Neuroprotective Effects of Long-term TaVNS in Early Parkinson's Disease Patients (NLTVNSPD)

A Double-blinded, Randomized, Parallel-group, Superiority Study to Explore the Neuroprotective Effects of Long-term Transcutaneous Auricular Vagus Nerve Stimulation(taVNS) in Early Parkinson's Disease(PD) Patients

This study is a randomized, double-blind, controlled trial exploring the effects of long-term taVNS intervention in patients with early-stage Parkinson's disease.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease, Idiopathic
• Intervention / Treatment: Device: taVNS real stimulation; Device: taVNS sham stimulation

Detailed Description

This study is a randomized, double-blind, controlled trial exploring the effects of long-term taVNS intervention in patients with early-stage Parkinson's disease, , aiming to investigate a novel therapeutic approach for delaying PD progression.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kezhong Zhang, Professor; Phone Number: 400-13770840575; Email: kezhong_zhang1969@126.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 211200
      • Recruiting
      • The First Affiliated Hospital with Nanjing Medical University
      • Contact: Kezhong Zhang; Phone Number: 13770840575; Email: kezhong_zhang1969@126.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age 55-75 years.
2. Clinically diagnosed Idiopathic Parkinson's disease patients according to the 2016 Chinese diagnostic criteria for Parkinson's disease.
3. Hoehn and Yahr (H&Y) stage ≤ 2.5 at medication initiation.
4. Parkinson's disease duration ≤ 3 years.
5. Receiving standard anti-Parkinson's disease medication treatment.

Exclusion Criteria:

1. Patients with cognitive impairment (MMSE < 24 and/or MoCA < 26) or mental illnesses, or those unable to cooperate for other reasons.
2. Use of neuroprotective medications within 90 days prior to baseline, including monoamine oxidase B inhibitors (rasagiline, selegiline), certain dopamine receptor agonists (ropinirole), and GLP-1 receptor agonists such as Exenatide and NLY-01.
3. Use of any medications that may affect dopamine metabolism and/or dopamine receptors within 90 days prior to baseline, including typical and atypical antipsychotics, metoclopramide, α-methyl-dopa, flunarizine, apomorphine, amphetamine derivatives, bupropion, buprenorphine, cocaine, meperidine, methamphetamine, norephedrine, phentermine, modafinil, methylphenidate, procyclidine, reserpine, phenylpropanolamine, or MAO-A inhibitors.
4. Previous treatment with vagus nerve stimulation.
5. MRI contraindications (e.g., claustrophobia unresponsive to comfort or low-dose anxiolytics, dental implants) or MRI scans indicating clinically significant abnormalities in the brain, including but not limited to past hemorrhages or infarcts > 1 cm³ or > 3 lacunar infarcts.
6. Contraindications for taVNS, such as patients with cardiac pacemakers or a history of DBS surgery, or those planning surgery during the trial; ear conditions, such as tympanic membrane perforation.
7. Atypical or secondary Parkinsonian syndromes, including but not limited to those caused by trauma, brain tumors, infections, cerebrovascular diseases, or other neurological disorders, or symptoms confirmed by the investigator as drug, chemical, or toxin-related.
8. Previous history of stroke or intracranial mass lesions.
9. Patients with existing or potential cardiovascular diseases.
10. Ophthalmic diseases affecting eye movements.
11. Any neurological disorders other than Parkinsonian motor symptoms that interfere with gait or balance (e.g., chronic pain) or musculoskeletal injuries (e.g., fractures, stroke sequelae).
12. Severe organic diseases, such as late-stage tumors, with a life expectancy of less than 2 years.
13. Concurrent participation in other clinical trials.
14. Inability to receive the required treatment and follow-up due to geographic reasons.
15. Any subject with an upper limb UPDRS tremor score of 3 or higher.
16. Patients with a history of PD-related freezing episodes or falls.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard anti-Parkinson's disease medication treatment + taVNS real stimulation; For the real stimulation group, two modified point electrodes will deliver stimulation near the auricular branch of the vagus nerve in the left concha cymba. Each Parkinson's disease patient will receive one 30-minute stimulation session per day(at least 5 days per week) for 270 consecutive days.	Device: taVNS real stimulation; For the real stimulation group, two modified point electrodes will deliver stimulation near the auricular branch of the vagus nerve in the left concha cymba. Stimulation parameters: frequency = 20 Hz; pulse width = 500 μs; continuous stimulation for 60 seconds, followed by a 10-second off period, repeated for 30 minutes.
Sham Comparator: Standard anti-Parkinson's disease medication treatment + taVNS sham stimulation; For the sham stimulation group, two modified point electrodes will deliver stimulation to the earlobes.Each Parkinson's disease patient will receive one 30-minute stimulation session per day(at least 5 days per week) for 270 consecutive days.	Device: taVNS sham stimulation; For the sham stimulation group, two modified point electrodes will deliver stimulation to the earlobes.Stimulation parameters: frequency = 20 Hz; pulse width = 500 μs; continuous stimulation for 60 seconds, followed by a 10-second off period, repeated for 30 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MDS-UPDRS-Ⅲ	Used to evaluate the motor function.	baseline, 180±7 days, 360±7 days, 540±7 days，570±7 days
Free water in the posterior substantia nigra (DTI)	Used to measure progression of early Parkinson's disease.	baseline, 180±7 days, 360±7 days, 540±7 days，570±7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Scales: MDS-UPDRS-II	Used to evaluate quality of life of PD.	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Step Length、Stride Length、Stride Velocity and Step Length Variability	Used to assess the patient's gait disturbances，including the Step Length、Stride Length、Stride Velocity and Step Length Variability	baseline,180±7 days, 360±7 days, 540±7 days，570±7 days
Scales: H&Y stage	Used to evaluate the stage of PD.	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Eye-Tracking Technology	Fixation Duration: The length of time the gaze remains on a single point. Saccade Velocity: The speed of eye movements between fixations. Scan Path: The trajectory of eye movements during visual exploration	baseline,180±7 days, 360±7 days, 540±7 days，570±7 days
Electroencephalogram (EEG)	Measurement: Brain wave activity (measured in microvolts, µV).	baseline,180±7 days, 360±7 days, 540±7 days，570±7 days
MRI	T1-weighted Imaging: Measurement: Structural brain volume (measured in cubic centimeters, cm³). BOLD fMRI: Measurement: Blood oxygen level-dependent signals (measured in percentage change). Diffusion Tensor Imaging (DTI): Fractional Anisotropy (FA): Measurement: FA values (unitless, scale from 0 to 1). Mean Diffusivity (MD): Measurement: MD values (measured in mm²/s). NM-MRI: Measurement: Neurochemical markers (unit as appropriate). Iron-sensitive MRI: Quantitative Susceptibility Mapping (QSM): Measurement: Susceptibility values (measured in parts per million, ppm). Susceptibility Weighted Imaging (SWI): Measurement: Signal intensity (unitless). R2*: Measurement: Relaxation rate (measured in Hz).	baseline,180±7 days, 360±7 days, 540±7 days，570±7 days
Number of participants with the following Serum biomarkers:	Brain-Derived Neurotrophic Factor (BDNF): Measurement: Concentration (measured in ng/mL). Glial Fibrillary Acidic Protein (GFAP): Measurement: Concentration (measured in ng/mL). Neurofilament Light Chain (NFL): Measurement: Concentration (measured in pg/mL). Tau Protein: Measurement: Concentration (measured in pg/mL). Tumor Necrosis Factor Alpha (TNF-α): Measurement: Concentration (measured in pg/mL). Interleukin-6 (IL-6): Measurement: Concentration (measured in pg/mL). Interleukin-1 Beta (IL-1β): Measurement: Concentration (measured in pg/mL).	baseline,180±7 days, 360±7 days, 540±7 days，570±7 days
Movement Disorder Society Unified Parkinson's Disease Rating Scale - Part I (MDS-UPDRS-I)	.Measurement: Score (range: 0-52; higher score indicates worse non-motor function).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Non-Motor Symptoms Scale (NMSS)	Measurement: Score (range: 0-100; higher score indicates more severe non-motor symptoms).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Activities of Daily Living (ADL) Scale	Measurement: Score (range: 0-100; higher score indicates greater independence).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Hamilton Anxiety Scale (HAMA)	Measurement: Score (range: 0-56; higher score indicates greater anxiety).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Hamilton Depression Rating Scale - 24 items (HAMD-24)	Measurement: Score (range: 0-76; higher score indicates greater depression severity).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Apathy Scale (AS)	Measurement: Score (range: 0-42; higher score indicates greater apathy).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Rapid Eye Movement Sleep Behavior Disorder Questionnaire (RBDSQ)	Measurement: Score (range: 0-25; higher score indicates more severe symptoms).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Epworth Sleepiness Scale (ESS)	Measurement: Score (range: 0-24; higher score indicates greater daytime sleepiness).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Montreal Cognitive Assessment (MoCA)	Measurement: Score (range: 0-30; higher score indicates better cognitive function).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Hopkins Verbal Learning Test - Revised (HVLT-R)	Measurement: Score (varies by subscale; higher score indicates better verbal memory).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Judgment of Line Orientation (JLO)	Measurement: Score (range: 0-30; higher score indicates better visual-spatial abilities).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Letter-Number Sequencing (LNS)	Measurement: Score (range: 0-30; higher score indicates better working memory).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Symbol Digit Modalities Test (SDMT)	Measurement: Score (varies based on response time; higher score indicates faster processing speed).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days
Levodopa Equivalent Dose (LED)	Measurement: Dose (measured in mg; higher dose indicates greater medication requirement).	baseline,30±3 days,90±5 days,180±7 days, 360±7 days, 540±7 days，570±7 days

Collaborators and Investigators

• Sponsor: Kezhong Zhang
• Collaborators: Beijing Tiantan Hospital; West China Hospital; Ruijin Hospital
• Investigators: Principal Investigator: Kezhong Zhang, Professor, The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: October 20, 2024
• First Submitted That Met QC Criteria: October 29, 2024
• First Posted (Actual): October 30, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 12, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Vagus Nerve Stimulation; Parkinson Disease, Idiopathic
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Parkinson Disease
• Other Study ID Numbers: 2024-SR-1019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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