates. Models included treatment, time since last known normal, and their interaction to test group differences in biomarker trajectories.

  5 days

Secondary Outcomes (4)

• Change in NIH Stroke Scale (NIHSS)

  30 days

• Modified Ranking Scale (mRS)

  90 days

• Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 - Hypotension (C143352)

  5 days

• Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 - Sinus Bradycardia (C54940)

  5 days

Study Arms (2)

Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator

EXPERIMENTAL

All patients will be fitted with the device, the investigator will attach adhesive contacts 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. The amplitude of stimulation may be reduced if a patient complains of discomfort at the site of stimulation.

Device: transcutaneous auricular vagal nerve stimulation

Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham

SHAM COMPARATOR

All patients will be fitted with the device, the investigator will attach adhesive contacts to the left ear. Stimulation sessions will occur for 20 minutes twice daily during the inpatient period. Patients assigned to the controls arm will have electricity applied to the the great auricular nerve (cervical nerve branch), the lobule of the ear. The investigator will stimulate the lobule of the ear. Patients' will be treated with the following parameters: frequency 20 Hz, pulse width 250 µm, and 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.

Device: Sham transcutaneous vagal nerve stimulation

Interventions

transcutaneous auricular vagal nerve stimulation DEVICE

Stimulus of the auricular branch of the vagal nerve with the transcutaneous auricular vagal nerve stimulation.

Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator

Sham transcutaneous vagal nerve stimulation DEVICE

Patients assigned to the controls arm will have no electricity applied to the Auricular Branch of the Vagus Nerve. Stimulus will be provided to the lobule of the ear, which is not innervated by the Auricular Branch of the Vagus Nerve.

Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• \<18 years old
• patients with presumed chronic large vessel occlusions
• NIHSS\<6
• pre-morbid modified Rankin score (mRS) \>2
• unable to initiate treatment under 36 hours from symptom discovery
• Chronic or severe infection
• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University in St. Louis School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (1)

• 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.

  PMID: 41428140 DERIVED

MeSH Terms

Conditions

Ischemic Stroke

Condition Hierarchy (Ancestors)

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Limitations and Caveats

1\) the small sample size introduces the possibility that our findings may be subject to chance variation. 2) not powered to detect clinical differences. 3) fundamental questions remain about optimal therapeutic parameters, including stimulation settings, treatment duration, and most relevant physiologic and biomarker endpoints when utilizing taVNS. Please see manuscript attached for further details.

Results Point of Contact

• Title: Dr. Osvaldo J. Laurido-Soto, PI
• Organization: Washington University School of Medicine - Neurology Department

ojlaurido-soto@wustl.edu

314-362-7382

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Patients enrolled in the trial will be randomized to treatment with electrical stimulation to the auricular branch of the vagus nerve (intervention) or stimulation to the great auricular nerve (cervical nerve branch)(Sham) via an auricular, transcutaneous vagus nerve stimulator.. All patients will be fitted with the device, the investigators will attach adhesive contacts to the left ear. Patients are blinded to the intervention and study personnel will be unblinded.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: This is a randomized open-label, with blinded outcome pilot study to evaluate the effect on inflammatory 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 Record Dates

• First Submitted: May 5, 2022
• First Posted: May 25, 2022
• Study Start: September 26, 2022
• Primary Completion: August 23, 2024
• Study Completion: August 23, 2024
• Last Updated: October 31, 2025
• Results First Posted: October 31, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)