Efficacy of Trigeminal Nerve Stimulation for ADHD

Efficacy of External Trigeminal Nerve Stimulation for Treatment of ADHD

This study is a large multisite randomized clinical trial to asses the efficacy of external trigeminal nerve stimulation (TNS), a novel, minimal risk, non-invasive neuromodulation treatment, for ADHD in children ages 7-12 years old (N=180).

Study hypotheses address potential differences in ADHD symptoms over 4 weeks treatment with active vs. sham TNS in an expanded multi-site investigation; whether resting state fronto-parietal connectivity mediates TNS impact on ADHD symptoms; if changes in fronto-parietal activation, as measured by electroencephalography (EEG), predict TNS-related treatment outcomes; and whether a baseline cognitive profile similarly predicts response to TNS therapy.

Study Overview

• Status: Recruiting
• Conditions: Attention-Deficit Hyperactivity Disorder
• Intervention / Treatment: Device: Active eTNS; Device: Sham eTNS

Detailed Description

Trigeminal Nerve Stimulation (TNS), an FDA-approved, non-invasive minimal risk intervention approved for treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), administers a low amount of electrical stimulus to the forehead during sleep and is shown to increase activity in brain regions associated with attention and impulse control.

The current study seeks to replicate previous efficacy and safety findings of TNS in a larger, multisite group of ADHD-diagnosed youth, ages 7-12. The study will be conducted at UCLA and Seattle Children's Hospital.

The study comprises 3 phases, with subsequent 12-month follow-up for participants who demonstrate positive response to active therapy. We will screen up to 280 participants to yield an overall study N=225 completers meeting Diagnostic and Statistical Manual-5 (DSM-5) ADHD criteria across the two sites.

Phase 1 is a 4-week double-blind, controlled trial of active vs. sham TNS. Once inclusion/exclusion criteria are assessed, eligible participants have an initial baseline assessment comprised of behavioral ratings, cognitive assessments, and electroencephalography (EEG), and are subsequently randomized 2:1 to active vs. sham treatment. Participants will begin use of TNS as directed each night during sleep for 4 weeks. Participants, families, and most of the study team will remain blind to treatment assignment. Weekly behavioral rating will be obtained from parents, teacher, and clinical investigators. EEG, along with other cognitive measures, will be repeated at week 4.

In Phase 2, participants initially randomized to sham will receive active TNS for an additional 4 weeks, with continued weekly assessments. Phase 3 entails brief naturalistic follow-ups via phone or Zoom at months 3 and 6 post-treatment.

• Study Type: Interventional
• Enrollment (Anticipated): 280
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California, Los Angeles
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. male and female children ages 7 to 12 years with DSM-5 ADHD, any current presentation, as determined by diagnostic interview, Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS), and clinical interview;
2. total score >= 24 on baseline ADHD-RS;
3. CGI-S score at baseline >= 4;
4. no current medication with CNS effects (Participants previously on psychostimulant medication will be required to be not optimally treated and off medication for one week or 5 half-lives for all other medications); stable use of supplements will be permitted;
5. parents able and willing to monitor proper use of the stimulation device and complete all required rating scales;
6. estimated Full Scale IQ >= 80 based on WASI subtests;
7. parent and participant able to complete rating scales and other measures in English;
8. able to cooperate during EEG

Exclusion Criteria:

1. impaired functioning to a degree that requires immediate initiation of ADHD medication in the opinion of the parents and/or investigator;
2. current diagnosis of autism spectrum disorder or major depression;
3. history of lifetime psychosis, mania, or seizure disorder;
4. baseline suicidality;
5. history of seizure disorder or head injury with loss of consciousness

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active eTNS; Following screening and determination of eligibility , participants at baseline are randomized to receive 4 weeks nightly treatment with active eTNS. Positive responders will be invited to participate in a 12-month open-label continuation phase.	Device: Active eTNS; Participants will receive active trigeminal nerve stimulation (eTNS) administered by the Monarch eTNS system nightly during sleep for 4 weeks. Participants deemed to be positive responders to blinded active treatment will be invited to continue open nightly eTNS in a 12 month extension period.; Other Names: Trigeminal Nerve Stimulation; Monarch eTNS SystemTM (NeuroSigma, Inc., Los Angeles, CA
Sham Comparator: Sham eTNS; Following screening and determination of eligibility, participants at baseline are randomize to receive 4 weeks nightly treatment with sham eTNS. At conclusion of the double-blind phase, participants randomized to sham will be provided an opportunity to receive an additional 4 weeks nightly treatment with active eTNS. Positive responders to active eTNS will be invited to participate in a 12-month open-label continuation phase.	Device: Active eTNS; Participants will receive active trigeminal nerve stimulation (eTNS) administered by the Monarch eTNS system nightly during sleep for 4 weeks. Participants deemed to be positive responders to blinded active treatment will be invited to continue open nightly eTNS in a 12 month extension period.; Other Names: Trigeminal Nerve Stimulation; Monarch eTNS SystemTM (NeuroSigma, Inc., Los Angeles, CA; Device: Sham eTNS; Participants will receive sham trigeminal nerve stimulation (eTNS) administered by the Monarch eTNS system nightly during sleep for 4 weeks. At conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open active eTNS treatment. Participants deemed to be positive responders to open active treatment will be invited to continue open nightly eTNS in a 12 month extension period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in ADHD Rating Scale-5 (ADHD-RS-5)	A dimensional rating of ADHD symptoms, with scores ranging from 0-54, and higher scores indicating worse outcomes.	Baseline, weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Global Impression - Severity (CGI-S)	Categorical measure indicating overall degree of clinical severity among patients with similar diagnoses. Minimum score = 1 (Normal); Maximum score = 7 (Among the most extremely ill patients).	Baseline, weeks 4, 8, 16, 20
Clinical Global Impression - Improvement (CGI-I)	Categorical measure indicating degree improved or not improved compared with baseline for each treatment group. Minimum score = 1 (very much improved); Maximum score = 7 (very much worse). Results reflect number of participants stratified as "Improved" (CGI-I <=2) or "Not Improved" (CGI-I > 2).	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20
Change in Strengths and Weakness of Attention-Deficit/Hyperactivity (SWAN) Rating Scale	A dimensional measure of ADHD symptoms measured on a 7-point scale, with scores ranging from -54 to +54, and lower scores indicating worse symptoms.	Baseline, weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20
Change in Conners Short Form - Parent	Parent completed dimensional measure of ADHD symptoms, with score range from 0-135, and higher scores indicating more severe symptoms.	Baseline, weeks 4, 8
Change in Conners Short Form - Teacher	Teacher completed dimensional measure of ADHD symptoms, with score range from 0-123, and higher scores indicating more severe symptoms.	Baseline, weeks 4, 8
Change in Height	A dimensional measure assessed in centimeters (cm).	Baseline, weeks 4, 8
Change in Weight	A dimensional measure assessed in kilograms (kg).	Baseline, weeks 4, 8
Change in Weiss Functional Impairment Rating Scale	A dimensional rating scale designed to evaluate the extent to which an individual's ability to function is impaired by emotional or behavioral problems, with scores ranging from 0 to 150, and higher scores signifying worse impairment.	Baseline, weeks 4, 8
Change in Child Depression Inventory	A child completed dimensional rating of depressive symptoms, with scores ranging from 0 to 54, with higher scores indicating greater severity of depressive symptoms.	Baseline, weeks 4, 8

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Electroencephalography (EEG)	A laboratory of cortical activity.	Baseline, weeks 4, 8, 16
Change in Attention Network Task - Go/NoGo	A computerized laboratory measure of response inhibition.	Baseline, weeks 4, 8
Change in Behavior Rating Inventory of Executive Functioning (BRIEF)	A parent completed rating of child executive function. Comprises 5 sub scales that measure various measures of behavior and cognition. Raw scores on each measure are converted to T scores ran ging from 28 to 103, with higher scores indicating greater difficulties.	Baseline, weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20
Change in Children's Sleep Habits Questionnaire (CSHQ)	A parent completed 33-item scale to assess sleep related problems. Total scores range from 33 to 99 divided among 8 subscales, with higher scores indicating more severe difficulties.	Baseline, weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20
Change in Happy CaFE	A computerized task of emotional reactivity administered in conjunction with EEG	Baseline, weeks 4, 8

Collaborators and Investigators

• Sponsor: University of California, Los Angeles
• Collaborators: National Institute of Mental Health (NIMH)

Publications and helpful links

General Publications

• McGough JJ, Loo SK, Sturm A, Cowen J, Leuchter AF, Cook IA. An eight-week, open-trial, pilot feasibility study of trigeminal nerve stimulation in youth with attention-deficit/hyperactivity disorder. Brain Stimul. 2015 Mar-Apr;8(2):299-304. doi: 10.1016/j.brs.2014.11.013. Epub 2014 Nov 28.
• McGough JJ, Sturm A, Cowen J, Tung K, Salgari GC, Leuchter AF, Cook IA, Sugar CA, Loo SK. Double-Blind, Sham-Controlled, Pilot Study of Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2019 Apr;58(4):403-411.e3. doi: 10.1016/j.jaac.2018.11.013. Epub 2019 Jan 28.
• Loo SK, Salgari GC, Ellis A, Cowen J, Dillon A, McGough JJ. Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder: Cognitive and Electroencephalographic Predictors of Treatment Response. J Am Acad Child Adolesc Psychiatry. 2021 Jul;60(7):856-864.e1. doi: 10.1016/j.jaac.2020.09.021. Epub 2020 Oct 15.
• McGough JJ, Loo SK, Cook IA. Reply to "Transcutaneous electric currents to target the peripheral and central nervous system in children with attention deficit hyperactivity disorder". Clin Neurophysiol. 2019 Oct;130(10):2008-2009. doi: 10.1016/j.clinph.2019.07.012. Epub 2019 Jul 23. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2022
• Primary Completion (Anticipated): January 31, 2026
• Study Completion (Anticipated): January 31, 2026

Study Registration Dates

• First Submitted: May 9, 2022
• First Submitted That Met QC Criteria: May 12, 2022
• First Posted (Actual): May 16, 2022

Study Record Updates

• Last Update Posted (Estimate): February 21, 2023
• Last Update Submitted That Met QC Criteria: February 17, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Neuromodulation; ADHD; Cognition; EEG; Trigeminal Nerve Stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Attention Deficit Disorder with Hyperactivity
• Other Study ID Numbers: NIHM R01 MH126041-01A1; 1R01MH126041-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The study will be registered on clinicaltrials.gov and all data will be uploaded to the National Database for Clinical Trials (NDCT) related to Mental Illness. Final de-identified data will be uploaded to NDCT databases by the PIs and trained research personnel at the completion of the study. All research data will be redacted to prevent the disclosure of personal identifiers.

All individual participant data collected during the trial will be shared, following de-identification.

• IPD Sharing Time Frame: Beginning 3 months and ending 5 years after study publication.
• IPD Sharing Access Criteria: External investigators will be able to apply for access via an online query system by submitting their affiliations and details of their proposed research.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes