Conditions: Attention Deficit Hyperactivity Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the effect of SPN-810 for the treatment of impulsive aggression (IA) in adolescents diagnosed with ADHD when taken in conjunction with standard ADHD treatment.

Detailed description:
This study was an addition to the pediatric studies (CHIME 1 and CHIME 2) to assess the efficacy and safety of SPN-810 in the improvement of impulsive aggression (IA) behaviors in adolescents with ADHD.

SPN-810 was administered in patients diagnosed with ADHD and associated features of IA, who were currently treated with an FDA-approved standard ADHD treatment and displayed persistent IA behaviors. The frequency of impulsive aggressive behaviors was assessed as a primary outcome.

.

Arms:
arm 1: Subjects treated with flexible dose of SPN-810 arm 2: Subjects treated with Placebo

Interventions: intervention 1: SPN-810 intervention 2: Placebo
Intervention descriptions: intervention 1: Flexible dose intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
Supernus® Pharmaceuticals, Inc 
CONFIDENTIAL    
810P503       
Version 3         
    Page 1 of 180 
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for the purpose of reviewing or performing this study. 
TITLE PAGE 
Protocol Number: 
810P503 
Title: Assessment of Efficacy and Safety of SPN-810 for the Treatment of 
Impulsive Aggression (IA) in Adolescent Subjects 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 in subjects with Attention 
Deficit/Hyperactivity Disorder (ADHD) in conjunction with standard 
ADHD treatment 
Medical Monitor 
Phase: 3 
Protocol Version: 3.0 
Release Date: 01 Nov 2018 
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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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 International Conference on 
Harmonization (ICH) and all applicable local Good Clinical Practice (GCP) guidelines, including 
the Declaration of Helsinki and all its accepted amendments to date. 
 
 
 
 
 
Principal Investigator 
 
Signature 
 
Date 
 


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SUPERNUS PHARMACEUTICALS, INC. PROTOCOL APPROVAL PAGE 






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Section 
Page 
Description of Change 
Rationale 
 
 
Additional Secondary Safety and Tolerability 
Endpoints: 
Exploratory Endpoints: 
Synopsis 
22 
The following text was added: 
Pharmacogenomic testing is optional. 
Administrative 
Synopsis 
22 
The following was changed: 
Assuming a mean difference deviation of 15 
between  SPN-810 dose group and placebo  with a 
common standard deviation of 35, a sample  of 93 
subjects per arm will yield  80 % power to detect a 
non-zero difference between the median of SPN-810 
treatment group and the placebo group using the 
Wilcoxon rank-sum test with a 2-sided significance 
level α=0.05. 
Administrative 
Synopsis 
22 
The following text was added: 
It is assumed that approximately 20% subjects will 
dropout before the completion of the study and 
hence, an adjusted total of 186 subjects will be 
randomized in a 1:1 ratio to obtain approximately 
150 subjects at the completion of the study. 
Improve study 
design 
Synopsis 
22 
The following text was changed: 
Per-Protocol (PP) Population:  will include all of the 
subjects in the FAS who completed the Treatment 
Phase with 70% diary completion compliance and who 
did not have major protocol deviations (as defined in 
the SAP). 
Improve study 
design 
Synopsis 
23 
The following was added: 
For the efficacy endpoint, the frequency of IA 
behaviors during the Treatment Phase will be 
calculated over the number of days with non-missing 
IA diary data in the Treatment Phase (titration + 
maintenance).  
To clarify 
Synopsis 
23 
The following text was added: 
 
Improve study 
design 


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Section 
Page 
Description of Change 
Rationale 
 
Each of the secondary endpoints will be analyzed 
using a Mixed-Effect Model for Repeated Measure 
(MMRM).  MMRM assumes missing data as Missing 
at Random. The model includes treatment, visit, and 
interaction between treatment and visit as fixed 
factors, baseline as covariate. The model parameters 
will be estimated using restricted maximum 
likelihood method with unstructured variance-
covariance matrix and Kenward-Roger 
approximation to estimate denominator degrees of 
freedom.  The between-group comparison will be 
performed using the simple contrast at the 
respective visits. 
The following text was removed: 
As a key secondary analysis, the above analysis will be 
repeated for percent change (PCHM) in the frequency 
of IA behaviors per 7 days in the Maintenance period 
relative to the Baseline period calculated over the 
number of days with non-missing IA diary data.   
Key and additional secondary endpoints (Investigator 
and Caregiver-completed-CGI-S, R-MOAS, Investigator 
and Caregiver completed-CGI-I, SNAP-IV, CHQ-PF28 
and SIPA) will be analyzed using the analysis of 
covariance method based on the FAS population with 
missing data imputed using the Last Observation 
Carried Forward (LOCF) method. The model includes 
treatment and baseline as fixed independent 
covariates and change from baseline to final 
maintenance visit as a response variable. 
Sec 2.5 
38 
The following was changed: 
The primary objective of 810P301 and 810P302 is to 
assess the efficacy and safety of SPN-810 in reducing 
the frequency of IA behaviors in children 6 to 12 years 
of age with ADHD and  comorbidassociated features 
of IA when taken in conjunction with standard ADHD 
treatment. 
To clarify 
Sec 3.2 
39 and 
40 
The following text were changed: 
 
To clarify 


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Section 
Page 
Description of Change 
Rationale 
 
3. R-MOAS remission rate Percent of children 
whose IA behaviors were remitted at the end of 
the study measured by R-MOAS score ≤ 10. 
 
Additional secondary objectives are to assess the 
effect of treating adolescents with SPN-810 on the 
following: 
 
1. Caregiver-rated CGI-I Scale; 
2. Caregiver-rated Clinical Global Impression – 
Severity Scale (CGI-S); 
3. Inattention and Hyperactivity-Impulsivity and 
ODD measured by the SNAP-IV rating scale; 
7. Safety Monitoring 
a. Incidence of Adverse Events  
b. Incidence of Extrapyramidal Symptoms 
(EPS) as assessed by Simpson-Angus 
Scale Barnes Akathisia Scale, Abnormal 
Involuntary Movement Scale 
c. Columbia Suicide Severity Rating Scale 
(C-SSRS) 
d. Laboratory Parameters (Hematology, 
Chemistry, Urinalysis, Insulin and 
Prolactin)  
e. Vital signs, Standardized BMI, Physical 
Examination and ECG (12-lead) 
f. Infrequent Behaviors Checklist 
Sec. 4.1 
41 
The following text was changed. 
“Key secondary measures of efficacy of SPN-810 will 
include the Clinical Global Impression - Severity Scale 
(CGI-S) scores completed by the Investigator, R-MOAS 
score and the percent of adolescents whose IA 
behaviors were remitted at the end of study (R-MOAS 
score ≤ 10). Additional secondary measures include the 
Investigator and Caregiver-rated Clinical Global 
Impression- Improvement Scale (CGI-I) scores, the 
Caregiver-rated Clinical Global Impression - Severity 
Scale (CGI-S) score, the inattention, hyperactivity-
impulsivity and ODD measured by the SNAP-IV…” 
To clarify 
Sec 4.1 
41 
The following text was changed: 
To clarify 


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for the purpose of reviewing or performing this study. 
 
 
 
Section 
Page 
Description of Change 
Rationale 
 
The incidence of these infrequent IA behaviors will be 
assessed on paper at Visit 2 and using the checklist in 
the electronic IA diary from Visit 3 to Visit 7. 
Sec. 4.2 
42 
The following text was added:   
Dose reduction will be allowed during maintenance 
in consultation with the Medical Monitor and the 
Sponsor; at Visit 6 the Investigator may adjust the 
dose based upon tolerability. 
To clarify 
Sec. 4.2 
42 
The following text was changed: 
 
 
 
 
 
 
 
 
 
 
 
   
Improve study 
design 
Sec 4.3 
42 
The following was changed; 
Treatment Phase: 3646 days 
Administrative 
Figures 1 
and 2 
44 and 
45 
Figures 1 and 2 were updated to clarify the increase 
of dosage at Visit 5 and to specify option for dose 
reduction from 45mg to 36mg/day during the third 
week of titration. 
To clarify 
Sec. 4.3.1.1 
46 
The following were changed: 
Both these scales measure severity of  aggressive 
behaviors; only those subjects with an R-MOAS score 
of ≥ 20 ≥ 24 and scoring of at least “moderately ill” 
(score of ≥ 4) on CGI-S will be eligible for the study 
 
The following was added: 
To increase study 
enrollment 


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for the purpose of reviewing or performing this study. 
 
 
 
Section 
Page 
Description of Change 
Rationale 
 
Serum pregnancy test will be performed at Screening 
for all female subjects. 
Sec 4.3.1.2 
46 
The following text was added: 
At Visit 2 infrequent behaviors will also be recorded 
on paper source. 
To clarify 
Sec 4.3.1.2 
47 
The following text was changed: 
Although there are up to 30 days available for each of 
the Screening andor the Baseline period, the total 
duration of Screening and Baseline periods may not 
exceed 45 days. 
To clarify 
Sec 4.3.2 
47 
The following text was changed: 
 
Treatment Phase:  (2-8 5 weeks) 
Administrative 
Sec 4.3.2.2
 
 
47 
Flexible Maintenance period (3 weeks), Day 15 to 
Day 3635 
The following text was added: 
Dose reduction will also be allowed during the 
second week of the Maintenance period in 
consultation with the Medical Monitor and the 
Sponsor; at Visit 6 the Investigator may adjust the 
dose based upon tolerability. 
Administrative 
Sec 4.3.3 
47 
Conversion Phase (10 days), Day 36 to day 4645 
Administrative 
 
Sec 4.3.4 
48 
Taper Phase (10 days), Day 36 to day  4645 
Administrative 
Sec 5.1 
48 
The following was changed: 
The population will be male and female subjects 
diagnosed with ADHD, comorbidwith associated 
features of IA and currently being treated with an 
FDA-approved standard ADHD treatment 
(psychostimulants and non-stimulants).   
To clarify 
Sec. 5.1.1 
49 
The following were changed: 
4. Retrospective Modified Overt Aggression Scale (R-
MOAS) score of ≥ 20 ≥ 24 at Screening and Visit 3 
To increase study 
enrollment 


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Section 
Page 
Description of Change 
Rationale 
 
5. CGI-S score at least moderately ill (≥4) at 
Screening and Visit 3. 
Sec. 5.1.2 
49 and 
50 
The following was changed: 
2. History or Ccurrent or lifetime diagnosis of 
epilepsy, major depressive disorder, bipolar 
disorder, schizophrenia and other psychotic 
disorders, personality disorder, Tourette’s 
disorder, dissociative disorder, substance 
abuse disorder or autism spectrum disorder. 
14. Use of an investigational drug or participation in 
an investigational study within 30 days prior Visit 2. 
Administrative 
Table 1 
51 and 
52 
The following were changed: 
 
• 
Recording of vital signs was added at each 
visit. 
• 
Urine drug screen was added at each visit. 
• 
PK sampling at Visits 4 and 7 were removed. 
• 
PK sampling at Visits 5 and 6 were added. 
• 
Footnote ‘e” was changed: Urine pregnancy 
test will be performed for all female 
subjects. pPrior to the administration of the 
first dose of SM subjects will have to be 
tested as negative to continue in the study. If 
Visit 1 and Visit 2 occur on the same day 
then both urine and serum pregnancy tests 
must be performed. 
• 
Serum pregnancy test was added at Screening 
for all female subjects and pregnancy test was 
added at Visit 2. 
• 
Footnote “f” was changed: Serum pregnancy 
test will be performed at Visit 2 Screening for 
all female subjects. 
• 
Footnote “i" was changed: PK blood samples 
will be obtained over two visits. Visit 4, 6 and 
7 the study medication will be taken at the 
clinic prior the first blood drawn. 
• 
Footnote “l: Optional” was added  
• 
Footnote “j” was changed: Only the 
Investigator-rated CGI-S will be completed at 
Procedural 


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Section 
Page 
Description of Change 
Rationale 
 
Screening; Caregiver and Investigator-rated 
CGI-S will be collected at every visit after 
randomization and every visit thereafter. 
Sec. 5.3.1  
53 
The following were changed: 
 
11. Collect Uurine sample for drug screen, and 
urinalysis and pregnancy test. 
12. Collect blood for serum pregnancy test (If Visit 1 
and Visit 2 occur on the same day then both 
urine and serum pregnancy tests must be 
performed) 
13. Record vital signs (HR, BP, temperature, and RR) 
15. Collect blood samples for optional PGx testing 
Administrative 
Sec. 5.3.2 
53 
The following was changed: 
Collect blood for serum pregnancy Collect urine for 
drug screen and pregnancy test (If Visit 1 and Visit 2 
occur on the same day then both urine and serum 
pregnancy tests must be performed) 
Procedural 
Sec. 5.3.3 
54 
The following was added: 
8. Record vital signs (HR, BP, temperature, and RR) 
Procedural 
Sec. 5.3.4 
54 
The following were added: 
3. Collect urine sample for pregnancy test and drug 
screen. 
4. Collect blood for PK analysis 
5. Record vital signs (HR, BP, temperature, and RR) 
 
The following text was removed. 
Subject will arrive at the clinic in the morning and will 
take the first dose of SM at the clinic 
Procedural 
Sec. 5.3.5 
55 
The following  were added: 
(Refer to Section 5.3.9 for details regarding timing of 
the dose of SM prior PK sampling.) 
4. Collect urine sample for pregnancy test and drug 
screen. 
6. Record vital signs (HR, BP, temperature, and RR) 
Procedural 


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Section 
Page 
Description of Change 
Rationale 
 
7. Collect blood for PK analysis 
Sec. 5.3.6 
55 
The following text was added: 
(Refer to Section 5.3.9 for details regarding timing of 
the dose of SM prior to PK sampling.) 
The following were added: 
4. Record vital signs (HR, BP, temperature, and RR) 
5. Collect urine sample for pregnancy test and drug 
screen 
The following text was removed. 
Subject will arrive at the clinic in the morning and will 
take the first dose of SM at the clinic 
Procedural 
Sec. 5.3.7 
56 
The following were added: 
6. Collect urine sample for urinalysis, and pregnancy 
test and drug screen. 
7. Record vital signs (HR, BP, temperature, and RR) 
The following were removed. 
Subject will arrive at the clinic in the morning and will 
take the first dose of SM at the clinic 
Collect blood for PK analysis 
Procedural 
Sec. 5.3.8 
56 
The following was changed: 
2. Collect urine for pregnancy test 
Collect urine for urinalysis, drug screen and 
pregnancy test 
Procedural 
Sec 5.3.9 
57 
The following text was changed: 
 
 
 
 
 
Procedural 


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Section 
Page 
Description of Change 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
Sec. 5.4.1 
57 
Subjects will take up to (6) six 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 the 
stable dose of the optimized ADHD medication. 
During the conversion phase, subjects will take up to 
(8) eight molindone hydrochloride extended release 
tablet (SPN-810) or placebo twice each day (BID). 
To clarify 


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Section 
Page 
Description of Change 
Rationale 
 
Sec. 5.4.1 
57 and 
58 
The following text was changed. 
Subjects will remain at the target dose of 36 mg/day 
or placebo for one week during maintenance.  In the 
second week of maintenance (Visit 65), the treatment 
dose could be increased in a blinded fashion to 45 mg 
(TTD) based on Investigator discretion or maintained 
at 36mg (TDD) or placebo. In the following week (Visit 
6), the Investigator will re-assess the dosage: the 
subject may remain at 36 mg (TDD) or 45 mg (TDD) or 
matching placebo (depending on the dosage from the 
previous week) or titrate up to the higher dose of 45 
mg or 54 mg (TDD) or placebo. At the same Visit, 
dose reduction will be allowed in consultation with 
the Medical Monitor and the Sponsor: the 
Investigator may adjust the dose based upon 
tolerability. 
To clarify 
Sec. 5.4.2 
58 
The following text was changed 
The Investigator is not allowed to adjust the FDA-
approved ADHD monotherapy (either IR or ER not 
both) medication and/or its dose at any time during 
the course of this study. 
To clarify 
Sec. 5.5  
61 
The following was added: 
5. For the treatment of Akathisia, propranolol is 
recommended up to 90 mg /day in divided 
doses, three times per day, starting at 10 mg BID 
and up to 30 mg TID, as needed. 
To clarify 
Sec  6.2  
63 
The following text was changed 
Secondary Efficacy VariablesEndpoints 
The secondary efficacy endpoint is the The effect of 
SPN-810 on the following scales will be measured as a 
change from Baseline to the end of the study where 
the Baseline is defined as the last observation prior 
to the first dose, Visit 3. The effect of SPN-810 will 
be measured on the following efficacy scales will be 
administered at visits designated in the Schedule of 
Visits and Procedures (Table 1). 
Administrative 


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Section 
Page 
Description of Change 
Rationale 
 
Sec. 6.2.3 
64 
The following was changed: 
6.2.32 Additional Secondary Variables Efficacy 
Endpoints 
Administrative 
Sec 6.2.3.3 
64 
The following was changed 
• 
ADHD-Combined subscales (items #1-18) 
• 
ODD (items #19-26)  the first two subscales are 
combined 
Administrative 
Sec. 6.3.3.3 
66 
The following was added: 
Pharmacogenomic testing is optional. 
Administrative 
Sec 6.4.2.2 
68 
“…occurrence of AEs will be assessed starting at 
Visit 7 8 of this study (810P503) or Visit 1 in the OLE.” 
Administrative 
Sec. 6.4.3.1 
70 
The following was changed: 
All SAEs must be reported to the Drug Safety 
Contact and DSC within 24 hours of first becoming 
aware of the SAE.   
Administrative 
Sec. 6.4.4.4 
72 
The following was added: 
For the treatment of Akathisia, propranolol is 
recommended up to 90 mg /day in divided doses, 
three times per day, starting at 10 mg BID and up to 
30 mg TID, as needed. 
To clarify 
Sec. 6.4.6 
73 
The following was changed: 
 
 
 
To adjust for PK 
sampling change 
Table 3 
74 
Table 3 was updated to specify Urine tests 
 
Urinalysis: Glucose, protein (total), ketones, bilirubin, 
urobilinogen, hemoglobin, leucocyte esterase, nitrite 
Urine: Cocaine, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, opioids, 
phencyclidine, propoxyphene, methadone  and 
alcohol 
Urine Pregnancy tests: hCG 
To clarify 


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Section 
Page 
Description of Change 
Rationale 
 
Sec 6.4.10 
75 
The following was added: 
At the following visits (Visit 3-7) any of these 
behaviors will be recorded on the electronic IA diary 
if they were observed since the patient’s last visit. 
Administrative 
Sec. 8.2 
76 
The following was added: 
For the primary efficacy end point, the frequency of 
IA behaviors during the Treatment Phase will be 
calculated over the number of days with non-missing 
IA diary data in the Treatment Phase (titration + 
maintenance).   
To clarify 
Sec. 8.3 
77 
The following was changed: 
Safety Population:  will include all 
subjects screened who received at least 1 dose of 
study drug and had at least one post-baseline safety 
assessment. 
 
Per-Protocol (PP) Population:  will include all of the 
subjects in the FAS who completed the Treatment 
Phase with 70% diary completion compliance and 
who did not have major protocol deviations as 
defined in the SAP). 
To clarify 
Sec. 8.7 
78 
The following was added: 
{(D-R)/T*(DL- DF)}*100 changed to {(D-R)/T*(DL- 
DF+1)}*100  
To clarify 
Sec. 12.10 
180 
SIPA scale was added 
Administrative 
 
 


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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:  810P503 
Phase of Development:  3 
Full Title of Study:  Assessment of Efficacy and Safety of SPN-810 for the Treatment of 
Impulsive Aggression (IA) in Adolescent Subjects with Attention Deficit/Hyperactivity 
Disorder (ADHD) in Conjunction with Standard ADHD Treatment. 
Investigator(s) / Center(s):  Approximately 35-40 US centers 
Objectives:  
Primary  
Efficacy and safety of SPN-810 treatment in reducing the frequency of impulsive aggression 
(IA) behaviors in adolescents with ADHD when taken in conjunction with standard ADHD 
treatment. 
Secondary 
Key secondary objectives of the study are to assess the effect of SPN-810 on the following: 
 
1. Investigator-rated Clinical Global Impression – Severity Scale (CGI-S) 
2. Retrospective Overt Modified Aggression Scale (R-MOAS)  
3. Percent of children whose IA behaviors were remitted at the end of the study 
measured by R-MOAS score ≤ 10. 
 
Additional secondary objectives  
These additional secondary objectives are to assess the effect of treating adolescents with 
SPN-810 on the following: 
 
1. Investigator-rated Clinical Global Impression – Improvement Scale (CGI-I); 
2. Caregiver-rated Clinical Global Impression – Improvement Scale (CGI-I); 
3. Caregiver-rated Clinical Global Impression – Severity Scale (CGI-S); 
4. Inattention, Hyperactivity-Impulsivity and ODD measured by the SNAP-IV; 
5. Child’s overall health as measured by the Child Health Questionnaire Parent Form 28-
item (CHQ-PF28); 
6. Parental stress measured by the Stress Index for Parents of Adolescents (SIPA); 
7. Safety of SPN-810 in adolescent subjects. 
 


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Exploratory 
1. Cross-validation of the electronic impulsive aggression (IA) Diary in adolescents; 
2. 
 
 
3. Pharmacogenomics (PGx). 
Study Design: This is a double-blind, randomized, parallel group, two-arm, placebo-controlled 
study with flexible dosing (36, 45 or 54 mg/day) of SPN-810.  Subjects will be randomized to 
the two arms in 1:1 ratio of SPN-810 or placebo.  
Number of Subjects:  Approximately 372 subjects aged 12-17 years (inclusive) will be 
screened to randomize approximately 186 subjects; 93 in the SPN-810 arm, 93 in the placebo 
arm.  
The sample size for the trial may be revised after the results of the ongoing 810P301 and 
810P302 studies become available. 
Key Criteria for Inclusion: 
Otherwise, healthy non-smoking, male and females adolescents (12-17 years of age at the 
time of screening) with a primary diagnosis of ADHD and currently taking an optimized FDA-
approved ADHD medication. IA will be confirmed at screening using R-MOAS scale and 
Vitiello Aggression Questionnaire.  
Key Criteria for Exclusion: 
History or current diagnosis of epilepsy, major depressive disorder, bipolar disorder, 
schizophrenia and other psychotic disorders, personality disorder, Tourette’s syndrome or 
dissociative disorder, autism spectrum disorder, pervasive developmental disorder, obsessive 
compulsive disorder, post-traumatic stress disorder, or intermittent explosive disorder. 
Known or suspected intelligence quotient (IQ) <70, active suicidal plan/intent or active 
suicidal thought, criminal arrest, alcohol or drug use or pregnancy. 
Treatment, Dose, and Mode of Administration: 
Molindone hydrochloride extended-release tablet dosage forms of 3 mg and 9 mg with 
matching placebo tablets.  Treatment to be administered orally twice daily with or without 
food.  Subjects will be force-titrated over a period of 2 weeks to 36 mg/day. 
• Treatment 1:  Placebo 
• Treatment 2:  Flexible dose of SPN-810 titrated to 36 mg, 45 mg, or 54 mg  
Duration of Treatment and Study Duration:  
Total duration of study:  Approximately 13 weeks 
• 
Pre-treatment Phase: Up to 45 days 
o Screening period: Up to 30 days 
o Baseline period:  At least 15 days 
• 
Treatment Phase: 36 days 
o Titration period:  2 weeks  
o Maintenance period:  3 weeks 


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Conversion/taper Phase:  10 days 
 
Pre-Treatment Phase: 
Screening and Baseline 
Subjects will be screened approximately 45 days before the Treatment Phase. 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 scale and the Vitiello Aggression Questionnaire will 
be administered to determine the subject’s IA eligibility for the study by evaluating the 
severity and the subtype of aggression, respectively. 
 
Following screening eligible subjects will enter a two-week flexible baseline period, at which 
time the caregivers will receive the IA diary and will receive training on how to use the diary 
to identify IA behaviors. 
 
Treatment Phase: 
After completing the Baseline period, eligibility criteria will be confirmed: only those subjects 
who achieve ≥70% compliance in completing the IA diary during Baseline period and have a 
baseline score of IA behaviors per 7 days ≥ 6 will be randomized. A dose titration schedule 
will be followed, where dosing will be initiated at 
 for all subjects in the active 
treatment group and will increase approximately every three days in the first two weeks of 
drug administration until 36 mg/day dose is reached.  
 
All subjects will remain at 36 mg/day during the first week of the Maintenance period.  At the 
following week during maintenance, the Investigator will assess whether to increase the dose 
to 45 mg/day SPN-810 or placebo, or remain on 36 mg/day of SPN-810 or placebo. A week 
later, the Investigator will re-assess whether the subject will remain at 36 mg or 45 mg/day or 
titrate up to the higher dose of 45 mg or 54 mg/day of SPN-810 or placebo. Dose reduction 
will be allowed during maintenance in consultation with the Medical Monitor and the 
Sponsor; at Visit 6 the Investigator may adjust the dose based upon tolerability. 
 
After completing the three-week Maintenance period, subjects will enter a taper down 
period if they decide to discontinue from the study, or will be given the option to convert to 
an open label extension (OLE) study (810P304). Subjects who choose to participate in the OLE 
will receive a blinded double-dummy conversion card to down or up-titrate the study 
medication and matching placebo to enter the study at a dose of 36 mg/day SPN-810. 
Endpoints: 
Primary Efficacy Endpoint: 
The primary efficacy variable will be based on a checklist of 15 IA behaviors collected in an 
electronic IA diary.  
 


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The primary efficacy endpoint is the percent change (PCHT) in the frequency (unweighted 
score) of IA behaviors per 7 days in the Treatment Phase (titration + maintenance) relative to 
the Baseline period calculated over the number of days with non-missing IA diary data.  
 
The primary efficacy endpoint PCHT will be calculated by PCHT= 100*(T – B)/B, where T and B 
are IA behavior frequencies per 7 days during the Treatment Phase and Baseline period, 
respectively. The IA behavior frequency per 7 days is defined as (SUM/DAY) x 7, where SUM 
is the total of the 15 IA behaviors reported in IA diary, and DAY is the number of days with 
non-missing IA score in the IA diary during the specified study period. 
Key Secondary Efficacy Endpoints: 
1. Investigator-rated CGI-S scale 
2. R-MOAS rating scale 
3. R-MOAS remission rate defined by a score ≤ 10 
 
Additional Secondary Endpoints: 
 
1. Investigator-rated CGI-I scale 
2. Caregiver-rated CGI-I scale 
3. Caregiver-rated CGI-S scale 
4. SNAP-IV rating scale 
5. CHQ-PF28 rating scale 
6. SIPA rating scale 
 
Additional Secondary Safety and Tolerability Endpoints: 
1. Incidence of Adverse Events  
2. Incidence of Extrapyramidal Symptoms (EPS) as assessed by Simpson-Angus Scale 
Barnes Akathisia Scale, Abnormal Involuntary Movement Scale 
3. Columbia Suicide Severity Rating Scale (C-SSRS) 
4. Laboratory Parameters (Hematology, Chemistry, Urinalysis, Insulin and Prolactin)  
5. Vital signs, Standardized BMI, Physical Examination and ECG (12-lead) 
6. Infrequent Behaviors Checklist 
 
Exploratory Endpoints: 
 
1. IA Diary Cross-Validation  
The data generated from 810P301 and 810P302 pediatric studies during the diary 
validation process may be used for cross-validation of the IA Diary in adolescents. If the 
decision is made to proceed with the analysis, the cross-validation plan and results will be 
provided in a separate stand-alone report. 


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2. Population Pharmacokinetics/Pharmacodynamics: 
 
3. Pharmacogenomics (PGx) Testing: 
Pharmacogenomic testing is optional. The DNA will be extracted and tested for any 
genetic variations associated with CYP2D6 enzyme. This enzyme is involved in the 
metabolism of molindone and genetic variations of the CYP2D6 gene may affect the 
pharmacokinetics of the drug. Test results in this study will identify the subject’s 
metabolizer phenotype. 
Sample size: 
Assuming a mean difference of 15 between  SPN-810 dose group and placebo  with a 
common standard deviation of 35, a sample  of 93 subjects per arm will yield  80 % power to 
detect a non-zero difference between the median of SPN-810 treatment group and the 
placebo group using the Wilcoxon rank-sum test with a 2-sided significance level α=0.05. 
It is assumed that approximately 20% subjects will dropout before the completion of the 
study and hence, an adjusted total of 186 subjects will be randomized in a 1:1 ratio to obtain 
approximately 150 subjects at the completion of the study. 
Sample size may be recalculated based on the effect size of the ongoing 810P301 and 
810P302 studies. 
Analysis Populations: 
Safety Population:  will include all subjects who received at least 1 dose of study drug and 
had at least one post-baseline safety assessment. 
FAS (Full Analysis Set): include all subjects who received at least 1 dose of study drug and 
have completed baseline and at least 1 valid post-randomization assessment of frequency of 
IA behaviors based on IA diary entry. 
Per-Protocol (PP) Population:  will include all of the subjects who completed the Treatment 
Phase and did not have major protocol deviations (as defined in the SAP). 
PK population:  will include all subjects in the safety population who have received at least 1 
dose of active study medication and had one PK sample drawn which had quantifiable 
concentration for molindone. 
Efficacy Hypothesis: 


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Let µ1, and µ2 represent the median percent change in the frequency of IA behaviors per 7 
days in the Treatment Phase relative to the Baseline period in the FAS population for subjects 
treated with placebo and SPN-810 treatment, respectively.  The null (H0) and the alternative 
(Ha) hypotheses are as in the following: 
H0: µ2= µ1, [there is no difference between the median of the SPN-810 treatment 
group and the median of placebo group] vs. Ha: µ2≠ µ1, [there is a difference between 
the median of the SPN-810 treatment group and the median of placebo]. 
Handling Missing Data: 
For the efficacy endpoint, the frequency of IA behaviors during the Treatment Phase will be 
calculated over the number of days with non-missing IA diary data in the Treatment Phase 
(titration + maintenance).  
For subjects who have partial IA diary data during Maintenance period (<7 days with non-
missing IA diary data), the IA behaviors from both Titration and partial Maintenance period 
will be counted together and used for the Maintenance period. For subjects with IA diary 
data only available during Titration period, the IA behaviors from the Titration period will be 
used for the Maintenance period. 
Statistical Methods: 
Summaries for continuous variables will include the sample size, mean, and standard 
deviation, median, minimum, and maximum. Summaries for discrete variables will include 
the tabulation of frequencies and percentages. 
Analysis of PCHT will be performed using the Wilcoxon rank-sum test to test the hypothesis 
of equality of the median of SPN-810 treatment group with the median of the placebo group.  
The Hodges-Lehmann estimate and the associated 95% confidence interval (CI) will be 
calculated.  
Each of the secondary endpoints will be analyzed using a Mixed-Effect Model for Repeated 
Measure (MMRM).  MMRM assumes missing data as Missing at Random. The model includes 
treatment, visit, and interaction between treatment and visit as fixed factors, baseline as 
covariate. The model parameters will be estimated using restricted maximum likelihood 
method with unstructured variance-covariance matrix and Kenward-Roger approximation to 
estimate denominator degrees of freedom.  The between-group comparison will be performed 
using the simple contrast at the respective visits.  
The least squares mean of the treatment groups, the difference in the least squares mean 
(SPN-810 minus placebo), and the 2-sided 95% CI for the difference will be obtained.     


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Safety Monitoring: 
An independent and unblinded Data and Safety Committee (DSC) will be established to 
assess the safety of the subjects participating in the study. An interim safety data analysis will 
be performed if required to support a registration filing.  The DSC will consist of 3 individuals. 
Safety Analysis: 
Safety analyses will be based on the safety population.  All AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) and preferred term.  All AEs with 
onset date on or after the first dose of double-blind study medication and prior to 7 days 
after the permanent discontinuation of study medication (onset date – last date of dose <=7) 
will be summarized using discrete summaries at the subject and event level by system organ 
class and preferred term for each treatment group. AEs with onset date after Visit 7, will be 
summarized in the OLE study (810P304) for subjects who decide to enroll in the OLE. 
Similarly, treatment-emergent AEs will be summarized by severity and relationship 
separately.  Vital signs and all other safety endpoints will be summarized using descriptive 
statistics by treatment groups.  If applicable, categorical laboratory tests will be summarized 
using number and percent of subjects by treatment groups. Data on infrequent behaviors will 
be listed.  
IA Diary Cross-Validation: 
Cross-validation model generated based on the results from the validation of the IA diary in 
the 810P301 and 810P302 studies may be used to predict and estimate the accuracy of 
electronic IA diary to measure aggressive behaviors in adolescents. 
Pharmacokinetic Analysis: 
Bioanalytical Analysis: 
 
Pharmacogenomics (PGx) Analysis: 
The DNA will be extracted and tested for any genetic variations associated with CYP2D6 
enzyme. The residual DNA will be stored for possible testing of genes involved in the efficacy 
and possible association with particular adverse events of the drug (e.g., understand the non-
responders to treatment and/or individuals who show unusual safety profile). The DNA 
analysis will not be used for individual genetic characterization and the subject identity will 
be kept confidential. The PGx report will be a stand-alone document.   
 
 


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TITLE PAGE ....................................................................................................................... 1 
SUPERNUS PHARMACEUTICALS, INC. PROTOCOL APPROVAL PAGE ................................... 3 
SUMMARY OF CHANGES ................................................................................................... 4 
CLINICAL PROTOCOL SYNOPSIS ....................................................................................... 18 
LIST OF TABLES AND FIGURES ......................................................................................... 29 
LIST OF ABBREVIATIONS ................................................................................................. 30 
1. 
ETHICS................................................................................................................. 32 
1.1 
Institutional Review Boards / Independent Ethics Committees ................. 32 
1.2 
Ethical Conduct of the Study ..................................................................... 32 
1.3 
Investigators and Study Personnel ............................................................ 32 
1.4 
Subject Information and Consent/Assent ................................................. 33 
2. 
INTRODUCTION ................................................................................................... 33 
2.1 
Background .............................................................................................. 33 
2.2 
Impulsive Aggression Comorbid with ADHD .............................................. 34 
2.3 
Current Treatment Options ...................................................................... 35 
2.4 
Sponsor’s Phase 2 Studies ........................................................................ 36 
2.5 
Sponsor’s Phase 3 Studies ........................................................................ 38 
2.6 
IA Diary .................................................................................................... 38 
2.7 
Study Rationale ........................................................................................ 38 
3. 
STUDY OBJECTIVES .............................................................................................. 39 
3.1 
Primary Objective .................................................................................... 39 
3.2 
Secondary Objectives ............................................................................... 39 
3.3 
Exploratory Objectives ............................................................................. 40 
4. 
INVESTIGATIONAL PLAN ...................................................................................... 40 
4.1 
Rationale for Study Design and Appropriateness of Measurements .......... 40 
4.2 
Overall Study Design and Plan .................................................................. 41 


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4.3 
Duration of Study Treatment .................................................................... 42 
 
Pre-Treatment Phase ........................................................................ 46 
 
Treatment Phase: (2-5 weeks) .......................................................... 47 
 
Conversion Phase (10 days), Day 36 to day 45 ................................. 47 
 
Taper Phase (10 days), Day 36 to day 45 ......................................... 48 
 
End of the Study (EOS)/Early Termination, Day 46 .......................... 48 
 
Early Termination ............................................................................. 48 
5. 
STUDY METHODS ................................................................................................ 48 
5.1 
Selection of Study Population ................................................................... 48 
 
Inclusion Criteria ............................................................................... 48 
 
Exclusion Criteria .............................................................................. 49 
5.2 
Schedule of Visits and Procedures ............................................................ 50 
5.3 
Study Procedures ..................................................................................... 53 
 
Screening/ Visit 1 (Day -45) .............................................................. 53 
 
Baseline/ Visit 2, Day -15 .................................................................. 53 
 
Visit 3, Day 1 ..................................................................................... 54 
 
Visit 4, Day 15 ................................................................................... 54 
 
Visit 5, Day 22 ................................................................................... 55 
 
Visit 6, Day 29 ................................................................................... 55 
 
Visit 7, Day 36 ................................................................................... 56 
 
Visit 8/ End of the Study, Day 46 ...................................................... 56 
 
Pharmacokinetic Blood Sampling ..................................................... 57 
5.4 
Treatments .............................................................................................. 57 
 
Treatment Administered .................................................................. 57 
 
ADHD medication ............................................................................. 58 
 
Identity of Investigational Product(s) ............................................... 58 
 
Study Medication Handling and Accountability ............................... 58 
 
Methods of Assigning Subjects to Treatment Group ....................... 59 
 
Treatment Replacement ................................................................... 59 
 
Dosing Schedule ............................................................................... 59 
 
Method of Administration ................................................................ 60 
 
Blinding ............................................................................................. 60 
5.5 
Allowed Concomitant Medications ........................................................... 61 
5.6 
Prohibited Medications ............................................................................ 61 
5.7 
Completion of Study and Discontinuation of Subjects ............................... 61 
6. 
STUDY ENDPOINTS .............................................................................................. 62 
6.1 
Primary Efficacy Endpoint ......................................................................... 62 
 
Primary Efficacy Variable .................................................................. 62 
6.2 
Secondary Efficacy Endpoints ................................................................... 63 


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Investigator-Rated Clinical Global Severity of Illness Scale 
(CGI-S) ............................................................................................... 63 
 
Retrospective-Modified Overt Aggression Scale (R-MOAS) ............. 63 
 
Additional Secondary Efficacy Endpoints ......................................... 64 
6.3 
Exploratory Endpoints .............................................................................. 65 
 
IA Diary Cross-Validation .................................................................. 65 
 
Pharmacokinetic Measurements ..................................................... 65 
 
Pharmacogenomics (PGx Testing) .................................................... 66 
6.4 
Safety and Tolerability Endpoints ............................................................. 66 
 
Data Safety Committee (DSC) ........................................................... 67 
 
Adverse Events ................................................................................. 67 
 
Serious Adverse Events (SAE) ........................................................... 69 
 
Assessment of Neurological Side Effects and EPS ............................ 72 
 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................. 72 
 
Laboratory Measurements ............................................................... 73 
 
Vital Signs and Weight Measurements ............................................ 74 
 
Medical History and Physical Examinations ..................................... 74 
 
Electrocardiograms (ECGs) ............................................................... 74 
 
Infrequent Behaviors Checklist......................................................... 75 
7. 
OTHER SPECIAL TESTS .......................................................................................... 75 
7.1 
MINI-KID .................................................................................................. 75 
7.2 
Vitiello Aggression Questionnaire ............................................................. 75 
8. 
STATISTICAL METHODS ........................................................................................ 76 
8.1 
Statistical and Analytical Plans ................................................................. 76 
8.2 
Handling Missing Data .............................................................................. 76 
8.3 
Analysis Populations ................................................................................ 77 
8.4 
Demographics .......................................................................................... 77 
8.5 
Subject Disposition ................................................................................... 77 
8.6 
Protocol Deviations .................................................................................. 78 
8.7 
Study Medication Exposure and Compliance ............................................ 78 
9. 
EFFICACY ANALYSES ............................................................................................ 79 
9.1 
Primary Efficacy Analysis .......................................................................... 79 
9.2 
Secondary Efficacy Analyses ..................................................................... 79 
 
Key secondary endpoints are: .......................................................... 79 
 
Additional secondary endpoints: ..................................................... 80 
 
Sensitivity Analysis ............................................................................ 81 
9.3 
Sample Size and Power Consideration ...................................................... 82 
9.4 
Exploratory Analyses ................................................................................ 82 


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IA Diary Cross Validation .................................................................. 82 
 
Pharmacokinetic ............................................................................... 82 
 
Pharmacogenomic (PGx) .................................................................. 83 
9.5 
Safety Analysis ......................................................................................... 83 
 
Adverse Events ................................................................................. 83 
 
C-SSRS ............................................................................................... 84 
 
Extrapyramidal Signs ........................................................................ 84 
 
Laboratory Values ............................................................................. 84 
 
Vital Signs, Height, Weight and BMI ................................................. 84 
 
ECG Results ....................................................................................... 84 
 
Physical Examinations ...................................................................... 85 
 
Infrequent Behaviors Checklist......................................................... 85 
10. 
PROCEDURES AND INSTRUCTIONS ....................................................................... 85 
10.1 
Adherence to the Protocol ....................................................................... 85 
10.2 
Changes to the Protocol ........................................................................... 85 
10.3 
Protocol Deviations .................................................................................. 86 
10.4 
Data Quality Assurance ............................................................................ 86 
 
Data Collection ................................................................................. 86 
 
Clinical Data Management ............................................................... 87 
 
Database Quality Assurance ............................................................. 87 
10.5 
Retention of Records ................................................................................ 87 
10.6 
Auditing Procedures ................................................................................. 88 
10.7 
Publication of Results ............................................................................... 88 
10.8 
Financing and Insurance ........................................................................... 89 
10.9 
Disclosure and Confidentiality .................................................................. 89 
10.10 Discontinuation of Study .......................................................................... 89 
11. 
REFERENCE LIST ................................................................................................... 89 
12. 
APPENDICES ........................................................................................................ 94 
12.1 
Retrospective-Modified Overt Aggression Scale (R-MOAS) ........................ 94 
12.2 
Mini International Neuropsychiatric Interview for Children and 
Adolescents (MINI-KID)  ........................................................................... 96 
12.3 
Clinical Global Impression (CGI) Scale ..................................................... 154 
 
 
12.4 
Columbia-Suicide Severity Rating Scales (C-SSRS) .................................... 155 
 
C-SSRS, Lifetime/Recent ................................................................. 155 
 
C-SSRS, Since Last Visit ................................................................... 158 
12.5 
Simpson-Angus Scale .............................................................................. 161 
12.6 
Barnes Akathisia Rating Scale (BARS) ...................................................... 165 


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12.7 
Abnormal Involuntary Movement Scale (AIMS) ...................................... 167 
12.8 
Swanson, Nolan, Pelham Rating Scale-Revised (SNAP-IV) ........................ 171 
12.9 
Child Health Questionnaire Parent Form 28-item (CHQ-PF28) ................. 172 
12.10 Stress Index for Parents of Adolescents (SIPA) ........................................ 180 
 
LIST OF TABLES AND FIGURES 
Table 1 
Schedule of Visits and Procedures .................................................................. 51 
Table 2 
Titration Dosing Schedule ............................................................................... 60 
Table 3 
Clinical Laboratory Tests ................................................................................. 74 
 
 
 
Figure 1 
 Schematic of Conversion to Open Label Study  ............................................. 44 
Figure 2  
Schematic of Tapering for Subjects who Discontinue  ................................... 45 
 


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LIST OF ABBREVIATIONS 
ADHD 
Attention-Deficit Hyperactivity Disorder 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine Aminotransferase 
AST 
 Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BARS 
Barnes Akathisia Rating Scale 
BID 
Twice a Day 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression – Severity of Illness 
CGI-I 
Clinical Global Impression – Global Improvement 
CHQ-PF28 
Child Health Questionnaire Parent Form 28 item 
CK 
Creatine Kinase 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSC 
Data Safety Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eOBsRO 
Electronic Observer-Reported Outcome 
EOS 
End of Study 
EPS 
Extrapyramidal Symptoms 
ER 
Extended Release 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
HCT 
Hematocrit 
HDL 
High Density Lipoprotein 
Hgb 
Hemoglobin 
HR 
Heart Rate 
IA 
Impulsive Aggression 
IAF 
Informed Assent Form 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 


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IR 
Immediate Release 
IRB 
Institutional Review Board 
 
 
LAR 
Legal Authorized Representative 
LDL 
Low Density Lipoprotein 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI-KID 
Mini International Neuropsychiatric Interview for Children and 
Adolescents 
MTA 
Multimodal Treatment of Children with ADHD 
ODD 
Oppositional Defiant Disorder 
OLE 
Open Label Extension 
RBC 
Red Blood Cells 
R-MOAS 
Retrospective Modified Overt Aggression Scale 
RR 
Respiratory Rate 
SADR 
Suspected Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SIPA 
Stress Index for Parents of Adolescents 
SM 
Study Medication 
SNAP-IV 
Swanson, Nolan and Pelham-IV 
SOP 
Standard Operating Protocol 
TEAE 
Treatment Emergent Adverse Event 
TEOSS 
Treatment of Early-Onset Schizophrenia Spectrum Disorders Study 
TID 
Three Times a Day 
TOSCA 
Treatment of Severe Childhood Aggression 
WBC 
White Blood Cells 


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1. 
ETHICS 
1.1 
Institutional Review Boards / Independent Ethics Committees 
A list of the Institutional Review Board(s) (IRB) and/or Independent Ethics Committee(s) (IEC) 
that approved this study 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 before subjects are enrolled.  IRB Approval is required and 
will be acquired prior to the distributing SM to investigational sites.  The Investigators or 
Sponsor will submit, depending on local regulations, periodic reports and inform the IRB of any 
reportable adverse events (AEs) per International Conference on Harmonization (ICH) 
guidelines and local IRB standards of practice. 
1.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures (SOPs) from the 
Sponsor.  These SOPs are designed to ensure adherence to GCP guidelines as required by: 
• 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. 
1.3 
Investigators and Study Personnel 
This study will be conducted by qualified Investigators under the sponsorship of Supernus 
Pharmaceuticals, Inc. (Sponsor) at US 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 Sponsor. The 
Sponsor will oversee and review the monitoring activities for the study. 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. 


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1.4 
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 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 consent/assent form and the original will 
be retained in the investigational site study records. 
All 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 consent form. All ongoing subjects must be reconsented per the IRB guidelines. All 
versions of the signed consent forms (including reconsents) must be retained by the sites. 
2. 
INTRODUCTION 
2.1 
Background 
Aggression refers to a behavior that can result in both physical and psychological harm to 
oneself, others or objects in the environment. Aggression is manifested verbally, mentally, and 
physically. Such behavior becomes maladaptive when it persists, occurs outside an acceptable 
social context, and is of an intensity, frequency, severity and/or duration detrimental to the 
child’s interests (Jensen, et al., 2007; Connor & McLauglin, 2006). 
Aggression can be categorized into two broad subtypes based on the aggressor’s motivation –  
1) reactive or impulsive and 2) proactive or instrumental (Vitiello & Stoff, 1997). Impulsive 
aggression (IA) is angry, retaliatory aggression arising out of frustration, annoyance, or hostility 


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triggered by real or perceived provocations – stressors that non-affected youth of the same age 
can typically control in a more socially acceptable manner. IA is an unplanned, immediate 
response and an out-of-control emotional state, reflecting the inability to contain rage in 
response to apparent threat that usually does not lead to a secondary benefit. In contrast, 
instrumental aggression is consciously planned, goal-oriented behavior with the specific intent 
of benefiting the aggressor, a planned act, used for personal gain (Jensen, et al., 2007). IA is 
then a behavior that implies an immediate action without thinking: this type of impulsivity 
seems to nurture internalizing behaviors leading to depression and anxiety due to poor parent-
child interaction, peer rejection or sensitivity to stress. 
2.2 
Impulsive Aggression Comorbid with ADHD 
ADHD is the most prevalent neurological disorder in youth with a parent-reported prevalence 
of 6.8-10.2% in children and adolescents (Visser, et al., 2010; Visser, et al., 2014). IA is a 
common feature in the clinical presentation of ADHD patients and has a much greater impact 
on parents’ overall impairment ratings than the core ADHD symptoms themselves. Among 
participants of the Multimodal Treatment of Children with ADHD (MTA) study, 54% of subjects 
with ADHD exhibited clinically significant aggression at baseline (Jensen, et al., 2007). IA 
amplifies the psychological, academic, emotional, and social problems associated with 
ADHD (Shelton, et al., 1998), markedly increasing the risk of persistent behavioral problems, 
conduct disorder, encounters with the justice system, deficits in academic achievement, 
behavioral and disciplinary problems at school, and substance experimentation/abuse. In 
adolescents, reactive aggression is strongly correlated with anxiety and ADHD problems. 
(Smeets, et al., 2017). 
Prospective longitudinal studies have established that consequences of childhood ADHD persist 
through adolescence. In younger adolescents, low or moderate levels of IA are considered 
normal as coping skills are not fully developed yet at younger age. However, in pediatric ADHD 
patients, IA may become more persistent and severe at older age (Smeets, et al., 2017).  
Pervasive IA in children, which is characterized by impulsive thoughts, emotional lability, and 
impulsive behavior is thought to represent a high-risk profile for progression from childhood 
ADHD to adult antisocial disorders (McKay & Halperin, 2001). Physical and emotional changes 
occur while transitioning from childhood to adolescence. A lack of self-regulation during this 
period adversely affects these changes and results in low self-esteem and sociability in 
adolescents with ADHD. While inattention and impaired executive functions mostly impact 
academic achievement, impulsivity affects the non-academic aspects of functionality that may 
lead to development of oppositional defiant disorder (ODD), drug experimentation, speeding 
while driving, risky sexual behavior, impulsive verbal behaviors and reactive aggression 
(Wehmeier, et al., 2010). Adolescents are at higher risks for more severe reactive aggression at 
older age hence, treatment is needed to prevent the progression of unwanted behaviors. 


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Children and adolescents are an especially vulnerable population that bear the brunt of ADHD-
related morbidity, and may therefore benefit from the addition of a drug specifically targeting 
residual aggressive behaviors refractory to primary ADHD therapy. A stepped-care approach 
with aggression-targeted therapy, such as an antipsychotic added to ADHD therapy has been 
recommended to treat residual aggressive behaviors (Scotto-Rosato, et al., 2012). IA represents 
a serious clinical and public health concern and requires effective and timely intervention 
(Saylor & Amann, 2016). For these reasons, it is important to understand and characterize IA 
behaviors and to assess the response to medication in adolescents with ADHD for an effective 
treatment.  
2.3 
Current Treatment Options 
Based largely on the beneficial effects of risperidone on disruptive behavior disorders in 
children of sub-average intelligence, antipsychotics are used as adjunctive therapy for treating 
aggression in children with ADHD (Pappadopulos, et al., 2003; Pliszka, 2007; Pliszka, et al., 
2006). The TOSCA (Treatment of Severe Childhood Aggression) study has provided empirical 
evidence to support a stepped-care approach in which children with ADHD and severe 
aggression are initially treated with primary ADHD therapy followed by adjunctive antipsychotic 
therapy targeting residual aggressive behaviors (Farmer, et al., 2011; Aman, et al., 
2014; Gadow, et al., 2014). However, risperidone had only a limited impact on aggression in the 
TOSCA study even though the dosage was flexible for optimal effect. Moreover, the TOSCA 
study confirmed that stimulant co-therapy does not attenuate the long-term effects of 
risperidone or similar agents on body composition, metabolic parameters, prolactin, or 
sedation (Penzner, et al., 2009; Calarge, et al., 2009). Use of the antipsychotics olanzapine, 
quetiapine, risperidone, and aripiprazole in children were all associated with significant 
increase in weight and BMI (8.5 kg/3.01 kg/m2, 6.1 kg/2.12 kg/m2, 5.3 kg/1.92 kg/m2, and 
4.4 kg/1.67 kg/m2, respectively) (Correll, et al., 2009). Olanzapine and quetiapine also produced 
significant increases in multiple metabolic parameters and risperidone significantly increased 
triglyceride levels.  
Molindone hydrochloride is a first-generation mid-potency compound for which the Sponsor 
has developed an extended release (ER) formulation (SPN-810), administered orally for the 
treatment of IA in children with ADHD. The immediate-release molindone (Moban®) was 
approved in 1974 for the management of schizophrenia in adults and adolescents but was 
discontinued due to commercial reasons by the original manufacturer.  Its effects relative to the 
second-generation antipsychotics (olanzapine and risperidone) were evaluated in a pediatric 
population with early-onset schizophrenia and schizoaffective disorder in the Treatment of 
Early-Onset Schizophrenia Spectrum Disorders Study (TEOSS) (McClellan, et al., 2007).  
Molindone was selected as the first generation antipsychotic based on its favorable safety 
profile in comparison with the second generation agents. At the average dose of 60 mg/day 
molindone was shown to be safe and well tolerated (Sikich, et al., 2008).  Molindone was not 
associated with significant increases in weight/BMI in contrast to olanzapine.  


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Molindone has been shown to be effective in treating aggressive behavior in children with 
undersocialized conduct disorder, aggressive type, in an open label and a double-blind 
study (Greenhill, et al., 1981; Greenhill, et al., 1985).  
Results of randomized controlled trials such as TEOSS and other studies has stimulated interest 
in the potential usefulness of molindone as a weight- and metabolically-neutral D2-receptor 
antagonist in children with ADHD and comorbid IA. The overall clinical profile of molindone in 
children makes it an attractive candidate for the treatment of IA in children and adolescents 
with ADHD, especially with the anticipated benefits of an ER formulation. 
2.4 
Sponsor’s Phase 2 Studies 
Study 810P201 was a proof-of-concept, open label, parallel-group, randomized, dose-ranging, 
safety and tolerability study using the investigational immediate-release (IR) formulation of 
molindone (Molindone IR)  dosed three times a day (TID) in children with ADHD and persistent 
serious conduct problems (Stocks, et al., 2012). Target subjects were healthy male or female 
children aged 6 to 12 years, with a diagnosis of ADHD accompanied by persistent serious 
conduct problems. A total of 78 subjects (19-20 per treatment group) in ten U.S sites were 
randomized. The primary objective was to evaluate the safety and tolerability of four weight-
based dosages of Molindone IR dosed three times daily in children with ADHD and persistent 
serious conduct problems 
). 
The secondary objectives were to 1) explore the relationship between molindone plasma 
concentration exposure and safety/tolerability endpoints and 2) assess the effect of Molindone 
IR after 6 weeks of maintenance treatment in reducing persistent serious conduct problems as 
measured by the Conduct Problem Subscale of the Nisonger Child Behavior Rating Form-Typical 
Intelligence Quotient (NCBRF-TIQ). 
 
 
 
Study 810P202 was a Phase 2b multicenter, randomized, double-blind, placebo-controlled trial 
in a pediatric population of subjects 6-12 years of age diagnosed with ADHD and IA that was not 
controlled by optimal stimulant and behavioral therapy (Study 810P202, 2013).  The primary 
objective of the study was to assess the effect of an extended-release (ER) tablet formulation of 
molindone hydrochloride (SPN-810) (12 to 54 mg/day) in reducing IA as measured by the 
Retrospective-Modified Overt Aggression Scale (R-MOAS) after at least three weeks of assigned 
treatment. Secondary endpoints included the rate of remission of IA and measurement of the 
effectiveness of SPN-810 on Clinical Global Impression (CGI) and ADHD scales as well as 
evaluation of the safety and tolerability of the drug.  Patients who completed the study could 
continue into an open-label phase of six months duration.  


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SPN-810 dose within treatment groups was stratified by weight (below/above 30 kg).  Both the 
Medium (24/36 mg) and Low (12/18 mg) dose groups showed a statistically significant 
difference from the Placebo group in the change from baseline to final visit (Visit 10) in R-MOAS 
but the High (36/54 mg) dose group was not significantly different from the Placebo group.  
SPN-810 ER formulation exhibited a satisfactory safety and tolerability profile, with low 
incidence of AEs and no unexpected, life threatening or dose-limiting safety issues. The adverse 
events (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 events was relatively low, as were 
discontinuations due to AEs. The frequency of AEs associated with extrapyramidal symptoms 
(EPS) was also low and the two serious adverse events that occurred were not drug-related.  
Other study results further supported a beneficial treatment effect on IA behaviors. The CGI 
results (Severity and Improvement) were consistent with the findings for the R-MOAS; notable 
improvement occurred primarily in the Low dose and Medium dose groups. Scores for 
Swanson, Nolan and Pelham Questionnaire (SNAP-IV) Hyperactivity and Impulsivity did not 
exhibit statistically significant differences across groups. Numeral trends in SNAP-IV 
Oppositional Defiant Disorder (ODD) scores, while not always significant, consistently favored 
the Low dose and Medium dose groups over Placebo. 
Study 810P203 was a multicenter open label extension (OLE) to the Phase 2b trial in a pediatric 
population of subjects 6-12 years of age diagnosed with ADHD and IA (Study 810P203, 2013). 
The starting dose for this open-label extension study was based on subjects’ weight at the end 
of 810P202. Subjects were initiated at doses of 18 and 36 mg/day, in children weighing less 
than 30 kg, and more than 30 kg, respectively. The dose was gradually adjusted based on 
tolerability or effectiveness, regardless of weight group to 9 mg/day, 18 mg/day, 27 mg/day or 
36 mg/day. Of the 121 subjects randomized into the double blind Study 810P202, 78 subjects 
continued on to the OLE study and received SPN-810 for up to 6 months.  
 
 
 
 
 
 
 
 
 
 


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2.5 
Sponsor’s Phase 3 Studies 
The Sponsor is conducting three Phase 3 multicenter studies, of which two are randomized, 
double-blind, placebo-controlled trials in pediatric population (810P301 and 810P302) and one 
is an open-label extension (OLE) study, 810P304. After completing the 810P301 or 810P302 
studies, subjects will have the option to enroll in the 810P304 study that is designed to assess 
long-term safety and tolerability of SPN-810.  
The primary objective of 810P301 and 810P302 is to assess the efficacy and safety of SPN-810 
in reducing the frequency of IA behaviors in children 6 to 12 years of age with ADHD and 
associated features of IA when taken in conjunction with standard ADHD treatment. In these 
two studies, the percent change in the frequency of 15 identified IA behaviors per 7 days during 
the treatment, is measured using and electronic diary that was developed by the Sponsor to 
characterize the nature of impulsive aggressive behaviors in children (6-12 years old) with a 
confirmed diagnosis of ADHD.  
2.6 
IA Diary 
From 2013 to 2015, Endpoint Outcomes (EO) in partnership with
 developed a new 
impulsive aggression diary (IA diary). The IA diary is an electronic observer-reported outcome 
(eObsRO) instrument that is comprised of an episodic diary (to be reported as soon as possible 
after the parent or other guardian or observer witnesses the child’s IA behavior) and an evening 
diary (to enable at a minimum, completion of the diary once each day). The development of 
this diary was as per FDA’s “Guidance for Industry Patient-Reported Outcome Measures: Use in 
Medical Product Development to Support Labeling Claims” (US FDA, 2009). 
Psychometric testing of the electronic diary was conducted in parents of children aged 6 to 12 
years with a primary diagnosis of ADHD (Sponsor Study 810P501, 2015) to establish the validity 
and reliability of the IA diary. The results indicate that 15 items of the original diary (30 items) 
best describe IA and demonstrate sufficient reporting prevalence at baseline and across all 
diaries exhibiting acceptable psychometric properties.  The following 15 items are: Yelling, 
Screaming, Threatening, Scratching, Throwing, Slamming, Hitting Self, Arguing, Cursing, Name 
Calling, Shoving, Hair Pulling, Fighting, Hitting Others, and Kicking Others. Hence, the IA diary is 
currently used for the first time in the pediatric studies (810P301 and 810P302) to monitor the 
frequency of these 15-items in children 6-12 years old with a primary diagnosis of ADHD. 
2.7 
Study Rationale 
Supernus was interested in expanding the potential age range of the subjects in future trials of 
SPN-810 and has conducted a preliminary concept elicitation and cognitive interviews, using 


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the original IA diary (15 items) in an adolescent (13-17 years old) population (Sponsor Study 
810P502, 2016).  The results from the study found the concepts that are present in the 15-item 
IA diary developed for children as relevant in the older population (i.e., Yelling, Arguing, 
Cursing, Name Calling, Threatening, Shoving/Pushing, Fighting, Throwing, Slamming, and Hitting 
were each reported by >60% of the subjects). Two items in the IA diary were not endorsed as 
frequently (Scratching and Pulling Hair) and were each reported by <25% of the population. The 
low reporting of these two behaviors may suggest them as outlier concepts in a sample of 
mostly boys who tend to have shorter hair and/or nails than girls, and therefore less likely to 
pull hair or scratch in the context of fighting. Even though these concepts were reported less 
frequently than other concepts, keeping these items in the current 15-item IA diary may help to 
comprehensively cover and adequately characterize the IA experience in girls.  
 
This research finding supports the content validity of the 15-item IA diary developed for 
children 6-12 years old as an adequate measure IA behaviors that can be applied to an older 
population (13-17 years old). Furthermore, the results suggested the appropriateness of a 
common parent/caregiver reported eObsRO diary for children and adolescents diagnosed with 
ADHD and exhibiting significant IA behaviors.  
3. 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to assess the efficacy and safety of flexible doses of 
SPN-810 (36 to 54 mg/day) in the improvement of IA behaviors in adolescents diagnosed with 
ADHD when taken in conjunction with standard ADHD treatment. 
3.2 
Secondary Objectives 
The key secondary objectives of this study are to assess the effect of SPN-810 on the following 
scales:  
1. Investigator-rated Clinical Global Impression – Severity Scale (CGI-S); 
2. Retrospective Overt Modified Aggression Scale (R-MOAS); 
3. Percent of children whose IA behaviors were remitted at the end of the study measured 
by R-MOAS score ≤ 10. 
 
Additional secondary objectives are to assess the effect of treating adolescents with SPN-810 
on the following: 
1. Investigator- rated Clinical Global Impression – Improvement Scale (CGI-I); 
2. Caregiver-rated CGI-I Scale; 
3. Caregiver-rated Clinical Global Impression – Severity Scale (CGI-S); 
4. Inattention, Hyperactivity-Impulsivity and ODD measured by the SNAP-IV rating scale; 
5. Child Health Questionnaire Parent Form 28-item (CHQ-PF28); 


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6. Stress Index for Parents of Adolescents (SIPA); 
7. Safety monitoring. 
a. Incidence of Adverse Events  
b. Incidence of Extrapyramidal Symptoms (EPS) as assessed by Simpson-Angus 
Scale Barnes Akathisia Scale, Abnormal Involuntary Movement Scale 
c. Columbia Suicide Severity Rating Scale (C-SSRS) 
d. Laboratory Parameters (Hematology, Chemistry, Urinalysis, Insulin and Prolactin)  
e. Vital signs, Standardized BMI, Physical Examination and ECG (12-lead) 
f. Infrequent Behaviors Checklist 
 
3.3 
Exploratory Objectives 
The following objectives will also be evaluated; the report from each results analysis will be a 
stand-alone document: 
1. A cross-validation of the electronic IA diary will be conducted using the parameters 
obtained from the psychometric validation in the two pediatric Phase 3 studies 
(810P301 and 810P302) to assess the minimal clinically important changes (MCIC) in this 
population; 
2.
 
3. Pharmacogenomics (PGx) of molindone. 
4. 
INVESTIGATIONAL PLAN 
4.1 
Rationale for Study Design and Appropriateness of Measurements  
The study is designed to assess the efficacy and safety of an extended release oral formulation 
of molindone as a treatment for reducing impulsive aggression in adolescents with ADHD when 
given in conjunction with each subject standard prescribed ADHD medication.   
The IA diary will serve as the primary assessment tool to measure the improvement in the 
frequency of the IA behaviors as it is used in the Phase 3 studies (810P301 and 810P302) in 
pediatric population. The content validity of the 15-item IA diary as an adequate measure of IA 
behaviors for older children (13-17 years old) was confirmed by the concept elicitation 
interviews study (Sponsor Study 810P502, 2016) conducted in adolescents (13-17 years of age) 
suggesting that the 15-item IA diary developed for children (i.e., Yelling, Screaming, 
Threatening, Scratching, Throwing, Slamming, Hitting Self, Arguing, Cursing, Name Calling, 
Shoving, Hair Pulling, Fighting, Hitting Others and Kicking Others) may also be used as an 
appropriate instrument to assess the frequency of the IA behaviors in adolescents with ADHD.  
 


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Key secondary measures of efficacy of SPN-810 will include the Clinical Global Impression - 
Severity Scale (CGI-S) scores completed by the Investigator, R-MOAS score and the percent of 
adolescents whose IA behaviors were remitted at the end of study (R-MOAS score ≤ 10). 
Additional secondary measures include the Investigator and Caregiver-rated Clinical Global 
Impression- Improvement Scale (CGI-I) scores, the Caregiver-rated Clinical Global Impression - 
Severity Scale (CGI-S) score, the inattention, hyperactivity-impulsivity and ODD measured by 
the SNAP-IV, the treatment effect of the child‘s overall heath as measured by the Child Heath 
Questionnaire Parent Form 28-item (CHQ-PF28), and parental and child stress measured by the 
Stress Index for Parents of Adolescents (SIPA). 
Besides routine safety monitoring, incidence of extrapyramidal symptoms will be assessed by 
special scales, i.e., Simpson-Angus Scale, the Barnes Akathisia Scale, and the Abnormal 
Involuntary Movement Scale (AIMS). Suicidal thoughts and ideation will be assessed by the 
Columbia Suicide Severity Rating Scale (C-SSRS).  
A list of 15 behaviors such as Teasing, Spitting, Biting, Weapons, Ripping, Breaking, Vandalizing, 
Destroying, Fire Setting, Hitting Animal, Kicking self, Kicking Animal, Severe Injury Self, Severe 
Injury Others and Severe Injury Animal, were considered infrequent in the qualitative study 
conducted during the IA diary development (Sponsor Study 810501, 2015). The incidence of 
these infrequent IA behaviors will be assessed on paper at Visit 2 and using the checklist in the 
electronic IA diary from Visit 3 to Visit 7.  
As an exploratory measure, this study will also permit us to psychometrically cross-validate, if 
needed, the IA diary as a tool to measure IA behaviors in subjects aged 12 to 17 years with 
ADHD and comorbid IA.  
Additional exploratory analyses include the pharmacokinetic/pharmacodynamics and 
pharmacogenomics of molindone. 
4.2 
Overall Study Design and Plan 
The study is a randomized, double-blind, multicenter, placebo-controlled, flexible-dose (36, 45 
or 54 mg/day), 2-arm, (1:1) parallel group study to evaluate the safety and efficacy of SPN-810 
(molindone extended release tablets) for reducing impulsive aggression in adolescents 
(12-17 years of age) with ADHD as an adjunctive treatment to an approved ADHD medication.  
The study will consist of 3 phases:  (1) Pre-Treatment Phase, (2) Treatment Phase and (3) 
Conversion/Taper Phase (Figure 1). 
Following Screening, eligible subjects will enter a flexible Baseline period, during which the 
subject’s primary caregiver (or secondary if assigned) will use the IA diary to record daily the 
occurrence of IA behaviors.    


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After the completion of the Baseline period, at Visit 3 eligibility criteria will be re-confirmed: 
only subjects who achieve ≥ 70% in the completion of the IA diary during baseline, with a 
threshold of ≥ 6 IA behaviors per 7 days observed during the flexible Baseline period, will be 
randomized in a 1:1 ratio to the SPN-810 group (n=93) or placebo group (n=93).    
Subsequently, the randomized subjects will follow a dose titration schedule as shown in 
(Figure 1). The titration will consist of dosing starting at
 and increasing approximately 
every 3 days until the target dose of 36 mg/day is reached within 2 weeks. This will be followed 
by a flexible three-week Maintenance period during which the Investigator will have the option 
to gradually increase the total daily dose (TDD) of SPN-810. 
During the first week of the Maintenance period, all subjects will remain at 36 mg/day. After 
the first week of maintenance, the Investigator will assess whether to increase the dose to 
45 mg/day SPN-810 or placebo, or remain on 36 mg/day of SPN-810 or placebo. In the following 
week, the Investigator will re-assess the dosage: the subject may remain at 36 mg/day or 45 
mg/day or matching placebo (depending on the dosage from the previous week) or titrate up to 
the higher dose of 45 mg/day or 54 mg/day of SPN-810 or placebo, respectively. Dose reduction 
will be allowed during maintenance in consultation with the Medical Monitor and the Sponsor; 
at Visit 6 the Investigator may adjust the dose based upon tolerability. 
At the end of the Maintenance period, all subjects who complete the study will have the option 
to participate in an OLE study (Study Protocol 810P304) in which all subjects will receive active 
SM treatment.  Subjects choosing to participate will receive a blinded double-dummy 
conversion medication card which will adjust the subject’s TDD to 36 mg for initiation into the 
open label extension study (Figure 1).  Those subjects who do not elect to participate in this 
extension will be tapered down prior to discontinuation of SM (Figure 2). 
A subject who discontinues early in the Maintenance period, i.e., prior to Visit 7 may be allowed 
to participate in the OLE on a case-by-case basis after consultation between the Investigator, 
Medical Monitor, and the Sponsor.  
 
 
   
4.3 
Duration of Study Treatment 
Total duration of study:  Approximately 13 weeks 
• 
Pre-treatment Phase: Up to 45 days 
o Screening period: Up to 30 days 
o Baseline period:  At least 15 days 
• 
Treatment Phase: 36 days 


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o Titration period:  2 weeks  
o Maintenance period:  3 weeks 
• 
Conversion/Taper Phase:  10 days






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Pre-Treatment Phase 
4.3.1.1 
Screening Period 
Screening procedures will be conducted within 45 days prior to subject randomization (Visit 3) 
and may be carried out over more than one visit if needed.  Prior to conducting any study 
related procedures, a written informed consent/assent must be obtained from the parent or 
legal representative, and subject (when required). Abnormal results on screening laboratory 
tests may be repeated only at the discretion of the Investigator, in consultation with the 
Medical Monitor and the Sponsor on a case by case basis. Re-screening of subjects is not 
allowed. Each screened subject will be assigned a subject number starting from 5001 to 5999 in 
a sequential order. Staff and study sites are encouraged to complete screening procedures as 
early as possible to allow more flexibility on the Baseline period for the caregiver to achieve 
the IA diary compliance. 
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 R-MOAS and CGI-S completed by the Investigator will be administered to determine if the 
subject is eligible to participate in the study. Both these scales measure severity of aggressive 
behaviors; only those subjects with an R-MOAS score of ≥ 20 and scoring of at least 
“moderately ill” (score of ≥ 4) on CGI-S will be eligible for the study.  
The Vitiello Aggression Questionnaire 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. 
Serum pregnancy test will be performed at Screening for all female subjects. 
4.3.1.2 
Baseline Period 
Subjects who meet all study criteria will proceed to the flexible 15-day Baseline period.  At Visit 
2 an IA diary electronic device will be issued: the subject’s primary caregiver and a secondary 
caregiver (if assigned) will be trained on how to use the device. Every effort will be made to 
provide adequate caregiver training on the use of the diary and acknowledgment of training will 
be captured on the device. At Visit 2 infrequent behaviors will also be recorded on paper 
source. 
Following at least 15 days of using the diary, caregiver’s compliance with the IA diary will be 
assessed. Compliance will be calculated as percentage of days over the past 15 days during the 
Baseline period for which an evening diary was completed.  A diary compliance ≥70 % in the 
completion of the diary is for eligibility. 


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for the purpose of reviewing or performing this study. 
 
 
 
Subjects whose caregivers do not reach 70% compliance (at least 11 out 15 days) during the 
first 15 days of the Baseline period may be allowed to continue to use the diary for up to 15 
additional days to improve caregivers’ performance with the IA diary and demonstrate ≥ 70% 
compliance over the past 15-day rolling window. For these subjects, caregivers will receive 
remedial training on the use of the IA diary. During this time, caregiver compliance with the IA 
diary will be monitored daily by study site personnel over the past 15-days as a “rolling 
window”.  
 
Although there are up to 30 days available for each of the Screening or the Baseline period, 
the total duration of Screening and Baseline periods may not exceed 45 days. 
A baseline score of ≥6 of IA behaviors per 7 days is required for randomization. The score 
represents the frequency of IA behaviors per 7 days and, will be calculated as the sum of the 
scores of the IA behaviors collected during the entire Baseline period, divided by the number of 
days with non-missing IA behaviors, then multiplied by 7 days. 
Subjects whose caregivers demonstrate ≥ 70% diary compliance and an IA baseline score ≥6 will 
be eligible for randomization and continue into the Titration period. 
 
Treatment Phase: (2-5 weeks) 
4.3.2.1 
Titration period (2 weeks), Day 1 to Day 14 
Inclusion/exclusion criteria will be re-assessed to verify eligibility prior to study randomization 
at the end of Visit 3. Eligible subjects will be randomized at Visit 3 (Day 1) in a 1: 1 ratio to 
receive 36 mg/day SPN-810 or placebo and proceed to the two-week Titration period in order 
to reach the maintenance dose of 36 mg/day over a period of 2 weeks.  
4.3.2.2 
Flexible Maintenance period (3 weeks), Day 15 to Day 35 
Following dose titration, all subjects will remain at the reached dose of SPN-810 (36 mg/day) or 
placebo on the first week of the Maintenance period.  After the first week, the Investigator will 
clinically assess whether to increase the dose to 45 mg/day SPN-810 or placebo, or remain at 36 
mg/day of SPN-810 or placebo. On the following week, the Investigator will re-assess the dosage: 
the subject may remain at 36 mg/day or 45 mg/day or matching placebo (depending on the 
dosage from the previous week) or titrate up to the higher dose of 45 mg/day or 54 mg/day of 
SPN-810 or placebo, respectively. Dose reduction will also be allowed during the second week of 
the Maintenance period in consultation with the Medical Monitor and the Sponsor; at Visit 6 the 
Investigator may adjust the dose based upon tolerability. 
 
 
Conversion Phase (10 days), Day 36 to day 45 
At the end of the 3-week Maintenance period (Visit 7), subjects will enter a 10 day Conversion 
Phase if the subject chooses to enroll into an ongoing open-label extension (OLE) study (i.e., 
810P304). A blinded double-dummy conversion card will be distributed to down or up-titrate 


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for the purpose of reviewing or performing this study. 
 
 
 
the study medication and matching placebo. Subjects will return to the study site for a final 
end-of-study (EOS) visit, (Visit 8), after completing the Conversion Phase (Figure 1). 
 
Taper Phase (10 days), Day 36 to day 45 
At Visit 7, subjects who opt to discontinue from the study will receive a blinded taper card to 
titrate down the study medication. At the completion of the Taper Phase, subjects will return to 
the study site to complete the EOS procedures (Figure 2). 
Subjects who choose to continue into the OLE, will enter the study at a dose of 36 mg/day 
SPN-810.  A subject who discontinues early in the Maintenance period, i.e., prior to Visit 7 may 
be allowed to participate in the OLE on a case-by-case basis after consultation between the 
Investigator, Medical Monitor, and the Sponsor.  
 
End of the Study (EOS)/Early Termination, Day 46 
Subjects will return to the study site for a final visit, after completing the 10 day period of Taper 
or Conversion Phase. Those subjects who choose to continue in the OLE study (810P304) will 
have baseline procedures performed for that study; eligibility criteria will be confirmed (at Visit 
1 of study protocol 810P304) or EOS (Visit 8) in this study (810P503).   
 
Early Termination 
All subjects who discontinue early (i.e. during Titration period, Day 1 to Day 14) will be 
instructed to return to the study site for a final visit (EOS), one week after discontinuation. 
Subjects who discontinue from the study following Day 15 in the Titration period or during the 
Maintenance period will be offered a taper card and will return to the study site for a final visit 
(EOS). 
5. 
STUDY METHODS 
5.1 
Selection of Study Population 
Approximately 372 subjects aged 12-17 years (inclusive) will be screened to enroll and 
randomize 186 subjects; 93 in the SPN-810 arm and 93 in the placebo arm. The population will 
be male and female subjects diagnosed with ADHD, with associated features of IA and currently 
being treated with an FDA-approved standard ADHD treatment (psychostimulants and non-
stimulants).   
 
Inclusion Criteria 
The following inclusion criteria must be met in order for a subject to be enrolled and 
randomized to treatment: 
1. 
Healthy male or female subjects, age 12-17 years at the time of screening, including 
outpatients in foster care living at home. 


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2. 
Diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental 
Disorders-5 (DSM-5) confirmed by MINI-KID. 
3. 
Monotherapy treatment with an FDA-approved optimized ADHD medication 
(psychostimulants and non-stimulants for at least one month prior to Screening and 
willing to maintain the dose throughout the duration of the study. 
4. 
Retrospective Modified Overt Aggression Scale (R-MOAS) score of ≥ 20 at Screening and 
Visit 3. 
5. 
CGI-S score at least moderately ill (≥4) at Screening and Visit 3. 
6. 
Vitiello Aggression Questionnaire score from -2 to -5 at Screening.  
7. 
Free of antipsychotic medication for at least 2 weeks or 5x drug’s half-life or whatever is 
longer prior to Visit 2.  
8. 
Discontinuation of α2-adrenergic agonists (e.g. clonidine and guanfacine) used for any 
other reason except for monotherapy treatment of ADHD (e.g. aggression or insomnia) 
at least two-weeks prior to Visit 2.  
9. 
Medically healthy with clinically normal laboratory profiles, vital signs and 
electrocardiograms (ECGs). 
10. 
Able and willing to swallow tablets whole and not chewed, cut or crushed. 
11. 
Written informed consent/assent obtained from the subject’s parent or legal authorized 
representative (LAR), and written informed assent from the subject if required. 
12. 
Compliance ≥ 70% for completion of the IA Diary during the Baseline period. 
13. 
IA score ≥ 6 during the Baseline period. 
 
Exclusion Criteria 
Any of the following will disqualify a subject from being enrolled and randomized: 
1. 
Body Mass Index (BMI) less than 25th and above 99th percentile.  
2. 
History or current diagnosis of epilepsy, major depressive disorder, bipolar disorder, 
schizophrenia and other psychotic disorders, personality disorder, Tourette’s disorder, 
dissociative disorder, or autism spectrum disorder. 
3. 
Currently meeting DSM-5 criteria for 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 strongly inhibit and induce CYP2D6 activity within (2) two weeks or 5x drug’s 
half-life or whatever is longer, before Screening. 
5. 
Use of herbal supplements one week prior Screening. 
6. 
Known or suspected intelligence quotient (IQ) < 70, including speech/language problems, 
non-verbal learning disabilities, lead intoxication and traumatic brain injury.   
7. 
Suicidality, defined as either active suicidal plan/intent or active suicidal thought in the 
six months before the Screening Visit or more than one lifetime suicide attempt 
confirmed by the Columbia-Suicide Severity Rating Scale (C-SSRS).  
8. 
Historical and current evidence of violence abuse or neglect. 


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for the purpose of reviewing or performing this study. 
 
 
 
9. 
Pregnancy, breastfeeding or refusal to use birth control during the study (for female 
subjects of childbearing potential and sexually active males). 
10. 
Substance or alcohol/abuse use during the last three months prior to Screening. 
11. 
Criminal arrest reports at least six months prior to Screening.      
12. 
Known allergy or sensitivity to molindone hydrochloride or inactive ingredients. 
13. 
Any reasons which, in the opinion of the Investigator or the Sponsor, would prevent the 
subject and the subjects’ caregiver from participating in the study or complying with the 
study procedures.  
14. 
Use of an investigational drug or participation in an investigational study within 30 days 
prior Visit 2. 
5.2 
Schedule of Visits and Procedures 
All subjects who are consented are required to follow the protocol procedures regardless of the 
number of doses of SM taken.  The Sponsor, or the Sponsor’s designee, must be notified of all 
deviations from the Schedule of Visits and Procedures (Table 1), and these procedures, if 
applicable, should be performed at the nearest possible time to the original schedule.  Subjects 
will be instructed to call study site personnel to report any issues or abnormal reactions during 
the intervals in 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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a. 
Written consent must be obtained prior to performing any study-related procedure. 
b. 
Subject number will be assigned via 
 
c. 
Assess for any clinically significant change in Medical History since screening. 
d. 
Confirm inclusion/exclusion criteria. 
e. 
Urine pregnancy test will be performed for all female subjects. Prior to the administration of the first dose of SM subjects will have to be tested as negative to continue in the study. If Visit 1 and 
Visit 2 occur on the same day then both urine and serum pregnancy tests must be performed. 
f. 
Serum pregnancy test will be performed at Screening for all female subjects.  
g. 
Diary compliance must be at least 70% (minimum of 11 days out of 15) to qualify for randomization. 
h.     Heart Rate (HR), blood pressure (BP), temperature, and respiratory rate will be measured. 
i.   PK blood samples will be obtained over two visits 
j.     Only the Investigator-rated CGI-S will be completed at Screening; Caregiver and Investigator-rated CGI-S will be collected at randomization and every visit thereafter. 
k.     The checklist will be recorded on a paper source and entered on EDC only at Visit 2. 
l.     Optional 
 
 
Columbia Suicide Severity 
Rating Scale (CSSRS) 
X 
 
X 
X 
X 
X 
X 
X 
Caregiver and Investigator 
CGI-S 
Xj 
 
X 
X 
X 
X 
X 
 
Caregiver and Investigator 
CGI-I 
 
 
 
X 
X 
X 
X 
 
SNAP-IV, CHQ-PF28, SIPA 
 
 
X 
 
 
 
X 
 
Infrequent Behaviors 
Checklist 
 
Xk 
X 
X 
X 
X 
X 
 
Simpson-Angus, Barnes & 
AIMS 
 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispensation 
 
 
Xb 
X 
X 
X 
X 
 
Drug Return and Compliance 
 
 
 
X 
X 
X 
X 
X 
Diary Return 
 
 
 
 
 
 
 
X 


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for the purpose of reviewing or performing this study. 
 
 
 
 
5.3 
Study Procedures 
 
Screening/ Visit 1 (Day -45) 
Prior to conducting any procedures, written Informed Consent will be obtained from the parent 
or LAR, and, if appropriate, Informed Assent from the subject. Subjects screening procedures 
will be performed within 45 days prior Visit 3 and may be done on more than one day. 
Abnormal results on screening laboratory tests may be repeated at the discretion of the 
Investigator. 
The following procedures will be performed at screening (Visit 1): 
1. Obtain written informed consent and assent 
2. Administer R-MOAS scale 
3. Administer MINI-KID for ADHD diagnosis 
4. Administer Vitiello Aggression Questionnaire 
5. Record medical history 
6. Record demographic information 
7. Perform physical examination 
8. Perform 12-lead ECG 
9. Confirm Inclusion/Exclusion criteria 
10. Access 
 for subject number 
11. Collect urine sample for drug screen and urinalysis  
12. Collect blood for serum pregnancy test (If Visit 1 and Visit 2 occur on the same day then 
both urine and serum pregnancy tests must be performed) 
13. Record vital signs (HR, BP, temperature, and RR) 
14. Record weight, height, BMI 
15. Collect blood samples for hematology and chemistry  
16. Collect blood samples for optional PGx testing 
17. Administer Columbia Suicide Severity Rating Scale (C-SSRS) 
18. Administer Investigator CGI-S scale 
19. Record concomitant medications 
 
Baseline/ Visit 2, Day -15 
Visit 2 will occur at least 15 days prior to Visit 3 as per the Schedule of Events and Procedures.  
1. Administer R-MOAS scale 
2. Collect urine for drug screen and pregnancy test (If Visit 1 and Visit 2 occur on the same 
day then both urine and serum pregnancy tests must be performed) 
3. Conduct training for the electronic IA diary  
4. Distribution of IA diary 


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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. 
 
 
 
5. Record Infrequent IA Behaviors 
6. Record and assess concomitant medications 
 
Visit 3, Day 1 
Visit 3 will occur at least 14 days (±2 days) following Visit 2 as per the Schedule of Events and 
Procedures. 
1. Administer R-MOAS scale 
2. Assessment for any clinically significant changes in medical history 
3. Confirm eligibility to randomize subject  
4. Assess IA diary compliance/review training as necessary 
5. Randomize subject 
6. Collect urine sample for drug screen, urinalysis and pregnancy test  
7. Record weight, height and BMI 
8. Record vital signs (HR, BP, temperature, and RR) 
9. Collect blood samples for hematology and chemistry  
10. Administer Columbia Suicide Severity Rating Scale (C-SSRS) 
11. Administer Caregiver and Investigator-completed CGI-S scale 
12. Administer SNAP-IV, CHQ-PF 28 and SIPA scales 
13. Administer safety scales (Simpson-Angus, Barnes-Akathisia, AIMS) 
14. Record adverse events 
15. Record Infrequent IA Behaviors 
16. Record concomitant medications 
17. Dispense SM via I
 
 
Visit 4, Day 15 
Visit 4 will occur 14 days (±2 days) following Visit 3 according to the Schedule of Visits and 
Procedures.  
1. Administer R-MOAS scale 
2. Review IA diary compliance and provide training as needed 
3. Record dosing diary compliance and provide training as needed 
4. Collect urine sample for pregnancy test and drug screen  
5. Record vital signs (HR, BP, temperature, and RR) 
6. Administer Columbia Suicide Severity Rating Scale (C-SSRS) 
7. Administer Caregiver and Investigator-completed CGI-S scale 
8. Administer Caregiver and Investigator- completed CGI-I scale 
9. Administer safety scales (Simpson-Angus, Barnes-Akathisia, AIMS) 
10. Record adverse events 
11. Record Infrequent IA Behaviors 
12. Record concomitant medications 
13. Collect returned SM assess treatment compliance 


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14. Dispense SM 
 
Visit 5, Day 22 
Visit 5 will occur 21 days (±2 days) following Visit 3 according to the Schedule of Visits and 
Procedures. Refer to Section 5.3.9 for details regarding timing of the dose of SM prior PK 
sampling. 
1. Administer R-MOAS scale 
2. Review IA diary compliance and provide training as needed 
3. Record dosing diary compliance and provide training as needed 
4. Collect urine sample for pregnancy test and drug screen 
5. Record vital signs (HR, BP, temperature, and RR) 
6. Collect blood for PK analysis 
7. Administer Columbia Suicide Severity Rating Scale (C-SSRS) 
8. Administer Caregiver and Investigator-completed CGI-S scale 
9. Administer Caregiver and Investigator- completed CGI-I scale 
10. Administer safety scales (Simpson-Angus, Barnes-Akathisia, AIMS) 
11. Record adverse events 
12. Record Infrequent IA Behaviors 
13. Record concomitant medications 
14. Collect returned SM; assess treatment compliance 
15. Dispense SM 
 
Visit 6, Day 29 
Visit 6 will occur 28 days (±2 days) following Visit 3 according to the Schedule of Visits and 
Procedures. Refer to Section 5.3.9 for details regarding timing of the dose of SM prior to PK 
sampling. 
1. Administer R-MOAS scale 
2. Review IA diary compliance and provide training as needed 
3. Record dosing diary compliance and provide training as needed 
4. Record vital signs (HR, BP, temperature, and RR) 
5. Record weight, height and BMI 
6. Collect blood for PK analysis 
7. Collect urine sample for pregnancy test and drug screen 
8. Administer Columbia Suicide Severity Rating Scale (C-SSRS) 
9. Administer Caregiver and Investigator-completed CGI-S scale 
10. Administer Caregiver and Investigator- completed CGI-I scale 
11. Administer safety scales (Simpson-Angus, Barnes-Akathisia, AIMS) 
12. Record adverse events 
13. Record Infrequent IA Behaviors 
14. Record concomitant medications 


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for the purpose of reviewing or performing this study. 
 
 
 
15. Collect returned SM; assess treatment compliance 
16. Dispense SM 
 
Visit 7, Day 36 
Visit 7 will occur 7 days (±2 days) following Visit 6 according to the Schedule of Visits and 
Procedures.  
1. Administer R-MOAS scale 
2. Perform physical examination 
3. Perform 12-lead ECG 
4. Review IA diary compliance and provide training as needed 
5. Record dosing diary compliance and provide training as needed 
6. Collect urine sample for urinalysis, pregnancy test and drug screen 
7. Record vital signs (HR, BP, temperature, and RR) 
8. Collect blood samples for hematology and chemistry  
9. Administer Columbia Suicide Severity Rating Scale (C-SSRS) 
10. Administer Caregiver and Investigator-completed CGI-S scale 
11. Administer Caregiver and Investigator-completed CGI-I scale 
12. Administer SNAP-IV, CHQ-PF 28 and SIPA scales 
13. Administer safety scales (Simpson-Angus, Barnes-Akathisia, AIMS) 
14. Record adverse events 
15. Record Infrequent IA Behaviors 
16. Record concomitant medications 
17. Collect returned SM; assess treatment compliance 
18. Dispense SM (either taper or conversion card based upon the subject’s decision about 
participation in the open-label extension) 
 
Visit 8/ End of the Study, Day 46 
Visit 8 will occur 10 days (±1 day) following Visit 7 according to the Schedule of Visits and 
Procedures. These procedures will be performed for all subjects who complete the 
Maintenance period and for those who discontinue early. Subjects who discontinue after Visit 4 
will be offered a taper kit and return to the study site to complete Visit 8. Any subject, who 
discontinues between Visit 3 and Visit 4, will be instructed to return to the study site for the 
final visit, within one week after discontinuation. 
1. Administer R-MOAS scale 
2. Record vital signs (HR, BP, temperature, and RR) 
3. Record height, weight and BMI 
4. Collect blood for hematology and chemistry 
5. Collect urine for urinalysis, drug screen and pregnancy test 
6. Administer Columbia Suicide Severity Rating Scale (C-SSRS) 
7. Administer safety scales (Simpson-Angus, Barnes-Akathisia, AIMS) 


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8. Record adverse events 
9. Record concomitant medications 
10. Collect SM and assess treatment compliance 
11. Collect Diary 
12. Complete/Discontinue subject 
 
Pharmacokinetic Blood Sampling 
 
 
 
 
 
 
 
 
 
 
 
  
5.4 
Treatments 
 
Treatment Administered 
Subjects will take up to (6) six 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 the stable dose of the optimized ADHD medication. During the conversion phase, 
subjects will take up to (8) eight molindone hydrochloride extended release tablet (SPN-810) or 
placebo twice each day (BID). 
If dosing starts before noon, the subject should start with the morning dose; if dosing starts 
after noon, the subject should start with the evening dose.  Subjects will be randomized to one 
of the two treatments at Visit 3 and will be titrated to the final randomized total daily dose 
(TDD) of 36 mg/day.  
o Treatment 1:  Placebo, PO, BID 
o Treatment 2: Flexible dose titrated to one of SPN-810 45 mg, or 54 mg, PO, BID 
Subjects will remain at the target dose of 36 mg/day or placebo for one week during 
maintenance.  In the second week of maintenance (Visit 5), the treatment dose could be 
increased in a blinded fashion to 45 mg (TTD) based on Investigator discretion or maintained at 


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36mg (TDD) or placebo. In the following week (Visit 6), the Investigator will re-assess the 
dosage: the subject may remain at 36 mg (TDD) or 45 mg (TDD) or matching placebo 
(depending on the dosage from the previous week) or titrate up to the higher dose of 45 mg or 
54 mg (TDD) or placebo. At the same Visit, dose reduction will be allowed in consultation with 
the Medical Monitor and the Sponsor: the Investigator may adjust the dose based upon 
tolerability. 
 
ADHD medication 
The Investigator is not allowed to adjust the FDA-approved ADHD monotherapy (either IR or ER 
not both) medication and/or its dose at any time during the course of this study. 
 
Identity of Investigational Product(s) 
SM and reference (matching placebo) products are either purple (3mg) or yellow (9mg) round 
tablets printed on one side with the tablet dose strength (“3” or “9”) that will be supplied in 
labeled blister cards by the Sponsor. The Sponsor will package the SM in a double-blind 
configuration.  
Each SM blister card will contain combinations of molindone extended-release and/or placebo 
tablets, which will supply a subject with 7 (seven) days of dosing as well as some extras to 
account for visit delays associated with patient/site schedules.  A single SM kit contains a total 
of 7 pre-packaged blister cards (two Titration blister cards, three maintenance blister cards, one 
tapering blister card and one conversion blister card) and is marked with a unique 4-digit SM kit 
number. 
Instructions will be provided to site staff and caregiver(s) on how to move between the 
different dose-levels during the Maintenance period (36mg, 45mg and 54mg TDD). 
 
Study Medication Handling and Accountability  
All SM is supplied to the Investigator by the Sponsor.  SM must be kept in an appropriate secure 
area (e.g., locked cabinet) and stored according to the conditions specified on the SM labels.  
SM must be stored between 59°F – 86°F (15°C – 30°C). 
Following Sponsor instructions and in compliance with 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, shipment, dispensing, inventory, and record keeping) in a SM 
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 SM 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; dispensing of SM to the 
subject; collection of unused supplies returned by the subject; and subsequent return of 


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unused SM to the Sponsor must be maintained with dates.  This SM accountability log includes, 
but may not be limited to: (a) documentation of receipt of clinical supplies, (b) SM inventory 
log, (c) SM 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 CRA will 
review these documents along with all other study conduct documents at each and every visit 
to the study site once SM 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 
subject 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 
SM accountability and reconciliation procedures by study site personnel and documentation 
procedures by Sponsor personnel, SM is to be returned to the Sponsor with a copy of the 
completed SM disposition form as outlined in the Study Medication Manual. 
 
Methods of Assigning Subjects to Treatment Group 
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. Dispending of the SM will be completed 
centrally through the use of an 
 that will determine 
which kit to assign to the subject. 
Upon enrollment to the study, subjects will be assigned site (01-99) and subject numbers (5001-
5999), in the sequence that they are entered.  On Visit 3, subjects who complete the IA Diary 
Baseline period and met all eligibility criteria will be assigned kit numbers, according to the 
randomization schedule, by using the 
 
 
Treatment Replacement 
In the event that a subjects’ original kit is lost, damaged or consumed prior to the end of 
treatment, the Investigator will use the 
 which will specify a new kit number to be 
dispensed to that subject from the supplies already at that site. Separate reserve will not be 
provided to the Investigators.  
 
Dosing Schedule 
At Visit 3, subject will be randomized to Placebo or SPN-810 in a 1:1 ratio and the dosing will 
begin. Table 2 below presents the details of the dosing for each treatment group throughout 
the 2-week titration phase for this study. During Maintenance period, the Investigator will 
assess the dosage at his discretion. Dose reduction will be discussed with the Medical Monitor.  




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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. 
5.5 
Allowed Concomitant Medications 
The dose of the ongoing ADHD therapy will not be adjusted during the study, starting at Visit 1. 
No additional concomitant medications are allowed, with the following exceptions: 
1. Emla or other numbing cream for PK venipuncture 
2. Standard childhood vaccinations and prophylactic flu shots 
3. Nutritional supplements (e.g. multivitamins, fish oil) 
4. 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 three 
times daily) and clonazepam (0.25 to 1 mg per dose not to exceed twice daily) is also 
permitted to treat extrapyramidal symptoms. 
5. For the treatment of Akathisia, propranolol is recommended up to 90 mg /day in divided 
doses, three times per day, starting at 10 mg BID and up to 30 mg TID, as needed. 
6. Common over-the-counter (OTC) therapies for minor transient ailments (e.g. 
acetaminophen for headache, ibuprofen for fever) will be allowed without exception. 
7. Treatment for AEs other than EPS or minor transient ailments is permitted in 
consultation with the Medical Monitor and Sponsor.   
All concomitant medications will be recorded in the eCRF. 
5.6 
Prohibited Medications 
1. 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. 
2. Use of herbal supplements. 
3. α2-adrenergic agonists (e.g. clonidine and guanfacine) used for other reasons except for 
monotherapy treatment of ADHD. 
5.7 
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 8.  Any subject, who discontinues from the study during the Maintenance period 
or following day 15 in the Titration period, will be offered a taper kit, whereas subjects who 


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discontinue prior Visit 4 (i.e. during Titration period, Day 1 to Day 14) will be instructed to 
return to the study site for a final visit, one week after discontinuation. All subjects who 
discontinue early will complete Visit 8, EOS procedures.   
The Investigator(s) or subjects themselves may stop SM 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 should be discussed where possible and as 
applicable with the Medical Monitor, the Investigator and the Sponsor before the subject stops 
SM.  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. 
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. 
STUDY ENDPOINTS 
6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change (PCHT) in the frequency (unweighted score) 
of IA behaviors per 7 days in the Treatment Phase (titration + maintenance) relative to the 
Baseline period calculated over the number of days with non-missing IA diary data.  
 
The primary efficacy endpoint PCHT will be calculated by PCHT= 100*(T – B)/B, where T and B are 
IA behavior frequencies per 7 days during the Treatment Phase and Baseline period, respectively. 
The IA behavior frequency per 7 days is defined as (SUM/DAY) x 7, where SUM is the total of the 
15 IA behaviors reported in the subject IA diary, and DAY is the number of days with non-missing 
IA score in the subject IA diary during the specified study period. 
 
Primary Efficacy Variable 
The primary efficacy outcome variable will be based on a checklist of 15 IA behaviors collected 
in the electronic IA diary. These behaviors were described in the non-interventional study 
(Sponsor Study 810P502, 2016); they include Yelling, Screaming, Threatening, Scratching, 
Throwing, Slamming, Hitting Self, Arguing, Cursing, Name Calling, Shoving, Hair Pulling, Fighting, 
Hitting Others and Kicking Others. The IA diary consists of two parts:  1) an episodic diary that 
will be used by the primary or alternate caregiver to enter events as soon as possible after they 
are observed; and 2) an evening diary that will prompt the caregiver to review events for the 


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day and to enter any events that were not previously captured.  Events can be directly observed 
by the caregiver or could be reported to the caregiver by another observer such as a teacher, a 
friend of the subject or the parent of a friend. 
 
Each event will be characterized by a checklist of one or more behaviors observed during the 
day. The checklist will indicate whether each behavior was observed (coded 1) or was not 
observed (coded 0) during the incidence of an event.  Each day can have multiple events.  A day 
can have no event, as can be attested in the evening diary.  In this case, if no event is reported 
during a day, and the evening diary confirms this, the daily event score for that subject will be 
0.  Behaviors not on this list will not be captured. 
6.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoint is the change from Baseline to the end of the study where the 
Baseline is defined as the last observation prior to the first dose, Visit 3. The effect of SPN-810 
will be measured on the following efficacy scales administered at visits designated in the 
Schedule of Visits and Procedures (Table 1). 
 
Investigator-Rated Clinical Global Severity of Illness Scale (CGI-S) 
Effect of SPN-810 on the Clinical Global Impression – Severity of Illness Scale (CGI-S) completed 
by the Investigator will be assessed as a key secondary efficacy measure. The CGI scale was 
developed to provide a brief, stand-alone assessment of the clinician’s view of a subject’s global 
functioning (Guy, 1976).  Successful therapy is indicated by a lower overall score in subsequent 
testing.  Investigators should consider their total clinical experience with children who have IA 
comorbid with ADHD and rate how severe the subject’s condition is at the time.  
CGI-S will be evaluated on a 7-point scale: 
• 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 assessed at Screening and at each visit after randomization (Visit 3). 
 
Retrospective-Modified Overt Aggression Scale (R-MOAS) 
The treatment effect on the Retrospective-Modified Overt Aggression Scale (R-MOAS) will be 
assessed to capture the severity of the aggressive behaviors and to correlate with the IA 
behaviors in the diary. 
This scale was developed to gauge the severity of aggressive behavior (Blader, et al., 2010).  
Parents rate the frequency over the past week of 16 aggressive behaviors in four areas: verbal 
aggression; physical aggression toward others; aggression toward oneself; and destruction or 
hostile misuse of property. 
The remission rate will be defined as a score ≤ 10. 


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The scale will be administered at each visit. 
 
Additional Secondary Efficacy Endpoints 
6.2.3.1 
Clinical Global Impression – Improvement Scale (CGI-I) 
Effect of SPN-810 on the Clinical Global Impression – Improvement Scale (CGI-I) completed by 
the Investigator and the Caregiver will be assessed as an additional secondary efficacy measure.  
CGI-I, relative to the condition at baseline, will be evaluated by the Investigator and the 
Caregiver on a 7-point scale:  
• 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 assessed at Visit 4-7. 
6.2.3.2 
Caregiver-Rated Clinical Global Severity of Illness Scale (CGI-S) 
The Clinical Global Impression – Severity of Illness Scale (CGI-S) completed by the Caregiver will 
be assessed as an additional secondary efficacy measure. 
CGI-S will be evaluated on a 7-point scale: 
• 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 assessed at each visit after randomization (Visit 3). 
6.2.3.3 
Swanson, Nolan, Pelham Rating Scale-Revised (SNAP-IV) 
The SNAP-IV rating scale includes 18 ADHD and 8 oppositional defiant disorder (ODD) 
symptoms as specified in the DSM-IV-TR and International Statistical Classification of Diseases 
and Health Related Problems 10th Revision (ICD-10) Classification of Mental and Behavioral 
Disorders.  The symptoms are scored by assigning a severity estimate for each symptom on a 4-
point scale (Swanson 2001).  The SNAP-IV rating should be performed by the same parent or 
legal representative. 
The ratings from the SNAP-IV scale are grouped into the following 4 subscales:   
• ADHD-Inattention (items #1-9),  
• ADHD-Hyperactivity/Impulsivity (items #10-18) 
• ADHD-Combined subscales (items #1-18) 
• ODD (items #19-26)   
Each subscale score is calculated by averaging the items scores within each subscale. 
The SNAP-IV rating scale will be administered at Visit 3 and Visit 7. 


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6.2.3.4 
Child Health Questionnaire Parent Form 28-Item (CHQ-PF28) 
The Child Health Questionnaire Parent Form 28-item (CHQ-PF28) is a short generic measure of 
health status and health related quality of life (Landgraf 1996).  CHQ-PF28 items have four, five, 
or six response options, divided over eight multi-item scales (physical functioning, general 
behavior, mental health, self-esteem, general health perceptions, parental impact: emotional, 
parental impact: time, and family activities) and five single item concepts (role functioning: 
emotional/behavior, role functioning: physical, bodily pain, family cohesion, and change in 
health). The CHQ-PF28 should be performed by the primary caregiver.   
The CHQ-PF28 will be administered at Visit 3 and Visit 7. 
6.2.3.5 
Stress Index for Parents of Adolescents (SIPA) 
The Stress Index for Parents of Adolescents (SIPA) is a screening and diagnostic instrument that 
identifies areas of stress in parent–adolescent interactions, allowing examination of the 
relationship of parenting stress to adolescent characteristics, parent characteristics, the quality 
of the adolescent–parent interactions, and stressful life circumstances in parents of adolescents 
(11-19 years old). The SIPA consists of 90 items divided in three major domains, the 
Adolescents Domain (AD), the Parent Domain (PD) and the Adolescent-Parent Relationship 
Domain (APRD), which include the following subscales:  moodiness/emotional lability, social 
isolation/withdrawal, delinquency/antisocial, failure to achieve and persevere, relationship 
with spouse/partner, social alienation and incompetence/guilt. The SIPA includes 22 item Life 
Stressors (LS) Scale and the Index of Total Parenting Stress (TS). 
Parents respond to the first 90 items using a 5-point rating scale ranging from Strongly Disagree 
(5) to Strongly Agree (1) and the final 22 items by indicating Yes (Y) or No (N). 
The SIPA will be administered at Visit 3 and Visit 7. 
6.3 
Exploratory Endpoints 
 
IA Diary Cross-Validation 
The data generated from 810P301 and 810P302 pediatric studies during the diary validation 
process will be used for cross-validation of the IA Diary in adolescents. The parameters used will 
be specified in the statistical analysis plan (SAP). 
 
Pharmacokinetic Measurements 
 
 
 


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6.3.2.1 
Pharmacokinetic Variables 
The pharmacokinetic variables are: 
• Apparent clearance (CL/F) of molindone  
• Apparent volume of distribution (V/F) of molindone  
6.3.2.2 
Additional Pharmacokinetic Variables 
 
 
 
 
 
  
 
 
 
Pharmacogenomics (PGx Testing) 
Blood samples will be collected at Visit 1 after confirmation of subject’s eligibility. 
Pharmacogenomic testing is optional. The DNA will be extracted and tested for any genetic 
variations associated with CYP2D6 enzyme. This enzyme is involved in the metabolism of 
molindone and genetic variations of the CYP2D6 gene may affect the pharmacokinetics of the 
drug. Test results in this study will identify the subject’s metabolizer phenotype. 
 
The residual DNA will be stored for possible testing of genes involved in the efficacy and possible 
association with particular adverse events of the drug (e.g., to understand the non-responders 
to treatment and/or individuals who show unusual safety profile). The DNA analysis will not be 
used for individual genetic characterization and the subject identity will be kept confidential. 
6.4 
Safety and Tolerability Endpoints 
The secondary outcome measures include the safety and tolerability of the SM.  Safety 
assessment will consist of monitoring and recording of all AEs, concomitant medications and 
assessment of suicidality ideation and behaviors at every visit. Clinical laboratory tests, 
including prolactin and insulin plasma levels, vital signs, physical examinations, 12-lead ECG are 
performed at visits specified in the Schedule of Events and Procedures and can be repeated as 
necessary as per the judgment of the Investigator and the Medical Monitor. 
Assessment of possible neurological side effects and EPS will be performed using the Simpson-
Angus scale, the Barnes Akathisia scale and the Abnormal Involuntary Movement scale.  A 
positive rating or finding on any safety scale will be captured as an Adverse Event at the 
discretion of the Investigator if it satisfied the criteria for Adverse Event. 


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Data Safety Committee (DSC) 
An independent and unblinded Data and Safety Committee (DSC) will be established to assess 
the safety of the subjects participating in the study.  An interim safety data analysis will be 
performed if required to support a registrational filing.  The DSC will not evaluate the efficacy 
data. The duties and responsibilities of the DSC will be described in a separate DSC charter.  
 
Adverse Events 
As defined by the ICH Guideline for 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: 
• 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. 
• Any new disease, intercurrent injuries, or exacerbation of an existing disease. 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG) that results in 
symptoms, a change in treatment, or discontinuation from SM. 
• Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 
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. 
6.4.2.1 
Causality 
AEs may be categorized as either Adverse Drug Reactions or Suspected Adverse Drug Reactions 
based on their relationship to SM and the degree of certainty about causality. 
• Suspected adverse drug reactions (SADRs) are a subset of adverse events 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 adverse event.   
• Adverse drug reactions (ADRs) are a subset of all SADRs for which there is reason to 
conclude that the drug caused the event. 
6.4.2.2 
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/procedure, 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 


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occurs after study treatment/procedure has started.  TEAEs occurring prior to the 
administration of the study medication (Day 1) will become part of the subject’s 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. 
All AEs occurring after enrollment and throughout the study period must be recorded.  A 
treatment-emergent adverse event (TEAE) is defined as an AE with a start date on or after the 
first dose of study drug, or that worsened following first administration of study drug. For 
subjects who receive SM, TEAEs will be collected starting from the first dose of SM.  The clinical 
course of each AE should be followed until resolution or until, in the medical judgment of the 
Investigator, the event has stabilized or is assessed as chronic.   
For subjects who opt to enroll in the OLE (810P304) study, occurrence of AEs will be assessed 
starting at Visit 8 of this study (810P503) or Visit 1 in the OLE. AEs occurred in this double-blind 
study or ongoing after Visit 7, will be part of the medical history in the OLE study. 
An increase in the CSSRS, Simpson Angus Scale, Barnes Akathisia Scale, or the AIMS will not 
necessarily be rated as an AE unless the event meets AE criteria. 
The Investigator is responsible for evaluating AEs and determining the following: 
• Serious vs. Non-serious: Is the event a Serious Adverse Event (SAE)? 
• Causality: Was AE related or possibly related to the SM? 
• Severity: How pronounced is the incapacity/discomfort caused by an AE? 
6.4.2.3 
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. 


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6.4.2.4 
Criteria for Assessing Causality 
The Investigator is responsible for determining the relationship between the administration of 
SM and the occurrence of an AE as not suspected or as a suspected reaction to SM.  These are 
defined as follows: 
Not suspected: The temporal relationship of the AE to SM 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 SM administration is missing or implausible, or 
there is an evident other cause. 
• Unlikely related:  Temporal relationship to SM administration makes a causal 
relationship improbable; and other drugs, chemicals, or underlying disease provide 
plausible explanations. 
Suspected: The temporal relationship of the AE to SM 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 SM administration is plausible, but 
concurrent disease or other drugs or chemicals could also explain event.  Information on 
drug withdrawal may be lacking or unclear.  This will be reported as a Suspected 
Adverse Drug Reaction (SADR). 
• Definitely related: Temporal relationship to SM administration is plausible, and 
concurrent disease or other drugs or chemicals cannot explain event.  The response to 
withdrawal of the medication (dechallenge) should be clinically plausible.  The event 
must be definitive pharmacologically or phenomenologically, using a satisfactory 
rechallenge procedure if necessary.  This will be reported as an Adverse Drug Reaction 
(ADR). 
 
Serious Adverse Events (SAE) 
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.) 
• in-patient 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 


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• 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 in-patient hospitalization, or intensive treatment for allergic bronchospasm in an emergency 
department would typically be considered serious. 
6.4.3.1 
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. 
All SAEs must be reported to the Drug Safety Contact within 24 hours of first becoming aware 
of the SAE.  The Investigator must complete an SAE eCRF in EDC 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).  Should the site be unable to 
access EDC, a paper SAE form must be completed and sent to 
 Drug Safety by email or fax. 
The Investigator will keep a copy of this SAE Report form on file at the study site. Once EDC 
becomes available, the site must complete the SAE eCRF in EDC.  
The Investigator or study physician, after thorough consideration of all facts that are available, 
must include an assessment of causality of an AE to SM in the report to the Sponsor.   
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: 
 
 
 
 
6.4.3.2 
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 
Medical Monitor; the Investigator must follow any pregnant subject for 3 months after the child 
is born.  The Investigator must complete a Pregnancy Outcome Form as a follow up. Any AEs 
concerning the pregnancy of the subject during pregnancy or the child after birth must be 
documented and reported to the Sponsor. 


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Treatment-emerging EPS (e.g. akathisia, dystonia, Parkinsonism, tardive dyskinesia) and 
neuroleptic malignant syndrome should be reported to the Drug Safety Contact person(s) by 
completing the Adverse Event of Special Interest (AESI) eCRF in EDC.  Should the site be unable 
to access EDC, a paper AESI form must be completed and sent to 
 Drug Safety by email or 
fax within 24 hours of first becoming aware of the event. Once EDC becomes available the site 
must complete AESI eCRF in EDC. EPS incidence will be summarized and shared with study 
Investigators throughout the 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 molindone which is freely soluble in water. Since the adsorption of 
molindone 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 molindone in animals, this blocking effect has not been determined 
in humans. 
6.4.3.3 
Sponsor Responsibilities for Expedited Reporting of SAEs 
The Sponsor will inform Investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (i.e., within specific 
timeframes).  For this reason, it is imperative that study sites submit SAE information to the 
Sponsor in the manner described above. 
Investigators must comply with the applicable regulatory requirements related to the reporting 
of SAEs to the IRB/IEC.  Investigators must also submit the safety information provided by the 
Sponsor to the IRB/IEC unless the country legal regulation requires that the Sponsor should be 
responsible for the safety reporting to the IRB/IEC. 
It is the responsibility of the Sponsor to notify all participating Investigators, in a written IND 
safety report, of any SADR that is both serious and unexpected.  The Sponsor will also notify 
participating Investigators of any findings from other sources (other studies, animal and in vitro 
testing, etc.) that suggest a significant risk for human subjects.  Such findings will typically lead 
to safety-related changes in the study protocol, Informed Consent, and/or Investigator’s 
Brochure. 


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Assessment of Neurological Side Effects and EPS 
6.4.4.1 
Simpson-Angus Scale 
The Simpson-Angus scale is a 10-item rating scale that is widely used for assessment of 
neuroleptic-induced Parkinsonism (Simpson 1970).  It consists of 1 item measuring gait, 6 items 
measuring rigidity, and three items measuring glabella tap, tremor and salivation, respectively.  
This assessment will be administered at Visit 3 and all subsequent visits. 
6.4.4.2 
Barnes Akathisia Scale 
The Barnes Akathisia scale 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 3 and all subsequent visits. 
6.4.4.3 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS test is a rating scale used to measure tardive dyskinesia (Munetz 1988).  There are 12 
items that rate involuntary movements of various areas of the subject’s body.  This assessment 
will be administered at Visit 3 and all subsequent visits.  
6.4.4.4 
Management of Treatment-Emerging EPS 
If a subject experiences treatment-emerging 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 three times daily) and 
clonazepam (0.25 to 1 mg per dose not to exceed twice daily) will also be permitted to treat 
emerging EPS. 
For the treatment of Akathisia, propranolol is recommended up to 90 mg /day in divided doses, 
three times per day, starting at 10 mg BID and up to 30 mg TID, as needed. 
A positive finding on an EPS safety assessment scale (Barnes Akathisia, Simpson-Angus, 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. 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire that prospectively assesses suicidal ideation and behavior using a 
semi-structured interview to probe patient responses (Posner 2011).  The C-SSRS versions 
applicable to the current study are the Baseline version and the Since Last Visit version. 
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 all the 
other study visits. 
 
Laboratory Measurements 
With the exception of urine pregnancy test, 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 
detailed 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. A subject will be 
excluded if the Screening blood test results indicates > 2 times the upper limit of normal (ULN) 
of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl 
transpeptidase (GGT), and/or serum creatinine. Laboratory tests will not be repeated for these 
subjects. 
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 testing at the 
discretion of the Investigator.  Any repeat laboratory testing will be conducted under fasting 
condition. Any laboratory abnormality may qualify as an AE in the Investigator’s judgment. 
 




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The ECG will be recorded while the subject is resting in a supine position.  The ECG will 
electronically measure the PR, QRS, QT, and QTc intervals, and heart rate. 
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). 
 
Infrequent Behaviors Checklist 
The infrequent behaviors checklist is a list of 15 behaviors that (along with the 15 IA Diary 
behaviors) were qualitatively linked to IA during the development of the IA diary (Sponsor 
Study 810P501, 2015).  These behaviors include Teasing, Spitting, Biting, Weapons, Ripping, 
Breaking, Vandalizing, Destroying, Fire Setting, Hitting Animal, Kicking Self, Kicking Animal, 
Severe Injury Self, Severe Injury Others and Severe Injury Animal.  At Visit 2 the caregivers will be 
asked which, if any, of these behaviors have been observed since Screening. At the following 
visits (Visit 3-7) any of these behaviors will be recorded on the electronic IA diary if they were 
observed since the patient’s last visit.   
7. 
OTHER SPECIAL TESTS 
The following special tests will be administered in the clinic at visits designated in the Schedule 
of Visits and Procedures (Table 1).  
7.1 
MINI-KID  
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. 
7.2 
Vitiello Aggression Questionnaire 
The Vitiello Aggression Questionnaire is a 10-item rating scale that uses a cluster analysis to 
categorize aggression into two subtypes, predatory (or planned) and affective (or impulsive) 
(Vitiello 1990).  This assessment will be administered at Visit 1. 


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8. 
STATISTICAL METHODS 
8.1 
Statistical and Analytical Plans 
Tabular summaries of the data collected during the study will be presented to provide a general 
description of the subjects studied and an overview of the efficacy, PK and safety results.  Data 
from all sites will be combined in the computation of these summaries and summaries will be 
presented by treatment group.  Continuous variables will be summarized using descriptive 
statistics (number of subjects, mean, standard deviation [SD], median, and minimum and 
maximum values).  Categorical (nominal) variables will be summarized using frequency tables 
(number 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.  Additional subject data listings to be provided for this study 
are listed under the relevant subsections below. All data analyses will be performed by 
 
 which is designated CRO, after the study is completed and the database is 
released.  Statistical programming and analyses will be performed using SAS® and/or other 
validated statistical software as required. 
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 database lock and will be included 
in the Clinical Study Report (CSR) as an appendix.  The SAP will supersede the statistical analysis 
methods described in this clinical protocol. Any deviation from the statistical plan will be 
documented and described in the CSR.  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. 
In general, the baseline value for a variable is defined as the last observation prior to the first 
dose of double-blind study medication, ideally Visit 3, but including the screening value, if 
necessary. 
8.2 
Handling Missing Data 
For the primary efficacy end point, the frequency of IA behaviors during the Treatment Phase 
will be calculated over the number of days with non-missing IA diary data in the Treatment 
Phase (titration + maintenance).  For subjects who have partial IA diary data during 
Maintenance period (<7 days with non-missing IA diary data), the IA behaviors from both 
titration and partial maintenance period will be counted together and used for the 
maintenance period. For subjects with IA diary data only available during titration period, the IA 
behaviors from the titration period will be used for the maintenance period.  


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8.3 
Analysis Populations 
The population of “all enrolled subjects” consists of all those screened subjects who meet the 
requirements for study participation and are entered in the Baseline period of the study.  The 
population of “all randomized subjects” consists of all those enrolled subjects who complete 
the Baseline Period, meet the inclusion/exclusion criteria and are randomized. 
Safety Population:  will include all subjects who received at least 1 dose of study drug and had 
at least one post-baseline safety assessment. 
 
Full Analysis Set (FAS):  will include all screened subjects who received at least 1 dose of study 
drug and have completed baseline and at least 1 valid post-randomization assessment of 
frequency of IA behaviors based on IA diary entry. 
 
Per-Protocol (PP) Population:  will include all subjects who completed Treatment Phase and did 
not have major protocol deviations (as defined in the SAP). 
 
PK population:  will include all subjects in the safety population who have received at least 1 
dose of study drug and had one PK sample drawn which had quantifiable concentration for 
molindone. 
The safety, psychometric, FAS, PP, and PK populations are based on randomized treatment 
received. 
8.4 
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 
safety, psychometric, FAS, and PP populations, except for medical history, which will be 
summarized for the safety population. 
8.5 
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 in the FAS population 
• Subjects treated (safety population) 
• Subjects in the PP study population 
 
The reasons for study discontinuation may include one of the following: 
• Subject withdrew consent 


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• Lost to follow-up 
• Administrative reason 
• Adverse event 
• Investigator decision 
• Failure to follow required study procedures 
• Other 
 
Only one reason for study discontinuation will be recorded for each subject. 
8.6 
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 
• Non-compliance with study treatment 
• Disallowed concomitant medications 
• Non-compliance with study inclusion or exclusion criteria 
• Non-compliance with study assessment procedures 
8.7 
Study Medication Exposure and Compliance 
Duration of 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)/T*(DL- DF + 1)}*100, where D=number of tablets dispensed, R= number of tablets 
returned, T= number of tablets administered, DL = date of last visit (dose) and DF= date 
of first visit (dose) 
 
The number of tablets (T) taken each day may vary during the flexible Maintenance period: 
during the first week of maintenance a total of 6 tablets per day will be taken, whereas during 
week 2 and 3 of maintenance, the number of tablets taken will be between 4 and 6 depending 
upon the 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 


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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. 
9. 
EFFICACY ANALYSES 
9.1 
Primary Efficacy Analysis 
The primary efficacy analysis is the percent change (PCHT) in the frequency (unweighted score) 
of IA behaviors per 7 days in the Treatment Phase (titration + maintenance) relative to the 
Baseline period calculated over the number of days with non-missing IA diary data. The 
frequency of the IA behaviors per 7 days is the sum of the scores for all the events collected in a 
given period of sequential days, adjusted per 7 days. 
The primary efficacy endpoint PCHT will be calculated by PCHT= 100*(T – B)/B, where T and B 
are IA behavior frequencies per 7 days during the Treatment Phase and Baseline period, 
respectively. The IA behavior frequency per 7 days is defined as (SUM/DAY) x 7, where SUM  is  
the sum of the IA behaviors reported in the subject IA diary, and DAY is the number of days 
with non-missing IA frequency data in the subject IA diary during the specified study period. 
Let µ1, and µ2 represent the median percent change in the frequency of IA behaviors per 7 days 
in the Treatment Phase, relative to the Baseline period in the FAS population for subjects treated 
with placebo and SPN-810 treatment, respectively.  The null (H0) and the alternative (Ha) 
hypotheses are as in the following: 
H0: µ2= µ1, [there is no difference between the median of the SPN-810 treatment group 
and the median of placebo group] vs. Ha: µ2≠ µ1, [there is a difference between the 
median of the SPN-810 treatment group and the median of placebo]. 
To test the above hypothesis, the primary efficacy analysis will be performed using the 
Wilcoxon rank-sum test to compare the median of SPN-810 with the median of the Placebo. 
The Hodges-Lehmann estimate of the difference (SPN-810 minus placebo) and the associated 
95% confidence interval (CI) around the difference will be calculated.   
When the median PCHT from subjects in SPN-810 treatment group is significantly different from 
the placebo, further exploratory testing may be performed between other doses (45mg and 
54mg) and placebo depending on the available sample size at each dose level. 
9.2 
Secondary Efficacy Analyses 
 
Key secondary endpoints are: 
1. Change from Visit 3 to Visit 7 in the Investigator-rated CGI-S score 


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2. Change from Visit 3 to Visit 7 in R-MOAS score 
3. R-MOAS remission rate at Visit 7 
 
Additional secondary endpoints: 
1. Actual Investigator CGI-I score at Visit 7 and change from Visit 4 
2. Actual Caregiver CGI-I score at Visit 7 and change from Visit 4 
3. Change from Visit 3 to Visit 7 in the Caregiver-rated CGI-S score 
4. Change from Visit 3 to Visit 7 in the SNAP-IV ADHD scores in: 
a. Inattention ratings 
b. Hyperactivity/Impulsivity ratings 
c. ODD ratings 
d. Combined scale ratings 
5. Change from Visit 3 to Visit 7 in the CHQ-PF28 score 
6. Change from Visit 3 to Visit 7 in the SIPA scores in: 
a. Adolescents domain 
b. Parent domain 
c. Adolescents-Parents Relationship domain 
d. Life Stressor domain 
 
Each of the secondary endpoints will be analyzed using a Mixed-Effect Model for Repeated 
Measure (MMRM).  MMRM assumes missing data as Missing at Random. The model includes 
treatment, visit, and interaction between treatment and visit as fixed factors, baseline as 
covariate. The model parameters will be estimated using restricted maximum likelihood 
method with unstructured variance-covariance matrix and Kenward-Roger approximation to 
estimate denominator degrees of freedom.  The between-group comparison will be performed 
using the simple contrast at the respective visits. The least squares mean of the treatment 
group, the difference in the least squares mean (SPN-810 minus placebo), and the 2-sided 95% 
CI for the difference will be obtained.   
 
To preserve the overall type I error rate at 0.05 for the secondary endpoints, only SPN-810 
treatment group is significantly different from placebo for the primary endpoint will be tested 
for secondary endpoints.  
The ordering of the three (3) key secondary endpoints from first to be tested to third is: 
Investigator-completed Clinical Global Impression – Severity Scale (CGI-S) (Endpoint 1); 
Retrospective Modified Aggression Scale (R-MOAS)(Endpoint 2); Retrospective Modified 
Aggression (R-MOAS) remission (Endpoint 3). 
The ordering for the additional six (6) secondary endpoints from the first to the sixth is: 
Investigator-completed Clinical Global Impression – Improvement Scale (CGI-I)(Endpoint 1); 
Caregiver-completed Clinical Global Impression – Improvement Scale (CGI-I)(Endpoint 2); 
Caregiver-completed Clinical Global Impression – Severity Scale (CGI-S)(Endpoint 3);SNAP-IV 


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Rating Scale (Endpoint 4); Child Health Questionnaire (CHQ-PF28) (Endpoint 5) and SIPA Rating 
scale (Endpoint 6). 
 
Sensitivity Analysis 
The purpose of the sensitivity analysis is to see whether different methods of handling missing 
data provide consistent and similar results for the primary efficacy analysis. To this end, the 
following sensitivity analysis will be considered: 
1. Multiple imputation under MAR  
2. Placebo-based imputation under MNAR 
3. Percent change (PCHM) in the frequency of IA behaviors per 7 days in the Maintenance 
period relative to the Baseline period calculated over the number of days with non-
missing IA diary data.  
 
9.2.3.1 
Multiple imputation under Missing at Random (MAR) 
The multiple imputation (MI) method assumes that the missing data are missing at random 
(MAR), that is, the probability that an observation is missing may depend on the observed 
values but not the missing values. For example, if a subject’s Diary values are available on Day 1 
and Day 2 but missing on Day 3, then the missing value on Day 3 is related to the non-missing  
value on Day 1 and Day 2. 
MI is implemented using the following three steps.  
1. SAS PROC MI is applied with input dataset containing some missing values for all days 
during the titration and maintenance period to create 100 datasets. The data sets will 
include separate columns for the frequency of incidences during each day starting from 
baseline. The Markov Chain Monte Carlo (MCMC) method will be used to complete the 
missingness pattern to a monotone pattern separately by treatment arm.  The 
monotone patterns will be achieved by applying sequential imputation based on 
Bayesian regression with the treatment arm included as a covariate.  All copies contain 
identical values of the non-missing data items, but different values imputed for missing 
values.  
2. For each of these MI data sets, the percent change will be computed as in the observed 
data set and the primary analysis based on the Wilcoxon rank-sum test will be 
conducted and asymptotic 95% confidence intervals will be constructed. 
3. To produce a single confidence interval for each dose placebo comparison (e.g., Dose 1 
versus placebo), PROC MIANALYZE will be used and Rubin’s combination rules will be 
applied to the treatment effect estimates and associated asymptotic standard errors 
from the MI data sets.  The treatment effect estimates will be defined as the midpoints 


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of the asymptotic confidence intervals and the standard errors will be defined as the 
asymptotic standard errors (based on the width of the associated 95% confidence 
intervals) from the Hodges-Lehmann estimate of the individual datasets (Rubin 1987). 
9.2.3.2 
Multiple imputation under Missing Not at Random (MNAR) 
This approach can be labeled “worst-case” sensitivity analyses as it assumes that after 
discontinuation subjects from the dosing arms would adopt the outcome model estimated from 
the placebo arm.  To generate missing values from this “placebo-based” imputation model, 
PROC MI with the MNAR statement (available in SAS 9.3 and later versions) will be used or, 
alternatively, SAS macros available at the DIA Missing Data Working Group site (Ratitch et al., 
2013; Ayele et al., 2014) can be used. 
9.2.3.3 
Per Protocol Analysis 
This analysis will be conducted by repeating the primary analysis on the per protocol 
population. 
9.3 Sample Size and Power Consideration 
Assuming a mean difference of 15 between  SPN-810 dose group and placebo  with a common 
standard deviation of 35, a sample  of 93 subjects per arm will yield  80 % power to detect a non-
zero difference between the median of SPN-810 treatment group and the placebo group using 
the Wilcoxon rank-sum test with a 2-sided significance level α=0.05.  
It is assumed that approximately 20% subjects will dropout before the completion of the study 
and hence, an adjusted total of 186 subjects will be randomized in a 1:1 ratio to obtain 
approximately 150 subjects at the completion of the study. 
Sample size may be recalculated based on the effect size of the ongoing 810P301 and 810P302 
studies. 
9.4 
Exploratory Analyses 
 
IA Diary Cross Validation 
Cross-validation model will be generated based on the results from the IA diary validation in the 
810P301 and 810P302 studies. The model will estimate the minimal clinical important change 
(MCIC) for improvement of IA behaviors in adolescents. The cross-validation plan and results 
will be provided in a separate report. 
 
Pharmacokinetic  
A population PK model will be developed for molindone using the nonlinear mixed-effects 
modeling program NONMEM.  The structural model for molindone will incorporate data from 


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studies in which sampling was more intensive than in the present study.   Results from the data 
analysis will be provided in a separate and stand-alone report. 
 
Pharmacogenomic (PGx) 
Genetic variations associated with CYP2D6 enzyme will be analyzed using the FAS population. 
Paired t-test will be used to compare the treatment groups, results will be summarized by 
treatment group using descriptive statistics. A stand-alone analysis and report will be 
generated. 
9.5 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 3 to each subsequent visit for each of 
the Simpson-Angus scale, Barnes Akathisia scale, and AIMS. Suicidal ideation and suicidal 
behavior will be measured by 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 first dose of study medication (after Visit 3) to the 
end of the study. These AEs include those that emerge 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 two 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).  For the combined Titration and Maintenance 
Periods, the incidence of TEAEs will also be presented by highest severity reported and the dose 
of SM 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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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 applicable if appropriate. 
 
Extrapyramidal Signs   
The occurrence of neurological side effects will be assessed by looking at the changes in scores 
from Baseline to each of the post-Baseline visit for each of the Simpson-Angus scale, Barnes 
Akathisia 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. 
 
Laboratory Values 
Clinical laboratory values will be summarized by visit and by treatment group using descriptive 
statistics for hematology and chemistry.  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 three by three tables (shift tables) that, for a particular laboratory test, compare the 
LNH classification at baseline to the LNH classification at visit. By subject-listings of all abnormal 
laboratory values, 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 by treatment group. 
 
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.   


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Physical Examinations 
Findings from the physical examinations will be listed for each system or area examined. 
 
Infrequent Behaviors Checklist 
Infrequent behaviors will be listed for each subject by treatment group. 
10. 
PROCEDURES AND INSTRUCTIONS 
10.1 Adherence to the Protocol 
The Investigator agrees, when signing the 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 
IRB constituted and functioning in accordance with ICH E6 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 with a copy to 
the Sponsor prior to study start and the release of SM to the site by the Sponsor or its designee.  
If the IRB decides to suspend or terminate the study, the Investigator will immediately send the 
notice of study suspension or termination by the IRB to the Sponsor. 
Study progress is to be reported to 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.   
10.2 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 IRB [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 the IRB for the site 
must be informed promptly. 


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Changes affecting only administrative aspects of the study 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. 
10.3 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.  
10.4 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. 
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 Good Clinical Practice 
(GCP). 


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The Investigator will permit representatives of the Sponsor to inspect all CRFs and 
corresponding study subject original medical records (source documents) at regular intervals 
throughout the study. Subject original medical records and other relevant data must be 
available to support all data recorded in the eCRF. 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 is being entered on the case report forms. A 
Monitoring Log will be maintained at each study site. The Monitoring Log will be signed by the 
monitor, dated and stated the type of visit. The Investigator should be aware that the study site 
and subject records may be inspected by the Sponsor and/or their designees, 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. 
10.5 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, SM inventory records, Investigator's 
Brochure, and regulatory agency registration documents (e.g., FDA form 1572, ICFs, and IRB/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 
two years after the last approval of a marketing application or after formal discontinuation of 
clinical development of the investigational product.  These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an 


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for the purpose of reviewing or performing this study. 
 
 
 
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 US FDA in accordance with the US 21 
CFR 312.68 or other national or foreign regulatory authorities in accordance with regulatory 
requirements. 
10.6 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. 
All study-related records must be made available at reasonable times for inspection and 
duplication, if required, by a properly authorized representative of the US FDA in accordance 
with the US 21 CFR 312.68 or other national or foreign regulatory authorities in accordance 
with regulatory requirements. 
10.7 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. 


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for the purpose of reviewing or performing this study. 
 
 
 
10.8 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). 
10.9 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 
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. 
10.10 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. 
11. 
REFERENCE LIST 
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2. Ayele BT, Lipkovich I, Molenberghs, G, Mallinckrodt, CH., 2014. A multiple imputation 
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3. Barnes, T. R., 1989. A rating scale for drug-induced akathisia. Br. J. Psychiatry, Volume 154, 
pp. 672-676. 
4. Blader, J. C. et al., 2010. Stimulant-responsive and stimulant-refractory aggressive behavior 
among children with ADHD. Pediatrics, 126(4), pp. e796-806. 


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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. 
 
 
 
5. Calarge, C. A., Acion, L. & Kuperman, S., 2009. Weight gain and metabolic abnormalities 
during extended risperidone treatment in children and adolescents. J Child Adolesc 
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for the purpose of reviewing or performing this study. 
 
 
 
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for the purpose of reviewing or performing this study. 
 
 
 
29. Shelton, T. L., Barkley, R. A. & Crosswait, C., 1998. Psychiatric and psychological morbidity 
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impulsive-inattentive behavior. J Abnorm Child Psychology, Volume 26, pp. 475-94. 
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for the purpose of reviewing or performing this study. 
 
 
 
Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry , Volume 56, pp. 
1073-86. 
40. US FDA, 2009. Guidance for industry. Patient-reported outcome measures: use in medical 
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Volume 46, pp. 209-217. 
 
 


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re 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
 
 
y 
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12. 
APPENDICES 
12.1 Retrospective-Modified Overt Aggression Scale (R-MOAS) 
 
 


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12.2 Mini International Neuropsychiatric Interview for Children and Adolescents 
(MINI-KID)  


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12.3 Clinical Global Impression (CGI) Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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C-SSRS, Since Last Visit 


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12.5 Simpson-Angus Scale 


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12.6 Barnes Akathisia Rating Scale (BARS) 


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12.7 Abnormal Involuntary Movement Scale (AIMS) 


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12.8 Swanson, Nolan, Pelham Rating Scale-Revised (SNAP-IV) 
 


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12.9 Child Health Questionnaire Parent Form 28-item (CHQ-PF28) 
 


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12.10 Stress Index for Parents of Adolescents (SIPA) 

SAP_001.pdf: 


Supernus Pharmaceuticals, Inc.                        Statistical Analysis Plan 
      Protocol 810P503 
 
Version 2 
Page 2 of 16 
   11/29/2023 
 


Supernus Pharmaceuticals, Inc.                        Statistical Analysis Plan 
      Protocol 810P503 
 
Version 2 
Page 3 of 16 
   11/29/2023 
 
Table of Contents 
 
LIST OF ABBREVIATIONS AND TABLE .....................................................................................4 
1 
INTRODUCTION ....................................................................................................................5 
2 
STUDY OBJECTIVES .............................................................................................................5 
3 
STUDY ENDPOINTS ...............................................................................................................5 
3.1 
PRIMARY EFFICACY ENDPOINT ......................................................................................................................... 5 
3.2 
KEY SECONDARY ENDPOINTS .......................................................................................................................... 5 
3.3 
ADDITIONAL SECONDARY ENDPOINTS ............................................................................................................. 5 
3.4 
SAFETY ENDPOINTS ......................................................................................................................................... 5 
4 
STUDY METHODS .................................................................................................................6 
4.1 
STUDY DESIGN ................................................................................................................................................. 6 
TABLE 1 SCHEDULE OF EVENTS AND ASSESSMENTS ............................................................6 
4.2 
SAMPLE SIZE AND POWER CONSIDERATION ..................................................................................................... 9 
5 
STATISTICAL METHODS AND ANALYSES ........................................................................9 
5.1 
GENERAL CONSIDERATIONS ............................................................................................................................ 9 
5.2 
ANALYSIS POPULATION ................................................................................................................................... 9 
5.3 
SUBJECT DISPOSITION ...................................................................................................................................... 9 
5.4 
PROTOCOL DEVIATIONS ................................................................................................................................. 10 
5.5 
DEMOGRAPHIC CHARACTERISTICS ................................................................................................................. 10 
5.6 
STUDY DRUG EXPOSURE ................................................................................................................................ 10 
5.7 
HANDLING OF MISSING DATA ........................................................................................................................ 10 
6 
EFFICACY ANALYSES ........................................................................................................ 10 
6.1 
PRIMARY EFFICACY ENDPOINT ....................................................................................................................... 10 
6.2 
KEY SECONDARY ENDPOINTS ........................................................................................................................ 11 
6.3 
ADDITIONAL SECONDARY ENDPOINTS ........................................................................................................... 11 
7 
SAFETY ANALYSES ............................................................................................................. 15 
7.1 
ADVERSE EVENTS .......................................................................................................................................... 15 
7.1.1 
Treatment-emergent Adverse Events ................................................................................................... 15 
7.1.2 
Adverse Events with Treatment Relatedness ........................................................................................ 15 
7.1.3 
Serious Adverse Events ........................................................................................................................ 15 
7.1.4 
Adverse Events Leading to Study Drug Discontinuations ................................................................... 15 
7.1.5 
Adverse Events of Special Interest ....................................................................................................... 15 
7.2 
CLINICAL LABORATORY TESTS ...................................................................................................................... 16 
7.3 
VITAL SIGNS .................................................................................................................................................. 16 
7.4 
ECG ............................................................................................................................................................... 16 
7.5 
C-SSRS ......................................................................................................................................................... 16 
7.6 
EXTRAPYRAMIDAL SYMPTOMS ...................................................................................................................... 16 


Supernus Pharmaceuticals, Inc.                        Statistical Analysis Plan 
      Protocol 810P503 
 
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Page 4 of 16 
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 LIST OF ABBREVIATIONS AND TABLE 
ADHD 
Attention-Deficit Hyperactivity Disorder 
AE 
Adverse Event 
CGI-S 
Clinical Global Impression – Severity of Illness 
CGI-I 
Clinical Global Impression – Global Improvement 
CHQ-PF28 
Child Health Questionnaire Parent Form 28 item 
C-SSRS 
Columbia Suicide Severity Rating Scale 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI-KID 
Mini International Neuropsychiatric Interview for Children and 
Adolescents 
R-MOAS 
Retrospective Modified Overt Aggression Scale 
SAE 
Serious Adverse Event 
SIPA 
Stress Index for Parents of Adolescents 
SM 
Study Medication 
SNAP-IV 
Swanson, Nolan and Pelham-IV 
 
Table 1 Schedule of Events and Assessments ............................................................................. 6 
 
 
 


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1 INTRODUCTION 
The study is a randomized, double-blind, multicenter, placebo-controlled, flexible-dose (36, 45 
or 54 mg/day), 2-arm, (1:1) parallel group study to evaluate the safety and efficacy of SPN-810 
(molindone extended release tablets) for reducing impulsive aggression in adolescents 
(12-17 years of age) with ADHD as an adjunctive treatment to an approved ADHD medication. 
 
2 STUDY OBJECTIVES  
The primary objective of this study is to assess the efficacy and safety of flexible doses of 
SPN-810 (36 to 54 mg/day) in the improvement of IA behaviors in adolescents diagnosed with 
ADHD when taken in conjunction with standard ADHD treatment. 
 
The key secondary objectives, additional secondary objectives and exploratory objectives are to 
assess the effect of SPN-810 on the key secondary endpoints, additional secondary endpoints and 
safety endpoints described below.    
 
3 STUDY ENDPOINTS 
3.1 Primary efficacy endpoint  
The primary efficacy endpoint is the percent change (PCHT) in the frequency (unweighted score) 
of IA behaviors per 7 days in the Treatment Phase (titration + maintenance) relative to the 
Baseline period calculated over the number of days with non-missing IA diary data.  
3.2 Key Secondary Endpoints  
The key secondary endpoints include the following: 
1. Investigator-rated Clinical Global Impression – Severity Scale (CGI-S)  
2. Retrospective Overt Modified Aggression Scale (R-MOAS)   
3. Percent of children whose IA behaviors were remitted at the end of the study measured 
by R-MOAS score ≤ 10. 
3.3 Additional Secondary Endpoints  
The additional secondary endpoints include the following: 
1. Investigator-rated Clinical Global Improvement (CGI-I) scale. 
2. Caregiver-rated CGI-I scale. 
3. Caregiver-rated CGI-S scale. 
4. Swanson, Nolan, and Pelham Rating Scale (SNAP-IV) rating scale 
5. Child Health Questionnaire Parent Form 28 (CHQ-PF28) rating scale 
6. Stress Index for Parents of Adolescents (SIPA) rating scale 
3.4 Safety Endpoints  
1. Incidence of Adverse Events  
2. Incident of Extrapyramidal Symptoms (EPS)  


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3. Clinical laboratory evaluations  
4. Vital signs and ECG  
5. Suicidal symptoms (C-SSRS)  
6. Infrequent behaviors   
 
4 STUDY METHODS 
4.1 Study Design 
This study is a randomized, double-blind, multicenter, placebo-controlled, flexible-dose (36, 45 
or 54 mg/day), 2-arm, (1:1) parallel group study to evaluate the safety and efficacy of SPN-810 
(molindone extended release tablets) for reducing impulsive aggression in adolescents 
(12-17 years of age) with ADHD as an adjunctive treatment to an approved ADHD medication.  
Schedule of Visits and Procedures. 
All subjects who are consented are required to follow the protocol procedures regardless of the 
number of doses of SM taken.  The Schedule of Visits and Procedures are presented in Table 1. 
 
 
Table 1 Schedule of Events and Assessments 




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a. Written consent must be obtained prior to performing any study-related procedure. 
b. Subject number will be assigned via
. 
c. Assess for any clinically significant change in Medical History since screening. 
d. Confirm inclusion/exclusion criteria. 
e. Urine pregnancy test will be performed for all female subjects. Prior to the administration of the first dose of SM subjects will have 
to be tested as negative to continue in the study. If Visit 1 and Visit 2 occur on the same day then both urine and serum pregnancy 
tests must be performed. 
f. 
Serum pregnancy test will be performed at Screening for all female subjects.  
g. Diary compliance must be at least 70% (minimum of 11 days out of 15) to qualify for randomization. 
h.     Heart Rate (HR), blood pressure (BP), temperature, and respiratory rate will be measured. 
i.   PK blood samples will be obtained over two visits 
j.     Only the Investigator-rated CGI-S will be completed at Screening; Caregiver and Investigator-rated CGI-S will be collected at 
randomization and every visit thereafter. 
k.     The checklist will be recorded on a paper source and entered on EDC only at Visit 2. 
l.     Optional 
 
Columbia Suicide Severity Rating 
Scale (CSSRS) 
X 
 
X 
X 
X 
X 
X 
X 
Caregiver and Investigator CGI-S 
Xj 
 
X 
X 
X 
X 
X 
 
Caregiver and Investigator CGI-I 
 
 
 
X 
X 
X 
X 
 
SNAP-IV, CHQ-PF28, SIPA 
 
 
X 
 
 
 
X 
 
Infrequent Behaviors Checklist 
 
Xk 
X 
X 
X 
X 
X 
 
Simpson-Angus, Barnes & AIMS 
 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Dispensation 
 
 
Xb 
X 
X 
X 
X 
 
Drug Return and Compliance 
 
 
 
X 
X 
X 
X 
X 
Diary Return 
 
 
 
 
 
 
 
X 


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4.2 Sample Size and Power Consideration  
Assuming a mean difference of 15 between SPN-810 dose group and placebo with a common 
standard deviation of 35, a sample of 93 subjects per arm will yield 80 % power to detect a non-
zero difference between the median of SPN-810 treatment group and the placebo group using the 
Wilcoxon rank-sum test with a 2-sided significance level α=0.05.  
5 STATISTICAL METHODS and ANALYSES 
5.1 General Considerations  
Because SPN-810 did not show efficacy for the Treatment of Impulsive Aggression in the two 
previous Double-Blind Studies (810P301 and 810P302), the conduct of this study (810P503) was 
halted. Therefore, the analysis will be limited to the primary, key secondary endpoints and safety 
data, which will include adverse events (AEs), Extrapyramidal Symptoms (EPS), Simpson-
Angus Scale, Barnes Akathisia Scale, and Abnormal Involuntary Movement Scale, clinical 
laboratory evaluations, vital signs, suicidal symptoms (C-SSRS) and ECG results.   
All descriptive statistical analyses will be performed using SAS (Version 9.4), unless otherwise 
noted and will be presented by treatment groups (Placebo, SPN-810). 
Continuous variable summaries will include the number of subjects (n) with non-missing values, 
mean, standard deviation (SD), median, interquartile range (Q1 and Q3), minimum, and 
maximum. 
Categorical variable summaries will include the frequency and percentage of subjects who are in 
the category or each possible value. In general, the denominator for the percentage calculation 
will be based upon the total number of subjects in the study population for the treatment groups, 
unless otherwise specified. The denominator for by visit displays will be the number of subjects 
in the relevant study population with non-missing data at each study visit. 
In general, the baseline value for a variable is defined as the last observation prior to the first 
dose of double-blind study medication, ideally Visit 3, but including the screening value, if 
necessary. 
All data will be presented in Listings. 
5.2 Analysis Population  
The population of “all enrolled subjects” consists of all those screened subjects who meet the 
requirements for study participation and are entered in the Baseline period of the study. The 
population of “all randomized subjects” consists of all those enrolled subjects who complete 
the Baseline Period, meet the inclusion/exclusion criteria and are randomized via the 
. 
The safety population will include all subjects who received at least 1 dose of study drug and has 
at least one post-baseline safety assessment. 
 
5.3 Subject Disposition  
The number and percentage of subjects who were enrolled, dosed, completed, or early 
discontinued will be displayed. Reasons for early discontinuation will include: 


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• Adverse event 
• Lost to follow-up 
• Investigator decision 
• Administrative reason 
• Failure to follow required study procedures  
• Withdrawal by subject and other. 
5.4 Protocol Deviations  
Protocol deviations will be presented in listings. Protocol deviations may include, but are not 
limited to: 
• Non-compliance with any scheduled study visit 
• Non-compliance with study treatment 
• Disallowed concomitant medications 
• Non-compliance with study inclusion or exclusion criteria 
• Non-compliance with study assessment procedures 
5.5 Demographic Characteristics   
Descriptive statistics for Age, Baseline Height, Weight, and BMI will be presented using n, 
mean, STD, Min and Max.  Frequencies and percentages will be presented for Race, Ethnicity 
and Sex.  
5.6 Study Drug Exposure   
Duration of exposure in days will be calculated from the first and last dates of the study drug 
administration.  The duration of exposure will be calculated as date of last dose minus date of 
first dose + 1.   Duration of exposure (days) will be summarized by categories and descriptive 
statistics. The categories for duration of exposure are Weeks 1-2 (Titration period), Weeks 3-5 
(Maintenance Period).  
5.7 Handling of Missing Data   
There will be no substitutions made for missing data points.  The number of missing values will 
be presented in the analysis tabulations, as applicable, but without a percentage. 
 
6 EFFICACY ANALYSES       
The efficacy analysis will be based on the safety population for subjects who have sufficient 
baseline and post baseline IA diary to calculate percent change as defined below. 
6.1 Primary efficacy endpoint  
The primary efficacy endpoint, percent change (PCHT) in the frequency (unweighted score) of 
IA behaviors per 7 days, will be calculated as PCHT= 100*(T – B)/B, where T and B are IA 
behavior frequencies per 7 days during the Treatment Phase (titration + maintenance periods) 
and Baseline period, respectively. The IA behavior frequency per 7 days is defined as 
(SUM/DAY) x 7, where SUM is the total of the 15 IA behaviors reported in IA diary, and DAY 


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is the number of days with non-missing IA score in the IA diary during the specified study 
period. 
PCHT will be summarized by treatment groups as described for continuous variables in Section 
5.1. Individual subject listings supporting the summary will be presented. 
6.2 Key Secondary Endpoints  
The absolute and change from baseline for CGI-S and R-MOAS will be summarized by 
treatment groups and visit using descriptive statistics for continuous variables as described 
Section 5.1.  
The CGI-S is evaluated on a 7-point scale, where 1 = Normal, not at all ill, asymptomatic, 2 = 
Borderline Ill, 3 = Mildly Ill, 4 = Moderately Ill, 5 = Markedly Ill, 6 = Severely Ill, and 7 = 
Extremely Ill. 
The percentage of subjects with remission of R-MOAS ≤ 10 will be summarized by treatment 
groups and visit using descriptive statistics for categorical variables as described Section 5.1. 
Individual subject listings supporting the summaries will be presented. 
6.3 Additional Secondary Endpoints  
The absolute value of investigator-rated Clinical Global Improvement (CGI-I) scale, Caregiver-
rated CGI-I scale and Caregiver-rated CGI-S scale will be summarized the same way as for CGI-
S described in the above Section. 
The CGI-I is evaluated on a 7-point scale, where 1 = Very much improved, 2 = Much 
improved,3 = Minimally improved, 4 = No change,5 = Minimally worse,6 = Much worse, and 7 
= Very much worse. 
The absolute Caregiver-rated CGI-S scale score and change from baseline will be summarized 
the same as for CGI-S as described above.  
With respect to CHQ-PF28, z-score will be derived and be summarized by treatment group at 
visit 1 and 7.  The recorded score needs to be transformed in 0-100 range before calculating 
subscales and summary scores.  
CHQ-PF28 Questionnaire 
Item 
Recorded on CRF 
Final Raw 
Transformed Score 
1.1;  
5.2; 
9.4 
1 
5 
((Final -1)/4) * 100 
2 
4.4 
3 
3 
4 
2.2 
5 
1 
2.1a-2.1c;  
3.1;  
1 
1 
((Final -1)/3) * 100 
2 
2 


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3.2;  
9.2 
3 
3 
4 
4 
4.1 
1 
6 
((Final -1)/5) * 100 
2 
5 
3 
4 
4 
3 
5 
2 
6 
1 
5.1a-5.1c;  
6.1a-6.1c;  
8.1a-8.1c;  
9.3a-9.3b 
1 
1 
((Final -1)/4) * 100 
2 
2 
3 
3 
4 
4 
5 
5 
 
7.1a-7.1c; 
8.2; 
9.1a-9.1b 
1 
5 
((Final -1)/4) * 100 
2 
4 
3 
3 
4 
2 
5 
1 
 
 The physical functioning (PHS) and psychosocial health (PSS) summary scores are calculated in 
three steps.  
• Step1: z-score standardizations. 
Subscale 
Sum of items 
Formulas for z-score standardizations 
Physical Functioning (PF) 
2.1a–2.1c 
PF_Z=(PF - 90.8525408) / 16.3826344 
Role/Social Limitations - 
Physical (RP) 
3.2 
RP_Z=(RP - 91.4951246) / 18.9079749 


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General Health Perceptions 
(GH) 
8.1a-8.1c,1.1 
GH_Z=(GH - 66.6958379) / 19.3564297 
Bodily Pain/Discomfort (BP) 
4.1 
BP_Z=(BP - 78.6833515) / 20.7355708 
Role/Social Limitations - 
Emotional/Behavior (REB) 
3.1 
REB_Z=(REB - 90.4013015) / 19.5067502 
Parental Impact - Time (PT) 
9.2a-9.2b 
PT_Z=(PT - 83.8816188) / 20.2901603 
Parental Impact - Emotional 
(PE) 
9.1a-9.1b 
PE_Z=(PE - 73.9788476) / 21.406013 
Self-Esteem (SE) 
7.1a-7.1c 
SE_Z=(SE - 79.2555314) / 17.8308361 
Mental Health (MH) 
6.1a–6.1c 
MH_Z=(MH - 77.2595806) / 13.6861999 
Behavior (BE) 
5.1a-5.1c,5.2 
BE_Z=(BE - 72.3086051) / 17.1447913 
Family Activities (FA) 
9.3a-9.3b 
NA 
Global Health (GGH) 
1.1 
NA 
Global Behavior (GBE) 
5.2 
NA 
Family Cohesion (FC) 
9.4 
NA 
Change in Health (CH) 
8.2 
NA 
• Step 2. PHS and PSS raw scores 
PHS_raw = (PF_Z * .37138) + (RP_Z * .34493) + (BP_Z * .27883) + (GH_Z * .29460) + 
(REB_Z *-.01178) + (PT_Z * .09113) + (PE_Z * .06063) + (SE_Z * -.09480) + (MH_Z * -
.08263)+ (BE_Z * -.12675) 
PSS_raw = (PF_Z * -.09243) + (RP_Z * -.06973) + (BP_Z * -.05514) + (GH_Z * -.05547) + 
(REB_Z* .21155) + (PT_Z * .16944) + (PE_Z * .19823) + (SE_Z * .24792) + (MH_Z * .25335) 
+ (BE_Z * .27911) 
• Step 3. Transformation of PHS_raw and PSS-raw 
Transformed physical (PHS) = 50 + (PHS_raw * 10) 
Transformed psychosocial (PSS) = 50 + (PSS_raw * 10) 
More details can be found in the Child Health Questionnaire (CHQ) Scoring and Interpretation 
Manual (HealthActCHQ). 
 
The ratings from the SNAP-IV scale are grouped into the following 4 subscales:   
• ADHD-Inattention (items #1-9),  


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• ADHD-Hyperactivity/Impulsivity (items #10-18) 
• ADHD-Combined subscales (items #1-18) 
• Oppositional Defiant Disorder (ODD) (items #19-26)   
Each subscale score is calculated by averaging the items scores within each subscale. 
 
The absolute and change from baseline for SNAP-IV will be summarized by treatment group at 
visit 7.  
 
Stress Index for Parents of Adolescents (SIPA) rating scale includes 112 items.  The first 90 
items use a 5-point rating scale ranging from Strongly Disagree (5) to Strongly Agree (1): 1=SD 
(Strongly Disagree), 2=DA (Disagree), 3=NS (Not Sure), 4=A (Agree), and 5=SA (Strongly 
Agree).  
Note: Items 2, 3, 4, 5, 9, 10, 15, 25, 28, 34, 40, 45, 49, 54, 66, 69, 74, 81, 83, 85, 87, and 88 are 
rated from Strongly Disagree (5) to Strongly Agree (1). To be consistent with other items, they 
have to be reversed (15, 24, 33, 42, and 51) prior to calculating subscales and 
domains. 
Domain 
Subscale 
Sum of Items 
Adolescent 
Domain 
(AD) 
Moodiness/Emotional Lability (MEL) 
10 items (1, 6, 11, 16, 21, 26, 31, 36, 41, 46) 
Social Isolation/ Withdrawal (ISO) 
10 items (2, 7, 12, 17, 22, 27, 32, 37, 42, 47) 
Delinquency/Antisocial (DEL) 
10 items (3, 8, 13, 18, 23, 28, 33, 38, 43, 48) 
Failure to Achieve or Persevere (ACH) 
10 items (4, 9, 14, 19, 24, 29, 34, 39, 44, 49) 
Parent 
Domain (PD) 
Life Restrictions (LFR) 
10 items (51, 52, 55, 56, 59, 63, 67, 71, 75, 
79) 
Relationship with Spouse/Partner (REL) 
9 items (60, 64, 68, 72, 73, 76, 77, 80, 81) 
Social Alienation (SOC) 
7 items (53, 54, 57, 58, 61, 65, 69); 
Incompetence/Guilt (INC) 
8 items (62, 66, 70, 74, 78, 82, 86, 90) 
Adolescent-
Parent 
Relationship 
Domain 
(APRD) 
 
16 items (5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 
83, 84, 85, 87, 88, and 89) 
 
AD = MEL + ISO + DEL+ACH 
PD =  LFR + REL + SOC + INC 
Total Parenting Stress (TS) = AD + PD + APRD 
The last 22 items (91-112) with responses of 1=Yes and 0=No. 


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Life Stressors (LS) = Sum of last 22 items (Items 91-112) 
TS, each domain, each subscale, and LS scale will be summarized by treatment group at visit 3 
and 7 using descriptive statistics for continuous variable as described in Section 5.1.  
Individual subject listings supporting the additional secondary endpoint summaries will be 
presented. 
7 SAFETY ANALYSES      
7.1 Adverse Events  
AEs will be coded using MedDRA Version 18.1.  
Adverse events will be categorized by MedDRA system organ class (SOC) and/or preferred 
term.  A subject experiencing the same AE multiple times will only be counted once for that 
preferred term.  Similarly, if a subject experiences multiple AEs within the same SOC, that 
subject will be counted only once for that SOC.  
7.1.1  Treatment-emergent Adverse Events 
Overview of Treatment-emergent adverse events (TEAEs) will be provided.  The incidence of 
TEAEs will be summarized by MedDRA SOC, preferred term and severity.  The number and 
percentage of subjects who experienced at least one TEAE will be tabulated by treatment group.   
7.1.2 Adverse Events with Treatment Relatedness 
TEAE relatedness to SM will be summarized based on derived binary values as: “Drug  
Related” if the relationship to SM is probably or related or “Not Related” if the relationship to 
SM is not related or unlikely related. 
7.1.3 Serious Adverse Events 
The incidences of SAEs will be presented by SOC and preferred term, and a listing of all SAEs 
will be presented.   
7.1.4 Adverse Events Leading to Study Drug Discontinuations 
The incidences of TEAEs leading to study drug discontinuation will be presented in listings by 
SOC and preferred term.   
7.1.5 Adverse Events of Special Interest 
Treatment-emerging EPS (e.g., akathisia, dystonia, Parkinsonism, tardive dyskinesia) and 
neuroleptic malignant syndrome are reported to the Drug Safety Contact person(s) by completing 
the Adverse Event of Special Interest (AESI) eCRF in EDC. 
The AESIs will be presented by SOC and preferred term. 
 
Subject listings of AEs will be presented. 


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7.2 Clinical Laboratory Tests 
The absolute value and change from baseline to EOS for laboratory tests will be summarized 
using descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) by 
Treatment groups, laboratory category (Chemistry, Hematology, Immunochemistry, and 
Urinalysis). The summary will be presented by Treatment group in for Chemistry, Hematology, 
Immunochemistry and Urinalysis respectively. 
Subject listings of clinical laboratory data will be presented. 
7.3 Vital Signs 
The absolute value and change from baseline to EOS for vital signs (body temperature, heart 
rate, respiration rate, systolic blood pressure, weight, height, BMI and diastolic blood pressure) 
will be summarized using descriptive statistics for continuous variables by treatment group as 
described in Section 5.1. The summary will be presented by treatment groups. 
Subject listings of Vital signs will be presented. 
7.4 ECG 
The absolute value and change from baseline to EOS for ECG parameters (heart rate, PR interval 
(msec), QRS interval (msec), QT interval (msec), and QT corrected for heart rate using 
Fridericia's (QTcF) correction formula, RR interval (msec)) will be summarized using 
descriptive statistics for continuous variable by treatment groups as described in Section 5.1.  
Subject listings of ECGs will be presented. 
7.5 C-SSRS 
C-SSRS outcomes will be summarized using number and percent of subjects by categories for 
Actual Attempts, suicidal ideation, suicidal behavior, and suicidality (ideation and behavior 
combined). The summary will be presented by treatment group. C-SSRS will be presented in 
Listings. 
7.6 Extrapyramidal Symptoms  
Extrapyramidal Symptoms collected using Simpson-Angus Scale, Barnes Akathisia Scale, and 
Abnormal Involuntary Movement Scale will be summarized and listed by treatment group.