Clinical trial NCT02618434
Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
Sponsor: Supernus Pharmaceuticals, Inc.
Start date: 2016-02-16; Completion date: 2020-02-14
Enrollment: 297 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to demonstrate the efficacy, safety, and tolerability of SPN-810 in the treatment of impulsive aggression in patients with Attention-Deficit/Hyperactivity Disorder (ADHD) in conjunction with standard ADHD treatment. Approximately 297 subjects aged 6 to 12 years with ADHD and comorbid impulsive aggression will be recruited in this study. The frequency of impulsive aggression behaviors will be assessed as a primary outcome. Additionally, the severity and improvement in impulsive aggression and quality of life measures for the subject and caregiver will be assessed using validated scales.

Detailed description:
This study is a randomized, placebo-controlled, double-blind, multicenter, parallel group, fixed dose study to demonstrate the efficacy, safety, and tolerability of SPN-810 in the treatment of IA in subjects aged 6 to 12 years with ADHD in conjunction with standard ADHD treatment.

Arms: arm 1: Oral arm 2: Oral arm 3: Oral
Interventions: intervention 1: SPN-810 (18 mg) intervention 2: SPN-810 (36 mg) intervention 3: Placebo
Intervention descriptions: intervention 1: Subjects were randomized to receive SPN-810 9 mg twice each day with food, in addition to the stable dose of the optimized ADHD medication determined from the lead-in period. If initiating treatment before noon, patients should start with the morning dose; if afternoon, the evening dose. intervention 2: Subjects were randomized to receive SPN-810 18 mg twice each day with food, in addition to the stable dose of the optimized ADHD medication determined from the lead-in period. If initiating treatment before noon, patients should start with the morning dose; if afternoon, the evening dose. intervention 3: Subjects were randomized to receive Placebo twice each day with food, in the morning and in the evening, in addition to the stable dose of the optimized ADHD medication determined from the lead-in period. If initiating treatment before noon, patients should start with the morning dose; if afternoon, the evening dose.

Protocol documents:
Prot_000.pdf: 
Supernus® Pharmaceuticals, Inc. 
CONFIDENTIAL 
810P302     
    Version 7.0     
  Page 1 of 225 
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TITLE PAGE 
Protocol Number: 
810P302 
Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Molindone Hydrochloride Extended-Release Tablets 
for the Treatment of Impulsive Aggression in Pediatric Patients with 
Attention Deficit/Hyperactivity Disorder (ADHD) in Conjunction with 
Standard ADHD Treatment 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
IND number: 
106,515 
Investigational 
Medicinal Product: 
Molindone Hydrochloride Extended-Release Tablets (SPN-810) 
Indication: 
Treatment of Impulsive Aggression in patients with Attention 
Deficit/Hyperactivity Disorder (ADHD) in conjunction with standard ADHD 
treatment 
Clinical CRO: 
Medical Monitor 
Phase: 
3 
Protocol Version: 
7.0 
Release Date: 
29 March 2019 
Good Clinical Practice 
(GCP) Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonization (ICH) GCP and all applicable local regulations.  
All required study documentation will be archived as required by regulatory 
authorities. 


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




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SUMMARY OF CHANGES 
This summary table lists all clarifications, administrative changes or amendments to Supernus protocol 
810P302. Additions are denoted by bold letters and deletions by strikethrough. 
 
Section 
Page 
Description of Change 
Rationale 
Changes to 810P302 V3.0 Dated 21 Dec 2015 
Title Page 
1 
Protocol version and date was updated 
Administrative 
Signature page 
3 
The authorship  was revised 
For clarification 
Synopsis 
10 
The following was added:  
 
 
 
 
 
To understand exposure 
of metabolites in 
children 
Synopsis 
11 
The following was changed: 
Total subject duration on study:  Approximately 13 10 12 weeks 
• 
Pre-treatment phase: Up to 45 days 4 6 weeks 
o 
Screening period:  Up to 30 days 2- 4 weeks 
o 
Baseline period:  At least 15 days 2 weeks 
To facilitate study 
conduct 
Synopsis 
13 
The following was added:  
 
 
 
 
To understand exposure 
of metabolites in 
children 
Synopsis 
13 
The following was added:  
 
 
 
 
To understand exposure 
of metabolites in 
children 
List of 
Abbreviations 
20 
List of Abbreviations was updated to include Adverse Event of 
Special Interest (AESI)  
For clarification 
2.3 
26 
The following was changed:  
 
 
 
 
 
To understand exposure 
of metabolites in 
children 
3.2 
27 
The following was changed:  
Following screening, eligible subjects will enter a two week 
flexible baseline period, at which time the IA diary will be issued 
to the subject’s primary caregiver.  At the end of the two week 
baseline period, eligible subjects whose primary caregiver has 
maintained at least 80% compliance with the IA diary will be 
randomized 1:1:1 to 18 mg/day SPN-810, 36 mg/day SPN-810, or 
placebo.    
To give caregivers the 
opportunity to improve 
diary compliance 
3.2.1.1 
27 
The following was changed:  
To facilitate study 
conduct 


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Screening will take place for up to 28 45 days prior to 
randomization and may be carried out over more than one visit 
if necessary.   
3.2.1.1 
27 
The following was added:  
Staff at study sites are encouraged to complete screening 
procedures as early as possible to provide more flexibility in 
the baseline period for the caregivers to achieve IA diary 
compliance (see Section 3.2.1.2). 
For clarification 
3.2.1.2 
28 
The following was changed: 
Subjects who meet study entry requirements will proceed to the 
two week flexible 15-day baseline period.  At Visit 2 primary and 
(if assigned) secondary caregivers will receive training on the use 
of the IA diary.  Aan IA diary device (LogPad) will be issued to the 
primary caregiver.  The primary and (if assigned) secondary 
caregivers will receive training on the use of the IA diary. Every 
effort will be made to provide adequate caregiver training on 
the use of the IA diary at Visit 2 and acknowledgement of 
training will be captured on the device. The caregiver will be 
instructed to maintain the diary for two weeks.  At the end of 
this period, caregiver compliance with the IA diary will be 
assessed.   
Following at least 15 days of IA diary use, caregiver compliance 
with the IA diary will be assessed.  Compliance will be 
calculated as the percentage of days over the past 15 days 
during the baseline period for which an evening diary was 
completed.  Compliance of at least 80% must be demonstrated 
to continue into the titration period and to be eligible for 
randomization. Compliance will be measured by the percentage 
of evening diary entries completed during the baseline period. 
Subjects whose caregivers demonstrate at least 80% 
compliance  will be eligible for randomization and continue 
into the titration period. 
Subjects whose caregivers do not reach 80% compliance during 
the first 15 days of the baseline period may be allowed to 
continue to use the diary for up to 15 additional days.  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”.  When the 
caregivers’ performance with the IA diary improves such that 
the caregivers are able to demonstrate at least 80% compliance 
over the past 15-day rolling window, the subject will be eligible 
for randomization and allowed to continue into the titration 
period.  
Although there are up to 30 days available for each of the 
screening and the baseline period, the total duration of 
screening and baseline periods may not exceed 45 days.  
Rescreening 
As a general rule, rescreening of subjects is not allowed.  The 
only exception to this will be for subjects who had failed 
screening due to caregiver non-compliance with the IA diary 
under protocol version 3.0. These subjects may be rescreened 
To give caregivers the 
opportunity to improve 
diary compliance 


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for the purpose of reviewing or performing this study. 
to participate in the study under protocol 4.0. These subjects 
will be assigned a new subject ID number and will complete all 
study screening procedures. 
3.2.4 
29 
The following was changed: 
Subjects will return to the study site for a final visit, after 
completing the 1-week Taper/Conversion Period.  Those subjects 
who elect to continue in the OLE study will have procedures 
performed for that study as well.  All subjects who discontinue 
early will return to the study site for a final visit.  Any sSubject 
who discontinues from the study during the maintenance period 
will be offered a Taper kit and will return to the study site for a 
follow-up visit (EOS).  Subjects who discontinue during the 
titration period will not receive a taper kit and will only 
complete the EOS procedures.   
For clarification 
Figure 1 and 2 
30, 
31 
These figures were updated with the new visit windows and 
screening period 
Updated as per changes 
in the protocol 
4.1.1 
32 
The following was added:  
8. 
α 2- adrenergic agonists (e.g. clonidine and 
guanfacine) used for any other reason except for monotherapy 
treatment for ADHD (e.g. aggression or insomnia) must be 
discontinued at least two weeks prior to Visit 2. 
To facilitate study 
conduct 
Table 1 
34, 
35 
Table 1 was updated with the new visit windows, screening 
period, baseline period, and footnotes. Due to the addition of a 
new footnote, this section had to be renumbered 
Updated as per changes 
in the protocol 
Table 1 
34, 
35 
The following new foot note “c” was added for Visit 3 window 
days:  Visit 3 will occur at least 15 days following Visit 2. 
 
Footnote “g” was renumbered to “h” and changed as follows:  
gh       Total of 5 PK blood samples will be obtained over one or 
two visits (Visit 4 and/or Visit 5) to be divided between Visit 4 
and Visit 5. 
 
Footnote “d” was renumbered to “e” and changed as follows:  
de 
Diary compliance must be at least 80% (minimum of 12 
days out of 1415) to qualify for randomization. 
Updated as per changes 
in the protocol 
4.2.1 
36 
The following was changed:  
Subject screening procedures will be performed within 28 45 
days prior to Visit 3 and may be done on more than one day.   
To facilitate study 
conduct 
4.2.2 
36 
The following was changed:   
Visit 2 will occur at least 14 15 days prior to Visit 3.   
To facilitate study 
conduct 
4.2.2 
36 
The following was added:   
Please note that, per protocol and within the EDC, Visit 1 and 
Visit 2 may occur on the same day. 
For clarification 
4.2.3 
36 
The following was changed:  
Visit 3 will occur at least 1415 days following Visit 2 according to 
the Schedule of Visits and Procedures.  
To facilitate study 
conduct 
4.2.3 
37 
The following was changed: 
10. 
Collect urine samples for urinalysis, urine drug screen 
(all subjects), and pregnancy test (FOCP only) 
For clarification 
4.2.4 
37 
The following was changed:  
To facilitate study 
conduct 


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Visit 4 will occur 7 (±12) days following Visit 3 according to the 
Schedule of Visits and Procedures. 
4.2.5 
37 
The following was changed:  
Visit 5 will occur 14 (±12) days following Visit 3 according to the 
Schedule of Visits and Procedures. 
To facilitate study 
conduct 
4.2.6 
38 
The following was changed:  
Visit 6 will occur 21 (±13) days following Visit 5 according to the 
Schedule of Visits and Procedures.   
To facilitate study 
conduct 
4.2.8 
38, 
39 
The following was changed: 
These will include pre and post-dose samples obtained over 
one visit (Visit 4 or Visit 5) or can be obtained over two visits 
(Visit 4 and Visit 5) Blood will be drawn for quantitative PK 
analysis at Visit 4 and Visit 5.     
If the subject decides to complete the PK sampling over one 
visit then he/she will arrive at the clinic in the morning prior to 
taking the morning dose.   
A PK sample will be drawn pre-dose; then the dose will be 
observed in the clinic.  Post-dose PK samples will be taken at 
approximately 1 hour, 2 hours, 4 hours and 6 hours  after the 
time of the observed dose.  PK samples should be obtained 
within 15 minutes of the  1 hour and 2 hour timepoints and 
within 30 minutes of the 4 hour and 6 hour timepoint. At one of 
these visits, subjects will arrive at the clinic in the morning, prior 
to taking their morning dose.  A PK sample will be drawn pre
dose; then the dose will be observed in the clinic.  Post dose PK 
samples will be taken at approximately 1 hour and 2 hours after 
the time of the observed dose.  PK samples should be obtained 
within 15 minutes of the targeted timepoints.  
If the subject decides to come for the PK sampling over two 
visits, then on one visit the subject will arrive at the clinic in the 
morning, prior to taking their morning dose. A PK sample will 
be drawn pre-dose; then the dose will be observed in the clinic.  
Post-dose PK samples will be taken at approximately 1 hour 
and 2 hours after the time of the observed dose. PK samples 
should be obtained within 15 minutes of the targeted 
timepoints.   
To facilitate study 
conduct 
4.4 
42 
The following was added: 
4.4 
Prohibited Medications: 
Subjects may not be on any prohibited medication while on 
study as indicated in the Inclusion/Exclusion Criteria. These 
medications include:  
• 
α 2- adrenergic agonists (e.g. clonidine and 
guanfacine) used for any other reason except for 
monotherapy treatment for ADHD  
• 
Anti-psychotics including aripiprazole,  
risperidone, quetiapine, and ziprasidone  
• 
Anticonvulsants including carbamazepine and 
valproic acid, antidepressants, mood stabilizers 
including lithium, benzodiazepines, 
cholinesterase inhibitors or any drug known to 
inhibit CYP2D6 activity 
• 
Herbal supplements 
For clarification 


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4.5 
42 
 
The following was deleted:  
Subjects may not be on any prohibited medication as indicated 
in the Inclusion/Exclusion Criteria.  
For clarification 
5.2.1 
44 
The following was changed: 
• 
CGI-I, relative to the condition at baseline Visit 3, will be 
evaluated by the caregiver and by the Investigator at each post-
baseline visit on a 7-point scale with 1=Very much improved, 
2=Much improved, 3=Minimally improved, 4=No change, 
5=Minimally worse, 6=Much worse, and 7=Very much worse. 
For clarification 
5.3 
45 
The following was added:  
 
 
 
 
To understand exposure 
of metabolites in 
children 
5.3.2 
45 
The following was added:  
 
 
To understand exposure 
of metabolites in 
children 
5.4.2.1 
48 
The following was changed: 
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  Form and include a detailed 
description of the SAE, as well as other available information 
pertinent to the case (e.g., hospital records, autopsy reports and 
other relevant documents).  Should the site be unable to access 
EDC, a paper SAE form must be completed and sent to WCT 
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. 
For Clarification 
5.4.2.1 
49 
The E-mail address for drug safety contact was updated: 
 
Administrative 
5.4.2.2. 
49 
The following was added:  
The Investigator must complete a Pregnancy Outcome Form as 
a follow up. 
For Clarification 
5.4.2.2 
49 
The following was changed: 
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 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 faxing 
or scanning the appropriate source documentation 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.   
For Clarification 
5.4.4 
50 
The following was added:  
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. 
For Clarification 


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for the purpose of reviewing or performing this study. 
 
 
Any repeat laboratory testing will be conducted under fasting 
condition. 
6.5 
55 
The following was added:  
Only one (primary) reason for study discontinuation will be 
recorded for each subject. 
For Clarification 
 
 
6.9.2 
57 
The following was changed:  
The secondary endpoints are: 
1. 
Actual Caregiver CGI-I score at Visit 6   
2. 
Actual Investigator CGI-I score at Visit 6 
2.3. 
Change from Visit 3 to Visit 6 in Investigator CGI-S score 
3.4. 
Change from Visit 3 to Visit 6 in CHQ-28 score 
5. 
Change from Visit 3 to Visit 6 in PSI-4-SF scores in: 
a. 
Parental Distress 
b. 
Parent-Child Dysfunctional Interaction 
a.c. 
Difficult Child 
4. 
Change from Visit 3 to Visit 6 in Caregiver completed 
CGI I  
5.6. 
Change from Visit 3 to Visit 6 in SNAP-IV ADHD scores 
in: 
a. 
Inattention ratings 
b. 
Hyperactivity/Impulsivity ratings 
c. 
Combined Scale ratings 
For Clarification 
6.12 
59 
 The following was added:  
 
 
 
 
 
 
 
 
To understand exposure 
of metabolites in 
children 
7.4.4 
63 
The following was added:  
 
 
 
 
To understand exposure 
of metabolites in 
children 
Changes to 810P302 V4.0 Dated 16 Dec 2016 
 
Section 
Page 
Description of Change 
Rationale 
Title page 
1 
Protocol version and date was updated 
Administrative 
Signature Page 
3 
The signature page was updated 
Administrative 
Signature Page 
3 
One of the reviewers was changed: 
 
 
 
 
Administrative 
Synopsis 
15 
The  following was added: 
 
Based on the 810P301 study Interim Analysis result decision, 
the 18 mg dose arm was dropped partway through the study. 
As a result, subjects in the 18 mg dose arm will be re-
Updated as per changes 
in the protocol due to 
interim analysis results  
in the 810P301 study. 


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randomized in a ratio of 2:1 to receive 36 mg/day SPN-810 or 
placebo. 
Synopsis 
15 
The following was changed: 
 
Approximately 378 subjects aged 6-12 years (inclusive) will be 
screened to achieve 291 subjects randomized; 97 per treatment 
arm 
Updated as per changes 
in the protocol due to 
interim analysis results  
in the 810P301 study 
Synopsis 
16 
Treatment, Dose and Mode of Administration 
The following was added: 
 
Based on the Interim Analysis results from the 810P301 study, 
Treatment 2 (18 mg) arm is discontinued. 
Updated as per changes 
in the protocol due to 
interim analysis results  
in the 810P301 study 
Synopsis 
17 
Sample size: 
The following was changed: 
 
It is assumed that approximately 20% subjects will dropout 
before the completion of the study and hence, an adjusted total 
of 291 subjects will be randomized in a 1:1:1 ratio to obtain 231 
subjects in the ITT population at the completion of the study.  
Based on the 810P301 study Interim Analysis result decision, 
the 18 mg dose arm was dropped partway through the study. 
As a result, subjects in the 18 mg dose arm will be re-
randomized in a ratio of 2:1 to receive 36 mg/day SPN-810 or 
placebo. 
 
The sample size was calculated using the nQuery Advisor 
Software, Version 7.  
The above sample size may be increased depending on the 
results of the interim analysis from study 810P301. If the results 
of the interim analysis warrant increased sample size for study 
810P301, then the same increase will be applied to study 
810P302, which will be described in a protocol amendments. 
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 
Synopsis  
17 
Hypotheses: 
The following was changed: 
 
Let 1 and  2, and 3 represent the median percent change in 
the frequency of IA behaviors per 7 days in the Maintenance 
period relative to the Baseline period in the ITT population for 
subjects treated with Placebo, 18 mg and 36 mg doses of SPN-
810, respectively.  The null (H0) and the alternative (Ha) 
hypotheses are as in the following. 
 
H01: 2= 1, (there is no difference between the median 
of the 18 36 mg dose SPN-810 and the median of 
placebo) vs. Ha1: 2≠ 1,(there is a difference between 
the median of the 18 36mg dose SPN-810  and the 
median of placebo) 
H02: 3= 1, (there is no difference between the median of the 36 
mg dose SPN 810 and the median of placebo) vs. Ha2: 3≠ 
1,(there is a difference between the median of the 36 mg dose  
SPN 810  and the median of placebo) 
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 


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Synopsis 
18 
Statistical Methods: 
The following was changed: 
 
The primary efficacy analysis will be performed using the 
Wilcoxon rank-sum test to compare the medians of each of the 
two doses of SPN-810 (18 and 36 mg and) with the median of 
the Placebo. 
 
The least squares mean of each treatment group, the difference 
in the least squares mean (18mg dose minus placebo and 36 mg 
dose minus placebo), and the 2-sided 95% CI for the difference 
will be obtained. 
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 
List of 
Abbreviation 
25 
FOCP changed to FOCBP 
To Clarify 
3.2 
32  
The following was added: 
 
Following screening, eligible subjects will enter a flexible 
baseline period, at which time the IA diary will be issued to the 
subject’s primary caregiver.  At the end of the baseline period, 
per the original plan, eligible subjects whose primary caregiver 
has maintained at least 80% compliance with the IA diary will be 
randomized to 1:1:1 to 18 mg/day SPN-810, 36 mg/day SPN-810, 
or placebo.  However, based on the 810P301 study Interim 
Analysis result decision, the 18 mg arm was dropped partway 
through the study. As a result, subjects planned to be 
randomized to the 18 mg arm will be re-allocated to the 36 mg 
or placebo arm in a ratio of 2:1. 
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 
3.2.1.2 
33 
The following was changed: 
 
These subjects may be rescreened to participate in the study 
under current protocol 4.0 
To clarify 
3.2.2.1 
34 
The following change was made: 
 
Per the original randomization, Eeligible subjects who complete 
the baseline period and meet the requirements for the double 
blind study will be randomized at Visit 3 (Day 1) in a 1:1:1 ratio 
to receive 18 mg/day, 36 mg/day SPN-810, or placebo and 
proceed to the titration period, which will be two weeks.   
However, based on the 810P301 study Interim Analysis result 
decision, the 18 mg arm was dropped partway through the 
study. As a result, subjects planned to be randomized to the 18 
mg arm will be re-allocated to the 36 mg or placebo arm in a 
ratio of 2:1. 
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 
3.2.3 
34 
The following was added:  
 
The 18 mg line in the 2 figures below will not be applicable to 
subjects re-randomized following the 810P301 interim analysis 
decision to drop the 18 mg dose. 
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 
Table 1  
40 
f 
To be performed for female subjects of childbearing 
potential prior to administration of first dose of SM and will 
have to be tested as negative for the subject to continue in the 
study. 
Procedural 
 
 


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4.2.1. 4.2.3 
and 4.2.7 
41.4
2, 43 
FOCP changed to FOCBP 
To Clarify 
4.3.1 
44 
Treatments Administered 
The following was added:  
 
Based on the 810P301 study Interim Analysis result decision, 
the 18 mg dose arm is dropped partway through the study.    
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 
4.3.4 
45,4
6 
The following change was made: 
 
The original randomization scheme assigns treatments to each 
randomization number in a 1:1:1. 
However, based on the 810P301 study Interim Analysis result 
decision, the 18 mg arm was dropped  partway through the 
study. As a result, subjects planned to be randomized to the 18 
mg arm will be re-allocated to the 36 mg or placebo arm in a 
ratio of 2:1. 
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 
4.3.6 
46 
The following was added: 
 
The 18 mg dose (Treatment 2) arm was dropped partway 
through the study as described in section 4.3.4.    
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 
Table 3  
56 
FOCP changed to FOCBP 
To clarify 
6.7 
61  
The following change was made: 
 
Percent of study drug compliance is defined as {(number of 
tablets dispensed – number of tablets returned) / 24*(date of 
last dose – date of first dose + 1)}* 100%.  
 
Each subject is expected to take 4 tablets per day. For each 
treatment, SM compliance will be summarized by compliance 
category (<80%, 80-120%, and >120%) and number of subjects in 
each compliance category.   
To clarify 
6.9.1 
61,6
2 
The following was changed: 
 
Let μ1, and μ2, and μ3 represent the median percent change in 
the frequency of IA behaviors per 7 days in the Maintenance) 
period relative to the Baseline period in the ITT population for 
subjects treated with Placebo, 18 mg and 36 mg doses of SPN-
810, respectively. The null (H0) and the alternative (Ha) 
hypotheses are as in the following.  
• H01: μ2= μ1, (there is no difference between the median of the 
18  36 mg dose SPN-810 and the median of placebo) vs. Ha1: μ2≠ 
μ1,(there is a difference between the median of the 3618 mg 
dose SPN-810 and the median of placebo)  
• H02: μ3= μ1, (there is no difference between the median of the 
36 mg dose SPN 810 and the median of placebo) vs. Ha2: μ3≠ 
μ1,(there is a difference between the median of the 36 mg dose 
SPN 810 and the median of placebo) 
 
The primary efficacy analysis will be performed using the 
Wilcoxon rank-sum test to compare the medians of each of the 
two doses of SPN-810 36 mg dose  with the median of the 
Placebo.   
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 


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To preserve the overall Type I error rate at 0.050 for the primary 
efficacy endpoint, a step up Hochberg procedure (Hochberg  
1988) will be used to compare SPN 810 36 mg dose group with 
Placebo. If the observed p value from the comparison is < 0.050 
in favor of the SPN 810 dose group, then 36mg dose group will 
be declared statistically significantly better than placebo. 
 
The superiority of 36 mg dose to placebo will be claimed if the 
p-value from this analysis < 0.05 at alpha of 5% significance 
level. There is no multiplicity adjustment with respect to the 
primary endpoint since only 2 treatments are compared. 
6.9.2 
62 
The following was changed: 
 
The least squares mean of each treatment group, the difference 
in the least squares mean (18 36mg dose minus placebo and 36 
mg dose 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, a sequential testing procedure will be used 
with the following features. First only dose or doses that are 
significantly different from placebo for the primary endpoint will 
be tested for secondary endpoints. The first of the secondary 
endpoints will be compared to placebo using the Hochberg step 
up procedure but only using those doses retained as a result of 
testing the primary endpoint. The second secondary endpoint 
will be tested in the same manner but only using those doses 
that were retained from the primary and the first secondary 
endpoint and so forth. As the endpoints are gone through in the 
pre defined order doses will only be retained if significant for all 
endpoints tested so far and at the given stage the Hochberg 
step up procedure will be applied. 
The ordering of the  6 secondary endpoints from first to be 
tested to sixth is: Investigator Clinical Global Impression  
Improvement Scale (CGI I)(Endpoint 1), Clinical Global 
Impression  Severity Scale (CGI S)(Endpoint 2), Child Health 
Questionnaire (CHQ 28) (Endpoint 3), Parenting Stress Index 
(PSI 4 SF) (Endpoint 4), Caregiver completed CGI I (Endpoint 
5)and SNAP IV Rating Scale (Endpoint 6). 
 
The superiority of 36 mg dose to placebo will be claimed if the 
p-value from this analysis < 0.05 at alpha of 5% significance 
level. There is no multiplicity adjustment with respect to the 
primary endpoint since only 2 treatment groups are compared. 
The Type I error rate of the tests involving the secondary 
efficacy endpoints will be controlled by the Hochberg’s method 
at the 0.05 two-sided level. 
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 
6.10 
64 
The  following changes were made: 
 
A sample size of 77 subjects per arm (231 subjects for 3 arms per 
the original plan). 
Updated as per changes 
in the protocol due to 
interim analysis results 
in the 810P301 study 


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The above sample size may be increased depending on the 
results of the interim analysis from study 810P301. If the results 
of the interim analysis warrant increased sample size for 
810P301, then the same increase will be applied to study 
810P302, which will be described in a protocol amendment. 
 
It is assumed that approximately 20% subjects will dropout 
before the completion of the study and hence, an adjusted total 
of 291 subjects will be randomized in a 1:1:1 ratio to obtain 231 
subjects in the ITT population at the completion of the study.  
However, based on the 810P301 study Interim Analysis result 
decision, the 18 mg arm was dropped  partway through the 
study. As a result, subjects planned to be randomized to the 18 
mg arm will be re-allocated to the 36 mg or placebo arm in a 
ratio of 2:1. 
 
 
 
Changes to Version 6.0 dated 13 Oct 2017 
 
Section 
Page 
Description of Change 
Rationale 
Title page 
1 
Protocol version and date was updated 
Administrative 
Signatures 
3 
Reviewers: 
 
 
 
 
 
 
 
 
 
 
 
. 
Administrative 
Synopsis 
23 
Objectives, Secondary 
The key secondary objective of the study is to assess the effect 
of SPN-810 on the Clinical Global Impression – Severity Scale 
(CGI-S). 
 
Additional secondary objectives of the study are to assess the 
following: 
(Deleted) 
 
the effect of SPN 810 on the Clinical Global Impression  
Severity Scale (CGI S) 
(Added) 
 
the effect of SPN-810 on the responder rate (defined as 
≥ 50% in the reduction of the frequency of IA behaviors) 
 
the effect of SPN-810 on the responder rate (defined as 
≥ 30% in the reduction of the frequency of IA behaviors) 
Clarification 
Synopsis 
24 
Number of Subjects: 
Approximately 378 398 subjects aged 6-12 years (inclusive) will 
be screened to achieve 291 306 subjects randomized. 
Revised following re-
estimation of sample 
size 


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Synopsis 
24 
Endpoints, Primary Efficacy Endpoint: 
The primary efficacy endpoint is the percent change (PCHM PCHT) 
in the frequency (unweighted score) of IA behaviors per 7 days 
in the Maintenance Treatment (Titration and Maintenance) 
period relative to the Baseline period calculated over the 
number of days with non-missing IA diary data.    
 
The primary efficacy endpoint  PCHM PCHT will be calculated by  
PCHM PCHT = 100*(M T – B)/B, where M T and B are IA behavior 
frequencies per 7 days during the maintenance treatment 
period and baseline period, respectively. 
Clarification  
Synopsis 
24-
25 
Endpoints, (Added) Key Secondary Efficacy Endpoint 
Change from Visit 3 to Visit 6 in Investigator CGI-S score 
 
Additional Secondary Efficacy Endpoints  
1. Investigator-rated CGI-I score at Visit 6 
2. CGI S 
3. 2.  CHQ-PF28 score at Visit 6 
4. 3.  PSI-4-SF scores at Visit 6 in: 
5. Caregiver rated CGI I 
a. Parental Distress 
b. Parent-Child Dysfunctional Interaction 
c. Difficult Child 
4. Caregiver CGI-I score at Visit 6 
5. SNAP-IV Rating ADHD scores at Visit 6 in: 
a. Inattention ratings 
b. Hyperactivity/Impulsivity ratings 
c. Oppositional Defiant Disorder 
a. d.  Combined Scale ratings  
6. Percent of responders with ≥50% reduction in the frequency 
of IA behaviors from baseline 
7. Percent of responders with ≥30% reduction in the frequency 
of IA behaviors from baseline 
Clarification 
Synopsis 
25 
Sample size: 
Based on results from the Phase 2 study, it is assumed that the a 
15-point average difference in favor of the SPN-810 treatment 
difference between SPN 810 dose groups and arms compared 
with placebo is 15 with assumed; the change from baseline to 
endpoint in total R-MOAS rating was used to evaluate the 
difference. The R-MOAS was used because there have been no 
prior studies with the IA diary.  A common standard deviation of 
27.3. A 34.83 was obtained from a blinded analysis of SPN-
810P301 data. Based on these parameter assumptions, a 
sample size of 77 122 subjects per arm (231 subjects for 3 arms)  
will yield 90% power to detect a non-zero difference between 
the median of 18 mg or 36 mg dose group SPN-810 treatment 
and the placebo groups using the Wilcoxon rank-sum test with a 
2-sided significance level alpha α=0.05. 
 
It is assumed that approximately 20% subjects will dropout 
before the completion of the study and hence, an adjusted total 
The original sample size of 291 subjects will be randomized in a 
Revised sample size 
estimate based on 
updated parameter 
assumptions 


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1:1:1 ratio to obtain 231 subjects in the ITT population at was 
based on having 3 treatment groups (97 subjects per arm) and 
specific assumptions on the completion of the study.  Based on 
drug placebo difference, standard deviation and 
discontinuation rate. 
 
After the 810P301 study Interim Analysis result decision, the 18 
mg dose arm was dropped partway through the study. As a 
result, subjects in was completed, the 18 mg dose arm will was 
discontinued and subjects planned to be randomized to the 18 
mg arm would be re-randomized allocated to the 36 mg or 
placebo arm in a ratio of 2:1 to receive 36 mg/day SPN 810 or 
placebo. As such there will be an unequal randomization 
between the 36 mg dose group and placebo. With this post-
interim analysis un-equal randomization,  the placebo arm is 
expected to approach approximately 121 subjects of the total 
of 306 subjects randomized. 
 
The sample size was calculated using the nQuery Advisor 
Software, Version 7. 
Synopsis 
26 
Hypotheses Hypothesis: 
Per the adaptive design feature of protocol 810P301 that led to 
discontinuation of the 18 mg dose group,  SPN-810 36 mg vs. 
placebo will be tested. 
Let µ1, and µ2 represent the median percent change in the 
frequency of IA behaviors per 7 days in the Maintenance period 
relative to the Baseline period in the ITT population for subjects 
treated with Placebo and 36 mg dose of SPN 810, respectively.  
The null (H0) and the alternative (Ha) hypotheses are as in the 
following. 
 
H01: µ2= µ1, (tThere is no difference between the median of 
the 36 mg dose SPN-810 and the median of placebo) vs. Ha1:  
µ2≠ µ1, (tThere is a difference between the median of the 36 
mg dose SPN-810 and the median of placebo.) 
Testing the 18 mg dose 
is no longer applicable 
after discontinuation of 
this arm 
Synopsis 
26 
Handling Missing Data: 
For the primary efficacy endpoint, the frequency of IA behaviors 
during the maintenance Treatment period will be calculated 
over the number of days with non-missing IA diary data in the 
maintenance Treatment period. 
Clarification 
Synopsis 
27 
Statistical Methods: 
The primary efficacy endpoint is the percent change in the 
frequency  (unweighted score) of IA behaviors per 7 days in the 
Maintenance Treatment (Titration and Maintenance) period 
relative to the Baseline period in the ITT population calculated 
over the number of days with non-missing IA diary data. 
 
(Deleted) The robustness of the primary analyses will be checked 
by performing at least two sensitivity analyses. 
 
Each one of the six The key secondary endpoint will be analized 
using Mixed-Effect Model for Repeated Measure (MMRM). The 
model includes treatment, visit, and interaction between 
Clarification  


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treatment and visit as fixed factors, and baseline as covariate. 
The between-group comparison will be performed using the 
simple contrast at the respective visits. The least squares 
means for 36 mg dose and placebo, the difference in the least 
squares mean (36 mg dose minus placebo), and the 2-sided 
95% CI for the difference will be calculated at Visit 6 using the 
simple contrast. 
 
The other secondary endpoints will be analyzed as follows: 
•  Actual scores of CGI-I  (investigator and caregiver) will be 
analyzed using a Mixed-Effect Model for Repeated Measure 
(MMRM) similar to the key secondary outcome. 
•  Actual Scores for CHQ-PF28, PSI-4-SF, and SNAP-IV will be 
analyzed using the analysis of covariance method based on the 
ITT 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 Visit 6 value 
as a response variable. The least squares mean of each 
treatment group, the difference in the least squares mean (36 
mg dose minus placebo), and the 2-sided 95% CI for the 
difference will be obtained.  
•  The percentage of responders with at least 30% reduction 
and with at least 50% reduction in the frequency of IA 
behaviors per 7 days in the Treatment (Titration and 
Maintenance) period relative to the Baseline period will be 
derived analyzed using the logistic regression model with 
treatment as explanatory variables and baseline as covariate. 
Odds ratio (36 mg dose/placebo), and 95% CI for the odds ratio 
and p-value will be presented. In addition, the number and 
percentage of responders will also be tabulated. 
1.1 
35, 
36 
IA is a commonly associated with comorbidity in attention-
deficit/hyperactivity disorder (ADHD) and is often refractory to 
primary ADHD therapy. 
 
Risperidone and other “atypical” antipsychotics have historically 
been at the forefront of treatment recommendations regarding 
combination therapy for managing comorbid aggression in 
children associated with ADHD in children (Pappadopulos et al. 
2003; Pliszka et al. 2006; Pliszka et al. 2007). 
 
Results of randomized controlled trials such as TEOSS stimulated 
interest in the potential usefulness of molindone as a weight- 
and metabolically-neutral D2-receptor antagonist in children 
with ADHD and comorbid associated with IA. 
Clarification 
1.3 
37 
One (1) subject patient in the low dose arm and 2 subjects 
patients in the medium dose arm had severe AEs that were 
considered either possibly or definitely related to the drug. Six 
(6) subjects patients in total discontinued the study because of 
AEs in the active treatment arms: 1 in low dose; 2 in medium 
dose; and 3 in high dose. 
Clarification 


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2.2 
39 
The key secondary objectives objective of the study is to assess 
the effect of SPN-810 on the Clinical Global Impression – 
Severity Scale (CGI-S).  
Additional secondary objectives of the study are to assess the 
following: 
 
(Deleted) 
 
the effect of SPN 810 on the Clinical Global Impression  
Severity Scale (CGI S) 
 
(Added) 
 
the effect of SPN-810 on the responder rate (defined as 
≥ 50% in the reduction of the frequency of IA behaviors) 
 
the effect of SPN-810 on the responder rate (defined as 
≥ 30% in the reduction of the frequency of IA behaviors) 
Clarification  
3.1 
39 
The present study is designed to evaluate the efficacy, safety, 
and tolerability of SPN-810 in patients aged 6 to 12 years with 
ADHD and comorbid associated with IA, when taken in 
conjunction with a standard ADHD treatment.   
Clarification 
3.2.3 
42 
All subjects who complete the randomized, double blind portion 
of study 810P301 810P302 will have the option to participate in 
an OLE study (study protocol 810P304) in which all subjects will 
receive active SM treatment.   
Correction 
Figure 1 
43 
(Added) 
NOTE: Based on the 810P301 study Interim Analysis result 
decision, the 18 mg dose arm was dropped partway through 
the study. 
Clarification 
Figure 2 
44 
(Added) 
NOTE: Based on the 810P301 study Interim Analysis result 
decision, the 18 mg dose arm was dropped partway through 
the study. 
Clarification 
4.1 
45 
Approximately 291 306 subjects will be randomized in this 
clinical investigation. 
Revised sample size 
estimate based on 
updated parameter 
assumptions 
Table 1 
48 
Footnote e: 
Diary compliance must be at least 80% (minimum of 12 days out 
of 1415 15) to qualify for randomization 
Correction 
5.2.1 
57 
Investigators should consider their total clinical experience with 
children who have IA comorbid associated with ADHD and rate 
how severe the subject’s condition is at the time. 
Clarification 
5.2.1 
57 
•  CGI-I, relative to the condition at Baseline (Visit 1) 3, will be 
evaluated by the caregiver and by the Investigator at each post-
baseline visit on a 7-point scale with 1=Very much improved, 
2=Much improved, 3=Minimally improved, 4=No change, 
5=Minimally worse, 6=Much worse, and 7=Very much worse. 
Correction 
6.2 
67 
For the primary efficacy endpoint, the frequency of IA behaviors 
during the maintenance Treatment period will be calculated 
over the number of days with non-missing IA diary data in the 
maintenance Treatment period. 
Clarification 
6.9.1 
69-
70 
The primary efficacy endpoint is the percent change (PCHM PCHT) 
in the frequency (unweighted score) of IA behaviors per 7 days 
Clarification  


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in the Maintenance Treatment (Titration and Maintenance) 
period relative to the Baseline period calculated over the 
number of days with non-missing IA diary data. 
 
The primary efficacy endpoint  PCHM PCHT will be calculated by  
PCHM PCHT = 100*(T M – B)/B, where M T and B are IA behavior 
frequencies per 7 days during the maintenance treatment 
period and baseline period, respectively. 
 
(Deleted) 
Let µ1 and µ2 represent the median percent change in the 
frequency of IA behaviors per 7 days in the treatment 
Maintenance period relative to the Baseline period in the ITT 
population for subjects treated with Placebo and 36 mg doses of 
SPN 810, respectively.   
 
(Added) 
Per the adaptive design feature of protocol 810P301 that led to 
discontinuation of the 18 mg dose group,  SPN-810 36 mg vs. 
placebo will be tested. 
 
•  H0: µ2=  µ1, (H01: There is no difference between the median of 
the 36 mg dose SPN-810 and the median of placebo) vs. Ha:  µ2≠  
µ1, (  
•  Ha1: There is a difference between the median of the 36 mg 
dose SPN-810  and the median of placebo). 
6.9.2 
70 
6.9.2 Key Secondary Efficacy Analyses 
The key secondary endpoints are: 
1. Actual Caregiver CGI I score at Visit 6 
2. Actual Investigator CGI I score at Visit 6   
efficacy analysis is the change from Visit 3 to Visit 6 in 
Investigator CGI-S score. 
Change from Visit 3 to Visit 6 in The Key Secondary endpoint 
will be analyzed using Mixed-Effect Model for Repeated 
Measure (MMRM) for the ITT population. The model includes 
treatment, visit, and interaction between treatment and visit 
as fixed factors, and 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 36 mg dose and 
placebo, the difference in the least squares mean (36 mg dose 
minus placebo), and the 2-sided 95% CI for the difference will 
be calculated. 
Clarification 
6.9.3 
70 
6.9.3 Additional Secondary Efficacy Analyses 
1. Investigator CGI-I score at Visit 6   
3. 2.  CHQ-28 score at Visit 6 
4. 3.  Change from Visit 3 to Visit 6 in PSI-4-SF scores at Visit 6 in: 
4. Change from Visit 3 to Visit 6 in Caregiver CGI-I score at Visit 
6 
Clarification 


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5. SNAP-IV ADHD scores at Visit 6 in: 
a. Inattention ratings 
b. Hyperactivity/Impulsivity ratings 
c. Oppositional Defiant Disorder 
c. d.  Combined Scale ratings  
6. Each one of the six Percentage of responders with ≥50% 
reduction in the frequency of IA behaviors from baseline 
7. Percentage of responders with ≥30% reduction in the 
frequency of IA behaviors from baseline 
 
The other secondary endpoints will be analyzed using the ITT 
Population as follows: 
 
Scores of CGI-I  (investigator and caregiver) will be analyzed 
using a Mixed-Effect Model for Repeated Measure (MMRM) 
similar to the key secondary outcome. 
 
Scores for CHQ-PF28, PSI-4-SF, and SNAP-IV will be analyzed 
using the analysis of covariance method based on the ITT 
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 Visit 6 value as a response 
variable. 
 
The superiority of 36 mg dose to placebo will be claimed if the p
value < 0.05 at alpha 5% significance level. There is no 
multiplicity adjustment with respect to the primary endpoint 
since only 2 treatments groups are compared. 
 
The Type I error rate of the tests involving the secondary efficacy 
endpoints will be controlled by the Hochberg’s method at the 
0.05 two sided level. 
 
The percentage of responders with at least 30% reduction and 
with at least 50% reduction in the frequency of IA behaviors 
per 7 days in the Treatment (Titration and Maintenance) period 
relative to the Baseline period will be derived analyzed using 
the logistic regression model with treatment as explanatory 
variables and baseline as covariate. Odds ratio (36 mg 
dose/placebo), and 95% CI for the odds ratio and p-value will 
be presented. In addition, the number and percentage of 
responders will also be tabulated. 
  
If the null hypothesis for the primary analysis is not rejected, 
then no multiplicity adjustment will be done for the key 
secondary endpoint. If the key secondary endpoint hypothesis 
is rejected then, a sequential testing procedure to preserve the 
type I error rate at 0.05 will be conducted for the additional 
secondary endpoints as described below: 
 


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First, the first of the additional secondary endpoints 
(Investigator CGI-I score at Visit 6) will be used to test H01: no 
difference between SPN-810 36 mg and Placebo in the 
treatment of IA in subjects with ADHD in conjunction with 
standard ADHD treatment.  If this test is rejected, then the 2nd 
test using the same hypothesis will be repeated using the 2nd 
additional secondary endpoint (CHQ-28 score at Visit 6). If the 
first hypothesis is not rejected then no other additional 
secondary endpoint test will be performed. If the 2nd  test is 
rejected then the 3rd  test will be conducted for the 3rd 
additional secondary endpoint (PSI-4-SF scores) and so on until 
the last  additional secondary endpoint is used for testing in 
the above pre-specified order above. 
 
6.9.4 
71 
To this end, the three two sensitivity analyses will be performed: 
1.  Multiple imputation under MAR using available data on the 
primary endpoint  
2.  Placebo- based imputation under MNAR 
3.  Per Protocol Analysis 
Correction 
6.9.4 
de-
lete
d 
(Deleted) 
6.9.4  Per Protocol Analysis 
This analysis will be conducted by repeating the primary analysis 
on the per protocol population. 
Correction 
6.9.5 
72 
(Added) 
6.9.5  Supplementary Analysis 
A supplementary analysis based on the per-protocol 
population will be performed. 
Clarification 
6.10 
72-
73 
Based on results from the Phase 2 study, it is assumed that the a 
15-point average treatment difference between in favor of the 
SPN-810 dose groups and treatment arms compared with 
placebo =15 with is assumed; the change from baseline to 
endpoint in total R-MOAS rating was used to evaluate the 
difference. The R-MOAS was used because there have been no 
prior studies with the IA diary.  A common standard deviation of 
27.3. A 34.83 was obtained from a blinded analysis of SPN-
810P301 data.  
 
Based on these parameter assumptions, a sample size of 77 
subjects per arm (231 subjects for 3 arms per the original plan)  
approximately 122 per arm will yield 90% power to detect a 
non-zero difference between the median of 18 mg or 36 mg 
dose group SPN-810 treatment and the placebo groups using 
the Wilcoxon rank-sum test with a 2-sided significance level 
alpha α=0.05. 
 
It is assumed that approximately 20% subjects will dropout 
before the completion of the study and hence, an adjusted total 
The original sample size of 291 subjects will be randomized in a 
1:1:1 ratio to obtain 231 subjects in the ITT population at the 
completion of the study.  However, was based on having 3 
treatment groups (97 subjects per arm) and specific 
Revised sample size 
based on updated 
parameter assumptions 


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assumptions on the drug placebo difference, standard 
deviation and discontinuation rate.  
 
After the 810P301 study Interim Analysis result decision was 
completed, the 18 mg dose arm was dropped partway through 
the study. As a result, discontinured and subjects planned to be 
randomized to be randomized to the 18 mg arm will would be 
re-allocated to the 36 mg or placebo arm in a ratio of 2:1.  As 
such there will be an unequal randomization between the 36 
mg dose group and placebo.  With this post-interim analysis 
un-equal randomization, the placebo arm is expected to 
approach approximately 121 subjects of the total of 306 
subjects randomized. 
 


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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:  810P302 
Phase of Development:  3 
Full Title of Study:  A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of Molindone Hydrochloride Extended-Release Tablets for the Treatment of Impulsive 
Aggression in Pediatric Patients with Attention Deficit/Hyperactivity Disorder (ADHD) in Conjunction 
with Standard ADHD Treatment 
Investigator(s) / Center(s):  Approximately 25 US centers 
Objectives: 
Primary 
The primary objective is to assess the efficacy and safety of SPN-810 in reducing the frequency of 
impulsive aggression (IA) behaviors in pediatric patients with ADHD when taken in conjunction with 
standard ADHD treatment 
 
Secondary 
The key secondary objective of the study is to assess the effect of SPN-810 on the Clinical Global 
Impression – Severity Scale (CGI-S). 
 
Additional secondary objectives are to assess the following:  
 
the effect of SPN-810 on the Investigator-rated Clinical Global Impression – Improvement 
Scale (CGI-I)  
 
the effect of SPN-810 on the child’s overall health as measured by the Child Health 
Questionnaire Parent Form 28-item (CHQ-PF28) 
 
the effect of treating the child with SPN-810 on the parent-child relationship as measured by 
the Parenting Stress Index – Short Form (PSI-4-SF)  
 
the effect of SPN-810 on the Caregiver-rated CGI-I 
 
the effect of SPN-810 on inattention and hyperactivity-impulsivity measured by the SNAP-IV 
Rating Scale  
 
the effect of SPN-810 on the responder rate (defined as ≥ 50% in the reduction of the 
frequency of IA behaviors) 
 
the effect of SPN-810 on the responder rate (defined as ≥ 30% in the reduction of the 
frequency of IA behaviors) 
 
Tertiary 
 
 
 
 
Study Design:  Double-blind, placebo-controlled, 3-arm, randomized (1:1:1), parallel group study. 
Based on the 810P301 study Interim Analysis result decision, the 18 mg dose arm was dropped 
partway through the study. As a result, subjects in the 18 mg dose arm will be re-randomized in a 
ratio of 2:1 to receive SPN-810 36 mg/day or placebo. 


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Number of Subjects:  Approximately 398 subjects aged 6-12 years (inclusive) will be screened to 
achieve 306 subjects randomized. 
Criteria for Inclusion: 
Otherwise healthy male or female subjects, age 6 to 12 years at the time of screening with a primary 
diagnosis of ADHD and currently receiving monotherapy treatment with an optimized FDA-approved 
ADHD medication.  IA will be confirmed at screening using R-MOAS and Vitiello Aggression Scale. 
Criteria for Exclusion: 
Current or lifetime diagnosis of epilepsy, major depressive disorder, bipolar disorder, schizophrenia or 
related disorder, personality disorder, Tourette’s disorder, or psychosis not otherwise specified.  
Currently meeting DSM criteria for autism spectrum disorder, pervasive developmental disorder, 
obsessive compulsive disorder, post-traumatic stress disorder, or any other anxiety disorder as 
primary diagnosis.  Known or suspected intelligence quotient (IQ) < 70, suicidality, pregnancy, or 
substance or alcohol abuse.   
Treatment, Dose, and Mode of Administration: 
Molindone hydrochloride extended-release tablet dosage forms of 3mg and 9mg with matching 
placebo tablets.  Treatment to be administered orally twice daily with food.  Subjects will be force-
titrated over a period of 2 weeks to their final randomized dose. 
 
Treatment 1:  placebo  
 
Treatment 2:  18mg 
 
Treatment 3:  36mg 
Based on the Interim Analysis results from the 810P301 study, Treatment 2 (18 mg) arm was 
discontinued. 
Duration of Treatment and Study Duration: 
Total subject duration on 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:  5 weeks 
o Titration period:  2 weeks  
o Maintenance period:  3 weeks 
 
Conversion/taper phase:  1 week 
Endpoints: 
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 (Titration and Maintenance) period 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 period 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 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.  
 
Key Secondary Efficacy Endpoint 
Change from Visit 3 to Visit 6 in Investigator CGI-S score 
 


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Additional Secondary Efficacy Endpoints  
1. Investigator CGI-I score at Visit 6 
2. CHQ-PF28 score at Visit 6 
3. PSI-4-SF scores at Visit 6 in: 
a. Parental Distress 
b. Parent-Child Dysfunctional Interaction 
c. Difficult Child 
4. Caregiver CGI-I score at Visit 6 
5. SNAP-IV ADHD scores at Visit 6 in: 
a. Inattention ratings 
b. Hyperactivity/Impulsivity ratings 
c. Oppositional Defiant Disorder 
d. Combined Scale ratings  
6. Percent of responders with ≥50% reduction in the frequency of IA behaviors from baseline 
7. Percent of responders with ≥30% reduction in the frequency of IA behaviors from baseline 
 
Safety and Tolerability Endpoints 
1. Adverse events (AE) 
2. Extrapyramidal symptoms (EPS) scales (Simpson-Angus Scale, Barnes Akathisia Scale, 
Abnormal Involuntary Movement Scale) 
3. Clinical laboratory tests (Hematology, Chemistry and Urinalysis) 
4. ECGs 
5. Vital signs 
6. Columbia Suicide Severity Rating Scale (C-SSRS) 
7. Infrequent Behaviors Checklist 
Sample size: 
Based on results from the Phase 2 study, a 15-point average difference in favor of the SPN-810 
treatment arms compared with placebo is assumed; the change from baseline to endpoint in total R-
MOAS rating was used to evaluate the difference. The R-MOAS was used because there have been no 
prior studies with the IA diary.  A common standard deviation of 34.83 was obtained from a blinded 
analysis of SPN-810P301 data. Based on these parameter assumptions, a sample size of 122 subjects 
per arm will yield 90% power to detect a non-zero difference between the median of SPN-810 
treatment and the placebo groups using the Wilcoxon rank-sum test with a 2-sided significance level 
α=0.05. 
 
The original sample size of 291 was based on having 3 treatment groups (97 subjects per arm) and 
specific assumptions on the drug placebo difference, standard deviation and discontinuation rate.  
 
After the 810P301 study Interim Analysis result was completed, the 18 mg dose arm was discontinued 
and subjects planned to be randomized to the 18 mg arm would be re-allocated to the 36 mg or 
placebo arm in a ratio of 2:1. As such there will be an unequal randomization between the 36 mg 
dose group and placebo. With this post-interim analysis un-equal randomization,  the placebo arm is 
expected to approach approximately 121 subjects of the total of 306 subjects randomized. 
 
The sample size was calculated using the nQuery Advisor Software, Version 7. 
 


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Analysis Populations: 
Safety Population:  will include all randomized subjects who received at least 1 dose of study drug. 
Intent-to-Treat (ITT) Population:  will include all subjects who received at least 1 dose of study drug 
and have a 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 in the ITT population who completed the 
treatment period with 80% diary completion compliance and who did not have major protocol 
deviations. 
PK population:  will include all subjects in the safety population who had at least one PK sample 
drawn which had a quantitatable concentration for at least one analyte of interest. 
Hypothesis: 
Per the adaptive design feature of protocol 810P301 that led to discontinuation of the 18 mg dose 
group, SPN-810 36 mg vs. placebo will be tested. 
The null (H0) and the alternative (Ha) hypotheses are as in the following. 
 
H01: There is no difference between the median of the 36 mg dose SPN-810 and the median of 
placebo vs. Ha1: There is a difference between the median of the 36 mg dose SPN-810  and 
the median of placebo. 
Handling Missing Data: 
For the primary efficacy endpoint, the frequency of IA behaviors during the Treatment period will be 
calculated over the number of days with non-missing IA diary data in the Treatment period. No 
explicit imputation of missing data will be used, but this approach is implicitly equivalent to using the 
frequency of IA behaviors during the days with non-missing IA diary data to impute the frequency for 
days after study discontinuation and days with missing IA diary data.  
Pharmacokinetic Methods: 
Sampling: 
5 blood samples divided between 2 visits. 
 
Bioanalytical Analysis: 
 
 
 
 
Pharmacokinetic Analysis: 
  
 
 
   
 
 
 
 
 
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.  
 


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The primary efficacy analysis will be based on the ITT population.  The primary efficacy endpoint is the 
percent change in the frequency  (unweighted score) of IA behaviors per 7 days in the Treatment 
(Titration and Maintenance) period relative to the Baseline period in the ITT population calculated 
over the number of days with non-missing IA diary data. 
 
The primary efficacy analysis will be performed using the Wilcoxon rank-sum test to compare the 
median of SPN-810 36 mg and the median of the Placebo.  The Hodges-Lehmann estimate and the 
associated 95% confidence interval (CI) will be calculated.   
 
The key secondary endpoint will be analized using Mixed-Effect Model for Repeated Measure 
(MMRM). The model includes treatment, visit, and interaction between treatment and visit as fixed 
factors, and baseline as covariate. The between-group comparison will be performed using the simple 
contrast at the respective visits. The least squares means for 36 mg dose and placebo, the difference 
in the least squares mean (36 mg dose minus placebo), and the 2-sided 95% CI for the difference will 
be calculated at Visit 6 using the simple contrast.  
 
The other secondary endpoints will be analyzed as follows: 
 
Actual scores of CGI-I  (investigator and caregiver) will be analyzed using a Mixed-Effect 
Model for Repeated Measure (MMRM) similar to the key secondary outcome. 
 
Actual Scores for CHQ-PF28, PSI-4-SF, and SNAP-IV will be analyzed using the analysis of 
covariance method based on the ITT population. The model includes treatment and baseline 
as fixed independent covariates and Visit 6 value as a response variable. The least squares 
mean of each treatment group, the difference in the least squares mean (36 mg dose minus 
placebo), and the 2-sided 95% CI for the difference will be obtained.  
 
The percentage of responders with at least 30% reduction and with at least 50% reduction in 
the frequency of IA behaviors per 7 days in the Treatment (Titration and Maintenance) period 
relative to the Baseline period will be derived analyzed using the logistic regression model 
with treatment as explanatory variables and baseline as covariate. Odds ratio (36 mg 
dose/placebo), and 95% CI for the odds ratio and p-value will be presented. In addition, the 
number and percentage of responders will also be tabulated. 
  
Interim analysis: 
There will be no planned interim analysis. 
 
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 will be summarized using discrete summaries at 
the subject and event level by system organ class and preferred term for each treatment group.  
Similarly, treatment-emergent AEs will be summarized by severity and relationship separately.  Vital 
signs will be summarized using descriptive statistics by treatment groups.  The summary includes 
sample size, mean, and standard deviation, median, minimum, and maximum.  Continuous laboratory 
parameters will be summarized similarly.  If applicable, categorical laboratory tests will be 
summarized using number and percent of subjects by treatment groups.  Data on infrequent 
behaviors will be listed. 
 
 


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TABLE OF CONTENTS 
 
TITLE PAGE ............................................................................................................................ 1 
SUMMARY OF CHANGES ........................................................................................................ 4 
CLINICAL PROTOCOL SYNOPSIS ............................................................................................ 23 
TABLE OF CONTENTS ........................................................................................................... 28 
LIST OF TABLES AND FIGURES .............................................................................................. 32 
LIST OF ABBREVIATIONS ...................................................................................................... 33 
1 
INTRODUCTION ............................................................................................................ 35 
1.1 
Background .................................................................................................................. 35 
1.2 
Sponsor’s Phase 2a Study ............................................................................................. 36 
1.3 
Sponsor’s Phase 2b Study ............................................................................................. 37 
1.4 
Impulsive Aggression Diary (IA Diary) ............................................................................ 38 
1.5 
Study Rationale ............................................................................................................ 38 
2 
STUDY OBJECTIVES ....................................................................................................... 38 
2.1 
Primary Objective ......................................................................................................... 38 
2.2 
Secondary Objectives ................................................................................................... 39 
2.3 
Tertiary Objective ......................................................................................................... 39 
3 
INVESTIGATIONAL PLAN ............................................................................................... 39 
3.1 
Rationale for Study Design, Including Choice of Treatment Groups, Appropriateness of 
Measurements ............................................................................................................................. 39 
3.2 
Overall Study Design and Plan ...................................................................................... 40 
3.2.1 
Pre-Treatment Phase .......................................................................................................... 40 
3.2.1.1 
Screening Period ........................................................................................................................... 40 
3.2.1.2 
Baseline Period.............................................................................................................................. 41 
3.2.2 
Treatment Phase ................................................................................................................. 42 
3.2.2.1 
Randomization .............................................................................................................................. 42 
3.2.2.2 
Titration Period ............................................................................................................................. 42 
3.2.2.3 
Maintenance Period ...................................................................................................................... 42 
3.2.3 
Conversion/Taper Phase ..................................................................................................... 42 
3.2.4 
End of Study / Early Termination ........................................................................................ 42 
4 
STUDY METHODS .......................................................................................................... 45 
4.1 
Selection of Study Population ....................................................................................... 45 
4.1.1 
Inclusion Criteria ................................................................................................................. 45 
4.1.2 
Exclusion Criteria ................................................................................................................. 45 
4.2 
Schedule of Visits and Procedures ................................................................................. 46 


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4.2.1 
Visit 1 ................................................................................................................................... 49 
4.2.2 
Visit 2 ................................................................................................................................... 49 
4.2.3 
Visit 3 ................................................................................................................................... 49 
4.2.4 
Visit 4 ................................................................................................................................... 50 
4.2.5 
Visit 5 ................................................................................................................................... 50 
4.2.6 
Visit 6 ................................................................................................................................... 51 
4.2.7 
Visit 7 ................................................................................................................................... 51 
4.2.8 
Pharmacokinetic Sample Collection .................................................................................... 51 
4.3 
Treatments .................................................................................................................. 52 
4.3.1 
Treatments Administered ................................................................................................... 52 
4.3.2 
Identity of Investigational Product(s) ................................................................................. 52 
4.3.3 
Study Medication Handling and Accountability .................................................................. 53 
4.3.4 
Method of Assigning Subjects to Treatment Groups .......................................................... 53 
4.3.5 
Treatment Replacement ..................................................................................................... 54 
4.3.6 
Dosing Schedule .................................................................................................................. 54 
4.3.7 
Method of Administration .................................................................................................. 54 
4.3.8 
Blinding ............................................................................................................................... 54 
4.4 
Prohibited Medications: ............................................................................................... 55 
4.5 
Concomitant Medication .............................................................................................. 55 
4.6 
Completion of Study and Discontinuation of Subjects .................................................... 56 
5 
ANALYSIS VARIABLES .................................................................................................... 56 
5.1 
Primary Efficacy Variable .............................................................................................. 56 
5.2 
Secondary Efficacy Variables ......................................................................................... 57 
5.2.1 
Clinical Global Impression (CGI) Scales ............................................................................... 57 
5.2.2 
Swanson, Nolan, Pelham Rating Scale- Revised (SNAP-IV) ................................................. 57 
5.2.3 
Child Health Questionnaire Parent Form 28- Item (CHQ-PF28) ......................................... 58 
5.2.4 
Parenting Stress Index-Short Form (PSI-4-SF) ..................................................................... 58 
5.3 
Pharmacokinetic Measurements ................................................................................... 58 
5.3.1 
Pharmacokinetic Variables .................................................................................................. 58 
5.3.2 
Exploratory Pharmacokinetic Variables .............................................................................. 58 
5.4 
Safety Assessments ...................................................................................................... 59 
5.4.1 
Adverse Events .................................................................................................................... 59 
5.4.1.1 
Causality ........................................................................................................................................ 59 
5.4.1.2 
Recording and Evaluation of Adverse Events ................................................................................ 59 
5.4.1.3 
Criteria for Assessing Severity ....................................................................................................... 60 
5.4.1.4 
Criteria for Assessing Causality ..................................................................................................... 60 
5.4.2 
Serious Adverse Events (SAE) .............................................................................................. 61 
5.4.2.1 
Investigator Responsibilities for Reporting SAEs .......................................................................... 61 
5.4.2.2 
Other Events Requiring Immediate Reporting .............................................................................. 62 
5.4.2.3 
Sponsor Responsibilities for Expedited Reporting of SAEs ........................................................... 63 
5.4.3 
Management of Treatment-Emerging EPS ......................................................................... 63 


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5.4.4 
Laboratory Measurements ................................................................................................. 63 
5.4.5 
Vital Sign and Height/Weight Measurements .................................................................... 64 
5.4.6 
Medical History ................................................................................................................... 64 
5.4.7 
Physical Examinations and Electrocardiograms (ECGs) ...................................................... 64 
5.4.8 
Other Special Tests .............................................................................................................. 65 
5.4.8.1 
K-SADS-PL 2013 Diagnostic Interview ........................................................................................... 65 
5.4.8.2 
Simpson-Angus Scale .................................................................................................................... 65 
5.4.8.3 
Barnes Akathisia Scale ................................................................................................................... 65 
5.4.8.4 
Abnormal Involuntary Movement Scale (AIMS) ........................................................................... 65 
5.4.8.5 
Vitiello Aggression Scale ............................................................................................................... 66 
5.4.8.6 
Retrospective-Modified Overt Aggression Scale (R-MOAS) .......................................................... 66 
5.4.8.7 
Columbia Suicide Severity Rating Scale (C-SSRS) .......................................................................... 66 
5.4.8.8 
Infrequent Behaviors Checklist ..................................................................................................... 66 
6 
STATISTICAL METHODS ................................................................................................. 66 
6.1 
Statistical and Analytical Plans ...................................................................................... 66 
6.2 
Handling Missing Data .................................................................................................. 67 
6.3 
Analysis Populations ..................................................................................................... 67 
6.4 
Demographic and Baseline Characteristics .................................................................... 68 
6.5 
Subject Disposition ....................................................................................................... 68 
6.6 
Protocol Deviations ...................................................................................................... 68 
6.7 
Study Medication Exposure and Compliance ................................................................. 69 
6.8 
Concomitant Medications ............................................................................................. 69 
6.9 
Efficacy Analyses .......................................................................................................... 69 
6.9.1 
Primary Efficacy Analysis ..................................................................................................... 69 
6.9.2 
Key Secondary Efficacy Analyses ......................................................................................... 70 
6.9.3 
Additional Secondary Efficacy Analyses .............................................................................. 70 
6.9.4 
Sensitivity Analysis .............................................................................................................. 71 
6.9.4.1 
Multiple imputation under Missing at Random (MAR) ................................................................. 71 
6.9.4.2 
Multiple imputation under Missing Not at Random (MNAR) ....................................................... 72 
6.9.5 
Supplementary Analysis ...................................................................................................... 72 
6.10 
Sample Size and Power Considerations ......................................................................... 72 
6.11 
Interim Analysis ........................................................................................................... 73 
6.12 
Pharmacokinetic Analyses ............................................................................................ 73 
6.13 
Safety Analyses ............................................................................................................ 73 
6.13.1 
Adverse Events .................................................................................................................... 73 
6.13.2 
Laboratory Values ............................................................................................................... 74 
6.13.3 
Vital Signs, Height and Weight ............................................................................................ 74 
6.13.4 
ECG Results ......................................................................................................................... 74 
6.13.5 
Physical Examinations ......................................................................................................... 75 
6.13.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................ 75 
6.13.7 
Infrequent Behaviors Checklist ........................................................................................... 75 
6.13.8 
Other Special Tests .............................................................................................................. 75 


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7 
DOCUMENTATION ........................................................................................................ 75 
7.1 
Adherence to the Protocol ............................................................................................ 75 
7.2 
Changes to the Protocol ................................................................................................ 75 
7.3 
Protocol Deviations ...................................................................................................... 76 
7.4 
Data Quality Assurance ................................................................................................ 76 
7.4.1 
Data Collection .................................................................................................................... 76 
7.4.2 
Clinical Data Management .................................................................................................. 77 
7.4.3 
Database Quality Assurance ............................................................................................... 77 
7.4.4 
Bioanalytical Data Management and Quality Control ........................................................ 77 
7.5 
Retention of Records .................................................................................................... 77 
7.6 
Auditing Procedures ..................................................................................................... 78 
7.7 
Publication of Results ................................................................................................... 78 
7.8 
Financing and Insurance ............................................................................................... 78 
7.9 
Disclosure and Confidentiality ...................................................................................... 78 
7.10 
Discontinuation of Study .............................................................................................. 79 
8 
ETHICS .......................................................................................................................... 79 
8.1 
Institutional Review Boards / Independent Ethics Committees ...................................... 79 
8.2 
Ethical Conduct of the Study ......................................................................................... 79 
8.3 
Investigators and Study Personnel ................................................................................ 80 
8.4 
Subject Information and Consent/Assent ...................................................................... 80 
9 
REFERENCE LIST ............................................................................................................ 80 
10 
APPENDICES .............................................................................................................. 85 
10.1 
Retrospective Modified Overt Aggression Scale (R-MOAS) ............................................. 85 
10.2 
Clinical Global Impression (CGI) Scale ............................................................................ 87 
10.3 
Vitiello Scale ................................................................................................................ 88 
10.4 
Kiddie-Sads-Present and Lifetime Version (K-SADS-PL) 2013 .......................................... 89 
10.5 
Columbia-Suicide Severity Rating Scales (C-SSRS) ........................................................ 200 
10.6 
Swanson, Nolan and Pelham Rating Scale-Revised (SNAP IV) ....................................... 207 
10.7 
Simpson-Angus Rating Scale ....................................................................................... 208 
10.8 
Barnes Akathisia Rating Scale (BARS) .......................................................................... 212 
10.9 
Abnormal Involuntary Movement Scale (AIMS) ........................................................... 214 
10.10 
Child Health Questionnaire Parent Form 28-item (CHQ-PF28) ...................................... 219 
10.11 
Parenting Stress Index-Short Form (PSI-4-SF) ............................................................... 223 
 
 
 


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LIST OF TABLES AND FIGURES 
 
Table 1:  Schedule of Visits and Procedures ............................................................................................... 47 
Table 2: Dosing Schedule (Total Daily Dose) ............................................................................................... 54 
Table 3: Clinical Laboratory Tests ............................................................................................................... 64 
 
Figure 1: Treatment Schedule (Conversion) ............................................................................................... 43 
Figure 2: Treatment Schedule (Taper) ........................................................................................................ 44 
 
 
 


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LIST OF ABBREVIATIONS 
 
ADHD 
Attention-Deficit Hyperactivity Disorder 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIMS 
Abnormal Involuntary Movement Scale 
ASD 
Autism Spectrum Disorder 
BID 
Twice a Day 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression – Severity of Illness 
CGI-I 
Clinical Global Impression – Global Improvement 
CHQ-PF 28 
CL/F 
Child Health Questionnaire Parent Form 28-item  
Apparent Clearance 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
eCRF 
Electronic Case Report Form 
EPS 
Extrapyramidal Symptoms 
FOCBP 
Females of Childbearing Potential 
IA 
Impulsive Aggression 
IAF 
Informed Assent Form 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
KBIT-2 
Kaufman Brief Intelligence Test, Second Edition 
K-SADS-PL 2013 
Schedule for Affective Disorders and Schizophrenia for School-aged 
Children – Present and Lifetime Versions 2013 
LSM 
Least-square Means 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MNAR 
Missing Not at Random 
ODD 
Oppositional Defiant Disorder 
PK 
PSI-4-SF 
Pharmacokinetic(s) 
Parenting Stress Index – Short Form 
QD 
Once a Day 
R-MOAS 
Retrospective Modified Overt Aggression Scale 
SAE 
Serious Adverse Event 


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SAP 
Statistical Analysis Plan 
SM 
Study Medication 
SNAP-IV 
Swanson, Nolan and Pelham Rating Scale - Revised 
TDD 
Total Daily Dose 
ULN 
Upper Limit of Normal 
V/F 
Apparent Volume of Distribution 
 
 


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1 INTRODUCTION 
1.1 Background 
Behavior with the immediate intent to cause harm – whether to self, others, objects, or property – 
constitutes aggression. Aggressive 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 (Connor 2006; Jensen 2007). Maladaptive aggression is an expression of central nervous 
system dysfunction and may therefore be amenable to treatments targeting its neurobiologic substrate.  
Aggression can be categorized into two broad subtypes based on the aggressor’s motivation – 1) 
reactive or impulsive and 2) proactive or instrumental (Vitiello 1997). Impulsive aggression (IA) is angry, 
retaliatory aggression arising out of frustration, annoyance, or hostility to real or perceived provocations 
– stressors that youth of the same age typically experience with equanimity. IA is therefore an 
unplanned and immediate response reflecting out-of-control emotionality that satisfies immediate 
emotional pressures, albeit with negative consequences to the aggressor. In contrast, instrumental 
aggression is consciously planned, goal-oriented behavior with the specific intent of benefiting the 
aggressor (Jensen 2007).   
IA is commonly associated with attention-deficit/hyperactivity disorder (ADHD) and is often refractory to 
primary ADHD therapy. In the Multimodal Treatment of Children with ADHD (MTA) study (MTA 1999), 
54% of preadolescent study participants with ADHD Combined subtype displayed clinically significant 
aggression at baseline. Of these, 44% remained significantly symptomatic in terms of aggressive 
behavior after 14 months of optimal medication (stimulants) with/without behavioral therapy (Jensen 
2007).  
IA amplifies the psychological, academic, emotional, and social problems associated with ADHD (Shelton 
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. Early-onset, pervasive and unremitting IA in the context 
of 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 2001). In the context 
of ADHD it represents a serious clinical and public health concern and warrants effective and timely 
intervention. 
Since primary ADHD therapy has limited effect on IA, a stepped-care approach has been recommended, 
with aggression-targeted therapy such as an antipsychotic added to ADHD therapy to manage residual 
aggressive behaviors (Scotto Rosato 2012). Risperidone and other “atypical” antipsychotics have 
historically been at the forefront of treatment recommendations regarding combination therapy for 
managing aggression associated with ADHD in children (Pappadopulos et al. 2003; Pliszka et al. 2006; 
Pliszka et al. 2007). However, only two double-blind randomized placebo-controlled trials of risperidone 
as adjunctive therapy in children with ADHD and aggression refractory to stimulants have been 
published – 1) a pilot study in 25 children that was likely underpowered and did not detect a significant 
treatment effect (Armenteros 2007; Aman 2014) and 2) the recently completed TOSCA (Treatment of 


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Severe Childhood Aggression) study (Farmer et al. 2011; Aman 2014; Gadow 2014). The effect size for 
risperidone’s effect on IA was small (0.29), even though the dosage could be adjusted to optimal effect. 
The TOSCA study provides initial empirical evidence supporting a stepped-care approach in which ADHD 
children with severe aggression are initially treated with primary ADHD therapy followed by adjunctive 
antipsychotic therapy targeted to IA.  However, the long-term effects of risperidone and similar 
antipsychotics in terms of metabolic derangements predictive of diabetes and cardiovascular disease, 
have become cause for considerable concern, especially in the face of very limited evidence of efficacy 
as aggression-targeted therapy in ADHD.  The TOSCA study confirmed that stimulant co-therapy does 
not attenuate the adverse effects of risperidone or similar agents on body composition, metabolic 
parameters, prolactin, or sedation (Calarge 2009; Penzner 2009). 
Molindone hydrochloride (molindone) is a medium potency antipsychotic, and is currently under 
development by the Sponsor as an extended-release formulation (SPN-810), for its potential utility in 
treating IA in children with ADHD.  
In an open-label study, molindone improved aggressive behavior in children (N=6, 6-11 years of age) 
with undersocialized conduct disorder, aggressive type (Greenhill 1981).  The optimum dose was 0.5 
mg/kg/day.  Molindone was also shown to be effective in treating aggressive behavior in a double-blind, 
8-week, inpatient study of 31 children, ages 6 to 11, with undersocialized conduct disorder, aggressive 
type (Greenhill 1985).  
Prior to its withdrawal from the US market for commercial reasons, Immediate-Release Molindone 
(Moban®) was approved for the treatment of schizophrenia in adults and adolescents. Its use was also 
evaluated in a pediatric population with early-onset schizophrenia and schizoaffective disorder when it 
was selected as the first-generation antipsychotic on the basis of its more favorable safety profile for 
comparison with second-generation agents (risperidone, olanzapine) in an NIH-sponsored study (TEOSS, 
Treatment of Early-Onset Schizophrenia Spectrum Disorders Study) (McClellan 2007). At an average 
dose of 60 mg/day (range, 10-140 mg/day), molindone was shown to be safe and well-tolerated (Sikich 
2008). Molindone (10-140 mg/day) was not associated with significant increases in weight/BMI (in 
contrast to olanzapine). Molindone was also not associated with more dystonic or parkinsonian 
symptoms when given with benztropine, although akathisia was reported by more molindone-treated 
subjects. Results of randomized controlled trials such as TEOSS stimulated interest in the potential 
usefulness of molindone as a weight- and metabolically-neutral D2-receptor antagonist in children with 
ADHD and associated with IA. 
1.2 Sponsor’s Phase 2a Study 
Study 810P201, was a proof-of-concept, multicenter, open-label, parallel-group, randomized, dose-
ranging, safety, and tolerability study of molindone administered as experimental Molindone Immediate 
Release (IR) capsules in children with ADHD and persistent serious conduct problems (Stocks 2012). 
Target subjects were healthy male or female children aged 6 to 12 years, inclusive, 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 


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and persistent serious conduct problems (<30 kg: 
day; ≥30 kg
 
mg/day). 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). 
 
 
 
1.3 Sponsor’s Phase 2b Study 
Sponsor completed a Phase 2b multicenter, randomized, double-blind, placebo-controlled trial in the 
United States in pediatric subjects 6 to 12 years of age diagnosed with ADHD and IA that was not 
controlled by optimal stimulant and behavioral therapy (Sponsor Study 810P202).  The primary objective 
of the study was to assess the effect of an extended-release 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 were offered the opportunity to continue into an open-label 
phase of six months duration.   
SPN-810 dose within treatment groups was stratified by weight (below/above 20 kg).  Both the medium 
(24/36 mg) and low (12/18 mg) dose groups showed statistically significant difference from the placebo 
group in the change from baseline to Visit 10 in R-MOAS but the high (36/54 mg) dose group was not 
significantly different from the placebo group. Furthermore, both the low dose and medium dose groups 
were significantly different from the high dose based on pair-wise comparison among the dose groups.  
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4 Impulsive Aggression Diary (IA Diary)  
Sponsor has developed and validated a new measurement tool to assess behaviors associated with IA. 
The impulsive aggression diary (IA diary) is an electronic observer-reported outcome (eObsRO) 
instrument that comprises 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 IA diary monitors the frequency of occurrence of 15 IA 
behaviors: Yelling, Screaming, Threatening, Scratching, Throwing, Slamming, Hitting Self, Arguing, 
Cursing, Name Calling, Shoving, Hair Pulling, Fighting, Hitting Others, Kicking Others.  The development 
process followed FDA’s “Guidance for Industry Patient-Reported Outcome Measures: Use in Medical 
Product Development to Support Labeling Claims.”  Through this process, the IA diary was demonstrated 
to be a psychometrically valid and reliable tool to assess IA in children (Sponsor Study 810P501).   
1.5 Study Rationale 
The results of the Phase 2b study indicated that doses ranging from 
 were safe, effective 
and well tolerated.  This Phase 3 study seeks to demonstrate the efficacy, safety, and tolerability of SPN-
810 in the treatment of IA in patients with ADHD in conjunction with standard ADHD treatment. Study 
medication (SM) will be given as a divided dose twice daily (BID) with food.  A randomized, placebo-
controlled, double blind, multicenter, parallel group, fixed dose study design will be used. Frequency of 
IA behaviors will serve as a proxy for IA severity.  The IA diary will be used to assess the frequency of IA 
behaviors.  The IA diary was developed and validated for use as a contemporaneous, event-driven, 
observer-reported outcome measure.  It monitors behaviors that have been specifically linked to IA.  It 
does not rely on long periods of recall or subjective weighting of behaviors.  For these reasons, the IA 
diary is uniquely suited to detect changes in the frequency IA behaviors, which in turn is indicative of the 
severity of IA.    
Additionally, IA severity and improvement will be assessed using Clinical Global Impression (CGI) scales 
completed by both investigator and caregiver.  Subject and caregiver quality of life will also be 
evaluated.   
The effect of molindone on body composition, metabolic parameters, and prolactin will be evaluated.  
Emergence of extrapyramidal symptoms will be monitored. 
2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective is to assess the efficacy and safety of SPN-810 in reducing the frequency of IA 
behaviors in pediatric patients with ADHD when taken in conjunction with standard ADHD treatment. 


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2.2 Secondary Objectives 
The key secondary objective of the study is to assess the effect of SPN-810 on the Clinical Global 
Impression – Severity Scale (CGI-S).  
Additional secondary objectives are to assess the following:  
 
the effect of SPN-810 on the Clinical Global Impression – Improvement Scale (CGI-I)  
 
the effect of SPN-810 on the child’s overall health as measured by the Child Health 
Questionnaire Parent Form 28-item (CHQ-PF28) 
 
the effect of treating the child with SPN-810 on the parent-child relationship as measured by the 
Parenting Stress Index – Short Form version 4 (PSI-4-SF)  
 
the effect of SPN-810 on the caregiver-completed CGI-I 
 
the effect of SPN-810 on inattention and hyperactivity-impulsivity measured by the SNAP-IV 
Rating Scale 
 
the effect of SPN-810 on the responder rate (defined as ≥ 50% in the reduction of the frequency 
of IA behaviors) 
 
the effect of SPN-810 on the responder rate (defined as ≥ 30 %in the reduction of the frequency 
of IA behaviors) 
2.3 Tertiary Objective 
 
 
 
3 INVESTIGATIONAL PLAN 
3.1 Rationale for Study Design, Including Choice of Treatment Groups, 
Appropriateness of Measurements 
The present study is designed to evaluate the efficacy, safety, and tolerability of SPN-810 in patients 
aged 6 to 12 years with ADHD associated with IA, when taken in conjunction with a standard ADHD 
treatment.  In this patient population, IA behaviors persist, despite monotherapy treatment with an 
FDA-approved ADHD medication, stimulant or non-stimulant, at an FDA-approved optimized dose. 
A titration schedule will be followed to ensure a safe escalation to each dose level.   The titration rate 
and dose range under investigation in the present study were demonstrated to be safe, efficacious, and 
well tolerated in a similar patient population in the previous Phase 2b study.  Administration of study 
medication will be recorded using an electronic dosing diary. 
The IA diary will serve as the primary assessment tool for efficacy.  The IA diary is a new electronic 
observer-reported outcome (eObsRO) instrument developed by the Sponsor to record  behaviors 
associated with IA.  Secondary measures of efficacy will include the effect of SPN-810 on the Clinical 
Global Impression – Improvement Scale (CGI-I), the effect of SPN-810 on the Clinical Global Impression – 


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Severity Scale (CGI-S), the effect of SPN-810 on the child’s overall health as measured by the Child 
Health Questionnaire Parent Form 28-item (CHQ-PF28), and the effect of treating the child with SPN-810 
on the parent-child relationship as measured by the Parenting Stress Index – Short Form (PSI-4-SF).  The 
child’s ADHD symptoms will be measured using the Swanson, Nolan and Pelham Rating Scale - Revised 
(SNAP-IV). 
Safety will be assessed by the monitoring of AEs, concomitant medications, vital signs, clinical laboratory 
tests, physical examinations, and ECGs, as well as by the Simpson-Angus Scale, the Barnes Akathisia 
Scale, and the Abnormal Involuntary Movement Scale (AIMS).  The scales were chosen to specifically 
monitor EPS, since youth treated with antipsychotics are at greater risk for EPS side effects than adults 
(Findling 2005).  These scales were utilized in Phase 2 studies and have been used in other clinical 
studies of atypical antipsychotics in children. 
3.2 Overall Study Design and Plan 
Protocol 810P301 is a randomized, placebo-controlled, double blind, multicenter, parallel group, fixed 
dose study to demonstrate the efficacy, safety, and tolerability of SPN-810 in the treatment of IA in 
patients aged 6-12 years with ADHD in conjunction with standard ADHD treatment.   The study is 
presented schematically in Figure 1 and Figure 2.  The study is divided into three phases: Pre-Treatment, 
Treatment, and Conversion/Taper. 
Following screening, eligible subjects will enter a flexible baseline period, at which time the IA diary will 
be issued to the subject’s primary caregiver.  At the end of the baseline period, per the original plan, 
eligible subjects whose primary caregiver has maintained at least 80% compliance with the IA diary will 
be randomized to 1:1:1 to 18 mg/day SPN-810, 36 mg/day SPN-810, or placebo. However, based on the 
810P301 study Interim Analysis result decision, the 18 mg arm was dropped partway through the study. 
As a result, subjects planned to be randomized to the 18 mg arm will be re-allocated to the 36 mg or 
placebo arm in a ratio of 2:1.  A dose titration schedule will be followed, with dosing in the active 
treatment groups initiated at 3 mg/day and increased approximately every 3 days until the target dose is 
reached.   After completing the two-week titration period and the three-week maintenance period, 
subjects will enter the conversion or tapering phase prior to discontinuing SM, at which time subjects 
will have the option to enter an open label extension (OLE) study.  A subject who discontinues during 
the maintenance period prior to Visit 6 may be allowed to participate in the OLE on a case-by-case basis 
only after consultation between the Investigator, the Medical Monitor and the Sponsor. The OLE study 
will be conducted under a separate protocol.  Subjects who choose to participate in the OLE will enter 
that study at a dose of 18 mg/day SPN-810. 
3.2.1 
Pre-Treatment Phase 
3.2.1.1 
Screening Period 
Screening will take place for up to 45 days prior to randomization and may be carried out over more 
than one visit if necessary.  Prior to conducting any screening procedures, written informed 
consent/assent must be obtained from the parent or legal representative, and subject (when required). 
Each screened subject will be assigned a subject number starting from 2001 to 2999 in a sequential 


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manner. Staff at study sites are encouraged to complete screening procedures as early as possible to 
provide more flexibility in the baseline period for the caregivers to achieve IA diary compliance (see 
Section 3.2.1.2). 
The R-MOAS and CGI-S will be administered to determine entry to the baseline period of the study and 
also to determine eligibility for randomization to treatment.  The Vitiello Aggression Scale will be used to 
evaluate subtype of aggression (planned vs. impulsive); only those children who score as predominantly 
impulsive will be included. The diagnosis of ADHD will be confirmed with the Schedule for Affective 
Disorders and Schizophrenia for School-aged Children—Present and Lifetime Versions 2013 (K-SADS-PL 
2013). The K-SADS-PL 2013 is a semi-structured diagnostic interview designed to diagnose current and 
past episodes of psychopathology in children and adolescents according to DSM-5 criteria.   The 
Introductory and Screen Interviews will be completed.  The Screen Interview will assess the different 
diagnoses and determine which supplements should be completed.  Supplement 4 (Neurodevelopment, 
Disruptive and Conduct Disorders) must be completed to assess ADHD, ODD, CD, Tic and ASD (Autism 
Spectrum Disorder).  If an exclusionary diagnosis is confirmed, the remainder of the diagnostic will not 
be completed and the subject will be deemed a screen failure.   
3.2.1.2 
Baseline Period 
Subjects who meet study entry requirements will proceed to the flexible 15-day baseline period.  At Visit 
2, an IA diary device (LogPad) will be issued to the primary caregiver.  The primary and (if assigned) 
secondary caregivers will receive training on the use of the IA diary. Every effort will be made to provide 
adequate caregiver training on the use of the IA diary at Visit 2 and acknowledgement of training will be 
captured on the device.   
Following at least 15 days of IA diary use, caregiver compliance with the IA diary will be assessed. 
Compliance will be calculated as the percentage of days over the past 15 days during the baseline period 
for which an evening diary was completed.    Subjects whose caregivers demonstrate at least 80% 
compliance will be eligible for randomization and continue into the titration period. 
Subjects whose caregivers do not reach 80% compliance during the first 15 days of the baseline period 
may be allowed to continue to use the diary for up to 15 additional days.  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”.  
When the caregivers’ performance with the IA diary improves such that the caregivers are able to 
demonstrate at least 80% compliance over the past 15-day rolling window, the subject will be eligible 
for randomization and allowed to continue into the titration period.  
Although there are up to 30 days available for each of the screening and the baseline period, the total 
duration of screening and baseline periods may not exceed 45 days. 
Rescreening 
As a general rule, rescreening of subjects is not allowed.  The only exception to this will be for subjects 
who failed screening due to caregiver non-compliance with the IA diary under protocol version 3.0. 


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These subjects may be rescreened to participate in the study under current protocol. These subjects will 
be assigned a new subject ID number and will complete all study screening procedures. 
3.2.2 
Treatment Phase 
3.2.2.1 
Randomization 
Inclusion/exclusion criteria will be re-assessed to verify eligibility prior to study randomization at the end 
of Visit 3 (Randomization).  Eligible subjects whose primary caregiver has maintained at least 80% 
compliance with the IA diary will be randomized.  Per the original randomization eligible subjects who 
complete the baseline period and meet the requirements for the double blind study will be randomized 
at Visit 3 (Day 1) in a 1:1:1 ratio to receive 18 mg/day, 36 mg/day SPN-810 or placebo and proceed to 
the titration period, which will be two weeks.  However, based on the 810P301 study Interim Analysis 
result decision, the 18 mg arm was dropped partway through the study. As a result, subjects planned to 
be randomized to the 18 mg arm will be re-allocated to the 36 mg or placebo arm in a ratio of 2:1. 
3.2.2.2 
Titration Period 
Subjects will be titrated to maintenance dose over a period of 2 weeks. 
3.2.2.3 
Maintenance Period 
Following dose titration, subjects on active treatment will be maintained at their designated dose level 
for 3 weeks.   
3.2.3 
Conversion/Taper Phase 
All subjects who complete the randomized, double blind portion of study 810P302 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 blinded conversion medication kits, and their 
total daily dose for the open label extension will be converted to 18 mg/day (Figure 1).  Those subjects 
who do not elect to participate in this extension will be tapered off SM (Figure 2).   
The 18 mg line in the 2 figures below will not be applicable to subjects re-randomized following the 
810P301 interim analysis decision to drop the 18 mg dose. 
3.2.4 
End of Study / Early Termination 
Subjects will return to the study site for a final visit, after completing the 1-week Taper/Conversion 
Period.  Those subjects who elect to continue in the OLE study will have procedures performed for that 
study as well.  Subject who discontinues from the study during the maintenance period will be offered a 
Taper kit and will return to the study site for a follow-up visit (EOS).  Subjects who discontinue during 
the titration period will not receive a taper kit and will only complete the EOS procedures.   






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4 STUDY METHODS 
4.1 Selection of Study Population 
The target population will be male and female subjects aged 6 to 12 years with IA and ADHD.  SM will be 
administered in conjunction with the subject’s standard ADHD treatment.  Approximately 306 subjects 
will be randomized in this clinical investigation.   
4.1.1 
Inclusion Criteria 
1. Healthy male or female subjects, age 6 to 12 years at the time of screening.  
2. Diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders- 5  
(DSM-5 confirmed by the Schedule for Affective Disorders and Schizophrenia for School-aged 
Children – Present and Lifetime Version 2013 (K-SADS-PL 2013).  
3. Retrospective Modified Overt Aggression Scale (R-MOAS) score of 24 at screening. 
4. CGI-S score of at least moderately ill at both Screening and Randomization.  
5. Vitiello Aggression Scale score from -2 to -5 at Screening. 
6. Free of antipsychotic medication for at least two weeks prior to Visit 2.  
7. Monotherapy treatment with FDA-approved optimized ADHD medication (psychostimulant or 
non-stimulant) at an FDA-approved dose for at least one month prior to Screening, and willing 
to maintain that dose throughout the Baseline and Treatment period. 
8. α 2- adrenergic agonists (e.g. clonidine and guanfacine) used for any other reason except for 
monotherapy treatment for ADHD (e.g. aggression or insomnia) must be discontinued at least 
two-weeks prior to Visit 2. 
9. Medically healthy and with clinically normal laboratory profiles, vital signs, and 
electrocardiograms (ECGs). 
10. Weight of at least 20 kg. 
11. Able and willing to swallow tablets whole and not chewed, cut or crushed.  
12. Written Informed Consent obtained from the subject’s parent or legal representative, and 
written Informed Assent obtained from the subject if appropriate. 
13. Measurement of compliance ≥ 80% for completion of IA Diary during Baseline Period. 
4.1.2 
Exclusion Criteria 
1. Body Mass Index (BMI) in 99th percentile or above. 
2. Current or lifetime diagnosis of epilepsy, major depressive disorder, bipolar disorder, 
schizophrenia or related disorder, personality disorder, Tourette’s disorder, or psychosis not 
otherwise specified. 
3. Currently meeting DSM-5 criteria for autism spectrum disorder, pervasive developmental 
disorder, obsessive compulsive disorder, post-traumatic stress disorder, or any other anxiety 
disorder as primary diagnosis. 
4. Use of anticonvulsants including carbamazepine and valproic acid, antidepressants, mood 
stabilizers including lithium, benzodiazepines, cholinesterase inhibitors or any drug known to 
inhibit CYP2D6 activity within two weeks of Visit 2.  


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5. Use of herbal supplements within one week of Visit 2. 
6. Known or suspected intelligence quotient (IQ) < 70. 
7. Unstable endocrinological or neurological conditions which confound the diagnosis or are a 
contraindication to treatment with antipsychotics. 
8. Suicidality, defined as either active suicidal plan/intent or active suicidal thoughts in the six 
months before the Screening Visit or more than one lifetime suicide attempt.   
9. Pregnancy or refusal to practice contraception during the study (for female subjects of 
childbearing potential). 
10. Substance or alcohol use during the last three months. 
11. Urine drug test at screening that is positive for alcohol or drugs of abuse. 
12. Known allergy or sensitivity to molindone hydrochloride. 
13. Any reason which, in the opinion of the Investigator or the Sponsor, would prevent the subject 
and subject’s 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 to 
Visit 2. 
4.2 Schedule of Visits and Procedures 
All subjects who are randomized and take any SM will be followed according to the protocol regardless 
of the number of doses of SM taken, unless consent for follow-up is withdrawn.  The Sponsor, or the 
Sponsor’s designee, must be notified of all deviations from the protocol visits or procedures, and these 
procedures, if applicable, will be rescheduled or performed at the nearest possible time to the original 
schedule.  Subjects will be instructed to call study personnel to report any abnormalities during the 
intervals in between study visits and to come to the study site if medical evaluation is needed and as the 
urgency of the situation indicates.  Unscheduled visits may be conducted at the discretion of the 
investigator throughout all study periods. The medical monitor must be contacted promptly in the event 
that any clinically significant findings or information are obtained during the unscheduled visit. This 
should be captured in the appropriate eCRF. 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. 
Table 1 presents the schedule of visits and procedures for the study. 


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Table 1:  Schedule of Visits and Procedures 
Phase 
Pre-treatment 
Treatment 
Conversion/ 
Taper 
Period 
Screening 
Baseline 
Titration 
Maintenance 
VISIT NUMBER 
1 
2 
3 
4 
5 
6 
7 
DAY 
-45 
-15 
1 
8 
15 
36 
43 
WINDOW (DAYS) 
45d prior to 
Visit 3 
≥15d prior to 
 Visit 3 
Oc 
7d±2d from 
Visit 3 
14d±2d from 
Visit 3 
21d±3d from  
Visit 5 
7d±1d from  
Visit 6 
Informed Consent/Assent a 
X b 
 
 
 
 
 
 
R-MOAS, K-SADS-PL 2013 & Vitiello Aggression 
Scale 
X 
 
 
 
 
 
 
Medical History 
X 
 
X d 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Physical Examination  
X 
 
 
 
 
X 
 
ECG (12-lead) 
X 
 
 
X 
 
X 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Randomization 
 
 
X b,e 
 
 
 
 
Urine Drug Screen 
X 
 
X 
 
 
 
 
Urine Pregnancy Test f 
X 
 
X 
 
 
 
X 
Diary Training & Distribution or Evaluation 
 
X 
X e 
X 
X 
X 
 
Vital Signsg 
X 
 
 
 
 
 
X 
Weight, height, BMI 
X 
 
X 
X 
X 
X 
X 
Hematology/chemistry/Urinalysis 
X 
 
X 
 
 
X 
X 
PK Blood Sampling 
 
 
 
X h 
X h 
 
 
Columbia Suicide Severity Rating Scale (CSSRS) 
X 
 
X 
X 
X 
X 
X 
Investigator CGI-S 
X 
 
X 
X 
X 
X 
 
Caregiver and investigator CGI-I 
 
 
 
X 
X 
X 
 
Efficacy scales (SNAP-IV, CHQ-PF28, PSI-4-SF) 
 
 
X 
 
 
X 
 
Safety Scales (Simpson-Angus, Barnes, AIMS) 
 
 
X 
X 
X 
X 
X 
Infrequent Behaviors Checklist 
 
 
X 
X 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Drug Dispensation 
 
 
X b 
 
X 
X 
 


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Phase 
Pre-treatment 
Treatment 
Conversion/ 
Taper 
Period 
Screening 
Baseline 
Titration 
Maintenance 
VISIT NUMBER 
1 
2 
3 
4 
5 
6 
7 
DAY 
-45 
-15 
1 
8 
15 
36 
43 
WINDOW (DAYS) 
45d prior to 
Visit 3 
≥15d prior to 
 Visit 3 
Oc 
7d±2d from 
Visit 3 
14d±2d from 
Visit 3 
21d±3d from  
Visit 5 
7d±1d from  
Visit 6 
Drug Return and Compliance 
 
 
 
 
X 
X 
X 
Diary Return 
 
 
 
 
 
 
X 
a 
Written consent must be obtained prior to performing any study-related procedure. 
b 
Access IWRS. 
c 
Visit 3 will occur at least 15 days following Visit 2 
d 
Assess for any clinically significant change in Medical History since screening 
e 
Diary compliance must be at least 80% (minimum of 12 days out of 15) to qualify for randomization   
 
f 
To be performed for female subjects of childbearing potential prior to administration of first dose 
        of SM and will have to be tested as negative for the subject to continue in the study. 
g 
Heart rate (HR), blood pressure, temperature, and respiratory rate will be measured.  
h 
Total of 5 PK blood samples will be obtained over one or two visits (Visit 4 and/or Visit 5). 
 
 


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for the purpose of reviewing or performing this study. 
4.2.1 
Visit 1 
Prior to conducting any screening procedures, written Informed Consent must be obtained from the 
parent or legal representative, and, if appropriate, Informed Assent from the subject.  Subject screening 
procedures will be performed within 45 days prior to 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 Visit 1: 
1. Obtain written informed consent and assent. 
2. Obtain demographic information, medical history 
3. Access Interactive Web Response System (IWRS) for subject number 
4. Administer K-SADS-PL 2013 for confirmation of ADHD diagnosis 
5. Administer Vitiello Aggression Scale 
6. Administer R-MOAS 
7. Administer Investigator CGI-S 
8. Perform physical examination 
9. Record vital signs (HR, BP, temperature, and RR), height, weight and BMI 
10. Perform 12-lead ECG 
11. Collect blood samples for hematology and chemistry 
12. Administer C-SSRS 
13. Collect urine sample for urinalysis and urine drug screen (all subjects), and pregnancy test 
(FOCBP only) 
14. Assess and record concomitant medications 
15. Assess inclusion/exclusion criteria 
4.2.2 
Visit 2 
Visit 2 will occur at least 15 days prior to Visit 3.  Please note that, per protocol and within the EDC, Visit 
1 and Visit 2 may occur on the same day. 
1. Provide training for IA diary and dosing diary module 
2. Distribute device  
3. Assess and record concomitant medications 
4.2.3 
Visit 3 
Visit 3 will occur at least 15 days following Visit 2 according to the Schedule of Visits and Procedures. 
1. Administer efficacy scales (SNAP-IV, CHQ-PF28, PSI-4-SF) 
2. Assess IA diary compliance / review training as necessary 
3. Confirm eligibility to randomize to study medication treatment 
4. Randomize subject via IWRS 
5. Administer Investigator CGI-S 
6. Administer Infrequent Behaviors Checklist 
7. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 


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8. Record height, weight, and BMI 
9. Collect blood samples for hematology/chemistry 
10. Collect urine samples for urinalysis, urine drug screen (all subjects), and pregnancy test (FOCBP 
only) 
11. Administer C-SSRS 
12. Record concomitant medication 
13. Assess for any clinically significant change in Medical History 
14. Dispense SM via IWRS.   
15. Review training on dosing diary module 
16. Assess adverse events (post-dose) 
4.2.4 
Visit 4 
Visit 4 will occur 7 (±2) days following Visit 3 according to the Schedule of Visits and Procedures. 
1. Administer Investigator CGI-S 
2. Administer caregiver and investigator-completed CGI-I 
3. Administer Infrequent Behaviors Checklist 
4. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
5. Record height, weight, and BMI 
6. Perform 12-lead ECG 
7. Collect blood samples for PK analysis 
8. Administer C-SSRS 
9. Record concomitant medication 
10. Review IA diary compliance and provide training as required 
11. Collect AEs 
12. Review dosing diary compliance and provide training as required 
4.2.5 
Visit 5 
Visit 5 will occur 14 (±2) days following Visit 3 according to the Schedule of Visits and Procedures. 
1. Administer Investigator CGI-S 
2. Administer caregiver and investigator-completed CGI-I 
3. Administer Infrequent Behaviors Checklist 
4. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
5. Record height, weight, and BMI 
6. Collect blood samples for PK analysis 
7. Administer C-SSRS 
8. Record concomitant medication 
9. Review IA diary compliance and provide training as required 
10. Collect AEs 
11. Collect returned SM; assess treatment compliance 
12. Review dosing diary compliance and provide training as required  
13. Dispense SM 


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4.2.6 
Visit 6 
Visit 6 will occur 21 (±3) days following Visit 5 according to the Schedule of Visits and Procedures.   
1. Administer efficacy scales (Investigator CGI-S, caregiver and investigator CGI-I, SNAP-IV, CHQ-
PF28, PSI-4-SF) 
2. Administer Infrequent Behaviors Checklist 
3. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
4. Record height, weight, and BMI 
5. Perform 12-lead ECG 
6. Perform physical examination 
7. Collect blood samples for hematology/chemistry 
8. Collect urine sample for urinalysis 
9. Administer C-SSRS 
10. Record concomitant medication 
11. Review IA diary compliance and provide training as required 
12. Collect AEs 
13. Collect returned SM; assess treatment compliance 
14. Review dosing diary compliance and provide training as required  
15. Determine whether subject wishes to participate in open-label extension  
16. Dispense SM (either Conversion or Taper based upon subject’s decision about participation in 
open-label extension) 
4.2.7 
Visit 7 
Visit 7 will occur 7 (±1) days following Visit 6 according to the Schedule of Visits and Procedures.  These 
procedures will also be performed for patients who discontinue early.  Patients who discontinue early 
after Visit 5 will be offered a taper kit. 
1. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
2. Record vital signs (HR, BP, temperature, and RR), height, weight and BMI 
3. Collect urine sample for pregnancy test (FOCBP only) 
4. Administer C-SSRS 
5. Record concomitant medication 
6. Collect AEs 
7. Collect SM and assess treatment compliance 
8. Collect device 
9. Complete/discontinue subject 
10. Collect blood samples for hematology/chemistry 
11. Collect urine sample for urinalysis 
4.2.8 
Pharmacokinetic Sample Collection 
All blood samples for PK analysis will be drawn at the clinical site.  A total of 5 blood samples (4 mL each) 
will be taken for PK analysis over the course of the study.  These will include pre- and post-dose samples 
obtained over one visit (Visit 4 or Visit 5) or can be obtained over two visits (Visit 4 and Visit 5).   


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If the subject decides to complete the PK sampling over one visit then he/she will arrive at the clinic in 
the morning prior to taking the morning dose.  A PK sample will be drawn pre-dose; then the dose will 
be observed in the clinic.  Post-dose PK samples will be taken at approximately 1 hour, 2 hours, 4 hours 
and 6 hours after the time of the observed dose.  PK samples should be obtained within 15 minutes of 
the 1 hour and 2 hour timepoints and within 30 minutes of the 4 hour and 6 hour timepoints.  
If the subject decides to come for the PK sampling over two visits, then on one visit the subject will 
arrive at the clinic in the morning, prior to taking their morning dose. A PK sample will be drawn pre-
dose; then the dose will be observed in the clinic.  Post-dose PK samples will be taken at approximately 
1 hour and 2 hours after the time of the observed dose. PK samples should be obtained within 15 
minutes of the targeted timepoints. At the other visit, subjects will arrive at the clinic after taking their 
morning dose.  PK samples will be taken at approximately 4 hours and 6 hours after the time that the 
morning dose was taken.  PK samples should be obtained within 30 minutes of the targeted timepoints. 
Blood samples will be collected and processed as per instructions in the Laboratory Manual. 
4.3 Treatments 
4.3.1 
Treatments Administered 
Subjects will take molindone hydrochloride extended-release tablet (SPN-810) or placebo twice each 
day (BID) with food, in the morning and in the evening, in addition to the stable dose of the optimized 
ADHD medication determined from the lead-in period.  If initiating treatment before noon, patients 
should start with the morning dose; if after noon, the evening dose. 
Subjects will be randomized to one of three treatments at Visit 3.  Subjects will be titrated up to the final 
randomized total daily dose (TDD).   
 
Reference treatment 
o Treatment 1: Placebo tablets, PO, BID 
 
Test treatments  
o Treatment 2: Molindone extended-release tablets, 18 mg TDD, PO, BID 
o Treatment 3: Molindone extended-release tablets, 36 mg TDD, PO, BID 
Based on the 810P301 study Interim Analysis result decision, the 18 mg dose arm was dropped 
partway through the study.    
4.3.2 
Identity of Investigational Product(s) 
Test 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 6 (six) to 8 (eight) days of dosing as well as some extras for lost product 
and/or to account for visit delays associated with patient/site schedules.  The SM blister card types 


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include: Titration (two blister cards), Maintenance (three blister cards), Taper (one blister card), and 
Conversion (one blister card).   
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.   
4.3.3 
Study Medication Handling and Accountability 
All SM will be supplied to the Investigator by the Sponsor.  SM supplies 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 randomized 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 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 service receipts.  All forms will be provided by the Sponsor.  Any comparable forms that the 
study site wishes to use must be approved by the Sponsor. 
The supplies and inventory records must be made available, upon request, for inspection by the 
designated representative of the Sponsor, a representative of the FDA, or a representative of a non-US 
health authority.  The assigned Clinical Research Associate (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. 
4.3.4 
Method of Assigning Subjects to Treatment Groups 
Allocation of study drug will be completed centrally through the use of an interactive web response 
system (IWRS) that will determine which kit to assign to the subject. The 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 list will be  created. The original 
randomization scheme assigns treatment to each randomization number in a 1:1:1. However, based on 




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which a subject is assigned. Randomization schedule data will be kept strictly confidential, filed securely 
by the IWRS vendor, and accessible only to authorized persons until the time of unblinding. 
The test tablets have matching placebo tablets.  The blind is maintained primarily through the IWRS.  
The blind will be maintained through the end of the Conversion/Taper period. 
The Investigator must try to avoid breaking the blind.  The decoding information will not be viewed 
unless an actual medical or medication safety emergency occurs.  The Investigator can access the 
subject’s randomized treatment information via IWRS only if knowledge of the treatment regimen will 
influence or assist with medical management of the subject in an acute emergency.  Before breaking the 
blind, every effort must be made to contact the Medical Monitor to ascertain the necessity of breaking 
the code.  If the Investigator is unsuccessful in contacting the Medical Monitor, he/she will contact the 
backup Medical Monitor (or other appropriate designee if the backup Medical Monitor is unavailable).  
If it is not possible to contact the Medical Monitor or the backup Medical Monitor (or designee), and the 
situation is an emergency, the Investigator may break the blind and contact the Medical Monitor as 
soon as possible.  The Investigator is to make a careful note of the date and time of decoding, the reason 
that necessitated breaking the code, and the signature of the person who broke the code.  Upon 
breaking the randomization code, the subject should be withdrawn from the study but should be 
followed up for safety purposes. 
4.4 Prohibited Medications: 
Subjects may not be on any prohibited medication while on study as indicated in the Inclusion/Exclusion 
Criteria. These medications include:  
 
α 2- adrenergic agonists (e.g. clonidine and guanfacine) used for any other reason except for 
monotherapy treatment for ADHD  
 
Anti-psychotics including aripiprazole,  risperidone, quetiapine, and ziprasidone  
 
Anticonvulsants including carbamazepine and valproic acid, antidepressants, mood stabilizers 
including lithium, benzodiazepines, cholinesterase inhibitors or any drug known to inhibit 
CYP2D6 activity 
 
Herbal supplements 
4.5 Concomitant Medication 
The dose of the ongoing ADHD medication will not be adjusted during the study, starting at Visit 1. No 
additional concomitant medications are allowed during the study, with the following exceptions: 
 
Chronic medication for conditions not related to ADHD or IA that are allowed by Investigator at 
Screening 
 
Nutritional supplements (e.g. multivitamins, fish oil) 
 
Emla or other numbing cream for PK venipuncture 
 
Benztropine is permitted for the treatment of emerging EPS at a starting dose of 0.5mg BID up 
to a range of 1 to 4mg/day.  Lorazepam (1 to 2 mg per dose not to exceed three times daily) and 


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clonazepam (0.25 to 1 mg per dose not to exceed twice daily) will also be permitted to treat 
emerging EPS.   
 
Common over-the-counter (OTC) therapies for minor transient ailments (e.g. acetaminophen for 
headache, ibuprofen for fever) will be allowed without exception. 
 
Treatment for AEs other than EPS or minor transient ailments is only permitted in consultation 
with the Medical Monitor.  
All concomitant medications will be recorded in the eCRF. 
4.6 Completion of Study and Discontinuation of Subjects  
Subjects will be considered to have completed the study if they complete all visits up to and including 
Visit 6.  All subjects who discontinue early will complete Visit 7.  Any subject who discontinues from the 
study after Visit 5 will be offered a Taper kit.  
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 with the Medical Monitor and/or CRA 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. 
5 ANALYSIS VARIABLES 
5.1 Primary Efficacy Variable 
The primary efficacy endpoint will be based on a checklist of 15 IA behaviors collected in an electronic IA 
diary.  The IA diary comprises two parts:  1) an episodic diary that will be used by the primary caregiver 
(or alternate) 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 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.   Each event will be characterized by a checklist of 15 observed 
behaviors:  Yelling, Screaming, Threatening, Scratching, Throwing, Slamming, Hitting Self, Arguing, 
Cursing, Name Calling, Shoving, Hair Pulling, Fighting, Hitting Others, Kicking Others.  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 


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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.   
5.2 Secondary Efficacy Variables 
The following efficacy scales will be administered at visits designated in the Schedule of Visits and 
Procedures (Table 1). 
5.2.1 
Clinical Global Impression (CGI) Scales 
The CGI scale was developed to provide a brief, stand-alone assessment of the clinician’s view of a 
subject’s global functioning prior to and after administration of a SM (Guy 1976).  Severity of illness (CGI-
S) and global improvement (CGI-I) are both rated on a scale of 1 to 7 with 7 being “extremely ill” or “very 
much worse”, respectively.  Successful therapy is indicated by a lower overall score in subsequent 
testing.  Investigators should consider their total clinical experience with children who have IA 
associated with ADHD and rate how severe the subject’s condition is at the time.  
 
CGI-S will be evaluated by the Investigator at each visit on a 7-point scale with 1=Normal,    
2=Borderline ill, 3=Mildly ill, 4=Moderately ill, 5=Markedly ill, 6=Severely ill, and 7=Extremely ill.    
 
CGI-I, relative to the condition at Baseline (Visit 1), will be evaluated by the caregiver and by the 
Investigator at each post-baseline visit on a 7-point scale with 1=Very much improved, 2=Much 
improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, and 7=Very 
much worse.   
CGI-S will be assessed by the Investigator at Visit 1, Visit 3, Visit 4, Visit 5 and Visit 6.  CGI-I will be 
assessed by the caregiver and the Investigator at Visit 4, Visit 5 and Visit 6.   
5.2.2 
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 at each visit when possible. 
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) 
 
ODD (items #19-26)   
 
ADHD-Combined subscale: the first two subscales are combined   
Each subscale score is the sum of the scores for the individual items included in the subscale. 
The SNAP-IV rating scale will be administered at Visit 3 and Visit 6. 


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for the purpose of reviewing or performing this study. 
5.2.3 
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 when possible.   
The CHQ-PF28 will be administered at Visit 3 and Visit 6. 
5.2.4 
Parenting Stress Index-Short Form (PSI-4-SF) 
Reduction in stress is considered important for parents of children with disruptive behavior problems, 
developmental disabilities, and chronic illness (Haskett 2006).  The Parenting Stress Index – Short Form 
(PSI-4-SF) is a 36-item self-report measure of parenting stress (Abidin 1995). Three subscales (Parental 
Distress, Parent-Child Dysfunctional Interaction, and Difficult Child) consist of 12 items each.  Parents 
use a 5-point scale to indicate the degree to which they agree with each statement.   
The PSI-4-SF will be administered at Visit 3 and Visit 6. 
5.3 Pharmacokinetic Measurements 
 
 
 
 
5.3.1 
Pharmacokinetic Variables 
The pharmacokinetic variables are: 
 
Apparent clearance (CL/F) of molindone in the pediatric population 
 
Apparent volume of distribution (V/F) of molindone in pediatric population 
 
Effect on molindone apparent clearance (CL/F) of co-administration of amphetamines, 
methylphenidate, clonidine, guanfacine and atomoxetine  
5.3.2 
Exploratory Pharmacokinetic Variables 
 
 
 
 
 
 
 
 
 


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5.4 Safety Assessments 
Safety assessments will consist of monitoring of and recording of all concomitant medications and AEs, 
clinical laboratory tests, measurement of vital signs and 12-lead ECGs, suicidality monitoring, and the 
performance of physical examinations at visits designated in the Schedule of Visits and Procedures 
(Table 1). 
Assessment of possible neurological side effects and EPS will be performed using the Simpson-Angus 
scale, the Barnes Akathisia scale and the AIMS.  A positive rating or finding on the safety scale will be 
captured as an AE at the discretion of the Investigator. 
5.4.1 
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. 
5.4.1.1 
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. 
5.4.1.2 
Recording and Evaluation of Adverse Events 
All subjects who are enrolled (starting at Visit 3) will be questioned regarding the occurrence of AEs.  At 
each contact with the subject, 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 adverse event module of the eCRF.  All clearly related 


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signs, symptoms, and abnormal diagnostic procedures results should be recorded in the source 
document, though they may be grouped under one diagnosis.  For example, fever, elevated WBC, cough, 
abnormal chest X-ray, etc., can 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.   
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? 
5.4.1.3 
Criteria for Assessing Severity 
The Investigator will evaluate the comments of the subject and the response to treatment in order that 
he or she may judge the true nature and severity of the AE.  Severity refers to the accumulated intensity 
of discomfort/impairment of health since the last recording of AEs and will be assessed according to the 
following criteria: 
 
Mild:  Awareness of sign, symptom, or event, but easily tolerated 
 
Moderate: Discomfort enough to interfere with usual activity and may warrant intervention 
 
Severe: Incapacitating with inability to do usual activities or significantly affects clinical status 
and warrants intervention 
The criteria for assessing severity are different from those used for seriousness. 
5.4.1.4 
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. 


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 
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). 
5.4.2 
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 
 
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. 
5.4.2.1 
Investigator Responsibilities for Reporting SAEs 
The Investigator must immediately report to the Sponsor all SAEs, regardless of whether the Investigator 
believes they are drug related. 
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, 


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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: 
 
 
 
 
5.4.2.2 
Other Events Requiring Immediate Reporting 
The Investigator must report a pregnancy that occurs in a subject during a clinical study to the Drug 
Safety Contact within 24 hours of first becoming aware of the event.  Pregnancy should be reported on a 
Pregnancy Report Form.  The Investigator should discuss the case with the 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. 
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 
 
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. 


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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. 
5.4.2.3 
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. 
5.4.3 
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. 
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. 
5.4.4 
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 


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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. 
A total of approximately 42 mL of blood per subject will be drawn during the study: 22 mL is for clinical 
laboratory tests and 20 mL is for PK sampling. 
Table 3: Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
RBC, WBC, Hgb, HCT, MCH, MCHC, MCV, platelet count, and WBC with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils, 
large unstained cells) 
Chemistry  
 
 
 
Electrolytes:  Na+, K+, chloride, bicarbonate 
Liver function tests:  alkaline phosphatase, AST, ALT, total bilirubin, direct 
bilirubin ,indirect bilirubin 
Renal function parameters: BUN, creatinine 
Other:  glucose, Ca+2, albumin, phosphorus, lactate dehydrogenase, total 
protein, CK/CPK, globulin, uric acid, triglycerides, insulin, prolactin, 
cholesterol – total, HDL and LDL 
Amylase, gammaGT (GGT), Iron, Lipase, Magnesium 
Urine 
Urinalysis 
Urine Drug Screen 
Urine pregnancy test (FOCBP only) 
 
5.4.5 
Vital Sign and Height/Weight Measurements 
Vital sign measurements (e.g., blood pressure, heart rate, temperature, and respiratory rate) and height, 
weight and BMI will be obtained at visits designated on the Schedule of Visits and Procedures (Table 1).  
Blood pressure and heart rate will be measured after the subject has been sitting for 5 minutes. Vital 
signs may be taken at any other time, as deemed necessary by the Investigator. 
5.4.6 
Medical History  
Medical history will be collected at visits designated on the Schedule of Visits and Procedures (Table 1).   
5.4.7 
Physical Examinations and Electrocardiograms (ECGs) 
A physical examination and a 12-lead ECG will be obtained at visits designated on the Schedule of Visits 
and Procedures (Table 1).  Additional ECGs may be performed at other times if deemed necessary by the 
Investigator. 


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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). 
5.4.8 
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).   
5.4.8.1 
K-SADS-PL 2013 Diagnostic Interview 
The K-SADS-PL 2013 is a semi-structured diagnostic interview designed to diagnose current and past 
episodes of psychopathology in children and adolescents according to DSM-5 criteria (Kaufman 1997). 
We will use a version of K-SADS 2013 that was revised to be compatible to the DSM-5 criteria.  It 
includes  the parent and child DSM-5 cross-cutting symptoms measures  (DSM-5 CC-SM); an 
unstructured Introductory Interview; the Diagnostic Screening Interview; the Supplement Completion 
Checklist; the Diagnostic Supplements and the Summary Lifetime Diagnostic Checklist.  The K-SADS-PL 
2013 will be used at screening to confirm the diagnosis of ADHD, as well as to rule out exclusionary 
diagnoses.  The Screen Interview will assess the different diagnoses and determine which supplements 
should be completed.  Supplement 4 (Neurodevelopment, Disruptive and Conduct Disorders ) must be 
completed to assess ADHD, ODD, CD Tic and ASD.  If an exclusionary diagnosis is confirmed, the 
remainder of the diagnostic will not be completed.  This assessment will be administered at Visit 1. 
5.4.8.2 
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. 
5.4.8.3 
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. 
5.4.8.4 
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.  


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5.4.8.5 
Vitiello Aggression Scale 
The Vitiello Aggression Scale 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. 
5.4.8.6 
Retrospective-Modified Overt Aggression Scale (R-MOAS) 
The Retrospective-Modified Overt Aggression Scale (R-MOAS) was developed to gauge the severity of 
aggressive behavior (Blader 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.  Numeric weighting amplifies the seriousness of 
more harmful behaviors in the total score.  This assessment will be administered at Visit 1. 
5.4.8.7 
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. 
The Since Last Visit version of the scale assesses any suicidal thoughts or behaviors the subjects may 
have had since the last administration of the C-SSRS.  This version will be used for the other study visits. 
5.4.8.8 
Infrequent Behaviors Checklist 
The infrequent behaviors checklist is a checklist of 15 behaviors that (along with the 15 IA Diary 
behaviors) were qualitatively linked to IA during the development of the IA diary.  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, severe injury animal.  
Caregivers will be asked which, if any, of these behaviors have been observed since the patient’s last 
visit.  This assessment will be administered at Visit 3, Visit 4, Visit 5, and Visit 6. 
6 STATISTICAL METHODS 
6.1 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). 


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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 the 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) for this protocol.  The statistical analysis plan will supersede the statistical analysis 
methods described in this clinical protocol. Any deviation from the statistical plan will be documented 
and described in the final report.  If changes to principal features stated in the protocol are required, 
these will be documented in a protocol amendment.  The final SAP will take into account any 
amendment to the protocol. 
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. 
6.2 Handling Missing Data 
For the primary efficacy endpoint, the frequency of IA behaviors during the Treatment period will be 
calculated over the number of days with non-missing IA diary data in the Treatment period. No explicit 
imputation of missing data will be used, but this approach is implicitly equivalent to using the frequency 
of IA behaviors during the days with non-missing IA diary data to impute the frequency for days after 
study discontinuation and days with missing IA diary data.   
6.3 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 randomized subjects who received at least 1 dose of study drug. 
Intent-to-Treat (ITT) Population:  will include all subjects who received at least 1 dose of study drug and 
have a 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 in the ITT population who completed the 
treatment period with 80% diary completion compliance and who did not have major protocol 
deviations. 
PK population:  will include all subjects in the safety population who had at least one PK sample drawn 
which had a quantifiable concentration for at least one analyte of interest. 
The safety, ITT, PP, and PK populations are based on randomized treatment received. 


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6.4 Demographic and Baseline Characteristics 
Demographic/baseline variables include age, sex, ethnicity, race, and height at screening, weight at 
screening and baseline, and medical history. Tabular summaries of the demographic/baseline variables 
will be presented for the safety, ITT, and PP populations, except for medical history, which will be 
summarized for the safety population only. 
6.5 Subject Disposition 
A disposition of subjects will include the number and percentage of subjects in each of the following 
categories: 
 
Subjects in the randomized population 
 
Subjects in the ITT population 
 
Subjects treated (safety population) 
 
Subjects in the PP study population 
 
Within each of the previous categories, the number and percentage of subjects who completed and 
discontinued from the study will be summarized. The reasons for study discontinuation will also be 
summarized. The reason for discontinuation may include any of the following: 
 
Subject withdrew consent 
 
Lost to follow-up 
 
Administrative reason 
 
Adverse event 
 
Investigator decision 
 
Failure to follow required study procedures 
 
Other 
Only one (primary) reason for study discontinuation will be recorded for each subject. 
6.6  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 
will 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 
 


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6.7 Study Medication Exposure and Compliance 
Duration of exposure is defined as the total number of days a subject is exposed to any 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 is defined as {(number of tablets dispensed – number of tablets 
returned) / 4*(date of last dose – date of first dose + 1)}* 100%.  
Each subject is expected to take 4 tablets per day. For each treatment, SM compliance will be summarized 
by compliance category (<80%, 80-120%, and >120%) and number of subjects in each compliance 
category.  Study medication compliance will also be summarized as a continuous variable using descriptive 
statistics (n, mean, standard deviation, median, minimum, and maximum) for each treatment.    
Summaries of treatment compliance and exposure will be presented separately for the Titration Period, 
Maintenance Period, and combined Titration and Maintenance Periods. 
6.8 Concomitant Medications 
Concomitant medications will be assigned an 11-digit code using the World Health Organization Drug 
Dictionary (WHO DD) drug codes.  Concomitant medications will be further coded to the appropriate 
Anatomical-Therapeutic-Chemical (ATC) code indicating therapeutic classification.  A tabular summary of 
concomitant medications by drug class will be presented for the safety population. 
6.9 Efficacy Analyses 
6.9.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is the percent change (PCHT) in the frequency (unweighted score) of IA 
behaviors per 7 days in the Treatment (Titration and Maintenance) period relative to the Baseline period 
calculated over the number of days with non-missing IA diary data.   The frequency of IA behaviors per 7 
days is the sum of scores for all events in a given period of sequential days, adjusted to 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 period 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. 
Per the adaptive design feature of protocol 810P301 that led to discontinuation of the 18 mg dose 
group, SPN-810 36 mg vs. placebo will be tested. 
The null (H0) and the alternative (Ha) hypotheses are as in the following: 


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 
H01: There is no difference between the median of the 36 mg dose SPN-810 and the median of 
placebo vs.  
 
Ha1: There is a difference between the median of the 36 mg dose SPN-810  and the median of 
placebo. 
The primary efficacy analysis will be performed using the Wilcoxon rank-sum test to compare the 
median of 36 mg dose of SPN-810 with the median of the Placebo.  The Hodges-Lehmann estimate and 
the associated 95% confidence interval (CI) will be calculated. The superiority of 36 mg dose to placebo 
will be claimed if the p-value from this analysis < 0.05 at alpha of 5% significance level. There is no 
multiplicity adjustment with respect to the primary endpoint since only 2 treatments are compared.         
6.9.2 
Key Secondary Efficacy Analyses 
The key secondary efficacy analysis is the change from Visit 3 to Visit 6 in Investigator CGI-S score. 
The Key Secondary endpoint will be analyzed using Mixed-Effect Model for Repeated Measure (MMRM) 
for the ITT population. The model includes treatment, visit, and interaction between treatment and visit 
as fixed factors, and 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 36 mg dose and 
placebo, the difference in the least squares mean (36 mg dose minus placebo), and the 2-sided 95% CI 
for the difference will be calculated. 
6.9.3 
Additional Secondary Efficacy Analyses 
1. Investigator CGI-I score at Visit 6   
2. CHQ-28 score at Visit 6 
3. PSI-4-SF scores at Visit 6 in: 
a. Parental Distress 
b. Parent-Child Dysfunctional Interaction 
c. Difficult Child 
4. Caregiver CGI-I score at Visit 6 
5. SNAP-IV ADHD scores at Visit 6 in: 
a. Inattention ratings 
b. Hyperactivity/Impulsivity ratings 
c. Oppositional Defiant Disorder 
d. Combined Scale ratings  
6. Percentage of responders with ≥50% reduction in the frequency of IA behaviors from baseline 
7. Percentage of responders with ≥30% reduction in the frequency of IA behaviors from baseline 
The other secondary endpoints will be analyzed using the ITT Population as follows: 
Scores of CGI-I  (investigator and caregiver) will be analyzed using a Mixed-Effect Model for Repeated 
Measure (MMRM) similar to the key secondary outcome. 


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Scores for CHQ-PF28, PSI-4-SF, and SNAP-IV will be analyzed using the analysis of covariance method 
based on the ITT population. The model includes treatment and baseline as fixed independent 
covariates and Visit 6 value as a response variable. The least squares mean of each treatment group, the 
difference in the least squares mean (36 mg dose minus placebo), and the 2-sided 95% CI for the 
difference will be obtained.   
The percentage of responders with at least 30% reduction and with at least 50% reduction in the 
frequency of IA behaviors per 7 days in the Treatment (Titration and Maintenance) period relative to the 
Baseline period will be derived analyzed using the logistic regression model with treatment as explanatory 
variables and baseline as covariate. Odds ratio (36 mg dose/placebo), and 95% CI for the odds ratio and 
p-value will be presented. In addition, the number and percentage of responders will also be tabulated.  
If the null hypothesis for the primary analysis is not rejected, then no multiplicity adjustment will be 
done for the key secondary endpoint. If the key secondary endpoint hypothesis is rejected then, a 
sequential testing procedure to preserve the type I error rate at 0.05 will be conducted for the adiidtinal 
secondary endpoints as described below: 
First, the first of the additional secondary endpoints (Investigator CGI-I score at Visit 6) will be used to 
test H01: no difference between SPN-810 36 mg and Placebo in the treatment of IA in subjects with 
ADHD in conjunction with standard ADHD treatment.  If this test is rejected, then the 2nd test using the 
same hypothesis will be repeated using the 2nd additional secondary endpoint (CHQ-28 score at Visit 6). 
If the first hypothesis is not rejected then no other additional secondary endpoint test will be 
performed. If the 2nd  test is rejected then the 3rd  test will be conducted for the 3rd additional secondary 
endpoint (PSI-4-SF scores) and so on until the last  additional secondary endpoint is used for testing in 
the above pre-specified order above. 
6.9.4 
Sensitivity Analysis 
In the presence of a high drop-out rate, performance of sensitivity analysis is crucial.  The purpose of 
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, two sensitivity analyses will be performed: 
1. Multiple imputation under MAR using available data on the primary endpoint  
2. Placebo- based imputation under MNAR 
 
6.9.4.1 
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.  
 
 


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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 
(Rubin 1987).  The treatment effect estimates will be defined as the midpoints 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. 
6.9.4.2 
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. 
6.9.5 
Supplementary Analysis 
A supplementary analysis based on the per-protocol population will be performed. 
6.10 Sample Size and Power Considerations 
Based on results from the Phase 2 study, a 15-point average difference in favor of the SPN-810 
treatment arms compared with placebo is assumed; the change from baseline to endpoint in total R-
MOAS rating was used to evaluate the difference. The R-MOAS was used because there have been no 
prior studies with the IA diary.  A common standard deviation of 34.83 was obtained from a blinded 
analysis of SPN-810P301 data.  
Based on these parameter assumptions, a sample size of approximately 122 per arm will yield 90% 
power to detect a non-zero difference between the median of SPN-810 treatment and the placebo 
groups using the Wilcoxon rank-sum test with a 2-sided significance level α=0.05. 
The original sample size of 291 was based on having 3 treatment groups (97 subjects per arm) and 
specific assumptions on the drug placebo difference, standard deviation and discontinuation rate.  


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After the 810P301 study Interim Analysis result was completed, the 18 mg dose arm was discontinued 
and subjects planned to be randomized to the 18 mg arm would be re-allocated to the 36 mg or placebo 
arm in a ratio of 2:1.  As such there will be an unequal randomization between the 36 mg dose group 
and placebo.  With this post-interim analysis un-equal randomization, the placebo arm is expected to 
approach approximately 121 subjects of the total of 306 subjects randomized. 
The sample size was calculated using the nQuery Advisor Software, Version 7.   
6.11 Interim Analysis 
There will be no interim analysis. 
6.12 Pharmacokinetic Analyses 
 
 
 
 
 
 
 
 
 
   
 
 
 
6.13 Safety Analyses 
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. 
6.13.1 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 
treatment group.  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. 


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All AEs occurring after randomization and throughout the study period will be recorded.  For subjects 
who receive SM, treatment-emergent AEs (TEAEs) will be collected starting after the first dose of SM 
(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 three 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. 
6.13.2 Laboratory Values 
Clinical laboratory values will be summarized by visit by treatment group using descriptive statistics for 
hematology and biochemistry.  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. 
6.13.3 Vital Signs, Height and Weight 
Vital signs will be summarized by visit by treatment group using descriptive statistics.  Both actual values 
changes from baseline to 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. 
6.13.4 ECG Results 
By-visit 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 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 screening values will be 
summarized.   


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6.13.5 Physical Examinations 
Findings from the physical examinations will be listed for each system or area examined. 
6.13.6 Columbia Suicide Severity Rating Scale (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 groups.  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.  
6.13.7 Infrequent Behaviors Checklist 
Infrequent behaviors will be listed for each subject by treatment group. 
6.13.8 Other Special Tests 
The occurrence of neurological side effects will be assessed by looking at the changes in scores from 
baseline to post-baseline visits 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.  
7 DOCUMENTATION 
7.1 Adherence to the Protocol 
The Investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in the protocol and to adhere to the principles of ICH GCP to which the protocol conforms 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 Chairman must be sent to the Investigator with a copy to 
the Sponsor prior to study start and the release of any 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.   
7.2 Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor.   


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for the purpose of reviewing or performing this study. 
Any change to the protocol requires a written protocol amendment or administrative change that must 
be approved by the Sponsor before implementation.  Amendments specifically affecting the safety of 
subjects, the scope of the investigation, or the scientific quality of the study require additional approval 
by the applicable IRBs and, in some countries, by the regulatory authority.  These requirements should 
in no way prevent any immediate action from being taken by the Investigator, or by the Sponsor, in the 
interest of preserving the safety of all subjects included in the study.  If an immediate change to the 
protocol is warranted as per the Investigator, for safety reasons, the Medical Monitor and IRB must be 
notified promptly. 
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. 
7.3 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. 
7.4 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 visit audits may be made periodically by the Sponsor’s Quality Assurance team or qualified 
designee, which is an independent function from the study conduct team. 
7.4.1 
Data Collection 
The primary source document will be the subject’s medical record.  If separate research records are 
maintained by the Investigator(s), both the medical record and the research record will be considered 
the source documents for the purposes of monitoring and auditing the study. 
Electronic data collection techniques will be used to collect data directly from the study sites using 
eCRFs.  The electronic data will be stored centrally in a fully validated clinical database. 
 
 
 
 


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Data recorded on source documents will be transcribed into the eCRFs in accordance with the eCRF 
Completion Instructions that are provided to the study sites.  The Investigator is responsible for ensuring 
that all sections of each eCRF are completed correctly, and that entries can be verified against source 
documents.  The eCRFs will be monitored for completeness and accuracy against the source documents 
by the CRA(s) on a regular basis.  Inconsistencies between the eCRFs and source documents will be 
resolved in accordance with the principles of GCP. 
Completed eCRFs will be extracted from the clinical database, stored as PDF files on a CD-ROM and sent 
to the respective study site for archiving.  A CD-ROM containing all eCRFs will be kept by the Sponsor in 
the Sponsor’s Trial Master File. 
7.4.2 
Clinical Data Management 
Data from eCRFs and other external data (e.g., laboratory data) will be entered into or merged with a 
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 clinical database. 
7.4.3 
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. 
7.4.4 
Bioanalytical Data Management and Quality Control 
 
 
 
 
 
7.5 Retention of Records 
The Investigator has the responsibility to retain all study “essential documents”, as described in ICH E6.  
Essential documents include but not limited to the protocol, copies of paper CRFs or eCRFs, source 
documents, laboratory test results, SM inventory records, Investigator's Brochure, 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 agreement with the Sponsor.  The Investigator must obtain written permission 
from the Sponsor prior to the destruction of any study document. 


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for the purpose of reviewing or performing this study. 
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. 
7.6 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).  If an inspection is requested by a regulatory authority, the Investigator 
must inform the Sponsor and the CRO immediately that this request has been made. 
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. 
7.7 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’s 
site.  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. 
7.8 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). 
7.9 Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the course of this study 
will be kept confidential by the Investigator, the Investigator’s staff, and 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. 


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for the purpose of reviewing or performing this study. 
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. 
7.10 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. 
8 ETHICS 
8.1 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 and the approval letters will be included in the clinical study report for this protocol. 
The protocol, any protocol amendments, and the informed consent form (ICF) will be reviewed and 
approved by the appropriate IRB before subjects are screened for entry.  Verification of the IRB 
unconditional approval of the protocol will be transmitted to the Sponsor prior to the shipment of study 
medication to the investigational site.  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. 
8.2 Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures (SOPs) of the Sponsor 
and 
, the Contract Research Organizations (CRO) that will conduct the study.  These SOPs are 
designed to ensure adherence to Good Clinical Practice (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, national legal guidelines. 


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8.3 Investigators and Study Personnel 
This study will be conducted by qualified Investigators under the Sponsorship of Supernus 
Pharmaceuticals, Inc. (Sponsor) at approximately 25 study sites in the US. 
Contact persons at the Sponsor and the CROs are listed in the reference binder provided to each 
investigational site.  The study will be monitored by qualified personnel from the designated CRO
 
by visiting the study sites. The Sponsor will oversee and review the monitoring activities of the 
 
monitors. Medical writing, data management, and statistical analyses will be performed by the CROs.  
Laboratory tests will be conducted by a central laboratory as designated in the reference binder. 
8.4 Subject Information and Consent/Assent 
The Investigator (or designee) will inform the subject and their parent(s), or legal representative, of all 
aspects pertaining to the subject’s participation in the study and will provide oral and written 
information describing the nature and duration of the study, the procedures involved, the expected 
duration, the potential risks and benefits involved, and any potential discomfort. 
The process for obtaining informed consent/assent will be in accordance with all applicable regulatory 
requirements.  The Investigator (or designee) and the parent (or legal representative) must sign and 
date the Informed Consent Form (ICF)/Informed Assent Form (IAF) before the subject can participate in 
the study.  The parent or legal representative and the subject will be given a copy of the signed and 
dated consent/assent form and the original will be retained in the investigational site study records. 
The decision regarding subject participation in the study is entirely 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 informed 
consent form (including ongoing subjects). 
9 REFERENCE LIST 
Abidin RR. Parenting Stress Index. (3rd ed.) Odessa, FL: Psychological Assessment Resosurces, Inc., 1995. 
Aman MG, Bukstein OG, Gadow KD et al. What does risperidone add to parent training and stimulant for 
severe aggression in child attention-deficit/hyperactivity disorder? J Am Acad Child Adolesc Psychiatry 
2014; 53:47-60 e1. 


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This document is confidential.  It contains proprietary information of Supernus® Pharmaceuticals, Inc.  Any viewing or disclosure 
of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
Armenteros JL, Lewis JE, Davalos M. Risperidone augmentation for treatment-resistant aggression in 
attention-deficit/hyperactivity disorder: A placebo-controlled pilot study. J Am Acad Child Adolesc 
Psychiatry 2007; 46:558-65. 
Ayele BT, Lipkovich I, Molenberghs, G, Mallinckrodt, CH. A multiple imputation based approach to 
sensitivity analyses and effectiveness assessments in longitudinal clinical trials. Journal of 
Biopharmaceutical Statistics 2014; 24, 211-228. 
Barnes TRE. A rating scale for drug-induced akathisia. Br. J. Psychiatry 1989; 154:672-676. 
Blader JC, Pliszka SR, Jensen PS, Schooler NR, Kafantaris V. Pediatrics 2010;126(4):e796-806. 
Calarge CA, Acion L, Kuperman S et al. Weight gain and metabolic abnormalities during extended 
risperidone treatment in children and adolescents. J Child Adolesc Psychopharm 2009; 19:101-9. 
Chen YH, DeMets  DL, Lan KKG. Increasing the sample size when the unblinded interim result is 
promising. Statistics in Medicine 2004; 23: 1023-1038. 
Connor DF, Mc Laughlin TJ. Aggression and diagnosis in psychiatrically referred children. Child Psychiatry 
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10 APPENDICES 
10.1 Retrospective Modified Overt Aggression Scale (R-MOAS) 
 


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10.2 Clinical Global Impression (CGI) Scale 
 


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10.3 Vitiello Scale 
 


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10.4 Kiddie-Sads-Present and Lifetime Version (K-SADS-PL) 2013 
 


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10.5 Columbia-Suicide Severity Rating Scales (C-SSRS) 
 


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


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10.7 Simpson-Angus Rating Scale 
 


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CONFIDENTIAL 
 
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10.8 Barnes Akathisia Rating Scale (BARS) 
 


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CONFIDENTIAL 
 
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CONFIDENTIAL 
 
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10.9 Abnormal Involuntary Movement Scale (AIMS) 
 


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


Supernus® Pharmaceuticals, Inc. 
CONFIDENTIAL 
 
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This document is confidential.  It contains proprietary information of Supernus® Pharmaceuticals, Inc.  Any viewing or disclosure 
of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
10.10 Child Health Questionnaire Parent Form 28-item (CHQ-PF28) 
 


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CONFIDENTIAL 
 
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10.11 Parenting Stress Index-Short Form (PSI-4-SF) 
 


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SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Molindone Hydrochloride 
Extended-Release Tablets for the Treatment of Impulsive 
Aggression in Pediatric Patients with Attention 
Deficit/Hyperactivity Disorder (ADHD) in Conjunction with 
Standard ADHD Treatment 
Protocol Number  
810P302  
Protocol Version 
V7.0 
Protocol Date: 
29 March 2019 
Study Drug 
Molindone Hydrochloride Extended-Release Tablets (SPN-810) 
Study Phase 
III 
IND Number 
106,515 
Sponsor  
Supernus Pharmaceuticals, Inc.  
  
 
  
 
SAP Version 
2.1 
Date 
21 January 21, 2020 
 




Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P302 
 
SAP v2.0 
Page 3 
17 Dec 2019 
Table of Contents 
LIST OF ABBREVIATIONS .................................................................................................................... 5 
REVISION HISTORY ............................................................................................................................ 6 
1 
INTRODUCTION ......................................................................................................................... 7 
2 
STUDY OBJECTIVES .................................................................................................................... 7 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................................ 7 
2.2 
SECONDARY OBJECTIVES ...................................................................................................................................... 7 
2.2.1 
Key Secondary Objective ....................................................................................................................... 7 
2.2.2 
Secondary Objective .............................................................................................................................. 7 
2.3 
TERTIARY OBJECTIVES .......................................................................................................................................... 7 
3 
STUDY DESIGN .......................................................................................................................... 8 
3.1 
GENERAL DESCRIPTION ........................................................................................................................................ 8 
3.2 
SCHEDULE OF VISITS AND PROCEDURES ................................................................................................................... 9 
3.3 
STUDY TREATMENT ........................................................................................................................................... 12 
3.3.1 
Treatment, Dose, and Mode of Administration .................................................................................. 12 
3.3.2 
Duration of Treatment and Study Duration ........................................................................................ 12 
3.3.3 
Methods of Assigning Subjects to Treatment Group ........................................................................... 12 
3.3.4 
Blinding ............................................................................................................................................... 12 
3.4 
HYPOTHESES .................................................................................................................................................... 13 
3.5 
DETERMINATION OF SAMPLE SIZE ........................................................................................................................ 13 
3.6 
CHANGES TO ANALYSES PLANNED IN THE PROTOCOL ............................................................................................... 13 
4 
DEFINITIONS AND DERIVED DATASETS ..................................................................................... 13 
5 
EFFICACY AND SAFETY VARIABLES ........................................................................................... 15 
5.1 
PRIMARY EFFICACY VARIABLE.............................................................................................................................. 15 
5.2 
SECONDARY EFFICACY VARIABLES ........................................................................................................................ 16 
5.2.1 
Key Secondary Variables ..................................................................................................................... 16 
5.2.2 
Additional Secondary Variables .......................................................................................................... 16 
5.3 
PHARMACOKINETIC VARIABLES ............................................................................................................................ 18 
5.4 
SAFETY VARIABLES ............................................................................................................................................ 18 
5.4.1 
Medical History and Adverse Events (AEs) .......................................................................................... 18 
5.4.2 
Prior, Concomitant, and Prohibited Medications ................................................................................ 18 
5.4.3 
Clinical Laboratory Tests (Hematology, Chemistry, and Urinalysis) .................................................... 19 
5.4.4 
Vital Signs, Height and Weight............................................................................................................ 19 
5.4.5 
12-Lead ECG ........................................................................................................................................ 19 
5.4.6 
Physical Examinations ......................................................................................................................... 19 
5.4.7 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................................. 19 
5.4.8 
Infrequent Behaviors Checklist ............................................................................................................ 20 
5.4.9 
Extrapyramidal symptoms (EPS) scales ............................................................................................... 20 
6 
STATISTICAL METHODS ........................................................................................................... 21 
6.1 
GENERAL METHODOLOGY .................................................................................................................................. 21 
6.2 
VISIT WINDOW AND UNSCHEDULED ASSESSMENTS ................................................................................................. 22 
6.3 
ADJUSTMENT FOR COVARIATES ........................................................................................................................... 22 
6.4 
HANDLING OF DROPOUTS, MISSING DATA, AND DATA DISCREPANCIES ...................................................................... 22 
6.4.1 
Adverse Event or Concomitant Medications Dates or Times .............................................................. 23 
6.5 
INTERIM ANALYSIS AND ADAPTIVE DESIGN ............................................................................................................ 24 
6.6 
TIMING OF FINAL ANALYSES ................................................................................................................................ 24 
6.7 
MULTICENTER STUDY......................................................................................................................................... 24 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P302 
 
SAP v2.0 
Page 4 
17 Dec 2019 
6.8 
MULTIPLE COMPARISONS/MULTIPLICITY ADJUSTMENT ........................................................................................... 24 
6.9 
EXAMINATION OF SUBGROUPS ............................................................................................................................ 25 
7 
STATISTICAL ANALYSIS ....................................................................................................... 25 
7.1 
ANALYSIS POPULATIONS..................................................................................................................................... 25 
7.1.1 
Safety Population ................................................................................................................................ 25 
7.1.2 
Modified Intent-to-treat (mITT) Population ........................................................................................ 25 
7.1.3 
Intent-to-treat (ITT) Population........................................................................................................... 25 
7.1.4 
Per Protocol (PP) Population ............................................................................................................... 26 
7.2 
ANALYSIS FOR THE DISCONTINUED TREATMENT ARM .............................................................................................. 26 
7.3 
DISPOSITION OF SUBJECTS .................................................................................................................................. 26 
7.4 
PROTOCOL DEVIATIONS ..................................................................................................................................... 27 
7.5 
DEMOGRAPHICS AND BASELINE SUBJECT CHARACTERISTICS ...................................................................................... 27 
7.6 
BASELINE DISEASE CHARACTERISTICS .................................................................................................................... 28 
7.7 
TREATMENTS .................................................................................................................................................... 28 
7.7.1 
Treatment Compliance and Extent of Exposure .................................................................................. 28 
7.7.2 
Prior and Concomitant Medications ................................................................................................... 29 
7.8 
EFFICACY ANALYSES ........................................................................................................................................... 29 
7.8.1 
Primary Efficacy Analysis..................................................................................................................... 29 
7.8.2 
Sensitivity Analyses ............................................................................................................................. 30 
7.8.3 
Supplementary Analysis ...................................................................................................................... 32 
7.8.4 
Analysis Based on Adjustment of Covariates ...................................................................................... 32 
7.8.5 
Examination of Subgroups .................................................................................................................. 33 
7.8.6 
Analysis of Secondary Efficacy Endpoints ............................................................................................ 33 
7.9 
SAFETY ANALYSES ............................................................................................................................................. 36 
7.9.1 
Adverse Events .................................................................................................................................... 36 
7.9.2 
Laboratory Test ................................................................................................................................... 37 
7.9.3 
Vital Signs, Height, Weight, and BMI .................................................................................................. 38 
7.9.4 
12-Lead ECG ........................................................................................................................................ 38 
7.9.5 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................................. 38 
7.9.6 
Infrequent Behaviors Checklist ............................................................................................................ 38 
7.9.7 
Other Special Tests .............................................................................................................................. 38 
8 
VALIDATION ............................................................................................................................ 39 
9 
REFERENCES ............................................................................................................................ 39 
APPENDIX 1. EXCLUSION CRITERIA FOR THE PER PROTOCOL POPULATIONS ...................................... 41 
APPENDIX 2. LIST OF TABLES, LISTINGS, AND FIGURES ...................................................................... 42 
 
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P302 
 
SAP v2.0 
Page 5 
17 Dec 2019 
LIST OF ABBREVIATIONS  
AE  
Adverse event 
AESI  
Adverse event of Special Interest 
BID  
Bis in die, twice daily 
CRO 
Contract Research Organization 
CRF  
Case report form 
ECG  
Electrocardiogram 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
IA 
Impulsive Aggression 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonisation  
IND  
ITT 
Investigational New Drug Application 
Intent-to-Treat 
IV  
Intravenous 
IWRS  
Interactive web-based randomization system 
kg  
kilogram  
mcg  
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg  
Milligram 
msec 
Millisecond 
PK  
Pharmacokinetic(s) 
PO 
Oral 
PP 
Per Protocol 
PT 
Preferred term in MedDRA and WHODD 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation  
SM 
Study Medication 
SOC 
TDD 
System Organ Class in MedDRA 
Total Daily Dose 
TEAE  
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
WHODD 
WHO Drug Dictionary 
 
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P302 
 
SAP v2.0 
Page 6 
17 Dec 2019 
REVISION HISTORY 
This is Version 2.1 of the Statistical Analysis Plan (SAP).   
Summary of changes to the SAP from Version 2 submitted to FDA on 17Dec2019. 
Section 
Page 
Description of Change 
Rationale 
7.1.2 
25 
The modified ITT is 
defined to exclude 
subjects with baseline IA 
frequency <6 per week 
Retrospective Modified Overt Aggression 
Scale (R-MOAS) score was used for inclusion 
criteria but the primary analysis was 
analyzed based on data collected using IA 
diary Instrument. Based on discussion with 
KOLs, subjects with baseline IA frequency <6 
per week for primary endpoint are 
considered to be normative. The original 
definition of the primary efficacy analysis 
population is modified based on advise from 
KOLs to detect treatment difference. This 
population will be called mITT and will be 
used for the primary analysis. 
 7.1.3 
25 
The ITT population is 
moved to Section 7.1.3 
 Per FDA advise to submit results under the 
original definition of the primary efficacy 
analysis population  
 7.8.1 
29 
The first paragraph and the 
first sentence  of 2nd 
paragraph  re-phrased 
Clarification 
 7.8.2 
30 
Added a sentence   
 Clarification 
 7.8.6 
33 
Subsection 7.8.6.1 and 
7.8.6.2 for key secondary 
analysis and additional 
secondary analysis created. 
 Clarification 
 
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P302 
 
SAP v2.0 
Page 7 
17 Dec 2019 
1 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to ensure the credibility of the study findings 
by specifying the statistical approaches to the analysis of the data prior to database lock. This SAP 
covers the planned analyses of all data collected on the eCRFs and diary pages, and will identify 
handling of data issues. The statistical analysis plan presented in this document will supersede 
the statistical analysis methods described in the clinical protocol. Any deviations/changes from 
the planned analyses described in this SAP will be identified, with justification, in the appropriate 
section of the clinical study report. This SAP is based on the clinical study protocol 810P302, 
version 7.0, dated 29 March 2019 and its associated electronic case report forms (eCRF).  
2 STUDY OBJECTIVES  
2.1 Primary Objective 
The primary objective is to assess the efficacy and safety of SPN-810 in reducing the frequency 
of impulsive aggression (IA) behaviors in pediatric patients with attention-deficit/hyperactivity 
disorder (ADHD) when taken in conjunction with standard ADHD treatment.  
2.2 Secondary Objectives 
2.2.1 Key Secondary Objective 
The key secondary objective of the study is to assess the effect of SPN-810 on the Clinical Global 
Impression – Severity Scale (CGI-S). 
2.2.2 Secondary Objective 
The secondary objectives of the study are to assess the following:  
• The effect of SPN-810 on the Investigator-rated Clinical Global Impression – Improvement 
Scale (CGI-I)  
• The effect of SPN-810 on the child’s overall health as measured by the Child Health 
Questionnaire Parent Form 28-item (CHQ-PF28)  
• The effect of treating the child with SPN-810 on the parent-child relationship as measured 
by the Parenting Stress Index – Short Form version 4 (PSI-4-SF)  
• The effect of SPN-810 on the caregiver-completed CGI-I  
• The effect of SPN-810 on inattention, hyperactivity-impulsivity and oppositional defiant 
disorder measured by the SNAP-IV Rating Scale  
• The effect of SPN-810 on the responder rate (defined as ≥ 50 % in the reduction of the 
frequency of IA behaviors) 
• The effect of SPN-810 on the responder rate (defined as ≥ 30 % in the reduction of the 
frequency of IA behaviors) 
2.3 Tertiary Objectives 
 






Supernus Pharmaceuticals, Inc. 
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Protocol 810P302 
 
SAP v2.0 
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Table 1:  Schedule of Visits and Procedures 
Phase 
Pre-treatment 
Treatment 
Conversion/ 
Taper 
Period 
Screening 
Baseline 
Titration 
Maintenance 
VISIT NUMBER 
1 
2 
3 
4 
5 
6 
7 
DAY 
-45 
-15 
1 
8 
15 
36 
43 
WINDOW (DAYS) 
≤45d prior to 
Visit 3 
≥15d prior  
to Visit 3 
0c 
7d±2d from 
Visit 3 
14d±2d from 
Visit 3 
21d±3d from 
Visit 5 
7d±1d from 
Visit 6 
Informed Consent/Assent a 
X b 
 
 
 
 
 
 
R-MOAS, K-SADS-PL 2013 & Vitiello Aggression 
Scale 
X 
 
 
 
 
 
 
Medical History 
X 
 
X d 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Physical Examination  
X 
 
 
 
 
X 
 
ECG (12-lead) 
X 
 
 
X 
 
X 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Randomization 
 
 
X b,e 
 
 
 
 
Urine Drug Screen 
X 
 
X 
 
 
 
 
Urine Pregnancy Test f 
X 
 
X 
 
 
 
X 
Diary Training & Distribution or Evaluation 
 
X 
X e 
X 
X 
X 
 
Vital Signsg 
X 
 
 
 
 
 
X 
Weight, height, BMI 
X 
 
X 
X 
X 
X 
X 
Hematology/chemistry/Urinalysis 
X 
 
X 
 
 
X 
X 
PK Blood Sampling 
 
 
 
X h 
X h 
 
 
Columbia Suicide Severity Rating Scale (CSSRS) 
X 
 
X 
X 
X 
X 
X 
Investigator CGI-S 
X 
 
X 
X 
X 
X 
 
Caregiver and investigator CGI-I 
 
 
 
X 
X 
X 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P302 
 
SAP v2.0 
Page 11 
17 Dec 2019 
Phase 
Pre-treatment 
Treatment 
Conversion/ 
Taper 
Period 
Screening 
Baseline 
Titration 
Maintenance 
VISIT NUMBER 
1 
2 
3 
4 
5 
6 
7 
DAY 
-45 
-15 
1 
8 
15 
36 
43 
WINDOW (DAYS) 
≤45d prior to 
Visit 3 
≥15d prior  
to Visit 3 
0c 
7d±2d from 
Visit 3 
14d±2d from 
Visit 3 
21d±3d from 
Visit 5 
7d±1d from 
Visit 6 
Efficacy scales (SNAP-IV, CHQ-PF28, PSI-4-SF) 
 
 
X 
 
 
X 
 
Safety Scales (Simpson-Angus, Barnes, AIMS) 
 
 
X 
X 
X 
X 
X 
Infrequent Behaviors Checklist 
 
 
X 
X 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Drug Dispensation 
 
 
X b 
 
X 
X 
 
Drug Return and Compliance 
 
 
 
 
X 
X 
X 
Diary Return 
 
 
 
 
 
 
X 
a Written consent must be obtained prior to performing any study-related procedure. 
b Access IWRS. 
c Visit 3 will occur at least 15 days following Visit 2 
d Assess for any clinically significant change in Medical History since screening. 
e Diary compliance must be at least 80% (minimum of 12 days out of 15) to qualify for randomization. 
f To be performed for female subjects of childbearing potential prior to administration of first dose of SM and will have to be tested as 
negative for the subject to continue in the study. 
g Heart Rate (HR), blood pressure (BP), temperature, and respiratory rate will be measured. 
h Total of 5 PK blood samples will be obtained over one or two visits (Visit 4 and/or Visit 5) 


Supernus Pharmaceuticals, Inc. 
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Protocol 810P302 
 
SAP v2.0 
Page 12 
17 Dec 2019 
3.3 Study Treatment 
3.3.1 Treatment, Dose, and Mode of Administration 
SPN-810 (molindone hydrochloride extended-release tablet) or matching placebo tablets will be 
administered orally (PO) twice daily (BID). Subjects will be force-titrated over a period of 2 weeks 
to their final randomized dose at Visit 3.  Subjects will be titrated up to the final randomized total 
daily dose (TDD).   
• Treatment 1: placebo  
• Treatment 2: 18mg total daily dose (TDD) 
• Treatment 3: 36mg TDD 
Based on the 810P301 study Interim Analysis result decision, the 18 mg dose arm was dropped 
partway through the study.    
3.3.2 Duration of Treatment and Study Duration 
Total subject duration on study is approximately 13 weeks. 
• Pre-treatment phase: 45 days  
o Screening period: up to 30 days  
o Baseline period: at least 15 days  
• Treatment phase: 5 weeks  
o Titration period: 2 weeks  
o Maintenance period: 3 weeks  
• Conversion/Tapering phase: 1 week  
3.3.3 Methods of Assigning Subjects to Treatment Group 
Allocation of study drug will be completed centrally using an interactive web response system 
(IWRS) that will determine which kit to assign to the subject. Separate schedules for subject 
randomization and drug list will be created. The original randomization scheme assigns treatment 
to each randomization number in a 1:1:1. However, based on the 810P301 study Interim Analysis 
result decision, the 18 mg arm was dropped partway through the study. As a result, subjects 
planned to be randomized to the 18 mg arm will be re-allocated to the 36 mg or placebo arm in 
a ratio of 2:1.  
3.3.4 Blinding 
Subjects, all site personnel, the Sponsor and its designated Contract Research Organizations 
(CROs) are blinded with the following exceptions.  The CRO and Sponsor personnel who are 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P302 
 
SAP v2.0 
Page 13 
17 Dec 2019 
involved in the randomization generation, study drug supply, and PK concentration assays are 
unblinded.  However, they are not involved in the routine study monitoring, data cleaning and 
review, the design of this SAP or data analysis.   
3.4 Hypotheses  
The null and the alternative hypotheses are as in the following. 
• H0: There is no difference between SPN-810 36 mg and placebo in the treatment of IA in 
subjects with ADHD in conjunction with standard ADHD treatment.   
• Ha: There is a difference between SPN-810 36 mg and placebo in the treatment of IA in 
subjects with ADHD in conjunction with standard ADHD treatment.  
3.5 Determination of Sample Size 
The original sample size was based on the results from the Phase 2 study. It was assumed that 
the average treatment difference between SPN-810 dose groups and placebo is 15 with a 
common standard deviation (SD) =27.3.  A sample size of 77 subjects per arm (1:1:1 allocation 
ratio) would yield 90% power to detect a non-zero difference between the median of 18 mg or 
36 mg dose group and the placebo using the Wilcoxon rank-sum test with a 2-sided significance 
level of alpha=0.05. 
After the interim analysis for Study 810P301, the 18 mg dose arm was discontinued for 
randomization.  Subjects planned to be randomized to the 18 mg arm were re-randomized to the 
36 mg or placebo arms at a 2:1 allocation ratio.  A blinded review of the 810P301 data indicates 
that the SD for the interim data was actually 34.83 instead of the protocol assumed 27.3.  This 
new SD leads to a total sample size of 306 (adjusted for 20% attrition) subjects.  Approximately 
167 subjects were randomized prior to the implementation of the 2:1 randomization.  It follows 
that 139 subjects would be randomized in a 2:1 ratio of 36 mg to following the re-calculation of 
sample size with the new SD.  
The sample size was calculated using the nQuery Advisor Software, Version 7. 
3.6 Changes to Analyses Planned in the Protocol 
This SAP will be updated as necessary if any changes in the protocol occur due to the expected 
protocol amendment impacting the SAP.  
 
4 DEFINITIONS AND DERIVED DATASETS 
Table 1. Terminology and Definition 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P302 
 
SAP v2.0 
Page 14 
17 Dec 2019 
Terminology 
Definition 
Study Medication 
SPN-810 or the matching placebo. 
Study Day 
The first dose date (Day 1) is defined as the date on which a subject 
took the first dose of double-blind study medication (SM), Other study 
days are defined relative to the Study Day 1.  For visits prior to the first 
dose of the SM, Study Day is calculated as Visit Date – Day 1.  For visits 
after the first dose, Study Day is calculated as Visit Date – Day 1 +1. 
Enrolled 
Subject has provided signed informed consent. 
Randomized 
Subject is assigned with the kit number for the SM. 
Completer for the 
Study 
Subject who completes the maintenance period (Visit 6). 
Baseline 
Unless specified otherwise, baseline is defined as the non-missing 
value collected most recent to and before the time of the very first 
dose of the SM.  For example, Visit 3 CGI-S, CHQ-PF28, PSI-4-SF, and 
SNAP-IV are collected prior to the first dose.  Their values are 
considered baseline for the covariate analysis. 
Baseline Period 
For subject daily IA diaries, on and prior to Visit 3 (inclusive, ≤Day 1). 
Prior Medication 
Medication collected on the Prior/Concomitant Medication CRF, with 
the start date prior to Study Day 1. 
Concomitant 
Medication 
Medication collected on the Prior/Concomitant Medication CRF, with 
end date on/after Study Day 1. 
Titration Period 
For subject daily IA diaries from Visit 3 through Visit 5 (v3< to ≤ V5) 
Maintenance Period 
For subject daily IA diaries from Visit 5 through Visit 6 (V5< to ≤ V6) 
Treatment Period 
Titration and Maintenance Periods combined 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P302 
 
SAP v2.0 
Page 15 
17 Dec 2019 
Terminology 
Definition 
Derived Dataset 
Derived dataset (analysis dataset) is any permanently stored collection 
of data containing raw and/or derived variables created to support the 
production of statistical summary tables. Derived variables will be 
created from the “raw” data.  Analysis datasets to be created will 
include ADEFF (efficacy analysis dataset), ADSL (subject-level analysis 
dataset), ADAE (Adverse event analysis dataset) and other as 
appropriate.  In deriving ADEFF, the source data include both the 
episodic diary and evening diary data files.  
Specifications for derived datasets will be developed which will include 
the names and definitions of derived variables in the derived SAS 
datasets. 
 
5 EFFICACY AND SAFETY VARIABLES  
5.1 Primary Efficacy Variable 
The primary efficacy endpoint is percent change (PCHT) in the frequency (unweighted score) of 
IA behaviors per 7 days in the treatment (titration and maintenance) period relative to the 
Baseline period calculated over the number of days with non-missing IA diary data.  
PCHT will be calculated as 100 x (T – B)/B, where T and B are IA behavior frequencies per 7 days 
during the treatment period 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 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.  
This primary efficacy variable will be based on a checklist of 15 IA behaviors collected in an 
electronic IA diary. The IA diary comprises two parts: 1) an episodic diary that will be used by the 
primary caregiver (or alternate) 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 day and to enter any 
events that were not previously captured. Each event will be characterized by a checklist of 15 
observed behaviors: Yelling, Screaming, Threatening, Scratching, Throwing, Slamming, Hitting 
Self, Arguing, Cursing, Name Calling, Shoving, Hair Pulling, Fighting, Hitting Others, and Kicking 
Others. 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 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol 810P302 
 
SAP v2.0 
Page 16 
17 Dec 2019 
during a day, and the evening diary confirms this, the daily event score for that subject will be 0 
for each of the 15 IA variables. Behaviors not on this list will not be captured.   
5.2 Secondary Efficacy Variables 
5.2.1 Key Secondary Variables 
The key secondary efficacy variable is the change from Baseline (Visit 3) to Visit 6 in Investigator 
CGI-S score. 
5.2.2 Additional Secondary Variables 
1. 
Investigator CGI-I score at Visit 6 
2. 
CHQ-PF28 score at Visit 6 
• Physical functioning summary score 
• Psychosocial health summary score 
3. 
PSI-4-SF (Parenting Stress Index – Short Form) score at Visit 6 in 
• Parental Distress 
• Parent-Child Dysfunctional Interaction 
• Difficult Child 
4. Caregiver CGI-I score at Visit 6 
5. SNAP-IV ADHD (Swanson, Nolan and Pelham-IV Rating Scale for Inattention, 
hyperactivity-impulsivity and oppositional defiant disorder measured) score at Visit 6 in 
• Inattention ratings 
• Hyperactivity/Impulsivity ratings 
• Oppositional Defiant Disorder 
• Combined subscale ratings 
6. % of responders with ≥50% reduction in the frequency of IA behaviors from baseline to 
the treatment period 
7. % of responders with ≥30% reduction in the frequency of IA behaviors from baseline to 
the treatment period 
The CGI scale was developed to provide a brief, stand-alone assessment of the clinician’s view of 
a subject’s global functioning prior to and after administration of a SM (Guy 1976).  Severity of 
illness (CGI-S) and global improvement (CGI-I) are both rated on a scale of 1 to 7 with 7 being 
“extremely ill” or “very much worse”, respectively.  Successful therapy is indicated by a lower 
overall score in subsequent testing.  Investigators should consider their total clinical experience 
with children who have IA associated with ADHD and rate how severe the subject’s condition is 
at the time. 


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• CGI-I, relative to the condition at Visit 3, will be evaluated by the caregiver and by the 
Investigator at each post baseline visit on a 7-point scale with 1=Very much improved, 
2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much 
worse, and 7=Very much worse.  
• CGI-S will be evaluated by the Investigator at –each visit on a 7-point scale with 1=Normal, 
2=Borderline ill, 3=Mildly ill, 4=Moderately ill, 5=Markedly ill, 6=Severely ill, and 
7=Extremely ill.  
The Child Health Questionnaire Parent Form 28-item (CHQ-PF28) (Protocol Appendix 10.11) is 
evaluated by the primary caregiver at Visit 3 and Visit 6 for the subject’s health status and health 
related quality of life. CHQ-PF28 items have four, five, or six response options, divided over eight 
multi-item scales (Physical Functioning [PF, Q2.1a–2.1c], Behavior [BE, Q5.1a-5.1c, Q5.2], Mental 
Health [MH, Q6.1a–6.1c], Self-Esteem [SE, Q7.1a-7.1c], General Health Perceptions [GH, Q1.1, 
Q8.1a-8.1c], Parental Impact - Emotional [PE, Q9.1a-9.1b], Parental Impact - Time [PT, Q9.2a-
9.2b], and Family Activities [FA, Q9.3a-9.3b]) and five single item concepts (Global Health [GGH, 
Q1.1], Role/Social Limitations - Emotional/Behavior [REB, 3.1], Role/Social Limitations - Physical 
[RP, Q3.2], Bodily Pain/Discomfort [BP, Q4.1], Global Behavior [GBE, Q5.2], Family Cohesion [FC, 
Q9.4], and Change in Health [CH, Q8.2]).  In addition, the individual scale scores will be 
aggregated to derive 2 summary component scores: the physical functioning and psychosocial 
health summary scores. Range on subscales and the overall scale is 0–100, where 0 is the worst 
possible health state and 100 the best possible health state. Details for item and multi-item scale 
scoring, calculation of standardized scores and Aggregate Physical and Psychological Summary 
Scores can be found in the Child Health Questionnaire (CHQ) Scoring and Interpretation Manual 
(HealthActCHQ). 
The Parenting Stress Index – Short Form (PSI-4-SF) is a 36-item self-report measure of parenting 
stress at Visit 3 and Visit 6. Three subscales (Parental Distress [PD: Q1-12], Parent-Child 
Dysfunctional Interaction [P-CDI: Q13-24], and Difficult Child [DC: Q25-36]) consist of 12 items 
each. Parents use a 5-point scale to indicate the degree to which they agree with each statement.  
The subscale score is the sum of the respective item scores.  “Total Stress” score is the sum of 
the 3 subscale scores. The subscale will be set to missing if 2 or more (>1) item scores in the 
subscale are missing. Total Stress score is set to missing if 1 or more subscale score is missing. 
The SNAP-IV (Protocol Appendix 10.7) 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. The SNAP-IV rating is performed by the parent or legal 


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representative at each visit. 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)  
• ODD (items #19-26)  
• ADHD-Combined subscale: (items #1 – 18)  
Each subscale score is the average of the available item scores in the subscale.  The SNAP-IV rating 
scale will be administered at Visit 3 and Visit 6. 
5.3 Pharmacokinetic Variables 
Not applicable 
5.4 Safety Variables 
5.4.1 Medical History and Adverse Events (AEs) 
AEs that occur on/after signing ICF will be recorded on the AE CRF.  Medical history and AEs will 
be coded for preferred term (PT) and system organ class (SOC) using Medical Dictionary for 
Regulatory Activities (MedDRA).  AEs are evaluated by the investigators for seriousness, 
relationship, and severity.   
5.4.2 Prior, Concomitant, and Prohibited Medications  
Prior medications and concomitant medications will be extracted from the Prior/Concomitant 
Medication CRF.  Medications taken prior to Study Day 1 will be considered as prior medications 
and medications taken on or after Study Day 1 will be considered as concomitant medications.  
Prior and concomitant medications will be coded using WHO Drug Dictionary (WHODD) for PT 
and Anatomical Therapeutic Chemistry (ATC) classification.   
Prohibited medications include, but are not limited to, 
• α2-adrenergic agonists (e.g. clonidine and guanfacine) used for any other reason except 
for monotherapy treatment for ADHD  
• Anti-psychotics including aripiprazole, risperidone, quetiapine, and ziprasidone  
• Anticonvulsants including carbamazepine and valproic acid, antidepressants, mood 
stabilizers including lithium, benzodiazepines, cholinesterase inhibitors or any drug 
known to inhibit CYP2D6 activity  
• Herbal supplements  


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5.4.3 Clinical Laboratory Tests (Hematology, Chemistry, and Urinalysis) 
Laboratory tests will be converted to follow the International System (SI) units.  Laboratory tests 
will be collected at Visits 1, 3, 6, and 7.  The tests include hematology, serum chemistry and 
urinalysis panels.  Laboratory values will be categorized according to the appropriate laboratory 
reference ranges. 
5.4.4 Vital Signs, Height and Weight 
Vital signs include body temperature, heart rate, respiratory rate, systolic blood pressure, and 
diastolic blood pressure.  They will be collected at Visits 1 and 7.  Subject height, weight, and BMI 
will be collected at Visits 1 and 3 – 7. 
5.4.5 12-Lead ECG 
The following ECG variables will be collected at Visits 1, 4, and 6: HR (heart rate), PR (respiratory 
rate), QRS interval, QT interval, and QTcF (QT interval corrected using the Fridericia’s method). 
5.4.6 Physical Examinations 
Physical examinations will be conducted at Visit 1 and Visit 6.  Clinically significant findings will 
be reported as adverse events. 
5.4.7 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS (Protocol Appendix 10.6) is a questionnaire assessing suicidal ideation and behavior 
at baseline and since last visit. This assessment will be conducted at Visits 1, and 3 – 7. The 
following outcomes are C-SSRS categories and have binary responses (yes/no). 
Category 1 – Wish to be dead  
Category 2 – Non-specific Active Suicidal Thoughts  
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act  
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
Category 5 – Active Suicidal Ideation with Specific Plan and Intent  
Category 6 – Preparatory Acts or Behavior  
Category 7 – Aborted Attempt  
Category 8 – Interrupted Attempt  
Category 9 – Actual Attempt (non-fatal)  
Category 10 – Completed Suicide 


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Three composite binary endpoints and one severity score are derived from the above categories. 
Suicidal ideation: A “yes” answer at any time during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS.  
Suicidal behavior: A “yes” answer at any time during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS.  
Suicidal ideation or behavior: A “yes” answer at any time during treatment to any one of 
the ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS. 
Suicidal Ideation score: The maximum suicidal ideation category (1-5 on the C-SSRS) 
present at the assessment.  Assign a score of 0 if no ideation is present. 
5.4.8 Infrequent Behaviors Checklist 
The infrequent behaviors checklist is a checklist of 15 behaviors that (along with the 15 IA Diary 
behaviors) were qualitatively linked to IA during the development of the IA diary. 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, severe injury 
animal.  Caregivers will be asked which, if any, of these behaviors have been observed since the 
patient’s last visit. This assessment will be administered at Visits 3 – 6 by the site coordinator. 
5.4.9 Extrapyramidal symptoms (EPS) scales  
The EPS symptom and neuroleptic malignant syndrome will be evaluated using the Simpson-
Angus scale (Protocol Appendix 10.8), the Barnes Akathisia scale (Protocol Appendix 10.9), and 
the Abnormal Involuntary Movement scale (AIMS) (Protocol Appendix 10.10). The Simpson-
Angus scale is a 10-item rating scale, consisting of 1 item measuring gait, 6 items measuring 
rigidity, and 3 items measuring glabella tap, tremor and salivation. The Barnes Akathisia scale is 
a rating scale for drug-induced akathisia.  It includes Objective Akathisia, Subjective Awareness 
of Restlessness, Subjective Distress Related to Restlessness, and Global Clinical Assessment of 
Akathisia subscales.  Additionally, total score will be calculated by summing up the Objective and 
two Subjective scale scores (Barnes 1989). The objective and two subjective symptoms are rated 
on a 4-point scale ranging from 0 to 3.  The global clinical assessment is rated on a 5-point scale 
ranging from 0 to 4.  The AIMS test is a rating scale used to measure tardive dyskinesia (Munetz 
1988).  It includes 12 items to rate involuntary movements of various areas of the subject’s body. 
These assessments will be administered at Visit 3 and all subsequent visits. 


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6 STATISTICAL METHODS 
6.1 General Methodology  
All statistical analyses will be conducted using SAS Version 9.4 or later on the Microsoft® 
Windows Operating System. 
 
All tabulations of results will include summaries for the three treatment groups: SPN810 36mg, 
SPN810 18mg and placebo, however, statistical test will only include SPN810 36mg and placebo. 
 
Continuous data will be summarized using n (number of subjects with non-missing observations), 
mean, median, standard deviation (SD), minimum value, and maximum value.  Categorical data 
will be summarized using the frequency count and percentage (n, %) of subjects in each category. 
Number of subjects with non-missing values or number of subjects with missing values (e.g., Not 
Done) will be presented, where appropriate.  Subjects with missing values will not contribute to 
the denominator of percentage calculations. Counts of zero in any category will be presented 
without percentage. 
 
Treatment differences will be evaluated as SPN-810 dose minus placebo. Unless otherwise 
specified, all statistical hypothesis tests will be 2-sided with a significance level of α=0.05.  All 
confidence interval will be calculated 2-sided from the unadjusted 5% significance level. P-values 
will be reported to 4 decimal places.  P-values <0.0001 will be presented as “<0.0001”.  Similarly, 
p-values >0.9999 will be presented as “>0.9999” 
 
The precision rules for the presentation of summary statistics will be: 
• Sample size (n, N) and number of missing responses (if displayed) – Integer 
• Mean, median, percentiles, and confidence interval – One additional decimal place than 
reported/collected 
• Standard deviation – Two additional decimal places than reported/collected 
• Minimum, maximum – Same number of decimal places as reported/collected 
• Ratios – two decimal places 
• Percentages – one decimal place generally, or two decimal places for <0.1% 
 
The data summaries will be accompanied by individual subject data listings. All data available 
from diary, eCRF, and external transfer (labs) will be listed and will include relevant and pertinent 
subject information, e.g., treatment, center, age/gender/race, and study day.  The listings will be 
sorted in the order of treatment group, unique subject ID, and assessment date/time and 
assessment name. The unique subject ID consists of 3-digit study number followed by
digit site 


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number 
and 
digit 
subject 
number 
separated 
by 
hyphen 
(e.g.,  
).  
 
For each summary table, a supporting listing will be identified in the footnote.   
 
Dates will be presented in the ISO-8601 format YYYY-MM-DD.  Times will be displayed in 24-hour 
clock format. Numbering for tables, figures and listings will follow ICH E3 Guidelines. 
 
Alternative methods of analysis of the data may be considered prior to un-blinding when some 
of the assumptions underlying the proposed analyses not be met.  However, the reason for any 
departure from the planned approach and methods will be fully documented as an amendment 
to the SAP or in the clinical study report. 
6.2 Visit Window and Unscheduled Assessments 
There is no visit window for the by visit analysis.  Data will be analyzed according to the visit they 
are associated with. Data collected at unscheduled time points will not be summarized at the 
unscheduled time points.  However, the unscheduled data will be used for analysis if data are 
missing at the next scheduled visit due to early termination. 
6.3 Adjustment for Covariates 
An exploratory analysis of the primary efficacy endpoint will be performed using a 
randomization-based approach (Dmitrienko and Koch 2017).  This analysis will include age 
(categorical and continuous), gender, pooled site and baseline IA adjusted to 7 days as covariates.   
6.4 Handling of Dropouts, Missing Data, and Data Discrepancies 
For the primary analysis of the primary efficacy endpoint, the frequency of IA behaviors during 
the treatment (titration + maintenance) period will be calculated over the number of days with 
non-missing IA diary data in the treatment period. No explicit imputation of missing data will be 
used, but this approach is implicitly equivalent to using the frequency of IA behaviors during the 
days with non-missing IA diary data to impute the frequency for days after study discontinuation 
or days with missing IA diary data. In addition to this implicit imputation, multiple imputations 
under the assumption of missing at random (MAR) and missing not at random (MNAR) will be 
used for handling missing data for sensitivity analysis. Details of imputation methods are 
specified in Section 7.8.2  
For analysis of frequency of IA behaviors during the treatment period (titration or maintenance), 
the following methods will be followed.  


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1) If subjects discontinued the study during or prior to the maintenance period, their 
maintenance period will be counted from Visit 5 (exclusive) through the date of last dose as 
documented on the End of Study eCRF page (inclusive). If the date of last dose is not collected, it 
will be imputed by the subjects’ last visit for the study.  
2) If subjects have ≥7 daily diaries in the maintenance period, their maintenance IA frequencies 
will be based on maintenance daily diaries.  
3) If subjects have <7 daily diaries in the maintenance period, their maintenance IA frequencies 
will be calculated pooling the titration period diaries with the maintenance period diaries.   
4) If subjects do not have any maintenance diaries, their maintenance IA frequencies will be 
entirely derived from the titration period diaries. 
Missing data for secondary efficacy endpoints (investigator CGI-S, investigator CGI-I and caregiver 
CGI-I) will be handled by using the Mixed Model for Repeated Measures method, which is 
implemented via SAS® PROC MIXED procedure. MMRM assumes 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 in the previously scheduled visits. 
6.4.1 Adverse Event or Concomitant Medications Dates or Times 
For AEs with missing or partially missing start date/time, the following imputation rules will be 
applied for the determination of treatment-emergent status: 
For partial start date/time: 
• If the year is unknown, then the date will be assigned the date and time of first dose of 
study treatment. 
• If the year is known to be different from the year of the first dose, then missing month 
and day will be imputed as the first month and first day of the month. 
• If the year is known to be the year of the first dose, 
a) If the month is unknown or is the same as the month of the first dose, then the 
missing month and day will be imputed by the month and day of the first dose. 
b) If the month is known to be different from the month of the first dose, then the 
missing day is imputed as 01 (first day of the month). 
• If the time is unknown, then: 


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a) If the date (day, month, and year) matches the date of the administration of study 
drug, then the time of the study treatment will be used to impute the missing 
time. 
b) Otherwise, ’00:00’ will be assigned. 
For the determination of the prior and concomitant status, the follow rules will be followed for 
incomplete dates. 
• If the medication stop date is partially missing,  
o If the year and month indicate the stop date is before study drug administration, 
it is Prior medication.  
o Otherwise, it is concomitant medication. 
• If the medication stop date is completely missing, it is concomitant medication. 
6.5 Interim Analysis and Adaptive Design 
There is no planned interim analysis. 
6.6 Timing of Final Analyses 
Data summary and statistical analysis will commence after all subjects have completed study Visit 
7 (or discontinued prior to Visit 7) and the study database is cleaned and locked. 
6.7 Multicenter Study 
This is a multicenter study. The primary analysis will have all sites pooled.  Where applicable, 
analysis adjusting for site effect or analysis evaluating homogeneity across sites may be carried 
out.  If conducted, small sites (defined as those with sample size <9 ITT subjects/site) will be 
pooled with larger sites based on the geographic proximity.   
6.8 Multiple Comparisons/Multiplicity Adjustment 
Because of the early termination of the 18 mg arm based on the external data, there will be no 
formal hypothesis test and statistical comparison between the 18 mg arm and the placebo arm 
for any of the efficacy endpoints.  Thus, there is no multiplicity adjustment due to the multiple 
dose arms to placebo comparisons with respect to the primary and key secondary endpoint 
analysis.  Multiplicity adjustment for the multiple endpoints with respect to additional secondary 
end points will be carried out in a fixed sequential gate-keeping approach. The test of the null 
hypothesis of 36 mg vs placebo for additional secondary endpoints from one endpoint to the next 
endpoint will be carried out in such a way that the test of the subsequent endpoint will be 
conducted if and only if the test rejects the null hypothesis for the previous additional secondary 
endpoint.  If any test fails to reject the null hypothesis with respect to a certain additional 


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secondary endpoint then there will be no test of hypothesis with respect to all subsequent 
additional secondary endpoints and these tests will all be considered failure. 
6.9 Examination of Subgroups 
In addition to the analysis adjusted for the confounding effects by the covariates (see 
Section 6.3), primary and key secondary efficacy variables will be summarized by subgroup to 
explore the heterogeneity of the treatment effect across subgroups.  Subgroups are defined as 
follows: 
• Gender (Male, Female) 
• Age (6-9, 10-12) 
• Race (White, Non-white) 
7 STATISTICAL ANALYSIS 
7.1 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 (i.e., distributed IA 
diary) 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. 
7.1.1 Safety Population 
The safety population will include all randomized subjects who received at least 1 dose of study 
drug and have at least one post-randomization safety measurements. 
7.1.2 Modified Intent-to-treat (mITT) Population  
The modified intent-to-treat population will include all subjects who received at least 1 dose of 
study drug and have a baseline IA frequency ≥ 6 per week and at least 1 valid post-randomization 
assessment of frequency of IA behaviors based on IA diary entry. Subjects will be analyzed 
according to the treatment they were randomized to.  
7.1.3 Intent-to-treat (ITT) Population  
The intent-to-treat population will include all subjects who received at least 1 dose of study drug 
and at least 1 valid post-randomization assessment of frequency of IA behaviors based on IA diary 
entry. Subjects will be analyzed according to the treatment they were randomized to.  
 


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7.1.4 Per Protocol (PP) Population 
The per protocol population will include all of the subjects in the ITT population who completed 
the treatment period (Completed Maintenance Visit 6) with 80% diary completion compliance 
and who did not have major protocol deviations.  Diary compliance is calculated as  
 
diary compliance = number of days diary completed within the treatment period 
Number of treatment days
× 100% 
Detailed specification of the PP population will be provided prior to the database lock for the 
final analysis. 
7.2 Analysis for the Discontinued Treatment Arm 
As stated in Section 3.5, the enrollment for the 18 mg arm was discontinued after the interim 
analysis for Study 810P301, a study separate from this one.  As a result, there will be no formal 
hypothesis tests and statistical comparison between the 18 mg arm and placebo for any efficacy 
endpoints.  However, for completeness in the presentation, 18 mg arm will remain in the table 
with summary statistics presented.  
7.3 Disposition of Subjects 
Subject disposition and reasons for screening failure will be summarized for screen-failed 
subjects (Table 14.1.2.2). 
Subject randomization schedule will be listed.  Subjects whose randomization codes are 
unblinded during the conduct of the study will be listed along with the reason for un-blinding 
(Listing 16.1.7). 
The following summaries and listings will be based on all randomized subjects.   
Subjects (n and %) who completed and discontinued from the study will be tabulated by the 
treatment group and study period (titration, maintenance, titration and maintenance combined, 
and all period combined) for randomized population (Table 14.1.1).  The primary reasons for 
study discontinuation will be included in the tabulation.  The primary reasons may include any of 
the following: 
• Subject withdrew consent 
• Lost to follow-up 
• Administrative reason 
• Adverse event  
• Investigator decision 


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• Failure to follow required study procedures 
• Other 
 
Also, subject’s enrollment will be summarized by study site among ITT population (Table 
14.1.2.3).   
A data listing will be presented for subject’s disposition and reasons for discontinuation (Listing 
16.2.1.1). 
7.4 Protocol Deviations 
Protocol deviations will include, but are not limited to 
• Non-compliance with any scheduled study visit  
• Non-compliance with study treatment  
• Prohibited medications  
• Non-compliance with study inclusion or exclusion criteria  
• Non-compliance with study assessment procedures  
Subjects with major protocol deviations will be listed based on all randomized subjects.  The 
listing will include a brief description of the deviation, deviation category, and if applicable, study 
day when deviation occurred along with other pertinent information (Listing 16.2.1.2). 
If warranted, subjects (n and %) with major protocol deviations will be tabulated by treatment 
group and deviation category for ITT population (Table 14.1.2.4). 
Subject’s inclusion/exclusion from each analysis population will be listed along with the 
applicable reasons for exclusion (Listing 16.2.1.3).  
7.5 Demographics and Baseline Subject Characteristics 
Subject age, sex, ethnicity, race, height at screening, weight at screening and baseline will be 
summarized based on the ITT population by treatment group.  Age will be summarized as a 
continuous variable as well as a categorical variable (6 to 9 [i.e., <10], and 10 to 12 [i.e., ≥10 and 
≤ 12] years, inclusive) (Table 14.1.2.1).   
All demographic and baseline characteristics will be included in the subject data listing (Listing 
16.2.1.4). 


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7.6 Baseline Disease Characteristics 
Summaries of baseline disease characteristics will be based on the ITT population, except for 
medical history, which will be based on the Safety population. 
Subject incidence (n and %) of medical history will be tabulated by MedDRA System Organ Class 
(SOC) and Preferred Term (PT) for each treatment group as per Section 7.9.1 (Table 14.1.3.1).  
R-MOAS (item, and domain scores [Table 14.1.5.1.1and Table 14.1.5.1.2]) and Vitiello Aggression 
Scale (item, and domain scores [Table 14.1.5.2.1 and Table 14.1.5.2.2]) will be summarized by 
treatment group as per Section 6.1. 
All baseline disease characteristics will be listed (Listing 16.2.1.5 – Listing 16.2.1.7). 
7.7 Treatments 
7.7.1 Treatment Compliance and Extent of Exposure 
Summaries of treatment compliance and exposure will be based on the ITT population. 
Duration of exposure is defined as the total number of days a subject is exposed to any 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 be summarized using descriptive statistics (n, mean, SD, 
median, minimum, and maximum).  
Percent of SM compliance is defined as  
Treatment Compliance
= Number of Tablets Dispensed −Number of Tablets Returned
4x(Date of Last Dose −Date of First Dose + 1)
∙100%. 
Each subject is expected to take 4 tablets per day as in the following. Subjects randomized to 
placebo group will take 2 placebo tablets in the morning and 2 placebo tablets in the evening.  
Subjects randomized to SPN-810 18 mg will take one 9 mg active tablet and 1 placebo tablet in 
the morning and one 9 mg active tablet and 1 placebo tablet in the evening.  Subjects randomized 
to SPN-810 36 mg will take two 9 mg active tablets in the morning and two 9 mg active tablets in 
the evening. For each treatment, SM compliance will be summarized with number of subjects (n 
and %) by compliance category (<80%, 80-120%, and >120%). SM compliance will also be 
summarized as a continuous variable using descriptive statistics (n, mean, standard deviation, 
median, minimum, and maximum) for each treatment.  


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Summaries of treatment compliance and exposure will be presented separately for the Titration 
Period, Maintenance Period, and combined Titration and Maintenance Periods (Table 14.1.4 and 
Listing 16.2.1.8). 
7.7.2 Prior and Concomitant Medications  
Prior and concomitant medications will be tabulated separately based on the Safety Population.  
The number (n and %) of subjects taking at least one medication and the number (%) of subjects 
taking each medication at the WHODD preferred term level will be tabulated by treatment group, 
Anatomical-Therapeutic-Chemical classification 4 (ATC4), and PT.  Subjects taking the same PT 
medication twice will only be counted once (Table 14.1.3.2 and Table 14.1.3.3). In addition, the 
number and percent for subjects with ≥5% allowed concomitant medications by ATC code and 
preferred term will be reported (Table 14.1.3.4).  
A subject data listing will be provided to include the reported medication name, the WHODD PT, 
ATC4, study day and pertinent subject information (Listing 16.2.1.9.1 and Listing 16.2.1.9.2). 
A separate data listing will include subjects who received prohibited medications (Listing 
16.2.1.9.3). 
7.8 Efficacy Analyses 
7.8.1 Primary Efficacy Analysis 
The primary analysis will be based on the mITT population and the primary efficacy endpoint 
is percent change (PCHT) in the frequency (unweighted score) of IA behaviors per 7 days in the 
treatment period relative to the Baseline period calculated over the number of days with non-
missing IA diary. The analysis will be repeated for the ITT population, which follows the original 
primary efficacy analysis population definition.  
 
Both of the above analyses will be performed using the Wilcoxon rank-sum test to compare the 
median SPN-810 36 mg with the median of the Placebo. The Hodges-Lehmann estimate of the 
difference (SPN-810 36 mg dose minus placebo) and the associated 95% confidence interval (CI) 
around the difference will be calculated.   The statistical analysis will be presented in the table 
along with the summary of the change from baseline frequency (Table 14.2.1.1).  The daily IA 
behavior diary will be listed.  The daily frequency, the derived 7-day frequency for each week, 
and the derived 7-day frequency for the treatment period will be included (Listing 16.2.2.1.1 – 
Listing 16.2.2.1.2). Histogram of median percent change from baseline in the frequency of IA 
Behaviors in treatment will be created for 36 mg dose and Placebo (Figure 14.2.1.1 ).  


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7.8.2 Sensitivity Analyses  
Sensitivity analyses will be performed both on the mITT and ITT populations. 
7.8.2.1 Multiple Imputation Assuming Missing at Random 
This sensitivity analysis assumes that the diary 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 (e.g., the probability of missing Week 5 diary is related to the observed Week 4 or Week 
3 value but not the unobserved Week 5 value).  In this sensitivity analysis, missing data is imputed 
multiple times, thus creating the multiply-imputed diary data.  The final analysis incorporates the 
between-imputation variability with the within-imputation variability. 
The 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 vs 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 (Rubin 1987).  The treatment effect estimates will be defined as the 
midpoints 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.  
An example of SAS code is as follows. 
PROC MI DATA=adqs NIMPUTE=100 SEED=123456789 OUT=adqs_imp ; 
BY trtp ; 
VAR age sex bwk  twk1 twk2 twk3  twk4  twk5 ; 
MCMC CHAIN=multiple IMPUTE=full INITIAL=em PRIOR=jeffreys ; 


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RUN ; 
where trtp is treatment group, bwk, twk1, twk2, twk3, twk4, and twk5 are variables of weekly IA 
scores during the baseline, and treatment (titration + maintenance) periods. These are derived 
as (SUM/DAY)*7, where SUM is the total of the IA scores reported on the IA diary in that analysis 
week, and DAY is the number of days with non-missing IA score in the IA diary in that analysis 
week. Analysis week is defined as: 1st week is the 1st 7 days after visit 3 (exclusive) during titration, 
2nd week is the rest of the days up to Visit 5 (inclusive) in titration period, 3rd week is the 1st 7 
days after Visit 5 (exclusive), 4th week is the following 7 days after 3rd week, the 5th week is the 
rest of the days in maintenance period up to Visit 6 (inclusive). Adqs is the input data set with 
missing values, and adqs_imp is the complete imputed data set after 100 imputations. For the 
weekly IA score calculation, if the week has <3 daily diaries, the weekly IA score for this week will 
be set to missing and imputed using the above procedure. 
From the above multiply-imputed IA data, the Hodges-Lehmann confidence interval will be 
calculated for each imputed data set.  The point estimate for the between group difference and 
the associated standard error (sem) will be derived from the confidence interval.  These point 
estimates and the sem’s will be summarized by the SAS MIANALYZE procedure.  An example SAS 
code is as follows. 
PROC MIANALYZE DATA=parmest ; 
MODELEFFECTS estim ; 
STDERR sem ; 
ODS OUTPUT PARAMETERESTIMATES=parmest2(KEEP= paramcd label estimate 
stderr lclmean uclmean probt) ; 
RUN ; 
where estim and sem are the point estimate and standard error from each imputed set, estimate, 
stderr, lclmean, uclmean, and probt are the final summarized point estimate, standard error, 
lower and upper confidence limits, and the p-value for the between group comparison (Table 
14.2.1.2.1). 
7.8.2.2 Multiple Imputation Assuming Missing Not at Random 
This sensitivity analysis assumes that the diary data are missing not at random (MNAR), that is, 
the probability that an observation is missing may depend on its underlying unobserved value. 
This approach may be considered “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 will be used (Table 14.2.1.2.2). An example of SAS code is as follows. 


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PROC MI DATA=adqs NIMPUTE=100 SEED=123456789 OUT=adqs_imp ; 
CLASS trtp ; 
VAR age sex bwk twk1 twk2 twk3 twk4 twk5; 
FCS REG ; 
MNAR MODEL(bwk twk1 twk2 twk3 twk4 twk5 / MODELOBS=(trtp=’PLACEBO’)) ; 
RUN ; 
where multivariate imputation is carried out by the fully conditional specification (FCS) method. 
Histogram of median percent change from baseline in the frequency of IA Behaviors by 
imputation status in treatment and maintenance will be created for 36 mg dose and Placebo 
(Figure 14.2.1.2.1 – Figure 14.2.1.2.2). 
7.8.2.3 Analysis of PCH Based on Data from Maintenance Period 
For this sensitivity analysis, the primary analysis will be repeated using data restricted to the 
maintenance period only (Table 14.2.1.2.3). 
7.8.3 Supplementary Analysis  
A supplementary analysis will be performed based on the Per Protocol population and will be 
presented in Table 14.2.1.2.4.   
7.8.4 Analysis Based on Adjustment of Covariates  
An exploratory analysis of the primary efficacy endpoint will be performed using a 
randomization-based approach (Dmitrienko and Koch 2017). Separate models will be produced 
for the following key prognostic baseline characteristics (age [categorical and continuous] and 
gender [categorical]).  In addition, pooled site and baseline IA adjusted to 7 days will be used as 
covariates (Table 14.2.1.3).    
This analysis will be done by calling the following macro: 
/* Linear Model with Adjustment for Covariates for Treatment period*/ 
%NPARCOV4(OUTCOMES = PCHT, COVARS = gender age blsum, C=1, STRATA = center, TRTGRPS 
= trtp, HYPOTH = NULL, TRANSFORM = NONE, COMBINE = FIRST, DSNIN = XXXX, DSNOUT = 
XXXX, ALPHA = 0.05, SEED = XXXX, NREPS = 500, EXACT = NO, DETAILS = YES); 
The above macro call will provide estimates of treatment effect and p-value. To obtain the 95% 
confidence interval, the macro will be called again specifying HYPOTH = ALT. 


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7.8.5 Examination of Subgroups  
The primary efficacy variables will be summarized by subgroup to explore the heterogeneity of 
the treatment effect across subgroups.  This analysis will be done for the following subgroups: 
gender (male, female), age (6-9 and 10-12), and race (White, Non-white) and baseline body 
weight (approximate median baseline weight: <median vs >=median). (Table 14.2.1.4.1 - Table 
14.2.1.4.4). 
7.8.6 Analysis of Secondary Efficacy Endpoints   
The analyses of all secondary endpoints except CHQ-PF28, PSI-4-SF and SNAP-IV ADHD 
 will be based on both the mITT and ITT population but the analysis of CHQ-PF28, PSI-4-SF and 
SNAP-IV ADHD will be based on the ITT population only. 
 
7.8.6.1 Analysis of Key Secondary Efficacy Endpoint  
The key secondary efficacy endpoint is the change from baseline (Visit 3) to Visit 6 in the 
Investigator CGI-S score. 
This endpoint will be analyzed using Mixed-Effect Model for Repeated Measure (MMRM) for the 
mITT and ITT populations. The model includes treatment, visit, and interaction between 
treatment and visit as fixed factors, and 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.  In case 
there is a convergence problem in the MMRM model with the unstructured variance covariance 
matrix, the first (co)variance structure which does not have convergence problem will be used 
for the analysis from the following ordered list: 1) Toeplitz [TOEP], 2) Autoregressive of Order 1 
[AR(1)], and 3) Compound Symmetry [CS]. 
The least squares means of SPN-810 36 mg dose and placebo, the difference in the least squares 
mean (SPN-810 36 mg dose minus placebo), and the 2-sided 95% CI for the difference will be 
calculated (Table 14.2.2.1, Listing 16.2.2.2).  
An example of SAS code is provided as follows. 
ODS output DIFFS=DIF LSMEANS=LSMN; 
PROC MIXED DATA=XXXX ; 
CLASS trtp (ref=’Placebo’) usubjid visit; 
MODEL Response = base trtp visit trtp*visit / DDFM=kr ;  
REPEATED visit / SUBJECT=usubjid TYPE=UN ; 
LSMEANS trtp*visit/PDIFF ALPHA=0.05; 
RUN ; 


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Note: usubjid is subject ID, trtp is treatment variable, visit is the nominal study visit, and Response 
is respective endpoints. 
In addition, the mean change from baseline by visit will be presented in Figure 14.2.4.1. 
7.8.6.2 Analyses of Additional Secondary Efficacy Points  
The following summaries and listings will be presented. 
1. 
Investigator CGI-I score (continuous and binary) at Visits 4, 5, and 6 (Table 
14.2.2.2.1 – Table 2.2.2.2, Figure 14.2.3.1, and Listing 16.2.2.3) 
2. 
PSI-4-SF score at visit 6 in total score and domains will be summarized in Table 
14.2.2.4 (Listing 16.2.2.5.1 – Listing 16.2.2.5.2). 
a. Total Score  
b. Parental Distress  
c. Parent-Child Dysfunctional Interaction  
d. Difficult Child  
3. 
Caregiver CGI-I score (continuous and binary) by Visit (Table 14.2.2.5.1 – Table 
14.2.2.5.2, Figure 14.2.2.1,  and Listing 16.2.2.3) 
4. 
SNAP-IV ADHD scores at visit 6 will be summarized in Table 14.2.2.6 (Listing 
16.2.2.6.1 - Listing 16.2.2.6.2): 
a. Inattention ratings  
b. Hyperactivity/Impulsivity ratings  
c. Oppositional Defiant Disorder  
d. Combined Scale ratings  
5. 
Percentage of responders with 50% or more reduction in the frequency of IA from 
baseline to treatment period (Table 14.2.2.7) 
6. 
Percentage of responders with 30% or more reduction in the frequency of IA from 
baseline to treatment period (Table 14.2.2.8) 
1. 
 
 
Scores of CGI-I (investigator and caregiver) will be analyzed using a Mixed-Effect Model for 
Repeated Measure (MMRM) similar to the key secondary outcome. CGI-S will be used as baseline 
covariate. 
Scores for CHQ-PF28, PSI-4-SF, and SNAP-IV will be analyzed using analysis of covariance 
(ANCOVA) on the ITT population. The model includes treatment and baseline as fixed 
independent covariates and Visit 6 value as a response variable. The least squares mean of each 
treatment group, the difference in the least squares mean (SPN-810 36 mg dose minus placebo), 
and the 2-sided 95% CI for the difference will be obtained. 


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The SAS code for the ANCOVA will be: 
PROC MIXED DATA=XXXX ; 
CLASS trtp usubjid; 
MODEL Response = base trtp / DDFM=kr ;  
LSMEANS trtp t/PDIFF=control (‘PLACEBO’) ALPHA=0.05; 
RUN ; 
Where usubjid is subject ID, trtp is treatment variable and Response is CHQ-PF28, PSI-4-SF, and 
SNAP-IV at Visit 6. 
The Percentage of responders defined as 50% or more reduction (and 30% or more reduction) in 
the frequency of IA from baseline to treatment period will be analyzed using the logistic 
regression model with treatment as explanatory variables. Odds ratio (36 mg Dose / Placebo), 
and 95% CI for the odds ratio and p-value will be presented.  In addition, the number and 
percentage of responders will be tabulated.  
An example of SAS code follows.  
ODS OUTPUT OddsRatios=or /* ODDS RATIO AND 95% CL*/ 
LSMeans=lsm(keep=trtpn mu) /* PROB OF RESPONDERS */ ; 
PROC LOGISTIC DATA=ef1 PLOTS=none ; 
CLASS siteid trtpn / PARAM=glm ; 
MODEL avalc(EVENT="Yes")=trtpn; 
LSMEANS trtpn / PDIFF=controll('2') ILINK ; 
RUN; 
 
To control family-wise error rate at 0.05 for multiple endpoints, the key secondary endpoint and 
additional secondary endpoints will be ordered as follows: CGI-S, investigator CGI-I, CHQ-PF28, 
PSI-4-SF, caregiver CGI-I, SNAP-IV ADHD, Percentage of responders with 50% or more reduction 
in the frequency of IA, percentage of responders with 30% or more reduction in the frequency of 
IA.  The testing will proceed in the following order. 
1. Test the null hypothesis H0: There is no difference between the 36 mg dose SPN-810 and 
placebo will be performed with respect to CGI-S. If not rejected then the hypothesis will 
not be tested with respect to any additional secondary endpoint.  
2. If H0 is rejected above, then proceed to test the same null hypothesis with respect to the 
1st additional secondary endpoint (CGI-I). If not rejected then the hypothesis will not be 
tested with respect to any additional secondary endpoint after CGI-I.   
3. If H0 is rejected above for CGI-I, then test of H0 for the 2nd additional secondary endpoint 
(CHQ-PF28) will follow. If not rejected then the hypothesis testing will stop with respect 
to any subsequent additional secondary endpoint after CHQ-PF28.  Otherwise, proceed 


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to test the same null hypothesis with respect to the 3rd additional secondary endpoint 
(PSI-4-SF).  
The process will be repeated until all the secondary endpoints are gone through in the pre-
defined order above in the same manner. 
Subgroup (age, gender and race) analyses will be performed for the key secondary endpoint to 
explore the heterogeneity of the treatment effect across subgroups (Table 14.2.3.1.1-Table 
14.2.3.1.3). 
Supportive analyses will also be performed by summarizing the descriptive statistics for primary 
and secondary endpoints (Table 14.2.4.1 – Table 2.4.7).  
7.9 Safety Analyses 
Subject safety is assessed by AEs, labs, vital signs, 12-lead ECGs, and findings from the physical 
examinations. The occurrence of neurological side effects will be assessed by looking at any 
worsening in scores for each of the Simpson-Angus scale, Barnes Akathisia scale, and AIMS.  
Suicidal ideation and suicidal behavior will be measured by C-SSRS.  All summaries related to 
safety analyses will use the safety population and will be presented by treatment groups. 
7.9.1 Adverse Events 
AEs will be summarized using subject incidence table by treatment period (titration, 
maintenance, combined titration and maintenance, and tapering).  An overview of TEAE will be 
presented.  This table will include numbers and percentages of subjects experiencing at least 1 
TEAE, study drug-related TEAE, AE leading to study drug discontinuation, severe TEAE, serious 
TEAE, related TESAE, AESI, and TEAE with outcome of death (Table 14.3.1.1). 
Additionally, the number and percent (%) are calculated based on the number of unique subjects 
within each category (e.g., preferred term) by treatment group.  A subject reporting multiple 
events of the same category will be counted only once for that category.  For summary purpose, 
AE relationship to the study drug will be grouped into “Unrelated” for “unrelated” or “unlikely 
related” and “Related” for “possibly”, “probably”, or “definitely related”.  For subjects with more 
than one event coded to the same PT, the subjects will be counted for the categories with the 
strongest relationship and the greatest severity. The following subject incidence tables will be 
presented.  
• TEAEs by PT (Preferred Term) sorted by the decreasing order of subject incidence in the 
combined active dose group (Table 14.3.1.6) 
• TEAEs by SOC (System Organ Class) and PT sorted alphabetically (Table 14.3.1.2) 


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• Study Drug-Related TEAEs by SOC and PT (Table 14.3.3) 
• Severity of TEAEs by SOC and PT (Table 14.3.1.4) 
• TESAEs by SOC and PT when applicable (Table 14.3.1.5) 
• Number and percent of patients reporting common AEs (≥5% in any group) by PT (Table 
14.3.1.7) 
• TEAEs leading to study drug discontinuation by SOC and PT (Table 14.3.1.8) 
• Treatment Emergent AESI by SOC and PT (Table 14.3.1.9) 
Where warranted by the subject incidence, these same tables may be presented by treatment 
period (Titration, Maintenance and Conversion/Tapering). 
A subject data listing will be provided for all adverse events (Listing 16.2.3.1.1).  Included in the 
listing are the reported term, PT, SOC, TEAE flag, study day when AE starts, duration, relationship, 
severity, action taken, outcome, and seriousness category.  
Data listings will be provided for subjects who die on study, experience SAEs, have TEAEs leading 
to study drug discontinuation, or AEs of special interest (Listing 16.2.3.1.2 – Listing 16.2.3.1.5). 
7.9.2 Laboratory Test 
Clinical laboratory values will be summarized by treatment group and visit using descriptive 
statistics for hematology, biochemistry, and urinalysis.  For quantitative laboratory parameters, 
both actual values and change from baseline values will be summarized (Table 14.3.2.1.1, Table 
14.3.2.2.1, and Table 14.3.2.3.1).  
Laboratory test result will be assigned a low, normal, high (LNH) classification according to 
whether the value is below (L), within (N), or above (H) the reference range provided by the 
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 laboratory values will be provided for subjects who 
have L or H classification in any of their laboratory tests (Table 14.3.2.1.2, Table 14.3.2.2.2, and 
Table 14.3.2.3.2).  
Note the summary and shift tables will only use the planned/scheduled tests.  However, both 
scheduled and repeat tests will be in the data listing. 
A complete lab data listing, including hematology, biochemistry, and urinalysis will be provided 
for all subjects.  Investigator assessment of clinical significance is based on the local laboratory 
reference ranges (Listing 16.2.3.2.1 – Listing 16.2.3.2.3). 


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7.9.3 Vital Signs, Height, Weight, and BMI 
Vital signs (body temperature, heart rate, respiration rate, systolic blood pressure, and diastolic 
blood pressure), and their changes from baseline will be summarized by treatment group and 
visit (Table 14.3.3.1, Listing 16.2.3.3.1 - Listing 16.2.3.3.2).  Subject body size (weight, height, and 
BMI) will be summarized similarly (Table 14.3.3.2, Listing 16.2.3.3.3). 
7.9.4 12-Lead ECG 
By-visit 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 interval will be corrected using Fridericia’s method.  
ECG results will be summarized by visit 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 
screening values will be summarized (Table 14.3.4.1 and Table 14.3.4.2).  
Data listings will be presented for ECG parameters by visit.  QTcF meeting the criteria of >450 but 
≤480, >480 but ≤500 or >500 msec for the absolute value, or >30 msec or >60 msec increase from 
baseline will be identified (Listing 16.2.3.4.1 and Listing 16.2.3.4.3). 
7.9.5 Columbia Suicide Severity Rating Scale (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 groups. (Table 14.3.5 and Listing 16.2.3.5).  
7.9.6 Infrequent Behaviors Checklist 
Infrequent behaviors will be listed for each subject by treatment group (Table 14.3.7 and Listing 
16.2.3.7).  
7.9.7 Other Special Tests 
The occurrence of neurological side effects will be assessed by looking at the changes in scores 
from baseline to post-baseline visits for each of the Simpson-Angus scale (Table 14.3.6.1.1 - Table 
14.3.6.1.2 and Listing 16.2.3.6.1), Barnes Akathisia scale (Table 14.3.6.2.1 - Table 14.3.6.2.2 and 
Listing 16.2.3.6.2), and AIMS (Table 14.3.6.3.1 - Table 14.3.6.3.2 and Listing 16.2.3.6.3). 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.  


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8 VALIDATION  
The Clinical Operations, Clinical Research, and Statistics groups at Supernus will work with 
 
and 
to ensure that the data collected for the study are of the highest quality possible. The 
study monitor will be responsible for reviewing and verifying the accuracy of the data recorded 
on the electronic case report forms (eCRFs) direct from source documents at the investigative 
site. DSG will be responsible for performing edit checks and reviewing all data entered into the 
electronic database to identify discrepant and/or inconsistent values and to send queries to the 
clinical sites. The Investigator will be responsible for answering queries about discrepant data 
and providing electronic signatures to confirm data integrity.  
The programming of Tables, Listings and Figures (TLFs) based on the clinical data is outsourced 
to
 Supernus seeks to ensure the quality of the reports 
provided by
 in the form of TLFs must pass a rigorous validation process involving the 
following processes.  
 
• Derived datasets must be independently reprogrammed by a second programmer. The 
separate datasets produced by the 2 programmers must match 100%.  
• Tables must be independently reprogrammed by a second programmer for and the 
results from both programs must match.  
• Figures must be checked for consistency against corresponding tables and listings, or 
independently reprogrammed if there are no corresponding tables or listings.  
• Listings must be checked for consistency against corresponding tables, figures, and 
derived datasets.  
 
The entire set of TLF must be checked for completeness and consistency prior to its delivery to 
Supernus.  
 
The above validation process must be repeated any time TLFs are redelivered using different 
data. Execution of this validation process must be documented through the study Table of 
Programs that will be provided to Supernus at study conclusion. 
9 REFERENCES 
Brannath W, M Posch, P Bauer. Recursive combination tests. Journal of the American Statistical 
Association. 2002; 97: 236-244.  
Chang, M. Adaptive Design Theory and Implementation Using SAS and R. Chapman & Hall/CRC, 
Boca Raton, Florida. 2008a. 


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Change, M. Classical and Adaptive Clinical Trial Designs Using ExpDesign Studio. Wiley, New 
Jersey. 2008b. 
Chen, YH, DL DeMets, and KKG Lan. “Increasing the sample size when the unblinded interim result 
is promising.” Statistics in Medicine, 2004. 23: 1023-1038. 
HealthActCHQ. The CHQ Scoring and Interpretation Manual. Boston, MA: HealthActCHQ, 2013.  
2013.   
Dmitrienko, A, RB D’Agostino. Tutorial in Biostatistics: Traditional multiplicity adjustment 
methods in clinical trials. Statistics in Medicine. 2013; 32:5172-5218.  
Dmitrienko A, AC Tamhane, and F Bretz. Multiple Testing Problems in Pharmaceutical Statistics. 
Chapman & Hall/CRC, Boca Raton, Florida. 2010. 
Dmitrienko, A and GG Koch. Analysis of Clinical Trials Using SAS: A Practical Guide. 2nd Ed. Cary, 
NC: SAS Institute Inc. 2017. 
Hintze, J. PASS 12, NCSS, LLC. Kaysville, Utah, USA. 2013. 
Hommel, G. Adaptive modifications of hypotheses after an interim analysis. Biometrical Journal. 
2005; 5: 581-589.  
Jennison C and Turnbull BW. Group Sequential Methods with Applications to Clinical Trials. 
Chapman & Hall/CRC, Boca Raton, Florida. 2000. 
Mehta CR and SJ Pocock. “Adaptive increase in sample size when interim results are promising: 
a practical guide with examples.” Statistics in Medicine, 2000. 00:1-6. 
Wang, SJ, HMJ Hung, Y Tsong, L Cui. Group sequential test strategies for superiority and non-
inferiority hypotheses in active controlled clinical trials. Statistics in Medicine. 2001; 20: 1903-
1912.  
 
 


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Appendix 1. Exclusion Criteria for the Per Protocol Populations 
 
 
 
 


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Appendix 2. List of Tables, Listings, and Figures 
Tables 
Table 14.1.1   Summary of Subject Disposition and Reason for Discontinuation by Treatment Group and 
Period   (Randomized Population) 
Table 14.1.2.1 Demographics and Baseline Characteristics  (ITT Population) 
Table 14.1.2.2  Subject Demographic Characteristics and Reason for Screening Failure  (Screening 
Failure Subjects) 
Table 14.1.2.3  Subject Enrollment Distribution by Study Site  (ITT Population) 
Table 14.1.2.4  Summary of Major Protocol Deviations During the Study, by Treatment Group  (ITT 
Population) 
Table 14.1.3.1  Medical History by System Organ Class and Preferred Term  (Safety Population) 
Table 14.1.3.2 Prior Medications by ATC Code and Preferred Term  (Safety Population) 
Table 14.1.3.3  Concomitant Medications by ATC Code and Preferred Term  (Safety Population) 
Table 14.1.3.4  Subjects with ≥5% Allowed Concomitant Medications by ATC Code and Preferred Term  
(Safety Population) 
Table 14.1.4  Exposure to Study Medication and Compliance  (ITT Population) 
Table 14.1.5.1.1  Retrospective Modified Overt Aggression Scale at Baseline – Item Scores  (ITT 
Population) 
Table 14.1.5.1.2  Retrospective Modified Overt Aggression Scale at Baseline – Domain and Total Scores  
(ITT Population) 
Table 14.1.5.2.1  Vitiello Aggression Scale (VAS) at Baseline – Item Scores  (ITT Population) 
Table 14.1.5.2.2  Vitiello Aggression Scale (VAS) at Baseline – Domain and Total Scores  (ITT Population) 
Section 14.2 – Efficacy Tables 
Table 14.2.1.1   Percent Change from Baseline in the Average Weekly Frequency of IA Behaviors During 
the Treatment Period [1] - (mITT and ITT Population) 
Table 14.2.1.2.1 Percent Change from Baseline in the Average Weekly Frequency of IA Behaviors 
During the Treatment Period [1] - Sensitivity Analysis, Multiple Imputation with MAR Assumption  (mITT 
and ITT Population) 
Table 14.2.1.2.2  Percent Change from Baseline in the Average Weekly Frequency of IA Behaviors 
During the Treatment Period [1] – Sensitivity Analysis, Multiple Imputation (mITT and ITT Population) 
Table 14.2.1.2.3  Percent Change from Baseline in the Average Weekly Frequency of IA Behaviors 
During the Maintenance Period - Sensitivity Analysis  (mITT and ITT Population) 
Table 14.2.1.3  Percent Change from Baseline to Treatment Period in Frequency of IA Behaviors: 
Adjustment for Covariates using Randomization-Based Approach of Dmitrienko and Koch  (mITT and ITT 
Population) 
Table 14.2.1.4.1  Percent Change from Baseline in the Average Weekly Frequency of IA Behaviors 
During the Treatment Period by Gender - Subgroup Analysis  (mITT and ITT Population) 
Table 14.2.1.4.2  Percent Change from Baseline in the Average Weekly Frequency of IA Behaviors 
During the Treatment Period by Age - Subgroup Analysis  (mITT and ITT Population) 
Table 14.2.1.4.3  Percent Change from Baseline in the Average Weekly Frequency of IA Behaviors 
During the Treatment Period by Race - Subgroup Analysis  (mITT and ITT Population) 


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Table 14.2.1.4.4  Percent Change from Baseline in the Average Weekly Frequency of IA Behaviors 
During the Treatment Period by Baseline Body Weight - Subgroup Analysis  (mITT and ITT Population) 
Table 14.2.2.1  Investigator Clinical Global Impression – Severity (CGI-S) Score and Change from 
Baseline by Visit  (mITT and ITT Population) 
Table 14.2.2.2.1  Investigator Clinical Global Impression – Improvement (CGI-I) Score by Visit (mITT and 
ITT Population) 
Table 14.2.2.2.2  Summary of Investigator Clinical Global Impression – Improvement (CGI-I) Score by 
Visit (mITT and ITT Population) 
Table 14.2.2.3.1  Child Health Questionnaire Parent Form 28 (CHQ-PF28)- Scale Scores and Change from 
Baseline to Visit 6  (ITT Population) 
Table 14.2.2.3.2  Child Health Questionnaire Parent Form 28 (CHQ-PF28)-Component Scores and 
Change from Baseline to Visit 6  (ITT Population) 
Table 14.2.2.4  Parenting Stress Index - Short Form (PSI-4-SF) Observed Scores and Change from 
Baseline to Visit 6  (ITT Population) 
Table 14.2.2.5.1 Caregiver Clinical Global Impression – Improvement (CGI-I) Score by Visit  (mITT and 
ITT Population) 
Table 14.2.2.5.2  Summary of Caregiver Clinical Global Impression – Improvement (CGI-I) Score by Visit 
(mITT and ITT Population) 
Table 14.2.2.6  SNAP-IV ADHD Inattention Subscale Score and Actual Value at Visit 6  (ITT Population) 
Table 14.2.2.7  Percentage of responders with 50% or more reduction in the frequency of IA from 
baseline by the Treatment Period (mITT and ITT Population) 
Table 14.2.2.8  Percentage of responders with 30% or more reduction in the frequency of IA from 
baseline by the Treatment Period (mITT and ITT Population) 
Table 14.2.3.1.1  Subgroup Analysis of Investigator Clinical Global Impression – Severity (CGI-S) Score by 
Age Group and Visit  (mITT and ITT Population) 
Table 14.2.3.1.2 Subgroup Analysis of Investigator Clinical Global Impression – Severity (CGI-S) Score by 
Gender and Visit  (mITT and ITT Population) 
Table 14.2.3.1.3  Subgroup Analysis of Investigator Clinical Global Impression – Severity (CGI-S) Score by 
Race and Visit (mITT and ITT Population) 
Table 14.2.4.1  Descriptive Statistics for Frequency of IA Behaviors Per 7 Days and Change from Baseline 
by Study Period (mITT and ITT Population) 
Table 14.2.4.2  Descriptive Statistics of Observed Investigator Clinical Global Impression – Severity (CGI-
S) by Visit - Supportive Analysis (mITT and ITT Population) 
Table 14.2.4.3  Descriptive Statistics of Observed Investigator Clinical Global Impression (CGI-I) by Visit - 
Supportive Analysis (mITT and ITT Population) 
Table 14.2.4.4  Descriptive Statistics of Child Health Questionnaire Parent Form 28 (CHQ-PF28) by Visit - 
Supportive Analysis  (ITT Population) 
Table 14.2.4.5  Descriptive Statistics of Parenting Stress Index - Short Form (PSI-4-SF) by Visit - 
Supportive Analysis  (ITT Population) 
Table 14.2.4.6  Descriptive Statistics of Observed Caregiver Clinical Global Impression – Improvement 
(CGI-I) by Visit - Supportive Analysis (ITT Population) 
Table 14.2.4.7  Descriptive Statistics of SNAP-IV ADHD Observed Scores by Visit - Supportive Analysis  
(ITT Population) 


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Table 14.3.1.1  Overall Incidence of Treatment-Emergent Adverse Events by Study Period  (Safety 
Population) 
Table 14.3.1.2  Subject Incidence of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Period  (Safety Population) 
Table 14.3.1.3  Subject Incidence of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, Treatment-Relatedness, and Treatment Period  (Safety Population) 
Table 14.3.1.4  Subject Incidence of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, Severity, and Treatment Period  (Safety Population) 
Table 14.3.1.5  Subject Incidence of Treatment-Emergent Serious Adverse Events by System Organ 
Class, Preferred Term and Treatment Period  (Safety Population) 
Table 14.3.1.6  Subject Incidence of Treatment-Emergent Adverse Events by Preferred Term and 
Treatment Period  (Safety Population) 
Table 14.3.1.7  Incidence of Common Treatment-Emergent Adverse Events Reported for >=5% of 
Subjects in Any Group by Preferred Term and Treatment Period  (Safety Population) 
Table 14.3.1.8  Subject Incidence of Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class, Preferred Term and Treatment Period  (Safety Population) 
Table 14.3.1.9  Subject Incidence of Treatment-Emergent Adverse Events of Special Interest by System 
Organ Class, Preferred Term and Treatment Period  (Safety Population) 
Table 14.3.2.1.1  Hematology: Change from Baseline by Visit  (Safety Population) 
Table 14.3.2.1.2  Hematology: Shift from Baseline Classification by Visit  (Safety Population) 
Table 14.3.2.2.1  Blood Chemistry: Change from Baseline by Visit  (Safety Population) 
Table 14.3.2.2.2  Blood Chemistry: Shift from Baseline Classification by Visit  (Safety Population) 
Table 14.3.2.3.1  Urinalysis: Change from Baseline by Visit  (Safety Population) 
Table 14.3.2.3.2  Urinalysis: Shift from Baseline Classification by Visit  (Safety Population) 
Table 14.3.3.1  Vital Signs: Change from Baseline by Visit  (Safety Population) 
Table 14.3.3.2  Subject Body Size, Change from Baseline by Visit  (Safety Population) 
Table 14.3.4.1  12-Lead ECG Intervals: Change from Baseline by Visit  (Safety Population) 
Table 14.3.4.2  12-Lead ECG Overall Findings: Shift from Baseline Classification by Visit  (Safety 
Population) 
Table 14.3.5  Columbia Suicide Severity Rating Scale by Visit  (Safety Population) 
Table 14.3.6.1.1 Simpson-Angus Scale (SAS) Item Score and Change from Baseline by Visit  (Safety 
Population) 
Table 14.3.6.1.2  Simpson-Angus Scale (SAS) Item Score: Shift from Baseline by Visit  (Safety Population) 
Table 14.3.6.2.1  Barnes Akathisia Rating Scale (BAS) Item Score and Change from Baseline by Visit  
(Safety Population) 
Table 14.3.6.2.2  Barnes Akathisia Rating Scale (BAS): Shift from Baseline by Visit  (Safety Population) 
Table 14.3.6.3.1  Abnormal Involuntary Movement Scale (AIMS) Item Score and Change from Baseline 
by Visit  (Safety Population) 
Table 14.3.6.3.2  Abnormal Involuntary Movement Scale (AIMS): Shift from Baseline by Visit  (Safety 
Population) 
Table 14.3.7  Infrequent Behaviors Checklist by Visit  (Safety Population) 
 


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Figures 
Figure 14.2.1.1 Median Percent Change from Baseline in the Frequency of IA Behaviors in Treatment 
Period by Stage (ITT Population) 
Figure 14.2.1.2.1 Median Percent Change from Baseline in the Frequency of IA Behaviors by Imputation 
Status (ITT Population) 
Figure 14.2.1.2.2 Median Percent Change from Baseline in the Frequency of IA Behaviors in the 
Maintenance Period (ITT Population) 
Figure 14.2.2.1 Mean of Caregiver Clinical Global Impression – Improvement (CGI-I) Score by Visit  (ITT 
Population) 
Figure 14.2.3.1 Mean of Investigator Clinical Global Impression – Improvement (CGI-I) Score by Visit (ITT 
Population) 
Figure 14.2.4.1 Mean Change from Baseline of Investigator Clinical Global Impression – Severity (CGI-S) 
Score by Visit (ITT Population) 
Figure 14.2.5.1 Median Change from Baseline of Child Health Questionnaire Parent Form 28 (CHQ-
PF28)- Physical Functioning Summary Score by Visit (ITT Population) 
Figure 14.2.5.2 Median Change from Baseline of Child Health Questionnaire Parent Form 28 (CHQ-
PF28)- Psychosocial Health Summary Score by Visit (ITT Population) 
 
Listings  
Listing 16.1.7 Subject Randomization Schedule(Randomized Population) 
Listing 16.2.1.1  Subjects Disposition and Reason for Disposition  (Randomized Population) 
Listing 16.2.1.2  Subjects Who had Major Protocol Deviations  (Randomized Population) 
Listing 16.2.1.3  Subjects Inclusion and the Reason for Exclusion from Analysis Populations  
(Randomized Population) 
Listing 16.2.1.4  Demographic and Baseline Characteristics  (Randomized Population) 
Listing 16.2.1.5  Medical History  (Randomized Population) 
Listing 16.2.1.6  R-MOAS Scale at Baseline  (Randomized Population) 
Listing 16.2.1.7  Viteillo Aggression Scale at Baseline (Randomized Population) 
Listing 16.2.1.8  Study Drug Accountability and Compliance  (Randomized Population) 
Listing 16.2.1.9.1  Prior Medications  (Randomized Population) 
Listing 16.2.1.9.2  Concomitant Medications  (Randomized Population) 
Listing 16.2.1.9.3  Prohibited Medications  (Randomized Population) 
Listing 16.2.2.1.1  Impulsive Aggression Behavior Daily Diary  (ITT Population) 
Listing 16.2.2.1.2  Derived Primary Endpoint  (ITT Population) 
Listing 16.2.2.2  Investigator Clinical Global Impression – Severity (CGI-S)  (ITT Population) 
Listing 16.2.2.3  Investigator and Caregiver Clinical Global Impression – Improvement (CGI-I)  (ITT 
Population) 
Listing 16.2.2.4.1  Child Health Questionnaire Parent Form 28 (CHQ-PF28)– Question Text 
Listing 16.2.2.4.2  Child Health Questionnaire Parent Form 28 (CHQ-PF28) – Individual Questions  (ITT 
Population) 


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Listing 16.2.2.4.3  Child Health Questionnaire Parent Form 28 (CHQ-PF28) – Items, Components and 
General Health Scores  (ITT Population) 
Listing 16.2.2.5.1  Parenting Stress Index – Short Form (PSI-4-SF) – Individual Questions  (ITT Population) 
Listing 16.2.2.5.2  Parenting Stress Index – Short Form (PSI-4-SF) – Domain and Total Scores  (ITT 
Population) 
Listing 16.2.2.6.1  SNAP-IV ADHD Teacher and Parent Rating Scale – Individual Questions  
(ITT Population) 
Listing 16.2.2.6.2  SNAP-IV ADHD Teacher and Parent Rating Scale – Subscales  (ITT Population) 
Listing 16.2.3.1.1  All Adverse Events  (Safety Population) 
Listing 16.2.3.1.2  Serious Adverse Events  (Safety Population) 
Listing 16.2.3.1.3  Adverse Events with Outcome of Death  (Safety Population) 
Listing 16.2.3.1.4  Adverse Events Leading to Study Drug Discontinuation  (Safety Population) 
Listing 16.2.3.1.5  Adverse Events of Special Interest  (Safety Population) 
Listing 16.2.3.2.1  Clinical Laboratory Tests-Hematology  (Safety Population) 
Listing 16.2.3.2.2 Clinical Laboratory Tests - Blood Chemistry  (Safety Population) 
Listing 16.2.3.2.3  Clinical Laboratory Tests – Urinalysis  (Safety Population) 
Listing 16.2.3.3.1  Vital Signs  (Safety Population) 
Listing 16.2.3.3.2  Derived Vital Signs Variables  (Safety Population) 
Listing 16.2.3.3.3  Subject Body Size  (Safety Population) 
Listing 16.2.3.4.1  12-Lead ECG Intervals  (Safety Population) 
Listing 16.2.3.4.2  12-Lead ECG Overall Interpretation  (Safety Population) 
Listing 16.2.3.4.3  Derived 12-Lead ECG Variables  (Safety Population) 
Listing 16.2.3.5  Columbia Suicidal Severity Rating Scale  (Randomized Population) 
Listing 16.2.3.6.1  Simpson-Angus Rating Scale  (Safety Population) 
Listing 16.2.3.6.2  Barnes Akathisia Rating Scale  (Safety Population) 
Listing 16.2.3.6.3  Abnormal Involuntary Movement Scale  (Safety Population) 
Listing 16.2.3.7  Infrequent Behaviors  (Safety Population) 
 
 
 
Appendix 3. Table, Figures and Listing Shells  
Shells are presented as a separate document.