Proof of Concept Study of Vagus Nerve Stimulation

Proof of Concept Study of Vagus Nerve Stimulation Using an External Device for the Treatment of Behaviour Problems in People With Neurodevelopmental Disorders, Specifically Prader Willi Syndrome

The investigator's recent pilot study of vagus nerve stimulation (VNS) from a surgically implanted medical device to control the excess eating behaviour characteristic of Prader-Willi Syndrome (PWS) found that it was safe and acceptable. In addition, there were unanticipated marked improvements in rates of problem behaviours, such as emotional disturbances and verbal and physical outbursts. These observations indicated the need for a trial specifically focusing on the effects of VNS on problem behaviour and also that the use of VNS might be extended to include people with other neurodevelopmental disorders, such as autism spectrum conditions (ASC). The primary aims of this study are: a) to investigate whether VNS, now given by an external medical device, is associated with a significant reduction in the number and severity of maladaptive behaviours in adults with PWS; and b) to undertake a pilot study that includes others with a different neurodevelopmental syndrome who have histories of similar behaviours.

The study will be a single case cross-over design with 4 to 6 months baseline phase and a similar period of active treatment. The study cannot be blind as the stimulation is apparent but the participants will wear the device initially for four hours a day, at times convenient to them, with it switched off in the baseline phase and activated, according to standard protocols, in the treatment phase. Six adults with PWS and six with a different neurodevelopmental disorder with histories of significant problem behaviours will be included initially, with a view to extending if the analysis indicates a likely effect. Behaviours will be operationally defined and measured over time using participant and informant diaries with additional secondary outcome measures. Before and during the treatment phases autonomic nervous system and brain biomarkers will be assessed using ambulatory monitoring of heart rate variability and fMRI brain scans.

Study Overview

• Status: Completed
• Conditions: Prader-Willi Syndrome; Transcutaneous Vagal Nerve Stimulation (tVNS)
• Intervention / Treatment: Device: Transcutaneous vagus nerve stimulation (tVNS)

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female aged over 18 years of age.
• Genetically and clinically determined diagnosis of PWS or meeting clinical or the presence of another neurodevelopmental syndrome such as an autistic spectrum condition.
• History of problem behaviours of, on average, at least one significant informant-reported episode each week.
• Capacity to consent.
• Able to commit to the study duration and to attend assessments in Cambridge.

Exclusion Criteria:

• Meet exclusion criteria for MRI scanning and/or unable to tolerate MRI environment.
• Serious co-morbid physical or psychiatric disorder which would disrupt ability to comply with study demands (e.g. a history of serious bipolar disorder; sleep apnoea not well-controlled with CPAP; insulin dependent diabetes).
• Current or past history of neurological disorders or trauma, including epilepsy, and head injury.
• Currently or recently (within 12 months) participating in a clinical trial of an investigational medicinal product (CTIMP) or another medical device.
• Lacking the capacity to consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Transcutaneous vagal nerve stimulation (tVNS); tVNS administered for 4 hours each day and behaviour is recorded.	Device: Transcutaneous vagus nerve stimulation (tVNS)
Placebo Comparator: Baseline; tVNS worn but not switched on whilst collecting behavioural data.	Device: Transcutaneous vagus nerve stimulation (tVNS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of operationally defined outbursts	Measured using participant and informant diaries.	15-17 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Challenging Behaviour Checklist	Scores on rating scale, repeated over time. Score range 50-55. higher score indicates more severe behaviour.	15-17 months
Repetitive Behaviour Questionnaire	Scores on rating scale, repeated over time. Total scores range between 20-60. The higher toe score the worse behaviours are.	15-17 months
Life Experiences Checklist.	Intended to gather information about the potentially traumatic experiences a person has experienced. There is no formal scoring protocol or interpretation per se, other than identifying whether a person has experienced one or more of the events listed. Respondents indicate varying levels of exposure to each type of potentially traumatic event included on a 6-point nominal scale, and respondents may endorse multiple levels of exposure to the same trauma type.	15-17 months
fMRI at resting and on-task	FMRI data will be analysed using both 1st and 2nd level general linear model (GLM) analyses to compare within cases and across time points. Network analyses of functional connectivity may also be appropriate	15-17 months
Participants response to challenge	Using methodology developed by Prof Oliver, filmed and subsequently rated blind for emotional and behavioural changes.	15-17 months
Semi-structured interviews	With participants and carers to probe about any observed subtle changes in behaviour. Analysed thematically.	15-17 months
Attention shifting ability	Tested via go-no-go task developed for people with PWS by Woodcock et al (2009). Reaction times analysed.	15-17 months
Salival cortisol measures	recorded across the course of four separate days during the course of study (at waking, 30 minutes post-waking, 45 minutes post-waking, 1 hour post-waking and then four more times throughout the day at approximately +3h, +6h, +9h and +14h after waking).	15-17 months
Vocal prosody	Two voice recordings of the participant talking will be collected on each of these occasions. Each recording will be at least 20 seconds long, with the participant asked to talk about a positive experience (e.g. favourite birthday, best friend etc.) in one, a less positive time (e.g. a time when he/she was disappointed or sad) in the other. These will be analysed for changes in vocal prosody with t-VNS.	15-17 months
Heart Rate Variability	derived from ECG and respiration measured using an Intelesens (Belfast) 3-axis 'Zensor' wearable monitor. For each participant ECG recording will take place in 24-hour blocks. HRV will be determined from R-R intervals as root mean of squared successive differences and average HRV will be determined for each participant for brief (15 minutes) and prolonged (24 hours) periods.	15-17 months

Collaborators and Investigators

• Sponsor: Jessica Beresford-Webb
• Collaborators: Foundation for Prader-Willi Research
• Investigators: Principal Investigator: Tony Holland, Prof., University of Cambridge

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): December 31, 2018
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: September 26, 2018
• First Submitted That Met QC Criteria: September 27, 2018
• First Posted (Actual): September 28, 2018

Study Record Updates

• Last Update Posted (Actual): April 17, 2019
• Last Update Submitted That Met QC Criteria: April 16, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Overnutrition; Nutrition Disorders; Genetic Diseases, Inborn; Intellectual Disability; Abnormalities, Multiple; Chromosome Disorders; Obesity; Syndrome; Prader-Willi Syndrome
• Other Study ID Numbers: 15/EE/0450

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