Efficacy of Trigeminal Nerve Stimulation for ADHD

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Efficacy of External Trigeminal Nerve Stimulation for Treatment of ADHD

Conditions
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Attention-Deficit Hyperactivity Disorder

Intervention / Treatment
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* Device: Active eTNS
* Device: Sham eTNS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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; total score >= 24 on baseline ADHD-RS; CGI-S score at baseline >= 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; parents able and willing to monitor proper use of the stimulation device and complete all required rating scales; estimated Full Scale IQ >= 80 based on WASI subtests; parent and participant able to complete rating scales and other measures in English; able to cooperate during EEG Exclusion Criteria: impaired functioning to a degree that requires immediate initiation of ADHD medication in the opinion of the parents and/or investigator; current diagnosis of autism spectrum disorder or major depression; history of lifetime psychosis, mania, or seizure disorder; baseline suicidality; history of seizure disorder or head injury with loss of consciousness

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active eTNS<br>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<br>* 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.<br>* Other names: Monarch eTNS SystemTM (NeuroSigma, Inc., Los Angeles, CA;|
| Sham Comparator: Sham eTNS<br>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<br>* 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.<br>* Other names: Monarch eTNS SystemTM (NeuroSigma, Inc., Los Angeles, CA;Device: Sham eTNS<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EEG, ADHD, Neuromodulation, Trigeminal Nerve Stimulation, Cognition