Trigeminal Nerve Stimulation for ADHD

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to develop external Trigeminal Nerve Stimulation (eTNS) as a potential nonmedication treatment for attention-deficit/hyperactivity disorder (ADHD). Study hypothesis address potential differences over 4 weeks of active vs. sham eTNS treatment on ADHD symptoms, measures of executive function, electroencephalography (EEG) profiles, other dimensional measures of height, weight, mood, anxiety, and sleep, and side effect profiles.

Detailed Description
-----------------
This three-year developmental study is a double-blind randomized trial of active vs. inactive sham eTNS for ADHD, with four weeks acute treatment followed by an additional one week of clinical observation and testing after treatment cessation. The study will enroll 85-90 participants aged 8-12 years to achieve a completion target of N=36 for each study condition (total final N = 72). Participants will meet Diagnostic and Statistical Manual-5 (DSM-5) criteria for ADHD, any current presentation, as established by the Behavior Disorders Module of the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-PL) and clinical interview. Other screening procedures include measures of ADHD symptom severity, other behavioral ratings, and cognitive assessments. Once inclusion/exclusion criteria have been reviewed and verified, participants in Phase 1A will have a pre-treatment visit to establish behavioral and cognitive baseline ratings and to obtain an EEG. Participants and parents will be instructed in the use of eTNS, and participants will begin use of the eTNS as directed during sleep each night. Participants will be randomized 1:1 to active or inactive sham eTNS. Participants, families, and most of the study team will remain blind to treatment assignment. Participants will have weekly assessments over the five-week study to assess behavioral, cognitive, and brain activation change and to monitor safety, tolerability, and compliance. Weekly ratings will be obtained from a parent, teacher, and clinician investigator. EEG will occur at baseline, end of treatment (week 4). In Phase 1B, all participants remain blinded for one week after cessation of the intervention and return for a final visit to assess residual effects of eTNS therapy vs. sham.

Official Title
-----------------
Developmental Pilot Study of External Trigeminal Nerve Stimulation for ADHD

Conditions
-----------------
Attention Deficit Hyperactivity Disorder (ADHD)

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: male and female children ages 8 to 12 years with DSM-5 ADHD, any current presentation, as determined by KSADS and clinical interview minimum scores of 12 on both the inattentive and hyperactive/impulsive subscales of the baseline ADHD-RS CGI-S score at baseline ≥ 4 no current medication with CNS effects parents able and willing to monitor proper use of the stimulation device and complete all required rating scales estimated Full Scale IQ ≥ 85 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, seizure disorder or head injury with loss of consciousness baseline suicidality

Ages Eligible for Study
-----------------
Minimum Age: 8 Years
Maximum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. | Device: Active eTNS<br>* Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open 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 randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. | Device: Sham eTNS<br>* Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly eTNS in a 12 month extension period.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ADHD-IV Rating Scale (ADHD-RS) | A dimensional rating of ADHD symptoms, with scores ranging from 0 - 54, and higher scores indicating greater symptom severity. | Change over baseline and weeks 1, 2, 3, 4 and 5. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Change over weeks 1, 2, 3, 4, and 5 compared with baseline. | 
| Conners Global Index - Parent Report | Parent completed dimensional measure of ADHD symptoms, with score range from 0- 30, and higher scores indicating more severe symptoms. | Change over baseline and weeks 1, 2, 3, 4, 5. | 
| Affective Reactivity Index (ARI) - Child | A child completed dimensional measure of emotional reactivity, with scores ranging from 0-12, and higher scores indicating greater severity. | Change over baseline and weeks 4 and 5. | 
| Affective Reactivity Index (ARI) - Parent Report | A parent completed dimensional measure of emotional reactivity, with scores ranging from 0-12, and higher scores indicating greater severity. | Change over baseline and weeks 4 and 5. | 
| Multidimensional Anxiety Scale for Children (MASC) - Child Report | A child completed rating of child anxiety, with scores ranging from 0-300, and higher scores indicating greater severity. | Change over baseline and weeks 4 and 5. | 
| Multidimensional Anxiety Scale for Children (MASC) - Parent Report | A parent completed rating of child anxiety, with scores ranging from 0-300, and higher scores indicating greater severity. | Change over baseline and weeks 4 and 5. | 
| Height | A dimensional measure assessed in centimeters (cm). | Change over baseline and weeks 1, 4, and 5. | 
| Weight | A dimensional measure assessed in kilograms (kg). | Change over baseline and weeks 1, 4, and 5. | 
| Systolic Blood Pressure | A dimensional measure expressed in mm mercury (Hg). | Change over baseline and weeks 1, 4, and 5. | 
| Diastolic Blood Pressure | A dimensional measure assessed in mm mercury (Hg). | Change over baseline and weeks 1, 4, and 5. | 
| Pulse | Heart rate in beats per minute (bpm). | Change over baseline and weeks weeks 1, 4, and 5. | 
| Children's Depression Inventory (CDI) | A child completed self-report dimensional measure of depressive symptoms, with range of scores from 0 to 54. Higher scores reflect increasing depression. Cutoff scores < 17 to 20 are generally considered to be in the normative range. A score of 36 or higher reflects a relatively severe depression. | Change over baseline and weeks 4 and 5. | 
| Conners Global Index - Teacher | Teacher completed dimensional measure of ADHD symptoms, with scores ranging from 0-30, and higher scores indicating more severe symptoms. | Change over baseline and weeks 1, 2, 3, 4, 5. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ADHD, neuromodulation, trigeminal nerve stimulation, cognition