Conditions: Attention Deficit Hyperactivity Disorder (ADHD) Impulsive Aggression
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: Functional Magnetic Resonance Imaging (fMRI) intervention 2: Magnetic Resonance Spectroscopy (MRS) intervention 3: Point Subtraction Aggression Paradigm (PSAP) Task intervention 4: SPN-810 intervention 5: Placebo
Intervention descriptions: intervention 1: Neural brain activity measured by fMRI intervention 2: Glutamate and GABA levels measured by MRS intervention 3: Aggression score measured by the PSAP task intervention 4: Treatment of SPN-810 (36 mg) on neuronal brain activity, GABA and Glutamate levels and on the aggression score intervention 5: Treatment of placebo on neuronal brain activity, GABA and Glutamate levels and on the aggression score

Protocol document:
Prot_000.pdf: 
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TITLE PAGE 
Protocol Number: 
810P204 
Title: 
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 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
  
 
 
 
 
IND number: 
106,515  
Investigational 
Medicinal Product: 
Molindone Hydrochloride Extended-Release Tablets (SPN-810) 
Indication: 
Treatment of Impulsive Aggression (IA) in subjects with Attention-
Deficit/Hyperactivity Disorder (ADHD) in conjunction with standard 
ADHD treatment 
Medical Monitor 
 
 
 
 
Phase: 
2 
Protocol Version: 
3.0 
Release Date: 
12 Apr 2019 
Good Clinical 
Practice (GCP) 
Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonization (ICH) GCP and all applicable local 
regulations. All required study documentation will be archived as 
required by regulatory authorities. 
 


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PROTOCOL SIGNATURE PAGE 
 
I, the undersigned, have read this protocol and agree to conduct this trial in accordance with all 
stipulations of the protocol and in accordance with ICH GCP and all applicable local guidelines, 
including the Declaration of Helsinki and all its accepted amendments to date. 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
 
 
 
Date 
Print Name 
 
 
 
 
 
 
Site Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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CLINICAL PROTOCOL SYNOPSIS 
Name of Company: 
Supernus Pharmaceuticals, Inc.  
IND Number: 106,515 
Name of Product: 
Molindone Hydrochloride Extended-Release 
Tablets (SPN-810) 
Name of Active Ingredient:  
Molindone hydrochloride 
Protocol Number: 810P204 
Phase of Development: 2 
Title of the Study: 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. 
Objectives:   
Primary Objective: 
The primary objective is to evaluate the effect of SPN-810 treatment on brain activity in 
subjects aged 8-12 years with ADHD and IA using functional Magnetic Resonance Imaging 
(fMRI). 
Secondary Objectives: 
Secondary objectives are to evaluate the effect of SPN-810 treatment on: 
 The functional connectivity between brain regions using resting-state fMRI (rs-fMRI) 
 The concentration of neurotransmitters glutamate and gamma-aminobutyric acid 
(GABA) using Magnetic Resonance Spectroscopy (MRS) 
 Safety of SPN-810  
Tertiary Objectives: 
Tertiary objectives are to evaluate the following: 
 
  
 Effect of SPN-810 treatment on the Clinical Global Impression-Severity (CGI-S) 
and -Improvement (CGI-I) scores 
 Effect of SPN-810 on the Retrospective-Modified Overt Aggression Scale (R-MOAS) score 
Study Design: 
A multi-center, double-blind, randomized (1:1), placebo-controlled, parallel-group, 2-arm study 
Number of Subjects: 
The study will screen approximately 40 male and female subjects, aged 8-12 years inclusive, 
with ADHD and IA, to achieve an approximate enrollment of 30 subjects. 


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Criteria for Inclusion:   
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. IA will be confirmed at 
screening using the R-MOAS and the Vitiello Aggression Scale. Subjects who qualified to 
participate in one of the ongoing double-blind Phase 3 studies (CHIME-1 and CHIME-2) but 
screen failed (i.e., non-compliance with the electronic diary or currently on ADHD treatment 
with more than one FDA-approved medication) will be eligible to enroll in Study 810P204 if 
they meet the study criteria. 
Criteria for Exclusion: 
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). 
Treatment, Dose, and Mode of Administration: 
Molindone Hydrochloride Extended-Release Tablets, dosage forms of 3 mg and 9 mg or 
matched placebo. Treatment to be administered orally twice daily, with or without food. 
Subjects will be up-titrated over a period of approximately 15 days to the final dose. 
 Treatment 1: placebo 
 
Treatment 2: 36 mg 
Duration of Treatment and Study Duration:   
Total subject duration on study: approximately 9 weeks 
 Pre-treatment Phase: Up to 30 days  
o Screening: 1 day 
o Baseline MRI: 1 day 
 Treatment Phase: 28 days 
o Titration period: 14 days  
o Maintenance period: 14 days 
 Taper/Conversion Phase: 7 days 


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Pre-treatment Phase:  
Screening (Visit 1): 
Subjects will be screened approximately 30 days before titration. Prior to conducting any 
screening procedures, written Informed Consent/Assent must be obtained from the subject’s 
parents or legal representative, and the subject (when required). During the Screening Visit 
(Visit 1), the R-MOAS and the Vitiello Aggression Scale will be administered to determine the 
subject’s eligibility for study treatment by evaluating the severity and the subtype of 
aggression, respectively. Only subjects whose scores indicate impulsivity will be included in the 
study. At Screening the ADHD diagnosis will also be confirmed with the Mini International 
Neuropsychiatric Interview for Children and Adolescents (MINI-KID) diagnostic tool, according 
to DSM-5 criteria. During the screening visit, subjects will also have their head shape scanned 
(approximately 2 minutes) using a noninvasive handheld 3D scanning system from Caseforge. 
Baseline MRI (Visit 2): 
After completing the screening procedures, subjects who satisfy the inclusion and exclusion 
criteria will proceed to the Baseline MRI visit (Visit 2) at the Imaging Center where the pre-
treatment scans will be performed, which includes the aggression task (PSAP), resting state 
BOLD, structural scans and MR spectroscopy. 
 Habituation Phase:  
Prior to the MR imaging session in the magnet, subjects will practice the Point Subtraction 
Aggression Paradigm (PSAP) Task outside of the MRI environment, which will be followed by a 
mock MRI acquisition to habituate the subject to the horizontal position and MRI scanner 
sounds. During the mock session, subjects will learn to keep their head still via feedback from 
the sensor based on the MoTrak head motion feedback system. 
 MR Imaging Session: 
After a short break, the subject will be placed on the MR scanner bed and positioned in the 32-
channel head coil using the Caseforge customized helmet, such that the subject can see the 
projection screen at the back of the magnet via a mirror system. The subject will be given ear 
plugs, have a respiratory belt placed around their chest, may have a pulse sensor placed on 
their toe, and given the button box for the PSAP Task and the emergency squeeze ball. Subjects 
will undergo an approximately 1-hour long MR imaging session with the following acquisitions: 
3-plane localizer, followed by two 12-minute fMRI sessions of the PSAP Task,  a three-
dimensional magnetization-prepared rapid acquisition with gradient echo (3D MPRAGE) 
anatomical scan (6 minutes), a Magnetic Resonance Spectroscopy (MRS) acquisition (8 
minutes), a resting-state fMRI scan (8 minutes), and a 3-minute Fluid Attenuated Inversion 
Recovery (FLAIR) clinical anatomical scan. All scanning will be performed on a Siemens-Skyra 3T 
MRI scanner. MR imaging parameters were optimized in the 810P204a study. 
PSAP 
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. However, at the beginning of the game subjects will be told that they will be playing 


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against a fictitious opponent located in a different building. The subject can steal points 
(simulating an aggressive behavior) or have points stolen by the opponent (i.e., provocation). At 
the beginning of the task, subjects will be instructed that they and their opponent could earn as 
many points as possible that can be turned into money. The subject can press 1 of 3 buttons on 
a keypad (Option 1, 2 or 3) a set number of times to achieve a specific outcome.  
BOLD fMRI 
BOLD (blood oxygenation level-dependent) fMRI is a method used to investigate brain activity 
by measuring the change in blood oxygenation. When a brain area is active, the flow of 
oxygenated blood increases to that region in response to increased oxygen demand. Changes in 
the relative levels of oxyhemoglobin and deoxyhemoglobin can be detected due to their 
differences in magnetic susceptibility. Deoxygenated hemoglobin is paramagnetic while 
oxygenated hemoglobin is diamagnetic. An Echo Planar Imaging (EPI) MRI sequence is sensitive 
to changes in magnetization (T2*) and can therefore be used to measure blood oxygenation as 
a proxy for brain activity during the task. 
BOLD Resting fMRI 
A resting-state BOLD fMRI (rs-fMRI) will be measured (subjects will look at the image of a 
crosshair during an 8-minute scan) after the completion of the PSAP Task fMRI and MR 
spectroscopy. The rs-fMRI will be used to identify functional connectivity in brain networks in 
subjects “at rest.” Connectivity is measured by the spontaneous fluctuations in the BOLD signal. 
The more synchronized these fluctuations are, the more connected the brain regions. 
 
Randomization (Visit 3): 
After the completion of the baseline procedures, eligibility will minimally require completion of 
(1) two PSAP sessions and (2) the MPRAGE structural scan. Eligible subjects will be randomized 
in a 1:1 ratio to receive placebo or 36 mg/day SPN-810 and will proceed to the Treatment 
Phase.  
Treatment Phase: 
Subjects will be titrated for 2 weeks and the final dose will be maintained for 2 weeks. Subjects 
will return for PK sampling at Visit 4. 
At the end of the Maintenance period, subjects will return to the Imaging Center to complete 
the post-treatment MRI session with the same MR imaging acquisition procedures as 
performed at the Baseline MRI session. The visit (Visit 5) will be scheduled within 3 hours +/- 1 
hour from the time the dose of study medication was taken. 
 
Subjects who successfully complete the study will have the option to participate in the ongoing 
open-label extension (OLE) study (SPN-810P304). Subjects can choose to participate in the OLE 
at Visit 4 and will receive a blinded conversion card at the same visit. They will enter the OLE 
study at a dose of 18 mg/day. Subjects who choose not to enter the OLE will receive their taper 
card at Visit 4. All subjects will be instructed to return to the site within 1 week of Visit 5 for the 
end of study (EOS) procedures (Visit 6). 


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Endpoints: 
Primary Endpoint: 
 Change in the whole brain in BOLD fMRI contrast in response to the PSAP task from 
Baseline (Visit 2) to Visit 5.  
Secondary Endpoints: 
 Change in functional connectivity as reflected in the Fisher’s Z-transformation of 
correlation coefficients between brain regions during rs-fMRI from Baseline (Visit 2) to 
Visit 5. 
 Change in the concentrations of neurotransmitters GABA and glutamate in the anterior 
cingulate cortex (ACC) from Baseline (Visit 2) to Visit 5 as determined by MR 
spectroscopy. 
 Safety endpoints: 
1. Adverse events. 
2. Safety scales (Simpson-Angus Scale, Barnes Akathisia Rating Scale [BARS], and 
Abnormal Involuntary Movement Scale [AIMS]). 
3. Clinical laboratory tests (hematology, chemistry, and urinalysis). 
4. Vital signs. 
5. Electrocardiograms (ECGs). 
6. Columbia-Suicide Severity Rating Scale (C-SSRS). 
Tertiary Endpoints: 
1. 
  
2. Change from baseline to Visit 4 in Investigator- rated CGI-I and CGI-S scores 
3. Change from baseline to Visit 4 in the R-MOAS score 
Sample size: 
Approximately 30 subjects will be enrolled. 
Pharmacokinetic Method: 
 
 
 
 
Bioanalytical Analysis: 
 
 


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Analysis populations: 
Safety Population: includes all subjects randomized to the study and who received at least 1 
dose of study drug. 
Completed Population: includes all subjects randomized to the study and have a baseline 
imaging scans (including the anatomical scan) and post-treatment imaging scans. 
PK Population: includes all subjects in the safety population who had at least one PK sample 
drawn with a quantifiable concentration of molindone. 
Statistical Methods: 
Descriptive analysis will be performed for data collected. The mean, standard deviation, 
median, minimum, and maximum will be reported for continuous variables. Frequency and 
percentage will be summarized for categorical variables. 
Imaging Analysis: 
All functional imaging data will be analyzed using statistical parametric mapping software 
SPM12 (Wellcome Trust Centre for Neuroimaging, Institute of Neurology; London, UK), Analysis 
of Functional Neuroimages (AFNI, NIH, USA), and in-house software developed in Dr. Todd 
Parrish’s lab at Northwestern University, Chicago, by Dr. Lana Kaiser, and at Supernus. 
Additional software that may be used includes FSL (Oxford, Cambridge, UK), Freesurfer (MGH, 
USA), and Matlab (Mathworks, USA).  
While performing the PSAP Task, neuronal activation is anticipated in the ACC, ventromedial 
PFC (VmPFC), amygdala, insular regions, and ventral striatum including the nucleus accumbens, 
etc. Therefore these regions of interest (ROIs) will be emphasized during the imaging analysis. 
Primary Analysis: 
Both primary and secondary analyses will be based on the completed population. 
The primary endpoint will be analyzed by assessing the difference in the change in BOLD fMRI 
contrast related to the response to the PSAP Task from Baseline (Visit 2) to Visit 5 between 
each treatment group (SPN-810 36 mg group and placebo).  
Secondary Analysis: 
Secondary endpoints will be the difference in the change in functional connectivity values 
(Fisher’s Z-transformation of the correlation coefficient) between relevant brain regions 
obtained during resting state, from Baseline (Visit 2) to Visit 5 between each treatment group 
(SPN-810 36 mg group and placebo). The relevant variables for the correlation matrices will be 
calculated by Northwestern University. 
Concentrations of GABA and Glu in the ACC will be analyzed descriptively. The statistics will be 
assessed by treatment group, at Baseline (Visit 2) and at Visit 5. The 2-sided 95% CI for the 
mean difference between two treatment groups, pre- and post-treatment will be examined.   
Details of the analyses will be provided in the SAP. 


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Safety Analysis: 
Safety analysis will be based on the safety population. All AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) and will be summarized at subject and event 
levels by System Organ Class (SOC), Preferred Term (PT), and study treatment. The treatment-
emergent AEs will be analyzed similarly by severity, and study drug relatedness. The descriptive 
statistics will be summarized for continuous measures, and percentage will be reported for 
categorical measures from the clinical laboratory results, AEs, vital signs, ECGs, and findings 
from the physical examinations. 
Pharmacokinetic Analysis: 
 
 
 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................................ 1 
PROTOCOL SIGNATURE PAGE ............................................................................................................. 2 
SUPERNUS PHARMACEUTICALS, INC. PROTOCOL APPROVAL PAGE ..................................................... 3 
CLINICAL PROTOCOL SYNOPSIS .......................................................................................................... 4 
TABLE OF CONTENTS ........................................................................................................................ 11 
LIST OF TABLES AND FIGURES ........................................................................................................... 15 
LIST OF ABBREVIATIONS .................................................................................................................. 16 
1 
INTRODUCTION ........................................................................................................................ 18 
1.1 
Background ....................................................................................................................... 18 
1.2 
Impulsive Aggression in the Context of Psychiatric Disorders .............................................. 18 
1.3 
Neurobiology of Impulsive Aggression ............................................................................... 19 
1.4 
Treatment Options for Impulsive Aggression ...................................................................... 20 
1.5 
Sponsor’s Phase 2 and Phase 3 Studies .............................................................................. 21 
1.6 
Study Rationale and Appropriateness of Measurements .................................................... 22 
2 
STUDY OBJECTIVE ..................................................................................................................... 23 
2.1 
Primary Objective.............................................................................................................. 23 
2.2 
Secondary Objectives ........................................................................................................ 23 
2.3 
Tertiary Objectives: ........................................................................................................... 23 
3 
INVESTIGATIONAL PLAN ........................................................................................................... 23 
3.1 
Overall Study Design ......................................................................................................... 23 
3.2 
Imaging Acquisition and fMRI Set-up ................................................................................. 24 
 
BOLD fMRI ........................................................................................................................... 24 
 
Point Subtraction Aggression Paradigm (PSAP) Task .......................................................... 25 
 
Data Acquisition .................................................................................................................. 25 
 
Magnetic Resonance Spectroscopy (MRS).......................................................................... 26 
3.2.4.1 
GABA and Glutamate Brain Concentrations .................................................................................................... 26 
3.2.4.2 
MRS Data Acquisition ............................................................................................................................................... 26 
3.3 
Duration of Study Treatment ............................................................................................. 27 
3.4 
Pre-Treatment Phase (Up to 30 days) ................................................................................. 30 
 
Screening Period (Up to 30 days): Visit 1, Day -30 .............................................................. 30 
 
Baseline MRI (Visit 2) and Randomization (Visit 3): Day -5 to Day 0 .................................. 30 
3.5 
Treatment Phase (4 weeks) ............................................................................................... 31 
 
Titration Period, Day 1 to Day 14 ........................................................................................ 31 
 
Maintenance Period, (14 days) Day 15 to Day 28 ............................................................... 31 
3.6 
Taper/Conversion Phase (7 days), Day 29 to Day 35 ........................................................... 31 
3.7 
End of Study (EOS)/Early Termination, Visit 6 (Day 35) ....................................................... 31 


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4 
STUDY METHODS ..................................................................................................................... 32 
4.1 
Study Population ............................................................................................................... 32 
 
Inclusion Criteria ................................................................................................................. 32 
 
Exclusion Criteria ................................................................................................................. 32 
4.2 
Schedule of Visits and Procedures ...................................................................................... 33 
 
Screening/Visit 1 (Day -30) .................................................................................................. 38 
 
Baseline MRI Scans/ Visit 2, (Day -5 to 0) ........................................................................... 38 
4.2.2.1 
MR Safety Questionnaire and Edinburgh Handedness Inventory ............................................................ 39 
4.2.2.2 
Habituation Phase ..................................................................................................................................................... 39 
4.2.2.3 
MRI Session ................................................................................................................................................................. 39 
 
Randomization/ Visit 3, (Day 0) .......................................................................................... 40 
 
Maintenance/Visit 4 (Day 21) ............................................................................................. 40 
 
Maintenance/Visit 5 (Day 28) ............................................................................................. 41 
 
Taper/Conversion/Visit 6 (Day 35)/EOS .............................................................................. 41 
 
Pharmacokinetic Blood Sampling ....................................................................................... 42 
5 
Treatments .............................................................................................................................. 42 
5.1 
Treatments Administered .................................................................................................. 42 
 
Identity of Investigational Product(s) ................................................................................. 43 
 
Study Medication Handling and Accountability .................................................................. 43 
 
Method of Assigning Subjects to Treatment Groups .......................................................... 44 
 
Treatment Replacement ..................................................................................................... 44 
 
Dosing Schedule .................................................................................................................. 44 
 
Method of Administration .................................................................................................. 45 
 
Blinding ............................................................................................................................... 45 
 
Allowed Medication ............................................................................................................ 45 
 
Study Restrictions ............................................................................................................... 46 
5.2 
Completion of Study and Discontinuation of Subjects ......................................................... 46 
6 
ANALYSIS VARIABLES ................................................................................................................ 47 
6.1 
Primary Variable ............................................................................................................... 47 
6.2 
Secondary Variables .......................................................................................................... 47 
 
Functional Connectivity ...................................................................................................... 47 
 
GABA and Glutamate Brain Concentrations ....................................................................... 47 
6.3 
Safety Assessments ........................................................................................................... 48 
 
Adverse Events .................................................................................................................... 48 
6.3.1.1 
Causality........................................................................................................................................................................ 48 
6.3.1.2 
Recording and Evaluation of Adverse Events .................................................................................................. 48 
6.3.1.3 
Criteria for Assessing Severity ............................................................................................................................... 49 
6.3.1.4 
Criteria for Assessing Causality ............................................................................................................................. 49 
 
Serious Adverse Events (SAEs) ............................................................................................ 50 
6.3.2.1 
Investigator Responsibilities for Reporting SAEs ............................................................................................ 50 
6.3.2.2 
Other Events Requiring Immediate Reporting ................................................................................................ 51 
6.3.2.3 
Sponsor Responsibilities for Expedited Reporting of SAEs ......................................................................... 51 


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Management of Treatment-Emergent Extrapyramidal Symptoms .................................... 52 
 
Laboratory Measurements ................................................................................................. 52 
 
Vital Signs and Height/Weight Measurements ................................................................... 53 
 
Medical History ................................................................................................................... 53 
 
Physical Examinations and Electrocardiograms (ECGs) ...................................................... 53 
 
Electrocardiograms ............................................................................................................. 54 
 
Special Safety Assessments ................................................................................................. 54 
6.3.9.1 
Simpson-Angus Scale (Section 12.3) ................................................................................................................... 54 
6.3.9.2 
Barnes Akathisia Rating Scale (BARS) (Section 12.4) .................................................................................... 54 
6.3.9.3 
Abnormal Involuntary Movement Scale (AIMS) (Section 12.5) ................................................................ 54 
6.3.9.4 
Columbia-Suicide Severity Rating Scale (C-SSRS) (Section 12.6) .............................................................. 54 
6.4 
Tertiary Variables .............................................................................................................. 55 
 
Pharmacokinetic Measurements ........................................................................................ 55 
6.4.1.1 
Pharmacokinetic Variables ..................................................................................................................................... 55 
 
Clinical Global Impression Scale (Section 12.1) .................................................................. 55 
 
Retrospective-Modified Overt Aggression Scale (R-MOAS) (Section 12.2) ........................ 55 
6.5 
Other Special Tests ............................................................................................................ 56 
 
MINI-KID (Section 12.7) ....................................................................................................... 56 
 
Vitiello Aggression Scale (Section 12.8) .............................................................................. 56 
 
Edinburgh Handedness Inventory (Section 12.9) ............................................................... 56 
7 
STATISTICAL METHODS ............................................................................................................. 56 
7.1 
General Notions ................................................................................................................ 56 
7.2 
Handling of Dropout or Missing Data ................................................................................. 57 
7.3 
Analysis Populations ......................................................................................................... 57 
7.4 
Demographics ................................................................................................................... 57 
7.5 
Subject Disposition ............................................................................................................ 57 
7.6 
Protocol Deviations ........................................................................................................... 58 
7.7 
Study Medication Exposure and Compliance ...................................................................... 58 
8 
Statistical Analysis .................................................................................................................... 58 
8.1 
Primary Endpoint Analysis ................................................................................................. 58 
 
Imaging Analysis .................................................................................................................. 59 
8.1.1.1 
PSAP Task ..................................................................................................................................................................... 59 
8.2 
Secondary Endpoint Analyses ............................................................................................ 59 
 
Functional Connectivity (Resting State fMRI) ..................................................................... 59 
 
GABA and Glutamate Concentrations ................................................................................. 60 
8.3 
Safety Analysis .................................................................................................................. 60 
 
Adverse Events .................................................................................................................... 60 
 
Laboratory Values ............................................................................................................... 61 
 
Vital Signs, Height, Weight, and BMI .................................................................................. 61 
 
ECG Results ......................................................................................................................... 61 
 
Physical Examinations ......................................................................................................... 61 


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for the purpose of reviewing or performing this study. 
 
Concomitant Medications ................................................................................................... 61 
 
C-SSRS.................................................................................................................................. 61 
 
Extrapyramidal Symptoms .................................................................................................. 62 
8.4 
Tertiary Variable Analysis .................................................................................................. 62 
 
Pharmacokinetic Analysis ................................................................................................... 62 
 
Behavioral Scales ................................................................................................................. 62 
9 
DOCUMENTATION .................................................................................................................... 62 
9.1 
Adherence to the Protocol ................................................................................................. 62 
9.2 
Changes to the Protocol .................................................................................................... 63 
9.3 
Protocol Deviations ........................................................................................................... 63 
9.4 
Data Quality Assurance ..................................................................................................... 63 
 
Data Collection .................................................................................................................... 63 
 
Clinical Data Management .................................................................................................. 64 
 
Database Quality Assurance ............................................................................................... 64 
9.5 
Retention of Records ......................................................................................................... 64 
9.6 
Auditing Procedures .......................................................................................................... 65 
9.7 
Publication of Results ........................................................................................................ 65 
9.8 
Financing and Insurance .................................................................................................... 65 
9.9 
Disclosure and Confidentiality ........................................................................................... 65 
9.10 
Discontinuation of Study ................................................................................................... 66 
10 
ETHICS .................................................................................................................................. 66 
10.1 
Institutional Review Boards / Independent Ethics Committees ........................................... 66 
10.2 
Ethical Conduct of the Study .............................................................................................. 66 
10.3 
Investigators and Study Personnel ..................................................................................... 67 
10.4 
Subject Information and Consent/Assent ........................................................................... 67 
11 
REFERENCE LIST .................................................................................................................... 68 
12 
APPENDICES ......................................................................................................................... 73 
12.1 
Clinical Global Impression (CGI) Scale ................................................................................. 73 
12.2 
Retrospective-Modified Overt Aggression Scale (R-MOAS) ................................................. 74 
12.3 
Simpson-Angus Scale ......................................................................................................... 76 
12.4 
Barnes Akathisia Rating Scale (BARS) ................................................................................. 80 
12.5 
Abnormal Involuntary Movement Scale (AIMS) .................................................................. 82 
12.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................................. 87 
 
C-SSRS, Children’s Baseline/Screening ................................................................................ 87 
 
C-SSRS, Since Last Visit ........................................................................................................ 90 
12.7 
Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) ..... 93 
12.8 
Vitiello Aggression Scale .................................................................................................. 151 
12.9 
Edinburgh Handedness Inventory .................................................................................... 152 
12.10 
PSAP Questionnaire ..................................................................................................... 153 
12.11 
MR Safety Questionnaire ............................................................................................. 154 


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LIST OF TABLES AND FIGURES 
 
Table 1: Schedule of Events and Procedures .............................................................................................. 35 
Table 2: Titration Dosing Schedule ............................................................................................................. 44 
Table 3: Clinical Laboratory Tests ............................................................................................................... 52 
 
Figure 1: Study Schematic: Conversion to Open-Label Extension Study .................................................... 28 
Figure 2: Study Schematic: Taper and Complete/Discontinue ................................................................... 29 
 
 
 


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LIST OF ABBREVIATIONS 
ACC 
Anterior Cingulate Cortex 
AC-PC 
Anterior Commissure-Posterior Commissure 
ADHD 
Attention-Deficit/Hyperactivity Disorder 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AIMS 
ANCOVA 
Abnormal Involuntary Movement Scale 
Analysis of Covariance 
BARS 
Barnes Akathisia Rating Scale 
BID 
Twice a Day 
BMI 
Body Mass Index 
BOLD 
CFB 
Blood Oxygenation Level-Dependent 
Change from Baseline 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression – Severity of Illness 
CGI-I 
Clinical Global Impression – Improvement 
CNS 
Central Nervous System 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
ECRF 
Electronic Case Report Form 
EOS 
End of Study 
EPI 
Echo Planar Imaging 
EPS 
Extrapyramidal Symptoms 
FDA 
Food and Drug Administration 
fMRI 
Functional Magnetic Resonance Imaging 
FOCP 
Females of Childbearing Potential 
GABA 
Gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
Glu 
Glutamate 
IA 
Impulsive Aggression 
IAF 
Informed Assent Form 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IQ 
Intelligence Quotient 
IRB 
Institutional Review Board 
LAR 
Legal Authorized Representative 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MINI-KID 
Mini International Neuropsychiatric Interview for Children and 
Adolescents 
MPRAGE 
MRS 
Magnetization-Prepared Rapid Acquisition with Gradient Echo 
Magnetic Resonance Spectroscopy 
MTA 
Multimodal Treatment Study of Children with ADHD 
OFC 
Orbitofrontal Cortex 
OLE 
Open-Label Extension 
PFC 
Prefrontal Cortex 
PSAP 
Point Subtraction Aggression Paradigm 
R-MOAS 
Retrospective-Modified Overt Aggression Scale 
rs-fMRI 
Resting State Blood Oxygenation Level-Dependent Functional 
Magnetic Resonance Imaging 
SADR 
Suspected Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
SPECT 
Single-Photon Emission Computed Tomography 
TE 
Echo Time 
TEAE 
Treatment-Emergent Adverse Event 
TID 
Three Times a Day 
TR 
Repetition Time 
 
 


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1 INTRODUCTION 
1.1 Background 
Human aggressive behavior is complex, heterogeneous, and multifactorial, but can generally be 
divided into 2 subsets: functional, adaptive aggression and pathological, maladaptive 
aggression (Miczek et al. 2014). Adaptive aggression is a behavior that is considered 
contextually appropriate, constrained by certain rules and rituals, and may occur to ensure the 
integrity or survival of the individual (e.g., the ritualized violence seen in sport, or an adolescent 
fighting those who would attempt to steal his or her possessions) (Miczek et al. 2014; Connor, 
2002). In contrast, maladaptive aggression is defined as being out of context, unstructured, 
and/or outside of the norms of community behavior (e.g., explosive aggression intended to 
harm another person, often elicited by minimal or routine environmental cues) (Miczek et al. 
2014; Connor, 2016). Maladaptive aggression can be proactive or premeditated, but the more 
common form of pathological aggression is characterized as reactive or impulsive (Miczek et al. 
2014; Miles et al., 2016). Whereas premeditated aggression is planned, covert, and associated 
with the anticipation of a positive outcome for the aggressor, impulsive aggression (IA) is 
unplanned, explosive in nature, and often accompanied by negative emotions in the aggressor 
(Barratt et al., 1999; Gurnani, 2016; Connor, 2016). Maladaptive aggression, including IA, is one 
of the most common reasons that children are referred to mental health settings.  Limited 
research that has been conducted into the subtypes of human aggression, most has been in 
children and adolescents (Connor, 2002; Vitiello & Stoff, 1997).   
1.2 Impulsive Aggression in the Context of Psychiatric Disorders  
IA is a common comorbidity that has been compared to fever or pain (Saylor & Amann, 2016), 
as it presents in numerous disorders, but only provides information about the severity and not 
the type of illness (Jensen, 2007). Among psychological disorders, IA is often associated with 
attention-deficit/hyperactivity disorder (ADHD) (King & Waschbusch, 2010), autism spectrum 
disorders (Doyle & McDougle, 2012), bipolar disorder (Hoptman, 2015), schizophrenia 
(Hoptman, 2015), Alzheimer’s disease (Bidzan et al., 2012), and post-traumatic stress disorder 
(PTSD) (Miles et al., 2016). In children and adolescents with ADHD, the prevalence of aggressive 
behavior is particularly high. The large Multimodal Treatment Study of Children with ADHD 
(MTA), which included pre-adolescent children aged 7 to 9.9 years with ADHD, showed that 
more than half of the 491 subjects (54%) had clinically significant aggression prior to treatment 
(MTA, 1999; Jensen, 2007; Saylor & Amann, 2016). Furthermore, aggression is often refractory 
to treatment in children with ADHD; in the MTA, 26% of subjects continued to exhibit moderate 
to high levels of aggressive behavior after 14 months of multimodal therapy (Jensen, 2007). 
 
Children with both elevated levels of aggressiveness and ADHD are at greater risk for 
psychological, academic, emotional, and social problems, which can manifest as persistent 
behavioral problems, encounters with the justice system, poor academic achievement, 
disciplinary problems at school, and substance experimentation/abuse (Shelton et al., 1998; 
Saylor & Amann, 2016). As ADHD-related psychosocial impairment has been suggested to stem 
more from aggression/irritability than from ADHD symptoms themselves, treatment of 


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aggressive behavior should be emphasized in subjects with ADHD and IA (Saylor & Amann, 
2016). 
1.3 Neurobiology of Impulsive Aggression   
Although the pathophysiology of IA is not fully understood, functional and neuroimaging 
studies have detected subtle abnormalities in the subcortical regions and frontal lobes of 
children with ADHD and inhibition deficits or high levels of impulsivity (Connor, 2002). For 
instance, magnetic resonance imaging (MRI) has shown that children with ADHD have reversed 
asymmetry of the head of the caudate, smaller volume of the left caudate head, and smaller 
volumes of white matter in the right frontal lobe when compared to controls (Semrud-Clikeman 
et al., 2000). Subjects in this study with reversed caudate asymmetry were more disinhibited, 
and more likely to have externalizing behaviors, including hyperactivity, aggression and conduct 
problems (Semrud-Clikeman et al., 2000). Data regarding the relationship between the 
neuroanatomy and behavior seen in children with ADHD and high levels of impulsivity are in 
agreement with the suggestion that IA may result from a functional imbalance in the central 
nervous system (CNS) (Connor, 2002; Blair, 2016). 
Within the CNS, the functions of the prefrontal cortex (PFC) and the mesolimbic areas of the 
brain are generally thought to include providing “control” and “emotion,” respectively (Gan et 
al., 2016). Models suggest that IA results from a functional imbalance in these control 
mechanisms, and poor executive regulation of emotion (Ahmed et al., 2015; Bubenzer-Busch et 
al., 2015; Gan et al., 2016). More specifically, increased reactivity from the regions, including 
the amygdala, striatum, and the insula, drive excessive emotional arousal, whereas impaired 
functioning in the anterior cingulate cortex (ACC) and ventromedial PFC fail to adequately 
regulate these emotions (Bubenzer-Busch et al., 2015; Blair, 2016; Gan et al., 2016; Skibsted et 
al., 2017). Dysfunction in this circuit may heighten the risk of impulsive aggressive behavior 
(Skibsted et al., 2017). Furthermore, for patients with ADHD, impairment in regions of the PFC 
involved in planning behavior and attentional guidance is also implicated in their disinhibited 
behaviors (Bubenzer-Busch et al., 2015).  
Functional neuroimaging studies have revealed some of the mechanistic details underlying 
human aggressive behavior. Serotonin transporter availability has been shown by positron 
emission tomography (PET) to be reduced in the ACC of subjects with intermittent explosive 
disorder (Frankle et al., 2005). This abnormality in serotonergic innervation has been suggested 
to affect impulse modulation, and may contribute to increased impulsivity and aggression 
(Frankle et al., 2005). Furthermore, PET studies measuring brain glucose utilization have also 
shown the orbitofrontal cortex (OFC) to have less neural activity in healthy subjects presented 
with images of aggressive scenarios (Pietrini et al., 2000). Subcortical regions of the brain have 
also been implicated in the presentation of aggressive behavior. In a single-photon emission 
computed tomography (SPECT) study of 40 adolescents and adults with exhibited aggressive 
behavior, and 40 psychiatric patients who had never demonstrated such behavior, those 
identified with aggressive behavior showed decreased activity in the PFC, increased activity in 
the anteromedial portions of the frontal lobes, increased left-sided activity in the basal 
ganglia/limbic system, and focal abnormalities in the left temporal lobe (Amen et al., 1996). 
Functional magnetic resonance imaging (fMRI) studies to analyze the neural systems behind the 


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basic human threat response have consistently shown that activity is increased in the amygdala, 
hypothalamus, and periaqueductal gray when subjects are presented with approaching threats 
(Mobbs et al., 2009; Coker-Appiah et al., 2013). FMRI can identify which regions of a subject’s 
brain are activated in response to a stimulus by evaluating changes in the blood oxygenation 
level-dependent (BOLD) signal (Czerniak et al., 2013). Subjects with intermittent explosive 
disorder who are exposed to a display of angry faces during fMRI have been shown to 
experience increased activity in the amygdala, ACC, OFC, and ventrolateral PFC (Gan et al., 
2016; Skibsted et al., 2017). Combining fMRI with the Point Subtraction Aggression Paradigm 
(PSAP) Task, a well-established test for evaluating behavioral responses related to aggression, 
has shown that provocation activates the amygdala, dorsal striatum, insula, and prefrontal 
areas in control subjects (Skibsted et al., 2017). In children with ADHD, fMRI has shown lower 
activation in the ACC and temporoparietal junction (a region associated with processes involved 
in theory of mind, social cognition, and attentional guidance) during the aggression phase of 
the modified version of the Point Subtraction Aggression game compared to controls 
(Bubenzer-Busch et al., 2015). Combined with established paradigms for evaluating aggression-
related behavior, fMRI studies in healthy populations and clinical populations with high levels of 
IA have provided evidence for the brain regions involved in the manifestation of IA (Gan et al., 
2016).  
1.4 Treatment Options for Impulsive Aggression   
Psychosocial interventions, psychostimulants, antipsychotics, and other adjunctive therapies to 
primary ADHD treatment are often used to control aggressive behavior in children with ADHD 
and IA (Pappadopulos et al., 2003; Blader et al., 2010; Gurnani et al., 2016). However, there 
remains an unmet need in this population, as there is currently no US Food and Drug 
Administration (FDA)-approved medication for the treatment of IA in children with ADHD 
(Stocks et al., 2012). 
Molindone hydrochloride was previously marketed in the United States as Moban®, an 
immediate-release tablet for the management of schizophrenia in adults and adolescents, and 
was discontinued by the original manufacturer for reasons not related to its safety or 
effectiveness (Moban Prescribing Information, 2009; United States Food and Drug 
Administration, 2013). In a single-blind, dose-ranging pilot study, molindone at an optimized 
dose of 0.5 mg/kg/day was found to improve symptoms of aggressive-type behavior in children 
with undersocialized conduct disorder, aggressive type (Greenhill et al., 1985; Stocks et al., 
2012). Molindone was also shown to be effective in treating aggressive behavior in a double-
blind, 8-week, inpatient study of 31 children, aged 6-11 years, with undersocialized conduct 
disorder, aggressive type (Greenhill et al., 1985). Molindone is not associated with significant 
increases in weight/body mass index (BMI), in contrast to olanzapine (Sikich et al., 2008), and 
elicits little to no parkinsonism or extrapyramidal symptoms (EPS), as compared to other 
antipsychotics (Seeman & Tallerico, 1998; Sikich et al., 2008). The overall clinical profile of 
molindone has made it an attractive candidate for the treatment of IA in children with ADHD, 
especially with the anticipated benefits of an extended-release formulation. 


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1.5 Sponsor’s Phase 2 and Phase 3 Studies  
Three Phase 2 studies have been undertaken to develop molindone as a potential therapeutic 
for the treatment of IA. Study 810P201 was a proof-of-principle, open-label, parallel-group, 
randomized, dose-ranging, safety and tolerability study using the investigational immediate-
release (IR) formulation of molindone (Molindone IR) dosed 3 times a day (TID) in children with 
ADHD and persistent serious conduct problems (Stocks et al., 2012). This study demonstrated 
that treatment with Molindone IR TID was safe and well tolerated. Preliminary efficacy results 
suggested that treatment with Molindone IR resulted in behavioral improvements and that 
those improvements were more marked in higher dose groups than in lower dose groups.  
Study 810P202 was a Phase 2b multicenter, randomized, double-blind, placebo controlled trial 
in subjects aged 6-12 years diagnosed with ADHD and IA that was not controlled by optimal 
stimulant and behavioral therapy (Supernus Pharmaceuticals, 2013). SPN-810 treatment in the 
medium- and low-dose groups (24/36 mg, and 12/18 mg, respectively) showed a statistically 
significant difference from the placebo group in the change from baseline to the end of the 
study (6 weeks) in Retrospective-Modified Overt Aggression Scale (R-MOAS) score, suggesting 
improvement in aggressive behaviors.  
SPN-810 exhibited a satisfactory safety and tolerability profile, with low incidence of adverse 
events (AEs) and no unexpected, life-threatening, or dose-limiting safety issues. The AEs 
reported in this study were consistent with the types of events that could be expected in a 
pediatric population taking low-dose antipsychotic medication and psychostimulant ADHD 
medication. The overall frequency of AEs was relatively low, as were discontinuations due to 
AEs. The frequency of AEs associated with EPS was also low, and the two serious AEs that 
occurred were not drug-related.  
Study 810P203 was a multicenter open-label extension (OLE) to Study 810P202 in a pediatric 
population of subjects 6-12 years of age diagnosed with ADHD and IA. The starting dose for this 
OLE study was based on subjects’ weight at the end of 810P202, with dosing gradually adjusted 
based on tolerability or effectiveness, regardless of weight group to 9, 18, 27, or 36 mg/day. Of 
the 121 subjects randomized into the double-blind Study 810P202, 78 continued on to the OLE 
study and received SPN-810 for up to 6 months. 
SPN-810 was well tolerated when dosages were adjusted according to clinical response. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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. 
The Sponsor is currently conducting 3 Phase 3 multicenter, randomized, double-blind, placebo-
controlled trials in a population of subjects 6-12 years of age diagnosed with ADHD and IA 
(810P301, 810P302 and 810P304). The primary objective of all 3 studies is to assess the efficacy 
and safety of SPN-810 in reducing the frequency of IA behaviors in pediatric patients with ADHD 
when taken in conjunction with standard ADHD treatment.  
1.6 Study Rationale and Appropriateness of Measurements 
Results from Phase 2 studies and the associated OLE study have shown that SPN-810 added to 
optimized ADHD therapy resulted in remission of aggression and significantly improved 
impulsive aggressive behavior in children with ADHD, in addition to exhibiting a good 
tolerability profile in children with ADHD and associated feature of IA.  
This Phase 2 (810P204) study seeks 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 IA. This will 
be achieved using fMRI in conjunction with the PSAP Task, a behavioral aggression paradigm in 
which subjects are provoked by having money indirectly taken from them by a (unbeknownst to 
the subject) fictitious opponent during a money acquisition task. 
The PSAP Task is a well-established test for evaluating aggressive behavioral responses related 
to IA, and has been previously used in fMRI studies to elucidate the neural activation involved 
in aggressive behaviors (Bubenzer-Busch et al., 2015; Cherek et al., 1997; Skibsted et al., 2017; 
Cunha-Bang et al., 2017; Kose et al., 2015).  
The PSAP Task parameters for this study (810P204) were optimized in a non-interventional 
Study (810P204a) conducted in typically developed children 8-12 years old. 
Prospective evaluation of subjects using well-established diagnostic tests will confirm that 
enrollees have both ADHD (by MINI-KID) and moderate to severe IA (by R-MOAS, CGI-S, and the 
Vitiello Aggression Scale). Subjects in this double-blind, placebo-controlled, 2-arm, randomized 
(1:1), parallel-group will receive study medication twice daily (BID) with or without food. 
Enrolled subjects will follow a titration schedule that has been shown to be safe, efficacious, 
and well-tolerated in a similar patient population in a previous Phase 2b study.  
Safety will be assessed by the monitoring of AEs, vital signs, ECGs and clinical laboratory tests, 
as well as by the Simpson-Angus Scale, the Barnes Akathisia Rating Scale (BARS), the Abnormal 
Involuntary Movement Scale (AIMS), and the Columbia-Suicide Severity Rating Scale (C-SSRS).  
The effect of Molindone on body composition, metabolic parameters, and prolactin will be 
evaluated.  


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2 STUDY OBJECTIVE 
2.1 Primary Objective  
The primary objective of Study 810P204 is to evaluate the effect of SPN-810 treatment on brain 
activity in subjects aged 8-12 years with ADHD and IA using fMRI. 
2.2 Secondary Objectives  
The secondary objectives are to evaluate the effect of SPN-810 treatment on:  
 The functional connectivity between brain regions using resting-state fMRI (rs-fMRI) 
 The concentration of neurotransmitters glutamate and GABA using MRS 
 The safety of SPN-810 
2.3 Tertiary Objectives: 
Tertiary objectives are to evaluate the following: 
 
  
 Effect of SPN-810 treatment on CGI-S and CGI-I scores 
 Effect of SPN-810 treatment on the R-MOAS score 
3 INVESTIGATIONAL PLAN 
3.1 Overall Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled, 2-arm, parallel-group 
study to evaluate the functional effect of SPN-810 treatment on IA in subjects aged 8-12 years 
diagnosed with ADHD in conjunction with approved ADHD medication. Figure 1 and Figure 2 
depict the study design schematically. 
This study consists of 3 phases: Pre-Treatment, Treatment, and Conversion/Taper.  
The Pre-Treatment Phase comprises of Screening and a Baseline MRI Visit for a total duration of 
up to 30 days. Following Screening (Visit 1), eligible subjects will proceed to the Baseline MRI 
visit (Visit 2) at the Imaging Center, where the brain MRI scans will be performed. At Visit 3, 
eligible subjects will be randomized to study medication or placebo.  
Eligible subjects will follow a dose-titration schedule as shown in Figure 1 and Figure 2, with 
dosing starting at
 and increasing approximately every 2 days until the target dose (36 
mg/day) is reached. The final dose will be maintained for 2 weeks (Maintenance period) during 
which time subjects will return for PK sampling (Visit 4) prior to receiving the final MRI scan at 
the Imaging Center (Visit 5). At the intervening visit during the maintenance phase (Visit 4), 
subjects will be given the option to taper down/discontinue study medication or convert to an 
ongoing OLE study (810P304) upon completion of the current study and will receive the blinded 
taper or the conversion study medication kit. 


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Subjects will return to the study site for a final EOS visit (Visit 6), after completing the 1-week 
Taper or Conversion phases. Subjects who choose to convert into the ongoing OLE (SPN-810 
304) will enter the study at a dose of 18 mg/day SPN-810.  
A subject who discontinues early in the Maintenance period, i.e., prior to Visit 5, may be 
allowed to participate in the OLE on a case-by-case basis after consultation by the Investigator, 
Medical Monitor, and Sponsor.  
 
 
 
 
Safety will be assessed by the monitoring of AEs, vital signs, ECGs and clinical laboratory tests, 
as well as by the Simpson-Angus Scale, the Barnes Akathisia Rating Scale (BARS), the Abnormal 
Involuntary Movement Scale (AIMS), and the Columbia-Suicide Severity Rating Scale (C-SSRS). 
These scales were chosen to specifically monitor EPS, since youths treated with antipsychotics 
are at greater risk for EPS side effects than adults (Findling et al., 2005). The Simpson-Angus 
Scale, BARS, and AIMS were utilized in Phase 2 studies and have been used in other clinical 
studies of atypical antipsychotics in children (Sikich et al., 2008; Stocks et al., 2012). 
3.2 Imaging Acquisition and fMRI Set-up 
This study is designed to use fMRI in conjunction with the PSAP aggression task. MR imaging 
parameters for the PSAP Task were optimized in the non-interventional 810P204a study that 
was conducted by the Sponsor in typically developing children 8-12 years of age. 
 BOLD fMRI  
BOLD fMRI is a method used to investigate brain activity by measuring the change in blood 
oxygenation. When a brain area is active, the flow of oxygenated blood increases to that region 
in response to increased oxygen demand. Changes in the relative levels of oxyhemoglobin and 
deoxyhemoglobin can be detected due to their differences in magnetic susceptibility. 
Deoxygenated hemoglobin is paramagnetic while oxygenated hemoglobin is diamagnetic. An 
Echo-Planar Imaging (EPI) MRI sequence is sensitive to changes in magnetization (T2*) and can 
therefore be used to measure blood oxygenation as a proxy for brain activity. 
This technique can be used during task-based fMRI, where the T2* contrast between a task and 
control condition can be used to identify regions of the brain that show a change in 
oxygenation as a result of the task. BOLD fMRI is therefore highly spatially selective, but less 
temporally specific (due to the slow time-course of blood flow). For instance, it can be used to 
see what regions are active during viewing of aggressive scenes, or what regions of the brain 
become active during a choice-inhibition task. Subsequently, the difference in the strength, 
location, or extent of brain activation between groups can be assessed.  
Another approach to assessing brain function is resting-state BOLD fMRI (rs-fMRI), where BOLD 
fMRI is measured during rest (during which the participant looks at an image of a crosshair 
during an 8-minute scan). Rs-fMRI can be used to study brain networks by looking at 
correlations in the time-course of the spontaneous BOLD signal time-courses ‘at rest’ between 


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different regions of the brain. These networks are thought to have specific functions and are 
considered connected, and many have been identified (e.g., the default mode network, 
executive control network, praxis network). Studies of different disorders have shown 
differences in the functional connectivity in these networks in different populations and can be 
indicative of differences in brain function. 
 Point Subtraction Aggression Paradigm (PSAP) Task 
The PSAP is a behavioral aggression paradigm in which each subject competes against a 
fictitious opponent (in reality, the computer) to earn points. At the start of the task, subjects 
will be instructed that they and another subject of the same age, who is located in a different 
building, will be competing to earn as many as points as possible.  Subjects are told that they 
will win prizes for their participation and can win additional prizes (money) if they complete the 
task. The subjects can press 1 of 3 buttons on a keypad (Option 1, 2 or 3) a set number of times 
to achieve a specific outcome.  
 
The PSAP Task will be presented using custom E-Prime 3.0 software (Psychology, Software Tools 
Pittsburgh, PA) developed by Dr. Todd Parrish’s Lab at Northwestern University in Chicago. The 
program will be run from a laptop computer synchronized to the MRI scanner. 
 
During each study visit at the Imaging Center, subjects will complete two PSAP-fMRI sessions, 
each lasting 12 minutes. For each run, the subject can remove points from his or her opponent 
(simulating aggressive behaviors) or have points stolen by the opponent (i.e., provocations). 
Options 1, 2 and 3 correspond to the index, middle, and ring finger of the dominant hand. The 
game status is presented on a screen, which includes the numbers of points earned and the 
current number of button presses.  
 
By pressing the button for Option 1, 100 times, the subject will earn a point ($1.00); pressing 
the button for Option 2, 20 consecutive times is the aggression action that results in stealing a 
point ($1.00) from the opponent; pressing Option 3, 20 times protects the subject from the 
opponent’s attempt to steal points (i.e., money) for a 60 second time frame. Once an option is 
selected, subjects are required to complete that option before choosing a new option. There 
will be a minimum of 170 ms between button presses to regulate how quickly they can choose 
the button to press. Provocations can occur at any time during the game and will be spaced at 
least 6-60s apart depending on the participant’s use of the protection option. 
 
When subjects reach 100 consecutive button presses, black flashing points (‘+’) are presented 
around the point total, which will then increase. When the subjects are provoked by having a 
point stolen, a red flashing ‘-‘ sign is displayed around the point total. 
 Data Acquisition 
All scanning will be performed on a Siemens-Skyra 3T MRI scanner using a 32-channel head coil. 
Functional images for the PSAP Task will be collected at an angle of 30° from the anterior 
commissure-posterior commissure (AC-PC) axis, which reduces signal dropout in the 


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orbitofrontal cortex (Deichmann et al., 2003). Seventy-two slices will be acquired at a resolution 
of 2 mm x 2 mm x 2 mm, providing whole-brain coverage. A GRE EPI pulse sequence will be 
used (repetition time (TR) = 2000 ms, echo time (TE) = 25 ms, multiband factor of 2, field-of-
view = 220 mm, flip angle = 80°).  
 
Resting-state data will be collected using a similar sequence for a duration of 8 minutes. 
 
Physiological measures of respiration and/or blood oxygen saturation will be measured during 
the scans to clean rs-fMRI data from physiological noise arising from these sources (Murphy et 
al., 2013). 
 Magnetic Resonance Spectroscopy (MRS) 
MRS relies on the observation of hydrogen protons, which have a magnetic moment when 
placed in a magnetic field (such as the MRI scanner). Water is the most abundant hydrogen-
containing compound in the brain, but when the water signal is suppressed, other H-proton-
containing metabolites can be observed. MRS allows for the measurement and therefore 
quantification of different metabolites within the human brain. An MRS spectrum contains all 
metabolites from a predefined region of brain tissue plotted along a chemical shift axis.  
3.2.4.1 GABA and Glutamate Brain Concentrations 
GABA and Glu are the human brain’s primary inhibitory and excitatory neurotransmitters, 
respectively, and play a key role in driving and regulating brain activity and function. While 
detectable using MRS, GABA and glutamate, though found at abundant concentrations in the 
human brain, have signals that overlap and are obscured by larger signals in conventional 
spectra. Therefore, use of conventional PRESS (Bottomley et al., 1987) sequence acquisition will 
be enhanced by dual echo time scheme, which allows additional information to be obtained on 
the spectral characteristics of the metabolites, lipids, and macromolecules. Furthermore, 
advanced numerical simulations that predict the exact pattern of the metabolites would be 
used during data fitting, which facilitates deconvolution of the spectral content (Kaiser et al., 
2008; Veshtort et al., 2006). In this study, glutamate (Glu) concentrations will be measured 
using advanced fitting software on the spectra. 
Due to the low sensitivity of MRS, these measurements are typically made from a large voxel in 
an approximately 8-minute scan duration to obtain sufficient signal to noise ratio to reliably 
estimate these neurotransmitters. There is no additional risk involved as this is a typical MRI 
scan protocol. Data will be acquired from the anterior cingulate cortex (ACC) region. 
3.2.4.2 MRS Data Acquisition 
MRS data will be acquired on a Siemens-Skyra 3T MRI scanner. Prior to MRS, a T1 
Magnetization-Prepared Rapid Acquisition with Gradient Echo (MPRAGE) will be acquired for 
voxel localization. MRS will be acquired in the ACC (Ende et al., 2016).  
A spatial localization in PRESS is performed using a 90° Hamming-filtered sync pulse (bandwidth 
time product = 8.75, duration = 2.12 msec, bandwidth [FWHM] = 4.2 kHz) and two 180° mao 


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pulses (duration = 5.25 msec, bandwidth = 1.2 kHz). All localization pulses are executed at 
3 ppm. The sequence will utilize two echo times (TE=23 ms and TE=140 ms, with TR=4 s).  
 
Variable power with optimized relaxation delays (VAPOR) and outer volume suppression are 
used to suppress water and to improve the localization of the volume of interest. The model 
spectra will be created using state-of-the art software Spinevolution, which employs advanced 
numerical simulation algorithms. Experimental parameters, such as echo time, pulse sequence 
delays, and RF pulse shapes will be utilized within the simulation to reproduce experimental 
conditions as close as possible (https://spinevolution.com). Other software packages may be 
used as needed to analyze the MRS data. 
The analysis allows the calculation of the best fit of the experimental spectrum as a linear 
combination of model spectra. All metabolites (including GABA and Glu) will be calculated from 
the combined spectral information from dual echo time scheme.  
The concentrations of the different metabolites of interest are expressed as ratios over creatine 
(Cr). 
3.3 Duration of Study Treatment 
The total subject duration on study: approximately 9 weeks. 
 Pre-treatment Phase: Up to 30 days 
o Screening: 1 day 
o Baseline MRI: 1 day 
 Treatment Phase: 28 days 
o Titration Period: 14 days 
o Maintenance Period: 14 days  
 Taper/Conversion Phase: 7 days 
 






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3.4 Pre-Treatment Phase (Up to 30 days) 
 Screening Period (Up to 30 days): Visit 1, Day -30 
Screening procedures will be conducted approximately 30 days before titration, and may be 
carried out over more than 1 visit if needed. Prior to conducting any study-related procedures, 
a written Informed Consent/Assent must be obtained from the subject’s parent or legal 
representative, and the subject (when required). Abnormal results on screening laboratory 
tests may be repeated at the discretion of the Investigator and the Medical Monitor. Each 
screened subject will be assigned a subject number in a sequential order.  
The population will be male and female subjects with IA and diagnosed with ADHD, currently 
being treated with an FDA-approved standard ADHD treatment. In addition, subjects who had 
qualified to participate in 1 of the ongoing double-blind Phase 3 studies (CHIME 1 and CHIME 2) 
but screen failed (i.e., non-compliance with the electronic diary or currently on ADHD 
treatment with more than one FDA-approved medication) may be eligible to participate in the 
810P204 study if they meet the study criteria. 
The diagnosis of ADHD will follow the definition found in the Diagnostic and Statistical Manual 
of Mental Disorders-5 (DSM-5), as confirmed with the Mini International Neuropsychiatric 
Interview for Children and Adolescents (MINI-KID). The MINI-KID instrument is designed to be 
used for children aged 6-17 years, and has been shown to have substantial to excellent 
concordance with the diagnosis of ADHD, among other Axis I psychiatric disorders (Sheehan et 
al., 2010; Leffler et al., 2015). The interview can take from 15 to 50 minutes, and can be given 
to parents or children, together or separately (Leffler et al., 2015).  
The R-MOAS and the CGI-S scale will be administered to determine if the subject is eligible to 
participate in the study. Both of these scales measure severity of IA, and only those subjects 
with an R-MOAS score of ≥20 and a score of at least “moderately ill” on the CGI-S will be eligible 
for the study.  
The Vitiello Aggression Scale will be used to evaluate the subtype of aggression (planned vs. 
impulsive); only those children who score between -2 and -5 and are considered predominantly 
impulsive will be included. 
During the screening visit at the clinical site, subjects will have their head shape scanned 
(approximately 2 minutes) using a noninvasive handheld 3D scanning system from Caseforge. 
 Baseline MRI (Visit 2) and Randomization (Visit 3): Day -5 to Day 0 
Baseline visits can be carried out in more than one day, within 30 days from screening. At 
Visit 2, subjects will receive the pre-treatment MRI scan at the Imaging Center. The subject’s 
MRI eligibility will be re-confirmed using the MR Safety Questionnaire prior the MRI scan.  
To be eligible for randomization at Visit 3, subjects must have minimally completed:  
 two (2) sessions of the PSAP Task fMRI and 
 the MPRAGE structural scan.  


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Subjects unable to finish these scans will not proceed to randomization.  
 
At Visit 3 the study site will randomize (1:1 ratio) qualified subjects to receive placebo or 
36 mg/day SPN-810. Subjects will be dispensed their study medication. 
 
3.5 Treatment Phase (4 weeks) 
 Titration Period, Day 1 to Day 14 
Subjects will be instructed to titrate to reach the maintenance dose over a period of 15 days, 
according to the dose titration schedule shown in Figure 1 and Figure 2. Dosing will begin at 
 SPN-810, and increase to
 on Day 3, 9 mg/day on Day 5, 
 on 
Day 8, 
 on Day 11, and 
 on Day 15. 
 Maintenance Period, (14 days) Day 15 to Day 28 
Following dose titration, treatment will be maintained for 2 weeks at 36 mg/day SPN-810 or 
placebo.  
At Visit 4, before the end of the Maintenance period, blood will be drawn for quantitative PK 
analysis. The morning dose of study medication will be administered in the clinic. The following 
PK samples will be collected: pre-dose (-30 minutes), and 2, 3, 4 and 6 hours post-dose (± 15 
minutes). 
At Visit 4, all subjects will also have the option to participate in an OLE study (Protocol 810P304) 
in which all subjects will receive active treatment. At the visit, subjects will receive a blinded 
conversion medication card that will adjust the subject’s total daily dose to 18 mg SPN-810 for 
initiation into the OLE (Figure 1). Those subjects who do not elect to participate in this 
extension study will be tapered down prior to discontinuation of the study medication and will 
receive a taper down card at Visit 4 (Figure 2). 
At Visit 5, subjects will return to the Imaging Center for the post-treatment fMRI/PSAP Task and 
will use (when applicable) the same Caseforge helmet used at Visit 2. 
 
At the completion of the MRI scans (Visit 2 and Visit 5), subjects will be administered the 
questionnaire to validate their understanding of the task and to describe the characteristics of 
their opponent. The results of the questionnaire will be provided to the study site. 
3.6 Taper/Conversion Phase (7 days), Day 29 to Day 35 
Subjects will complete the 1-week Taper or Conversion phase. 
3.7 End of Study (EOS)/Early Termination, Visit 6 (Day 35) 
Subjects will return to the study site for a final visit, after completing the 1-week Taper or 
Conversion phase. Those subjects who choose to continue into the OLE study will have 
procedures performed for that study; eligibility criteria will be confirmed at Visit 1 of study 
protocol 810P304. Only the subjects who discontinue from the study during the Maintenance 


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period or following Day 14 in the Titration period will be offered a Taper card at the study site 
one week prior the EOS. All subjects who discontinue early (i.e., during the Titration period, 
Day 1 to Day 14) will be instructed to return to the study site for a final visit (EOS), within 
1 week after discontinuation. 
4 STUDY METHODS 
4.1  Study Population 
Approximately 40 subjects aged 8-12 years (inclusive) will be screened to randomize 30 
subjects; 15 in the SPN-810 arm and 15 in the placebo arm. The population will be male and 
female subjects with IA and diagnosed with ADHD, currently being treated with an FDA-
approved standard ADHD treatment. In addition, subjects who had qualified to participate in 
one of the ongoing double-blind Phase 3 studies (CHIME 1 and CHIME 2) but screen failed (i.e., 
non-compliance with the electronic diary or currently on ADHD treatment with more than one 
FDA-approved medication) may be eligible to participate in the 810P204 study if they meet the 
study criteria. 
 Inclusion Criteria 
1. Male or female subjects, aged 8-12 years (inclusive) at the time of screening. 
2. Diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental 
Disorders-5 (DSM-5) confirmed by MINI-KID. 
3. R-MOAS score of 20 at screening. 
4. CGI-S score 4 at screening.  
5. Vitiello Aggression Scale score from -2 to -5 at screening. 
6. Treatment with FDA-approved optimized ADHD medication (i.e., psychostimulants) at an 
FDA-approved dose for at least 1 month prior to screening, and willing to maintain that 
dose throughout the Treatment phase.   
7. Free of antipsychotic medication for at least 2 weeks prior to the treatment.  
8. Medically healthy and with clinically normal laboratory profiles, vital signs, and ECGs. 
9. Weight of at least 20 kg. 
10. Able and willing to swallow tablets whole and not chewed, cut or crushed. 
11. Written Informed Consent obtained from the subject’s parent or legal representative, 
and written Informed Assent obtained from the subject, if appropriate. 
 Exclusion Criteria 
1. Body mass index (BMI) ≥99th percentile. 
2. 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. 


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3. Currently meeting DSM-5 criteria for autism spectrum disorder, pervasive developmental 
disorder, obsessive-compulsive disorder, post-traumatic stress disorder, or intermittent 
explosive disorder. 
4. Use of anticonvulsants including carbamazepine and valproic acid, antidepressants, 
mood stabilizers including lithium, benzodiazepines, cholinesterase inhibitors, or any 
drug known to inhibit or induce CYP2D6 activity within 2 weeks before the Treatment 
Period.  
5. Use of herbal supplements within 1 week prior to Treatment Period. 
6. Known or suspected IQ <70. 
7. Unstable endocrine or neurologic conditions that confound the diagnosis or are a 
contraindication to treatment with antipsychotics. 
8. Suicidality, defined as either active suicidal plan/intent or active suicidal thoughts in the 6 
months before the Screening Visit or more than 1 lifetime suicide attempt.   
9. Pregnancy, breastfeeding, or refusal to practice contraception during the study (for 
female subjects of childbearing potential and sexually active males). 
10. Major visual impairment. 
11. Documented hearing impairment ≥25 dB loss in either ear and or cochlear implants. 
12. Known history of implanted brain stimulator, vagal nerve stimulator, ventriculoperitoneal 
shunt, cardiac pacemaker, orthodontic braces, or implanted medication port. 
13. Pre-existing medical or psychological conditions that preclude being in the scanner (e.g., 
claustrophobia, morbid obesity, or marked anxiety about the procedure). 
14. Substance or alcohol use during the last 3 months. 
15. Urine drug test at screening that is positive for alcohol or drugs of abuse. 
16. Known allergy or sensitivity to molindone hydrochloride. 
17. Lack of IA symptoms due to current medication treatment. 
18. Any condition that in the opinion of the Investigator or the Sponsor would prevent the 
subject or the subject’s caregiver from participating in the study or complying with the 
study procedures. 
19. Use of an investigational drug or participation in an investigational study within 30 days 
prior Visit 2.  
20. Participation in a previous clinical trial with SPN-810 and received molindone 
hydrochloride (i.e., subjects who completed or discontinued from the CHIME studies or 
the OLE study 810P304). 
21. Siblings of study participants. 
4.2 Schedule of Visits and Procedures  
All subjects who have consented are required to follow the protocol procedures, regardless of 
the number of doses of study medication taken. The Sponsor, or the Sponsor’s designee, must 
be notified of all deviations from the Schedule of Events and Procedures (Table 1), and these 


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procedures, if applicable, should be performed at the nearest possible time to the original 
schedule. Subjects will be instructed to call study personnel to report any issues or abnormal 
reactions during the intervals between study visits and to return to the study site if medical 
evaluation is needed, especially when urgent. Unscheduled visits may be conducted at the 
discretion of the Investigator throughout all study periods. The Medical Monitor must be 
promptly contacted in the event that any clinically significant findings or information is 
obtained during the unscheduled visit. For emergency and other unscheduled visits to a medical 
facility other than the study site, medical records will be obtained by the Investigator or 
qualified designee as source data for study follow-up by the Investigator.


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Table 1: Schedule of Events and Procedures 
Phase 
Pre-treatment 
Treatment 
Taper/Conversion 
Period 
Screening 
Baseline 
Titration 
Maintenance  
EOS 
VISIT NUMBER 
1 
2a 
3 
 
4b 
5a 
6c 
Day 
-30 
-5 to 0 
1-14 
21 
28 
35 
Window (days) 
≤30d prior  
to  
titration 
≤5d prior to 
titration 
0 
- 2/+1 d  
from titration 
-/+ 1d  
from titration  
7d±2d from Visit 5 
Informed Consent/Assentd 
X 
 
 
 
 
 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
R-MOAS, MINI-KID, CGI-S, and 
Vitiello Scales 
X 
 
 
 
Xe 
 
Xe 
CGI-I Scale 
 
 
 
 
X 
 
X 
Medical History and 
Demographic Data 
X 
 
 
X 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
 
X 
ECG (12-lead) 
X 
 
 
 
X 
 
X 
Vital Signs  
X 
 
 
 
X 
 
X 
Hematology/Chemistry/ 
Urinalysis 
X 
 
 
 
 
 
X 
PK Blood Sampling 
 
 
 
 
X 
 
 
Weight, Height, and BMI 
X 
 
 
 
X 
 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
Urine Pregnancy Test f 
X 
 
 
 
 
 
X 
Caseforge Scan 
X 
 
 
 
 
 
 


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Phase 
Pre-treatment 
Treatment 
Taper/Conversion 
Period 
Screening 
Baseline 
Titration 
Maintenance  
EOS 
VISIT NUMBER 
1 
2a 
3 
 
4b 
5a 
6c 
Day 
-30 
-5 to 0 
1-14 
21 
28 
35 
Window (days) 
≤30d prior  
to  
titration 
≤5d prior to 
titration 
0 
- 2/+1 d  
from titration 
-/+ 1d  
from titration  
7d±2d from Visit 5 
Edinburgh Handedness 
Inventory 
 
X 
 
 
 
 
 
MRI Safety Questionnaire 
 
X 
 
 
 
X 
 
Habituation Phase (Practice 
and Mock Scan) 
 
X 
 
 
 
X 
 
MRI Session 
 
X 
 
 
 
X 
 
PSAP Questionnaire 
 
X 
 
 
 
X 
 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
X 
 
 
 
X 
 
X 
Safety Scales (Simpson-Angus, 
BARS, and AIMS) 
 
 
 
 
X 
 
X 
Adverse Events 
 
 
X 
 
X 
Xi 
X 
Concomitant Medication 
X 
 
X 
 
X 
Xi 
X 
Randomization 
 
 
Xg 
 
 
 
 
Drug Compliance 
 
 
 
 
X 
 
X 
Drug Dispensation 
 
 
Xj 
 
Xh 
 
 
Drug Return  
 
 
 
 
X 
 
X 


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a. 
The fMRI for Visit 2 and Visit 5 will be performed at the Imaging Center. At Visit 5 the fMRI will be schedule preferably in the morning 3 hours +/- 1 hour from the time the study medication was taken 
in the maintenance period. 
b. 
Subjects will decide if they will participate in the OLE 
c. 
Subjects who choose to participate in the OLE will consent at Visit 6. 
d. 
Written Informed Consent must be obtained prior to performing any study-related procedures. 
e. 
Only R-MOAS and CGI-S scale will be administered. 
f. 
To be performed for female subjects of childbearing potential  
g. 
Randomization will be performed by the study site once eligibility from the two PSAP fMRI sessions and structural scan are completed at the Imaging Center.   
h. 
Taper or Conversion kit will be dispensed. 
i. 
AEs and Con Meds will be recorded through a follow up call from the site 
j. 
Subjects will start their first dose the next day after dispensation (Day 1). 
 
 


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 Screening/Visit 1 (Day -30) 
Prior to conducting any procedures, written Informed Consent must be obtained from the 
parent or LAR, and, if appropriate, Informed Assent will be obtained from the subject. Subject 
screening procedures will be performed within 30 days prior to titration, and may be done on 
more than 1 day. At Visit 1, subjects will have their head shape scanned at the clinical site using 
a noninvasive handheld 3D scanning system from Caseforge system. A fitted and custom 
designed foam helmet will be ordered to be used inside the MRI scanner (Caseforge, California). 
The helmet has been shown to limit head motion in an fMRI scanner (Gao et al., 2015). 
The following procedures will be performed at Visit 1: 
1. Obtain written Informed Consent and Assent. 
2. Confirm Inclusion/Exclusion criteria. 
3. Administer MINI-KID for ADHD diagnosis. 
4. Administer Vitiello Aggression Scale. 
5. Administer R-MOAS. 
6. Administer CGI-S. 
7. Record Medical History. 
8. Record Demographic Information. 
9. Perform Physical Examination. 
10. Perform 12-lead ECG. 
11. Collect Urine for Urine Drug Screen and Urinalysis (all subjects) and Pregnancy Test 
(females of childbearing potential [FOCP] only). 
12. Record Vital Signs (Heart Rate [HR], Blood Pressure [BP], Temperature, and Respiration 
Rate [RR]). 
13. Record Weight, Height, and BMI. 
14. Collect Blood Samples for Hematology and Chemistry.  
15. Administer C-SSRS. 
16. Record Concomitant Medications. 
17. Access IWRS for subject number. 
18. Scan head shape using the Caseforge system. 
 Baseline MRI Scans/ Visit 2, (Day -5 to 0) 
Baseline may be carried out in more than one day but will occur within 5 days prior to the 
Titration period per the Schedule of Events and Procedures.  
At Visit 2 the pre-treatment MRI session will be performed at the Imaging Center with the 
following activities: 
1. Administer MRI Safety Questionnaire  
2. Administer Edinburgh Handedness Inventory 


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3. Habituation Phase 
4. MRI Session  
5. Administer the PSAP Questionnaire 
4.2.2.1 MR Safety Questionnaire and Edinburgh Handedness Inventory 
Prior to any MRI procedures, subjects will complete the MR Safety Questionnaire to confirm 
their eligibility to proceed with the MRI scan.  
 
The Edinburgh Handedness Inventory is a well-known short questionnaire used to objectively 
determine whether one is left or right handed (Oldfield, 1971),   
 
The MR Safety Questionnaire and the Edinburgh Handedness Inventory will be recorded on a 
paper source and collected at the Imaging Center.  
4.2.2.2 Habituation Phase 
Eligible subjects will undergo a habituation phase, during which they will learn and practice the 
PSAP Task outside of the MRI environment. During this phase, subjects will perform a short, 3 
to 5 minute version of the PSAP Task to habituate them to the task. In order to habituate to the 
horizontal position inside a head coil, subjects will undergo a 20-minute mock MRI acquisition. 
During the mock session, subjects will learn to keep their head still via feedback from the 
sensor based on the MoTrak head motion feedback system (Psychology Software Tools, 
Pennsylvania). The MoTrak system has been shown in multiple studies to be effective in 
training pediatric populations to limit their head motion inside an MRI scanner (Epstein et al., 
2007; Greene et al., 2016). Subjects will also acclimate themselves to the MRI scanner sounds 
during this time. 
4.2.2.3 MRI Session 
After a short break, the subject will be placed on the MR scanner bed and positioned in the 32-
channel head coil using the Caseforge customized helmet, such that the subject can see the 
projection screen at the back of the magnet via a mirror system. The subject will be given ear 
plugs, may have a respiratory belt placed around their chest, a pulse sensor placed on their toe, 
and given the button box for the PSAP Task and the emergency squeeze ball. Subjects will 
undergo approximately 1-hour MR imaging session with the following acquisitions: 
1. 3-plane localizer scan 
2. First 12-minute PSAP Task fMRI scan 
3. Second 12-minute PSAP Task fMRI scan 
4. A 6-minute 3D MPRAGE anatomical scan (subjects will be watching a short movie) 
5. One 8-minute MRS acquisition 
6. rs-fMRI scan to establish their resting-state BOLD signal (subjects will view a crosshair 
during 8 minutes) 
7. A 3-minute T2 fluid-attenuated inversion recovery (FLAIR) clinical anatomical scan 


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Although breaks are not recommended during the imaging sessions, subjects may be allowed to 
take a short break (approximately 10 minutes) if they request it or once they complete the 
sessions up to the 3D MPRAGE scan. 
Subjects who are not able to complete the aggression task session(s) and the structural scan 
(3D MPRAGE anatomical scan) will be considered early discontinued and not included in the 
analysis. 
 
After the MRI session, subjects will be administered the PSAP Questionnaire to validate their 
understanding of the task and to describe their opponent. Subjects will be excluded from the 
analysis if they do not believe they played against a real person (e.g., they were thinking they 
were playing against a computer). The results of the questionnaire will be provided to the study 
site. 
 
Once all the procedures are completed at the Imaging Center, eligible subjects will be 
instructed to return to the study site for Visit 3. 
 
 Randomization/ Visit 3, (Day 0) 
The following procedures will be performed at the study site: 
 
1. Randomization. 
2. Record Concomitant Medications. 
3. Record Adverse Events. 
4. Assess for any clinical significant changes in Medical History. 
5. Dispense Study Medication 
 Maintenance/Visit 4 (Day 21) 
Visit 4 will occur 21 days after the start of the Titration period. Subjects will be instructed to 
take their morning dose at the site. The following procedures will be performed: 
 
1. Administer CGI-I and CGI-S. 
2. Administer R-MOAS. 
3. Record Vital Signs (Heart Rate [HR], Blood Pressure [BP], Temperature, and Respiration 
Rate [RR]). 
4. Perform Physical Examination. 
5. Record Height, Weight, and BMI. 
6. Perform 12-lead ECG.  
7. Collect blood samples for PK. 
8. Administer C-SSRS. 


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9. Administer Safety Scales (Simpson-Angus, Barnes Akathisia Rating, and AIMS). 
10. Record Adverse Events. 
11. Record Concomitant Medications. 
12. Assess Drug Compliance. 
13. Drug Return. 
14. Dispense Study Medication (Either Conversion or Taper dose based on subject’s decision 
to participate in OLE. 
 Maintenance/Visit 5 (Day 28) 
Visit 5 will occur 28 days (± 1 day) after starting the Titration Period and no more than 1 day 
after completion of Maintenance period per the Schedule of Events and Procedures. Subjects 
will take the morning dose of study medication and the ADHD medication before the visit. 
 
The post-treatment MRI session will be scheduled preferably in the morning, within 3 hours 
+/- 1 hour from the time the study medication was taken during the maintenance period.  
 
The following activities will be performed at the Imaging Center. 
 
1. Administer MR Safety Questionnaire 
2. Habituation Phase 
3. MRI session 
4. Administer the PSAP Questionnaire 
Upon completion of the post-treatment MRI session, the study site will follow up with a call to 
collect the following activities: 
 
1. Record Adverse Events. 
2. Record Concomitant Medications.  
 Taper/Conversion/Visit 6 (Day 35)/EOS 
Visit 6 will occur approximately 7 days (±2 days) following Visit 5 according to the Schedule of 
Events and Procedures. These procedures will be performed for all subjects who complete the 
Maintenance period and for those who discontinue early. Subjects who discontinue during the 
Maintenance period (between Day 15 and 28) will be offered a Taper card and return to the 
study site to complete Visit 6. Any subject who discontinues during the Titration period (Days 1-
14), will be instructed to return to the study site for the final visit, within 1 week after 
discontinuation. 
1. Administer R-MOAS. 
2. Administer CGI-I and CGI-S. 
3. Perform Physical Examination. 
4. Perform 12-lead ECG. 


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5. Collect Urine for Pregnancy Test (FOCP only).  
6. Record Vital Signs (Heart Rate [HR], Blood Pressure [BP], Temperature, and Respiration 
Rate [RR]). 
7. Record Height, Weight, and BMI. 
8. Collect Blood for Hematology and Chemistry. 
9. Collect Urine for Urinalysis. 
10. Administer C-SSRS. 
11. Administer Safety Scales (Simpson-Angus, Barnes Akathisia Rating, AIMS). 
12. Record Adverse Events. 
13. Record Concomitant Medications. 
14. Collect Study Medication and Assess Treatment Compliance. 
15. Obtain written Informed Consent and Assent for OLE study. 
16. Complete/Discontinue Subject. 
 Pharmacokinetic Blood Sampling  
 
 
 
 
 
.  
5 TREATMENTS 
5.1 Treatments Administered 
SPN-810  
Subjects will take molindone hydrochloride extended-release tablet (SPN-810) or placebo twice 
each day (BID) with or without food, in the morning and in the evening, in addition to their 
stable dose of the optimized ADHD medication. Subjects should start the first dose the morning 
following Visit 3. Subjects will be randomized to one of the 2 treatments at the completion of 
Visit 3. Subjects will be titrated to the final randomized total daily dose (TDD).  
Reference Treatment 
 Treatment 1: Placebo (PBO) tablets (2 tablets), BID 
Test Treatment 
 Treatment 2: SPN-810, 36 mg (2 tablets) TDD, BID 


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ADHD Medication 
The Investigator is not allowed to adjust the FDA-approved ADHD monotherapy medication 
and/or its dose at any time during the course of this study. 
 Identity of Investigational Product(s) 
Study medication and reference (matching placebo) products are either purple (3 mg) or yellow 
(9 mg) round tablets which are printed with the appropriate dose strength in a black 
underscored font (“3” or “9”).   
A sufficient quantity of medication will be dispensed for the subject to take the designated dose 
every day until the next visit to the office, according to Table 1.  
Each study medication blister card will contain combinations of SPN-810 and/or placebo 
tablets, which will supply a subject with 7 days of dosing with one additional dosing for lost 
product and/or to account for visit delays associated with patient schedules.   
A single study medication kit contains a total of 6 pre-packaged blister cards (2 Titration blister 
cards, 2 Maintenance blister cards, 1 Taper blister card and 1 Conversion blister card) and is 
marked with a unique 4-digit study medication kit number.   
 Study Medication Handling and Accountability 
All study medication is supplied to the Investigator by the Sponsor. Study medication must be 
kept in an appropriately secure area (e.g., locked cabinet) and stored according to the 
conditions specified on the study medication labels.  Study medication must be stored between 
59 – 86°F (15 – 30°C). 
Following Sponsor instructions and in compliance with International Conference on 
Harmonization (ICH) E6 as well as local, state, and federal regulations, the Investigator and 
study staff will be responsible for the accountability of all clinical supplies (receiving, shipping, 
dispensing, maintaining inventory, and record-keeping) in a study medication accountability 
log, a copy of which will be collected by the Sponsor at the end of the study. 
Under no circumstances will the Investigator allow the study medication to be used other than 
as directed by this protocol.  Clinical supplies will not be dispensed to any individual who is not 
enrolled into the study. 
An accurate and timely record of the receipt of all clinical supplies, the dispensing of study 
medication to the subject, the collection of unused supplies returned by the subject, and the 
return of unused study medication to the Sponsor must be maintained with dates.  This study 
medication accountability log includes, but may not be limited to: (a) documentation of receipt 
of clinical supplies, (b) study medication inventory log, (c) study medication accountability log, 
and (d) all shipping notifications.  All forms will be provided by the Sponsor.  Any comparable 
forms that the study site wishes to use must be approved by the Sponsor. 
Supplies and inventory records must be made available upon request for inspection by the 
designated representative of the Sponsor or a representative of the FDA.  The assigned Clinical 
Research Associate (CRA) will review these documents along with all other study conduct 


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documents at each and every visit to the study site once study medication has been received by 
the study site.  All used, partly used, and unused clinical supplies, including empty containers, 
are to be returned to the Investigator by the subjects and ultimately to the Sponsor at the 
conclusion of the study, unless provision is made by the Sponsor for destruction of supplies and 
containers at the study site.  Upon completion of study medication accountability and 
reconciliation procedures by study site personnel and documentation procedures by Sponsor 
personnel, study medication is to be returned to the Sponsor with a copy of the completed 
study medication disposition form as outlined in the Study Medication Manual. 
 Method of Assigning Subjects to Treatment Groups 
Allocation of the study medication will be completed centrally through the use of an interactive 
web response system (IWRS) that will determine which kit to assign to the subject. The final 
randomization schedules will be created by a designated unmasked statistician using SAS (SAS 
Institute, Cary, North Carolina, Version 9.2 or higher). Separate schedules for subject 
randomization and drug kit list will be created. The randomization scheme assigns treatment 
codes to each randomization number in a 1:1 ratio.  
Upon enrollment to the study, subjects will be assigned site (01-99) and subject numbers in the 
sequence that they are entered.  Subjects who minimally complete the two (2) PSAP sessions 
and the MPRAGE structural scan and meet all eligibility criteria will be assigned kit numbers, 
according to the randomization schedule, by using the IWRS. 
 Treatment Replacement 
In the event that a subject’s original kit is lost, damaged, or consumed prior to the end of 
treatment, the Investigator will consult the IWRS, which will specify a replacement kit number 
to be sent to the site. Separate reserve supplies will not be provided to the Investigators. 
 Dosing Schedule 
At Visit 3, eligible subjects will be randomized to placebo or to SPN-810 in a 1:1 ratio and the 
study medication will be dispensed. Dosing will begin the following day after drug dispensation. 
Table 2 below presents the details of the dosing for each active treatment group throughout 
the 4-week Treatment Phase for this study. Dose reduction will not be permitted in the study.  
 
Table 2: Titration Dosing Schedule 
Treatment 
Arm 
Final Dose 
 
Study Days 
 
1-2 
3-4 
5-7 
8-10 
11-14 
15+ 
 
 
Period* 
T 
T 
T 
T 
T 
M 
1 
Placebo 
 
PBO 
PBO 
PBO 
PBO 
PBO 
PBO 
2 
36 mg 
 
 
 
 
 
 
 
*T=Titration period; M=Maintenance period; PBO=Placebo 


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 Method of Administration 
The study medication must be swallowed whole. Study medication must not be crushed, 
chewed or cut. The study medication may be taken with or without food in the morning and in 
the evening, preferably every 12 hours.  
 Blinding 
The subject and all study personnel involved with the conduct and interpretation of the study, 
including the Investigators, site personnel and the Sponsor will be blinded to the medication 
codes. A limited number of Supernus personnel will perform and interpret the plasma assays 
for the population PK analysis and will be aware of these PK data during the study. These 
personnel will not have access to the randomization schedule, are not associated with the 
clinical conduct of the study, and will not reveal to any clinical personnel involved in the study 
the treatment to which a subject is assigned. Randomization schedule data will be kept strictly 
confidential, filed securely by the IWRS vendor, and accessible only to authorized persons until 
the time of unblinding. 
The study medication tablets have matching placebo tablets. Blinding is maintained through the 
IWRS, and will be maintained through the end of the Conversion/Taper phase. 
The Investigator must try to avoid breaking the blind. The decoding information will not be 
viewed unless an actual medical or medication safety emergency occurs. The Investigator can 
access the subject’s randomized treatment information via IWRS only if knowledge of the 
treatment regimen will influence or assist with medical management of the subject in an acute 
emergency. Before breaking the blind, every effort must be made to contact the Medical 
Monitor to ascertain the necessity of breaking the code.  If the Investigator is unsuccessful in 
contacting the Medical Monitor, he/she will contact the backup Medical Monitor (or other 
appropriate designee if the backup Medical Monitor is unavailable). If it is not possible to 
contact the Medical Monitor or the backup Medical Monitor (or designee), and the situation is 
an emergency, the Investigator may break the blind and contact the Medical Monitor as soon 
as possible. The Investigator is to make a careful note of the date and time of decoding, the 
reason that necessitated breaking the code, and the signature of the person who broke the 
code. Upon breaking the randomization code, the subject should be withdrawn from the study 
but should be followed up for safety purposes. 
 Allowed Medication 
The following medications are allowed during this study:  
1. Current or other FDA-approved monotherapy ADHD medication (the ongoing 
medication will not be adjusted during the study). 
2. EMLA (lidocaine 2.5% and prilocaine 2.5%) or other numbing cream for pharmacokinetic 
venipuncture. 
3. Benztropine is permitted for the treatment of emerging EPS at a starting dose of 0.5 mg 
BID up to a range of 1 to 4 mg/day. Lorazepam (1 to 2 mg per dose not to exceed 3 


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times daily) and clonazepam (0.25 to 1 mg per dose not to exceed twice daily) is also 
permitted to treat EPS. 
4. For the treatment of akathisia, propranolol is recommended, up to 90 mg/day in divided 
doses, 3 times per day, starting at 10 mg twice daily and up to 30 mg 3 times daily, as 
needed. 
5. Common over-the-counter (OTC) therapies for minor transient ailments (e.g., 
acetaminophen for headache, ibuprofen for fever) will be allowed without exception. 
6. Treatment for AEs other than EPS or minor transient ailments is permitted in 
consultation with the Medical Monitor and Sponsor.   
All concomitant medications as well as the dosing of the FDA-approved ADHD medication will 
be recorded in the electronic case report form (eCRF). 
 Study Restrictions 
Subjects may not be on any prohibited medication while on study as indicated in the 
Inclusion/Exclusion Criteria. These medications include:  
 Anticonvulsants including carbamazepine and valproic acid, antidepressants, mood 
stabilizers including lithium, benzodiazepines, cholinesterase inhibitors, or any drug 
known to inhibit or induce CYP2D6 activity  
 α2-adrenergic agonists (e.g., clonidine and guanfacine) used for any other reason except 
for monotherapy treatment for ADHD  
 Herbal and nutritional supplements  
5.2 Completion of Study and Discontinuation of Subjects  
Subjects will be considered to have completed the study if they complete all visits up to and 
including Visit 6.  Any subject who discontinues from the study during the Maintenance period 
or following Day 14 in the Titration period will be offered a Taper card at the study site one 
week prior the EOS. Subjects who discontinue during the Titration period (i.e., Day 1 through 
Day 14) will be instructed to return 1 week after discontinuation to the study site for a final 
visit. All subjects who discontinue after Visit 2 will complete Visit 6, EOS procedures.   
The Investigator(s) or subjects themselves may stop study medication treatment at any time for 
safety or personal reasons.  A subject is free to withdraw from the study at any time for any 
reason without prejudice to their future medical care by the physician or at the institution.  The 
Investigator or Sponsor may also withdraw the subject at any time in the interest of subject 
safety.  The withdrawal of a subject from the study by the investigator should be discussed 
where possible with the Medical Monitor before the subject stops study medication. Subjects 
removed from the study for any reason will not be replaced. 
Reasons for withdrawal may include but are not limited to subject withdrawal of consent, 
occurrence of unmanageable AEs, or if it is in the best interest of the subject as per 
Investigator’s discretion. 


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The primary reason for withdrawal must be recorded in the subject’s medical record and on the 
eCRF. If a subject is withdrawn for more than one reason, each reason should be documented 
in the source document and the most medically significant reason should be entered on the 
eCRF. 
6 ANALYSIS VARIABLES 
 
6.1 Primary Variable 
The primary analysis variable will be the treatment effect of SPN-810 on the change in BOLD 
fMRI contrast associated with the aggressive response from Baseline (Visit 2) to Visit 5 
measured in subjects with ADHD and IA participating in the PSAP aggression Task.  
Briefly, the primary endpoint is the change in brain activity measured by a change in BOLD 
response in brain regions during provocation or during the aggressive response relative to the 
monetary response at baseline and following 4 weeks treatment with SPN-810, compared to 
placebo.  
Behavioral data may allow calculation of the aggressive score, defined as the number of Option 
2 presses (aggressive response) divided by the total number of button presses and the number 
of provocations received.   
Details of the analyses will be provided in the statistical analysis plan (SAP). 
6.2 Secondary Variables 
 Functional Connectivity 
Resting-state data will be used to generate maps of functional connectivity within brain 
networks and/or ROI and will be stored in a correlation matrix. To investigate brain networks, a 
seed to whole brain correlation map may be used to investigate changes in network 
connectivity. All correlation coefficients will be converted to a z-score using Fisher’s 
Z-transformation to normalize values.  
To look at connectivity between ROIs, seed to seed correlation values will be calculated. All 
correlation coefficients will be converted to a z-score using Fisher’s Z-transformation to 
normalize values. In addition, the relevant variables for the correlation matrices will be 
calculated by Northwestern University. 
 GABA and Glutamate Brain Concentrations 
The concentrations of neurotransmitters Glu and GABA will be achieved during the MRS scan 
and evaluated in the anterior cingulate cortex (ACC).  


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6.3 Safety Assessments 
 Adverse Events 
Although adverse events (AEs) for MRI scans are very rare, any medical occurrence during and 
after the study procedures will be recorded as an AE. 
As defined by the ICH Guideline for Good Clinical Practice (GCP), an adverse event (AE) is any 
untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
treatment. 
An AE can be:  
1. Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
2. Any new disease, intercurrent injuries, or exacerbation of an existing disease. 
3. Any deterioration in a laboratory value or other clinical test (e.g., ECG) that results in 
symptoms, a change in treatment, or discontinuation from study medication. 
4. Recurrence of an intermittent medical condition (e.g., headache) not present at the 
beginning of the study. 
Surgical procedures are not AEs; they are therapeutic measures for conditions that require 
surgery.  The condition for which the surgery is required is an AE if it occurs or is detected 
during the study period. 
6.3.1.1 Causality 
AEs may be categorized as either adverse drug reactions or suspected adverse drug reactions 
(SADRs) based on their relationship to the study medication or procedure and the degree of 
certainty about causality. 
SADRs are a subset of AEs for which there is evidence to suggest a causal relationship between 
the drug and the AE; i.e., there is a reasonable possibility that the drug caused the AE.   
Adverse drug reactions (ADRs) are a subset of all AEs for which there is reason to conclude that 
the drug or procedure caused the event. 
6.3.1.2 Recording and Evaluation of Adverse Events 
All subjects who provided written Informed Consent (starting at Visit 1) will be questioned 
regarding the occurrence of AEs. Treatment emergent adverse events (TEAE) are 
undesirable events not present prior to study treatment/procedures, or an already 
present event that worsens either in intensity or frequency following the study 
treatment/procedure. A treatment emergent adverse event (TEAE) is an adverse event that 
occurs after study treatment/procedures has started.  Adverse events occurring prior to the 
administration of the study medication/procedures (Day 1) will become part of the subject’s 


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medical history including the severity of the event. At each visit, the Investigator must seek 
information on AEs by specific questioning and, as appropriate, by examination.  Information on 
all AEs should be recorded immediately in the source document and also in the appropriate AE 
module of the eCRF. All clearly related signs, symptoms, and abnormal diagnostic 
procedures/laboratory results should be recorded in the source document, though they may be 
assessed as one diagnosis. For example fever, elevated white blood cells, cough, abnormal 
chest X-ray, etc., may all be reported as pneumonia. 
6.3.1.3 Criteria for Assessing Severity 
The Investigator will evaluate the comments of the subject and the response to treatment in 
order that he or she may judge the true nature and severity of the AE. Severity refers to the 
accumulated intensity of discomfort/impairment of health since the last recording of AEs and 
will be assessed according to the following criteria: 
 Mild: Awareness of sign, symptom, or event, but easily tolerated 
 Moderate: Discomfort enough to interfere with usual activity and may warrant 
intervention 
 Severe: Incapacitating with inability to do usual activities or significantly affects clinical 
status and warrants intervention 
The criteria for assessing severity are different from those used for seriousness. 
6.3.1.4 Criteria for Assessing Causality 
The Investigator is responsible for determining the relationship between the administration of 
study medication and the occurrence of an AE as not suspected or as a suspected reaction to 
study medication. These are defined as follows:  
Not suspected: The temporal relationship of the AE to study medication administration makes 
a causal relationship unlikely, or other drugs, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed event.  
 Not related: Temporal relationship to study medication administration is missing or 
implausible, or there is an evident other cause. 
 
Unlikely related: Temporal relationship to study medication administration makes a 
causal relationship improbable; and other drugs, chemicals, or underlying disease 
provide plausible explanations. 
Suspected: The temporal relationship of the AE to study medication administration makes a 
causal relationship possible, and other drugs, therapeutic interventions, or underlying 
conditions do not provide a sufficient explanation for the observed event. 
 Possibly related: Temporal relationship to study medication administration is plausible, 
but concurrent disease or other drugs or chemicals could also explain the event. 


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Information on medication withdrawal may be lacking or unclear. This will be reported 
as a SADR. 
 Definitely related: Temporal relationship to study medication administration is 
plausible, and concurrent disease or other drugs or chemicals cannot explain the 
event. The response to withdrawal of the medication (de-challenge) should be clinically 
plausible. The event must be definitive pharmacologically or phenomenologically, using 
a satisfactory re-challenge procedure if necessary. This will be reported as an adverse 
drug reaction (ADR). 
 Serious Adverse Events (SAEs) 
AEs are classified as serious or non-serious. An AE or ADR is considered “serious” if, in the view 
of either the Investigator or Sponsor, it results in one of the following outcomes:  
 Death 
 Life-threatening AE (I.e., the subject was at immediate risk of death from the AE as it 
occurred.  This does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death.) 
 Inpatient hospitalization or prolongation of existing hospitalization 
 Persistent or significant disability or incapacity or substantial disruption of the ability to 
conduct normal life functions 
 A congenital anomaly or birth defect 
 An important medical event 
Important medical events are those that may not be immediately life-threatening or result in 
death or hospitalization, but are clearly of major clinical significance. They may jeopardize the 
subject, and may require intervention to prevent one of the other serious outcomes noted 
above. For example, drug dependence or abuse, blood dyscrasias, a seizure that did not result 
in inpatient hospitalization, or intensive treatment for allergic bronchospasm in an emergency 
department would typically be considered serious. 
6.3.2.1 Investigator Responsibilities for Reporting SAEs 
The Investigator must immediately report to the Sponsor all SAEs, regardless of whether the 
Investigator believes they are drug related. 
The Investigator must report all SAEs to the Drug Safety Contact person(s) within 24 hours of 
first becoming aware of the SAE.  The Investigator must complete an SAE Form and include a 
detailed description of the SAE, as well as other available information pertinent to the case 
(e.g., hospital records, autopsy reports, and other relevant documents). The Investigator will 
keep a copy of this SAE Report Form on file at the study site. 
The Investigator or study physician, after thorough consideration of all facts that are available, 
must include an assessment of causality of an AE to study medication in the report to the 
Sponsor. 


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Follow-up information, or new information available after the initial report, should be actively 
sought and reported to the Sponsor as it becomes available using the SAE Report Form. 
The Drug Safety Contact for SAE reporting is: 
 
 
 
 
 
 
6.3.2.2 Other Events Requiring Immediate Reporting 
The Investigator must report a pregnancy that occurs in a subject during a clinical study to the 
Drug Safety Contact within 24 hours of first becoming aware of the event. Pregnancy should be 
reported on a Pregnancy Report Form. The Investigator should discuss the case with the 
Sponsor Medical Monitor; the Investigator must also follow any pregnant subject for 3 months 
after the child is born. Any AEs concerning the health of the subject during pregnancy or the 
child after birth must be documented and reported to the Sponsor. 
Treatment-emergent EPS (e.g., akathisia, dystonia, parkinsonism, tardive dyskinesia), and 
neuroleptic malignant syndrome should in addition to documenting in the CRF, be reported to 
the Drug Safety Contact by faxing or scanning the appropriate completed form/source 
documentation within 24 hours of first becoming aware of the event. EPS incidence will be 
summarized and shared with study Investigators throughout the clinical trial. 
Overdosage of molindone presumably may be manifested by severe EPS and sedation. Coma 
with respiratory depression and severe hypotension resulting in a shock-like syndrome could 
occur. In the event of a suspected overdose, the parent or legal representative should be 
instructed to call 911 or their local poison control center at
 
Symptomatic, supportive therapy should be the rule. Gastric lavage is indicated for the 
reduction of absorption of SPN-810, which is freely soluble in water. Since the adsorption of 
SPN-810 by activated charcoal has not been determined, the use of this antidote must be 
considered of theoretical value. 
Emesis in a comatose patient is contraindicated. Additionally, while the emetic effect of 
apomorphine is blocked by SPN-810 in animals, this blocking effect has not been determined in 
humans. 
6.3.2.3 Sponsor Responsibilities for Expedited Reporting of SAEs 
The Sponsor will inform Investigators and regulatory authorities of ADRs that are both serious 
and unexpected, in compliance with applicable regulatory requirements, on an expedited basis 
(i.e., within specific time frames). For this reason, it is imperative that study sites submit SAE 
information to the Sponsor in the manner described above. 


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 Management of Treatment-Emergent Extrapyramidal Symptoms 
If a subject experiences treatment-emergent EPS (including akathisia, dystonia, parkinsonism, 
or tardive dyskinesia), benztropine will be permitted at a starting dose of 0.5 mg BID up to a 
range of 1 to 4 mg/day. Lorazepam (1 to 2 mg per dose not to exceed 3 times daily) and 
clonazepam (0.25 to 1 mg per dose not to exceed twice daily) will also be permitted to treat the 
occurrence of EPS. For the treatment of akathisia, propranolol is recommended up to 
90 mg/day in divided doses, 3 times per day, starting at 10 mg twice daily and up to 30 mg 
three times daily, as needed. 
A positive finding on an EPS safety assessment scale (Barnes Akathisia Rating, Simpson-Angus, 
or AIMS) does not necessarily equate to an EPS event. Investigators should evaluate positive 
findings on the EPS safety assessment scales and integrate them into a global clinical 
observation to determine if an AE of EPS should be recorded. 
 Laboratory Measurements 
With the exception of urine pregnancy tests, clinical laboratory tests will be performed by a 
central laboratory as specified in the reference binder. 
Details for collecting, handling, and shipping samples (including shipment addresses) will be 
described in a separate laboratory manual. The Schedule of Visits and Procedures (Table 1) 
shows the time points at which urine samples will be collected for urinalysis and blood samples 
will be collected for clinical laboratory tests and plasma concentration levels.   
Table 3 presents the clinical laboratory tests to be performed. Metabolic parameters (including 
insulin, glucose, triglycerides, and cholesterol) and prolactin will be measured. 
All laboratory tests will be reviewed in a timely manner by qualified site personnel to ensure 
safety. Abnormal lab findings may be confirmed if necessary by one repeated test at the 
discretion of the Investigator. Any laboratory abnormality may qualify as an AE in the 
Investigator’s judgment. 
A total of approximately 42 mL of blood per subject will be drawn during the study: 22 mL is for 
clinical laboratory tests and 20 mL is for PK sampling. 
 
Table 3: Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
WBC with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, large unstained cells), Hgb, HCT, RBC, MCH, 
MCHC, MCV, and platelet count  


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Chemistry 
 
 
 
Electrolytes: Na+, K+, chloride, bicarbonate 
Liver function tests: alkaline phosphatase, AST, ALT, total bilirubin, 
direct bilirubin, indirect bilirubin 
Renal function parameters: BUN, creatinine 
Other: glucose, Ca2+, albumin, phosphorus, lactate dehydrogenase, 
total protein, CK/CPK, globulin, uric acid, triglycerides, insulin, 
prolactin, cholesterol (total, HDL, and LDL), amylase, GGT, iron, 
lipase, and magnesium 
Urinalysis 
Glucose, protein (total), ketones, bilirubin, urobilinogen, 
hemoglobin, leukocyte esterase, nitrite 
Urine drug test 
Cocaine, amphetamines, barbiturates, benzodiazepines, 
cannabinoids, opioids, phencyclidine, propoxyphene, methadone 
and alcohol 
Urine pregnancy test (FOCP 
only) 
hCG 
ALT: alanine transaminase; AST: aspartate transaminase; BUN: blood urea nitrogen; CK/CPK: creatinine 
kinase/creatinine phosphokinase; FOCP: females of childbearing potential; GGT: gamma glutamyl-transferase; 
hCG: human chorionic gonadotropin; HCT: hematocrit; HDL: high-density lipoprotein; Hgb: hemoglobin; LDL: low-
density lipoprotein; MCH: mean corpuscular hemoglobin; MCHC: mean corpuscular hemoglobin concentration; 
MCV: mean corpuscular volume; RBC: red blood cells; WBC: white blood cells. 
 Vital Signs and Height/Weight Measurements 
Vital signs’ measurements (e.g., blood pressure, heart rate, temperature, and respiratory rate) 
and height, weight, and BMI will be obtained at visits designated on the Schedule of Visits and 
Procedures (Table 1).  Blood pressure and heart rate will be measured after the subject has 
been sitting for 5 minutes. Vital signs may be taken at any other time, as deemed necessary by 
the Investigator. 
 Medical History  
Medical history will be collected at visits designated on the Schedule of Visits and Procedures 
(Table 1).   
 Physical Examinations and Electrocardiograms (ECGs) 
A complete physical examination will be conducted at visits designated on the Schedule of 
Visits and Procedures (Table 1). This will include assessments of the head, eye, ears, nose, 
throat, skin, thyroid, abdomen (liver and spleen), lymph nodes, and extremities and the 
cardiovascular and nervous systems (motor strength, cranial nerves, deep tendon reflexes, 
coordination, balance, and gait). 


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 Electrocardiograms 
A 12-lead ECG will be obtained at visits designated on the Schedule of Visits and Procedures 
(Table 1). Additional ECGs may be performed at other times if deemed necessary by the 
Investigator. The ECG will be recorded while the subject is resting in a supine position. The ECG 
will electronically calculate the heart rate and will measure the PR, QRS, QT, and QTc intervals. 
All ECG tracings will be reviewed within 24 hours by the Investigator or qualified Sub-
Investigator. PR intervals will be determined for each of these ECGs from a single reading.  
Invalid measurements will be repeated. QTc will be reported as QTcF (QT corrected using 
Fridericia's method). 
 Special Safety Assessments 
The following special scales will be administered in the clinic at visits designated in the Schedule 
of Visits and Procedures (Table 1): 
6.3.9.1 Simpson-Angus Scale (Section 12.3) 
The Simpson-Angus Scale is a 10-item rating scale that is widely used for assessment of 
neuroleptic-induced parkinsonism (Simpson & Angus, 1970). It consists of 1 item measuring 
gait, 6 items measuring rigidity, and 3 items measuring glabella tap, tremor, and salivation, 
respectively. This assessment will be administered at Visit 1, Visit 4, and Visit 6. 
6.3.9.2 Barnes Akathisia Rating Scale (BARS) (Section 12.4) 
The BARS is a rating scale for drug-induced akathisia and includes components for rating the 
observable, restless movements characteristic of akathisia, the awareness of restlessness, and 
any distress associated with the condition (Barnes, 1989). This assessment will be administered 
at Visit 1, Visit 4, and Visit 6. 
6.3.9.3 Abnormal Involuntary Movement Scale (AIMS) (Section 12.5) 
The AIMS test is a rating scale used to measure tardive dyskinesia (Munetz & Benjamin, 1988).  
There are 12 items that rate involuntary movements of various areas of the subject’s body.  
This assessment will be administered at Visit 1, Visit 4, and Visit 6. 
6.3.9.4 Columbia-Suicide Severity Rating Scale (C-SSRS) (Section 12.6) 
The C-SSRS is a questionnaire that prospectively assesses suicidal ideation and behavior using a 
semi-structured interview to probe patient responses (Posner et al., 2011).  The C-SSRS versions 
applicable to the current study are the Baseline version and the Since Last Visit version (Visit 1, 
Visit 4 and Visit 6). 
The Baseline version of the scale assesses lifetime suicidal ideation and behavior. This version is 
suitable as part of a subject’s first interview and will be used at Visit 1 to identify volunteers who 
must not participate in the trial due to their suicidal tendencies. 


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The Since Last Visit version of the scale assesses any suicidal thoughts or behaviors the subjects 
may have had since the last administration of the C-SSRS. This version will be used for the other 
study visits. 
6.4 Tertiary Variables  
 Pharmacokinetic Measurements 
 
 
. 
6.4.1.1 Pharmacokinetic Variables 
The pharmacokinetic variables of interest will be (but not limited to) the following: 
1. 
Apparent clearance (CL/F),  
2. 
Apparent volume of distribution (V/F) of molindone in the study population 
 Clinical Global Impression Scale (Section 12.1) 
The Clinical Global Impression scale was developed to provide a brief, stand-alone assessment 
of the clinician’s view of a subject’s global functioning prior to and after administration of a 
study medication (Guy, 1976). Severity of illness (CGI-S) and global improvement (CGI-I) are 
both rated on a scale of 1 to 7, with 7 being “extremely ill” or “very much worse,” respectively. 
Successful therapy is indicated by a lower overall score in subsequent testing. Investigators 
should consider their total clinical experience with children who have ADHD and associated 
feature of IA and rate how severe the subject’s condition is at the time.   
 CGI-S will be 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.  
CGI-S will be administered by the Investigator at Visit 1, Visit 4, and Visit 6. 
 
 CGI-I will be 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, and 7=Very much worse.  
CGI-I will be administered by the Investigator at Visit 4 and Visit 6. 
 Retrospective-Modified Overt Aggression Scale (R-MOAS) (Section 12.2) 
The R-MOAS was developed to gauge the severity of aggressive behavior (Blader et al., 2009).  
Parents rate the frequency over the past week of 16 aggressive behaviors in 4 areas: verbal 
aggression; physical aggression toward others; aggression toward oneself; and destruction or 
hostile misuse of property. Numeric weighting amplifies the seriousness of more harmful 
behaviors in the total score. The R-MOAS will be administered at Visit 1, Visit 4, and Visit 6.  


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6.5 Other Special Tests 
The following special tests will be administered in the clinic as per Schedule of Events during 
the Screening Period: 
 MINI-KID (Section 12.7) 
The MINI-KID is designed to be used for children aged 6 to 17 years old, and has been shown to 
have substantial to excellent concordance with the diagnosis of ADHD, among other Axis I 
psychiatric disorders (Sheehan et al., 2010; Leffler et al., 2015). The interview can take from 15 
to 50 minutes, and can be given to parents or children, together or separately (Leffler et al., 
2015). All the modules will be administered except for modules R, S, T, U, V and W. This 
assessment will be administered at Visit 1. 
 Vitiello Aggression Scale (Section 12.8) 
The Vitiello Aggression Scale is a 10-item rating scale that uses a cluster analysis to categorize 
aggression into 2 subtypes, predatory (or planned) and affective (or impulsive) (Vitiello et al., 
1990). This assessment will be administered at Visit 1. 
 Edinburgh Handedness Inventory (Section 12.9) 
The Edinburgh Handedness Inventory is a measurement scale designed to establish hand 
dominance. The shorter version, 10-item inventory is a self-report questionnaire on everyday 
common activities such as writing, drawing, throwing and using utensils. Subjects place 1 or 2 
“+” marks under “left” or “right,” indicating strength of preference for each activity; 2 “++” are 
to be used if the individual “would never try to use the other hand unless absolutely forced to” 
for the given function (Oldfield, 1971). This assessment will be administered at Visit 2. 
7 STATISTICAL METHODS 
7.1 General Notions 
Tabular summaries of the data collected during the study will provide a general description of 
the subjects studied and an overview of the treatment effect on brain functioning, GABA and 
Glu levels, PK, and safety results. Data from all sites will be combined in the computation of 
these summaries. Correlations between changes in neuronal activation and neurotransmitter 
concentrations will be analyzed. Continuous variables will be summarized using descriptive 
statistics (number of subjects, mean, standard deviation [SD], median, and minimum and 
maximum). Categorical (nominal) variables will be summarized by reporting the frequency and 
percentage of subjects in each category.  
In addition to tabular summaries, subject data listings, as specified in Sections 16.2 and 16.4 of 
ICH Guidance E3, will be provided. Analysis processing will be performed before the database is 
released. Statistical programming and analyses will be performed. 
Complete details of the statistical analysis will be provided in a separate Statistical Analysis Plan 
(SAP), which will be written, finalized, and approved prior to the database lock and will be 


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included in the Clinical Study Report (CSR) for this protocol. Any deviation from the statistical 
plan will be documented and described in the final report. If changes to principal features 
stated in the protocol are required, these will be documented in a protocol amendment. The 
final SAP will take into account any amendment to the protocol. 
7.2 Handling of Dropout or Missing Data 
No imputation will be implemented.      
7.3 Analysis Populations 
The population of “all enrolled subjects” consists of all those screened subjects who meet the 
requirements for study participation and have completed the imaging procedures prior to 
randomization. The population of “all randomized subjects” consists of all those enrolled 
subjects who complete the Baseline Period including imaging scans, meet the 
inclusion/exclusion criteria and are randomized. The following populations will be analyzed: 
Safety Population: includes all subjects randomized and who received at least 1 dose of study 
drug. 
Completed Population: includes all subjects randomized, who have baseline imaging scans 
(including the anatomical scan) and post-treatment imaging scans. 
PK population: includes all subjects in the safety population who had at least 1 PK sample 
drawn which had a quantifiable concentration of molindone. 
7.4 Demographics 
Demographic variables include age, sex, ethnicity, race, height, weight, and medical history at 
Screening. Tabular summaries of the demographic/baseline variables will be presented for the 
completed and safety populations, except for medical history, which will be summarized for the 
safety population. 
7.5 Subject Disposition 
The number and percentage of subjects who completed and discontinued from the study will 
be summarized in each of the following categories: 
 Subjects in the randomized population 
 Subjects treated (safety population) 
 Subjects in the completed population 
 
The reasons for study discontinuation may include one of the following: 
 Subject withdrew consent 
 Lost to follow-up 
 Lack of efficacy 
 Administrative reason 
 Adverse event 


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 Investigator decision 
 Failure to follow required study procedures 
 
Other 
Only one reason for study discontinuation will be recorded for each subject. 
7.6 Protocol Deviations 
Protocol deviations will be presented in listings. If applicable, the number and percent of 
subjects within each type of protocol deviation will be presented using discrete summary 
statistics. Protocol deviations may include, but are not limited to: 
 Non-compliance with any scheduled study visit 
 Compliance with study treatment <80% 
 Disallowed concomitant medications 
 Non-compliance with study inclusion or exclusion criteria 
 Non-compliance with study assessment procedures 
7.7 Study Medication Exposure and Compliance  
Duration of treatment exposure is defined as the total number of days a subject is exposed to 
study treatment. This will be calculated for each subject by taking the difference between the 
date of last dose minus the date of the first dose, plus 1 (date of last dose – date of first dose 
+1).  
Duration of treatment exposure will also be summarized using descriptive statistics (n, mean, 
SD, median, minimum, and maximum). 
Percent of study drug compliance will be calculated as:  
{(D-R)/ 4*(DL- DF)}*100, where D=number of tablets dispensed, R=number of tablets returned, 
DL=date of last visit (dose) and DF=date of first visit (dose) 
The study medication compliance will be summarized by compliance category (<80%, 80-120%, 
and >120%) and number of subjects in each compliance category. Study medication compliance 
will also be summarized as a continuous variable using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum). 
Summaries of treatment compliance and exposure will be presented separately for the 
Titration period, Maintenance period, and combined Titration and Maintenance periods. 
8 STATISTICAL ANALYSIS 
Both primary and secondary analyses will be based on the completed population.   
8.1 Primary Endpoint Analysis 
The primary endpoint will be analyzed by assessing the difference in the change in BOLD fMRI 
contrast related to the aggressive response in the PSAP Task from baseline (Visit 2) to the end 
of treatment (Visit 5) in each treatment group. 


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 Imaging Analysis 
All functional imaging data will be analyzed using statistical parametric mapping software 
SPM12 package (Wellcome Trust Centre for Neuroimaging, Institute of Neurology; London, UK), 
Analysis of Functional Neuroimages (AFNI, NIH, USA) and software developed in-house at Dr. 
Parrish’s lab, by Dr. Lana Kaiser, and at Supernus. Additional software that may be used 
includes FSL (Oxford, Cambridge, UK), Freesurfer (MGH, USA), and Matlab (MathWorks, USA). 
While performing the PSAP Task, neuronal activation is anticipated in the ACC, ventromedial 
PFC, amygdala, insular regions, and ventral striatum including nucleus accumbens, etc. 
Therefore these ROIs will be emphasized during the imaging analysis. 
8.1.1.1 PSAP Task 
For the PSAP Task data, the analyses will be mainly descriptive and will be assessed as the 
change in BOLD fMRI contrast associated with the aggressive response at baseline and post-
treatment. The primary endpoint may be analyzed by assessing the mean, standard deviation, 
median, minimum and maximum of the BOLD signal change related to aggression for each 
treatment group (SPN-810 36 mg group and placebo) and study visit (baseline and Visit 5).  
Additional analysis details will be described in the SAP. 
8.2 Secondary Endpoint Analyses 
 Functional Connectivity (Resting State fMRI) 
The secondary endpoints for functional connectivity will be the actual z-score, converted from 
the Fisher’s Z-transformation of correlation coefficients, acquired during the rs-fMRI at Baseline 
(Visit 2) and Visit 5. 
 
The analyses of the resting state data will be exploratory and informative of the connectivity 
between ROIs of the aggression network. Correlation matrices representing functional 
connectivity in the aggression network for each resting state scan will be generated at Visit 2 
(baseline) and at Visit 5. The correlation values will be converted to a z-score (Fisher’s Z-
transformation). The descriptive analyses will be performed to assess the z-scores by treatment 
group (SPN-810 36 mg group and placebo) and visit (baseline and Visit 5).   
 
The mean difference, of the z-scores between two treatment groups (SPN-810 36 mg group 
minus placebo) and pre- and post-treatment (post- minus pre-treatment) and the associated 2-
sided 95% CI of the differences will be reported.   
 
Additional analysis details will be provided in the SAP. 
 


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 GABA and Glutamate Concentrations 
The concentrations of GABA and Glu in the ACC will be obtained during MRS acquisition. The 
analyses will be descriptive by assessing the statistics for the concentrations of GABA and Glu 
by treatment group and visit (pre-treatment: Visit 2 fMRI scan and post-treatment: Visit 5). The 
change from baseline will be defined as the difference in concentration of GABA and Glu 
between Visit 2 and Visit 5 for each treatment group. The 2-sided 95% CI for the mean 
difference between treatment group and pre- and post-treatment will be also examined.    
8.3 Safety Analysis  
Evaluation of safety will be performed for the safety population. Safety data that will be 
evaluated include concomitant medications, AEs, clinical laboratory results, vital signs, ECGs, 
and findings from the physical examinations. The occurrence of neurological side effects will be 
assessed by looking at any worsening in scores from Visit 1 to the end of the study visit for each 
of the Simpson-Angus Scale, Barnes Akathisia Rating Scale, and AIMS. Suicidal ideation and 
suicidal behavior will be measured by the C-SSRS. 
All summary tables related to safety analyses will use the safety population. 
 Adverse Events 
AEs will be classified into standardized medical terminology from the verbatim description 
(Investigator term) using the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be 
summarized using discrete summaries at the subject and event level by system organ class and 
preferred term for each group of doses. Similarly, treatment-emergent AEs will be summarized 
by severity and relationship separately. Verbatim description and all MedDRA level terms, 
including the lower-level terms, for all AEs will be contained in the subject data listings. 
All AEs occurring throughout the study period will be recorded. Treatment-emergent AEs 
(TEAEs) will be collected starting after the baseline fMRI scan and after the first dose of study 
medication (after Visit 3) to the end of the study. These AEs include those that emerge after the 
fMRI procedures and during treatment or worsen in severity during treatment. These AEs will 
be tabulated, listed, and analyzed. 
Separate TEAE incidence tables will be presented for the 2 treatment groups. The incidence 
rates for all SADRs will also be summarized as described for all TEAEs.  
In addition, these same tables will be presented by treatment period (Titration, Maintenance, 
and combined Titration and Maintenance periods). For the combined Titration and 
Maintenance periods, the incidence of TEAEs will also be presented by highest severity 
reported and the dose of study medication at first occurrence. Listings (and tabular summaries, 
if warranted) of deaths, other SAEs, and other significant TEAEs, including TEAEs resulting in 
treatment discontinuation, will be provided.  


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 Laboratory Values 
Clinical laboratory values will be summarized by visit and by treatment group using descriptive 
statistics for hematology, chemistry, and urinalysis. For quantitative laboratory parameters, 
both actual values and change from Baseline values will be summarized.   
Laboratory test results will be assigned a low, normal, high (LNH) classification according to 
whether the values were below (L), within (N), or above (H) the laboratory parameters’ 
reference ranges provided by the central laboratory.  Within-treatment comparisons will be 
based on 3 x 3 tables (shift tables) that, for a particular laboratory test, compare the LNH 
classification at baseline to the LNH classification at visit. Listings of all abnormal laboratory 
values by subject (i.e., those with L or H classification) will be provided.  
 Vital Signs, Height, Weight, and BMI 
Vital signs will be summarized by the visit and by treatment group using descriptive statistics.  
Both actual values and changes from the baseline to final visit will be summarized. Descriptive 
summary statistics (mean, SD, median, and range) for vital sign data, height, weight, and BMI 
will be evaluated. 
 ECG Results 
Tabular summaries of the quantitative ECG parameters and the overall ECG findings (normal, 
abnormal not clinically significant, or abnormal clinically significant) will be presented. The QT 
will be corrected using Fridericia’s method. 
ECG results will be summarized by visit and by treatment group using descriptive statistics (for 
quantitative ECG parameters) and frequency tables (for qualitative ECG parameters, including 
the overall ECG finding). For quantitative ECG parameters, both actual values and change from 
Baseline values will be summarized.   
 Physical Examinations 
Findings from the physical examinations will be listed for each system or area examined. 
 Concomitant Medications 
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary (WHO DD) drug codes. Concomitant medications will be further coded to the 
appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating therapeutic classification.  
A tabular summary of concomitant medications by drug class will be presented. 
 C-SSRS 
C-SSRS outcomes will be summarized using number and percent of subjects by categories for 
suicidal ideation only, suicidal behavior only, and suicidality (ideation and behavior combined). 
The summary will be presented by treatment group. The proportion of subjects in each 
treatment group will be compared with the proportion of subjects in the placebo group using 
Fisher’s exact test or chi-square test as appropriate. 


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 Extrapyramidal Symptoms  
The occurrence of neurological side effects will be assessed by looking at the changes in scores 
from Baseline to Visit 4 and Visit 6 for each of the Simpson-Angus Scale, Barnes Akathisia Rating 
Scale, and AIMS.  For each item on each of these scales, the number (and percentage) of 
subjects with a worse score at any post-Baseline visit, compared to Baseline, will be presented.  
A listing of these subjects will also be provided. 
8.4 Tertiary Variable Analysis 
 Pharmacokinetic Analysis 
 
 
 
 Behavioral Scales 
Each of 3 variables (R-MOAS, CGI-I, and CGI-S) will be analyzed using two-sample t-test (or 
nonparametric analysis as appropriate) for the completed population. The means of each 
treatment group, the difference in means (36-mg dose minus placebo), and the 2-sided 95% CI 
for the difference will be obtained. The descriptive statistics will be reported for absolute value 
and change from baseline for each measurement (as appropriate) at each visit for both study 
treatment groups. 
9 DOCUMENTATION 
9.1 Adherence to the Protocol 
The Investigator agrees, when signing the study protocol, to adhere to the instructions and 
procedures described within and to the principles of ICH GCP as well as all governing local 
regulations and principles for medical research. 
The protocol, ICF, and appropriate related documents must be reviewed and approved by an 
Institutional Review Board (IRB) constituted and functioning in accordance with ICH E6, Section 
4, “Investigator Guideline for GCP”, and any local regulations. Documentation of IRB 
compliance with the ICH and any local regulations regarding constitution and review conduct 
will be provided to the Sponsor. 
A signed letter of study approval from the IRB must be sent to the Investigator, and a copy must 
be sent to the Sponsor prior to study start and the release of study medication to the site by 
the Sponsor or its designee. If the IRB decides to suspend or terminate the study, the 
Investigator will immediately send notice of study suspension or termination by the IRB to the 
Sponsor. 
Study progress is to be reported to the IRB annually (or as required) by the Investigator or 
Sponsor, depending on local regulatory obligations. If the Investigator is required to report to 
the IRB, he/she will forward a copy to the Sponsor at the time of each periodic report.   


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9.2 Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor.  
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the Sponsor before implementation. Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require additional approval by the applicable IRBs and, in some countries, by the 
regulatory authority. These requirements should in no way prevent any immediate action from 
being taken by the Investigator, or by the Sponsor, in the interest of preserving the safety of all 
subjects included in the study. If an immediate change to the protocol is felt by the Investigator 
to be necessary for safety reasons, the Medical Monitor and IRB must be notified promptly. 
Changes to the protocol that are administrative in nature do not require formal protocol 
amendments or IRB approval, but the IRB must be kept informed of such changes. In these 
cases, the Sponsor will send a letter to the IRB detailing such changes. 
9.3 Protocol Deviations 
There are to be no Investigator-initiated deviations from the protocol. Any subject whose 
treatment deviates from the protocol or who is not qualified for study participation may be 
ineligible for analysis and may compromise the study. The date of and reason for deviations 
must be documented in all cases. Significant or major protocol deviations impacting the safety 
of the subject or the integrity of the study must be reported by the Investigator to the IRB 
immediately. Reporting of all other protocol deviations must adhere to the requirements of the 
governing IRB. Protocol assessments will continue until the end of the study, unless the 
protocol deviations put the subject at risk or the subject’s condition requires that he/she be 
discontinued from the study. The Sponsor will make the determination as to whether the 
subject will continue in the study. The Sponsor also has the right to discontinue the subject for 
protocol violations. The IRB may also have to be contacted if safety to the subject or if the 
scientific soundness of the study is involved. All protocol deviations must be documented in the 
eCRFs.  
9.4 Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures (SOPs), working practice documents, and applicable regulations 
and guidelines. Site audits may be made periodically by the Sponsor’s Quality Assurance team 
or qualified designee, as an independent function from the study conduct team. 
 Data Collection 
The primary source document will be the subject’s medical record. If separate research records 
are maintained by the Investigator(s), both the medical record and the research record will be 
considered the source documents for the purposes of monitoring and auditing the study. 
Electronic data collection techniques will be used to collect data directly from the study sites 
using eCRFs. The electronic data will be stored centrally in a fully validated clinical database. 


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This document is confidential.  It contains proprietary information of Supernus® Pharmaceuticals, Inc.  Any viewing or disclosure 
of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
Data recorded on source documents will be transcribed into the eCRFs in accordance with the 
eCRF Completion Instructions provided to the study sites. The Investigator is responsible for 
ensuring that all sections of each eCRF are completed correctly, and that entries can be verified 
against source documents. The eCRFs will be monitored for completeness and accuracy against 
the source documents by the CRA(s) on a regular basis. Inconsistencies between the eCRFs and 
source documents will be resolved in accordance with the principles of GCP. 
The Investigator will permit representatives of the Sponsor to inspect all Case Report Forms 
(CRFs) and corresponding study subject original medical records (source documents) at regular 
intervals throughout the study. Subjects’ original medical records and other relevant data must 
be available to support all data recorded in the eCRFs. In addition to the original medical 
records, these data may include but are not limited to study, laboratory reports, etc. 
In accordance with federal regulations, site inspections will serve to verify strict adherence to 
the protocol and the accuracy of the data that are being entered on the CRFs. A Monitoring Log 
will be maintained at each study site, which will be signed by the Medical Monitor, stating the 
type and date of visit. The Investigator should be aware that the study site and subject records 
may be inspected by the Sponsor and the FDA, or other regional regulatory authority. At the 
conclusion of the clinical study, each site’s eCRF data will be extracted from the clinical 
database, stored on a CD-ROM and sent to the respective clinical study site for archiving.  A CD-
ROM containing all eCRFs will be kept by the Sponsor in the Sponsor’s Trial Master File. 
 Clinical Data Management 
Data from eCRFs and other external data sources (e.g., laboratory data) will be entered into 
and/or merged within a single clinical database as specified in the data management plan.  
Quality control and data validation procedures will be applied to ensure the validity and 
accuracy of the data in the clinical database. 
 Database Quality Assurance 
In accordance with the vendor’s procedures, the clinical database will be reviewed and checked 
for omissions, apparent errors, and values requiring further clarification using computerized 
and manual procedures. Data queries requiring clarification will be documented and returned 
to the study site for resolution. Only authorized personnel will make corrections to the clinical 
database, and all corrections will be documented in an audit trail. 
9.5 Retention of Records 
The Investigator has the responsibility to retain all study “essential documents”, as described in 
ICH E6. Essential documents include but are not limited to the protocol, copies of paper CRFs or 
eCRFs, source documents, laboratory test results, study medication inventory records, 
Investigator's Brochure, and regulatory agency registration documents (e.g., FDA form 1572, 
ICFs, and IRB/ Independent Ethics Committee [IEC] correspondence). The investigator should 
take measures to prevent accidental or premature destruction of these documents. Study-
essential documents should be retained until at least 2 years after the last approval of a 
marketing application or after formal discontinuation of clinical development of the 


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for the purpose of reviewing or performing this study. 
investigational product. These documents should be retained for a longer period, however, if 
required by the applicable regulatory requirements or by an agreement with the Sponsor. The 
Investigator must obtain written permission from the Sponsor prior to the destruction of any 
study document. 
It is requested that at the completion of the required retention period, or should the 
Investigator retire or relocate, the Investigator contact the Sponsor, allowing the Sponsor the 
option of permanently retaining the study records. 
These records must be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the FDA in accordance with the US 21 CFR 
312.68 or other national or foreign regulatory authorities in accordance with regulatory 
requirements. 
9.6 Auditing Procedures 
In addition to the routine monitoring procedures, the Sponsor’s Corporate Quality Assurance 
department or qualified designee may conduct audits of clinical research activities in 
accordance with the Sponsor’s written SOPs to evaluate compliance with the principles of ICH 
GCP and all applicable local regulations. A government regulatory authority may also wish to 
conduct an inspection (during the study or after its completion). Any inspections requested by a 
regulatory authority must be communicated immediately by the Investigator to the Sponsor. 
9.7 Publication of Results 
Any presentation or publication of data collected as a direct or indirect result of this trial will be 
considered as a joint publication by the Investigator(s) and the appropriate personnel at the 
Sponsor. Authorship will be determined by mutual agreement. All manuscripts, abstracts, or 
other modes of presentation arising from the results of the study must be reviewed and 
approved in writing by the Sponsor, prior to submission for publication or presentation. No 
publication or presentation with respect to the study shall be made until any Sponsor 
comments on the proposed publication or presentation have been addressed to the Sponsor’s 
satisfaction. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be outlined in the agreement 
between each Investigator and the Sponsor or designee. 
9.8 Financing and Insurance 
Financing and Insurance information will be set forth in a separate document between the 
Investigator and Sponsor (provided by the Sponsor or designee). 
9.9 Disclosure and Confidentiality 
The contents of this protocol, any amendments, and results obtained during the course of this 
study will be kept confidential by the Investigator, the Investigator’s staff, and the IRB and will 
not be disclosed in whole or in part to others or used for any purpose other than reviewing or 
performing the study without the written consent of the Sponsor. No data collected as part of 


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This document is confidential.  It contains proprietary information of Supernus® Pharmaceuticals, Inc.  Any viewing or disclosure 
of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
this study will appear in any written work, including publications, without the written consent 
of Sponsor. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in the Confidentiality Agreement between the Investigator 
and Sponsor. 
9.10 Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative reasons at 
any time. The Investigator will be reimbursed for reasonable expenses covering subjects, use of 
live-in facilities, laboratory tests, and other professional fees. The Investigator will refund the 
excess of payments made in advance. 
The Investigator reserves the right to discontinue the study should his/her judgment so dictate.  
The Investigator will notify the IRB in case of study discontinuation. Study records must be 
retained as noted above. 
10 ETHICS  
10.1 Institutional Review Boards / Independent Ethics Committees 
A list of the IRB(s) and/or IEC(s) that approved this study and the approval letters will be 
included in the clinical study report for this protocol. 
The protocol, any protocol amendments, and the Informed Consent form (ICF) will be reviewed 
and approved by the appropriate IRB/IEC before subjects are enrolled. IRB/IEC approval is 
required and will be acquired prior to the distributing study medication to investigational sites.  
The Investigators or Sponsor will submit, depending on local regulations, periodic reports and 
inform the IRB/IEC of any reportable AEs per ICH guidelines and local IRB/IEC standards of 
practice. 
10.2 Ethical Conduct of the Study 
This study will be conducted in accordance with SOPs from the Sponsor. These SOPs are 
designed to ensure adherence to GCP guidelines as required by the following: 
 Declaration of Helsinki, 1964 (“Recommendations Guiding Physicians in Biomedical 
Research Involving Human Patients”), and all its accepted amendments to date 
concerning medical research in humans. 
 ICH Guideline for GCP (Committee for Proprietary Medicinal Products/ICH/135/95) of 
the European Agency for the Evaluation of Medicinal Products, Committee for 
Proprietary Medicinal Products, ICH of Pharmaceuticals for Human Use. 
 United States (US) Code of Federal Regulations (CFR) dealing with clinical studies 
(21 CFR, including parts 50 and 56 concerning Patient Informed Consent and IRB 
regulations). 
 Local and national legal guidelines. 


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for the purpose of reviewing or performing this study. 
10.3 Investigators and Study Personnel 
This study will be conducted by qualified Investigators under the sponsorship of Supernus 
Pharmaceuticals, Inc. (Sponsor) at United States study sites. 
Contact persons at the Sponsor are listed in the reference binder provided to each 
investigational site. The study will be monitored by qualified personnel from the Sponsor. The 
Sponsor will oversee and review the monitoring activities of the CRA monitor. Medical writing, 
data management, and statistical analyses will be performed by qualified service partners. 
Laboratory tests will be conducted by a central laboratory as designated in the reference 
binder. 
10.4 Subject Information and Consent/Assent 
The Investigator (or designee) will inform the subject and their parent(s), or legal 
representative, of all aspects pertaining to the subject’s participation in the study and will 
provide oral and written information describing the nature and duration of the study, the 
procedures involved, the expected duration, the potential risks and benefits involved, and any 
potential discomfort. 
The process for obtaining Informed Consent/assent will be in accordance with all applicable 
regulatory requirements. The Investigator (or designee) and the parent (or legal representative) 
must sign and date the Informed Consent Form (ICF)/Informed Assent Form (IAF) before the 
subject can participate in the study. The parent or legal representative and the subject will be 
given a copy of the signed and dated ICF/IAF and the original will be retained in the 
investigational site study records. 
The decision regarding subject participation in the study is voluntary. The Investigator (or 
designee) must emphasize to the subject and their parent(s) or legal representative that 
consent regarding study participation may be withdrawn at any time without penalty or loss of 
benefits to which the subject is otherwise entitled. 
The ICF/IAF should be given by means of a standard written statement, written in non-technical 
language. The subject should understand the statement before signing and dating it. If written 
consent is not possible, oral consent may be obtained if witnessed by at least one person not 
involved in the study. The verbal consent will be documented and signed by the Investigator 
and the witness(es). No subject can enter the study before his/her ICF has been obtained.  
If the ICF/IAF is amended during the study, the Investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICF by the IRB and use the 
amended ICF (including ongoing subjects). 
 
 


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11 REFERENCE LIST 
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for the purpose of reviewing or performing this study. 
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12 APPENDICES 
12.1 Clinical Global Impression (CGI) Scale  
(1) NOT DONE 
INSTRUCTIONS:  Indicate only one response for the question by placing a cross (X) in the 
appropriate numbered box.  
 
 
SEVERITY OF ILLNESS: 
Considering your total clinical experience with this particular population (impulsive aggression 
comorbid with ADHD), how severe is the subject’s condition at this time? 
 
(0) NOT ASSESSED 
 
(1) Normal, not at all ill 
 
(4) Moderately ill 
 
 
(2) Borderline mentally ill 
 
(5) Markedly ill 
 
 
(3) Mildly ill 
 
(6) Severely ill 
 
 
 
(7) Among the most extremely ill patients 
 
 
GLOBAL IMPROVEMENT: Rate total improvement whether or not, in your judgment, it is due 
entirely to drug treatment. Compared to his/her condition at Visit 1/Baseline, how much has the 
subject’s impulsive aggression changed?  
 
 (0) NOT ASSESSED  
 
 (1) Very much improved  
 
 (4) No change  
 
 
 (2) Much improved  
 
 (5) Minimally worse  
 
 
 (3) Minimally improved  
 
 (6) Much worse  
 
 
 
 (7) Very much worse  
 
 
 
 
 
 


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12.2 Retrospective-Modified Overt Aggression Scale (R-MOAS) 
 


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12.3 Simpson-Angus Scale 
 


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CONFIDENTIAL 
 
810P204                                                              
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810P204                                                              
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810P204                                                              
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12.4 Barnes Akathisia Rating Scale (BARS) 
 


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810P204                                                              
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810P204                                                              
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12.5 Abnormal Involuntary Movement Scale (AIMS) 
 


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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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12.6 Columbia-Suicide Severity Rating Scale (C-SSRS) 
 C-SSRS, Children’s Baseline/Screening 


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810P204                                                              
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810P204                                                              
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810P204                                                              
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 C-SSRS, Since Last Visit 
 


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810P204                                                              
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810P204                                                              
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810P204                                                              
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12.7 Mini International Neuropsychiatric Interview for Children and Adolescents 
(MINI-KID)  


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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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810P204                                                              
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12.8 Vitiello Aggression Scale 
 
 


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CONFIDENTIAL 
 
810P204                                                              
Version 3.0                                                   
Page 152 of 154 
 
This document is confidential.  It contains proprietary information of Supernus® Pharmaceuticals, Inc.  Any viewing or disclosure 
of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
12.9 Edinburgh Handedness Inventory 
 


Supernus® Pharmaceuticals, Inc. 
CONFIDENTIAL 
 
810P204                                                              
Version 3.0                                                   
Page 153 of 154 
 
This document is confidential.  It contains proprietary information of Supernus® Pharmaceuticals, Inc.  Any viewing or disclosure 
of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
12.10 PSAP Questionnaire 
 


Supernus® Pharmaceuticals, Inc. 
CONFIDENTIAL 
 
810P204                                                              
Version 3.0                                                   
Page 154 of 154 
 
This document is confidential.  It contains proprietary information of Supernus® Pharmaceuticals, Inc.  Any viewing or disclosure 
of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
12.11 MR Safety Questionnaire 
 

SAP_001.pdf: 
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