Exploratory fMRI Study on the Treatment for Impulsive Aggression in Children With Attention-Deficit/Hyperactivity Disorder

Study Overview
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Brief Summary
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The purpose of this study is 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 will be 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
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Approximately 30 subjects aged 8-12 diagnosed with ADHD and associated feature of IA will be recruited in this study. The PSAP is a behavioral aggression test used to evaluate behavioral response related to impulsive aggression. The task will be 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 will also be measured using magnetic resonance spectroscopy (MRS). Additionally, the improvement and severity in impulsive aggression behaviors will be assessed using validated scales.

Official Title
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Exploratory Neuroimaging Study to Evaluate the Effect on Brain Activity of SPN-810 for Impulsive Aggression (IA) in Patients With Attention-Deficit/Hyperactivity Disorder (ADHD) in Conjunction With Standard ADHD Treatment

Conditions
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Attention Deficit Hyperactivity Disorder (ADHD), Impulsive Aggression

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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) will be 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).

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A multi-center, double-blind, randomized (1:1), placebo-controlled, parallel-group, 2-arm study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Single dose of SPN-810<br>Subjects will be treated with medium dose of SPN-810 | Diagnostic Test: Functional Magnetic Resonance Imaging (fMRI)<br>* Neural brain activity measured by fMRI<br>Diagnostic Test: Magnetic Resonance Spectroscopy (MRS)<br>* Glutamate and GABA levels measured by MRS<br>Behavioral: Point Subtraction Aggression Paradigm (PSAP) Task<br>* Aggression score measured by the PSAP task<br>Drug: SPN-810<br>* Treatment of SPN-810 36 mg on neuronal brain activity, GABA and Glutamate levels and on the aggression score<br>|
| Placebo Comparator: Placebo<br>Subjects will be treated with a matching Placebo | Diagnostic Test: Functional Magnetic Resonance Imaging (fMRI)<br>* Neural brain activity measured by fMRI<br>Diagnostic Test: Magnetic Resonance Spectroscopy (MRS)<br>* Glutamate and GABA levels measured by MRS<br>Behavioral: Point Subtraction Aggression Paradigm (PSAP) Task<br>* Aggression score measured by the PSAP task<br>Drug: Placebo<br>* Treatment of placebo on neuronal brain activity, GABA and Glutamate levels and on the aggression score<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BOLD fMRI contrast (beta value) at baseline and after 4 weeks of treatment with SPN-810 in response to the aggression task. The z-score acquired during resting state fMRI before and after the treatment with SPN-810. | BOLD fMRI contrast (neural activation) will be collected during the PSAP behavioral aggression task, while playing the game. The participant will play a computer game in which they can steal points (simulating an aggressive behavior) or have points stolen by the opponent. In addition, imaging data will be collected at resting state to understand the connectivity between regions of interest before and after the aggression task. | 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in GABA and Glutamate levels from baseline to the end of treatment | During the MRI scan, imaging data will be obtained while participants are able to listen to music. GABA and Glutamate signals measured using magnetic resonance spectroscopy (MRS) from two brain regions (anterior cingulate cortex and amygdala) will be used to quantify the two neurotransmitters. | 9 weeks |