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Efficacy of Trigeminal Nerve Stimulation for ADHD

Primary Purpose

Attention-Deficit Hyperactivity Disorder

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Active eTNS
Sham eTNS
Sponsored by
University of California, Los Angeles
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Attention-Deficit Hyperactivity Disorder focused on measuring ADHD, Neuromodulation, Trigeminal Nerve Stimulation, Cognition, EEG

Eligibility Criteria

7 Years - 12 Years (Child)All SexesDoes not accept healthy volunteers

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. minimum scores of 12 on both the inattentive and hyperactive/impulsive subscales of the 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

Sites / Locations

  • University of California, Los AngelesRecruiting
  • Seattle Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Active eTNS

Sham eTNS

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).
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 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.
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.
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.
Change in Height
A dimensional measure assessed in centimeters (cm).
Change in Weight
A dimensional measure assessed in kilograms (kg).
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.
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.

Full Information

First Posted
May 9, 2022
Last Updated
February 17, 2023
Sponsor
University of California, Los Angeles
Collaborators
National Institute of Mental Health (NIMH)
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1. Study Identification

Unique Protocol Identification Number
NCT05374187
Brief Title
Efficacy of Trigeminal Nerve Stimulation for ADHD
Official Title
Efficacy of External Trigeminal Nerve Stimulation for Treatment of ADHD
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 1, 2022 (Actual)
Primary Completion Date
January 31, 2026 (Anticipated)
Study Completion Date
January 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, Los Angeles
Collaborators
National Institute of Mental Health (NIMH)

4. Oversight

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
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Attention-Deficit Hyperactivity Disorder
Keywords
ADHD, Neuromodulation, Trigeminal Nerve Stimulation, Cognition, EEG

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double-blind, sham-controlled
Allocation
Randomized
Enrollment
280 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Active eTNS
Arm Type
Experimental
Arm Description
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.
Arm Title
Sham eTNS
Arm Type
Sham Comparator
Arm Description
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.
Intervention Type
Device
Intervention Name(s)
Active eTNS
Other Intervention Name(s)
Trigeminal Nerve Stimulation, Monarch eTNS SystemTM (NeuroSigma, Inc., Los Angeles, CA
Intervention Description
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.
Intervention Type
Device
Intervention Name(s)
Sham eTNS
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in ADHD Rating Scale-5 (ADHD-RS-5)
Description
A dimensional rating of ADHD symptoms, with scores ranging from 0-54, and higher scores indicating worse outcomes.
Time Frame
Baseline, weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20
Secondary Outcome Measure Information:
Title
Clinical Global Impression - Severity (CGI-S)
Description
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).
Time Frame
Baseline, weeks 4, 8, 16, 20
Title
Clinical Global Impression - Improvement (CGI-I)
Description
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).
Time Frame
Weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20
Title
Change in Strengths and Weakness of Attention-Deficit/Hyperactivity (SWAN) Rating Scale
Description
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.
Time Frame
Baseline, weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20
Title
Change in Conners Short Form - Parent
Description
Parent completed dimensional measure of ADHD symptoms, with score range from 0-135, and higher scores indicating more severe symptoms.
Time Frame
Baseline, weeks 4, 8
Title
Change in Conners Short Form - Teacher
Description
Teacher completed dimensional measure of ADHD symptoms, with score range from 0-123, and higher scores indicating more severe symptoms.
Time Frame
Baseline, weeks 4, 8
Title
Change in Height
Description
A dimensional measure assessed in centimeters (cm).
Time Frame
Baseline, weeks 4, 8
Title
Change in Weight
Description
A dimensional measure assessed in kilograms (kg).
Time Frame
Baseline, weeks 4, 8
Title
Change in Weiss Functional Impairment Rating Scale
Description
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.
Time Frame
Baseline, weeks 4, 8
Title
Change in Child Depression Inventory
Description
A child completed dimensional rating of depressive symptoms, with scores ranging from 0 to 54, with higher scores indicating greater severity of depressive symptoms.
Time Frame
Baseline, weeks 4, 8
Other Pre-specified Outcome Measures:
Title
Change in Electroencephalography (EEG)
Description
A laboratory of cortical activity.
Time Frame
Baseline, weeks 4, 8, 16
Title
Change in Attention Network Task - Go/NoGo
Description
A computerized laboratory measure of response inhibition.
Time Frame
Baseline, weeks 4, 8
Title
Change in Behavior Rating Inventory of Executive Functioning (BRIEF)
Description
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.
Time Frame
Baseline, weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20
Title
Change in Children's Sleep Habits Questionnaire (CSHQ)
Description
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.
Time Frame
Baseline, weeks 1, 2, 3, 4, 5, 6, 7, 8, 16, 20
Title
Change in Happy CaFE
Description
A computerized task of emotional reactivity administered in conjunction with EEG
Time Frame
Baseline, weeks 4, 8

10. Eligibility

Sex
All
Minimum Age & Unit of Time
7 Years
Maximum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Andrea Dillon, Ph.D.
Phone
(310) 825-3757
Email
andreadillon@mednet.ucla.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sandra K. Loo, Ph.D.
Organizational Affiliation
University of California, Los Angeles
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
James J. McGough, M.D.
Organizational Affiliation
University of California, Los Angeles
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mark A. Stein, Ph.D.
Organizational Affiliation
Seattle Children's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andrea Dillon, Ph.D.
Phone
310-825-3757
Email
andreadillon@mednet.ucla.edu
First Name & Middle Initial & Last Name & Degree
Sandra K. Loo, Ph.D.
First Name & Middle Initial & Last Name & Degree
James J. McGough, M.D.
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joanna Yuan, Ph.D.
Phone
206-884-1761
Email
joanna.yuan@seattlechildrens.org
First Name & Middle Initial & Last Name & Degree
Mark Stein, Ph.D.

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
PubMed Identifier
25533244
Citation
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.
Results Reference
background
PubMed Identifier
30768393
Citation
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.
Results Reference
background
PubMed Identifier
31377119
Citation
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.
Results Reference
background
PubMed Identifier
33068751
Citation
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.
Results Reference
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Efficacy of Trigeminal Nerve Stimulation for ADHD

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