Neuromodulation in Patients With Pulmonary Arterial Hypertension (NIP)

Patients with Group 1 pulmonary hypertension will be enrolled in this study. Investigators will test the hypothesis of low-level tragal stimulation in patients with pulmonary hypertension. The study will be conducted over 4 weeks and patients will undergo low-level tragus stimulation for 1 hour every day for 4 weeks. At baseline the following tests will be conducted-6-minute walk distance, vascular function testing using noninvasive device and blood samples will be collected. Patient will also undergo a limited echocardiography to assess right ventricular function. After 4 weeks of stimulation patients will come back to undergo these tests again. Investigators hypothesized that low-level tragus stimulation (neuromodulation) will lead to improvement in vascular function, 6-minute walk distance and blood based biomarkers in patients with pulmonary hypertension.

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Hypertension
• Intervention / Treatment: Device: Low-level tragus stimulation; Device: Sham stimulation

Detailed Description

Investigators propose the following aims:

Aim 1: Quantitatively measure effects of LLTS on exercise capacity and quality of life in Pulmonary hypertension. A 6MWD and QoL (using Pulmonary hypertension questionnaire) will be performed at baseline and follow up (1 months).

Hypothesis 1: Short term LLTS would lead to improvement in exercise capacity and QoL.

Aim 2: Measure effect of neuromodulation on autonomic tone and inflammation. Heart rate variability (frequency and time domains) will be measured at baseline and after 1 months of LLTS. Serum will be used to analyze NT-Pro BNP, circulating inflammatory markers (IL-6,IL-18,TNF-a, IL1ra and CRP).

Hypothesis 2: Short term LLTS would lead to improvement in autonomic tone and inflammation.

Aim 3: Measure the effect of LLTS on endothelial function . Endothelial function (using ENDOPAT test) will be determined at baseline and at 1 months.

Results from this study will help investigators better understand PAH pathogenesis and provide investigators with further therapeutic targets and opportunities.

EXPERIMENTAL DESIGN:

For this application, investigators propose a prospective randomized double-blind study of LLTS vs. sham treatment.

Inclusion criteria: Patients older than 18 years of age, with pulmonary arterial hypertension (Group 1 PH) and WHO functional class II/III Exclusion:Patients with Inability to walk, wheelchair-bound, amputations, expected survival less than 3 to 6 months, active malignancy patients who are Spanish-speaking. would be excluded from the study.

PROPOSED PROCEDURE:

Patients with PAH would be screened from the Pulmonary Hypertension clinic located at OU Physicians building by the pulmonary hypertension facutly. Patients who meet inclusion criteria and consent to the study would be recruited.

Demographic data, medications used for PH, co-morbid conditions would be recorded. Patients would be escorted to the cardiovascular lab at the O-Donoghue building by the PH co-ordinator. EKG for heart rate variability, Six minute walk test, Endopat test for endothelial dysfunction would re recorded. The visit is expected to take close to 60 minutes.

Device administration and treatment protocol: Subjects will be trained on the day of enrollment to use PARASYM unit for self-administration of LLTS. Investigators will spend ample time explaining the nuances of the devices and provide time to subjects to familiarize with the device. Patients will be instructed to apply LLTS to the Tragus or ear lobe. Instruction manual and batteries will be provided.

In case of device malfunction, new devices will be provided to subjects within 48-72 hours (via mail or in person). Device parameters will be set to pulse width of 200 us and pulse frequency of 20 Hz. Amplitude will be titrated to level of sensory threshold (minimum 1 mA). The frequency and pulse width settings have been chosen based on our preliminary studies of LLTS in atrial fibrillation, diastolic HF and systolic HF. The final stimulation strength will be below the threshold (final output ³1mA) and subjects will be barely able to sense it. Patients will maintain a diary log for 4 weeks and perform stimulation for 1 hour daily (typically between 4-8pm, during the 2nd diurnal phase of high sympathetic tone). The time between 4-8 pm was selected for patient convenience as certain patients work hours may restrict use during the first diurnal phase in the morning. Sympathetic tone is highest during these diurnal phases, hence the rationale to target therapy during those times. The PARASYMTM device is also equipped with a treatment time recorder to get accurate logs of treatment. Patients will be asked to avoid caffeine for 4 hrs. and alcohol, smoking, and exercise for 12 h before the visit to avoid any interference with the functional tests that are performed

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Tarun Dasari, MD; Phone Number: 4052714742; Email: tarun-dasari@ouhsc.edu
• Study Contact Backup: Name: Skylar Cheatham; Phone Number: 4052714742; Email: skylar-cheatham@ouhsc.edu

Study Locations

• United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
      • Principal Investigator: Tarun Dasari, MD
      • Contact: Tarun Dasari; Phone Number: 405-271-4742; Email: tarun-dasari@ouhsc.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria: Patients older than 18 years of age, with pulmonary arterial hypertension (Group 1 PH) and WHO functional class II/III

Exclusion:Patients with Inability to walk, wheelchair-bound, amputations, expected survival less than 3 to 6 months, active malignancy patients who are Spanish-speaking. would be excluded from the study.

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: LLTS arm; Patients in this group will undergo low-level tragus stimulation for 1 hour every day for 4 weeks.	Device: Low-level tragus stimulation; Low-level tragus stimulation will recruit the fibers from the inner part of the tragus of the external ear and sent afferent signals through the greater auricular branch of the vagus nerve. Ultimately the stimulation is transmitted to the dorsal vagal complex and the brainstem thereby modulating the neuronal activity in the vehicle output. Sham stimulation will be performed by clipping the electrode to the ear lobule which will not relay any afferent signals through the greater auricular branch of the vagus nerve.
Sham Comparator: Placebo arm; Patient will undergo stimulation but on the ear lobule which is devoid of any vagus nerve innervation. This will be used as a sham comparison group.	Device: Sham stimulation; In the sham stimulation the electrodes will be attached to the ear lobule which are devoid of any afferent nerves traveling to the greater auricular branch of the vagus nerve.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate variability	Change in the heart rate variability metrics. These are reflective of the autonomic tone and the imbalance. Investigators hypothesized that using low-level tragus stimulation in patients with pulmonary hypertension the heart rate variability will be favorably affected using low-level tragus stimulation compared to sham stimulation. Time domain metrics are usually measured using variation of the standard R-R interval on the EKG in milliseconds.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-minute walk distance	A 6-minute walk test will be performed and the distance walked in 6 minutes as measured in meters will be quantified. Investigators hypothesized that using low-level tragus stimulation 6-minute walk distance will improve in patients with pulmonary hypertension after using the device for 4 weeks. This is in comparison to sham stimulation.	4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Right ventricular function	Using low-level tragus stimulation and pulmonary hypertension for 4 weeks, Investigators hypothesized that L LTS will lead to improvement in right ventricular mechanics and function.This will be assessed using echocardiography and right ventricular function metrics using right ventricular ejection fraction (%) will be assessed.	4 weeks
Endothelial oxidative stress	Using low-level tragus stimulation and pulmonary hypertension for 4 weeks, investigators hypothesized that L LTS will lead to improvement in Endothelial oxidative stress. This will be assessed using vascular function assays that measure oxidative stress using units termed MITOSOX. This will be expressed as a continuous numerical variable.	4 weeks

Collaborators and Investigators

• Sponsor: University of Oklahoma
• Investigators: Principal Investigator: Tarun Dasari, MD, University of Oklahoma

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2025
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: December 6, 2024
• First Submitted That Met QC Criteria: January 24, 2025
• First Posted (Actual): January 31, 2025

Study Record Updates

• Last Update Posted (Estimated): August 27, 2025
• Last Update Submitted That Met QC Criteria: August 20, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Neuromodulation; Endothelial function; Right ventricular function; 6-minute walk distance
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary
• Other Study ID Numbers: 17677 (Other Identifier: OUHSC IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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.: No