Association of VAgus Nerve Stimulation and Treadmill Training for GAit Rehabilitation in DE Novo Parkinson's Disease (AVANTGARDE-PD)
Association of VAgus Nerve Stimulation and Treadmill Training for GAit Rehabilitation in DE Novo Parkinson's Disease (AVANTGARDE-PD)
The goal of this clinical trial is to learn if transcutaneous auricular vagus nerve stimulation (taVNS) can improve gait and brain function in people with diagnosis of idiopathic Parkinson's disease (PD) within 6 months. It will also help researchers learn about the safety and biological effects of taVNS when used together with physical therapy.
The main questions it aims to answer are:
- Does taVNS paired with physical therapy improve walking speed and gait performance in people with PD?
- Does taVNS change brain activity or breain perfusion related to movement?
- Does taVNS reduce markers of inflammation and neurodegeneration in blood and saliva? Researchers will compare active taVNS to sham (placebo) stimulation to see if active taVNS works better when paired with physical therapy.
Participants will:
- Attend 12 rehabilitation sessions over 4 weeks (three per week)
- Receive either active or sham taVNS during each session while doing treadmill and conventional physical therapy
- Undergo gait and cognitive testing, MRI scans, and blood and saliva collection before and after treatment
- Return for a follow-up visit four weeks after therapy to check how long the effects last
Study Overview
Status
Conditions
Detailed Description
Parkinson's disease (PD) is characterized by gait disturbance, impaired mobility, and progressive involvement of neural circuits responsible for locomotion and postural control. Although physical therapy is effective, its benefits are often modest and short-lived. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that activates the auricular branch of the vagus nerve and engages ascending brainstem pathways involved in motor control, arousal regulation, and inflammatory modulation. Previous studies have shown that taVNS can influence subcortical β-band oscillations, improve gait parameters, enhance cognitive performance, and modulate systemic inflammatory markers in individuals with PD.
This randomized, double-blind, sham-controlled clinical trial evaluates whether pairing taVNS with gait-focused rehabilitation enhances motor outcomes and neural plasticity in individuals with de novo PD. Participants are newly diagnosed (≤6 months) and undergo a 4-week rehabilitation program consisting of conventional physiotherapy, with or without sensorized treadmill training. Active or sham taVNS is administered during each therapy session. The study includes four parallel arms to independently assess the contributions of taVNS and treadmill-based gait training.
Outcomes are assessed at baseline (T0), immediately post-intervention (T1), and at a 4-week follow-up visit (T2). Primary and secondary outcomes include quantitative gait parameters, clinical motor scales, cognitive performance, and quality-of-life measures. Exploratory outcomes include changes in cerebral blood flow measured with pseudo-continuous arterial spin labeling (PCASL), functional connectivity during a simulated gait task using fMRI, and blood and salivary biomarkers of inflammation and neurodegeneration (e.g., TNF-α, interleukins, and α-synuclein).
The study aims to determine whether taVNS enhances rehabilitation-induced improvements in gait, whether these benefits persist beyond the treatment period, and whether taVNS induces measurable changes in brain perfusion, functional networks, or circulating biological markers relevant to PD pathophysiology. Results may support the development of a scalable, non-invasive therapeutic approach that can be integrated into early PD management.
Study Type
Enrollment (Estimated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Massimo Marano, MD, PhD
- Phone Number: +39 3333488802
- Email: m.marano@policlinicocampus.it
Study Contact Backup
- Name: Gaia Anzini, MD
- Phone Number: +39 3662007406
- Email: gaia.anzini@unicampus.it
Study Locations
-
-
RM
-
Roma, RM, Italy, 00128
- Recruiting
- Campus Biomedico
-
Contact:
- Massimo Marano, MD, PhD
- Phone Number: + 393333488802
- Email: m.marano@policlinicocampus.it
-
Contact:
- Gaia Anzini, MD
- Phone Number: +393662007406
- Email: gaia.anzini@unicampus.it
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Idiopathic PD diagnosis within 6 months, confirmed by neurologist specialized in Parkinson's disease and movement disorders;
- Ability to walking independently for at least 10 meters unassisted;
- Age included between 50 and 80;
- MMSE > 24;
- On stable therapy for at least 1 month prior to the experiment.
Exclusion Criteria:
- Clinical and radiological red flags for atypical, vascular parkinsonism or alternative diagnosis (e.g., normal pressure hydrocephalus);
- Levodopa equivalent daily dose > 300 mg;
- Any contraindication for taVNS (e.g., ear lesions, auditory prosthesis)
- Any contraindication for MRI (e.g., non compatible pacemakers or prosthesis, claustrophobic subjects);
- Concomitant neurological, orthopedic or active medical/oncological condition that would affect participating to the study;
- Attempting to other neurorehabilitation programs within 3 months.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Active Comparator: taVNS paired with sensorized treadmill training (STT) and conventional physical therapy (cPT)
Participants will receive active taVNS, stimulation parameters: 25 Hz frequency, 200 μs pulse width, and intensity adjusted to the individual's sensory threshold, delivered to the left auricular tragus for the duration of each session (~30 minutes).
During stimulation, participants will perform treadmill walking on a sensorized treadmill system with simultaneous conventional physical therapy exercises focused on posture, balance, and gait re-education.
Sessions will be delivered over a 4-week period, for a total of 10 sessions.
|
Active taVNS delivered at the inner tragus of the left ear (25 Hz, 200 μs, intensity at sensory threshold)
Other Names:
Conventional Physical Therapy delivered to all groups consist of exercises aimed at posture alignment, reduction of hypertone, balance improvement and overground gait training.
Other Names:
Sensorized Treadmill Training consist of a sensorized gait treadmill training with continuous visual feedback combined with dual cognitive tasks (e.g.
repeat digits, repeat sequence of words, counting down the dates).
Other Names:
|
|
Active Comparator: taVNS paired with conventional physical therapy (cPT)
Participants will receive active taVNS (same parameters and device as Arm 1) during conventional physical therapy sessions without treadmill training. Sessions will be delivered over a 4-week period, for a total of 10 sessions. |
Active taVNS delivered at the inner tragus of the left ear (25 Hz, 200 μs, intensity at sensory threshold)
Other Names:
Conventional Physical Therapy delivered to all groups consist of exercises aimed at posture alignment, reduction of hypertone, balance improvement and overground gait training.
Other Names:
|
|
Sham Comparator: Sham taVNS paired with STT and cPT
Sham stimulation will consist of few impulses delivered at 25 Hz for a duration of 60'' before waning, creating the same initial sensation without continuous current delivering. Participants will simultaneously undergo treadmill-based and conventional physical therapy as described above. Schedule: 10 sessions will be delivered over a 4-week period. |
Conventional Physical Therapy delivered to all groups consist of exercises aimed at posture alignment, reduction of hypertone, balance improvement and overground gait training.
Other Names:
Sensorized Treadmill Training consist of a sensorized gait treadmill training with continuous visual feedback combined with dual cognitive tasks (e.g.
repeat digits, repeat sequence of words, counting down the dates).
Other Names:
Sham taVNS using the electrode placement as active taVNS but without electrical stimulation beyond the initial sensation.
Other Names:
|
|
Sham Comparator: Sham taVNS paired with cPT
Participants will receive sham stimulation (same device and sham procedure as Arm 3) during conventional physical therapy sessions without treadmill training. Schedule: 10 sessions will be delivered over a 4-week period. |
Conventional Physical Therapy delivered to all groups consist of exercises aimed at posture alignment, reduction of hypertone, balance improvement and overground gait training.
Other Names:
Sham taVNS using the electrode placement as active taVNS but without electrical stimulation beyond the initial sensation.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Evaluation of objective changes in gait speed (m/s) through gait analysis.
Time Frame: Baseline (T0) and Post-intervention (T1, 4 weeks)
|
Gait speed (m/s) is measured using a 3D optoelectronic motion-capture system with inertial sensors during level walking on a 10-meter walkway with integrated force platforms.
Standard lower-limb reflective markers and surface EMG are used to capture kinematic and muscle-activation patterns.
Average gait speed is calculated as the mean forward velocity.
|
Baseline (T0) and Post-intervention (T1, 4 weeks)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Spatiotemporal and Kinematic Gait Parameters assessment (gait quality parameter).
Time Frame: Baseline (T0), Post-intervention at 4 weeks (T1)
|
Spatiotemporal and kinematic gait parameters are measured using a 3D motion-capture system with inertial sensors and surface EMG while participants walk across a walkway with integrated force platforms.
Parameters include stance and swing phase duration (s), single and double support time (s), step and stride length (cm) and variability (%), swing speed (m/s) and cadence (steps/min), lower-limb joint flexion-extension angles (°), peak vertical ground reaction force (N/kg), and muscle-activation timing (ms) from surface EMG.
All listed parameters will be analyzed collectively as a single composite secondary outcome and will not be reported as separate outcome measures.
|
Baseline (T0), Post-intervention at 4 weeks (T1)
|
|
Change in Motor Function (MDS-UPDRS Part III Total Score).
Time Frame: Baseline (T0) and Post-intervention at 4 weeks (T1).
|
Motor function will be assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (MDS-UPDRS III), which evaluates bradykinesia, rigidity, tremor, posture, and gait-related motor signs.
Total scores range from 0 to 132, with higher scores indicating worse motor impairment.
Improvement is reflected by a decrease in the MDS-UPDRS III score.
|
Baseline (T0) and Post-intervention at 4 weeks (T1).
|
|
Quality of Life (PDQ-39 Total and Domain Scores) assessment.
Time Frame: Baseline (T0) and Post-intervention at 4 weeks (T1)
|
Quality of life is assessed using the Parkinson's Disease Questionnaire-39 (PDQ-39), which measures mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort.
Domain and total scores range from 0 to 100, with higher scores indicating poorer quality of life.
Improvement is reflected by a decrease in PDQ-39 scores.
|
Baseline (T0) and Post-intervention at 4 weeks (T1)
|
|
Change in Gait Speed from Post-intervention to Follow-up.
Time Frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
Average gait speed (m/s) is measured using a 3D motion-capture system during level walking.
This outcome represents the change in gait speed between the post-intervention visit (T1) and the follow-up visit (T2) to evaluate persistence of treatment effects.
|
Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
|
Change in Spatiotemporal and Kinematic Gait Parameters (gait quality parameter) from Post-intervention to Follow-up.
Time Frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
Spatiotemporal and kinematic gait parameters (stance and swing duration (s), single and double support time (s), step and stride length (cm) and variability (%), swing speed (cm/s) and cadence (steps/min), joint flexion-extension angles (°), peak vertical ground reaction force (N/kg), and muscle-activation timing (ms)) are assessed with 3D motion capture, force platforms, and surface EMG.
All listed parameters will be analyzed collectively as a single composite secondary outcome and will not be reported as separate outcome measures.
This outcome reflects change in these parameters from T1 to T2.
|
Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
|
Change in Motor Function (MDS-UPDRS Part III Total Score) from Post-intervention to Follow-up.
Time Frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
Motor function will be assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (MDS-UPDRS III), which evaluates bradykinesia, rigidity, tremor, posture, and gait-related motor signs.
Total scores range from 0 to 132, with higher scores indicating worse motor impairment.
Improvement is reflected by a decrease in the MDS-UPDRS III score.
|
Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
|
Change in Quality of Life (PDQ-39) from Post-intervention to Follow-up.
Time Frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
Quality of life is assessed using the PDQ-39, which measures mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort.
This outcome represents the change in PDQ-39 total score from T1 to T2, where higher scores indicate poorer quality of life and improvement is reflected by a decrease in scores.
|
Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
|
Change in Inflammatory Biomarkers (Serum and Salivary Cytokines) from Post-intervention to Follow-up.
Time Frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
Serum and salivary levels of inflammatory cytokines (TNF-α, IL-1β, IL-13, IL-10, IL-6) will be measured using standardized ELISA or multiplex immunoassays.
Concentrations will be expressed in pg/mL.
Cytokines will be analyzed collectively as a composite inflammatory outcome.
|
Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
|
Change in Neurodegenerative Biomarker Levels (α-Synuclein) from Post-intervention to Follow-up.
Time Frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
Serum and salivary levels of α-synuclein will be measured using standardized immunoassays.
Concentrations will be expressed in ng/mL.
|
Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
|
Cognitive Function (MoCA Total Score) assessment
Time Frame: Baseline (T0) and Post-intervention at 4 weeks (T1)
|
Cognitive function is assessed using the Montreal Cognitive Assessment (MoCA), a validated screening tool designed to detect mild cognitive impairment.
The MoCA evaluates multiple cognitive domains including attention, executive functions, memory, language, visuospatial abilities, abstraction, calculation, and orientation.
Total scores range from 0 to 30, with higher scores indicating better cognitive performance.
|
Baseline (T0) and Post-intervention at 4 weeks (T1)
|
|
Change in Cognitive Function (MoCA Total Score) from Post-intervention to Follow-up
Time Frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
Cognitive function is assessed using the Montreal Cognitive Assessment (MoCA), a validated screening tool for the detection of mild cognitive impairment.
The MoCA evaluates multiple cognitive domains including attention, executive functions, memory, language, visuospatial abilities, abstraction, calculation, and orientation.
This outcome captures the change in MoCA total score from post-intervention (T1) to follow-up (T2) to evaluate the persistence of cognitive effects over time.
Total scores range from 0 to 30, with higher scores indicating better cognitive performance.
|
Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Imaging Outcomes (PCASL).
Time Frame: Baseline (T0) and Post-treatment at 4 weeks (T1)
|
Brain perfusion will be assessed using pseudo-continuous arterial spin labeling (PCASL). Imaging is performed at baseline (T0) and post-treatment (T1). Primary imaging endpoints include: - Change in cerebral blood flow (CBF) in locomotor and motor-control regions (PCASL) |
Baseline (T0) and Post-treatment at 4 weeks (T1)
|
|
Imaging Outcomes (fMRI).
Time Frame: Baseline (T0) and Post-treatment at 4 weeks (T1)
|
Functional connectivity will be assessed by functional MRI (fMRI). Imaging is performed at baseline (T0) and post-treatment (T1). The fMRI assessment includes a simulated gait task using a custom pedal system with synchronized visual feedback. Primary imaging endpoints include: - Change in functional connectivity within gait-related cortical-subcortical networks (fMRI). |
Baseline (T0) and Post-treatment at 4 weeks (T1)
|
|
Inflammatory Biomarkers (Serum and Salivary Cytokines)
Time Frame: Baseline (T0) and Post-treatment at 4 weeks (T1)
|
Serum and salivary levels of inflammatory cytokines (TNF-α, IL-1β, IL-13, IL-10, IL-6) will be measured using standardized ELISA or multiplex immunoassays.
Concentrations will be expressed in pg/mL.
Cytokines will be analyzed collectively as a composite inflammatory outcome.
|
Baseline (T0) and Post-treatment at 4 weeks (T1)
|
|
Neurodegenerative Biomarker (α-Synuclein)
Time Frame: Baseline (T0) and Post-treatment at 4 weeks (T1)
|
Serum and salivary levels of α-synuclein will be measured using standardized immunoassays.
Concentrations will be expressed in ng/mL.
|
Baseline (T0) and Post-treatment at 4 weeks (T1)
|
Collaborators and Investigators
Investigators
- Principal Investigator: Massimo Marano, MD, PhD, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
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
- Investigative Techniques
- Diagnostic Techniques and Procedures
- Diagnosis
- Diagnostic Techniques, Respiratory System
- Diagnostic Techniques, Cardiovascular
- Heart Function Tests
- Respiratory Function Tests
- Ergometry
- salicylhydroxamic acid
- Exercise Test
- 2-cyclohexylidenhydrazo-4-phenyl-thiazole
Other Study ID Numbers
- AVANTGARDE-PD
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.