Ameliorating Effects and Mechanisms of TaVNS on Constipation in PD Patients.

Ameliorating Effects and Mechanisms of Transcutaneous Auricular Vagus Nerve Stimulation on Constipation in Parkinson's Disease Patients: a Randomized, Double-blind Clinical Trial

The investigators intend to conduct a randomized, double-blind, sham-stimulation-controlled experiment, incorporating various clinical scales, gastrointestinal electrogram, and high-resolution anorectal manometry (HRAM), to investigate the improvement effect of taVNS on constipation symptoms in PD patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Constipation; Parkinson Disease, Idiopathic
• Intervention / Treatment: Device: active Transcutaneous auricular vagus nerve stimulation; Device: sham Transcutaneous auricular vagus nerve stimulation

Detailed Description

The investigators intend to conduct a randomized, double-blind, sham-stimulation-controlled experiment, incorporating various clinical scales, gastrointestinal electrogram, and high-resolution anorectal manometry (HRAM), to investigate the improvement effect of taVNS on constipation symptoms in PD patients. Meanwhile, the investigators aimed to verify mechanistic effects by investigating changes in proteins and cytokines related to inflammation and intestinal barrier function in serum and feces to verify mechanistic effects.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kezhong Zhang, Professor; 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. aged 40-70 years;
2. had a PD diagnosis designated by movement disorder neurologists (Ke-zhong Zhang and Yong-sheng Yuan) according to Movement Disorder Society Clinical Diagnostic Criteria;
3. fulfilled Rome IV criteria for functional constipation, including having < 3 spontaneous bowel movements (SBM; i.e., not induced by rescue medication) per week for the past 3 months with symptom duration of at least 6 months;
4. stable initiation of PD medications, leastways 3 month before this investigation; (5) provided written informed consent.

Exclusion Criteria:

1. a history of previous abdominal surgery (other than appendectomy);
2. the presence of carcinoma;
3. any organic diseases causing constipation or neurologic diseases such as multiple sclerosis, rachischisis, or spinal cord injury;
4. taking antidepressant agents including tricyclic antidepressants and selective serotonin reuptake inhibitors;
5. a serious concomitant disease of the heart, liver, kidney, or diabetes;
6. pregnancy or lactation;
7. participating in another trial or enrolled in a trial during the past month;
8. an allergic reaction to surface electrodes.

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: Active Transcutaneous auricular vagus nerve stimulation; For Experimental Arm, active transcutaneous auricular vagus nerve stimulation, Patients underwent 28 consecutive daily sessions of taVNS.	Device: active Transcutaneous auricular vagus nerve stimulation; Transcutaneous auricular vagus nerve stimulation was conducted by transcutaneous electrical stimulation therapy instrument to the cymba conchae of left ear in the vicinity of the auricular branch vagus nerve. Stimulation parameters: frequency = 20 Hz; pulse width = 500 μs, twice a day, 30 minutes each time.
Sham Comparator: Sham Transcutaneous auricular vagus nerve stimulation; For sham transcutaneous auricular vagus nerve stimulation arm, Sham Comparator, patients underwent 28 consecutive daily sessions of sham-taVNS (the electrodes were fixed at the the left earlobe).	Device: sham Transcutaneous auricular vagus nerve stimulation; In the sham stimulation group, the electrodes were fixed at the left earlobe with the same stimulus parameters. Stimulation parameters: frequency = 20 Hz; pulse width = 500 μs, twice a day, 30 minutes each time.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
alterations in complete spontaneous bowel movements per week (CSBMs/week)	By having patients record their bowel movements two weeks before the start of the experiment and two weeks before the end of the experiment, calculate the CSBMs/week.	Assessed at 2 weeks before baseline, 2 weeks before the last day of intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline Gastrointestinal Dysfunction Scale for Parkinson's Disease (GIDS-PD) at one day post intervention	The Gastrointestinal Dysfunction Scale for Parkinson's Disease is a novel disease-specific self-report tool to quantitatively assess the presence and severity of gastrointestinal dysfunction features in patients with PD, with strong reliability and validity. The GIDS-PD (Appendix S1) is a Likert self-report scale composed of 12 items. The total score of the GIDS-PD is computed by adding the total score of items 1 through 12, resulting in a minimum score of 1 and a maximum score of 108.	Assessed at baseline, one day post intervention
Change from Baseline Gastrointestinal Symptoms Rating Scales at one day post intervention	Used to evaluate the gastrointestinal symptoms and discomfort level of patients, from 0 to 105.	Assessed at baseline, one day post intervention
Change from Baseline constipation symptoms scores at one day post intervention	Used to evaluate the constipation symptoms , from 0 to 30.	Assessed at baseline, one day post intervention
Change from Baseline Patient Assessment of Constipation Quality of Life scale，PAC-QOL at one day post intervention	Used to evaluate quality of life, a total of 28 items are divided into 4 aspects: physiological discomfort, psychological discomfort, palpitations, and satisfaction. The PAC-QOL score range is 0-4, with lower scores indicating better results.	Assessed at baseline, one day post intervention
Change from Baseline Patient Assessment of Constipation Symptoms questionnaire at one day post intervention	Used to evaluate the constipation symptoms , from 0 to 48.	Assessed at baseline, one day post intervention
Change from Baseline HRAM at one day post intervention--Resting pressure (mmHg)	Following HRV test, HRAM was undertaken using a solid-state manometric instrument with 12 circumferential sensors spaced at 1 cm intervals and an outer diameter of 4.2 mm to evaluate anorectal sensorimotor function. Patients were asked to be in the left lateral position with the hips and knees flexed, and then the solid-state catheter was inserted into the rectum through the anal orifice. After a 3-minute period of stabilization, the sequential maneuver procedures are as follows: Resting pressure (mmHg), maximum squeeze pressure (mmHg). First-sensation volume, desire to defecate threshold, and maximum tolerance were tested by constant dilation of balloon	Assessed at baseline, one day post intervention
Change from Baseline HRAM at one day post intervention--maximum squeeze pressure (mmHg)	Following HRV test, HRAM was undertaken using a solid-state manometric instrument with 12 circumferential sensors spaced at 1 cm intervals and an outer diameter of 4.2 mm to evaluate anorectal sensorimotor function. Patients were asked to be in the left lateral position with the hips and knees flexed, and then the solid-state catheter was inserted into the rectum through the anal orifice. After a 3-minute period of stabilization, the sequential maneuver procedures are as follows: Resting pressure (mmHg), maximum squeeze pressure (mmHg). First-sensation volume, desire to defecate threshold, and maximum tolerance were tested by constant dilation of balloon	Assessed at baseline, one day post intervention
Change from Baseline HRAM at one day post intervention--First sensation (mL)	Following HRV test, HRAM was undertaken using a solid-state manometric instrument with 12 circumferential sensors spaced at 1 cm intervals and an outer diameter of 4.2 mm to evaluate anorectal sensorimotor function. Patients were asked to be in the left lateral position with the hips and knees flexed, and then the solid-state catheter was inserted into the rectum through the anal orifice. After a 3-minute period of stabilization, the sequential maneuver procedures are as follows: Resting pressure (mmHg), maximum squeeze pressure (mmHg). First-sensation volume, desire to defecate threshold, and maximum tolerance were tested by constant dilation of balloon	Assessed at baseline, one day post intervention
Change from Baseline HRAM at one day post intervention--desire to defecate threshold	Following HRV test, HRAM was undertaken using a solid-state manometric instrument with 12 circumferential sensors spaced at 1 cm intervals and an outer diameter of 4.2 mm to evaluate anorectal sensorimotor function. Patients were asked to be in the left lateral position with the hips and knees flexed, and then the solid-state catheter was inserted into the rectum through the anal orifice. After a 3-minute period of stabilization, the sequential maneuver procedures are as follows: Resting pressure (mmHg), maximum squeeze pressure (mmHg). First-sensation volume, desire to defecate threshold, and maximum tolerance were tested by constant dilation of balloon	Assessed at baseline, one day post intervention
Change from Baseline HRAM at one day post intervention--maximum tolerance	Following HRV test, HRAM was undertaken using a solid-state manometric instrument with 12 circumferential sensors spaced at 1 cm intervals and an outer diameter of 4.2 mm to evaluate anorectal sensorimotor function. Patients were asked to be in the left lateral position with the hips and knees flexed, and then the solid-state catheter was inserted into the rectum through the anal orifice. After a 3-minute period of stabilization, the sequential maneuver procedures are as follows: Resting pressure (mmHg), maximum squeeze pressure (mmHg). First-sensation volume, desire to defecate threshold, and maximum tolerance were tested by constant dilation of balloon	Assessed at baseline, one day post intervention
Change from Baseline serum indicators at one day post intervention	A blood sample was taken at 8 a.m. at baseline and after 4 weeks of treatment. For each patient, about 5 mL of blood was drawn into a procoagulant tube and 4 mL into 2 anticoagulant tubes with EDTA; it was centrifuged at 4°C and 1139g for 10 minutes and 5 minutes respectively. The serum in the procoagulant tube was divided into 3 portions, and the plasma in the anticoagulant tubes was divided into 2 portions - each about 0.5 mL - and placed at -80°C for assay within 6 months.	Assessed at baseline, one day post intervention
Change from Baseline feces indicators at one day post intervention	placed at -80°C for assay within 6 months.	Assessed at baseline, one day post intervention
Change from Baseline The motor part of the Unified Parkinson's Disease Rating Scale at one day post intervention	The measure mainly reflects the overall severity of Parkinson's disease motor symptoms. The minimum and maximum values of the motor part of the Unified Parkinson's Disease Rating Scale are 0 and 108. A higher score means a worse outcome.	Assessed at baseline, one day post intervention
Change from Baseline gastrointestinal electrogram at one day post intervention--amplitude	A total of 8 leads cover the body surface projection of the stomach and intestines, which can reflect the gastrointestinal motility	Assessed at baseline, one day post intervention
Change from Baseline gastrointestinal electrogram at one day post intervention--frequency	A total of 8 leads cover the body surface projection of the stomach and intestines, which can reflect the gastrointestinal motility.	Assessed at baseline, one day post intervention

Collaborators and Investigators

• Sponsor: Kezhong Zhang
• Investigators: Principal Investigator: Kezhong Zhang, The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): October 15, 2024
• Primary Completion (Estimated): November 30, 2024
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: September 30, 2024
• First Submitted That Met QC Criteria: September 30, 2024
• First Posted (Actual): October 2, 2024

Study Record Updates

• Last Update Posted (Actual): October 4, 2024
• Last Update Submitted That Met QC Criteria: October 3, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Parkinson's disease; constipation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Digestive; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Constipation
• Other Study ID Numbers: 2024-taVNS

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