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

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.

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

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

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.

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

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

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.

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

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

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.

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

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans

The Clinical Global Impression - Improvement Scale (CGI-I) is an assessment of how much the patient's illness has improved or worsened relative to a baseline state at the beginning of treatment. CGI-I was evaluated by the Investigator on a 7-point scale with 1=very much improved, 2= much improved, 3= minimally improved, 4= no change, 5= minimally worse, 6= much worse, 7= very much worse.

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

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

The Clinical Global Impression - Severity of Illness (CGI-S) is a single item clinician rating of clinician's assessment of the severity of IA behaviors. CGI-S was evaluated by the Investigator on a 7- point scale with 1=Normal, 2=Borderline ill, 3=Mildly ill, 4=Moderately ill, 5=Markedly ill, 6=Severely ill, and 7=Extremely ill. Data represent the change between Baseline (Visit 1/Day -30) and two time points: Visit 4 (Day 21) and Visit 6 (Day 35).

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

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

R-MOAS scale gauges the severity of aggressive behavior: the frequency of the 16 behaviors is rated over the past week in 4 areas (a-d). For each open question in each area, the parent rates the aggressive behaviors on a scale from 0 to 5 or more times. To each area corresponds a weighted category: 1(a), 4(b), 2(c) and 3(d). Therefore, the sum of each area yields a maximum weighted score of 20 (a), 120 (b), 60 (c) and 90 (c). The total score is the sum of the four area scores or 0-290, the higher the score, the more severe the aggressive behavior is. Data represent the change from baseline at each visit.

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

Population: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.