Exploratory fMRI Study on the Treatment for Impulsive Aggression in Children With ADHD

NCT03638466 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: 810P204
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 3

Brief Summary

The purpose of this study was to evaluate the effect of 4-week SPN-810 treatment on brain functioning in patients aged 8-12 years with ADHD and associated feature of impulsive aggression (IA). This was achieved using functional magnetic resonance imaging (fMRI) in conjunction with the point subtraction aggression paradigm (PSAP) Task, a behavioral aggression paradigm in which subjects are provoked by having money indirectly taken from them by a fictitious opponent, simulating an aggression response.

Conditions

Attention Deficit Hyperactivity Disorder (ADHD); Impulsive Aggression

Outcome Measures

Primary Outcomes (3)

• Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task

  The primary endpoint was the aggression-related change in the whole brain in BOLD signal fMRI contrast in response to the PSAP task. BOLD fMRI contrast (neural activation) investigates brain activity by measuring the change in blood oxygenation. Change in brain activity was measured by a change in BOLD response in brain regions during the aggressive response relative to the monetary response, where the aggression was defined as the number of Option 2 presses (aggressive response) divided by the total number of button presses and the number of provocations. Change of aggression-related MRI signal was acquired at baseline and 4 weeks after SPN-810 treatment. A positive number represents an increase in activity. Region of interest is described by the location of the peak value and described by Montreal Neurological Institute (MNI) X, Y, Z coordinates. Data represent the post-treatment minus baseline change in BOLD contrast Aggressive Response\> Monetary Response.

  Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.

• Provocation Event - Related Change in the Whole Brain in BOLD Signal fMRI Contrast in Response to the PSAP Task

  BOLD (blood oxygenation level-dependent) fMRI contrast (neural activation) investigates brain activity by measuring the change in blood oxygenation. It was collected during the PSAP behavioral task while playing the game: the participants play a computer game in which they can steal points (simulating an aggressive behavior) or have points stolen by the opponent (provocation event) by pressing Option 1, 2 or 3 on a keypad a set number of times to achieve a specific outcome. A positive number represents an increase in activity. The region of interest is described by the location of the peak value within that cluster and described by Montreal Neurological Institute (MNI) X, Y, and Z coordinates. Data represent the post-treatment minus baseline change in BOLD contrast Provocation Event \>Monetary Response.

  Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.

• Effect of SPN-810 on the Aggressions Score

  The Point Subtraction Aggression Paradigm (PSAP) is a behavioral aggression paradigm consisting of a computer game in which each participant plays against a computer to earn points. The subject can steal points (i.e., aggressive behavior) or have points stolen by the opponent (i.e., provocation). The subject can press 1 of 3 buttons on a keypad a set number of times. By pressing the button for Option 1, 100 times, the subject will earn a point; pressing the button for Option 2, 20 consecutive times is the "aggression" action that results in stealing a point from the opponent; pressing Option 3, 20 times protects the subject from the opponent's attempt to steal points (i.e., money). The aggression score is averaged across two sessions and calculated as the number of Option 2 button presses divided by the sum of total button presses and the number of provocation events received, with a range minimum = 1, maximum = 143. The higher scores reflect increased aggression.

  Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.

Secondary Outcomes (1)

• Effect of SPN-810 on GABA and Glutamate Levels Using Magnetic Resonance Spectroscopy (MRS)

  Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.

Other Outcomes (3)

• Effect of SPN-810 on Impulsive Aggression Measured by the Clinical Global Impression-Severity (CGI-S) Scale

  From Visit 1 (Day -30) to two time points: Visit 4 (Day 21) and Visit 6 (Day 35).

• Effect of SPN-810 on Impulsive Aggression Measured by the Clinical Global Impression-Improvement (CGI-I) Scale

  Visit 4 (Day 21) and Visit 6 (Day 35), for a total of 2 weeks.

• Effect of SPN-810 on the Retrospective-Modified Overt Aggression Scale (R-MOAS) Score

  Visit 1 (Day -30) to Visit 4 (Day 21) and Visit 6 (Day 35).

Study Arms (2)

High dose SPN-810 (36 mg)

ACTIVE COMPARATOR

Subjects were randomized to receive SPN-810 18 mg twice a day twice each day with and without food, in addition to the stable dose of the optimized ADHD medication.

Diagnostic Test: Functional Magnetic Resonance Imaging (fMRI); Diagnostic Test: Magnetic Resonance Spectroscopy (MRS); Behavioral: Point Subtraction Aggression Paradigm (PSAP) Task; Drug: SPN-810

Placebo

PLACEBO COMPARATOR

Subjects were randomized to receive Placebo twice a day twice each day with and without food, in addition to the stable dose of the optimized ADHD medication.

Diagnostic Test: Functional Magnetic Resonance Imaging (fMRI); Diagnostic Test: Magnetic Resonance Spectroscopy (MRS); Behavioral: Point Subtraction Aggression Paradigm (PSAP) Task; Drug: Placebo

Interventions

Functional Magnetic Resonance Imaging (fMRI) DIAGNOSTIC_TEST

Neural brain activity measured by fMRI

High dose SPN-810 (36 mg); Placebo

Magnetic Resonance Spectroscopy (MRS) DIAGNOSTIC_TEST

Glutamate and GABA levels measured by MRS

High dose SPN-810 (36 mg); Placebo

Point Subtraction Aggression Paradigm (PSAP) Task BEHAVIORAL

Aggression score measured by the PSAP task

High dose SPN-810 (36 mg); Placebo

SPN-810 DRUG

Treatment of SPN-810 (36 mg) on neuronal brain activity, GABA and Glutamate levels and on the aggression score

High dose SPN-810 (36 mg)

Placebo DRUG

Treatment of placebo on neuronal brain activity, GABA and Glutamate levels and on the aggression score

Placebo

Eligibility Criteria

• Age: 8 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Otherwise healthy male or female subjects, aged 8-12 years, inclusive, at the time of screening with primary diagnosis of ADHD and currently receiving monotherapy treatment with an optimized US Food and Drug Administration (FDA)-approved ADHD medication.
• Impulsive aggression (IA) confirmed at screening using the R-MOAS and the Vitiello Aggression Scale.

You may not qualify if:

• Current or lifetime diagnosis of epilepsy, major depressive disorder, bipolar disorder, schizophrenia or related disorder, personality disorder, Tourette's disorder, fetal alcohol syndrome, or psychosis not otherwise specified.
• Currently meeting DSM criteria for autism spectrum disorder, pervasive developmental disorder, obsessive-compulsive disorder, post-traumatic stress disorder.
• Known or suspected IQ \<70, pregnancy, substance or alcohol abuse.
• Known history of implanted brain stimulator, vagal nerve stimulator, ventriculoperitoneal shunt, cardiac pacemaker, orthodontic braces, or implanted medication port. Visual and hearing (≥25 dB) impairment.
• Pre-existing medical or psychological conditions that preclude being in the MRI scanner (e.g., claustrophobia, morbid obesity, or marked anxiety about the procedure).

Sponsors & Collaborators

• Supernus Pharmaceuticals, Inc.: lead

Study Sites (3)

Meridien Research aka Florida Clinical Research Center, LLC

Lakeland, Florida, 33805, United States

Location

Florida Clinical Research Center, LLC.

Maitland, Florida, 32751, United States

Location

University of South Florida- Dept. of Psychiatry and Neurosciences

Tampa, Florida, 33613, United States

Location

Related Publications (2)

• Cherek DR, Moeller FG, Schnapp W, Dougherty DM. Studies of violent and nonviolent male parolees: I. Laboratory and psychometric measurements of aggression. Biol Psychiatry. 1997 Mar 1;41(5):514-22. doi: 10.1016/s0006-3223(96)00059-5.

  PMID: 9046983 BACKGROUND

• Bubenzer-Busch S, Herpertz-Dahlmann B, Kuzmanovic B, Gaber TJ, Helmbold K, Ullisch MG, Baurmann D, Eickhoff SB, Fink GR, Zepf FD. Neural correlates of reactive aggression in children with attention-deficit/hyperactivity disorder and comorbid disruptive behaviour disorders. Acta Psychiatr Scand. 2016 Apr;133(4):310-23. doi: 10.1111/acps.12475. Epub 2015 Aug 21.

  PMID: 26292852 BACKGROUND

MeSH Terms

Conditions

Attention Deficit Disorder with Hyperactivity

Interventions

Magnetic Resonance Imaging; Positron-Emission Tomography; Saposins; potassium channel subfamily K member 3

Condition Hierarchy (Ancestors)

Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Tomography; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Tomography, Emission-Computed; Image Interpretation, Computer-Assisted; Image Enhancement; Photography; Radionuclide Imaging; Diagnostic Techniques, Radioisotope; Sphingolipid Activator Proteins; Coenzymes; Enzymes and Coenzymes

Results Point of Contact

• Title: Gianpiera Ceresoli-Borroni Director Clinical Research
• Organization: Supernus Pharmaceuticals

gceresoliborroni@supernus.com

3018382521

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: A multi-center, double-blind, randomized (1:1), placebo-controlled, parallel-group, 2-arm study

Study Record Dates

• First Submitted: August 16, 2018
• First Posted: August 20, 2018
• Study Start: May 30, 2019
• Primary Completion: November 7, 2019
• Study Completion: November 7, 2019
• Last Updated: May 2, 2025
• Results First Posted: May 2, 2025

Record last verified: 2025-02

Locations

US (3)