Efficacy of Trigeminal Nerve Stimulation for ADHD

• ClinicalTrials.gov Identifier: NCT05374187
• Recruitment Status: Recruiting
• First Posted: May 16, 2022
• Last Update Posted: February 21, 2023
• Sponsor: University of California, Los Angeles
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): James McGough, University of California, Los Angeles

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Attention-Deficit Hyperactivity Disorder	Device: Active eTNS; Device: Sham eTNS	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 280 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double-blind, sham-controlled
• Primary Purpose: Treatment
• Official Title: Efficacy of External Trigeminal Nerve Stimulation for Treatment of ADHD
• Actual Study Start Date: September 1, 2022
• Estimated Primary Completion Date: January 31, 2026
• Estimated Study Completion Date: January 31, 2026

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Clinical Global Impression - Severity (CGI-S) [ Time Frame: Baseline, weeks 4, 8, 16, 20 ]
   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).
2. Clinical Global Impression - Improvement (CGI-I) [ Time Frame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20 ]
   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).
3. Change in Strengths and Weakness of Attention-Deficit/Hyperactivity (SWAN) Rating Scale [ Time Frame: Baseline, weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20 ]
   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.
4. Change in Conners Short Form - Parent [ Time Frame: Baseline, weeks 4, 8 ]
   Parent completed dimensional measure of ADHD symptoms, with score range from 0-135, and higher scores indicating more severe symptoms.
5. Change in Conners Short Form - Teacher [ Time Frame: Baseline, weeks 4, 8 ]
   Teacher completed dimensional measure of ADHD symptoms, with score range from 0-123, and higher scores indicating more severe symptoms.
6. Change in Height [ Time Frame: Baseline, weeks 4, 8 ]
   A dimensional measure assessed in centimeters (cm).
7. Change in Weight [ Time Frame: Baseline, weeks 4, 8 ]
   A dimensional measure assessed in kilograms (kg).
8. Change in Weiss Functional Impairment Rating Scale [ Time Frame: Baseline, weeks 4, 8 ]
   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.
9. Change in Child Depression Inventory [ Time Frame: Baseline, weeks 4, 8 ]
   A child completed dimensional rating of depressive symptoms, with scores ranging from 0 to 54, with higher scores indicating greater severity of depressive symptoms.

Other Outcome Measures:

1. Change in Electroencephalography (EEG) [ Time Frame: Baseline, weeks 4, 8, 16 ]
   A laboratory of cortical activity.
2. Change in Attention Network Task - Go/NoGo [ Time Frame: Baseline, weeks 4, 8 ]
   A computerized laboratory measure of response inhibition.
3. Change in Behavior Rating Inventory of Executive Functioning (BRIEF) [ Time Frame: Baseline, weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20 ]
   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.
4. Change in Children's Sleep Habits Questionnaire (CSHQ) [ Time Frame: Baseline, weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20 ]
   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.
5. Change in Happy CaFE [ Time Frame: Baseline, weeks 4, 8 ]
   A computerized task of emotional reactivity administered in conjunction with EEG

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Andrea Dillon, Ph.D.; (310) 825-3757; andreadillon@mednet.ucla.edu

Locations

United States, California

University of California, Los Angeles; Recruiting

Los Angeles, California, United States, 90095

Contact: Andrea Dillon, Ph.D. 310-825-3757 andreadillon@mednet.ucla.edu

Principal Investigator: Sandra K. Loo, Ph.D.

Principal Investigator: James J. McGough, M.D.

United States, Washington

Seattle Children's Hospital; Recruiting

Seattle, Washington, United States, 98105

Contact: Joanna Yuan, Ph.D. 206-884-1761 joanna.yuan@seattlechildrens.org

Principal Investigator: Mark Stein, Ph.D.

Sponsors and Collaborators

University of California, Los Angeles

National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Sandra K. Loo, Ph.D.; University of California, Los Angeles
• Principal Investigator: James J. McGough, M.D.; University of California, Los Angeles
• Principal Investigator: Mark A. Stein, Ph.D.; Seattle Children's Hospital

More Information

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.

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.

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.

• Responsible Party: James McGough, Professor of Clinical Psychiatry, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT05374187
• Other Study ID Numbers: NIHM R01 MH126041-01A1; 1R01MH126041-01A1 ( U.S. NIH Grant/Contract )
• First Posted: May 16, 2022
• Last Update Posted: February 21, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

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.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Beginning 3 months and ending 5 years after study publication.
• 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.

• 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

Keywords provided by James McGough, University of California, Los Angeles:

ADHD; Neuromodulation; Trigeminal Nerve Stimulation; Cognition; EEG

Additional relevant MeSH terms:

Attention Deficit Disorder with Hyperactivity; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders