Clinical trial NCT05650775: Biomarkers of ADHD Treatment Response
Official title: Biomarkers of ADHD Treatment Response
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: ADHD
Keywords: Electroencephalography
ADHD
Event related potentials
Stimulants
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
First posted: 2022-12-14
Enrollment: 16
Sex: ALL
Minimum age (years): 7
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This is a sequential partial-crossover design. All participants will complete the Baseline visit, the methylphenidate trial, and a follow-up lab visit. Participants with \< 30% symptom improvement on methylphenidate will then complete a 1-2 week washout, followed by a trial of mixed amphetamine salts and a second follow-up lab visit.
Primary purpose: TREATMENT

Brief summary: The goal of this translational biomarker study is to use electroencephalography (EEG) to identify brain signatures that will predict a child's response to two of the most commonly prescribed ADHD medications, methylphenidate and mixed amphetamine salts. The main questions the investigators aim to answer are:

1. Do children with ADHD who show symptom reduction with methylphenidate have different EEG profiles than children who do not respond well to methylphenidate?
2. Do children who respond better to mixed amphetamine salts than to methylphenidate have unique EEG profiles?

The investigators will measure brain activity before the participating children have tried any stimulant medications, and then again after a 3-week trial of Concerta (methylphenidate). Participants who do not show significant symptom improvement on Concerta will then complete a 3-week trial of Adderall (mixed amphetamine salts), and the study will measure brain activity while those children are on the best dose of Adderall. The investigators will collect information from the child, caregivers, and teachers each week to measure ADHD symptom improvement and side effects. This study will therefore follow the typical treatment approach used in the Boston Children's Hospital Developmental Medicine Clinic, but the investigators will add measures of brain functioning before and after medication.

Detailed description: Attention deficit hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder associated with psychiatric, social, academic, occupational, and health impairments across the lifetime. Although pharmacological interventions for pediatric ADHD are safe and effective, there is considerable variability in treatment response at the individual level. As a result, identification of optimal medication class and dose is often not attained in community clinical settings. The current application constitutes a translational biomarkers study aimed at identifying electroencephalography (EEG) and event related potential (ERP) biomarkers of preferential response to two commonly prescribed psychostimulants among children with ADHD. The results of this investigation will improve understanding of individual differences in neurobiological mechanisms of ADHD and provide preliminary data for a large-scale clinical trial aimed at developing a precision medicine care model for pharmacological treatment of ADHD.

With the support of the Translational Neuroscience Center Clinical Research Operations services and in collaboration with the Boston Children's Hospital Primary Care Center (CHPCC), the investigators will execute a sequential crossover design study examining pre-treatment EEG and ERP biomarkers of response to methylphenidate (MPH; Concerta) among all children and to mixed amphetamine salts (MAS; Adderall-XR) among children with suboptimal response to MPH. Additional pre- and post-treatment assessments will be integrated with standard clinical care provided by Dr. Chan (co-PI) in the Division of Developmental Medicine. The study will recruit 30 stimulant-treatment-naïve children with ADHD, ages 7-11, from the CHPCC. Additionally, analyses will capitalize on Dr. Arnett's (co-PI) existing EEG/ERP data on 40 typically developing (TD) children in the same age range to maximize power for statistical comparisons.

The investigators hypothesize that, consistent with Dr. Arnett's prior work, the EEG and ERP profiles will differentiate children with positive response to MPH versus preferential response to MAS. Specifically, the investigators hypothesize that MPH responders will have reduced P3 ERP amplitude and normal aperiodic spectral slope, while MAS preferential responders will have normal P3 amplitude and flatter aperiodic spectral slope. The investigators expect that slow individual alpha peak will be associated with reduced response to both MPH and MAS, as suggested by prior literature. Additionally, the investigators hypothesize that at optimal dosing, treatment-related change in EEG/ERP biomarkers will be associated with ADHD symptom improvement; this will indicate that individual differences in psychostimulant response reflect individual differences in the neurobiological etiology of ADHD symptoms.

The results of this pilot study will support application for federal funding for a large-scale clinical trial. The long-term outcomes of this line of research stand to benefit children and families with ADHD, as well as children with other primary diagnoses commonly associated with ADHD (e.g., autism spectrum disorder; genetic syndromes). Moreover, differences in neurophysiological correlates of differential stimulant response have potential to increase our knowledge of neural mechanisms underlying psychostimulant medication effects.

Eligibility criteria: Inclusion Criteria:

* Pediatric patients ages 7-11 seen at the Children's Hospital Primary Care Center
* Have a diagnosis of ADHD or referred for an ADHD evaluation
* Have not previously trialed stimulant medication

Exclusion Criteria:

* Diagnoses of intellectual disability, autism, prior suicide attempt, current psychotropic medication use, known genetic syndrome, color-blindness
* History of nonfebrile seizures
* Gestational age \< 32 weeks
* Prenatal alcohol or substance exposure
* Medical conditions that contraindicate psychostimulant use (e.g., cardiac concerns).

Primary outcomes:
measure: Change in ADHD Symptom Severity from Baseline to End of Concerta Trial
timeFrame: Baseline and Concerta Trial Week 3
measure: Change in ADHD Symptom Severity from Baseline to End of Adderall-XR Trial
timeFrame: Baseline and Adderall-XR Trial Week 3
measure: Clinical Global Impressions-Improvement (CGI-I) in ADHD-related impairment on Concerta
timeFrame: Concerta Trial Week 3
measure: Clinical Global Impressions-Improvement (CGI-I) in ADHD-related impairment on Adderall-XR
timeFrame: Adderall-XR Trial Week 3
measure: Long-Term Clinical Global Impressions-Improvement (CGI-I) in ADHD-related impairment
timeFrame: 3 Months After Trial Completion
measure: Long-Term Clinical Global Impressions-Improvement (CGI-I) in ADHD-related impairment
timeFrame: 6 Months After Trial Completion
measure: Baseline EEG Resting Aperiodic Slope
timeFrame: Baseline
measure: Baseline EEG Resting Alpha Peak Frequency
timeFrame: Baseline
measure: Baseline EEG Novelty P3 Amplitude
timeFrame: Baseline
measure: Baseline EEG Cued P3 Amplitude
timeFrame: Baseline
measure: Change in EEG Resting Aperiodic Slope on Concerta
timeFrame: Baseline and Post-Concerta Trial
measure: Change in EEG Alpha Peak Frequency on Concerta
timeFrame: Baseline and Post-Concerta Trial
measure: Change in Novelty P3 ERP Amplitude on Concerta
timeFrame: Baseline and Post-Concerta Trial
measure: Change in Cued P3 ERP Amplitude on Concerta
timeFrame: Baseline and Post-Concerta Trial
measure: Change in EEG Resting Aperiodic Slope on Adderall-XR
timeFrame: Baseline and Post-Adderall-XR Trial
measure: Change in EEG Alpha Peak Frequency on Adderall-XR
timeFrame: Baseline and Post-Adderall-XR Trial
measure: Change in Novelty P3 ERP Amplitude on Adderall-XR
timeFrame: Baseline and Post-Adderall-XR Trial
measure: Change in Cue P3 ERP Amplitude on Adderall-XR
timeFrame: Baseline and Post-Adderall-XR Trial
Secondary outcomes:
measure: Medication Tolerance to Concerta
timeFrame: Post-Concerta Trial
measure: Medication Tolerance to Adderall-XR
timeFrame: Post-Adderall-XR Trial
measure: Change in Tests of Variables of Attention (TOVA) Commission errors on Concerta
timeFrame: Baseline and Post-Concerta Trial
measure: Change in Tests of Variables of Attention (TOVA) Commission errors on Adderall-XR
timeFrame: Baseline and Post-Adderall-XR Trial
measure: Tests of Variables of Attention (TOVA) Response Time on Concerta
timeFrame: Baseline and Post-Concerta Trial
measure: Tests of Variables of Attention (TOVA) Response Time on Adderall-XR
timeFrame: Baseline and Post-Adderall-XR Trial
measure: Tests of Variables of Attention (TOVA) Omission Errors on Concerta
timeFrame: Baseline and Post-Concerta Trial
measure: Tests of Variables of Attention (TOVA) Omission Errors on Adderall-XR
timeFrame: Baseline and Post-Adderall-XR Trial
measure: Tests of Variables of Attention (TOVA) Variability in Response Time on Concerta
timeFrame: Baseline and Post-Concerta Trial
measure: Tests of Variables of Attention (TOVA) Variability in Response Time on Adderall-XR
timeFrame: Baseline and Post-Adderall-XR Trial
measure: Change in Internalizing Symptoms
timeFrame: Baseline & 3 months after trial completion
measure: Long-term Change in Internalizing Symptoms
timeFrame: Baseline & 6 months after trial completion
measure: Change in Externalizing Symptoms
timeFrame: Baseline and 3 months after trial completion
measure: Long-term Change in Externalizing Symptoms
timeFrame: Baseline and 6 months after trial completion
Other outcomes:
Locations:
city: Brookline
country: United States
facility: 2 Brookline Place
state: Massachusetts
Study officials:
affiliation: Boston Children's Hospital
name: Anne B Arnett, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital
name: Eugenia Chan, MD
role: PRINCIPAL_INVESTIGATOR
References: