Trial Outcomes & Findings for Neuromodulation Using Vagus Nerve Stimulation Following Ischemic Stroke as Therapeutic Adjunct (NCT NCT05390580)

NCT ID: NCT05390580

Last Updated: 2025-10-31

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 40 participants
• Primary outcome timeframe: 5 days
• Results posted on: 2025-10-31

Participant Flow

We randomized 40 participants; after applying all study eligibility criteria, we excluded five participants post-hoc and included 35 participants (17 treated, 18 sham)

Patients were randomized in a 1:1 ratio to either the stimulation or sham treatment group using SAS software (Version 9.4, SAS). A total of 80 patients were assigned to one of two groups based on a computer-generated randomization sequence using the RANUNI function with a fixed seed (43523483) to ensure reproducibility. The generated sequence was then sorted, and the first 40 patients were allocated to the stimulation group, while the remaining 40 were assigned to the sham group.

Participant milestones

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham 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.
Overall Study STARTED	20	20
Overall Study COMPLETED	17	18
Overall Study NOT COMPLETED	3	2

Reasons for withdrawal

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham 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.
Overall Study Physician Decision	3	2

Baseline Characteristics

Mean value provided - calculated per group.

Baseline characteristics by cohort

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator n=17 Participants Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham n=18 Participants 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.	Total n=35 Participants Total of all reporting groups
Age, Continuous	68.1 years STANDARD_DEVIATION 15.2 • n=5 Participants	67.3 years STANDARD_DEVIATION 12.5 • n=7 Participants	67.7 years STANDARD_DEVIATION 13.4 • n=5 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	10 Participants n=7 Participants	17 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	8 Participants n=7 Participants	18 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	6 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) White	15 Participants n=5 Participants	12 Participants n=7 Participants	27 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Modified rankin scale	0.37 units on a scale STANDARD_DEVIATION 0.32 • n=5 Participants • Mean value provided - calculated per group.	0.28 units on a scale STANDARD_DEVIATION 0.21 • n=7 Participants • Mean value provided - calculated per group.	0.31 units on a scale STANDARD_DEVIATION 0.68 • n=5 Participants • Mean value provided - calculated per group.
NIH Stroke Scale (NIHSS)	16.4 units on a scale STANDARD_DEVIATION 6.6 • n=5 Participants	15.7 units on a scale STANDARD_DEVIATION 4.4 • n=7 Participants	16 units on a scale STANDARD_DEVIATION 5.5 • n=5 Participants
Reperfusion %	76 Percentage STANDARD_DEVIATION 27.1 • n=5 Participants	83.8 Percentage STANDARD_DEVIATION 31.5 • n=7 Participants	80 Percentage STANDARD_DEVIATION 29.3 • n=5 Participants
Time from Last Known Normal to recanalization attempt	13.2 hours STANDARD_DEVIATION 11.1 • n=5 Participants	9.8 hours STANDARD_DEVIATION 10.6 • n=7 Participants	11.5 hours STANDARD_DEVIATION 10.8 • n=5 Participants

PRIMARY outcome

Timeframe: 5 days

Population: The unit of measure below is a measurement of the trajectory of the values of the outcome measurement of interest, effectively a reflection of the graph of the results, with the number reflecting the slope of the curve. These values were compared based on their treatment arm and differences amongst treatment groups with mixed effect models utilizing p-interact values that allow the distinguishing of outcome trajectories. (i.e. were they statistically significant).

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.

Outcome measures

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator n=17 Participants Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham n=18 Participants 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.
Interleukin - 1b - Changes and Differences in the Levels	-0.222 percent change/day Interval -0.903 to 0.46	0.327 percent change/day Interval -0.047 to 0.702

PRIMARY outcome

Timeframe: 5 days

Population: The unit of measure below is a measurement of the trajectory of the values of the outcome measurement of interest, effectively a reflection of the graph of the results, with the number reflecting the slope of the curve. These values were compared based on their treatment arm and differences amongst treatment groups with mixed effect models utilizing p-interact values that allow the distinguishing of outcome trajectories. (i.e. were they statistically significant).

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.

Outcome measures

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator n=17 Participants Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham n=18 Participants 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.
Interleukin - 6 - Changes and Differences in the Levels	-4.099 percent change/day Interval -7.655 to -0.543	4.323 percent change/day Interval 2.369 to 6.277

PRIMARY outcome

Timeframe: 5 days

Population: The unit of measure below is a measurement of the trajectory of the values of the outcome measurement of interest, effectively a reflection of the graph of the results, with the number reflecting the slope of the curve. These values were compared based on their treatment arm and differences amongst treatment groups with mixed effect models utilizing p-interact values that allow the distinguishing of outcome trajectories. (i.e. were they statistically significant).

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.

Outcome measures

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator n=17 Participants Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham n=18 Participants 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.
Tumor Necrosis Factor Alpha - Changes and Differences in the Levels	-0.244 percent change/day Interval -0.545 to 0.058	-0.120 percent change/day Interval -0.597 to 0.357

PRIMARY outcome

Timeframe: 5 days

Population: The unit of measure below is a measurement of the trajectory of the values of the outcome measurement of interest, effectively a reflection of the graph of the results, with the number reflecting the slope of the curve. These values were compared based on their treatment arm and differences amongst treatment groups with mixed effect models utilizing p-interact values that allow the distinguishing of outcome trajectories. (i.e. were they statistically significant).

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.

Outcome measures

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator n=17 Participants Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham n=18 Participants 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.
White Blood Cell Total Count - Changes and Differences in the Levels	-0.914 percent change/day Interval -1.687 to -0.141	-0.050 percent change/day Interval -0.455 to 0.356

PRIMARY outcome

Timeframe: 5 days

Population: We were unable to analyze this outcome due to no patient (0/35) in the trial obtaining a repeat Complete blood count (CBC) with differential within the 5 days post baseline/recruitment. 15% patients underwent a repeat CBC with differential after day 7, outside of our analysis window.

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.

Outcome measures

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator n=17 Participants Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham n=18 Participants 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.
Neutrophil to Lymphocyte Ratio - Changes and Differences in the Levels	NA ratio We were unable to analyze this outcome due to a lack of CBC with differentials as standard of care, 0% of our patients underwent follow up CBC with differential in the initial 5 days.	NA ratio We were unable to analyze this outcome due to a lack of CBC with differentials as standard of care, 0% of our patients underwent follow up CBC with differential in the initial 5 days.

SECONDARY outcome

Timeframe: 30 days

Population: The unit of measure below is a measurement of the trajectory of the values of the outcome measurement of interest, effectively a reflection of the graph of the results, with the number reflecting the slope of the curve. These values were compared based on their treatment arm and differences amongst treatment groups with mixed effect models utilizing p-interact values that allow the distinguishing of outcome trajectories. (i.e. were they statistically significant).

The secondary endpoint was change in NIHSS from baseline to discharge (~ day 5) and 30 days. Change in the NIHSS stroke scale number (0-42 and a measure of severity) was the outcome of interest. 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 and linearly for in-hospital NIHSS scores based on panel data plots. Interaction terms were utilized to delineate differences amongst trajectories of the outcome of interest.

Outcome measures

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator n=17 Participants Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham n=18 Participants 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.
Change in NIH Stroke Scale (NIHSS)	-1.613 score change/day Interval -2.576 to -0.651	-1.562 score change/day Interval -5.25 to -0.978

SECONDARY outcome

Timeframe: 90 days

Population: There were three patients lost to follow up in the treatment group and one patient lost to follow up in the sham group, for which we utilized the 14 patients in the treatment group and the 17 patients left for the analyses, as we were not able to have data for the full recruited patients for this outcome.

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 was assessed at day 90. The investigators will assess differences in mRS dependent of the intervention arm.

0 = no symptoms at all

1. = No significant disability despite symptoms; able to carry out all usual duties and activities

2. = Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance.

3. = Moderate disability; requiring some help, but able to walk without assistance.

4. = Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance

5. = Severe disability; bedridden, incontinent and requiring constant nursing care and attention.

6. = Dead

Outcome measures

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator n=14 Participants Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham n=17 Participants 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.
Modified Ranking Scale (mRS)	3.27 score on a scale Standard Deviation 2.15	2.78 score on a scale Standard Deviation 2.07

SECONDARY outcome

Timeframe: 5 days

The investigator will monitor the patient's blood pressure (millimeters of mercury - mmHg) before, during, and after the transauricular vagal nerve stimulation or sham. If hypotension occurs (systolic blood pressure less than 80 mmHg or mean arterial pressure <60 mmHg) , the investigator will document it and assigned the appropriate grade from 1-5 based on the CTCAE.

Outcome measures

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator n=17 Participants Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham n=18 Participants 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.
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 - Hypotension (C143352)	0 Participants	2 Participants

SECONDARY outcome

Timeframe: 5 days

The investigator will monitor the patient's heart rate (beat per minute) before, during, and after the transauricular vagal nerve stimulation or sham. If Sinus Bradycardia (C54940) occurs (heart rate less than 60 beats per minute), the investigator will document it and assigned the appropriate grade from 1-5 based on the CTCAE.

Outcome measures

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator n=17 Participants Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham n=18 Participants 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.
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 - Sinus Bradycardia (C54940)	2 Participants	4 Participants

Adverse Events

Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator

Serious events: 0 serious events

Other events: 2 other events

Deaths: 3 deaths

Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham

Serious events: 0 serious events

Other events: 6 other events

Deaths: 2 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Stimulation with Transcutaneous Auricular Vagal Nerve Stimulator n=17 participants at risk Patients enrolled in the trial were randomized to treatment with electrical stimulation via an auricular, transcutaneous vagus nerve stimulator. All patients are fitted with a portable Soterix© device, a transcutaneous electrical nerve stimulation unit, and are connected to two ear electrodes, applied to the left ear during treatment periods. For taVNS treatment, these ear electrodes are placed along the concha of the ear, while in sham treatments the electrodes are placed along the ear lobe to avoid stimulation of the auricular vagus nerve from tactile pressure alone in the absence of current. Stimulation parameters were selected based on prior studies that sought to maximize vagus somatosensory evoked potentials while avoiding perception of pain. Stimulation parameters will be 20 minutes duration, frequency of 20 Hz, 250µs pulse width, and an intensity of 0.5mA. Sham treatments will involve no electrical current to the auricular branch of the vagal nerve.	Control - Transcutaneous Auricular Vagal Nerve Stimulator - Sham n=18 participants at risk 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.
Cardiac disorders The above patient events were bradycardia and hypotension, none were serious.	11.8% 2/17 • Number of events 2 • enrollment until end of follow-up (up to 105 days). All adverse events were address in real time while the patients were inpatient and later at follow up.	33.3% 6/18 • Number of events 6 • enrollment until end of follow-up (up to 105 days). All adverse events were address in real time while the patients were inpatient and later at follow up.

Additional Information

Dr. Osvaldo J. Laurido-Soto, PI

Washington University School of Medicine - Neurology Department

Phone: 314-362-7382

Email: ojlaurido-soto@wustl.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place