Effects of Transcutaneous Vagus Nerve Stimulation on Emotion Regulation and Executive Functioning in Prader-Willi Syndrome (STIM-PRADER)

Auricular Vagal Neuromodulation Therapy (aVNT) for Enhancing Emotion Regulation, Executive Functions, Hyperphagia, and Quality of Life in Prader-Willi Syndrome: A Multicenter Randomized Controlled Trial

The STIM-PRADER study aims to assess the effectiveness of auricular vagal neuromodulation therapy (aVNT) on emotional, behavioral, and cognitive domains impaired in Prader-Willi Syndrome (PWS). Currently, no treatment exists that addresses the multiple alterations associated with this rare neurodevelopmental disorder that significantly impact patients and their families. We will investigate the effects of daily, four-hour aVNT stimulation over a nine-month period on (a) emotion regulation, including assessing the persistence of effects following stimulation; (b) executive functions, including inhibition, flexibility, planning, and updating information in memory; (c) hyperphagia; (d) depression; (e) quality of life; (e) and the threshold at which effects on these dimensions can be observed.

We will conduct a longitudinal multicenter parallel randomized controlled single-blind exploratory trial. Twenty-four adults with PWS and 24 caregivers will be randomly assigned to receive either active or sham stimulation under identical conditions (four hours per day, seven days per week over nine months). The primary outcome, focusing on emotional control, will be assessed every two weeks for both participants and caregivers. Secondary outcomes (executive functions, hyperphagia, depression, and quality of life) will be measured at four time points: pre-intervention, at three months, six months, and at nine months.

As this is the first multicenter randomized controlled trial investigating the effects of aVNT as a treatment in PWS patients, we anticipate witnessing improved emotional regulation and reduced eating disorders, along with enhancements in executive functions and quality of life in the active stimulation group. The findings from this project could support the development of broader therapeutic approaches for other conditions in which behavioral disorders and emotional processing deficits affect patients and their caregivers.

Study Overview

• Status: Recruiting
• Conditions: Prader-Willi Syndrome
• Intervention / Treatment: Device: Auricular vagal neuromodulation therapy (aVNT); Device: Sham Auricular vagal neuromodulation therapy (aVNT)

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Virginie Postal, PhD; Phone Number: +33 (0)57 57 19 74; Email: virginie.postal@u-bordeaux.fr
• Study Contact Backup: Name: Camille Nahon, PhD student, neuropsychologist; Phone Number: +33 05 57 57 19 64; Email: camille.nahon@u-bordeaux.fr

Study Locations

• France
  • Bordeaux, France, 33600
    • Not yet recruiting
    • Reference Center of Prader-Willi Syndrome (PRADORT)
    • Contact: Blandine Gatta Cherifi, MD, PhD; Phone Number: +33 05 57 62 32 07; Email: blandine.gatta-cherifi@chu-bordeaux.fr
    • Principal Investigator: Blandine Gatta Cherifi, MD, PhD
  • Hendaye, France, 64700
    • Recruiting
    • Reference Center of Prader-Willi Syndrome (CRMR PRADORT)
    • Contact: Fabien Mourre, MD, PhD; Phone Number: + 33 05 59 48 08 00; Email: fabien.mourre@aphp.fr
    • Principal Investigator: Fabien Mourre, MD, PhD
  • Paris, France, 75013
    • Recruiting
    • Reference Center of Prader-Willi Syndrome (PRADORT)
    • Contact: Christine Poitou-Bernert, MD, PhD; Phone Number: +33 01 42 17 57 71; Email: christine.poitou-bernert@aphp.fr
    • Principal Investigator: Christine Poitou-Bernert, MD, PhD
  • Toulouse, France, 31000
    • Recruiting
    • Reference Center of Prader-Willi Syndrome (PRADORT)
    • Contact: Camille Nahon, PhD student, neuropsychologist; Phone Number: +33 05 57 57 19 64; Email: camille.nahon@u-bordeaux.fr
    • Contact: Emilie Montastier, MD, PhD; Phone Number: +33 (0)05 61 32 30 57; Email: montastier.e@chu-toulouse.fr
    • Principal Investigator: Emilie Montastier, MD, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Participant with PWS: Age : ≥ 18 years old; Diagnosis of Prader-Willi syndrome with identified genotype; Intellectual Quotient ≥ 55 measured by WAIS-IV (abbreviated version); Pathological or threshold score on at least one of the BRIEF-A subscales; Adults volunteering and able to comply with study procedures; Signature of informed consent form; Beneficiary of a social security regime
• Caregivers: Caregivers involved in the participant's family, medical or institutional environment; Caregiver who has signed the informed consent form.

Exclusion Criteria:

• Participant with PWS: Untreated and unstabilized psychiatric and/or behavioral disorders (psychological decompensation within the last year); Severe visual or hearing impairment; Untreated sleep apnea syndrome; Epileptic seizures; Previous significative ECG abnormality; Adults with pacemakers or defibrillators; Metal or electronic devices implanted in the head; Participation in other research involving an exclusion period still in progress at inclusion; Score ≥ 30 indicating severe depression (BDI-II self-report questionnaire); Pregnant or breast-feeding women.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham stimulation	Device: Sham Auricular vagal neuromodulation therapy (aVNT); The sham stimulation control condition will be performed using the same aVNT Parasym® device under similar conditions (four hours a day, seven days a week, for nine months) but with a different location (without afferent vagus nerve fibers) or a control condition integrated into the device.
Experimental: Active stimulation	Device: Auricular vagal neuromodulation therapy (aVNT); The aVNT device used in our study (Parasym ®) consists of a small portable unit connected to stimulation electrodes placed on the left ear. These electrodes deliver painless electrical microcurrents through the skin to stimulate the auricular branch of the vagus nerve (ABVN). The device parameters will be defined in accordance with the recommendations for use of the Parasym ® device and the pilot studies: frequency of 25 Hz, pulse width of 250 µS, and an intensity of 1 mA to 36 mA. Stimulation sessions will last for four hours each day, each of which can be divided into two sessions and conducted over a period of nine months. Patients will adjust the intensity at each session according to their comfort level, starting with a gradual increase until they feel a slight tingling sensation, followed by a decrease until discomfort disappears completely. Stimulation should take place during a relaxing activity but not should not take place during sleep, meals or major physical activity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of emotional control and regulation	The primary outcome measure will focus on assessing emotional control (EC) through a subscale of the BRIEF-A (Behavior Inventory Related to Executive Functions - Adult version).	Every 2 weeks for 11 months (including 3 times before and post-stimulation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of Behavioral manifestations of executive functioning	BRIEF-A (Behavior Inventory Related to Executive Functions - Adult version)	4 times (at 0, 3, 6 and 9 months)
Evaluation of Executive functions	Behavioral inhibition will be assessed using a computerized Go/NoGo task and cognitive flexibility with a computerized voluntary alternation task. Planning abilities will be assessed using the BADS Zoo Test (Behavioral Assessment of Dysexecutive Syndrome - BADS). Finally, the ability to update information will be assessed using an adapted computerized N-2-Back task.	4 times (at 0, 3, 6 and 9 months)
Evaluation of Hyperphagia	Hyperphagia will be assessed using a scale derived from the Dykens Hyperphagia Questionnaire: the HQ-CT (Hyperphagia Questionnaire for Use in Prader-Willi Syndrome Clinical Trials)	4 times (at 0, 3, 6 and 9 months)
Evaluation of Depression	Depression will be assessed using the Depression Self-Report Questionnaire (Beck Depression Inventory - BDI-II)	4 times (at 0, 3, 6 and 9 months)
Evaluation of Quality of life	We will assess the quality of life of participants with PWS using the WHOQOL-BREF questionnaire (World Health Organization Quality of Life-BREF)	4 times (at 0, 3, 6 and 9 months)

Collaborators and Investigators

• Sponsor: University of Bordeaux
• Collaborators: Groupe Hospitalier Pitie-Salpetriere; Prader-Willi Syndrome Association; CHU Bordeaux; John Bost Foundation; Hendaye hospital; CHU Toulouse
• Investigators: Principal Investigator: Virginie Postal, PhD, University of Bordeaux

Study record dates

Study Major Dates

• Study Start (Actual): November 22, 2023
• Primary Completion (Estimated): March 30, 2026
• Study Completion (Estimated): March 30, 2026

Study Registration Dates

• First Submitted: December 2, 2024
• First Submitted That Met QC Criteria: December 2, 2024
• First Posted (Estimated): December 6, 2024

Study Record Updates

• Last Update Posted (Estimated): December 6, 2024
• Last Update Submitted That Met QC Criteria: December 2, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Depression; Quality of life; Behavior; Cognition; Caregivers; Vagus nerve stimulation; Prader-Willi Syndrome; Emotion regulation; Hyperphagia; Executive functions; Planning; Inhibition; Flexibility; Updating; Multicenter randomized controlled trial; aVNT; t-VNS
• Additional Relevant MeSH Terms: Imprinting Disorders; Neurologic Manifestations; Nervous System Diseases; Pathologic Processes; Nutrition Disorders; Genetic Diseases, Inborn; Overnutrition; Disease; Neurobehavioral Manifestations; Congenital Abnormalities; Abnormalities, Multiple; Overweight; Intellectual Disability; Obesity; Chromosome Disorders; Syndrome; Prader-Willi Syndrome
• Other Study ID Numbers: 2023-A00915-40

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: No