Clinical trial NCT02691182
Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
Sponsor: Supernus Pharmaceuticals, Inc.
Start date: 2016-04-01; Completion date: 2021-05-01
Enrollment: 491 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Children between the ages of 6-12 years who are diagnosed with impulsive aggression comorbid with ADHD and have participated in the 810P301 or 810P302 study were invited to participate in this study. This was a Phase 3 open-label extension (OLE) study to collect long-term safety data on the use of SPN-810 in treating impulsive aggression in pediatric subjects with ADHD when taken in conjunction with standard ADHD treatment. After confirmation of eligibility, all subjects were treated with SPN-810. Subjects were given a choice to extend participation in this study every 6 months for up to 36 months.

Detailed description:
Study 810P304 is a multicenter, open-label, extension study aimed to assess safety of SPN-810 in the treatment of IA in patients aged 6-17 years with ADHD in conjunction with standard ADHD treatment.

The study has three phases: Optimization, Maintenance, and Taper. All subjects who complete the randomized, double-blind portion of study 810P301, 810P302, 810P503 or 810P204 will have the option to participate in the OLE study in which all subjects will receive active Study Medication (SM) treatment. Subjects who choose to participate in the OLE will receive blinded conversion medication kits at Visit 6 of the previous SPN-810 double-blind randomization study (810P301, 810P302) or at Visit 4 for subjects completing the 810P204 study. Subjects, who have completed the 810P503 study and, chose to participate in this study, will receive the blinded conversion card at Visit 7.

Arms: arm 1: Subjects aged 6-17 years were treated with SPN-810 starting on day 1 with 18 mg/day. The clinician was able to adjust the dose of SPN-810 throughout the study based on subject's response and tolerability within the limits of 6 mg/day and 36 mg/day or, up to 54 mg/day for subjects with a body weight ≥ 30 kg.

The subjects were given a choice of extending their participation in the study every 6-month period for up to 36 months
Interventions: intervention 1: SPN-810
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE 
Protocol Number: 
810P304 
Title: 
Open-Label Extension Study to Evaluate the Long-Term Safety of Molindone 
Hydrochloride Extended-Release Tablets for the Treatment of Impulsive 
Aggression in Pediatric and Adolescent Subjects with Attention 
Deficit/Hyperactivity Disorder (ADHD) in Conjunction with Standard ADHD 
Treatment 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
  
 
 
 
 
IND number: 
106,515  
Investigational 
Medicinal Product: 
Molindone Hydrochloride Extended-Release Tablets (SPN-810) 
Indication: 
Treatment 
of 
Impulsive 
Aggression 
in 
subjects 
with 
Attention 
Deficit/Hyperactivity Disorder (ADHD) in conjunction with standard ADHD 
treatment 
Medical Monitor 
 
 
 
 
  
 
 
Phase: 
3 
Protocol Version: 
5.0 
Release Date: 
22 Feb 2019 
Good Clinical Practice 
(GCP) Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonization (ICH) GCP and all applicable local regulations.  
All required study documentation will be archived as required by regulatory 
authorities. 
 


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


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PROTOCOL APPROVAL PAGE 


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SUMMARY OF CHANGES 
This summary table lists all clarifications, administrative changes, or amendments to Supernus protocol 
812P304.  Additions are denoted by bold letters, and deletions by strikethrough.  
Section 
Page 
Description of Change 
Rationale 
Changes to 810P304 V1.0 Dated 21 Jan 2015 
Title Page 
1 
Protocol version and date was updated 
Administrative 
List of 
Abbreviations 
14 
List of Abbreviations was updated to include Adverse 
Event of Special Interest (AESI)  
For clarification 
Table 1 
25, 26 
Table 1 was updated to include drug compliance during 
Visit 2, 3 and 4, visit windows and footnotes. 
For Clarification 
4.2.1-4.2.7 
27-30 
Each of these sections was updated to include:  
Administer Investigator and Caregiver CGI-I 
For Clarification 
4.4 
33 
The following was added: 
 
4.4 
Prohibited Medications: 
Subjects may not be on any prohibited medication. 
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 
 
activity 
• 
Herbal supplements 
For Clarification 
5.1.3.1 
37 
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 
 
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 


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5.1.3.1 
37 
The E-mail address for drug safety contact was updated: 
 
Administrative 
5.1.3.2. 
37, 
38 
The following was added:  
 
The Investigator must complete a Pregnancy Outcome 
Form as a follow up. 
For Clarification 
5.1.3.2 
38  
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 
5.1.5 
39 
The following was added:  
 
Any repeat laboratory testing will be conducted under 
fasting condition. 
For Clarification 
5.2.2 
40 
The following was changed: 
 
CGI-I, relative to the condition at baseline (Visit 3 in the 
double-blind study 810P301 or 810P302), 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 
6.4 
43 
The following was added:  
 
Only one (primary) reason for study discontinuation will 
be recorded for each subject. 
For Clarification 
6.9 
46 
The following was added: 
 
The quality of life endpoints (CHQ-PF28 and PSI-4-SF) 
subscales (Parental Distress, Parent-Child Dysfunctional 
Interaction and Difficult Child), will be listed and 
summarized by group of the optimized dose. 
 
For Clarification 
Changes to 810P304 V2.0 Dated 16 Dec 2016 
Protocol version 2.0 was amended to allow adolescents (subjects 13-17 years of age) inclusion in the open-
label study. 


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Title Page 
1 
Protocol version and date was updated 
Administrative 
Signature 
Page 
3 
The signature page was updated 
Administrative 
Signature 
Page 
3 
Authorship updated 
One of the  was changed: 
 
 
 
Administrative 
Synopsis 
8 
The following was added: 
 
5.    Weight of at least 20 kg for 6-12 year old subjects. 
Procedural 
Synopsis 
8 
The following was changed: 
 
Criteria for Exclusion: 
1. Body Mass Index (BMI) in less than 25th and above 99th 
percentile for 13-17 year old subjects only. 
3   4. Criminal arrest or report at least 6 months prior to 
Visit 2. 
Procedural 
List of 
Abbreviation 
16 
The following was changed: 
 
FOCP changed to FOCBP 
To Clarify 
3.1 
23 
The following was changed: 
 
The present study is designed to collect long-term safety 
data for the use of SPN-810 in the treatment of IA in 
subjects aged 6 to 12 17 
Procedural 
3.1 
23 
The following was added: 
 
SPN-810 was used in Phase 2 and Phase 3 studies for the 
treatment of IA in children and adolescents with ADHD 
Procedural 
3.2 
23 
The following was changed: 
 
Study 810P304 is a multicenter, open-label, extension 
study aimed to assess safety of SPN-810 in the treatment 
of IA in patients aged 6-12 17 years with ADHD 
Procedural 
4.1.1 
25 
The following was changed: 
 
Inclusion Criteria: 
5. Weight of at least 20 kg for 6-12 year old subjects. 
 
Procedural 
4.1.2 
25 
The following was changed: 
 
Exclusion Criteria 
1. Body Mass Index (BMI) in less than 25th and above 
99th percentile or above for 13-17 year old subjects 
only.  
Procedural 


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3. 4. Criminal arrest or report at least 6 months prior to 
Visit 2. 
Table 1 
28 
The following was added: 
 
d 
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 
4.2.1. 4.2.5, 
4.2.6, 4.2.7 
and 4.2.8 
29,30,3
1,32 
The following was changed: 
 
FOCP changed to FOCBP 
To Clarify 
Table 3  
41 
The following was changed: 
 
FOCP changed to FOCBP 
To Clarify 
Changes to 810P304 V3.0 Dated 17 August 2017 
The protocol Version 3.0 was submitted to the IRB but the submission was withdraw before approval. 
 
Summary of revisions in addition to administrative changes made to Version 3.0  
 
Allow inclusion of additional studies (i.e 810P503 and 810P204) 
 
Increase study medication dose-range due to adolescents inclusion 
 
Explore Molindone pharmacogenomics   
 
Socio-demographic characteristics addition as a quality of life variable 
 
Home urine pregnancy test at each visit during maintenance phase 
 
Urine sample for drug screen at each visit during maintenance phase 
 
Preferred Akathisia treatment 
Title Page 
1 
The following was added: 
 
Open-Label Extension Study to Evaluate the Long-Term 
Safety of Molindone Hydrochloride Extended-Release 
Tablets for the Treatment of Impulsive Aggression in 
Pediatric and Adolescent Subjects  with Attention 
Deficit/Hyperactivity Disorder (ADHD) in Conjunction with 
Standard ADHD Treatment 
 
 
 
Protocol version and date was updated 
Administrative 
Approval Page 
3 
The signature page was updated : 
 
 
 
 
 
  
Administrative 
 
 
 
 
 
 
 
 


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Synopsis
 
 
26 
 
The following was added: 
 
Full Title of Study:  Open-Label Extension Study to 
Evaluate the Long-Term Safety Molindone Hydrochloride 
Extended-Release Tablets for the Treatment of Impulsive 
Aggression in Pediatric and Adolescent Subjects with 
Attention Deficit/Hyperactivity Disorder (ADHD) in 
Conjunction with Standard ADHD Treatment. 
To Clarify 
Synopsis 
26 
The following was changed: 
 
The objective of this Phase 3 Open-Label Extension (OLE) 
study is to collect additional long-term safety data on the 
use of SPN-810 as a treatment for impulsive aggression 
(IA) in pediatric and adolescents subjects with ADHD 
when taken in conjunction with standard ADHD 
treatment 
These subjects would have completed a satisfactory 
participation in the double-blind studies 810P301, or 
810P302, 810P503 or 810P204. 
To clarify the inclusion 
of additional studies 
Synopsis 
26 
The following was changed: 
 
Approximately 600 subjects who have completed a 
satisfactory participation in 810P301 study or, 810P302, 
810P503 or 810P204 studyies and/or converted after 
discontinuation from one of these previous double-blind 
randomized studies. 
To clarify the inclusion 
of additional studies 
Synopsis 
26 
The following was changed: 
 
Criteria for Inclusion: 
1. Completed and converted from a satisfactory 
participation in the studyies 810P301, or 810P302, 
810P503 or 810P204, or discontinued early during 
the maintenance phase from one of these previous 
studies and allowed to enroll only after consultation 
between the Investigator, the Medical Monitor and 
the Sponsor, 
3. Existing diagnosis of ADHD, as described by DSM-5 
and confirmed by the K-SADS PL 2013 from study 
To account for the 
inclusion of additional 
studies 


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810P301 or 810P302 or by the MINI-KID from study 
810P503 or 810P204. 
5. Weight of at least 20 kg for 6-12 year old subjects. 
Synopsis
 
 
26, 27 
The following was changed: 
 
Criteria for Exclusion: 
1.     Body Mass Index (BMI) in the less than 25th and 
above 99th percentile or above for 13-17 year old subjects 
only. 
3. Pregnancy, breastfeeding or refusal to practice 
contraception during the study (for female subjects of 
childbearing potential and sexually active males). 
4. Criminal arrest or report at least 6 months prior to 
Visit 2. 
5. Suicidal thoughts or behaviors confirmed at Visit 7 
from for 810P301 or 810P302, Visit 8 for 810P503 or 
Visit 6 for 810P204 studies. 
To Clarify 
Synopsis 
27 
The following was changed: 
 
Treatment, Dose, and Mode of Administration: 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
To account for the 
inclusion of additional 
studies 


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Synopsis 
27 
The following was added: 
 
Just prior to the End of Study (EOS) visit, subjects who 
complete at least one maintenance phase will be 
instructed to taper off study medication over a period of 
2 weeks. 
To Clarify 
Synopsis
 
 
27 
The following was added: 
 
Once treatment on the previous clinical study is complete 
and consent obtained for this study, the Investigator will 
initiate the subjects at 
 
 
 
 
 
 
 
To account for the 
inclusion of additional 
studies 
Synopsis 
28 
The Following was added: 
 
2. Parenting Stress Index (PSI-4-SF) or Stress Index for 
Parents of Adolescents (SIPA) 
3. Socio-demographics 
For the inclusions of 
adolescents 
Synopsis 
28 
The following was added: 
 
Pharmacogenomic (PGx): 
For subjects already enrolled in this study a blood sample 
for PGx analysis will be collected at the next visit 
following this amendment. For newly enrolled subjects, 
the blood sample for PGx analysis will be obtained at 
screening. Prior to testing all subjects will be consented 
for PGx testing.  
The DNA will be extracted and tested for any genetic 
variations associated with 
 enzyme. This enzyme 
is involved in the metabolism of molindone and genetic 
variation may affect the pharmacokinetics of the drug. 
The residual DNA will be stored for possible testing of 
genes involved in the efficacy and possible association 
with particular adverse events of the drug (e.g., 
understand the non-responders to treatment and/or 
individuals who show unusual safety profile). The DNA 
analysis will not be used for individual genetic 
characterization and the subject identity will be kept 
confidential. The PGx report may be a stand-alone 
document.    
To explore the 
pharmacogenomics of 
the study medication 
List of 
Abbreviations 
36 
List of Abbreviations was updated to include MINI-KID 
(Mini 
International 
Neuropsychiatric 
Interview 
for 
Administrative 


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Children and Adolescents) and PGx (Pharmacogenomic) 
and SIPA (Stress Index for Parents of Adolescents) 
Sec. 1.4 
40, 41 
The following was added: 
 
The Sponsor is conducting two Phase 3 multicenter, 
randomized, double-blind, placebo controlled trials in a 
pediatric population of subjects 6-12 years of age and one 
in adolescents (12-17 years old) diagnosed with ADHD and 
IA (810P301, and  810P302 and 810P503, respectively). 
The primary objective of both these studies is to assess the 
efficacy and safety of SPN-810 in reducing the frequency 
of IA behaviors in pediatric and adolescent patients with 
ADHD when taken in conjunction with standard ADHD 
treatment. 
Additional secondary endpoints include the assessment of 
subjects and caregivers quality of life using the Child 
Health Questionnaire Parent Form 28-item (CHQ-PF28) 
and the Parenting Stress Index-Short Form (PSI-4-SF) or 
the Stress Index for Parents of Adolescents (SIPA). 
Children 6 to 12 years of age with ADHD and the 
associated feature of IA are randomized, with 97 subjects 
in each treatment arm 
). 
 
 
 
 
 
 
For the 810P503 study, 93 patients diagnosed with ADHD 
and the associated feature of IA are randomized to 
placebo or a flexible dose of SPN-810. After two weeks of 
titration, the dose will be maintained at
 
during the first week of maintenance and then increased 
up to
 the discretion of the Investigator 
during the following two weeks. After the completion of 
the maintenance phase, subjects will enter a taper down 
period if they decide to discontinue, or will be given the 
option to enroll in the OLE (810P304 study). Subjects who 
choose to enroll in the OLE will receive a blinded 
conversion card and enter the OLE study at
. 
To account for the 
inclusion of additional 
studies 
Sec. 1.5 
41, 42 
The following was changed: 
 
This Phase 3 study, 810P304, is available to eligible 
subjects who complete the randomized, double blind 
portion of one of the threewo Phase 3 studies, 810P301, 
or 810P302, 810P503 or the additional Phase 2 study, 
810P204.  Subjects who discontinue during the 
maintenance phase prior to Visit 6 may be allowed to 
To account for the 
inclusion of additional 
studies 


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participate in the OLE on a case-by-case basis only after 
consultation between the Investigator, the Medical 
Monitor and the Sponsor. 
In addition to safety, we will assess the frequency and 
severity 
of 
aggressive 
behaviors 
using 
the  
R-MOAS scale, and the severity and improvement of IA 
using the CGI scales. Changes in CHQ-PF28 and PSI-4-SF or 
SIPA scores will be used to evaluate improvement of 
quality of life of both the subject and the caregiver. 
Sec. 2.1 
42 
The following was added: 
 
The objective of this Phase 3 OLE study is to collect long-
term safety data on the use of SPN-810 as a treatment for 
IA in pediatric subjects (6-17 years of age) with ADHD 
when taken in conjunction with standard ADHD treatment 
only after satisfactory participation in a preceding double-
blind study (810P301, or 810P302, 810P503 or 810P204). 
To account for the 
inclusion of additional 
studies 
Sec 3.1 
42 
The following was changed: 
 
The present study is designed to collect long-term safety 
data for the use of SPN-810 in the treatment of IA in 
subjects aged 6 to 17 years comorbid diagnosed with 
ADHD. 
SPN-810 was used in Phase 2 and currently in Phase 3 
studies for the treatment of IA in children and adolescents 
with ADHD who experienced IA behaviors despite 
monotherapy treatment with an FDA-approved ADHD 
medication. 
The subjects patient population will be eligible to enroll 
enter in this study after the completion of the double-blind 
studies 810P301 or 810P302, 810P503 or 810P204. At Visit 
6 of 810P301 and 810P302 studies, or at Visit 4 of 
810P204, subjects are invited to convert from their 
randomized dose in a blinded fashion to a dose of 18 
mg/day 
 the initial total daily dose for this 
OLE study. Subjects participating in the 810P503 study 
will receive a blinded conversion card at Visit 7 and will 
initiate the OLE study at 
 
Additionally, subjects are eligible to enroll in this study on 
a case-by-case basis only after consultation between the 
Investigator, the Medical Monitor and the Sponsor if they 
discontinue from one of the double-blind studies 810P301 
or 810P302 during the maintenance phase prior to Visit 6 
(810P301 or 810P302) or Visit 5 (810P204).  
Subjects will be converted from their randomized dose to 
the initial total daily dose of 
 in a 
blinded fashion. 
To account for the 
inclusion of additional 
studies 


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If subjects discontinued from the 810P503 study prior to 
Visit 7 during the maintenance phase, they will be 
converted in a blinded fashion from the randomized dose 
to 
 
Sec. 3.2 
43 
The following was changed: 
 
All subjects who complete the randomized, double-blind 
portion of study 810P301, or 810P302, 810P503 or 
810P204 will have the option to participate in the OLE 
study in which all subjects will receive active Study 
Medication (SM) treatment.  Subjects who choose 
choosing to participate in the OLE will receive blinded 
conversion medication kits at Visit 6 of the previous SPN-
810 
double-blind 
randomization 
study 
(810P301, 
810P302) or at Visit 4 for subjects completing the 
810P204 study. Subjects, who have completed the 
810P503 study and, chose to participate in this study, will 
receive the blinded conversion card at Visit 7.  Visit 7 of 
810P301 or, 810P302 or Visit 8 for 810P503 will be Visit 1 
of 810P304. Visit 6 of the 810P204 will be Visit 1 of the 
810P304.  The initial total daily dose for the OLE is 
18 mg/day except for subjects who participated in the 
810P503 study, their initial dose in the OLE is
 
The Investigator may gradually increase the dose of SPN-
810 up to 
 for subjects with body weight ≥ 30 
kg. 
Procedural and to 
account for the 
inclusion of additional 
studies 
Sec. 3.2.1 
43, 44 
The following was added: 
 
Subjects may enter the study upon completion of one of 
the following double-blind studies:  810P301, or 
810P302, 810P503 or 810P204. 
 
Subjects who have completed one of the double-
blind randomized Phase 3 studies (810P301, 
810P302, 810P204 or 810P503) will be converted 
during their last week of participation and will 
initiate dosing at 
, 
respectively. 
 
On 
a 
case-by-case 
basis, 
subjects 
who 
discontinued early during the maintenance phase 
of 810P301 or, 810P302, 810P204 or 810P503 
studies and are approved for participation in this 
study will be converted and will initiate at 
 
 
respectively. 
 
In rare occasions, subjects who have discontinued 
early from the maintenance phase of 810P301 or, 
810P302, 810P204 or 810P503 studies and have 
To account for the 
inclusion of additional 
studies 


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washed out from the study medication for at least 
2 days may be approved to enroll in the OLE. 
 
These subjects will enter the study at a
 
dose and will be gradually titrated up to an 
optimized dose. 
Sec. 3.2.2 
44 
The following was added: 
 
For subjects already enrolled in this study, a blood 
sample will be collected at the next visit following this 
amendment. For newly enrolled subjects (from 810P301, 
810P302 or 810P204 study), the blood samples for PGx 
analysis will be obtained at Visit 1/Baseline. Prior to 
testing all subjects will be consented for PGx testing. The 
DNA will be extracted and tested for any genetic 
variations associated with 
 enzyme. 
 
 
 
 
 
 
 
 
 
 
 Test results in this study 
will identify the subject’s metabolizer phenotype. 
The residual DNA will be stored for possible testing of 
genes involved in the efficacy and possible association 
with particular adverse events of the drug (e.g., 
understand the non-responders to treatment and/or 
individuals who show unusual safety profile). The DNA 
analysis will not be used for individual genetic 
characterization and the subject identity will be kept 
confidential. 
To explore the 
pharmacogenomics of 
the study medication 
Sec. 3.2.3 
44 
The following was changed: 
 
During the optimization phase, the study medication dose 
should be optimized between 6 mg/day and 36 or 54 
mg/day given as divided doses BID in children (6-12 years 
of age) or adolescents (12-17 years of age), respectively.   
To account for the 
inclusion of adolescent 
study 
Sec. 3.2.4 
44,45 
The following was added: 
 
For subjects whose body weight is ≥ 30 kg, the 
Investigator may gradually increase the dose of SPN-810 
up to 54 mg/day based on safety and tolerability. 
 
During the maintenance phase, a urine pregnancy test 
will be requested for all Females of Child Bearing 
Potential (FOCBP). At each visit during Maintenance 
(Visit 5-Visit 16), FOCBP subjects will receive a urine 
pregnancy test to take at home and will be asked to 
complete the testing approximately 6 weeks following 
each visit. The site will call the caregiver as a reminder 
and follow-up to obtain the pregnancy test results. Sites 
To account for the 
inclusion of adolescent 
study 


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are encouraged to educate the caregivers and the 
subjects on the importance of preventing pregnancies 
during participation in the study. 
The distribution of the home pregnancy test as well as 
the results of the test will be recorded on paper source, 
at the clinical trial sites.  
If a positive result is reported, the subject will be brought 
to the clinic for an unscheduled visit to confirm through 
a serum pregnancy test. If pregnancy is confirmed, the 
subject will be withdrawn from the study. The 
Investigator will report the pregnancy and complete the 
follow-up procedures as outlined in Sec. 5.1.3.2. 
Sec. 4.1 
45 
The following was added: 
 
Approximately 60400 subjects will be enrolled in this 
clinical investigation. The population will be male and 
female subjects with IA and diagnosed with ADHD, 
currently treated with an FDA-approved standard ADHD 
treatment and who have completed a satisfactory 
participation in one of the double-blind randomized 
studies, 810P301 or, 810P302, 810P503 or 810P204.  
Subjects who discontinued early from 810P301 or 
810P302 the above double-blind randomized studies 
during the maintenance phase will be allowed to enroll in 
this study after consultation between the Investigator, 
the Medical Monitor and the Sponsor on a case-by case 
basis. 
To account for the 
inclusion of additional 
studies 
Sec. 4.1.1 
45 
The following was changed: 
 
Inclusion Criteria: 
1. Healthy male or female subjects, who completed and 
converted from a satisfactory participation in the 
studyies 810P301 or, 810P302, 810P503 or 810P204 
or discontinued early from the previous study during 
the maintenance phase and allowed to enroll only 
after consultation between the Investigator, the 
Medical Monitor and the Sponsor. 
3. Existing diagnosis of ADHD, as described by DSM-5 and 
confirmed by the K-SADS PL 2013 from study 810P301 
or 810P302 and by the MINI-KID from the 810P503 or 
810P204 studies. 
5. Weight of at least 20 kg for 6-12 year old subjects. 
To account for the 
inclusion of additional 
studies  
Sec. 4.1.2 
45, 46 
The following was changed: 
 
Exclusion Criteria: 
Procedural 


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1. Body Mass Index (BMI) in the less than 25th and 
above 99th percentile or above for 13-17 year old 
subjects only.  
3. Pregnancy, breastfeeding or refusal to practice 
contraception during the study (for female subjects of 
childbearing potential and sexually active males). 
4. Criminal arrest or report at least 6 months prior to 
Visit 2. 
Table 1 
47, 48 
Table 1 was updated to include:  
 
 
EOS Visit 7/Visit 1 
 
Socio-demographic Information at Baseline 
 
Urine Drug Screen at Baseline and at Visit 5, 7, 9, 11, 
13 and 15  
 
Urine Pregnancy Test at Visit 2, Visit 3 and Visit 4 
 
Home urine pregnancy test at Visits 5-16 
 
Blood Collection for Pharmacogenomic (PGx) 
Testings. 
 
SIPA for Adolescents 
 
 
Procedural 
Table 1 
48 
The following was added in the footnote: 
 
a. Assessment is completed as the EOS visit in the SPN-
810 preceding double-blind randomized study: Visit 7 
(810P301 and 810P302), Visit 8 (810P503) and Visit 6 
(810P204). 
b. At each visit, a home urine pregnancy test will be 
distributed to female subjects of childbearing 
potential. Subjects are required to complete testing 
6 weeks after each visit. The site will follow up with 
a call to record the results. 
h. PGx Testing will be performed in subjects enrolling 
from the following studies: 810P301, 810P302 or 
810P204.  Subjects already enrolled, will provide a 
blood sample during the next visit following this 
amendment is effective. 
i. 
The SIPA scale will be administered only to subjects 
13 and 17 years of age. 
For the adolescents 
inclusion  
Sec. 4.2.1 
49 
The following was added: 
 
Visit 7 of 810P301 or 810P302, Visit 8 of 810P503 will 
serve as Visit 1 of the OLE and Visit 6 of 810P204 will be 
Visit 1 of the OLE. Subjects who meet the requirements 
for study participation will begin titration at Visit 6 of 
810P301 or 810P302 studyies and at Visit 5 for the 
810P204 study to the dose level of 18 mg/day.  Subjects 
who have completed 810P503 study participation will 
Procedural  


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for the purpose of reviewing or performing this study. 
 
 
start titration at Visit 7 to the initial dose of 36 mg/day 
in this study. 
1. Confirm Interactive Web Response System (IWRS) 
subject number 
5. Record socio-demographic information 
8. Collect blood samples for hematology, chemistry and 
pharmacogenomic testing (when applicable) 
9. Collect urine sample for drug screen 
Sec. 4.2.2 
49, 50 
The following was added: 
 
3. Collect urine sample for pregnancy test (Females of 
Child Bearing Potential (FOCBP) only) 
11. Assess treatment compliance 
For the adolescents 
inclusion 
Sec. 4.2.3 
50 
The following was added: 
 
3. Collect urine sample for pregnancy test (Females of 
Child Bearing Potential (FOCBP) only) 
11. Assess treatment compliance 
For the adolescents 
inclusion 
Sec. 4.2.4 
50 
The following was added: 
 
4. Collect urine sample for pregnancy test (Females of 
Child Bearing Potential (FOCBP) only) 
12. Assess treatment compliance 
For the adolescents 
inclusion 
Sec. 4.2.5 
51 
The following was added: 
 
4. Collect urine sample for pregnancy test (FOCBP only) 
and dispense home pregnancy test kit 
5. Collect urine sample for drug screen 
6. Administer quality life scales (CHQ-PF28, PSI-4-SF or 
SIPA) 
For the adolescents 
inclusion 
Sec. 4.2.6  
51 
The following was added: 
 
4. Dispense home pregnancy test kit 
12. Administer quality life scales (CHQ-PF28, PSI-4-SF or 
SIPA) 
For the adolescents 
inclusion 


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for the purpose of reviewing or performing this study. 
 
Sec. 4.2.7 
51, 52 
The following was added: 
 
After completion of the initial 6-month period (at Visit 6), 
subjects will be offered the option to continue 
participation for another 6-month maintenance period 
for up to a total of 36 months (3 years) or until market 
availability . 
At Visits 7, 9, 11, 13 and 15, the following procedures will 
be conducted: 
4. Collect urine sample for pregnancy test (FOCBP only) 
and dispense home pregnancy test kit 
5. Collect urine sample for drug screen 
10. Administer quality life scales (CHQ-PF28, PSI-4-SF or 
SIPA) 
At Visit 8, 10, 12, 14 and 16, the following procedures will 
be conducted:  
4. Dispense home pregnancy test kit 
12. Administer quality life scales (CHQ-PF28, PSI-4-SF or 
SIPA) 
For the adolescents 
inclusion  
Sec. 4.2.8  
53 
The following was added: 
 
10. Administer quality life scales (CHQ-PF28, PSI-4-SF or 
SIPA, only for subjects who discontinue early) 
For the adolescents 
inclusion 
Sec. 4.3.1 
53, 54 
The following was added: 
 
Subjects will enter this study from one of the previous 
double-blind Phase 3 clinical studies (810P301, 810P302 
or 810P204) and will initiate at 
 for a total of 
. Subjects from the double-blind 810P503 
study will initiate this study at 
. Eligible 
subjects who discontinue early in one of the randomized, 
double-blind Phase 3 studies (810P301, 810P302 or 
810P204) and are approved for participation in the OLE 
study will receive blinded conversion medication card 
and initiate study at the same initial dose 
 
s outlined in Sec. 3.2.1. 
For subjects with body weight ≥ 30 kg and not fully 
responding to 
, the Investigator may 
gradually increase the dose of SPN-810 up to 54 mg/day.  
If at some point during the study the measured BMI is 
above 99th percentile, the Investigator may adjust the dose 
to the subject’s weight. 
A combination of extended-and immediate-release 
formulations of the same ADHD medication are not 
considered monotherapy.  
To account for the 
inclusion of additional 
studies  


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for the purpose of reviewing or performing this study. 
Sec. 4.34 
55 
The following was changed: 
 
Each subject who completes or discontinues the study 
from 810P301 or, 810P302, 810P503 or 810P204 and is 
eligible for enrollment in the OLE will maintain the same 
unique subject identification number that was given to 
them in the study 810P301 or 810P302 previousceding 
double-blind randomized study. 
To clarify the inclusion 
of additional studies 
Sec. 4.3.6 
55 
The following was added: 
 
Subjects will initiate dosing at 
 
in a blinded fashion, which is 
the starting dose for 810P304 and subsequently 
optimized. 
At the Investigator’s discretion, the dose may be gradually 
adjusted based upon tolerability and effectiveness 
between the doses of 
 
mg/day for subjects whose body weight is ≥ 30 kg. given 
as divided dose BID.  Doses should always remain BID and, 
whenever possible, evenly divided (same number of mg 
in morning and evening). 
To clarify the 
adolescents inclusion 
Sec. 4.4 
55 
The following was added: 
 
 
Non-FDA approved formulations of FDA for the 
treatment of ADHD (e.g. IR or ER formulations of the 
same compound) 
 
Combination of extended-and immediate-release 
formulation of the same compound (e.g. IR 
formulation in the morning and ER formulation in 
the evening)   
To Clarify 
Sec. 4.5 
56 
The following was added: 
 
3. For the treatment of Akathisia, propranolol is 
allowed up to 90 mg /day in divided doses three 
times per day, starting at 10 mg BID and up to 30 mg 
TID, as needed. 
4. Treatment for AEs other than EPS or minor transient 
ailments is permitted only in consultation with the 
Medical Monitor or his/her designee with the 
exception 
of 
required 
treatments 
for 
acute 
conditions in the emergency room/hospital and/or 
office visit as indicated.  
All concomitant medications as well as the changes onin 
the dosing of the ADHD medication or the changes to any 
other FDA-approved ADHD treatment will be recorded in 
the eCRF.  
To Clarify 


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Sec. 5.1.2.1 
 58 
The following was added: 
 
Adverse events occurring in the previous clinical study or 
ongoing at the end of the 810P301 or, 810P302, 810P503 
or 810P204 will become part of the subject’s medical 
history.  
 
Serious vs. Non-serious: Is the event an Serious 
Adverse Event (SAE)? 
To clarify the inclusion 
of additional studies 
Sec. 5.1.4 
61 
The following was added: 
 
For the treatment of Akathisia, propranolol is 
recommended up to 90 mg /day in divided doses three 
times per day, starting at 10 mg BID and up to 30 mg 
TID, as needed. 
To Clarify 
Sec. 5.1.5 
61, 62 
The following was added: 
 
With the exception of urine pregnancy test, clinical 
laboratory tests will be performed by a central laboratory 
as specified in the reference regulatory binder. 
Any repeat laboratory testing will be conducted under 
fasting condition as indicated. 
To Clarify 
Table 2 
62 
Table 2 was updated to include HbA1calab parameters 
only for subjects participating in the 810P503 study and to 
clarify the urine and urinalysis parameters. 
The following footnote was added: 
a. This parameter will be measured only in subjects 
who participated in the 810P503 study. 
To Clarify 
Sec. 5.1.6 
62 
The following was changed: 
Vital Signs and Height/Weight Measurements 
Vital signs’ measurements (e.g., blood pressure, heart 
rate, temperature, and respiratory rate) and height, 
weight and BMI will be obtained at visits designated on the 
Schedule of Visits and Procedures (Table 1).   
Administrative 
Sec. 5.1.8 
63 
The following was added: 
 
A total of 2 mL blood samples will be collected for 
 pharmacogenomic testing.  
For subjects already enrolled into this study (810P304) a 
blood sample will be collected at the next visit following 
this amendment. For newly enrolled subjects, the blood 
sample for PGx analysis will be obtained at screening. 
Results from individual tests will be used for research 
purposes only and will not be distributed.  
 
Samples will be identified only by the study subject 
number to maintain confidentiality. The DNA will be 
To explore the 
pharmacogenomics of 
the study medication 


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extracted and tested for any genetic variations 
associated with 
 enzyme. Collected samples will 
be stored for up to 10 years for potential future 
research purposes such as possible testing of genes 
involved in the efficacy and possible association with 
particular adverse events of the drug (e.g., understand 
the non-responders to treatment and/or individuals 
who show unusual safety profile). 
Data from samples will not have diagnostic value and 
will not be used for individual genetic characterization 
or development of a commercial product. At the end of 
testing or 10 years, any remaining samples will be 
destroyed. The subject may withdraw consent for 
pharmacogenomic testing at any time; if consent is 
withdrawn, the subject’s sample will be destroyed.   
Sec. 5.2.2 
64 
The following was added: 
 
 
CGI-I, relative to the condition at baseline (Visit 3 in 
the double-blind studyies 810P301, or 810P302, 
810P503 or 810P204), 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.   
To Clarify 
Sec. 5.3.2 
64 
The following was added: 
 
The PSI-4-SF will be administered to the caregivers of 
subjects 6-12 years of age, at each visit after the first 6 
months (Visits 5 to 17).  For subjects who discontinue 
early, this will be administered at the EOS (Visit 17).  
To Clarify 
Sec. 5.3.3 
 65 
The following was added: 
5.3.3   Stress Index for Parents of Adolescents (SIPA) 
The Stress Index for Parents of Adolescents (SIPA) is a 
screening and diagnostic instrument that identifies 
areas of stress in parent–adolescent interactions, 
allowing examination of the relationship of parenting 
stress to adolescent characteristics, parent 
characteristics, the quality of the adolescent–parent 
interactions, and stressful life circumstances in parents 
of adolescents (11-19 years old). The SIPA consists of 90 
items divided in three major domains, the Adolescents 
Domain (AD), the Parent Domain (PD) and the 
Adolescent-Parent Relationship Domain (APRD), which 
include the following subscales:  moodiness/emotional 
lability, social isolation/withdrawal, 
delinquency/antisocial, failure to achieve and 
To take into account 
the adolescents 
inclusion 


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persevere, relationship with spouse/partner, social 
alienation and incompetence/guilt. The SIPA includes 
22- item Life Stressors (LS) Scale and the Index of Total 
Parenting Stress (TS). 
Parents respond to the first 90 items using a 5-point 
rating scale ranging from Strongly Disagree (5) to 
Strongly Agree (1) and the final 22 items by indicating 
Yes (Y) or No (N). 
The SIPA will be administered to caregivers of 
adolescents (13-17 years of age) at each visit after the 
first 6 months (Visits 5 to 17).  For subjects who 
discontinue early, this will be administered at the EOS 
(Visit 17).  
Sec. 5.3.4 
65 
The following was added: 
5.3.4. Socio-demographic Characteristics 
Socio-demographic characteristics are valuable addition 
information that will be used to correlate with health-
related quality of life and clinical measures. The 
variables include the number of siblings in the study, 
siblings with IA, caregiver’s age and gender, living 
situation, marital status, household income and 
education level.  
The socio-demographic characteristics will be recorded 
at baseline for newly enrolled subjects and, for subjects 
already enrolled, at the next visit once this protocol 
amendment is effective.  
To explore an 
additional variable for 
correlation 
Sec. 5.4 
65 
The following was added: 
Pharmacogenomic Variable 
The extracted DNA will be tested for any genetic 
variations associated with
 enzyme. 
 
 
 
 
 
 
 
 
 
 
 The residual DNA will be 
stored for possible testing of genes involved in the 
efficacy and possible association with particular adverse 
events of the drug (e.g., understand the non-responders 
to treatment and/or individuals who show unusual 
safety profile).  
The DNA analysis will not be used for individual genetic 
characterization and the subject identity will be kept 
confidential.  
Blood samples will be collected at Screening (Visit 1) for 
eligible subjects who have not been previously tested in 
the blinded studies.  Subjects already enrolled in this 
study, will be tested at the next visit to the clinical site, 
once this protocol amendment is effective. 
To explore the 
pharmacogenomics of 
the study medication 


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Sec. 6.1 
66 
The following was added: 
 
All data analyses will be performed by the Clinical 
Research Organization (CRO) after 
the study is 
completioned and the database is released.  Statistical 
programming and analyses will be performed using SAS® 
Version 9.3 or above and/or other validated statistical 
software as required. 
In general, the baseline value for a variable is defined as 
the value observed at Visit 7 of 810P301 or and 810P302, 
Visit 8 of 810P503 and at Visit 6 of the 810P204 study or 
the first value observed before the first dose in the OLE 
study, i.e. at Visit 1 (see Table 1). 
To Clarify the inclusion 
of additional studies 
Sec. 6.2 
 67 
The following was added: 
 
The population of “all enrolled subjects” consists of all 
screened subjects from any of the precedingwho 
completed the double-blind studies (810P301 or, 
810P302, 810P503 and 810P204) and meet the eligibility 
requirements for this study including subjects who 
discontinued one from any of the Phase 3 double-blind 
studies early and approved for enrollment in this study.  
The safety population will include all subjects who have 
signed Informed Consent/Assent forms and received at 
least 1one dose of study drug during this study. 
To Clarify the inclusion 
of additional studies 
Sec. 6.3 
67 
The following was added: 
 
Demographics and Baseline Characteristics 
Demographic and baseline variables include age, sex, 
ethnicity, race, height, weight, and medical history and will 
be summarized as in the study 810P301 or, 810P302. 
To Clarify 
Sec. 6.4 
67 
The following was added: 
6.4   Socio-demographics 
Socio-demographic variables include number of siblings 
in the study, siblings with IA, caregiver’s age and gender, 
living situation, marital status, household income and 
education level will be summarized. 
To explore an 
additional variable for 
correlation 
Sec. 6.5 
67 
The following was moved up from the last paragraph: 
 
The number and percentage of subjects who completed 
and discontinued from the study will be summarized. Only 
one (primary) reason for study discontinuation will be 
recorded for each subject. 
To Clarify 
Sec. 6.7  
 68 
The following was changed: 
 
Duration of exposure is defined as the total number of 
days a subject is exposed to study treatment. This will be 
To clarify the increased 
dose  


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calculated for each subject by taking the difference 
between the date of last dose minus the date of the first 
dose, plus 1 one (date of last dose – date of first dose +1). 
  
{D-R)/(2T*(DL- DF + 1))}*100, where D=number of 
tablets dispensed, R= number of tablets returned, 
T= number of tablets administered per day , DL = 
date of last visit (dose) and DF= date of first visit 
(dose) 
 
The number of tablets (T) taken each day may vary during 
the maintenance phase: subjects can take up five tablets 
per day to the maximum dose of 54mg/day BID. 
Sec. 6.8.1 
68 
The following was changed: 
 
TEAE incidence tables will be listed and summarized by 
the group of the optimized doses (<18 mg/day; 18-24 
mg/day, or >24-36 mg/day, or 36-54 mg/day) the subject 
received. 
To clarify the increased 
dose due to the 
adolescents inclusion  
Sec. 6.8.3 
69 
The following was changed: 
 
Vital signs will be summarized by the group of the 
optimized doses (<18 mg/day; 18-24 mg/day, or >24-36 
mg/day, or 36-54 mg/day) the subject received using 
descriptive statistics. 
To clarify the increased 
dose due to the 
adolescents inclusion 
Sec. 6.8.4 
69 
The following was changed: 
 
ECG results will be summarized by visit by group of 
optimized doses (<18 mg/day; 18-24 mg/day, or >24-36 
mg/day, or 36-54 mg/day) using descriptive statistics (for 
quantitative ECG parameters) and frequency tables (for 
qualitative ECG parameters, including the overall ECG 
finding).   
To clarify the increased 
dose due to the 
adolescents inclusion  
Sec. 6.8.7 
70 
The following was changed: 
 
The summary will be presented by group of the optimized 
doses (<18 mg/day; 18-24 mg/day, or >24-36 mg/day or 
36-54 mg/day) the subject received. 
To clarify the increased 
dose due to the 
adolescents inclusion 
Sec. 6.10 
70 
The following was added: 
 
The quality of life endpoints CHQ-PF28, and PSI-4-SF 
subscales (Parental Distress, Parent-Child Dysfunctional 
Interaction and Difficult Child), and SIPA subscales 
(Adolescents Domain, Parent Domain, Adolescent-Parent 
Relationship Domain, Life Stressors Scale and Index of 
Total Parenting Stress) will be listed and summarized by 
group of the optimized doses (<18 mg/day; 18-24 mg/day, 
To clarify the inclusion 
of  adolescents 


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or >24-36 mg/day or 36-54 mg/day) the subject received. 
Socio-demographic variables will be presented as a listing 
and summaries will be tabulated using descriptive 
statistics. 
Sec. 6.11 
70 
The following was added: 
 
Pharmacogenomic Analysis 
Individual data will be presented as a listing and 
summaries will be tabulated using descriptive statistics. 
The pharmacogenomic report may be a stand-alone 
document. 
To explore the 
pharmacogenomics of 
the study medication 
Sec. 6.12 
70 
The following was changed: 
 
There is no consideration for power or sample size 
determination in this open label study. The present study 
is an extension to the double-blind randomized 801P301, 
or 810P302, 810P503 and 810P204 studies, where the 
planned samples size in each study is 291 subjects, for the 
purpose of evaluating long term safety of SPN-810. 
To take into account 
for the inclusion of 
additional studies 
Sec. 8.3 
75 
The following was changed: 
 
This study will be conducted by qualified Investigators 
under the sponsorship of Supernus Pharmaceuticals, Inc. 
(Sponsor) at US study sites used in the double-blind Phase 
3 studies, 810P301, and 810P302, 81P503 and 810P204. 
Contact persons at the Sponsor and the CROs are listed in 
the regulatoryreference binder provided to each 
investigational site.   
The study will be monitored by qualifiedQualified 
personnel will monitor the study.from the designated 
  The Sponsor will oversee and review 
the monitoring activities of the
  
Laboratory tests will be conducted by a central laboratory 
as designated in the regulatory reference binder. 
To Clarify 
Sec. 10 
79 
SIPA appendix was added 
For the adolescents 
inclusion 
Changes to 810P304 V4.0 Dated 04Sep2018 
Protocol Version 4.0 was amended to Version 5.0 to allow subjects who are receiving benefit from SPN-810 to 
continue to receive the study medication for another 2 years (i.e., a total of 5 years) or until commercial 
availability of the product. Additional changes made for clarity and correction include: 
 
Clarifying that PGx testing is optional 
 
Correcting the maximum number of study medication tablets that may be taken per day 
 
Other administrative changes as noted 
Title page 
1 
Protocol version and date were updated. 
 
Protocol title was corrected for grammar: 
Administrative 


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Open-Label Extension Study to Evaluate the Long-Term 
Safety of Molindone Hydrochloride Extended-Release 
Tablets for the Treatment of Impulsive Aggression in 
Pediatric and Adolescents Adolescent Subjects with 
Attention Deficit/Hyperactivity Disorder (ADHD) in 
Conjunction with Standard ADHD Treatment 
Protocol 
Approval page 
3 
Reviewers: 
 
 
 
Administrative 
Synopsis 
28 
Study Design: 
Long-term, flexible-dose, open-label, multi-center, up to 
36 60-month study 
To extend study 
duration up to 5 years 
Synopsis 
29 
Duration of Treatment and Study Duration: 
The subject can continue to receive study medication for 
up to 36 60 months. 
 
Treatment Schedule: 
Once treatment on the previous clinical study is complete 
and consent obtained for this study, the Investigator will 
initiate the subjects at 18 mg/day (810P301, 810P302 and 
810P204) or 36 mg/day (810P503), and may gradually 
adjust the dose of SPN-810 between 6 mg/day and 36 
mg/day for up to 36 60 months. 
 
Maximum duration of the study: Approximately 36 Up to 
60 months or until market availability. 
 
Optimization Phase: 8 weeks 
 
Maintenance Phase: initial period of 6 months, 
with the option for additional repeat periods of 
6 months each 
 
Taper Phase: 2 weeks 
To extend study 
duration up to 5 years 
Synopsis 
30 
Pharmacogenomics (PGx): 
(Added) Participation in PGx testing is optional. 
Clarification 
3.1 
44 
The duration of the study will continue up to 36 60 
months or until market availability. 
To extend study 
duration up to 5 years 
3.2.2 
46 
Pharmcogenomics (PGX) Pharmacogenomics (PGx) 
(Added) Participation in PGx testing is optional. 
Clarification 
3.2.4 
46 
At each visit during Maintenance (Visit 5-Visit 16 24), 
FOCBP subjects will receive a urine pregnancy test to take 
at home and will be asked to complete the testing 
approximately 6 weeks following each visit. 
To extend study 
duration up to 5 years 
4.2 
49 
Table 1 
Maintenance Phase: Visits 5 (Mo 3), 7, 9, 11,13, and 15, 17, 
19, 21, and 23 (Mo 33 57)  
Maintenance Phase: Visits 6 (Mo 6), 8, 10, 12, 14, and 16, 
18, 20, 22 and 24 (Mo 36 60) 
To extend study 
duration up to 5 years 


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Taper Phase: Visit 17 25 
Footnote b: Visit 7-16 24 will occur 3 months ± 1 week 
from the previous visit. 
4.2 
49 
Table 1 
Footnote h: (added) Participation in PGx testing is 
optional. 
Footnote i:  The SIPA scale will be administered only to 
subjects 13 and to 17 years of age. 
Clarification 
 
4.2.7 
53 
Subsequent Visits (Visits 7 through 16 24) (approximately 
every 3 months (+/- 1 week)) 
After completion of the initial 6-month period (at Visit 6), 
subjects will be offered the option to continue 
participation for another 6-month maintenance period 
for up to a total of 36 60 months (3 5 years) or until 
market availability. Each 6-month period will have two 
visits every 3-months. These will include Visits 7 through 
16 24. 
 
At Visits 7, 9, 11, 13, and 15, 17, 19, 21, and 23, the 
following procedures will be conducted: 
 
At Visit 8, 10, 12, 14, and 16, 18, 20, 22 and 24, the 
following procedures will be conducted: 
To extend study 
duration up to 5 years 
4.2.8 
54 
Visit 17 25 [(End of Study (EOS)] (Month 36 60 +/- 2 
weeks) 
Subjects who complete the study (36 60 months) will be 
instructed to down titrate for 2 weeks before returning to 
the office for the EOS Visit. 
 
The following procedures will be performed for patients 
subjects who complete the study (36 60 months) or 
discontinue early. 
To extend study 
duration up to 5 years 
5.1.8 
65 
Added: 
Participation in PGx testing is optional. 
Clarification 
5.2.1 
65 
This assessment will be administered at each visit after 
the first 6 months (Visits 5 to 17 25). For subjects who 
discontinue early, this will be administered at the EOS 
(Visit 17 25). 
To extend study 
duration up to 5 years 
5.3.1 
66 
The CHQ-PF28 will be administered at each visit after the 
first 6 months (Visit 5 to 17 25). For subjects who 
discontinue early, this will be administered at the EOS 
(Visit 17 25). 
To extend study 
duration up to 5 years 
5.3.2 
66 
The PSI-4-SF will be administered to the caregivers of 
subjects 6-12 years of age, at each visit after the first 6 
months (Visits 5 to 17 25).  For subjects who discontinue 
early, this will be administered at the EOS (Visit 17 25). 
To extend study 
duration up to 5 years 


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5.3.3 
67 
The SIPA will be administered to caregivers of 
adolescents (13-17 years of age) at each visit after the 
first 6 months (Visits 5 to 17 25).  For subjects who 
discontinue early, this will be administered at the EOS 
(Visit 17 25). 
To extend study 
duration up to 5 years 
5.4 
67 
Added: 
Participation in PGx testing is optional. 
Clarification 
6.5 
69 
The reasons for study discontinuation may include one of 
the following: 
(added) Lack of efficacy 
Clarification 
6.7 
71 
The number of tablets (T) taken each day may vary during 
the maintenance phase: subjects can take up five six 
tablets per day to the maximum dose of 54mg/day BID. 
Correction 


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for the purpose of reviewing or performing this study. 
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:  810P304 
Phase of Development:  3 
Full Title of Study:  Open-Label Extension Study to Evaluate the Long-term Safety of Molindone 
Hydrochloride Extended-Release Tablets for the Treatment of Impulsive Aggression in Pediatric and 
Adolescent Subjects with Attention Deficit/Hyperactivity Disorder (ADHD) in Conjunction with Standard 
ADHD Treatment. 
Investigator(s) / Center(s):  Approximately 50 US centers 
Objective:  
The objective of this Phase 3 Open-Label Extension (OLE) study is to collect additional long-term safety 
data on the use of SPN-810 as a treatment for impulsive aggression (IA) in pediatric and adolescent 
subjects with ADHD when taken in conjunction with standard ADHD treatment. These subjects would 
have completed a satisfactory participation in the double-blind studies: 810P301, 810P302, 810P503 or 
810P204. 
Study Design: Long-term, flexible-dose, open-label, multi-center, up to 60-month study 
Number of Subjects:  Approximately 600 subjects who have completed a satisfactory participation in 
810P301, 810P302, 810P503 or 810P204 studies and/or converted after discontinuation from one of 
these previous double-blind randomized studies. 
Criteria for Inclusion: 
1. Completed and converted from a satisfactory participation in the studies 810P301, 810P302, 
810P503 or 810P204, or discontinued early during the maintenance phase from one of these 
previous studies and allowed to enroll only after consultation between the Investigator, the 
Medical Monitor and the Sponsor. 
2. Continues to be medically healthy and with clinically normal laboratory profiles, vital signs, and 
electrocardiograms (ECGs). 
3. Existing diagnosis of ADHD, as described by DSM-5 and confirmed by the K-SADS PL 2013 from 
study 810P301 or 810P302 or by the MINI-KID from study 810P503 or 810P204. 
4. Currently receiving monotherapy with an optimized dose of FDA-approved ADHD medication 
(including stimulants and non-stimulants). 
5. Weight of at least 20 kg. 
6. Written informed consent/assent obtained from the subject’s parent or legally authorized 
representative (LAR), and written informed assent obtained from the subject if required. 
Criteria for Exclusion: 
1. Body Mass Index (BMI) in the 99th percentile or above. 
2. Clinically significant change in health status, safety concern or any other reason, which in the 
opinion of the Sponsor or the Investigator, would prevent the subject from participating in this 
study or successfully completing the study. 


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3. Pregnancy, breastfeeding or refusal to practice contraception during the study (for female 
subjects of childbearing potential and sexually active males). 
4. Current substance or alcohol use. 
5. Suicidal thoughts or behaviors confirmed at Visit 7 for 810P301 or 810P302, Visit 8 for 810P503 
or Visit 6 for 810P204 studies. 
6. Known allergy or sensitivity to molindone hydrochloride. 
Treatment, Dose, and Mode of Administration: 
Molindone Hydrochloride Extended-Release (SPN-810) tablet dosage forms of 3 mg, 9 mg and 18 mg 
are available.  Treatment is to be administered orally twice daily with or without food.  Subjects who 
completed one of the following double-blind studies (810P301, 810P302 or 810P204) will have 
converted during their last week of participation and will initiate dosing 
 
Subjects who completed the 810P503 study will initiate 
  
Subjects who discontinued early during the maintenance phase of study 810P301, 810P302 or 810P204 
and, on a case-by-case basis, are approved for participation in this study will receive a blinded 
conversion card and will initiate at 
 Subjects who discontinued early from 
810P503 study and approved to participate in this study will be blind-converted and initiate at 
 
 
However, in rare occasions, if subjects who have discontinued from the maintenance phase of any of 
the previous double-blind studies and have washed out from the study medication for at least 2 days, 
may be approved to enroll in the OLE. These subjects will enter the study on a 
 and 
receive instructions to gradually titrate to an optimized dose. Following the optimization phase and 
throughout the course of the study, the Investigator may gradually adjust the dose based upon 
tolerability or effectiveness within the limits of 
 for 
subjects with a body weight ≥ 30 kg.   
Duration of Treatment and Study Duration:  
The subject can continue to receive study medication for up to 60 months. During an initial dose 
optimization phase, visits will occur at 2, 4 and 8 weeks after study start and every 3 months thereafter 
to assess safety, perform drug accountability, and to dispense new study medication.  Every 6 months, 
subjects can extend their participation for an additional period of 6 months, during which subjects will 
visit the office every 3 months.  Subjects may discontinue at any time if the subject or LAR withdraws 
consent or if the treating physician feels it is no longer in the best interest of the subject. Efficacy and 
quality of life data will be collected during the study. Just prior to the End of Study (EOS) visit, subjects 
who complete at least one maintenance phase will be instructed to taper off study medication over a 
period of 2 weeks. 
Treatment Schedule: 
Once treatment on the previous clinical study is complete and consent obtained for this study, the 
Investigator will initiate the subjects at 
 
), and may gradually adjust the dose of SPN-810 between 
 for up to 
60 months. For subjects with body weight ≥ 30 kg and not fully responding to 36 mg/day doses, the 
Investigator may gradually increase the dose of SPN-810 up to 54 mg/day.  At the end of the 
maintenance phase, the subject will be tapered off study medication over a period of 2-weeks. 


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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
Maximum duration of the study: Up to 60 months or until market availability.  
 
Optimization Phase: 8 weeks 
 
Maintenance Phase: initial period of 6 months, with the option for additional periods of 6 
months each  
 
Taper Phase: 2 weeks 
Safety Variables:  
1. Adverse Events (AE) and Serious Adverse Events (SAE) 
2. Extrapyramidal Symptoms (EPS) scales (Simpson-Angus Scale, Barnes Akathisia Scale, and 
Abnormal Involuntary Movement Scale) 
3. Clinical Laboratory Tests (Hematology, Chemistry (Glucose, LDL, HDL, Triglycerides, Total 
cholesterol,  etc.), Insulin, Prolactin and Urinalysis) 
4. Concomitant Medications 
5. Vital signs, Standardized BMI, Physical Examination and ECG (12-lead) 
6. Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Efficacy Variables: 
1. Retrospective-Modified Overt Aggression Scale (R-MOAS) 
2. Clinical Global Impression – Improvement Scale (CGI-I) 
3. Clinical Global Impression – Severity Scale (CGI-S) 
 
Quality of Life Variables: 
1. Child Health Questionnaire (CHQ-PF28) 
2. Parenting Stress Index (PSI-4-SF) or Stress Index for Parents of Adolescents (SIPA) 
3. Socio-demographics 
 
Pharmacogenomics (PGx): 
Participation in PGx testing is optional. For subjects already enrolled in this study, a blood sample for 
PGx analysis will be collected at the next visit following this amendment. For newly enrolled subjects, 
the blood sample for PGx analysis will be obtained at screening. Prior to testing, all subjects will be 
consented for PGx testing.  
The DNA will be extracted and tested for any genetic variations associated with 
 enzyme.
 
 
The residual DNA will be stored for possible testing of genes involved in 
the efficacy and possible association with particular adverse events of the drug (e.g., understand the 
non-responders to treatment and/or individuals who show unusual safety profile). The DNA analysis 
will not be used for individual genetic characterization and the subject identity will be kept confidential. 
The PGx report may be a stand-alone document.    
Analysis Populations: 
All subjects who have documented Informed Consent/Assent and have taken at least one dose of  
SPN-810 during this study will be in the safety population.  


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for the purpose of reviewing or performing this study. 
Statistical Methods: 
All statistical analyses will be based on the safety population. Summary statistics for continuous 
variables will include sample size (N), mean, median, standard deviation, minimum, and maximum. 
Summary statistics for discrete variables will be presented in terms of frequencies and percentages in 
the safety population. 
 
 


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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................................1 
PROTOCOL SIGNATURE PAGE .............................................................................................................2 
PROTOCOL APPROVAL PAGE ..............................................................................................................3 
SUMMARY OF CHANGES ....................................................................................................................4 
CLINICAL PROTOCOL SYNOPSIS ......................................................................................................... 29 
TABLE OF CONTENTS ........................................................................................................................ 33 
LIST OF TABLES AND FIGURES ........................................................................................................... 37 
LIST OF ABBREVIATIONS ................................................................................................................... 38 
1 
INTRODUCTION ........................................................................................................................ 40 
1.1 
Background ....................................................................................................................... 40 
1.2 
Current Treatment Options ............................................................................................... 41 
1.3 
Sponsor’s Phase 2 Studies.................................................................................................. 42 
1.4 
Sponsor’s Phase 3 Studies.................................................................................................. 43 
1.5 
Study Rationale ................................................................................................................. 44 
2 
STUDY OBJECTIVE ..................................................................................................................... 45 
2.1 
Objective .......................................................................................................................... 45 
3 
INVESTIGATIONAL PLAN ........................................................................................................... 45 
3.1 
Rationale for Study Design, Including Choice of Treatment Groups, Appropriateness of 
Measurements ............................................................................................................................. 45 
3.2 
Overall Study Design and Plan ........................................................................................... 46 
3.2.1 
Baseline Phase .................................................................................................................... 46 
3.2.2 
Pharmacogenomics (PGx) ................................................................................................... 47 
3.2.3 
Optimization Phase (2-8 weeks) ......................................................................................... 47 
3.2.4 
Maintenance Phase (repeated 6 month periods) ............................................................... 47 
3.2.5 
Taper Phase (2 weeks) ........................................................................................................ 48 
3.2.6 
End of Study / Early Termination ........................................................................................ 48 
4 
STUDY METHODS ...................................................................................................................... 48 
4.1 
Study Population ............................................................................................................... 48 
4.1.1 
Inclusion Criteria ................................................................................................................. 48 
4.1.2 
Exclusion Criteria ................................................................................................................. 48 
4.2 
Schedule of Visits and Procedures ...................................................................................... 49 
4.2.1 
Baseline/Visit 1 .................................................................................................................... 52 
4.2.2 
Visit 2 ................................................................................................................................... 52 
4.2.3 
Visit 3 ................................................................................................................................... 53 
4.2.4 
Visit 4 ................................................................................................................................... 53 


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for the purpose of reviewing or performing this study. 
4.2.5 
Visit 5 ................................................................................................................................... 53 
4.2.6 
Visit 6 ................................................................................................................................... 54 
4.2.7 
Subsequent Visits (Visits 7 through 24) (approximately every 3 months (+/- 1 week)) ..... 54 
4.2.8 
Visit 25 [(End of Study (EOS)] (Month 60 +/- 2 weeks) ....................................................... 55 
4.3 
Treatments ....................................................................................................................... 56 
4.3.1 
Treatments Administered ................................................................................................... 56 
4.3.2 
Identity of Investigational Product(s) ................................................................................. 57 
4.3.3 
Study Medication Handling and Accountability .................................................................. 57 
4.3.4 
Method of Assigning Subjects to Treatment Groups .......................................................... 58 
4.3.5 
Treatment Replacement ..................................................................................................... 58 
4.3.6 
Dosing Schedule .................................................................................................................. 58 
4.3.7 
Method of Administration .................................................................................................. 58 
4.3.8 
Blinding ............................................................................................................................... 58 
4.4 
Prohibited Medication ....................................................................................................... 58 
4.5 
Concomitant Medication ................................................................................................... 59 
4.6 
Completion of Study and Discontinuation of Subjects ......................................................... 59 
5 
ANALYSIS VARIABLES ................................................................................................................ 60 
5.1 
Safety Variable .................................................................................................................. 60 
5.1.1 
Adverse Events .................................................................................................................... 60 
5.1.2 
Causality .............................................................................................................................. 60 
5.1.2.1 
Recording and Evaluation of Adverse Events .................................................................................................. 61 
5.1.2.2 
Criteria for Assessing Severity ............................................................................................................................... 61 
5.1.2.3 
Criteria for Assessing Causality ............................................................................................................................. 61 
5.1.3 
Serious Adverse Events (SAE) .............................................................................................. 62 
5.1.3.1 
Investigator Responsibilities for Reporting SAEs ............................................................................................ 63 
5.1.3.2 
Other Events Requiring Immediate Reporting ................................................................................................ 63 
5.1.3.3 
Sponsor Responsibilities for Expedited Reporting of SAEs ......................................................................... 64 
5.1.4 
Management of Treatment-Emergent EPS ......................................................................... 64 
5.1.5 
Laboratory Measurements ................................................................................................. 64 
5.1.6 
Vital Signs and Height/Weight Measurements ................................................................... 65 
5.1.7 
Physical Examinations and Electrocardiograms (ECGs) ...................................................... 66 
5.1.8 
Pharmacogenomic Sample Collection ................................................................................ 66 
5.2 
Efficacy Variables .............................................................................................................. 66 
5.2.1 
Retrospective-Modified Overt Aggression Scale (R-MOAS)................................................ 66 
5.2.2 
Clinical Global Impression  (CGI) ......................................................................................... 67 
5.3 
Quality of Life Variables .................................................................................................... 67 
5.3.1 
The Child Health Questionnaire Parent Form 28-item (CHQ-PF28) ................................... 67 
5.3.2 
The Parenting Stress Index – Short Form (PSI-4-SF) ........................................................... 67 
5.3.3 
Stress Index for Parents of Adolescents (SIPA) ................................................................... 68 
5.3.4 
Socio-demographic Characteristics ..................................................................................... 68 
5.4 
Pharmacogenomic Variable ............................................................................................... 68 
5.5 
Special Safety Assessments ............................................................................................... 68 


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5.5.1 
Simpson-Angus Scale .......................................................................................................... 69 
5.5.2 
Barnes Akathisia Scale......................................................................................................... 69 
5.5.3 
Abnormal Involuntary Movement Scale (AIMS) ................................................................. 69 
5.5.4 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................ 69 
6 
STATISTICAL METHODS ............................................................................................................. 69 
6.1 
Statistical and Analytical Plans ........................................................................................... 69 
6.2 
Analysis Populations ......................................................................................................... 70 
6.3 
Demographic and Baseline Characteristics ......................................................................... 70 
6.4 
Socio-demographics .......................................................................................................... 70 
6.5 
Subject Disposition ............................................................................................................ 70 
6.6 
Other Protocol Deviations ................................................................................................. 70 
6.7 
Study Medication Exposure and Compliance ...................................................................... 71 
6.8 
Safety Analysis .................................................................................................................. 71 
6.8.1 
Adverse Events .................................................................................................................... 71 
6.8.2 
Laboratory Values ............................................................................................................... 72 
6.8.3 
Vital Signs, Height, Weight and BMI ................................................................................... 72 
6.8.4 
ECG Results ......................................................................................................................... 72 
6.8.5 
Physical Examinations ......................................................................................................... 72 
6.8.6 
Concomitant Medications ................................................................................................... 72 
6.8.7 
C-SSRS.................................................................................................................................. 73 
6.8.8 
Extrapyramidal Symptoms .................................................................................................. 73 
6.9 
Efficacy Analysis ................................................................................................................ 73 
6.10 
Quality of Life Analysis ...................................................................................................... 73 
6.11 
Pharmacogenomic Analysis ............................................................................................... 73 
6.12 
Sample Size and Power Considerations .............................................................................. 73 
7 
DOCUMENTATION .................................................................................................................... 74 
7.1 
Adherence to the Protocol ................................................................................................. 74 
7.2 
Changes to the Protocol .................................................................................................... 74 
7.3 
Protocol Deviations ........................................................................................................... 74 
7.4 
Data Quality Assurance ..................................................................................................... 75 
7.4.1 
Data Collection .................................................................................................................... 75 
7.4.2 
Clinical Data Management .................................................................................................. 75 
7.4.3 
Database Quality Assurance ............................................................................................... 75 
7.5 
Retention of Records ......................................................................................................... 76 
7.6 
Auditing Procedures .......................................................................................................... 76 
7.7 
Publication of Results ........................................................................................................ 76 
7.8 
Financing and Insurance .................................................................................................... 77 
7.9 
Disclosure and Confidentiality ........................................................................................... 77 
7.10 
Discontinuation of Study ................................................................................................... 77 
8 
ETHICS ...................................................................................................................................... 77 


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8.1 
Institutional Review Boards / Independent Ethics Committees ........................................... 77 
8.2 
Ethical Conduct of the Study .............................................................................................. 78 
8.3 
Investigators and Study Personnel ..................................................................................... 78 
8.4 
Subject Information and Consent/Assent ........................................................................... 78 
9 
REFERENCE LIST ........................................................................................................................ 79 
10 
APPENDICES ......................................................................................................................... 82 
10.1 
Retrospective Modified Overt Aggression Scale (R-MOAS) .................................................. 82 
10.2 
Clinical Global Impression (CGI) Scale ................................................................................. 82 
10.3 
Columbia-Suicide Severity Rating Scales (C-SSRS) ............................................................... 82 
10.4 
Simpson-Angus Rating Scale .............................................................................................. 82 
10.5 
Barnes Akathisia Rating Scale (BARS) ................................................................................. 82 
10.6 
Abnormal Involuntary Movement Scale (AIMS) .................................................................. 82 
10.7 
Child Health Questionnaire Parent Form 28-item (CHQ-PF28) ............................................. 82 
10.8 
Parenting Stress Index-Short Form (PSI-4-SF) ..................................................................... 82 
10.9 
Stress Index for Parents of Adolescents (SIPA) .................................................................... 82 
 
 
 
 


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LIST OF TABLES AND FIGURES 
 
Table 1: Schedule of Events and Procedures .............................................................................................. 50 
Table 2: Clinical Laboratory Tests ............................................................................................................... 65 
 
 


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


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ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IR 
Immediate Release 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LAR 
Legal Authorized Representative 
LDL 
Low Density Lipoprotein 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI-KID 
Mini International Neuropsychiatric Interview for Children and 
Adolescents  
MTA 
Multimodal Treatment of Children with ADHD 
ODD 
Oppositional Defiant Disorder 
OLE 
Open Label Extension 
PGx 
Pharmacogenomic 
PSI-4-SF 
Parenting Stress Index-Short form 
RBC 
Red Blood Cells 
R-MOAS 
Retrospective Modified Overt Aggression Scale 
RR 
Respiratory Rate 
SADR 
Suspected Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SIPA 
Stress Index for Parents of Adolescents 
SOP 
Standard Operating Protocol 
SM 
Study Medication 
SNAP-IV 
Swanson, Nolan and Pelham-IV 
TEAE 
Treatment Emergent Adverse Event 
TEOSS 
Treatment of Early-Onset Schizophrenia Spectrum Disorders Study 
TID 
Three Times a Day 
TOSCA 
Treatment of Severe Childhood Aggression 
WBC 
White Blood Cells 
 
 
 
 


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1 INTRODUCTION 
1.1 Background  
Aggression refers to a behavior that can result in both physical and psychological harm to oneself, others 
or objects in the environment. The expression of aggression can occur in a number of ways, including 
verbally, mentally, and physically. 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 (Jensen 2007, Connor 2006). 
Aggression can be categorized into two broad subtypes based on the aggressor’s motivation –  
1) reactive or impulsive and 2) proactive or instrumental (Vitiello, 1997). Impulsive aggression (IA) is angry, 
retaliatory aggression arising out of frustration, annoyance, or hostility to real or perceived provocations 
– stressors that non-affected youth of the same age can typically control in a more socially acceptable 
manner. IA is an unplanned, immediate response and an out-of-control emotional state, reflecting the 
inability to contain rage in response to apparent threat that usually does not lead to a secondary benefit. 
In contrast, instrumental aggression is consciously planned, goal-oriented behavior with the specific intent 
of benefiting the aggressor (Jensen, 2007). IA is then a behavior that implies an immediate action without 
thinking: this type of impulsivity seems to nurture internalizing behaviors leading to depression and 
anxiety due to poor parent-child interaction, peer rejection or sensitivity to stress (Vitaro, 2002). 
IA is a common symptom in a distinct group of patients such as attention-deficit/hyperactivity disorder 
(ADHD), although it is not a criterion for diagnosis of ADHD. IA is a behavior, which requires specific 
pharmacological intervention in children with ADHD. In pre-adolescent children with ADHD Combined 
subtype participating in the Multimodal Treatment of Children with ADHD (MTA) study, (The MTA 
Cooperative Group, 1999) 54% displayed clinically significant aggression at baseline.  Of these, 44% 
remained aggressive even after 14 months of multimodal therapy (The MTA Cooperative Group, 1999; 
Jensen 2007). 
Moreover, aggressive behavior had a much greater impact on parents’ overall impairment ratings than 
the core ADHD symptoms themselves. Children with ADHD are an especially vulnerable population that 
bear the brunt of ADHD-related morbidity, including severe IA, and may therefore benefit from the 
addition of a drug specifically targeting residual aggressive behaviors refractory to primary ADHD therapy. 
A stepped care approach with aggression-targeted therapy, such as an antipsychotic added to ADHD 
therapy has been recommended to treat residual aggressive behaviors (Scotto-Rosato, 2012). IA in the 
context of ADHD represents a serious clinical and public health concern and requires effective and timely 
intervention. 
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).  


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1.2 Current Treatment Options 
Based largely on the beneficial effects of risperidone on disruptive behavior disorders in children of sub-
average intelligence, antipsychotics have been recommended as adjunctive therapy for treating 
aggression in children with ADHD (Pappadopulos at al. 2003; Pliszka et al. 2006; Pliszka et al. 2007). The 
TOSCA (Treatment of Severe Childhood Aggression) study has provided empirical evidence to support a 
stepped-care approach in which children with ADHD and severe aggression are initially treated with 
primary ADHD therapy followed by adjunctive antipsychotic therapy targeting residual aggressive 
behaviors (Farmer 2011; Aman 2014; Gadow 2014). However, risperidone, had only a limited impact on 
aggression (effect size, 0.29) in the TOSCA study even though the dosage could be adjusted for optimal 
effect. Moreover, the TOSCA study confirmed that stimulant co-therapy does not attenuate the long term 
effects of risperidone or similar agents on body composition, metabolic parameters, prolactin, or sedation 
(Calarge, 2009: Penzner 2009). Use of the antipsychotics olanzapine, quetiapine, risperidone, and 
aripiprazole in children were all associated with significant increase in weight and BMI (8.5 kg/3.01 kg/m2, 
6.1 kg/2.12 kg/m2, 5.3 kg/1.92 kg/m2, and 4.4 kg/1.67 kg/m2, respectively) (Correll et al. 2009). Olanzapine 
and quetiapine produced significant increases in multiple metabolic parameters and risperidone 
significantly increased triglyceride levels.  
Molindone hydrochloride is a first-generation mid-potency compound for which the Sponsor has 
developed an extended release (ER) formulation (SPN-810), administered orally for the treatment of IA in 
children with ADHD.  
The immediate-release molindone (Moban®) was approved in 1974 for the management of schizophrenia 
in adults and adolescents but was discontinued due to commercial reasons by the original manufacturer.  
Its effects relative to the second-generation antipsychotics (olanzapine and risperidone) were evaluated 
in a pediatric population with early-onset schizophrenia and schizoaffective disorder in the Treatment of 
Early-Onset Schizophrenia Spectrum Disorders Study (TEOSS) (McClellan et al. 2007).  Molindone was 
selected as the first generation antipsychotic based on its favorable safety profile in comparison with the 
second generation agents. At the average dose of 60 mg/day molindone was shown to be safe and well 
tolerated (Sikich 2008).  Molindone was also not associated with significant increases in weight/BMI in 
contrast to olanzapine. 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 IA. 
In an open-label study, molindone, at the optimized dose of 0.5 mg/kg/day, improved aggressive behavior 
in children (N=6, 6-11 years of age) with undersocialized conduct disorder, aggressive type (Greenhill 
1981).  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). The overall clinical profile of molindone makes it an attractive candidate for the 
treatment of IA in children with ADHD, especially with the anticipated benefits of an ER formulation. 


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1.3 Sponsor’s Phase 2 Studies 
Study 810P201 was a proof-of-principle, open label, parallel-group, randomized, dose-ranging, safety and 
tolerability study using the investigational immediate-release (IR) formulation of molindone (Molindone 
IR)  dosed three times a day (TID) in children with ADHD and persistent serious conduct problems (Stocks 
2012). Target subjects were healthy male or female children aged 6 to 12 years, with a diagnosis of ADHD 
accompanied by persistent serious conduct problems. A total of 78 subjects (19-20 per treatment group) 
in ten U.S sites were randomized. The primary objective was to evaluate the safety and tolerability of four 
weight-based dosages of Molindone IR dosed three times daily in children with ADHD and persistent 
serious conduct problems 
). The 
secondary objectives were to 1) explore the relationship between molindone plasma concentration 
exposure and safety/tolerability endpoints and 2) assess the effect of Molindone IR after 6 weeks of 
maintenance treatment in reducing persistent serious conduct problems as measured by the Conduct 
Problem Subscale of the Nisonger Child Behavior Rating Form-Typical Intelligence Quotient (NCBRF-TIQ). 
Treatment with Molindone IR three times daily was safe and well tolerated.  Preliminary efficacy results 
suggested that treatment with Molindone IR resulted in behavioral improvements and that those 
improvements were more marked in higher dose groups than lower dose groups. 
Study 810P202 was a Phase 2b multicenter, randomized, double-blind, placebo controlled trial in a 
pediatric population of subjects 6-12 years of age diagnosed with ADHD and IA that was not controlled by 
optimal stimulant and behavioral therapy (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 could continue into an open-label phase of six months duration.  
SPN-810 dose within treatment groups was stratified by weight (below/above 30 kg).  Both the Medium 
(24/36 mg) and Low (12/18 mg) dose groups showed a statistically significant difference from the Placebo 
group in the change from baseline to final visit (Visit 10) in R-MOAS but the High (36/54 mg) dose group 
was not significantly different from the Placebo group. Additionally, 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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Other study results further supported a beneficial treatment effect on IA behaviors. The CGI results 
(Severity and Improvement) were consistent with the findings for the R-MOAS; notable improvement 
occurred primarily in the Low dose and Medium dose groups. Scores for Swanson, Nolan and Pelham 
Questionnaire (SNAP-IV) Hyperactivity and Impulsivity did not exhibit statistically significant differences 
across groups. Numeral trends in SNAP-IV Oppositional Defiant Disorder (ODD) scores, while not always 
significant, consistently favored the Low dose- and Medium dose groups over Placebo. 
Study 810P203 was the multicenter open label extension (OLE) to the Phase 2b trial in a pediatric 
population of subjects 6-12 years of age diagnosed with ADHD and IA (Sponsor Study 810P203). The 
starting dose for this open-label extension study was based on subjects’ weight at the end of 810P202. 
Subjects were initiated at doses of 18 and 36 mg/day, in children weighing less than 30 kg, and more than 
30 kg, respectively. The dose was gradually adjusted based on tolerability or effectiveness, regardless of 
weight group to 9 mg/day, 18 mg/day, 27 mg/day or 36 mg/day. Of the 121 subjects randomized into the 
double blind Study 810P202, 78 subjects continued on to the OLE study and received SPN-810 for up to 6 
months.  
SPN-810 was well tolerated when dosages were adjusted according to clinical response. The overall 
incidence of AEs was dose-related: 9 mg/day, 26.7%; 18 mg/day, 32.7%; 27 mg/day, 39.1%; and 
36 mg/day, 55.2%. The most frequently reported AEs with 36 mg/day were abnormal weight gain (12.1%), 
sedation (10.3%), and increased appetite (8.6%). Other common AEs included somnolence, which 
occurred in 5.1% of subjects in any dose group. Of all AEs, nervous system disorders were reported with 
the 
highest 
frequency, 
with 
similar 
reporting 
frequency 
among 
all 
4 
dose 
groups  
(8.7-15.5%). The frequency of AEs associated with EPS was low (n=2, 2.6%), as was the frequency of 
discontinuations due to AEs (n=7, 9.0%). Over the course of 6 months, the average increase was  
2.18–3.70 kg in weight and 0.55–1.06 kg/m2 in BMI across the dose groups, most of this increase was 
considered to be due to normal growth. A total of seven subjects (9.0%) discontinued due to AEs. No 
unexpected, life-threatening, or dose-limiting safety issues were observed. The overall frequency of 
events was relatively low as were discontinuations due to AEs. Treatment effects achieved during the 
double-blind study 810P202 appeared to be maintained in the OLE study supporting the clinical relevance 
of SPN-810 as a treatment for IA in children diagnosed (comorbid) with ADHD. 
1.4 Sponsor’s Phase 3 Studies 
The Sponsor is conducting two Phase 3 multicenter, randomized, double-blind, placebo controlled trials 
in a pediatric population of subjects 6-12 years of age and one in adolescents (12-17 years old) diagnosed 
with ADHD and IA (810P301, 810P302 and 810P503, respectively).  The primary objective of these studies 
is to assess the efficacy and safety of SPN-810 in reducing the frequency of IA behaviors in pediatric and 
adolescent patients with ADHD when taken in conjunction with standard ADHD treatment. The Sponsor 
has recently developed a new measurement tool to assess the frequency of the behaviors associated with 
IA (Sponsor Study 810P501). This instrument is an electronic observer-reported outcome (eOBsRO) diary 
that monitors the occurrence of IA behaviors. Severity of IA is assessed using the Clinical Global Impression 
scales completed by both the caregiver and the Investigator.  


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Additional secondary endpoints include the assessment of subjects and caregivers quality of life using the 
Child Health Questionnaire Parent Form 28-item (CHQ-PF28) and the Parenting Stress Index-Short Form 
(PSI-4-SF) or the Stress Index for Parents of Adolescents (SIPA). The effect of molindone on body 
composition, metabolic parameters, prolactin and possible drug-drug interaction is also evaluated.   
Children 6 to 12 years of age with ADHD and the associated feature of IA are randomized, with 97 subjects 
in each treatment arm (18 mg, 36 mg and placebo). 
 
 
. After 
completing the two-week titration phase and the three-week maintenance phase, subjects will have the 
option to enroll in the OLE study (this study 810P304),  at which time they will enter either the conversion 
phase or the tapering phase prior to the completion of the double-blind study.  Subjects who choose to 
participate in this OLE will be converted from their maintenance study dose to a dose of 18 mg/day SPN-
810 in a blinded fashion.  
For the 810P503 study, 93 patients diagnosed with ADHD and the associated feature of IA are randomized 
to placebo or a flexible dose of SPN-810. After two weeks of titration, the dose will be maintained at 36 
mg/day during the first week of maintenance and then increased up to 54 mg/day at the discretion of the 
Investigator during the following two weeks. After the completion of the maintenance phase, subjects will 
enter a taper down period if they decide to discontinue, or will be given the option to enroll in the OLE 
(810P304 study). Subjects who choose to enroll in the OLE will receive a blinded conversion card and enter 
the OLE study at 36 mg/day. 
1.5 Study Rationale 
Results from Phase 2 studies and the associated open label study have shown that molindone 
hydrochloride extended-release (SPN-810) is safe and well tolerated in the target population of children 
6-12 years of age. The goal of the phase 3 studies is to support the efficacy, safety and tolerability of SPN-
810 in reducing the frequency of IA behaviors.  This Phase 3 study, 810P304, is available to eligible subjects 
who complete the randomized, double-blind portion of one of the three Phase 3 studies, 810P301, 
810P302, 810P503 or the additional Phase 2 study, 810P204. Subjects who discontinue during the 
maintenance phase 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 objective of this extension study is to collect additional long-term safety data on the use of SPN-810 
for the treatment of IA in subjects diagnosed with ADHD in conjunction with a standard ADHD treatment 
(stimulant or non-stimulant) and to collect additional data on the maintenance of the effect on IA 
behaviors and quality of life.  
Monitoring the occurrence of any treatment emergent AEs, concomitant medications and the frequency 
of extrapyramidal symptoms are the primary outcome measures for this study.   


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In addition to safety, we will assess the severity of aggressive behaviors using the R-MOAS scale, and the 
severity and improvement of IA using the CGI scales. Changes in CHQ-PF28 and PSI-4-SF or SIPA scores 
will be used to evaluate improvement of quality of life of both the subject and the caregiver. 
2 STUDY OBJECTIVE 
2.1 Objective 
The objective of this Phase 3 OLE study is to collect long-term safety data on the use of SPN-810 as a 
treatment for IA in subjects (6-17 years of age) with ADHD when taken in conjunction with standard ADHD 
treatment only after satisfactory participation in a preceding double-blind study (810P301, 810P302, 
810P503 or 810P204). 
3 INVESTIGATIONAL PLAN 
3.1 Rationale for Study Design, Including Choice of Treatment Groups, 
Appropriateness of Measurements 
The present study is designed to collect long-term safety data for the use of SPN-810 in the treatment of 
IA in subjects aged 6 to 17 years diagnosed with ADHD. SPN-810 was used in Phase 2 and currently in 
Phase 3 studies for the treatment of IA in children and adolescents with ADHD who experienced IA 
behaviors despite monotherapy treatment with an FDA-approved ADHD medication. 
The subject will be eligible to enroll in this study after the completion of the double-blind studies 810P301 
or 810P302, 810P503 or 810P204. At Visit 6 of 810P301 and 810P302 studies or at Visit 4 of 810P204, 
subjects are invited to convert from their randomized dose in a blinded fashion to a dose of 
 
 the initial total daily dose for this OLE study. Subjects participating in the 810P503 study will 
receive a blinded conversion card at Visit 7 and will initiate the OLE study at 
 
Additionally, subjects are eligible to enroll in this study on a case-by-case basis only after consultation 
between the Investigator, the Medical Monitor and the Sponsor if they discontinue from one of the 
double-blind studies during the maintenance phase prior to Visit 6 (810P301 or 810P302) or Visit 5 
(810P204). Subjects will be converted from their randomized dose to the initial total daily dose of 
 
n a blinded fashion. If subjects discontinued from the 810P503 study prior to Visit 7 during the 
maintenance phase, they will be converted in a blinded fashion from the randomized dose to 
 
  
The duration of the study will continue up to 60 months or until market availability. After the completion 
of an initial period of 6 months, subject will have an option to continue the enrollment for additional 
periods of 6 months each. 
Safety will be assessed throughout the study by the monitoring of AEs, concomitant medications, vital 
signs, clinical laboratory tests, physical examinations, and ECGs. Emergence of extrapyramidal symptoms 
will be assessed using the Simpson-Angus Scale, the Barnes Akathisia Scale, and the Abnormal Involuntary 


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Movement Scale (AIMS).  These scales were specifically chosen since youth treated with antipsychotics 
are at a greater risk for extrapyramidal side effects than adults (Findling, 2005) and they were also utilized 
in our Phase 2 and Phase 3 studies. 
3.2 Overall Study Design and Plan 
Study 810P304 is a multicenter, open-label, extension study aimed to assess safety of SPN-810 in the 
treatment of IA in patients aged 6-17 years with ADHD in conjunction with standard ADHD treatment.   
The study has three phases: Optimization, Maintenance, and Taper.  
All subjects who complete the randomized, double-blind portion of study 810P301, 810P302, 810P503 or 
810P204 will have the option to participate in the OLE study in which all subjects will receive active Study 
Medication (SM) treatment.  Subjects who choose to participate in the OLE will receive blinded conversion 
medication kits at Visit 6 of the previous SPN-810 double-blind randomization study (810P301, 810P302) 
or at Visit 4 for subjects completing the 810P204 study. Subjects, who have completed the 810P503 study 
and, chose to participate in this study, will receive the blinded conversion card at Visit 7.   
Visit 7 of 810P301, 810P302 or Visit 8 for 810P503 will be Visit 1 of 810P304. Visit 6 of the 810P204 will 
be Visit 1 of the 810P304.  The initial total daily dose for the OLE is 
 
 
After enrollment, eligible subjects will enter an optimization phase of two to eight weeks.  Subjects will 
return to the office for visits at weeks 2, 4 and 8 during which the SM dose may be gradually adjusted 
based upon tolerability or effectiveness within the limits of 
.  The Investigator 
may gradually increase the dose of SPN-810 up to 54 mg/day for subjects with body weight ≥ 30 kg.  
Following optimization, subjects will return to the office at each visit (every 3 months) during maintenance 
phase or until the subject discontinues or the study ends. The subject may discontinue at any time if the 
subject or the LAR withdraws IAF or ICF or if it is no longer in the best interest of the subject, at the 
investigator’s discretion. If the subject discontinues or is removed from the study, he/she will taper off 
the SM over a period of at least 2 weeks. 
3.2.1 
Baseline Phase 
There will be no screening period. Subjects may enter the study upon completion of one of the following 
double-blind studies:  810P301, 810P302, 810P503 or 810P204.   Prior to conducting any procedures, 
written informed consent/assent must be obtained from the parent or LAR, and subject (when required). 
Inclusion and exclusion criteria will be re-assessed to confirm the subjects’ eligibility. Each eligible subject 
will be assigned the same subject number used in the previous double-blind randomized study.   
 
Subjects who have completed one of the double-blind randomized studies (810P301, 810P302, 
810P204 or 810P503) will be converted during their last week of participation and will initiate 
dosing 
 respectively.  
 
On a case-by-case basis, subjects who discontinued early during the maintenance phase of 
810P301, 810P302, 810P204 or 810P503 and are approved for participation in this study will  
initiate at 
 respectively.  


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 
In rare occasions, subjects who have discontinued early from the maintenance phase of 810P301, 
810P302, 810P204 or 810P503 and have washed out from the study medication for at least 2 days 
may be approved to enroll in the OLE. These subjects will enter the study at
 and 
gradually titrated up to an optimized dose.  
3.2.2 
Pharmacogenomics (PGx) 
Participation in PGx testing is optional. For subjects already enrolled in this study, a blood sample will be 
collected at the next visit following this amendment. For newly enrolled subjects (from 810P301, 810P302 
or 810P204 study), the blood samples for PGx analysis will be obtained at Visit 1/Baseline. Prior to testing, 
all subjects will be consented for PGx testing.  
The DNA will be extracted and tested for any genetic variations associated with 
 enzyme. 
 
 
 
 
. 
 
The residual DNA will be stored for possible testing of genes involved in the efficacy and possible 
association with particular adverse events of the drug (e.g., understand the non-responders to treatment 
and/or individuals who show unusual safety profile). The DNA analysis will not be used for individual 
genetic characterization and the subject identity will be kept confidential.  
3.2.3 
Optimization Phase (2-8 weeks) 
During the optimization phase, the study medication dose should be optimized between
 
y given as divided doses BID in children (6-12 years of age) or adolescents (12-17 years of 
age), respectively.  
3.2.4 
Maintenance Phase (repeated 6 month periods) 
During the maintenance phase, subjects will return to the office every 3 months to evaluate safety and 
efficacy, perform drug accountability and to receive new study medication, as required.  The Investigator 
may continue to adjust the dose as needed between 6 mg/day and 36 mg/day given as a divided dose 
(BID). For subjects whose body weight is ≥ 30 kg, the Investigator may gradually increase the dose of SPN-
810 up to 54 mg/day based on safety and tolerability.  After each 6-month period, subjects will be offered 
the option to extend their participation for an additional period of 6 months. 
During the maintenance phase, a urine pregnancy test will be requested for all Females of Child Bearing 
Potential (FOCBP). At each visit during Maintenance (Visit 5-Visit 24), FOCBP subjects will receive a urine 
pregnancy test to take at home and will be asked to complete the testing approximately 6 weeks following 
each visit. The site will call the caregiver as a reminder and follow-up to obtain the pregnancy test results. 
Sites are encouraged to educate the caregivers and the subjects on the importance of preventing 
pregnancies during participation in the study. 
The distribution of the home pregnancy test as well as the results of the test will be recorded on paper 
source at the clinical trial sites.  


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If a positive result is reported, the subject will be brought to the clinic for an unscheduled visit to confirm 
through a serum pregnancy test. If pregnancy is confirmed, the subject will be withdrawn from the study. 
The Investigator will report the pregnancy and complete the follow-up procedures outlined in Sec. 5.1.3.2. 
3.2.5 
Taper Phase (2 weeks) 
All subjects who discontinue early or complete the OLE study 810P304 will taper off the study medication 
over a period of 2 weeks. 
3.2.6 
End of Study / Early Termination 
Subjects will return to the study site for a final visit, after completing the 2-weeks Taper Phase.  Subjects 
who discontinue early will return to the study site for a final visit. 
4 STUDY METHODS 
4.1  Study Population 
Approximately 600 subjects will be enrolled in this clinical investigation. The population will be male and 
female subjects with IA and diagnosed with ADHD, currently treated with an FDA-approved standard 
ADHD treatment and who have completed a satisfactory participation in one of the double-blind 
randomized studies 810P301, 810P302, 810P503 or 810P204.  Subjects who discontinued early from the 
above double-blind randomized studies during the maintenance phase will be allowed to enroll in this 
study after consultation between the Investigator, the Medical Monitor and the Sponsor on a case-by case 
basis. 
4.1.1 
Inclusion Criteria   
1. Healthy male or female subjects, who completed and converted from a satisfactory participation in 
the studies 810P301, 810P302, 810P503 or 810P204 or discontinued early from the previous study 
during the maintenance phase and allowed to enroll only after consultation between the Investigator, 
the Medical Monitor and the Sponsor. 
2. Medically healthy and with clinically normal laboratory profiles, vital signs, and electrocardiograms 
(ECGs). 
3. Existing diagnosis of ADHD, as described by DSM-5 and confirmed by the K-SADS PL 2013 from study 
810P301 or 810P302 and by the MINI-KID from the 810P503 or 810P204 studies. 
4. Currently receiving monotherapy treatment with FDA-approved ADHD medication (stimulants and 
non-stimulants). 
5. Weight of at least 20 kg. 
6. Written Informed Consent obtained from the subject’s parent or LAR, and written Informed Assent 
obtained from the subject if appropriate. 
4.1.2 
Exclusion Criteria 
1. Body Mass Index (BMI) in the 99th percentile or above.  


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2. Clinically significant change in health status, safety concern or any other reason that, in the opinion 
of the Sponsor or the Investigator, would prevent the subject from participating in this study or 
successfully completing this study. 
3. Pregnancy, breastfeeding or refusal to practice contraception during the study (for female subjects of 
childbearing potential and sexually active males). 
4. Current substance or alcohol use. 
5. Suicidal thoughts or behaviors confirmed at last visit in the previous double-blind randomized study. 
6. Known allergy or sensitivity to molindone hydrochloride. 
4.2 Schedule of Visits and Procedures 
All subjects who are enrolled and take the initial dose of SM are required to follow the protocol procedures 
regardless of the number of doses of SM taken.  The Sponsor, or the Sponsor’s designee, must be notified 
of all deviations from the Schedule of Visits and Procedures (Table 1), and these procedures, if applicable, 
should be performed at the nearest possible time to the original schedule.  Subjects will be instructed to 
call study personnel to report any issues or abnormal reactions during the intervals in between study visits 
and to return to the study site if medical evaluation is needed especially when urgent.  Unscheduled visits 
may be conducted at the discretion of the Investigator throughout all study periods.  The medical monitor 
must be contacted promptly in the event that any clinically significant findings or information is obtained 
during the unscheduled visit.  For emergency and other unscheduled visits to a medical facility other than 
the study site, medical records will be obtained by the Investigator or qualified designee as source data 
for study follow-up by the Investigator.


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Table 1: Schedule of Events and Procedures 
 
 
Treatment 
EOS 
Phase 
Baselinea 
Optimization 
Maintenance 
Taper 
Visit Number 
EOS 
Visita/ 
Visit 1 
Visit 2 
(Week 
2) 
Visit 3 
(Week 4) 
Visit 4 
(Week 8) 
bVisits 5 (Mo 3), 7, 9, 
11, 13, 15, 17, 19, 21, 
and 23 (Mo 57) 
bVisits 6 (Mo 6), 8, 10, 
12, 14, 16, 18, 20, 22, 
and 24 (Mo 60) 
Visit 
25 
Window (Days) 
 
2 weeks 
±1 week 
from  
Visit 1 
2 weeks 
±1 week 
from 
Visit 2 
4 weeks 
±1 week 
from 
Visit 3 
Visit 5 will occur 
4 weeks ±1 week 
from Visit 4 
Visit 6 will occur 3 
months ± 1 week  
from Visit 5 
 
Informed Consent/Assentc 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
X 
X 
ECG 
X 
 
 
 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Socio-demographic Information 
X 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
X 
X 
X 
Urine Pregnancy Testd 
Xa 
X 
X 
X 
X 
X 
X 
Home urine pregnancy follow-up (call)b 
 
 
 
 
X 
X 
 
Vital Signse 
Xa 
X 
X 
X 
X 
X 
X 
Weight, Height and BMI 
Xa 
X 
X 
X 
X 
X 
X 
Blood collection for Pharmacogenomic 
(PGx) Testingsh 
X 
 
 
 
 
 
 
Hematology/Chemistry/Urinalysis 
Xa 
 
 
X 
 
X 
X 
Columbia Suicide Severity Rating Scale 
(CSSRS) 
Xa 
X 
X 
X 
X 
X 
X 
Investigator CGI-S 
X 
X 
X 
X 
X 
X 
Xf 
Caregiver and Investigator CGI-I 
X 
X 
X 
X 
X 
X 
Xf 
R-MOAS 
 
 
 
 
X 
X 
Xf 


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Treatment 
EOS 
Phase 
Baselinea 
Optimization 
Maintenance 
Taper 
Visit Number 
EOS 
Visita/ 
Visit 1 
Visit 2 
(Week 
2) 
Visit 3 
(Week 4) 
Visit 4 
(Week 8) 
bVisits 5 (Mo 3), 7, 9, 
11, 13, 15, 17, 19, 21, 
and 23 (Mo 57) 
bVisits 6 (Mo 6), 8, 10, 
12, 14, 16, 18, 20, 22, 
and 24 (Mo 60) 
Visit 
25 
Window (Days) 
 
2 weeks 
±1 week 
from  
Visit 1 
2 weeks 
±1 week 
from 
Visit 2 
4 weeks 
±1 week 
from 
Visit 3 
Visit 5 will occur 
4 weeks ±1 week 
from Visit 4 
Visit 6 will occur 3 
months ± 1 week  
from Visit 5 
 
CHQ-PF28 
 
 
 
 
X 
X 
Xf 
PSI-4-SF/SIPAi 
 
 
 
 
X 
X 
Xf 
Safety Scales (Simpson-Angus, Barnes, 
AIMS) 
Xa 
X 
X 
X 
X 
X 
X 
Adverse Events 
Xa 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
Xa 
X 
X 
X 
X 
X 
X 
Drug Dispensation & Return 
Xa 
X 
X 
X 
X 
Xg 
X 
Drug Compliance 
 
X 
X 
X 
X 
X 
X 
a. 
Assessment is completed as the EOS visit in the preceding double-blind randomized study: Visit 7 (810P301 and 810P302), Visit 8 (810P503) and Visit 6 (810P204). 
b. 
Visit 7-24 will occur 3 months ±1 week from the previous visit. At each visit, a home urine pregnancy test will be distributed to female subjects of child-bearing potential. 
Subjects are required to complete testing 6 weeks after each visit. The site will follow-up with a call to record the results. 
c. 
Written consent and assent must be obtained prior to performing any 810P304 study-related procedures. 
d. 
To be performed for females subjects or childbearing potential prior administration of first dose of SM and will have to be tested as negative for the subjects to continue in 
the study. 
e. 
Heart rate (HR), blood pressure (BP), temperature, and respiratory rate (RR) will be measured. 
f. 
Assessments will be performed only for subjects who discontinue prior the end of the study 
g. 
Taper medication and instructions will be dispensed. 
h. 
Participation in PGx testing is optional. PGx Testing will be performed in subjects enrolling from the following studies: 810P301, 810P302 or 810P204. Subjects already 
enrolled, will provide a blood sample during the next visit after this amendment is effective. 
i. 
The SIPA scale will be administered only to subjects 13 to 17 years of age. 


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4.2.1 
Baseline/Visit 1 
Prior to conducting any procedures, written Informed Consent must be obtained from the parent or LAR, 
and, if appropriate, Informed Assent from the subject.  Visit 7 of 810P301 or 810P302, Visit 8 for 810P503 
and Visit 6 of 810P204 will be Visit 1 of the OLE. Subjects who meet the requirements for study 
participation will begin titration at Visit 6 of 810P301 or 810P302 studies and at Visit 5 for the 810P204 
study to the dose level of
  Subjects who have completed 810P503 study participation will start 
titration at Visit 7 to the initial dose of
 in this study. Subjects will receive instructions and begin 
the study at their designated dose and will then continue on their optimized dose until the subject 
discontinues. The SM dose may be adjusted throughout the study upon the Investigator’s discretion. 
The following procedures will be performed at Baseline or Visit 1: 
1. Obtain written informed consent and assent. 
2. Perform physical examination 
3. Perform 12-lead ECG 
4. Confirm Inclusion/Exclusion criteria 
5. Record socio-demographic information 
6. Record vital signs (Heart Rate (HR), Blood Pressure (BP), temperature, and Respiratory Rate (RR)) 
7. Record height, weight and BMI 
8. Collect blood samples for hematology, chemistry and pharmacogenomic testing (when applicable) 
9. Collect urine sample for drug screen 
10. Administer Investigator CGI-S 
11. Administer Investigator and Caregiver CGI-I 
12. Dispense SM 
13. Administer Columbia Suicide Severity Rating Scale (C-SSRS) 
14. Collect urine sample for pregnancy test (Females of Child Bearing Potential (FOCBP) only) and 
urinalysis 
15. Assess and record  concomitant medications 
16. Collect and assess adverse events 
17. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
4.2.2 
Visit 2 
Visit 2 will occur approximately 2 weeks (±1 week) following Visit 1.   
1. Record vital signs (HR, BP, temperature, and RR) 
2. Record height, weight and BMI 
3. Collect urine sample for pregnancy test (Females of Child Bearing Potential (FOCBP) only) 
4. Administer C-SSRS 
5. Administer Investigator CGI-S 
6. Administer Investigator and Caregiver CGI-I 
7. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 


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8. Collect and assess adverse events 
9. Dispense SM.   
10. Assess and record concomitant medications 
11. Assess treatment compliance 
4.2.3 
Visit 3 
Visit 3 will occur approximately 2 weeks (±1 week) following Visit 2 according to the Schedule of Visits and 
Procedures. 
1. Record vital signs (HR, BP, temperature, and RR) 
2. Record height, weight and BMI 
3. Collect urine sample for pregnancy test (Females of Child Bearing Potential (FOCBP) only) 
4. Administer C-SSRS 
5. Administer Investigator CGI-S 
6. Administer Investigator and Caregiver CGI-I 
7. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
8. Collect and assess adverse events 
9. Dispense SM.   
10. Assess and record concomitant medications 
11. Assess treatment compliance 
4.2.4 
Visit 4 
Visit 4 will occur approximately 4 weeks (±1 week) following Visit 3 according to the Schedule of Visits and 
Procedures. 
1. Record vital signs (HR, BP, temperature, and RR) 
2. Record height, weight and BMI 
3. Collect blood samples for hematology, chemistry and urinalysis 
4. Collect urine sample for pregnancy test (Females of Child Bearing Potential (FOCBP) only) 
5. Administer C-SSRS 
6. Administer Investigator CGI-S 
7. Administer Investigator and Caregiver CGI-I 
8. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
9. Collect and assess adverse events 
10. Dispense SM.   
11. Assess and record concomitant medications 
12. Assess treatment compliance 
4.2.5 
Visit 5 
Visit 5 will occur 4 weeks (±1 week) following Visit 4 according to the Schedule of Visits and Procedures. 
1. Perform 12-lead ECG 
2. Record vital signs (HR, BP, temperature, and RR) 


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3. Record height, weight and BMI 
4. Collect urine sample for pregnancy test (FOCBP only) and dispense home pregnancy test kit 
5. Collect urine sample for drug screen 
6. Administer C-SSRS 
7. Administer Investigator CGI-S 
8. Administer Investigator and Caregiver CGI-I 
9. Administer R-MOAS 
10. Administer quality life scales (CHQ-PF28, PSI-4-SF or SIPA) 
11. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
12. Collect and assess adverse events 
13. Dispense SM.   
14. Assess and record concomitant medications 
15. Assess treatment compliance 
4.2.6 
Visit 6 
Visit 6 will occur 3 months (±1 week) following Visit 5 according to the Schedule of Visits and Procedures. 
1. Perform physical examination 
2. Perform 12-lead ECG 
3. Collect urine sample for urinalysis and urine drug screen (all subjects), and pregnancy test (FOCBP 
only) 
4. Dispense home pregnancy test kit 
5. Record vital signs (HR, BP, temperature, and RR) 
6. Record height, weight and BMI 
7. Collect blood for samples for hematology and chemistry 
8. Administer C-SSRS 
9. Administer Investigator CGI-S 
10. Administer Investigator and Caregiver CGI-I 
11. Administer R-MOAS 
12. Administer quality life scales (CHQ-PF28, PSI-4-SF or SIPA) 
13. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
14. Collect and assess adverse events 
15. Collect SM and assess treatment compliance 
16. Confirm subject’s decision to continue or taper 
17. Dispense SM (continue or taper) 
18. Assess and record concomitant medications 
4.2.7 
Subsequent Visits (Visits 7 through 24) (approximately every 3 months (+/- 1 week))  
After completion of the initial 6-month period (at Visit 6), subjects will be offered the option to continue 
participation for another 6-month maintenance period for up to a total of 60 months (5 years) or until 
market availability. Each 6-month period will have two visits every 3-months. These will include Visits 7 
through 24.  


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At Visits 7, 9, 11, 13, 15, 17, 19, 21, and 23, the following procedures will be conducted:  
1. Perform 12-lead ECG 
2. Record vital signs (HR, BP, temperature, and RR) 
3. Record height, weight and BMI 
4. Collect urine sample for pregnancy test (FOCBP only) and dispense home pregnancy test kit 
5. Collect urine sample for drug screen 
6. Administer C-SSRS 
7. Administer Investigator CGI-S 
8. Administer Investigator and Caregiver CGI-I 
9. Administer R-MOAS 
10. Administer quality life scales (CHQ-PF28, PSI-4-SF or SIPA) 
11. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
12. Collect and assess adverse events 
13. Dispense SM 
14. Assess and record concomitant medications 
15. Assess treatment compliance 
At Visit 8, 10, 12, 14, 16, 18, 20, 22, and 24, the following procedures will be conducted:  
1. Perform physical examination 
2. Perform 12-lead ECG 
3. Collect urine sample for urinalysis and urine drug screen (all subjects), and pregnancy test (FOCBP 
only) 
4. Dispense home pregnancy test kit 
5. Record vital signs (HR, BP, temperature, and RR) 
6. Record height, weight and BMI 
7. Collect blood for samples for hematology and chemistry 
8. Administer C-SSRS 
9. Administer Investigator CGI-S 
10. Administer Investigator and Caregiver CGI-I 
11. Administer R-MOAS 
12. Administer quality life scales (CHQ-PF28, PSI-4-SF or SIPA) 
13. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
14. Collect and assess adverse events 
15. Collect SM and assess treatment compliance 
16. Confirm subject’s decision to continue or taper 
17. Dispense SM (continue or taper) 
18. Assess and record concomitant medications 
4.2.8 
Visit 25 [(End of Study (EOS)] (Month 60 +/- 2 weeks) 
Subjects who complete the study (60 months) will be instructed to down titrate for 2 weeks before 
returning to the office for the EOS Visit.  


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Subjects may discontinue prior the end of the study if the subject or the LAR withdraws assent and/or 
consent, or if the Investigator or the Sponsor decide it is no longer in the best interest of the subject.  If 
the decision is made to discontinue early then the subject will be contacted and instructed to down-titrate 
at least 2 weeks prior to the EOS Visit. 
The following procedures will be performed for subjects who complete the study (60 months) or 
discontinue early. 
1. Perform physical examination 
2. Perform 12-lead ECG 
3. Collect urine sample for urinalysis and urine drug screen (all subjects), and pregnancy test (FOCBP 
only) 
4. Record vital signs (HR, BP, temperature, and RR) 
5. Record height, weight and BMI 
6. Collect blood samples for hematology and chemistry 
7. Administer C-SSRS 
8. Administer safety scales (Simpson-Angus, Barnes Akathisia, AIMS) 
9. Administer efficacy scales (R-MOAS, CGI-I and CGI-S, only for subjects who discontinue early) 
10. Administer quality life scales (CHQ-PF28, PSI-4-SF or SIPA, only for subjects who discontinue early) 
11. Collect and assess adverse events 
12. Collect SM and assess treatment compliance 
13. Assess and record concomitant medications 
4.3 Treatments 
4.3.1 
Treatments Administered 
SPN-810  
Subjects will enter this study from one of the previous double-blind clinical studies (810P301, 810P302 or 
810P204) and will initiate at
. Subjects from the double-blind 810P503 
study will initiate this study at 
 Eligible subjects who discontinue early in one of the 
randomized, double-blind studies (810P301, 810P302 or 810P204) and are approved for participation in 
the OLE study will initiate study as outlined in Sec. 3.2.1. At the Investigator’s discretion, this initial dose 
may be gradually adjusted based upon tolerability and effectiveness between
 
For subjects with body weight ≥ 30 kg and  not fully responding to 36 mg/day doses, the Investigator may 
gradually increase the dose of SPN-810 up to 54 mg/day.  
In rare occasions, subjects who discontinue early and have washed out from the SM for at least 2 days 
may be approved to enroll in the OLE. These subjects will enter the study at
 will be 
instructed to gradually titrate at the optimized dose.  
Subjects will take molindone hydrochloride extended-release tablet (SPN-810) twice each day (BID) with 
or without food, in the morning and in the evening, in addition to the optimized dose of ADHD medication.  


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If dosing starts before noon, the subject should start with the morning dose; if dosing starts after noon, 
the subject should start with the evening dose.  
ADHD medication 
The Investigator is allowed to adjust the FDA-approved ADHD monotherapy medication and/or its dose 
at any time during the course of this study. 
A combination of extended-and immediate-release formulations of the same ADHD medication are not 
considered monotherapy.  
4.3.2 
Identity of Investigational Product(s) 
Study medications are either purple (3 mg) or yellow (9 mg) round tablets or a reddish-brown (18 mg) oval 
tablet which are all printed on one side with the appropriate dose strength in a black underscored font 
(“3” “9” or “18”).  Sites will dispense a sufficient quantity (60-120 day supply) of medications for the 
subject to take the designed dose every day until the next visit to the office, according to Table 1.  
The SM is supplied to the sites in bottles: the 3 mg and 9 mg (60-120 day supply) is packaged in a 60cc 
white, square high-density polyethylene bottle with a white child resistant closure. The 18 mg (60-day 
supply) drug product is packaged in a 60cc, while the 18 mg (120-day supply) drug product is packaged in 
a 90cc white, square high-density polyethylene bottle with a white child resistant closure. 
4.3.3 
Study Medication Handling and Accountability 
All SM is supplied to the Investigator by the Sponsor.  SM must be kept in an appropriate secure area (e.g., 
locked cabinet) and stored according to the conditions specified on the SM labels.  SM must be stored 
between 68°F – 77°F (20°C – 25°C). 
Following Sponsor instructions and in compliance with ICH E6 as well as local, state, and federal 
regulations, the Investigator and study staff will be responsible for the accountability of all clinical supplies 
(receiving, shipment, dispensing, inventory, and record keeping) in a SM accountability log, a copy of 
which will be collected by the Sponsor at the end of the study. 
Under no circumstances will the Investigator allow the SM to be used other than as directed by this 
protocol.  Clinical supplies will not be dispensed to any individual who is not enrolled into the study. 
An accurate and timely record of the receipt of all clinical supplies; dispensing of SM to the subject; 
collection of unused supplies returned by the subject; and subsequent return of unused SM to the Sponsor 
must be maintained with dates.  This SM accountability log includes, but may not be limited to: 
(a) documentation of receipt of clinical supplies, (b) SM inventory log, (c) SM accountability log, and (d) 
all shipping notifications.  All forms will be provided by the Sponsor.  Any comparable forms that the study 
site wishes to use must be approved by the Sponsor. 
Supplies and inventory records must be made available, upon request, for inspection by the designated 
representative of the Sponsor or a representative of the FDA.  The assigned CRA will review these 
documents along with all other study conduct documents at each and every visit to the study site once 


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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 
Each subject who completes or discontinues from 810P301, 810P302, 810P503 or 810P204, and is eligible 
for enrollment in the OLE, will maintain the same unique subject identification number that was given to 
them in the preceding double-blind randomized study. 
4.3.5 
Treatment Replacement 
In the event that a subjects’ original bottle is lost, damaged, or consumed prior to the end of treatment, 
a new bottle will be dispensed to that subject from the supplies already available at the site. Limited stock 
of study medication will be maintained at each site.  
4.3.6 
Dosing Schedule 
Subjects will initiate dosing at 18 mg/day (9 mg BID) or 36 mg/day (18 mg BID) in a blinded fashion and 
subsequently optimized.  At the Investigator’s discretion, the dose may be gradually adjusted based upon 
tolerability and effectiveness between the doses of 6 mg/day and 36 mg/day or 54 mg/day for subjects 
whose body weight is ≥ 30 kg.  Doses should always remain BID and, whenever possible, evenly divided 
(same number of mg in morning and evening).  
4.3.7 
Method of Administration 
The SM must be swallowed whole.  SM must not be crushed, chewed or cut. The SM may be taken with 
or without food in the morning and in the evening, preferably every 12 hours.  
4.3.8 
Blinding 
Blinding is not applicable. 
4.4 Prohibited Medication 
Subjects may not be on any prohibited medication while on study. These medications include:  
 
α 2- adrenergic agonists (e.g. clonidine and guanfacine) used for any other reason except for 
monotherapy treatment for ADHD  
 
Non-FDA approved formulations for the treatment of ADHD (e.g. IR or ER formulations of the same 
compound) 
 
Combination of extended-and immediate-release formulation of the same compound( e.g. IR 
formulation in the morning and ER formulation in the evening)   
 
Anti-psychotics including aripiprazole,  risperidone, quetiapine, and ziprasidone  


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 
Anticonvulsants including carbamazepine and valproic acid, antidepressants, mood stabilizers 
including lithium, benzodiazepines, cholinesterase inhibitors or any drug known to inhibit
 
activity 
 
Herbal supplements 
4.5 Concomitant Medication 
The following concomitant medications are allowed during this study:  
1. Current or other FDA-approved monotherapy ADHD medication. 
2. Benztropine is permitted for the treatment of emerging EPS at a starting dose of 0.5 mg BID up to 
a range of 1 to 4 mg/day.  Lorazepam (1 to 2 mg per dose not to exceed three times daily) and 
clonazepam (0.25 to 1 mg per dose not to exceed twice daily) is also permitted to treat  
extrapyramidal symptoms.   
3. For the treatment of Akathisia, propranolol is allowed up to 90 mg /day in divided doses, three 
times per day, starting at 10 mg BID and up to 30 mg TID, as needed.  
4. Treatment for AEs other than EPS or minor transient ailments is permitted only in consultation 
with the Medical Monitor or his/her designee with the exception of required treatments for acute 
conditions in the emergency room/hospital and/or office visit as indicated.  
All concomitant medications as well as the changes in the dosing of the ADHD medication or the changes 
to any other FDA-approved ADHD treatment 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 the 
end of study visit.  All subjects who discontinue early will be contacted by the study staff and instructed 
to down-titrate gradually over approximately 2 weeks prior to the EOS visit. 
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 the Investigator 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 at the 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. 


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5 ANALYSIS VARIABLES 
5.1 Safety Variable 
The primary outcome measure will be the safety and tolerability of the SM.  At every visit, safety 
assessment will consist of monitoring and recording of all AEs and concomitant medications, clinical 
laboratory tests, together with prolactin and insulin plasma levels, vital signs, physical examinations and 
12-lead ECG and suicidality thoughts and behaviors. 
Assessment of possible neurological side effects and EPS will be performed using the Simpson-Angus 
scale, the Barnes Akathisia scale and the Abnormal Involuntary Movement scale.  A positive rating or 
finding on any safety scale will be captured as an Adverse Event at the discretion of the Investigator if it 
satisfied the criteria for Adverse Event. 
5.1.1 
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. 
5.1.2 
Causality 
Adverse events 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 SM and the AE, i.e., there is a reasonable possibility that the 
SM caused the adverse event.   
Adverse Drug Reactions (ADRs) are a subset of all SADRs for which there is reason to conclude that the 
SM caused the event. 


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5.1.2.1 
Recording and Evaluation of Adverse Events 
All subjects who are enrolled (starting at Visit 1) will be questioned regarding the occurrence of AEs.  
Adverse events occurring in the previous clinical study or ongoing at the end of the 810P301, 810P302, 
810P503 or 810P204 will become part of the subject’s medical history. At each visit, the Investigator must 
seek information on AEs by specific questioning and, as appropriate, by examination.  Information on all 
AEs should be recorded immediately in the source document and also in the appropriate adverse event 
module of the electronic Case Report Form (eCRF).  All clearly related 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 
medication, or that worsened following first administration of study medication. 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 increased score in the C-SSRS, Simpson Angus Scale, Barnes Akathisia Scale, or the Abnormal 
Involuntary Scale 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? 
5.1.2.2 
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. 
5.1.2.3 
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: 


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for the purpose of reviewing or performing this study. 
Not suspected: The temporal relationship of the AE to SM administration makes a causal relationship 
unlikely, or other drugs, therapeutic interventions, or underlying conditions provide a sufficient 
explanation for the observed event.  
 
Not related:  Temporal relationship to SM administration is missing or implausible, or there is an 
evident other cause. 
 
Unlikely related:  Temporal relationship to SM administration makes a causal relationship 
improbable; and other drugs, chemicals, or underlying disease provide plausible explanations. 
Suspected: The temporal relationship of the AE to SM administration makes a causal relationship 
possible, and other drugs, therapeutic interventions, or underlying conditions do not provide a sufficient 
explanation for the observed event.  
 
Possibly related:  Temporal relationship to SM administration is plausible, but concurrent disease 
or other drugs or chemicals could also explain event.  Information on medication 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). 
5.1.3 
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. 


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5.1.3.1 
Investigator Responsibilities for Reporting SAEs 
The Investigator must immediately report to the Sponsor all SAEs, regardless of whether the Investigator 
believes they are drug related. 
All SAEs must be reported to the Drug Safety Contact person(s) within 24 hours of first becoming aware 
of the SAE.  The Investigator must complete an SAE ECRF in EDC and include a detailed description of the 
SAE, as well as other available information pertinent to the case (e.g., hospital records, autopsy reports 
and other relevant documents).  Should the site be unable to access EDC, a paper SAE form must be 
completed and sent to 
 Drug Safety by email or fax. The Investigator will keep a copy of this SAE 
Report Form on file at the study site.  Once EDC becomes available, the site must complete the SAE eCRF 
in EDC. 
The Investigator or study physician, after thorough consideration of all facts that are available, must 
include an assessment of causality of an AE to SM in the report to the Sponsor.   
Follow-up information, or new information available after the initial report, should be actively sought and 
reported to the Sponsor as it becomes available using the SAE Report Form.   
The Drug Safety Contact for SAE reporting is: 
 
 
 
 
 
5.1.3.2 
  Other Events Requiring Immediate Reporting 
The Investigator must report a pregnancy that occurs in a subject during a clinical study to the Drug Safety 
Contact within 24 hours of first becoming aware of the event.  Pregnancy should be reported on a 
Pregnancy Report Form.  The Investigator should discuss the case with the Medical Monitor also, he/she 
must follow any pregnant subject for 3 months after the child is born.  The Investigator must complete a 
Pregnancy Outcome Form as 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-emergent extrapyramidal symptoms (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 within 24 hours 
of first becoming aware of the event.  Once EDC becomes available, the site must complete the AESI eCRF 
in EDC. EPS incidence will be summarized and shared with study Investigators throughout the clinical trial.   
Overdosage of molindone presumably may be manifested by severe EPS and sedation.  Coma with 
respiratory depression and severe hypotension resulting in a shock-like syndrome could occur. In the 


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event of a suspected overdose, the parent or LAR should be instructed to call 911 or their local poison 
control center at 1-800-222-1222. 
Symptomatic, supportive therapy should be the rule.  Gastric lavage is indicated for the reduction of 
absorption of molindone which is freely soluble in water. Since the adsorption of molindone by activated 
charcoal has not been determined, the use of this antidote must be considered of theoretical value. 
Emesis in a comatose patient is contraindicated. Additionally, while the emetic effect of apomorphine is 
blocked by molindone in animals, this blocking effect has not been determined in humans. 
5.1.3.3 
Sponsor Responsibilities for Expedited Reporting of SAEs 
The Sponsor will inform Investigators and regulatory authorities of adverse drug reaction (ADRs) that are 
both serious and unexpected, 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. 
5.1.4 
Management of Treatment-Emergent EPS 
If a subject experiences treatment-emergent EPS (including akathisia, dystonia, Parkinsonism, or tardive 
dyskinesia), benztropine will be permitted at a starting dose of 0.5 mg BID up to a range of 1 to 4 mg/day.  
Lorazepam (1 to 2 mg per dose not to exceed three times daily) and clonazepam (0.25 to 1 mg per dose 
not to exceed twice daily) will also be permitted to treat the occurrence of extrapyramidal symptoms. 
For the treatment of Akathisia, propranolol is recommended up to 90 mg /day in divided doses, three 
times per day, starting at 10 mg BID and up to 30 mg TID, as needed. 
A positive finding on an EPS safety assessment scale (Barnes Akathisia, Simpson-Angus, AIMS) does not 
necessarily equate to an EPS event.  Investigators should evaluate positive findings on the EPS safety 
assessment scales and integrate them into a global clinical observation to determine if an AE of EPS should 
be recorded. 
5.1.5 
Laboratory Measurements 
With the exception of urine pregnancy test, clinical laboratory tests will be performed by a central 
laboratory as specified in the regulatory binder. 


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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 2 presents the clinical laboratory tests to be performed.  Metabolic parameters (including insulin, 
glucose, triglycerides, and total-cholesterol) and prolactin will be measured. 
All laboratory tests will be reviewed in a timely manner by qualified site personnel to ensure safety.  
Abnormal lab findings may be confirmed if necessary by one repeated testing at the discretion of the 
Investigator.  Any repeat laboratory testing will be conducted under fasting condition as indicated. Any 
laboratory abnormality may qualify as an AE in the Investigator’s judgment. 
Approximately 5.5 mL of blood per subject will be drawn at specified visits as per the schedule in Table 1.  
Table 2: Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
RBC, WBC, Hgb, HbA1ca, HCT, MCH, MCHC, MCV, platelet count, 
and WBC with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
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 
Urinalysis 
 
Glucose, protein (total), ketones, bilirubin, urobilinogen, 
hemoglobin, leucocyte esterase, nitrite 
Urine Drug Screen 
Cocaine, amphetamines, barbiturates, benzodiazepines, 
cannabinoids, opioids, phencyclidine, propoxyphene, methadone  
and alcohol 
Urine and Serum Pregnancy Test 
(FOCBP only) 
hCG 
a. 
 This parameter will be measured only in subjects who participated in the 810P503 study. 
5.1.6 
Vital Signs and Height/Weight Measurements 
Vital signs’ measurements (e.g., blood pressure, heart rate, temperature, and respiratory rate) and height, 
weight and BMI will be obtained at visits designated on the Schedule of Visits and Procedures (Table 1).  
Blood pressure and heart rate will be measured after the subject has been sitting for 5 minutes. Vital signs 
may be taken at any other time, as deemed necessary by the Investigator. 


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5.1.7 
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. 
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). 
5.1.8 
Pharmacogenomic Sample Collection 
Participation in PGx testing is optional. A total of 2 mL blood samples will be collected for 
 
pharmacogenomic testing.  For subjects already enrolled into this study (810P304) a blood sample will 
be collected at the next visit following this amendment. For newly enrolled subjects, the blood sample 
for PGx analysis will be obtained at screening. Results from individual tests will be used for research 
purposes only and will not be distributed.  
 
Samples will be identified only by the study subject number to maintain confidentiality. The DNA will be 
extracted and tested for any genetic variations associated with 
 enzyme. Collected samples will 
be stored for up to 10 years for potential future research purposes such as possible testing of genes 
involved in the efficacy and possible association with particular adverse events of the drug (e.g., 
understand the non-responders to treatment and/or individuals who show unusual safety profile). 
 
Data from samples will not have diagnostic value and will not be used for individual genetic 
characterization or development of a commercial product. At the end of testing or 10 years, any 
remaining samples will be destroyed. The subject may withdraw consent for pharmacogenomic testing 
at any time; if consent is withdrawn, the subject’s sample will be destroyed.  
5.2 Efficacy Variables 
The following scales will be administered at visits designated in the Schedule of Visits and Procedures 
(Table 1). 
5.2.1 
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 each visit after the first 6 
months (Visits 5 to 25). For subjects who discontinue early, this will be administered at the EOS (Visit 25).  


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for the purpose of reviewing or performing this study. 
5.2.2 
Clinical Global Impression  (CGI) 
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 comorbid 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 3 in the double-blind studies 810P301, 810P302, 
810P503 or 810P204), 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 and CGI-I will be assessed at each visit.  
5.3 Quality of Life Variables  
5.3.1 
The Child Health Questionnaire Parent Form 28-item (CHQ-PF28) 
The Child Health Questionnaire Parent Form 28-item (CHQ-PF28) is a short generic measure of health 
status and health related quality of life (Landgraf, 1996).  CHQ-PF28 items have four, five, or six response 
options, divided over eight multi-item scales (physical functioning, general behavior, mental health, self-
esteem, general health perceptions, parental impact: emotional, parental impact: time, and family 
activities) and five single item concepts (role functioning: emotional/behavior, role functioning: physical, 
bodily pain, family cohesion, and change in health). The CHQ-PF28 should be performed by the primary 
caregiver. 
The CHQ-PF28 will be administered at each visit after the first 6 months (Visit 5 to 25). For subjects who 
discontinue early, this will be administered at the EOS (Visit 25).  
5.3.2 
The 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 to the caregivers of subjects 6-12 years of age, at each visit after the 
first 6 months (Visits 5 to 25).  For subjects who discontinue early, this will be administered at the EOS 
(Visit 25).  


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5.3.3 
Stress Index for Parents of Adolescents (SIPA) 
The Stress Index for Parents of Adolescents (SIPA) is a screening and diagnostic instrument that 
identifies areas of stress in parent–adolescent interactions, allowing examination of the relationship of 
parenting stress to adolescent characteristics, parent characteristics, the quality of the adolescent–
parent interactions, and stressful life circumstances in parents of adolescents (11-19 years old). The SIPA 
consists of 90 items divided in three major domains, the Adolescents Domain (AD), the Parent Domain 
(PD) and the Adolescent-Parent Relationship Domain (APRD), which include the following subscales:  
moodiness/emotional lability, social isolation/withdrawal, delinquency/antisocial, failure to achieve and 
persevere, relationship with spouse/partner, social alienation and incompetence/guilt. The SIPA includes 
22-item Life Stressors (LS) Scale and the Index of Total Parenting Stress (TS). 
Parents respond to the first 90 items using a 5-point rating scale ranging from Strongly Disagree (5) to 
Strongly Agree (1) and the final 22 items by indicating Yes (Y) or No (N). 
The SIPA will be administered to caregivers of adolescents (13-17 years of age) at each visit after the first 
6 months (Visits 5 to 25).  For subjects who discontinue early, this will be administered at the EOS (Visit 
25).  
5.3.4 
Socio-demographic Characteristics 
Socio-demographic characteristics are valuable information that will be used to correlate with health-
related quality of life and clinical measures. The variables include the number of siblings in the study, 
siblings with IA, caregiver’s age and gender, living situation, marital status, household income and 
education level.  
The socio-demographic characteristics will be recorded at baseline for newly enrolled subjects and, for 
subjects already enrolled, at the next visit once this protocol amendment is effective.  
5.4 Pharmacogenomic Variable 
The extracted DNA will be tested for any genetic variations associated with 
 enzyme. 
 
 
 
 
 The residual DNA will be stored for possible testing of genes involved in the 
efficacy and possible association with particular adverse events of the drug (e.g., understand the non-
responders to treatment and/or individuals who show unusual safety profile).  
 
The DNA analysis will not be used for individual genetic characterization and the subject identity will be 
kept confidential.  
 
Participation in PGx testing is optional. Blood samples will be collected at Screening (Visit 1) for eligible 
subjects who have not been previously tested in the blinded studies. Subjects already enrolled in this 
study, will be tested at the next visit to the clinical site, once this protocol amendment is effective. 
5.5 Special Safety Assessments 
The following special scales will be administered in the clinic at visits designated in the Schedule of Visits 
and Procedures (Table 1). 


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5.5.1 
Simpson-Angus Scale 
The Simpson-Angus scale is a 10-item rating scale that is widely used for assessment of neuroleptic-
induced Parkinsonism (Simpson 1970).  It consists of 1 item measuring gait, 6 items measuring rigidity, 
and three items measuring glabella tap, tremor and salivation, respectively.  This assessment will be 
administered at each visit. 
5.5.2 
Barnes Akathisia Scale 
The Barnes Akathisia scale is a rating scale for drug-induced akathisia and includes components for rating 
the observable, restless movements characteristic of akathisia, the awareness of restlessness, and any 
distress associated with the condition (Barnes, 1989).  This assessment will be administered at each visit. 
5.5.3 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS test is a rating scale used to measure tardive dyskinesia (Munetz, 1988).  There are 12 items 
that rate involuntary movements of various areas of the subject’s body.  This assessment will be 
administered at each visit.  
5.5.4 
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. 
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 safety results.  Data from all sites will be combined 
in the computation of these summaries.  Continuous variables will be summarized using descriptive 
statistics (number of subjects, mean, standard deviation [SD], median, and minimum and maximum 
values).  Categorical (nominal) variables will be summarized using frequency tables (number and 
percentage of subjects in each category). 
In addition to tabular summaries, subject data listings, as specified in Sections 16.2 and 16.4 of ICH 
Guidance E3, will be provided.  Additional subject data listings to be provided for this study are listed 
under the relevant subsections below. All data analyses will be performed by the Clinical Research 
Organization (CRO) after study completion and database release.  Statistical programming and analyses 
will be performed using SAS® Version 9.3 or above and/or other validated statistical software as required. 


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In general, the baseline value for a variable is defined as the value observed at Visit 7 of 810P301 and 
810P302, Visit 8 of 810P503 and at Visit 6 of the 810P204 study or the first value observed before the first 
dose in the OLE study, i.e. at Visit 1. 
6.2 Analysis Populations 
The population of “all enrolled subjects” consists of all subjects from any of the preceding double-blind 
studies (810P301, 810P302, 810P503 and 810P204) and meet the eligibility requirements for this study 
including subjects who discontinued from any of the double-blind studies early and approved for 
enrollment in this study.  
The safety population will include all subjects who have signed Informed Consent/Assent forms and 
received at least one dose of study drug during this study. 
Safety population will be used for all safety, efficacy and quality life variables. 
6.3 Demographic and Baseline Characteristics  
Demographic and baseline variables include age, sex, ethnicity, race, height, weight, and medical history 
will be summarized. 
6.4 Socio-demographics 
Socio-demographic variables include number of siblings in the study, siblings with IA, caregiver’s age and 
gender, living situation, marital status, household income and education level will be summarized. 
6.5 Subject Disposition 
The number and percentage of subjects who completed and discontinued from the study will be 
summarized. Only one (primary) reason for study discontinuation will be recorded for each subject. 
The reasons for study discontinuation may include one of the following: 
 
Subject withdrew consent 
 
Lost to follow-up 
 
Administrative reason 
 
Adverse event 
 
Investigator decision 
 
Lack of efficacy 
 
Failure to follow required study procedures 
6.6 Other Protocol Deviations 
Protocol deviations will be presented in listings. If applicable, the number and percent of subjects within 
each type of protocol deviation will be presented using discrete summary statistics. Protocol deviations 
may include, but are not limited to: 
 
Non-compliance with any scheduled study visit 
 
Non-compliance with study treatment 


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 
Disallowed concomitant medications 
 
Non-compliance with study inclusion or exclusion criteria 
 
Non-compliance with study assessment procedures 
 
6.7 Study Medication Exposure and Compliance 
Duration of exposure is defined as the total number of days a subject is exposed to study treatment. This 
will be calculated for each subject by taking the difference between the date of last dose minus the date 
of the first dose, plus one (date of last dose – date of first dose +1).  
Duration of Treatment exposure will also be summarized using descriptive statistics (n, mean, SD, median, 
minimum, and maximum). 
Percent of study drug compliance will be calculated as  
{(D-R)/(T*(DL- DF  +1))}*100, where D=number of tablets dispensed, R= number of tablets 
returned, T= number of tablets administered per day, DL = date of last visit (dose) and DF= date of 
first visit (dose) 
 
The number of tablets (T) taken each day may vary during the maintenance phase: subjects can take up 
six tablets per day to the maximum dose of 54mg/day BID. 
The study medication compliance will be summarized by compliance category (<80%, 80-120%, and 
>120%) and number of subjects in each compliance category.  Study medication compliance will also be   
summarized as a continuous variable using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum).    
6.8 Safety Analysis 
Evaluation of safety will be performed for the safety population.  Safety data that will be evaluated include 
concomitant medications, AEs, clinical laboratory results, vital signs, ECGs, and findings from the physical 
examinations.  The occurrence of neurological side effects will be assessed by looking at any worsening in 
scores from Baseline (Visit 1) 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. 
6.8.1 
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 group 
of doses.  Similarly, treatment-emergent AEs will be summarized by severity and relationship separately.  
Verbatim description and all MedDRA level terms, including the lower level terms, for all AEs will be 
contained in the subject data listings. 


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All AEs occurring throughout the study period will be recorded. Treatment-emergent AEs (TEAEs) will be 
collected starting after the first dose of SM (Visit 1) 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. 
TEAE incidence tables will be listed and summarized by the group of the optimized doses (<18 mg/day; 
18-24 mg/day, 24-36 mg/day or 36-54 mg/day) the subject received.  The incidence rates for all SADRs 
will also be summarized as described for all TEAEs.  
Listings (and tabular summaries, if warranted) of deaths, other SAEs, and other significant TEAEs, including 
TEAEs resulting in treatment discontinuation, will be provided. 
6.8.2 
Laboratory Values 
Clinical laboratory values will be summarized by visit using descriptive statistics for hematology and 
chemistry.  For quantitative laboratory parameters, both actual values and change from Baseline values 
will be summarized.   
Laboratory test results will be assigned a low, normal, high (LNH) classification according to whether the 
values were below (L), within (N), or above (H) the laboratory parameters’ reference ranges provided by 
the central laboratory.  By subject-listings of all abnormal laboratory values, i.e., those with L or H 
classification will be provided. 
6.8.3 
Vital Signs, Height, Weight and BMI 
Vital signs will be summarized by the group of the optimized doses (<18 mg/day; 18-24 mg/day, 24-36 
mg/day or 36-54 mg/day) the subject received using descriptive statistics.  Both actual values and changes 
from the Baseline to final visit will be summarized.  Descriptive summary statistics (mean, SD, median, 
and range) for vital sign data, height, weight and BMI will be evaluated. 
6.8.4 
ECG Results 
Tabular summaries of the quantitative ECG parameters and the overall ECG findings (normal, abnormal 
not clinically significant, or abnormal clinically significant) will be presented.  The QT will be corrected 
using Fridericia’s method. 
ECG results will be summarized by visit by group of optimized doses (<18 mg/day; 18-24 mg/day, 24-36 
mg/day or 36-54 mg/day) using descriptive statistics (for quantitative ECG parameters) and frequency 
tables (for qualitative ECG parameters, including the overall ECG finding).  For quantitative ECG 
parameters, both actual values and change from Baseline values will be summarized.   
6.8.5 
Physical Examinations 
Findings from the physical examinations will be listed for each system or area examined. 
6.8.6 
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 


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for the purpose of reviewing or performing this study. 
Anatomical-Therapeutic-Chemical (ATC) code indicating therapeutic classification.  A tabular summary of 
concomitant medications by drug class will be presented. 
6.8.7 
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 group of the optimized doses (<18 mg/day; 18-24 mg/day, 24-36mg/day or 36-54 
mg/day) the subject received. 
6.8.8 
Extrapyramidal Symptoms  
The occurrence of neurological side effects will be assessed by looking at the changes in scores from 
Baseline to each of the post-Baseline visit for each of the Simpson-Angus scale, Barnes Akathisia scale, 
and AIMS.  For each item on each of these scales, the number (and percentage) of subjects with a worse 
score at any post-Baseline visit, compared to Baseline, will be presented.  A listing of these subjects will 
also be provided. 
6.9 Efficacy Analysis 
Each one of the three efficacy variables (R-MOAS, CGI-I and CGI-S) will be listed and summarized by group 
of the optimized dose.  
6.10 Quality of Life Analysis 
The quality of life endpoints CHQ-PF28, PSI-4-SF subscales (Parental Distress, Parent-Child Dysfunctional 
Interaction and Difficult Child), and SIPA subscales (Adolescents Domain, Parent Domain, Adolescent-
Parent Relationship Domain, Life Stressors Scale and Index of Total Parenting Stress) will be listed and 
summarized by group of the optimized doses (<18 mg/day; 18-24 mg/day, 24-36 mg/day or 36-54 mg/day) 
the subject received.  
Socio-demographic variables will be presented as a listing and summaries will be tabulated using 
descriptive statistics. 
6.11 Pharmacogenomic Analysis 
Individual data will be presented as a listing and summaries will be tabulated using descriptive statistics. 
The pharmacogenomic report may be a stand-alone document. 
6.12 Sample Size and Power Considerations 
There is no consideration for power or sample size determination in this open label study. The present 
study is an extension to the double-blind randomized 801P301, 810P302, 810P503 and 810P204 studies 
for the purpose of evaluating long term safety of SPN-810. 


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for the purpose of reviewing or performing this study. 
7 DOCUMENTATION 
7.1 Adherence to the Protocol 
The Investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described within and to the principles of ICH GCP as well as all governing local regulations and principles 
for medical research. 
The protocol, ICF, and appropriate related documents must be reviewed and approved by an IRB 
constituted and functioning in accordance with ICH E6 and any local regulations. Documentation of IRB 
compliance with the ICH and any local regulations regarding constitution and review conduct will be 
provided to the Sponsor. 
A signed letter of study approval from the IRB must be sent to the Investigator with a copy to the Sponsor 
prior to study start and the release of SM to the site by the Sponsor or its designee.  If the IRB decides to 
suspend or terminate the study, the Investigator will immediately send the notice of study suspension or 
termination by the IRB to the Sponsor. 
Study progress is to be reported to IRB annually (or as required) by the Investigator or Sponsor, depending 
on local regulatory obligations.  If the Investigator is required to report to the IRB, he/she will forward a 
copy to the Sponsor at the time of each periodic report.   
7.2 Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor.   
Any change to the protocol requires a written protocol amendment or administrative change that must 
be approved by the Sponsor before implementation.  Amendments specifically affecting the safety of 
subjects, the scope of the investigation, or the scientific quality of the study require additional approval 
by the applicable IRBs and, in some countries, by the regulatory authority.  These requirements should in 
no way prevent any immediate action from being taken by the Investigator, or by the Sponsor, in the 
interest of preserving the safety of all subjects included in the study.  If an immediate change to the 
protocol is felt by the Investigator to be necessary for safety reasons, the Medical Monitor and IRB must 
be notified promptly. 
Changes to the protocol, which are administrative in nature do not require formal protocol amendments 
or IRB approval, but the IRB must be kept informed of such changes.  In these cases, the Sponsor will send 
a letter to the IRB detailing such changes. 
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 


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for the purpose of reviewing or performing this study. 
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 audits 
may be made periodically by the Sponsor’s Quality Assurance team or qualified designee, as 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. 
Data recorded on source documents will be transcribed into the eCRFs in accordance with the eCRF 
Completion Instructions provided to the study sites.  The Investigator is responsible for ensuring that all 
sections of each eCRF are completed correctly, and that entries can be verified against source documents.  
The eCRFs will be monitored for completeness and accuracy against the source documents by the CRA(s) 
on a regular basis.  Inconsistencies between the eCRFs and source documents will be resolved in 
accordance with the principles of Good Clinical Practice (GCP). 
At the conclusion of the clinical study, each site’s eCRF data will be extracted from the clinical database, 
stored on a CD-ROM and sent to the respective clinical study site for archiving.  A CD-ROM containing all 
eCRFs will be kept by the Sponsor in the Sponsor’s Trial Master File. 
7.4.2 
Clinical Data Management 
Data from eCRFs and other external data sources (e.g., laboratory data) will be entered into and/or 
merged within a single clinical database as specified in the data management plan.  Quality control and 
data validation procedures will be applied to ensure the validity and accuracy of the data in the clinical 
database. 
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. 


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for the purpose of reviewing or performing this study. 
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 are not limited to the protocol, copies of paper CRFs or eCRFs, source 
documents, laboratory test results, SM inventory records, Investigator's Brochure, and regulatory agency 
registration documents (e.g., FDA form 1572, ICFs, and IRB/IEC correspondence).  The investigator should 
take measures to prevent accidental or premature destruction of these documents.  Study essential 
documents should be retained until at least two years after the last approval of a marketing application 
or after formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory requirements or 
by an agreement with the Sponsor.  The Investigator must obtain written permission from the Sponsor 
prior to the destruction of any study document. 
It is requested that at the completion of the required retention period, or should the Investigator retire 
or relocate, the Investigator contact the Sponsor, allowing the Sponsor the option of permanently 
retaining the study records. 
These records must be made available at reasonable times for inspection and duplication, if required, by 
a properly authorized representative of the US FDA in accordance with the US 21 CFR 312.68 or other 
national or foreign regulatory authorities in accordance with regulatory requirements. 
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).  Any inspections requested by a regulatory authority must be communicated immediately 
by the Investigator to the Sponsor and the CRO. 
All study-related records must be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the US FDA in accordance with the US 21 CFR 312.68 
or other national or foreign regulatory authorities in accordance with regulatory requirements. 
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.  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. 


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for the purpose of reviewing or performing this study. 
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, any amendments and results obtained during the course of this study will 
be kept confidential by the Investigator, the Investigator’s staff, and the IRB and will not be disclosed in 
whole or in part to others or used for any purpose other than reviewing or performing the study without 
the written consent of the Sponsor.  No data collected as part of this study will appear in any written work, 
including publications, without the written consent of Sponsor. 
All persons assisting in the performance of this study must be bound by the obligations of confidentiality 
and non-use set forth in the Confidentiality Agreement between the Investigator and Sponsor. 
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 enrolled.  IRB Approval is required and will be 
acquired prior to the distributing SM to investigational sites”.  The Investigators or Sponsor will submit, 
depending on local regulations, periodic reports and inform the IRB of any reportable adverse events (AEs) 
per International Conference on Harmonization (ICH) guidelines and local IRB standards of practice. 


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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
8.2 Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures (SOPs) from either the 
Sponsor or
.  These SOPs are designed to ensure adherence to GCP guidelines as required 
by: 
 
Declaration of Helsinki, 1964 (“Recommendations Guiding Physicians in Biomedical Research 
Involving Human Patients”), and all its accepted amendments to date concerning medical 
research in humans. 
 
ICH Guideline for GCP (Committee for Proprietary Medicinal Products/ICH/135/95) of the 
European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal 
Products, ICH of Pharmaceuticals for Human Use. 
 
United States (US) Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR, 
including parts 50 and 56 concerning Patient Informed Consent and IRB regulations). 
 
Local, national legal guidelines. 
8.3 Investigators and Study Personnel 
This study will be conducted by qualified Investigators under the sponsorship of Supernus 
Pharmaceuticals, Inc. (Sponsor) at US study sites used in the double-blind studies, 810P301, 810P302 
81P503 and 810P204. 
Contact persons at the Sponsor and the CROs are listed in the regulatory binder provided to each 
investigational site.  Qualified personnel will monitor the study. Medical writing, data management, and 
statistical analyses will be performed by qualified service partners/CROs.  Laboratory tests will be 
conducted by a central laboratory as designated in the regulatory 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. 


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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 
 
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Calarge CA, Acion L, Kuperman S et al. Weight gain and metabolic abnormalities during extended 
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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
Greenhill LL, Solomon M, Pleak R, Ambrosini P.  Molindone hydrochloride treatment of hospitalized 
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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
Pliszka SR, Crismon ML, Hughes CW et al. The Texas Children's Medication Algorithm Project: Revision of 
the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc 
Psychiatry 2006; 45:642-57. 
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Shen S, Mann JJ. The Columbia-Suicide Severity rating scale: initial validity and internal consistency 
findings from three multisite studies with adolescents and adults. Am J Psychiatry 2011; 68: 1266-1277. 
Scotto Rosato N, Correll CU, Pappadopulos E et al. Treatment of maladaptive aggression in youth: Cert 
guidelines ii. Treatments and ongoing management. Pediatrics 2012; 129:e1577-86. 
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early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008; 165:1420-31. 
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1970; 212:11-19 
Stocks JD, Taneja BK, Baroldi P et al. A phase 2a randomized, parallel group, dose-ranging study of 
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problems. J Child Adolesc Psychopharm 2012; 22:102-11. 
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as Adjunctive Therapy in Children with Impulsive Aggression Comorbid with Attention-
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Supernus® Pharmaceuticals, Inc. 
CONFIDENTIAL 
 
 
810P304                                                                  Version 5.0                                                        Page 82 of 82 
 
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 APPENDICES 
10.1 Retrospective Modified Overt Aggression Scale (R-MOAS) 
Refer to the Investigator Site File 
10.2 Clinical Global Impression (CGI) Scale 
Refer to the Investigator Site File 
10.3 Columbia-Suicide Severity Rating Scales (C-SSRS) 
Refer to the Investigator Site File 
10.4 Simpson-Angus Rating Scale 
Refer to the Investigator Site File 
10.5 Barnes Akathisia Rating Scale (BARS) 
Refer to the Investigator Site File 
10.6 Abnormal Involuntary Movement Scale (AIMS) 
Refer to the Investigator Site File 
10.7 Child Health Questionnaire Parent Form 28-item (CHQ-PF28) 
Refer to the Investigator Site File 
10.8 Parenting Stress Index-Short Form (PSI-4-SF)  
Refer to the Investigator Site File 
10.9 Stress Index for Parents of Adolescents (SIPA) 
Refer to the Investigator Site File 
 
 

SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Open-Label Extension Study to Evaluate the Long-Term Safety of Molindone 
Hydrochloride Extended-Release Tablets for the Treatment of Impulsive 
Aggression in Pediatric and Adolescent Subjects with Attention 
Deficit/Hyperactivity Disorder (ADHD) in Conjunction with Standard ADHD 
Treatment 
Protocol 810P304 
 
 
Protocol Version and Date:   
Version 5.0, 22FEB2019 
Study Drug:  
SPN-810 
Phase:  
Phase 3 
Sponsor: 
Supernus Pharmaceuticals, Inc.  
  
 
 
Analysis Plan Date:  
05JAN2024 
Analysis Plan Version:  
Version 1.0  
 
 
 
 
 
 
 
 
 


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STATISTICAL ANALYIS PLAN APPROVAL SIGNATURE PAGE 
 
Protocol Title:   
Open-Label Extension Study to Evaluate the Long-Term 
Safety of Molindone Hydrochloride Extended-Release 
Tablets for the Treatment of Impulsive Aggression in 
Pediatric and Adolescent Subjects with Attention 
Deficit/Hyperactivity Disorder (ADHD) in Conjunction 
with Standard ADHD Treatment 
Protocol Number:  
810P304 
Study Drug: 
SPN-810 
Version (Document Date): 
Version 1.0 (05JAN2024) 
 
 
Prepared by: 
Reviewed by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ......................................................................................................... 5 
1. 
OBJECTIVES AND ENDPOINTS .................................................................................... 6 
2. 
STUDY DESCRIPTION .................................................................................................... 7 
2.1. 
Study Design ................................................................................................................. 7 
2.2. 
Schedule of Visits and Study Procedures ..................................................................... 7 
2.3. 
Study Treatments .......................................................................................................... 7 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING ............ 8 
3.1. 
General Statistical Methods .......................................................................................... 8 
3.2. 
Definitions and Derivations .......................................................................................... 8 
3.3. 
Analysis Populations ..................................................................................................... 8 
3.4. 
Visit Windows .............................................................................................................. 9 
3.5. 
Data Pooling.................................................................................................................. 9 
3.6. 
Handling of Missing Data ............................................................................................. 9 
4. 
STUDY SUBJECTS AND EXPOSURE .......................................................................... 10 
4.1. 
Subjects Disposition.................................................................................................... 10 
4.2. 
Protocol Deviations ..................................................................................................... 10 
4.3. 
Demographic and Baseline Characteristics ................................................................ 11 
4.4. 
Medical History .......................................................................................................... 11 
4.5. 
Prior and Concomitant Medication ............................................................................. 11 
4.6. 
Study Treatment Exposure and Compliance ............................................................... 11 
5. 
SAFETY ANALYSES...................................................................................................... 12 
5.1. 
Adverse Events ........................................................................................................... 12 
5.2. 
Laboratory Data .......................................................................................................... 13 
5.2.1. Absolute Value and Change from Baseline .......................................................... 13 
5.3. 
Vital Signs and Body Size (Height/Weight/BMI) ...................................................... 14 
5.3.1. Absolute Value and Change from Baseline .......................................................... 14 
5.4. 
Electrocardiogram ....................................................................................................... 14 
5.4.1. Absolute Value and Change from Baseline .......................................................... 14 
5.4.2. Clinically Notable ECG ........................................................................................ 14 
5.5. 
Physical Examination.................................................................................................. 14 
5.6. 
Extrapyramidal Symptoms (EPS) ............................................................................... 14 
5.6.1. Simpson-Augus Scale ........................................................................................... 14 
5.6.2. Barnes Akathisia Scale ......................................................................................... 14 
5.6.3. Abnormal Involuntary Movement Scale (AIMS) ................................................. 14 
5.7. 
Columbia Suicide Severity Rating Scales (C-SSRS).................................................. 15 
6. 
EFFICACY ANALYSES ................................................................................................. 16 


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6.1. 
Retrospective-Modified Overt Aggression Scale (R-MOAS) .................................... 16 
6.2. 
Clinical Global Impression - Severity (CGI-S) .......................................................... 16 
6.3. 
Clinical Global Impression - Improvement (CGI-I) ................................................... 16 
7. 
EXPLORATORY ANALYSES ....................................................................................... 17 
7.1. 
The Child Health Questionnaire Parent Form 28-item (CHQ-PF28) ......................... 17 
7.2. 
The Parenting Stress Index – Short Form (PSI-4-SF) ................................................ 19 
7.3. 
Stress Index for Parents of Adolescents (SIPA) ......................................................... 19 
7.4. 
Socio-demographic Characteristics ............................................................................ 20 
8. 
CHANGE FROM THE PROTOCL ................................................................................. 21 
9. 
APPENDICES .................................................................................................................. 22 
9.1. 
Schedule of Events and Procedures ............................................................................ 22 
9.2. 
Clinically Notable ECG .............................................................................................. 25 
 
 
 
LIST OF TABLES 
Table 1: Objectives and Endpoints ..................................................................................................6 
Table 2: Definitions and Derivations ...............................................................................................8 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADHD 
Attention Deficit/Hyperactivity Disorder  
AE 
Adverse event 
AESI 
Adverse event of special interest 
ATC 
Anatomical therapeutic chemical 
BMI 
Body mass index 
CGI-I 
Clinical Global Impression – Improvement Scale 
CGI-S 
Clinical Global Impression – Severity Scale 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CFB 
Change from baseline 
CRF 
Case report form 
ECG 
Electrocardiogram 
EOS 
End of Study 
EPS 
Extrapyramidal Symptoms 
IA 
Impulsive aggression 
IPD 
Important protocol deviation 
MedDRA 
Medical dictionary for regulatory activities 
OLE 
Open label extension 
PD 
Parental Distress or Parent Domain 
PN 
Preferred name 
PSI 
Parenting Stress Index 
PT 
Preferred term 
QT 
QT interval  
QTcF 
QT interval corrected using Fridericia's method 
R-MOAS 
Retrospective-Modified Overt Aggression Scale 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SIPA 
Stress Index for Parents of Adolescents 
SM 
Study medication 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
WHO-DD 
World health organization drug dictionary 


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1. 
OBJECTIVES AND ENDPOINTS 
The objectives and endpoints are listed in Table 1. 
Table 1: Objectives and Endpoints 
Objectives 
Endpoints 
Safety Objective 
(Primary): 
Long-term safety on the use of 
SPN-810 as a treatment for 
impulsive aggression (IA) in 
subjects (6-17 years of age) with 
Attention Deficit/Hyperactivity 
Disorder (ADHD) when taken in 
conjunction with standard ADHD 
treatment only after satisfactory 
participation in a preceding double-
blind study (810P301, 810P302, 
810P503 or 810P204). 
1. Adverse Events  
2. Extrapyramidal Symptoms (EPS) scales (Simpson-Angus Scale, 
Barnes Akathisia Scale, and Abnormal Involuntary Movement 
Scale) 
3. Clinical Laboratory Tests (Hematology, Chemistry, Insulin, 
Prolactin and Urinalysis) 
4. Concomitant Medications 
5. Vital signs, Standardized BMI, Physical Examination and ECG (12-
lead) 
6. Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Efficacy Objective 
(Secondary): 
Long-term efficacy on the use of 
SPN-810 as a treatment for 
impulsive aggression (IA) in 
subjects (6-17 years of age) with 
ADHD when taken in conjunction 
with standard ADHD treatment. 
1. Change from Baseline (CFB) in Retrospective-Modified Overt 
Aggression Scale (R-MOAS) at each scheduled visit 
2. Clinical Global Impression – Improvement Scale (CGI-I) at each 
scheduled visit 
3. CFB in Clinical Global Impression – Severity Scale (CGI-S) at each 
scheduled visit 
 
Quality of Life Objective 
(Exploratory): 
Long-term quality of life on the use 
of SPN-810 as a treatment for 
impulsive aggression (IA) in 
subjects (6-17 years of age) with 
ADHD when taken in conjunction 
with standard ADHD treatment. 
1. CFB in Child Health Questionnaire Parent Form 28-item (CHQ-
PF28) at each scheduled visit 
2. CFB in Parenting Stress Index – Short Form (PSI-4-SF) or Stress 
Index for Parents of Adolescents (SIPA) at each scheduled visit 
3. Socio-demographics Characteristics 
 




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3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING  
3.1. General Statistical Methods 
All statistical analysis will be performed using SAS version 9.4 or higher. 
All data summaries will be presented by the optimized dose group (<18 mg/day; 18-<24 mg/day, 
24-<36 mg/day or 36-54 mg/day) and overall.  The optimized dose is defined as the first 
maintenance dose (at visit 5) for subjects entering maintenance period; otherwise using the end 
of study (EOS) dose for subjects discontinued prior to maintenance period. 
Continuous variables will be summarized descriptively using number of subjects (n), mean, 
standard deviation (SD), median, minimum, and maximum. 
Categorical variables will be summarized descriptively using counts and percentages. However, 
the number of patients with missing data will be excluded from the denominator for the 
percentage calculation. When the denominator for the percentage is different from the number of 
subjects in the treatment column header, the denominator will be clearly specified in the table or 
in a footnote for the table. 
Individual subject data will be listed by subject ID. Unscheduled measurements (unless defined 
as baseline) will be excluded from summary tables but will be included in data listings. For 
assessments that are repeated or unscheduled, unless otherwise specified, the non-missing values 
from the first assessment will be used for generating summary statistics. 
3.2. Definitions and Derivations 
The general definitions and derivations are listed in Table 2. 
Table 2: Definitions and Derivations 
Terminology 
Definition 
Safety Baseline 
Safety baseline is the last visit in double blinded studies (810P301, 
810P302, 810P503 and 810P204), which is visit 1 in 810P304.  
Efficacy Baseline (R-
MOAS and CGI-S 
assessments) 
Efficacy baseline is defined as the last non-missing value collected prior 
to the first dose of the SM in the double-blind studies (810P301, 
810P302,  810P503 and 810P204). 
Study Day 
Day 1 is defined as the date of safety baseline. For visits prior to safety 
baseline, Study Day is calculated as (Visit Date – safety baseline).  For 
visits after study safety baseline, Study Day is calculated as (Visit 
Date – safety baseline +1). 
3.3. Analysis Populations 
The enrolled subjects consist of all subjects from any of the preceding double-blind studies 
(810P301, 810P302, 810P503 and 810P204) and meet the eligibility requirements. 


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The Safety Population includes all subjects who have signed Informed Consent/Assent forms and 
received at least 1 dose of SM in the 810P304 study. 
The Safety Population will be used for all safety, efficacy and quality of life data analyses. 
3.4. Visit Windows 
Data from scheduled visits will be analyzed. Visits will be analyzed as scheduled. Unscheduled 
measurements will be excluded from the descriptive statistics and statistical analyses but will be 
included in listings. 
3.5. Data Pooling 
Data from all sites will be pooled together for all analyses.  
3.6. Handling of Missing Data 
No missing data imputation will be performed. For efficacy variables, if any item is missing, the 
subscale and summary score will be set to missing. 
 


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4. 
STUDY SUBJECTS AND EXPOSURE 
4.1. Subjects Disposition 
Subject disposition will be summarized descriptively by the optimized dose group and overall 
including the following categories: 
• Number of subjects enrolled. 
• Number of subjects in the Safety population 
• Number (%) of subject who completed the study 
• Number (%) of subjects who discontinued from the study  
• Primary reasons of discontinuation may include any of the following: 
o Withdrawal by subject 
o Withdrawal by parent/guardian 
o Lost to follow-up  
o Adverse event  
o Physician decision  
o Lack of efficacy  
o Protocol violation 
o Other 
4.2. Protocol Deviations 
A protocol deviation is defined as any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important protocol deviation (IPD) is defined as a 
protocol deviation that might significantly affect the completeness, accuracy, and/or reliability of 
the study data or that might significantly affect a subject's rights, safety, or well-being. 
Potential IPDs may include, but are not limited to: 
• Non-compliance with any scheduled study visit 
• Non-compliance with study treatment 
• Disallowed concomitant medications 
• Non-compliance with study inclusion or exclusion criteria  
• Non-compliance with study assessment procedures 
IPDs will be provided in subject data listings. 


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4.3. Demographic and Baseline Characteristics 
The summaries of demographic data and baseline characteristics will be provided for the Safety 
Populations. Subject demographic data (age, sex, race, and ethnicity) will be summarized 
descriptively by the optimized dose group and overall. 
4.4. Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities MedDRA 
version 18.1. The number and percent of subjects reporting various medical, family, and 
psychiatric histories, grouped by system organ class (SOC) and preferred term (PT), will be 
summarized for the Safety Population descriptively by the optimized dose group and overall. 
4.5. Prior and Concomitant Medication 
Prior and Concomitant medications will be coded using WHO DRUG Global version March 
2019, and will be summarized descriptively by the fourth level anatomical therapeutic chemical 
(ATC) classification and Preferred Name (PN), using counts and percentages for the Safety 
Population by the optimized dose group and overall. ATC fourth (ACT4) level is for the 
chemical, pharmacological or therapeutic subgroup. 
4.6. Study Treatment Exposure and Compliance 
Duration of treatment exposure will be calculated for each subject by taking the difference 
between the date of last dose minus the date of baseline, plus 1 (date of last dose – date of 
baseline +1). Duration of treatment exposure will be summarized descriptively by the optimized 
dose group and overall. 
Duration of treatment exposure will also be summarized by duration category (i.e., 0 to <3, 3 to 
<6, 6 to <9, 9 to <12, 12 to <15, 15 to <18, 18 to <21 21 to < 24, 24 to < 30, 30 to <36, 36 to 
<42, 42 to <48, 48 to <54, 54 to < 60, >= 60 months) using descriptive statistics. 
Percentage compliance will be calculated as the following: 
ቆ
∑
(𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑖𝑖𝑖𝑖 𝑚𝑚𝑚𝑚 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑖𝑖−𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑖𝑖𝑖𝑖 𝑚𝑚𝑚𝑚 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑖𝑖+1)
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣−1
𝑖𝑖=𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠  𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
൫∑
(𝑌𝑌𝑖𝑖 × # 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑖𝑖 𝑡𝑡𝑡𝑡 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑖𝑖+1)
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣−1
𝑖𝑖=𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
൯
ቇ× 100 
Where i=index of visits within a given period (e.g., titration, maintenance, and overall); Yi = 
Dose in mg that the subject was instructed to take daily between visits. 
Descriptive statistics for SM compliance along with the number and percent of subjects 
belonging to compliance categories (<80%, 80-120%, and >120%) will be provided. 
 
 


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5. 
SAFETY ANALYSES 
The assessment of overall safety and tolerability will be based on adverse events, laboratory 
values, vital signs, body size (Height/Weight/BMI), ECGs, physical examinations, Barnes 
Akathisia Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale (AIMS), and 
Columbia Suicide Severity Rating Scale (C-SSRS). 
5.1. Adverse Events 
All adverse events (AEs) will be coded using the MedDRA Version 18.1. All AEs reported in 
this study are considered treatment-emergent adverse events (TEAEs). 
The incidence of TEAEs (number and percent of subjects) will be summarized by System Organ 
Class (SOC), preferred term (PT), and by the optimized dose group and overall. A subject with 
multiple occurrences of an AE will be counted only once in the AE category per SOC and PT for 
summary tables. 
Based on the investigator’s determination, the severity of TEAEs will be classified as mild, 
moderate or severe. For summaries by severity, a patient experiencing multiple AE in the same 
preferred term with different intensities will only be counted once with the maximum severity. If 
severity is missing, then the maximum severity will be assumed for the analysis (i.e., severity = 
severe). 
The relationship between the study medication and a TEAE is determined by the investigator and 
will be classified as unrelated (i.e., unlikely related and not related) or related (possibly related 
and definitely related). TEAEs with missing relatedness will be counted as definitely related. For 
summaries by relationship, a patient experiencing multiple AE in the same preferred term with 
different relationship will only be counted once with the most related occurrence. 
The summary of TEAE will include incidence rates (number and percent of subjects) who had at 
least one TEAE, treatment related TEAE, serious TEAE, TEAE leading to death, TEAE by 
maximum severity, treatment related TEAE, treatment related SAE, and TEAE of special 
interest. 
In addition to the overview of TEAE summary, the following TEAE summary tables will be 
provided: 
• Number and Percent of Subjects with Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
 
• Number and Percent of Subjects with Common (≥ 5% in Any Treatment Group) 
Treatment-Emergent Adverse Events by Preferred Term 
 
• Number and Percent of Subjects with Treatment-Emergent Adverse Events 
by System Organ Class, Preferred Term, and Severity 
 


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• Number and Percent of Subjects with Treatment-Emergent Adverse Events 
by System Organ Class, Preferred Term, and Relationship to Study Medication 
 
• Number and Percent of Subjects with Serious Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
 
• Number and Percent of subjects with Treatment-Emergent Adverse Events Leading to 
Withdrawal of Study Medication by System Organ Class and Preferred Term 
 
• Number and Percent of Subjects with Treatment-Emergent Adverse Events of special 
interest by System Organ Class and Preferred Term 
Note: Adverse events of special interest (AESI) are collected and flagged on eCRF. 
 
• 
Listing of Deaths  
A data listing of death will be provided. If no death occurred, a blank listing with “No 
subject died on this study.” will be presented. 
 
Listing will be provided for AEs. 
5.2. Laboratory Data 
Laboratory data will be collected following the event schedule in Appendix 9.1. Data summaries 
and listings will be provided in International System of Units (SI). All laboratory data will be 
listed. 
Laboratory assessment values of the form of “< x, ≤ x” (i.e., below the lower limit of 
quantification) or “> x, ≥x” (i.e., above the upper limit of quantification) will be imputed as “x” 
in the calculation of summary statistics. For listings, however, the original ranges (i.e., “< x, ≤ x” 
or “> x, ≥x”) as stated in the database will be presented. 
5.2.1.  Absolute Value and Change from Baseline  
Absolute values and change from baseline (CFB) in hematology, chemistry, and urinalysis 
continuous variables will be summarized descriptively at each scheduled visit by the optimized 
dose group and overall. Insulin and Prolactin will be summarized at each scheduled visit by sex 
and by the optimized dose group and overall. 
 
For visit-based summary tables, in the event of repeat assessments within visit window, the first 
non-missing value will be used in the tabulations. Results from unscheduled visits will not be 
included in this summary. 
 
All laboratory data including repeated values and results from unscheduled visits will be 
provided in data listings with indication of higher or lower than the associated normal range of 
each laboratory test. 


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5.3. Vital Signs and Body Size (Height/Weight/BMI) 
5.3.1.  Absolute Value and Change from Baseline  
CFB in vital sign and body size (Height/Weight/BMI) variables will be calculated for each 
scheduled post-dose visit. The analyses will be the same as described in Section 5.2.1. 
5.4. Electrocardiogram 
5.4.1.  Absolute Value and Change from Baseline  
CFB in Electrocardiogram (ECG) variables will be calculated for each scheduled post-dose visit. 
The analyses will be the same as described in Section 5.2.1. 
5.4.2. Clinically Notable ECG 
The clinically notable QT interval corrected for Fridericia's method (QTcF) are presented in 
appendix 9.2. The number and percentage of subjects with potentially post-baseline Clinically 
Notable Value(CNV) will be summarized by optimized dose group and overall. The denominator 
includes all subjects with non-CNV baseline and at least one post-baseline assessment (including 
unscheduled visit) and the numerator is the number of subjects with non-CNV baseline and CNV 
at post-baseline.  
5.5. Physical Examination 
 
Data listing will be provided. 
5.6. Extrapyramidal Symptoms (EPS) 
Absolute value and CFB of each item in each of EPS scales will be analyzed descriptively at 
each scheduled visit by the optimized dose group and overall. Data listings will be provided. 
5.6.1. Simpson-Augus Scale 
The Simpson-Angus scale is a 10-item rating scale that is widely used for assessment of 
neuroleptic-induced Parkinsonism. It consists of 1 item measuring gait, 6 items measuring 
rigidity, and 3 items measuring glabella tap, tremor and salivation, respectively.  
5.6.2. Barnes Akathisia Scale 
The Barnes Akathisia scale is a rating scale for drug-induced akathisia and includes components 
for rating the observable, restless movements characteristic of akathisia, the awareness of 
restlessness, and any distress associated with the condition. 
5.6.3. Abnormal Involuntary Movement Scale (AIMS) 
The AIMS test is a rating scale used to measure tardive dyskinesia. There are 12 items that rate 
involuntary movements of various areas of the subject’s body. 


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5.7. Columbia Suicide Severity Rating Scales (C-SSRS) 
Suicidal ideation: A “yes” answer at any time during treatment to any one of the five suicidal 
ideation questions on the C-SSRS. 
Suicidal behavior: A “yes” answer at any time during treatment to any one of the five suicidal 
behavior questions 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 on the C-SSRS. 
The number and percentage of subjects will be presented at each visit by the optimized dose 
group and overall for suicidal ideation, suicidal behavior, and suicidal ideation or behavior. 
The data listing will be provided. 


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6. 
EFFICACY ANALYSES 
Absolute value and CFB (if applicable) of efficacy endpoints will be analyzed descriptively at 
each scheduled visit by the optimized dose group and overall using the Safety Population, unless 
otherwise specified. 
6.1. Retrospective-Modified Overt Aggression Scale (R-MOAS) 
The Retrospective-Modified Overt Aggression Scale (R-MOAS) was developed to gauge the 
severity of aggressive behavior. Parents rate the frequency over the past week of 16 aggressive 
behaviors in four areas: verbal aggression (VE); physical aggression toward others (PH); 
aggression toward oneself (PR); and destruction or hostile misuse of property (SE). 
VE, PH, PR, SE subdomain scores and total score will be collected on eCRF and no derivation is 
needed.  
6.2. Clinical Global Impression - Severity (CGI-S) 
The CGI-S is evaluated on a 7-point scale, where 1 = Normal, not at all ill, asymptomatic, 2 = 
Borderline Ill, 3 = Mildly Ill, 4 = Moderately Ill, 5 = Markedly Ill, 6 = Severely Ill, and 7 = 
Extremely Ill. 
6.3. Clinical Global Impression - Improvement (CGI-I) 
The CGI-I is evaluated on a 7-point scale where 1 = Very much improved, 2 = Much improved, 
3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very 
much worse. The CGI-I results will be summarized using the absolute value (i.e., no CFB). 
There are caregiver and investigator CGI-I assessments. 


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7. 
EXPLORATORY ANALYSES  
Absolute value and CFB (if applicable) of quality of life continuous variables will be analyzed 
descriptively at each scheduled visit by the optimized dose group and overall, unless otherwise 
specified. The quality of life categorical variables will be analyzed using count and percentage at 
each scheduled visit by the optimized dose group and overall, unless otherwise specified. 
7.1. The Child Health Questionnaire Parent Form 28-item (CHQ-PF28)  
 
The recorded score on CRF needs to be transformed in 0-100 range before calculating subscales 
and summary scores.  
 
Item 
Recorded Score 
on CRF 
Final Raw Score 
Transformed Score 
1.1;  
5.2; 
9.4 
1 
5 
((Final Raw Score -1)/4) * 100 
2 
4.4 
3 
3.4 
4 
2.2 
5 
1 
2.1a-2.1c;  
3.1;  
3.2;  
9.2a-9.2b 
1 
1 
((Final Raw Score -1)/3) * 100 
2 
2 
3 
3 
4 
4 
4.1 
1 
6 
((Final Raw Score -1)/5) * 100 
2 
5 
3 
4 
4 
3 
5 
2 
6 
1 
5.1a-5.1c;  
6.1a-6.1c;  
8.1a-8.1c;  
9.3a-9.3b 
1 
1 
((Final Raw Score -1)/4) * 100 
2 
2 
3 
3 
4 
4 
5 
5 
7.1a-7.1c; 
8.2; 
9.1a-9.1b 
1 
5 
((Final Raw Score -1)/4) * 100 
2 
4 
3 
3 
4 
2 
5 
1 
 
The physical functioning summary score (PHS) and psychosocial health summary score (PSS) 
are calculated in three steps. 


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• Step1: z-score standardizations. 
Subscale 
Sum of 
Transformed  
Score 
Formulas for z-score standardizations 
Physical Functioning (PF) 
2.1a–2.1c 
PF_Z=(PF - 90.8525408) / 16.3826344 
Role/Social Limitations - 
Physical (RP) 
3.2 
RP_Z=(RP - 91.4951246) / 18.9079749 
General Health Perceptions 
(GH) 
8.1a-8.1c,1.1 
GH_Z=(GH - 66.6958379) / 19.3564297 
Bodily Pain/Discomfort (BP) 
4.1 
BP_Z=(BP - 78.6833515) / 20.7355708 
Role/Social Limitations - 
Emotional/Behavior (REB) 
3.1 
REB_Z=(REB - 90.4013015) / 19.5067502 
Parental Impact - Time (PT) 
9.2a-9.2b 
PT_Z=(PT - 83.8816188) / 20.2901603 
Parental Impact - Emotional 
(PE) 
9.1a-9.1b 
PE_Z=(PE - 73.9788476) / 21.406013 
Self-Esteem (SE) 
7.1a-7.1c 
SE_Z=(SE - 79.2555314) / 17.8308361 
Mental Health (MH) 
6.1a–6.1c 
MH_Z=(MH - 77.2595806) / 13.6861999 
Behavior (BE) 
5.1a-5.1c,5.2 
BE_Z=(BE - 72.3086051) / 17.1447913 
 
 
 
Family Activities (FA) 
9.3a-9.3b 
NA 
Global Health (GGH) 
1.1 
NA 
Global Behavior (GBE) 
5.2 
NA 
Family Cohesion (FC) 
9.4 
NA 
Change in Health (CH) 
8.2 
NA 
• Step 2. PHS_raw and PSS_raw scores 
PHS_raw = (PF_Z * .37138) + (RP_Z * .34493) + (BP_Z * .27883) + (GH_Z * .29460) + 
(REB_Z *-.01178) + (PT_Z * .09113) + (PE_Z * .06063) + (SE_Z * -.09480) + (MH_Z * -
.08263)+ (BE_Z * -.12675) 
PSS_raw = (PF_Z * -.09243) + (RP_Z * -.06973) + (BP_Z * -.05514) + (GH_Z * -.05547) + 
(REB_Z* .21155) + (PT_Z * .16944) + (PE_Z * .19823) + (SE_Z * .24792) + (MH_Z * .25335) 
+ (BE_Z * .27911) 
• Step 3. Transformation of PHS_raw and PSS-raw 
PHS = 50 + (PHS_raw * 10) 
PSS = 50 + (PSS_raw * 10) 
Note: More details can be found in the Child Health Questionnaire (CHQ) Scoring and 
Interpretation Manual (HealthActCHQ). 
Subscales, PHS and PSS will be analyzed descriptively by the optimized dose group and overall 
and by visit. 
 


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7.2. The Parenting Stress Index – Short Form (PSI-4-SF)   
The PSI-4-SF is for 6-12 years of age only. 
PSI-4-SF consists of 36 items divided into three domains: parental distress, parent-child 
dysfunctional interaction, and difficult child, which is scored using a 5-point as 1 (Strongly 
disagree), 2 (Disagree), 3 (Not sure), 4 (Agree), 5 (Strongly agree). 
Note: For Item-32, the subject’s original response categories from the Answer Sheet are rated as 
1 = “much harder than I expected” to 5 = “much easier than I expected”. This will be reversed 
prior to calculating the subscale and total domain scores. The reversed Item-32 will be scored as 
from 5 = “much harder than I expected” to 1 = “much easier than I expected”. 
• Parental Distress (PD) = Sum responses items 1-12  
• Parental-Child Dysfunctional Interaction (P-CDI) = Sum responses items 13-24  
• Difficult Child (DC) = Sum responses items 25-36  
• Total Stress Score (TS) = PD + P-CDI + DC 
PD, P-CDI, DC and TS will be analyzed descriptively. 
7.3. Stress Index for Parents of Adolescents (SIPA) 
The SIPA is for 13-17 years of age only. 
The SIPA includes 112 items. The first 90 items are divided in three major domains and 8 
subscales showing in the table below.  They use a 5-point rating scale ranging from Strongly 
Disagree (5) to Strongly Agree (1): 1=SD (Strongly Disagree), 2=DA (Disagree), 3=NS (Not 
Sure), 4=A (Agree), and 5=SA (Strongly Agree). 
Note: Items 2, 3, 4, 5, 9, 10, 15, 25, 28, 34, 40, 45, 49, 54, 66, 69, 74, 81, 83, 85, 87, and 88 are 
rated from Strongly Disagree (5) to Strongly Agree (1). To be consistent with other items, they 
have to be reversed (15, 24, 33, 42, and 51) prior to calculating subscales and 
domains. 
Domain 
Subscale 
Sum of Items 
Adolescent 
Domain 
(AD) 
Moodiness/Emotional Lability (MEL) 
10 items (1, 6, 11, 16, 21, 26, 31, 36, 41, 46) 
Social Isolation/ Withdrawal (ISO) 
10 items (2, 7, 12, 17, 22, 27, 32, 37, 42, 47) 
Delinquency/Antisocial (DEL) 
10 items (3, 8, 13, 18, 23, 28, 33, 38, 43, 48) 
Failure to Achieve or Persevere (ACH) 
10 items (4, 9, 14, 19, 24, 29, 34, 39, 44, 49) 
Parent 
Domain (PD) 
Life Restrictions (LFR) 
10 items (51, 52, 55, 56, 59, 63, 67, 71, 75, 79) 
Relationship with Spouse/Partner (REL) 
9 items (60, 64, 68, 72, 73, 76, 77, 80, 81) 
Social Alienation (SOC) 
7 items (53, 54, 57, 58, 61, 65, 69); 
Incompetence/Guilt (INC) 
8 items (62, 66, 70, 74, 78, 82, 86, 90) 
Adolescent-
Parent 
Relationship 
Domain 
(APRD) 
 
16 items (5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 
83, 84, 85, 87, 88, and 89) 


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• AD = MEL + ISO + DEL+ACH 
• PD = LFR + REL + SOC + INC 
• Total Parenting Stress (TPS) = AD + PD + APRD 
The Life Stressors (LS) Scale includes the last 22 items (Items 91-112) with responses of 1=Yes 
and 0=No. 
• Life Stressors (LS) = Sum last 22 items (Items 91-112) 
TPS, each domain, each subscale, and LS scale will be analyzed descriptively by the optimized 
dose group and overall and by visit.  
7.4. Socio-demographic Characteristics 
Socio-demographic variables include the number of siblings in the study, siblings with IA, 
caregiver’s age and gender, living situation, marital status, household income and education 
level.  
The socio-demographic characteristics variables will be analyzed descriptively by the optimized 
dose group and overall.  


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8. 
CHANGE FROM THE PROTOCL 
Drug compliance in section 4.6 calculation was changed to use dose in mg instead of tablet 
because different tablet (ie.
 tablet) could be distributed in the same visit and 
patient can take them interchangeably.