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High-Frequency Transdermal Neuromodulation to Decrease Anxiety and Improve Sleep in ASD

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ClinicalTrials.gov Identifier: NCT03859336
Recruitment Status : Not yet recruiting
First Posted : March 1, 2019
Last Update Posted : March 1, 2019
Sponsor:
Information provided by (Responsible Party):
Richard Frye, MD, PhD, Phoenix Children's Hospital

Brief Summary:
The objective of this study is to investigate the feasibility of cervical TEN stimulation (TENS) delivered to the back of the neck to decrease anxiety and sleep issues in young adults with Autism Spectrum Disorder (ASD). The specific aim is to determine the effect of TENS delivered over 4 daily sessions, on anxiety and sleep quality in young adults with ASD, as compared to sham and baseline. The investigator will enroll up to 20 young adults, aged 10 to 25 years of age with confirmed ASD and measureable anxiety and sleep disturbance symptoms, and participation will last 3 weeks.

Condition or disease Intervention/treatment Phase
Autism Spectrum Disorder Device: Transdermal Neuromodulation Stimulation Not Applicable

Detailed Description:

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with life-long consequences that affects children during critical times in their development. ASD is associated with co-occurring problems such as anxiety and sleep disturbances. New approaches to managing stress, anxiety, and sleep quality would greatly enhance the quality of life and activities of daily living for children with ASD as they transition to adulthood and age out of services. Based on strong evidence from typically developing individuals, the technology for transdermal electrical neuromodulation (TEN) of the cranial nerves has shown to be a safe, effective, comfortable, and non-pharmacological therapy to modulate the central nervous system decreasing anxiety and enhancing sleep quality to improve the quality of life for people with ASD.

The therapy applies tuned, high-frequency TEN to the back of the neck which activates the brainstem modulating noradrenergic signaling shown to decrease anxiety in healthy adults. The low-amplitude of the stimulation means that it is painless and comfortable. Furthermore, the technology is being evaluated for improving sleep quality. The mechanism of these effects are well established in the neurophysiology literature, but modulating these brainstem areas is only now possible non-invasively with the technology. Participants entered into the trial wil have anxiety and sleep issues that are known to be associated with ASD. The investigators hypothesize that cervical TEN will decrease anxiety and improve sleep quality in a population with high-functioning ASD who are transitioning into adulthood.

The investigators will study 20 young adults, between the ages of 10 years to 25 years, with confirmed ASD and anxiety and sleep quality issues. All patients will undergo a one day sham stimulation session, which will be used to exclude placebo responders and those cannot tolerate study procedures. Additionally, the visit will serve as the baseline day to collect anxiety measures.The participants will then spend one week wearing a sleep actigraphy device to collect 7 days of baseline sleep measures. In the second week, the participants will return for 4 consecutive days of open label TEN stimulation treatment, while continuing to to wear the sleep actigraphy device on a nightly basis. Participation will conclude with a one day follow-up visit one week from the last treatment day. Anxiety will be measured primarily using physiological data from galvanic skin response (GSR) and heart rate variability (HRV). Secondary measures will include data from behavioral surveys and cortisol and amylase analysis from a buccal swab. Sleep quality will be measured primarily using the data from the sleep actigraphy. Secondary measures will include responses from a questionnaire.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Prospective 4 day open-label device trial across all subjects with 1 day single-blinded pre-treatment sham
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: High-Frequency Transdermal Neuromodulation to Decrease Anxiety and Improve Sleep in Autism Spectrum Disorder (ASD)
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Transdermal Neuromodulation Stimulation
Day 1 of Transdermal Neuromodulation Stimulation (TENS) is a one-day sham stimulation, consisting of: 30 seconds of sensation in which amplitude is increased up to the threshold of salient sensation, followed by 19 minutes of no stimulation (device is turned off), followed by 30 more seconds of salient stimulation. Day 1 is used to exclude those who cannot tolerate study procedures and placebo responders; it will also serve as baseline for anxiety measures. TENS treatment begins one week after sham, and lasts 4 days with 20 minutes of stimulation per day. Treatment amplitude is adjusted for each participant, in which the stimulation will be administered just below the participant's sensation threshold. Amplitude from the TENS device does not exceed 20mA. Frequency will be at 300hz.
Device: Transdermal Neuromodulation Stimulation
The TEN device administers a tuned high frequency electrical stimulation delivered to the cervical plexus (C2-C4) on the back of the neck for 20 minutes. This stimulation will activate common trigeminovagal pathways modulating noradrenergic signaling to attenuate sympathetic activity. This stimulation can subsequently regulate the activity of several deep-brain nuclei within the ascending reticular activating system (RAS). Nuclei in the RAS regulate powerful neuromodulators like norepinephrine (NE), acetylcholine (ACh), and serotonin (5-HT). The investigators will examine whether this modulation from TENS will decrease anxiety and improve sleep quality in the study participants.




Primary Outcome Measures :
  1. Change in physiological response measure of heart rate variability in the time-domain as measured by the standard deviation of the normal-to-normal heart beat (SDNN) [ Time Frame: Baseline Visit (day 1 of trial), Week 2 (days 8 - 11 of trial), Week 3 (day 18, End of Trial Visit) ]
    The standard deviation of the normal-to-normal heart beat (SDNN) is the time-domain based measured of heart rate variability. It is measured by calculating the standard deviation of the heart beat-to-beat time interval, which is measured in milliseconds. Anxiety reduction will be demonstrated by a reduction in the SDNN value during a stressor in response to TEN treatment, as compared to baseline.

  2. Change in physiological response measure of heart rate variability in the frequency-domain as measured by the power of the low frequency (LF) band [ Time Frame: Baseline Visit (day 1 of trial), Week 2 (days 8 - 11 of trial), Week 3 (day 18, End of Trial Visit) ]
    The low frequency (LF) component of heart rate variability (HRV) is the frequency band ranging from 0.04-0.15Hz of the waveform created by heart rate oscillations. Spectral power is calculated for this band in milliseconds squared. Anxiety reduction will be demonstrated by a reduction in the power value of the LF HRV component during a stressor in response to TEN treatment, as compared to baseline.

  3. Change in physiological response measure of heart rate variability in the frequency-domain as measured by the power of the high frequency (HF) band [ Time Frame: Baseline Visit (day 1 of trial), Week 2 (days 8 - 11 of trial), Week 3 (day 18, End of Trial Visit) ]
    The high frequency (HF) component of heart rate variability (HRV) is the frequency band ranging from 0.15-0.4Hz of the waveform created by heart rate oscillations. Spectral power is calculated for this band in milliseconds squared. Anxiety reduction will be demonstrated by a reduction in the power value of the HF HRV component during a stressor in response to TEN treatment, as compared to baseline.

  4. Change in physiological response measure of galvanic skin response (GSR) [ Time Frame: Baseline Visit (day 1 of trial), Week 2 (days 8 - 11 of trial), Week 3 (day 18, End of Trial Visit) ]
    Galvanic skin response (GSR) is an electrodermal conductance measurement that reflects the changes in sweat gland activity, which is measured in microsiemens (μS). Anxiety reduction will be analyzed through a suppression of GSR activity value during a stressor in response to TEN treatment, as compared to baseline data.

  5. Change in sleep actigraphy measure [ Time Frame: Daily measures for full trial length (18 days): from Baseline Visit (day 1) to End of Trial Visit (day 18) ]
    Improved sleep quality will be determined by improvement in the sleep efficiency score. The sleep efficiency score is determined by the total sleep duration hours recorded by the sleep actigraphy device. Improvement in sleep quality will be reflected by a higher sleep efficiency score.


Secondary Outcome Measures :
  1. Change in the Screen for Child Anxiety Related Disorders (SCARED) score [ Time Frame: Baseline Visit (day 1 of trial), Week 2 (days 8 - 11 of trial), Week 3 (day 18, End of Trial Visit) ]
    The Screen for Child Anxiety Related Disorders (SCARED) is a 41-item self-reported inventory that measures anxiety in youth with ASD. Each item rates the severity of a symptom or behavior on a 3 point scale from 0 (Not true or Hardly Ever True) to 2 (Very True or Often True). A decrease in the total score of the 41 items, ranging from 0 to 82, will be used as a secondary measure to define a positive response.

  2. Change in the Parent Reported Anxiety Scale (PRAS) score [ Time Frame: Baseline Visit (day 1 of trial), Week 2 (days 8 - 11 of trial), Week 3 (day 18, End of Trial visit) ]
    The Parent-rated Anxiety Scale for Autism Spectrum Disorder is a 25-item scale that measures anxiety in youth with ASD. Each item rates the severity of a behavior on a 4 point scale from 0 (None/not present) to 3 (Severe/Very frequent and a major problem). A decrease in the total score of the 25 items, ranging from 0 to 75, will be used as a secondary measure to define a positive response.

  3. Change in amylase and cortisol levels [ Time Frame: Baseline Visit (day 1 of trial), Week 2 (days 8 - 11 of trial), Week 3 (day 18, End of Trial visit) ]
    Another secondary outcome measure for anxiety will be to quantify α-amylase and cortisol levels in the collected saliva samples, comparing post-treatment sample levels to pre-treatment within a visit. Successful anxiety reduction will be demonstrated by reduced levels of α-amylase and cortisol in the sample as compared to pre-TEN treatment levels.

  4. Change in the Children's Sleep Habits Questionnaire (CSHQ) score [ Time Frame: Baseline Visit (day 1 of trial), Week 2 (days 8 - 11 of trial), Week 3 (day 18, End of Trial visit) ]

    The Children's Sleep Habits Questionnaire (CSHQ) is a 39-item informant-reported questionnaire that measures sleep quality in children. Each item rates the frequency of a sleeping behavior on a 3 point scale from 1 (Never/Rarely, 0-1 nights per week) to 3(Usually, 5-7 nights pers week). The questionnaire also consists of questions asking whether certain behaviors are a problem with the options of a "yes" or "no" response.

    Improved sleep quality will be determined by a decrease in scores on the CSHQ subscales and the CSHQ combined total score, ranging from 31-93.




Information from the National Library of Medicine

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Ages Eligible for Study:   10 Years to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • IQ > 80, to be evaluated during the screening visit using the Kaufman Brief Intelligence Test (KBIT)
  • Self-reported complaints about anxiety and/or sleep issues
  • Screen for Child Anxiety Related Disorders (SCARED) - Parent Form, score >= 25
  • Able to follow directions in English

Exclusion Criteria:

  • IQ ≤ 80, to be evaluated during the screening visit using the KBIT
  • SCARED - Parent Form, Score < 25
  • Has a medical implant (such as a pacemaker, cochlear implant, brain stimulation device, spinal stimulator)
  • History of significant face/head injury including cranial or facial metal plate or screw implants
  • Pregnant
  • History of migraines or frequent headaches (more than once a week)
  • Started taking anti-anxiety medications less than 3 months prior to study participation or has not been taking anti-anxiety medications consistently for at least 3 months prior to study participation
  • Fainting (vaso-vagal syncope or neurocardiogenic syncope)
  • Diagnosis of Raynaud's disease
  • Temporomandibular joint (TMJ) disorder or other facial neuropathy
  • Poor vision or hearing that is uncorrectable
  • Seizures in the last 2 years
  • Evidence of skin disease or skin abnormalities affecting the neck or upper back
  • Upper extremity contractures

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03859336


Contacts
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Contact: Richard E Frye, MD, PhD 602-933-0681 rfrye@phoenixchildrens.com
Contact: Stephen T Foldes, PhD 602-933-0683 sfoldes@phoenixchildrens.com

Locations
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United States, Arizona
Phoenix Children's Hospital Not yet recruiting
Phoenix, Arizona, United States, 85016
Contact: Richard E Frye, MD, PhD    602-933-0681    rfrye@phoenixchildrens.com   
Contact: Stephen T Foldes, PhD    602-933-0683    sfoldes@phoenixchildrens.com   
Principal Investigator: Richard E Frye, MD, PhD         
Principal Investigator: Foldes T Stephen, PhD         
Sponsors and Collaborators
Phoenix Children's Hospital
Investigators
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Principal Investigator: Richard E Frye, MD, PhD Phoenix Children's Hospital

Publications:
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Responsible Party: Richard Frye, MD, PhD, Chief of Neurodevelopmental Disorders at Barrow Neurological Institute, Phoenix Children's Hospital
ClinicalTrials.gov Identifier: NCT03859336     History of Changes
Other Study ID Numbers: TENS_ASD
First Posted: March 1, 2019    Key Record Dates
Last Update Posted: March 1, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Richard Frye, MD, PhD, Phoenix Children's Hospital:
Anxiety
Sleep Issues

Additional relevant MeSH terms:
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Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders