Predictors of Improvements in Irritability and Aggression in Children With ADHD Treated With CNS Stimulants

NCT06871488 | Recruiting Phase 4 DMC FDA Drug

• 1 other identifier: MH137647
• Study Type: interventional
• Target: 136
• Locations: 1 country
• Sites: 1

Brief Summary

Impulsive Aggression and chronic irritability (IACI) often occur together and are one of the most common reasons children present for behavioral health (BH) care. ADHD frequently associated with IACI as upwards of 50% of youth with ADHD manifest impairing IACI levels. IACI is the most common reason that children with ADHD are prescribed antipsychotics and admitted to inpatient BH units. Systematic dose optimization of CNS stimulants improves levels of IACI, reducing the need for these more intensive and burdensome treatments. However, response varies, with over half of children with ADHD showing meaningful improvement, upwards of 40% receiving minimal benefit and 3 to 10% exhibiting increased IACI levels. Symptom levels of ADHD or IACI and other demographic variables are of limited utility for predicting response, suggesting the need to move beyond symptoms in the search for treatment predictors. Youth with ADHD and IACI struggle with multiple aspects reinforcement learning (RL), defined as learning from interactions with the environment to reach a goal. Successful RL efforts tap multiple cognitive functions. In controlled laboratory tasks, youth with IACI and various BH disorders exhibit excessive behavioral and neural response to receiving reward (reward responsiveness), difficulty processing environmental cues to adapt behavior to meet a goal (set shifting/goal updating) and impaired ability to flexibly attend to relevant stimuli when blocked from a goal (frustrative nonreward). Event related potentials (ERP) are small electrical responses in the brain in response to specific events or stimuli measured by electroencephalogram (EEG) testing. ERPs exist that can serve as established neural measures of each of these cognitive functions offering a child friendly means to assess their contribution to observable levels of IACI. CNS stimulants improve functioning in these specific realms and impact associated ERPs to the degree that differences between ADHD and non-ADHD youth disappear. This study will examine the capacity of these ERPs to predict levels of IACI exhibited by children with ADHD when at home. Investigators will then assess if variability across children in the capacity of CNS stimulants to impact RL associated ERPs accounts for differences in the clinical effects of CNS stimulant medications to improve IACI at home using a multimethod battery integrating ERPs, parent report and task performance. Specifically, investigators will examine variance in the reward positivity (RewP) ERP when receiving reward feedback, the switch positivity (SwP) ERP measuring mental effort when cued to shift set and the change in P3b amplitude measuring attention allocation when transitioning from reward to nonreward on a go-no-go task. To achieve these aims, 136 children with ADHD and elevated IACI levels will have their CNS stimulant dose optimized over six weeks and then complete a two week within subjects crossover trial of placebo versus optimal dose. ERP collection will be completed within each blinded week. Parent ratings will be gathered 3 times per day including during peak and off-peak times of medication efficacy to capture the variance in IACI levels within the day and disentangle reports of worsening IACI related to loss of previously beneficial medication effects versus those most likely related to a direct adverse response to medication.

Conditions

Irritability; Aggression Childhood; ADHD - Attention Deficit Disorder With Hyperactivity

Keywords

ADHD; CNS Stimulants; Irritability; Aggression

Outcome Measures

Primary Outcomes (3)

• RCT phase: Guardian rated Affective reactivity Index (ARI)

  Thus study examines response markers for CNS stimulants to improve irritability and to improve aggression. For this second treatment phase comprised of the within subjects crossover of optimal med vs placebo, the primary outcome for irritability is the drug placebo difference in the guardian rated Affective Reactivity Index collected for 7 days over the blinded within subjects crossover phase. ARI has 6 items rated 0-2 for range of - to 14 with higher scores representing greater irritability levels. drug placebo difference on this measure will be correlated with drug placebo difference for RewP, P3b and switch positivity ERP

  7 days on med and for 7 days on placebo for 14 days of data collection

• Open label dose opt: ADHD RS 5 clinician interview

  For the first treatment phase (open label dose optimization) the primary outcome is the change in ADHD symptoms as measured by clinician interview using the ADHD RS 5. it has 18 items rates 0-3 with more symptoms reflecting higher scores. will measure change over time with drug;

  6 visits (over a max duration of 12 weeks)

• RCT phase abridged Revised modified overt aggression scale (RMOAS)

  The primary rating for aggression is the drug placebo difference in the guardian rated abridged (6 reduced to 6 items) Retrospective Modified Overt Aggression Scale (RMOAS) collected for 7 days over the blinded within subjects crossover phase. The RMOAS abridged version has 6 items rated 0-3 with higher scores equating to greater levels of aggression ; drug placebo difference on this measure will be correlated with drug placebo difference for RewP, P3b and switch positivity ERP

  7 days on med and 7 days on placebo for 14 days of data collection

Secondary Outcomes (26)

• Open label dose opt: affective reactivity index -guardians (ARI)

  every visit (every 1-2 weeks over max of 12 weeks)

• Open label dose opt: affective reactivity index teachers (ARI)

  every visit (every 1-2 weeks over max of 12 weeks)

• Open label dose opt: RMOAS by guardians

  every visit (every 1-2 weeks over max of 12 weeks)

• Open label dose opt: RMOAS by teachers

  every visit (every 1-2 weeks over max of 12 weeks)

• Columbia Suicide Severity Rating Scale (CSSRS)

  every visit (every 1-2 weeks over max of 12 weeks)

Study Arms (3)

Blinded optimal dose (phase two)

ACTIVE COMPARATOR

In this second treatment phase of the study, all participants will receive under blinded conditions their optimal dose of CNS stimulant from the prior phase for a total of 7 days

Drug: CNS Stimulant

Placebo (phase two)

PLACEBO COMPARATOR

In this second treatment phase of the study, all participants will receive placebo under blinded conditions for a total of 7 days

Drug: Placebo

open label dose optimization (phase one)

EXPERIMENTAL

In this first treatment phase, all participants will have their dose of CNS Stimulant optimized over 6 visits under open label conditions. This arm will use any FDA approved CNS stimulant for pediatric ADHD at their approved dose. By the end of this phase, the optimal dose for the next phase will be identified.

Other: CNS Stimulant open label first phase

Interventions

Placebo DRUG

Placebo is only used during the second of two treatment phases. The second treatment phase (blinded within subjects crossover) will compare one week of the optimal dose of CNS Stimulant (from the prior phase) to one week of placebo.

Placebo (phase two)

CNS Stimulant DRUG

The second treatment phase (blinded within subjects crossover) will compare one week of the optimal dose of CNS Stimulant (from the prior phase) to one week of placebo for a total of 14 days of data collection.

Also known as: CNS Simulant RCT phase (second phase)

Blinded optimal dose (phase two)

CNS Stimulant open label first phase OTHER

The first treatment phase will optimize CNS stimulant dose under open label conditions using any approved FDA medication for pediatric ADHD at the FDA approved doses.

open label dose optimization (phase one)

Eligibility Criteria

• Age: 7 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Meet criteria for any presentation of ADHD
• Moderate or worse impairment related to ADHD
• Elevated levels of irritability and/or aggression on guardian ratings of Affective Reactivity Index and Retrospective Modified Overt Aggression Scale
• fluent in English for child and guardian
• Guardian and child are willing to have child take CNS stimulant medication for ADHD

You may not qualify if:

• Medical contraindications to use of CNS stimulants
• Autism Spectrum Disorder,
• Bipolar Disorder,
• Intellectual/Developmental Delay
• current use of antipsychotic, mood stabilizing
• Use of other medications that impact EEG data collection (e.g. benzodiazepenes)
• hearing or visual deficits that impede ability to do computer tasks
• Current Major Depressive Episode
• Current suicidal ideation
• child has failed two fully optimized trials of methylphenidate products AND two for amphetamine products

Sponsors & Collaborators

• Milton S. Hershey Medical Center: lead

Study Sites (1)

Penn State Health Dept of Psychiatry

Hershey, Pennsylvania, 17033, United States

RECRUITING

MeSH Terms

Conditions

Attention Deficit Disorder with Hyperactivity; Aggression

Interventions

Central Nervous System Stimulants; Clinical Trials, Phase II as Topic

Condition Hierarchy (Ancestors)

Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders; Aberrant Motor Behavior in Dementia; Behavioral Symptoms; Behavior; Social Behavior

Intervention Hierarchy (Ancestors)

Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Central Nervous System Agents; Therapeutic Uses; Clinical Trials as Topic; Clinical Studies as Topic; Epidemiologic Study Characteristics; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Central Study Contacts

James G Waxmonsky, MD

CONTACT

1-800-243-1455; jwaxmonsky@pennstatehealth.psu.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: the child participants primary school teacher (secondary outcomes assessor)
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Psychiatry

Model Details: two phases- first is single group open label to identify optimal dose followed by blinded randomized within subjects crossover design of optimal dose vs placebo for each participant

Study Record Dates

• First Submitted: February 14, 2025
• First Posted: March 12, 2025
• Study Start: March 5, 2026
• Primary Completion (Estimated): February 28, 2030
• Study Completion (Estimated): June 30, 2030
• Last Updated: April 20, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: consistent with policies for NIMH Data archive, dependent on notice of award date
• Access Criteria: as per policies of the NIMH Data archive

Locations

US (1)