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

Phase 2

Terminated

Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
Impulsive Aggression

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

Registration Number: NCT03638466

Lead Sponsor: Supernus Pharmaceuticals, Inc.

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.

Detailed Description: Approximately 30 subjects aged 8-12 diagnosed with ADHD and associated feature of IA were recruited in this study. The PSAP is a behavioral aggression test used to evaluate behavioral response related to impulsive aggression. The task was combined with functional MRI to evaluate the change in brain activity measured as BOLD signal (blood oxygenation level-dependent) from baseline to the end of the treatment with SPN-810.

The level of neurotransmitters Glutamate and GABA were also measured using magnetic resonance spectroscopy (MRS).

Additionally, the improvement and severity in impulsive aggression behaviors were assessed using validated scales.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 7

Inclusion Criteria

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.

Exclusion Criteria

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
High dose SPN-810 (36 mg)	Functional Magnetic Resonance Imaging (fMRI)	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.
High dose SPN-810 (36 mg)	Magnetic Resonance Spectroscopy (MRS)	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.
High dose SPN-810 (36 mg)	Point Subtraction Aggression Paradigm (PSAP) Task	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.
High dose SPN-810 (36 mg)	SPN-810	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.
Placebo	Functional Magnetic Resonance Imaging (fMRI)	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.
Placebo	Magnetic Resonance Spectroscopy (MRS)	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.
Placebo	Point Subtraction Aggression Paradigm (PSAP) Task	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.
Placebo	Placebo	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.

Primary Outcome Measures

Name	Time	Method
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task	Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.	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.
Provocation Event - Related Change in the Whole Brain in BOLD Signal fMRI Contrast in Response to the PSAP Task	Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.	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.
Effect of SPN-810 on the Aggressions Score	Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.	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.

Secondary Outcome Measures

Name	Time	Method
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.	GABA and Glutamate concentrations (mM) were measured in the anterior cingulate cortex using magnetic resonance spectroscopy (MRS). Data represent the change from Baseline (Visit 2) to Visit 5.

Trial Locations

Locations (3): Florida Clinical Research Center, LLC.
🇺🇸
Maitland, Florida, United States
University of South Florida- Dept. of Psychiatry and Neurosciences
🇺🇸
Tampa, Florida, United States
Meridien Research aka Florida Clinical Research Center, LLC
🇺🇸
Lakeland, Florida, United States