Clinical trial NCT04786990
Conditions: Attention-Deficit/Hyperactivity Disorder (ADHD)
Sponsor: Supernus Pharmaceuticals, Inc.
Start date: 2021-07-27; Completion date: 2023-07-26
Enrollment: 96 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This open label, flexible-dose study evaluating the safety and efficacy of SPN-812 administered with psychostimulants in children and adolescents (6 to 17 years of age) with Attention-Deficit/Hyperactivity Disorder (ADHD).

Detailed description:
This is an open-label, multicenter, flexible-dose, safety study of SPN-812 in pediatric patients (6-17 years of age) diagnosed with ADHD, when administered with a FDA-approved medication (psychostimulant) in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in pediatric subjects. Participants will be screened for eligibility for up to 4 weeks, and he/she will continue to take their prescribed psychostimulant ADHD medication during that time. Following the screening period, eligible subjects will receive SPN-812 with their current psychostimulant treatment for ADHD for 8 weeks. For the first 4 weeks of treatment subjects will take SPN-812 dose in the morning (AM dosing), and for the last 4 weeks of treatment, subjects will take SPN-812 dose in the evening (PM dosing). The total duration of the study between the screening visit and the end of the treatment period/end of study (EOS) visit is up to 12 weeks.

Arms: arm 1: Subjects 6-11 years of age: 100 to 400mg SPN-812 (100 mg oral capsule)

Subjects 12-17 years of age: 100 to 600mg SPN-812 (100 mg, 200 mg oral capsule)
Interventions: intervention 1: SPN-812
Intervention descriptions: intervention 1: Viloxazine extended-release capsule

Protocol documents:
Prot_002.pdf: 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
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812P412 
 
Version 3.0 
 
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 . 
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COVER PAGE - PROTOCOL 
 
Protocol Number: 
812P412 
Title: 
A Phase IV, Open-Label, Flexible-Dose Safety Trial Evaluating 
SPN-812 Administered with Psychostimulants in Children and 
Adolescents (6 to 17 years of age) with Attention-
Deficit/Hyperactivity Disorder (ADHD) 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
9715 Key West Avenue 
Rockville, MD 20850 
United States 
Phone: (301) 838-2500 
Fax: (240) 403-0065 
Protocol Version: 
3.0 
Date: 
01Feb2022 
NCT: 
NCT04786990 


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TITLE PAGE  
 
 
 
Protocol 
Number: 
812P412 
Title: 
A Phase IV, Open-Label, Flexible-Dose Safety Trial Evaluating 
SPN-812 Administered with Psychostimulants in Children and 
Adolescents (6 to 17 years of age) with Attention-Deficit/Hyperactivity 
Disorder (ADHD) 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
9715 Key West Avenue 
Rockville, MD 20850 
United States 
Phone: (301) 838-2500 
Fax: (240) 403-0065 
IND number: 
108,864 
Investigational 
Medicinal 
Product: 
Viloxazine extended-release capsule  
Indication: 
Attention-deficit/hyperactivity disorder (ADHD)  
Medical 
Monitor 
Phase: 
4 
Protocol 
Version: 
3.0 
Date: 
01Feb2022 
Good Clinical 
Practice 
(GCP) 
Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonization (ICH) Good Clinical Practices (GCP) 
and all applicable local regulations. All required study documentation 
will be archived as required by regulatory authorities. 


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INVESTIGATOR’S 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SUPERNUS PHARMACEUTICALS, INC. PROTOCOL APPROVAL PAGE 
Authors: 
 
 
Reviewers: 
 
 
 
Approvers: 
 
 


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CLINICAL PROTOCOL SYNOPSIS 
Sponsor: Supernus Pharmaceuticals, Inc. 
Name of Product:  SPN-812 (viloxazine 
extended-release capsule) 
Name of Active Ingredient: Viloxazine 
hydrochloride 
Protocol Number: 812P412 
Phase of Development:  4 
Full Title of Study: A Phase IV, Open-Label, Flexible-Dose Safety Trial Evaluating SPN-812 
Administered with Psychostimulants in Children and Adolescents (6 to 17 years of age) with 
Attention-Deficit/Hyperactivity Disorder (ADHD) 
Number of Study Sites: Up to 20 sites in the United States (US) 
Number of Subjects: Approximately 60 subjects will enroll, and approximately 50 subjects 
are expected to complete study 
Indication: Attention-deficit/hyperactivity disorder (ADHD) 
Objectives:  
Primary Objective: 
• To evaluate the safety and tolerability of AM and PM dosing of SPN-812 administered with 
psychostimulants (methylphenidate or amphetamine) for ADHD in children and 
adolescents (6-17 years of age). 
Secondary Objectives: 
1. To evaluate the safety and tolerability of AM versus PM dosing of SPN-812 administered 
with psychostimulants (methylphenidate or amphetamine) for ADHD in children and 
adolescents (6-17 years of age). 
2. To evaluate the efficacy of AM and PM dosing of SPN-812 administered with 
psychostimulants (methylphenidate or amphetamine) for ADHD in children and 
adolescents (6-17 years of age) on:  
i. ADHD symptoms as measured by the Investigator-rated ADHD-RS-5 (IR-ADHD-RS-5). 
ii. the global assessment of severity for ADHD as measured by the Clinical Global 
Impression-Severity of Illness (CGI-S) scale. 
iii. the global assessment of improvement for ADHD as measured by the Clinical Global 
Impression-Improvement (CGI-I) scale. 
iv. sleep as measured by the Sleep Disturbance Scale for Children (SDSC). 
v. home functioning in the morning and evening as measured by the Weekly Parent 
Rating of Evening and Morning Behavior-Revised (WPREMB-R). 
3. To evaluate the efficacy of AM versus PM dosing of SPN-812 administered with 
psychostimulants (methylphenidate or amphetamine) for ADHD in children and 
adolescents (6-17 years of age) on:  
i. ADHD symptoms as measured by the IR-ADHD-RS-5. 
ii. the global assessment of severity as measured by the CGI-S scale. 
iii. the global assessment of improvement for ADHD as measured by the CGI-I scale. 
iv. sleep as measured by the SDSC. 
v. home functioning in the morning and evening as measured by the WPREMB-R. 


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4. To evaluate efficacy in the morning for AM and PM dosing of SPN-812 administered with 
psychostimulants (methylphenidate or amphetamine) for ADHD in children and 
adolescents (6-17 years of age) on ADHD symptoms as measured by the Morning Parent-
Rated-ADHD-RS-5 (PR-ADHD-RS-5). 
5. To evaluate efficacy in the evening for AM and PM dosing of SPN-812 administered with 
psychostimulants (methylphenidate or amphetamine) for ADHD in children and 
adolescents (6-17 years of age) on ADHD symptoms as measured by the Evening PR-
ADHD-RS-5. 
6. To evaluate duration of efficacy within day (morning versus evening) for AM and PM 
dosing of SPN-812 administered with psychostimulants (methylphenidate or 
amphetamine) for ADHD in children and adolescents (6-17 years of age) on ADHD 
symptoms as measured by the Morning and Evening PR-ADHD-RS-5. 
Endpoints: 
Primary Endpoints: 
• Safety endpoints for Weeks 1-4 (AM dosing) and Weeks 5-8 (PM dosing) are adverse 
events (AEs), clinical safety laboratory tests, vital signs, weight, height, BMI, 
electrocardiograms (ECGs), physical examination, and the Columbia Suicide Severity 
Rating Scale (C-SSRS). 
Secondary Endpoints: 
1. Safety endpoints for Weeks 1-4 (AM dosing) versus Weeks 5-8 (PM dosing) are AEs, 
clinical safety laboratory tests, vital signs, weight, height, BMI, ECGs, physical 
examination, and the C-SSRS. 
2. Secondary endpoints for evaluating the efficacy of SPN-812 at Week 4 (AM dosing) and 
Week 8 (PM dosing) are: 
i. Change from baseline (CFB) in the IR-ADHD-RS-5 Total Score at Week 4 and Week 8.  
ii. CFB in CGI-S score at Week 4 and Week 8. 
iii. CGI-I score at Week 4 and Week 8. 
iv. CFB in SDSC total score and subscale scores at Week 4 and Week 8 
v. CFB in WPREMB-R total score and subscale scores at Week 4 and Week 8. 
3. Secondary endpoints for evaluating the efficacy of SPN-812 Week 4 (AM dosing) versus 
Week 8 (PM dosing) are: 
i. CFB in the IR-ADHD-RS-5 Total Score at Week 4 versus Week 8.  
ii. CFB in CGI-S score at Week 4 versus Week 8. 
iii. CGI-I score at Week 4 versus Week 8. 
iv. CFB in SDSC total score and subscale scores at Week 4 versus Week 8 
v. CFB in WPREMB-R total score and subscale scores at Week 4 versus Week 8. 
4. The CFB in the Morning PR-ADHD-RS-5 Total Score at Week 4 (AM dosing) and Week 8 
(PM dosing). 
5. The CFB in the Evening PR-ADHD-RS-5 Total Score at Week 4 (AM dosing) and Week 8 
(PM dosing).  
6. The CFB in the Morning PR-ADHD-RS-5 Total Score versus the CFB in the Evening PR-
ADHD-RS-5 Total Score at Week 4 (AM dosing) and Week 8 (PM dosing).  


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Study Design:   
This is an open-label, flexible-dose, safety study of SPN-812 in pediatric patients diagnosed 
with ADHD per Diagnostic and Statistical Manual of Mental Disorders – 5th Edition (DSM-5™) 
criteria who are experiencing an inadequate efficacy response to psychostimulant therapy. 
Approximately 60 subjects will enroll, and approximately 50 subjects are expected to 
complete this study.  During screening period (up to 4 weeks), subjects will continue their 
psychostimulant ADHD treatment. Following the screening period, eligible subjects will 
receive SPN-812 with their current psychostimulant treatment for 8 weeks. The subject’s 
parent/guardian will record a daily medication diary between screening and end of study 
(EOS). Total duration of the study between screening visit and EOS visit is up to 12 weeks. 
At the Screening Visit (Visit 1), subjects will undergo an initial screening evaluation for 
eligibility including confirmation of prior ADHD diagnosis and inadequate response to current 
psychostimulant treatment. Subjects must washout of any prohibited medications at least 7 
days prior to Baseline Visit (Visit 2, Day 1). At Visit 2, the IR-ADHD-RS-5 scale, CGI-S, 
SDSC, and WPREMB-R will be administered, safety evaluations will be performed, and 
inclusion/exclusion criteria will be reviewed to confirm eligibility.   
Subject who are eligible to participate will begin dosing SPN-812 at Visit 2 (Day 1). Subjects 
will dose SPN-812 daily in the morning (AM) during Weeks 1-4, and then dose SPN-812 daily 
in the evening (PM) during Weeks 5-8. Children (6-11 years of age) will begin SPN-812 
dosing at 100 mg/day during Week 1 of Treatment period and may be titrated up or tapered 
down in increments/decrements of 100 mg/day per week between 100 and 400 mg/day 
during Weeks 2 to 8 of Treatment. Adolescents (12-17 years of age) will begin SPN-812 
dosing at 200 mg/day during Week 1 of Treatment period and may be titrated up or tapered 
down in increments/decrements of 100-200 mg/day per week between 100 and 600 mg/day 
during Weeks 2 to 8 of Treatment. All subjects must continue taking stable dose (mg) of 
psychostimulant medication at least 5 days per week during the 8-week SPN-812 treatment 
period. The subject’s psychostimulant medication dose (mg) cannot be increased during 8-
week SPN-812 treatment, but it may be decreased once; if any further adjustment is required 
due to safety reasons, the investigator must inform the medical monitor and sponsor. A urine 
drug screen will be performed at every study visit (V1-V10) to confirm use of psychostimulant 
medication, and (in addition to clinical laboratory testing) a single confirmatory blood sample 
will be collected at every study visit (V1-V10) to determine psychostimulant and viloxazine/its 
metabolite concentrations.  
During the Treatment period, subjects will complete weekly study visits (Visits 3-10) during 
the Treatment Period (Days 2-57). At each post-baseline study visit, safety evaluations will be 
conducted, efficacy assessments (IR-ADHD-RS-5, CGI-S, CGI-I) will be administered, drug 
compliance will be evaluated, and subject will return bottle of study medication and receive 
next bottle of study medication, if required. SDSC and WPREMB-R will only be administered 
at Visits 6 and 10 during Treatment Period. In addition, parent/guardian must complete a 
‘Morning’ PR-ADHD-RS-5 and ‘Evening’ PR-ADHD-RS-5 one or two days prior to Study Visits 
2, 6, and 10. Parent/guardian will rate their child’s behavior based upon interactions with their 
child during the morning hours in the past week and then rate their child’s behavior based 
upon interactions with their child during the evening hours in the past week.  


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Subjects who discontinue early from the study will undergo safety evaluations. Subjects will 
receive a telephone call approximately 1 week after EOS (or last dose of SPN-812) for final 
safety assessments. 
Duration of Subject’s Participation:  
Following the Screening period (up to 4 weeks), subjects will be treated with SPN-812 for 
8 weeks. The total duration of the study between the screening visit and the end of the 
Treatment Period/EOS visit is up to 12 weeks. 
Investigational Medicinal Products, Reference Therapy, Doses and Mode of 
Administration 
Study Medication (SM): SPN-812 (viloxazine extended-release capsule)   
Dose levels:  
• Children (6-11 years of age): 100 to 400 mg/day; titrate at 100 mg/day per week 
• Adolescents (12-17 years of age): 100 to 600 mg/day; titrate at 100 or 200 mg/day per week 
Reference Therapy: not applicable 
Mode of Administration:  Single oral dose daily, with or without food, as either an intact 
capsule or sprinkling the content of capsule on one tablespoon of applesauce followed by 
drinking water after having ingested the SM/applesauce mix. Subjects will dose SPN-812 
daily in the morning during Weeks 1-4 (AM Dosing), and then dose SPN-812 daily in the 
evening during Weeks 5-8 (PM Dosing). 
Statistical Methodology 
All statistical analyses will be based on the safety population. The Safety Population is all 
subjects enrolled into the study who receive at least one dose of SPN-812. 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. 
Each efficacy endpoint (ADHD-RS-5 [investigator-rated (IR) and parent-rated (PR)], CGI-S, 
CGI-I, SDSC and WPREMB-R) will be listed and summarized by group of the optimized dose, 
as applicable. Total scores for each efficacy scale will be summarized by dose and visit and 
will be examined for trends. 
There are approximately 50 subjects expected to complete this study. Based on an early 
discontinuation rate of 20%, approximately 60 subjects would need to be enrolled. Based on a 
screen failure rate of 40%, approximately 100 subjects will be screened to enroll 60 subjects. 
Inclusion Criteria: 
1. Is male or female, 6 to ≤17 years and 9 months of age at screening.  
2. Parent(s)/legal guardian(s) is able to read and understand the Informed Consent Form 
(ICF). 
3. Written informed consent obtained by parent(s)/legal guardian(s) and informed assent 
obtained from the subject, if applicable. 


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4. Subject and parent(s)/legal guardian(s) are willing and able to comply with all of the 
procedures and requirements defined in the protocol, including parents(s)/legal 
guardian(s) oversight of morning and evening dosing of the SPN-812 and recording a 
daily medication/dosing diary for psychostimulant and/or SPN-812 during the study. 
5. Has lived with the same parent(s)/legal guardian(s) at same residence for at least the 
last 6 months prior to screening. 
6. Has a primary diagnosis of ADHD (inattentive, hyperactive, or combined presentation) 
confirmed with the Mini International Neuropsychiatric Interview for Children and 
Adolescents (MINI-KID) at screening. 
7. Is currently on a single, stable psychostimulant regimen (see Inclusion Criterion 8 for 
definition) for treatment of ADHD with a partial, but inadequate efficacy response to at 
least 2 weeks of treatment with a psychostimulant (methylphenidate or amphetamine) 
prior to screening. An inadequate response is defined as an investigator-rated ADHD-
RS-5 Total score ≥24 and a CGI-S score ≥3 (mildly ill or worse) at Screening and 
Baseline. Subjects taking additional medication for ADHD (e.g., nonstimulant) are 
excluded. 
8. Is currently and expecting to continue and remain on a stable psychostimulant regimen 
throughout the study. A stable stimulant regimen is defined as taking dose at least 5 
days per week (morning), no significant change in dose or dosing frequency at least 2 
weeks prior to baseline (Visit 2), and the investigator believes the subject’s 
psychostimulant dose is optimized. 
9. Is functioning at an age-appropriate level intellectually, as judged by the Investigator.  
10. Is a child (6-11 years of age) with a body weight of at least 20 kg at screening or is an 
adolescent (12-17 years of age) with a body weight of at least 35 kg at screening. 
11. Has a resting (sitting) blood pressure (BP) and pulse rate measurement within the 95th 
percentile for age, sex, and height. 
12. Is considered medically healthy by the Investigator via assessment of physical 
examination, medical and psychiatric histories, clinical laboratory tests, vital signs, and 
electrocardiogram (ECG). 
13. Females of childbearing potential (FOCP) must be either sexually inactive (abstinent) 
or, if sexually active, must agree to use/practice one of the following acceptable, highly 
effective contraceptive methods beginning during the screening period prior to the first 
dose of SM and throughout the study:  
a. Simultaneous use of male condom and intra-uterine contraceptive device placed 
during screening period prior to first dose of SM 
b. Surgically sterile male partner (e.g., vasectomized partner is sole partner) 
c. Barrier method: condom with spermicidal foam/gel/film/cream/suppository or 
occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository 
d. Established use of oral, injected, or implanted hormonal methods of contraception 
With approval by the Investigator, subjects’ parents or legal guardians may select 
abstinence as a form of birth control if deemed more appropriate. For the purposes of 
this study, all females are considered to be of childbearing potential unless they are 
confirmed by the Investigator to be premenarchal, biologically sterile, or surgically 
sterile (e.g., hysterectomy with bilateral oophorectomy, tubal ligation). 


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14. Adolescent males, if sexually active, must: 
a. Use 2 methods of contraception in combination if his female partner is of 
childbearing potential; this combination of contraceptive methods must be used 
from the Baseline Visit to ≥ 1 month after the last dose of SM, or 
b. Have been surgically sterilized prior to the Screening Visit. 
Exclusion Criteria: 
1. Is currently participating in another clinical trial or has participated in a clinical trial 
within 60 days prior to screening. 
2. Is a member of the study personnel or of their immediate families, or is a subordinate 
(or immediate family member of a subordinate) to any of the study personnel. 
3. Is a female subject who is pregnant, lactating and/or sexually active and not agreeing to 
use one of the acceptable contraceptive methods throughout the study. 
4. Has history of severe drug allergy or hypersensitivity, or known hypersensitivity, to the 
study medication (SPN-812). 
5. Has history of moderate or severe head trauma or other neurological disorder or 
systemic medical disease that, in the Investigator's opinion, is likely to affect central 
nervous system functioning. This would include subjects with: 
a. a current diagnosis of a major neurological disorder;   
b. seizures, seizure disorder or seizure-like events;  
c. history of seizure disorder within the immediate family (siblings, parents); or 
d. encephalopathy 
Note: Febrile seizures are not exclusionary and will be assessed on a case-by-case 
basis. If for any reason the subject received medication for a febrile seizure or has a 
history of complex febrile seizures, this will be exclusionary.   
6. Has current diagnosis or history of major psychiatric disorders or intellectual disabilities 
other than ADHD per DSM-5 criteria (including schizophrenia, schizoaffective disorder, 
bipolar disorder, borderline personality disorder, antisocial personality disorder, 
narcissistic personality disorder, post-traumatic stress disorder, obsessive-compulsive 
disorder, severe oppositional defiant disorder, conduct disorder, and disruptive mood 
dysregulation disorder, and autism spectrum disorders). The following is not 
exclusionary:  
a. a history of mild social anxiety disorder or generalized anxiety disorder according 
to DSM-5 criteria; 
b. a history of mild to moderate ODD according to DSM-5 criteria;  
c. a history of Major Depressive Disorder, if he/she has not experienced a major 
depressive disorder episode or required psychiatric counselling; or 
pharmacotherapy within the 6 months prior to screening. 
7. Has a known history of physical, sexual, or emotional abuse in the last year prior to 
screening. 


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8. Has any other disorder for which its treatment takes priority over treatment of ADHD or 
is likely to interfere with study treatment, impair treatment compliance, or interfere with 
interpretation of study results. 
9. Has a current diagnosis of drug abuse or dependence disorder within the 12 months 
prior to screening, has a history of drug abuse or dependence disorder or has an 
immediate family member living at the study participant’s home who has current 
diagnosis drug abuse or dependence disorder (per DSM-5 criteria). 
10. Evidence of suicidality (defined as either active suicidal plan/intent or active suicidal 
thoughts, or more than one lifetime suicide attempt) within the six months before 
Screening or at Screening.  
11. Has positive findings on C-SSRS for suicidal ideation or behaviors at screening. Has 
attempted suicide within the 6 months prior to screening, or is at significant risk of 
suicide, either in the opinion of the Investigator or defined as a "yes" to suicidal ideation 
questions 4 or 5 or answering "yes" to suicidal behavior on the C-SSRS within the 6 
months prior to screening. 
12. Is currently using, or has a positive result on the urine drug screening for, drugs of 
abuse (alcohol, amphetamine, barbiturates, benzodiazepines, cannabis [THC], cocaine, 
cotinine, methadone, methamphetamine [including ecstasy], methylphenidate, 
phencyclidine, propoxyphene, and opiates) with the exception of the psychostimulant 
prescribed for the treatment of ADHD.  
13. Is unable to discontinue all prohibited medication at least 7 days prior to baseline. 
14. Has body mass index (BMI) greater than 95th percentile for her/his appropriate age and 
gender (per CDC’s gender specific “BMI-for-age percentiles” charts). 
15. Has a current diagnosis of significant systemic disease. 
16. Has uncontrolled thyroid disorder defined as thyroid stimulating hormone ≤ 0.8 x the 
lower limit of normal or ≥ 1.25 x the upper limit of normal for the reference laboratory 
range. 
17. Has resting (sitting) blood pressure and pulse rate greater than the 95th percentile for 
age and gender. 
18. Has a known personal history, or presence, of structural cardiac abnormalities, 
cardiovascular or cerebrovascular disease, serious heart rhythm abnormalities, 
syncope, tachycardia, cardiac conduction problems (e.g., clinically significant heart 
block or QT interval prolongation: QTc >0.44 seconds), exercise-related cardiac events 
including syncope and pre-syncope, or clinically significant bradycardia. 
19. Has any clinically significant abnormal clinical laboratory test, urine test, 
electrocardiogram (ECG) result, vital signs or physical examination finding at screening 
that, in the opinion of the Investigator, would interfere with the safety of the subject (see 
Note below). 


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20. Has a concurrent chronic or acute illness (such as severe allergic rhinitis or an 
infectious process requiring antibiotics), disability, or other condition that might 
confound the results of safety assessments. 
21. Has or has had one or more medical conditions considered clinically significant/relevant 
by the Investigator in the context of the study (e.g., cardiovascular disease, congestive 
heart failure, cardiac hypertrophy, arrhythmia, bradycardia [pulse < 70 bpm (6-11 
years), pulse < 60 bpm (12-17 years)], tachycardia [pulse > 120 bpm (6-11 years); 
pulse > 100 bpm (12-17 years)], respiratory disease, hepatic impairment or renal 
insufficiency, metabolic disorder, endocrine disorder, gastrointestinal disorder, 
hematological disorder, infectious disorder, any clinically significant immunological 
condition, and/or dermatological disorder. 
22. Has any disease or medication that could, in the Investigator's opinion, interfere with 
the assessments of safety, tolerability, or efficacy, or interfere with study conduct or 
interpretation of results. 
23. Lost or donated more than 450 mL of blood during the 30 days prior to screening. 
24. Use of any investigational drug or prohibited concomitant medications including known 
CYP1A2 substrates (e.g., theophylline, melatonin) within 28 days or 5 half-lives prior to 
Baseline Visit (Day 1) (whichever is longer) or anticipated for the duration of the study. 
25. History of unexplained loss of consciousness, unexplained syncope, unexplained 
irregular heartbeats or palpitations or near drowning with hospital admission. 
26. Has an allergy to applesauce and cannot swallow capsules whole. 
27. In the Investigator's opinion, is unlikely to comply with the protocol or is unsuitable for 
any other reason.  
Note: Repeat testing for clinical laboratory tests, vital signs, and ECG parameters is permitted 
one time for each test during screening period, at the discretion of the Investigator, as long as 
the repeat test result is available within the 28-day screening period to determine eligibility. 
 
 


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TABLE OF CONTENTS 
 
INVESTIGATOR’S SIGNATURE PAGE.............................................................................2 
SUPERNUS PHARMACEUTICALS, INC. PROTOCOL APPROVAL PAGE ...................3 
CLINICAL PROTOCOL SYNOPSIS ...................................................................................4 
TABLE OF CONTENTS .................................................................................................... 12 
LIST OF ABBREVIATIONS .............................................................................................. 17 
1 
INTRODUCTION ................................................................................................... 19 
1.1 
Background .................................................................................................................. 19 
1.2 
Clinical Information...................................................................................................... 20 
1.2.1 
Phase 1 Studies .................................................................................................. 20 
1.2.2 
Phase 2 Studies .................................................................................................. 21 
1.2.3 
Pediatric Phase 3 Studies .................................................................................. 22 
1.2.3.1 
Children (6 to 11 years of age) .................................................................. 22 
1.2.3.2 
Adolescents (12 to 17 years of age) ......................................................... 23 
1.2.3.3 
Pediatric Open-Label Extension Safety Trial (6 to 17 years of age) ... 24 
1.3 
Study Rationale ........................................................................................................... 25 
2 
STUDY OBJECTIVES AND ENDPOINTS ........................................................... 26 
2.1 
Primary Objective ........................................................................................................ 26 
2.1.1 
Primary Endpoints ............................................................................................... 26 
2.2 
Secondary Objectives ................................................................................................. 26 
2.2.1 
Secondary Endpoints .......................................................................................... 27 
3 
INVESTIGATIONAL STUDY PLAN ...................................................................... 28 
3.1 
Overall Study Design and Plan ................................................................................. 28 
3.1.1 
Screening Period (Visit 1) .................................................................................. 28 
3.1.2 
Baseline (Visit 2) .................................................................................................. 28 
3.1.3 
Treatment Period (Visits 3 to 10) ...................................................................... 29 
3.1.4 
Follow-up Period .................................................................................................. 30 
3.2 
Rationale for Study Design ........................................................................................ 30 
3.3 
Study Population ......................................................................................................... 31 
3.3.1 
Number of Subjects ............................................................................................ 31 
3.3.2 
Inclusion Criteria .................................................................................................. 31 
3.3.3 
Exclusion Criteria ................................................................................................ 32 
3.4 
Completion of Study and Discontinuation of Subjects ........................................... 35 
4 
STUDY TREATMENT ........................................................................................... 36 
4.1 
Study Medication Identity, Packaging and Labeling .............................................. 36 
4.2 
Study Medication Administration .............................................................................. 36 
4.2.1 
AM Dosing; Weeks 1-4 of Treatment Period .................................................. 36 


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4.2.2 
PM Dosing; Weeks 5-8 of Treatment Period .................................................. 36 
4.2.3 
Total Daily Dose by Age Group......................................................................... 37 
4.3 
Method of Assigning Subjects to Treatment Arm ................................................... 37 
4.4 
Study Medication Handling and Accountability ....................................................... 37 
4.5 
Blinding ......................................................................................................................... 38 
4.6 
Concomitant Medications ........................................................................................... 38 
5 
STUDY METHODS ................................................................................................ 39 
5.1 
Study Visits and Procedures ..................................................................................... 39 
5.1.1 
Visit 1 – Screening .............................................................................................. 42 
5.1.2 
Visit 2 – Baseline ................................................................................................. 42 
5.1.3 
Visit 3 – Treatment Period ................................................................................. 43 
5.1.4 
Visit 4 – Treatment Period ................................................................................. 43 
5.1.5 
Visit 5 – Treatment Period ................................................................................. 44 
5.1.6 
Visit 6 – Treatment Period ................................................................................. 44 
5.1.7 
Visit 7 – Treatment Period ................................................................................. 45 
5.1.8 
Visit 8 – Treatment Period ................................................................................. 45 
5.1.9 
Visit 9 – Treatment Period ................................................................................. 46 
5.1.10 
Visit 10 – End of Study ....................................................................................... 46 
5.1.11 
Follow-up Phone Call (FPC) .............................................................................. 47 
5.1.12 
Unscheduled Visits .............................................................................................. 47 
6 
STUDY VARIABLES AND ASSESSMENTS ....................................................... 48 
6.1 
Efficacy Assessments ................................................................................................. 48 
6.1.1 
ADHD Rating Scale-5 (ADHD-RS-5) ............................................................... 48 
6.1.1.1 
Investigator-Rated ADHD-RS-5 (IR-ADHD-RS-5) ................................. 48 
6.1.1.2 
Parent-Rated ADHD-RS-5 (PR-ADHD-RS-5) ......................................... 48 
6.1.2 
Clinical Global Impression – Severity of Illness Scale (CGI-S) .................... 49 
6.1.3 
Clinical Global Impression – Improvement Scale (CGI-I) ............................. 49 
6.1.4 
Sleep Disturbance Scale for Children (SDSC) ............................................... 49 
6.1.5 
Weekly Parent Rating of Evening and Morning Behavior-Revised 
(WPREMB-R) ...................................................................................................... 49 
6.2 
Safety Variables and Assessments .......................................................................... 50 
6.3 
Adverse Events............................................................................................................ 50 
6.3.1 
Adverse Events of Special Interest (AESI) ...................................................... 51 
6.3.2 
Causality ............................................................................................................... 51 
6.3.3 
Recording and Evaluation of Adverse Events ................................................ 51 
6.3.4 
Criteria for Assessing Severity .......................................................................... 51 
6.3.5 
Criteria for Assessing Causality ........................................................................ 52 
6.3.6 
Serious Adverse Events ..................................................................................... 53 
6.3.7 
Investigator Responsibilities for Reporting SAEs/AESIs ............................... 53 
6.3.8 
Other Events Requiring Immediate Reporting ................................................ 53 
6.3.9 
Sponsor Responsibilities for Reporting SAEs ................................................. 54 


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6.4 
Treatment-Emergent Suicidal Ideation .................................................................... 54 
6.4.1 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................... 54 
6.4.2 
Suicide Risk Management Plan ........................................................................ 55 
6.4.2.1 
Assessment of Suicide Risk ...................................................................... 55 
6.4.2.2 
Acute Suicidal Crisis ................................................................................... 55 
6.4.2.3 
Non-acute Suicidal Risk ............................................................................. 55 
6.5 
Clinical Measurements ............................................................................................... 55 
6.5.1 
Physical Examinations and Height ................................................................... 55 
6.5.2 
Vital Signs and Weight ....................................................................................... 55 
6.5.3 
Screening and Clinical Safety Laboratory Assessments .............................. 56 
6.5.4 
Electrocardiograms (ECGs) ............................................................................... 57 
6.6 
Confirmatory Blood Sample Assessment ................................................................ 57 
6.7 
Screening Scales and Assessment Tools ............................................................... 57 
6.7.1 
Mini-International Neuropsychiatric Interview for Children and Adolescents 
(MINI-KID) ............................................................................................................ 57 
7 
STATISTICAL METHODS .................................................................................... 58 
7.1 
General Considerations .............................................................................................. 58 
7.2 
Handling of Missing Data ........................................................................................... 58 
7.3 
Analysis Populations ................................................................................................... 58 
7.4 
Demographics and Baseline Analysis ...................................................................... 58 
7.5 
Subject Disposition...................................................................................................... 59 
7.6 
Study Medication Exposure and Compliance ......................................................... 59 
7.7 
Concomitant Medications ........................................................................................... 60 
7.8 
Primary Analysis .......................................................................................................... 60 
7.8.1 
Primary Safety Analysis ..................................................................................... 60 
7.8.2 
Adverse Events .................................................................................................... 61 
7.8.3 
Clinical Laboratory Values ................................................................................. 61 
7.8.4 
Vital Signs, Height, Weight and BMI ................................................................ 61 
7.8.5 
Electrocardiogram (ECG) Results .................................................................... 61 
7.8.6 
Concomitant medications ................................................................................... 62 
7.8.7 
C-SSRS ................................................................................................................ 62 
7.9 
Efficacy Analysis.......................................................................................................... 62 
7.10 
Sample Size and Power Considerations ................................................................. 62 
7.11 
Interim Analysis ........................................................................................................... 62 
7.12 
Pharmacokinetic Analyses ......................................................................................... 62 
8 
DOCUMENTATION ............................................................................................... 63 
8.1 
Adherence to the Protocol ......................................................................................... 63 
8.2 
Changes to the Protocol ............................................................................................. 63 
8.3 
Data Quality Assurance .............................................................................................. 63 
8.3.1 
Data Collection .................................................................................................... 63 
8.3.2 
Clinical Data Management ................................................................................. 64 


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8.3.3 
Database Quality Assurance ............................................................................. 64 
8.3.4 
Bioanalytical Sample Handling .......................................................................... 64 
8.4 
Retention of Records .................................................................................................. 64 
8.5 
Auditing Procedures.................................................................................................... 64 
8.6 
Publication of Results ................................................................................................. 65 
8.7 
Financing and Insurance ............................................................................................ 65 
8.8 
Disclosure and Confidentiality ................................................................................... 65 
8.9 
Discontinuation of Study ............................................................................................ 65 
9 
ETHICS .................................................................................................................. 66 
9.1 
Institutional Review Boards ....................................................................................... 66 
9.2 
Ethical Conduct of the Study ..................................................................................... 66 
9.3 
Investigators and Study Personnel ........................................................................... 66 
9.4 
Subject Information and Consent ............................................................................. 66 
10 
REFERENCES ...................................................................................................... 68 
11 
APPENDIX: ............................................................................................................ 70 
11.1 
ADHD-RS-5 .................................................................................................................. 70 
11.1.1 
Investigator-rated ADHD-RS-5 Home Version ............................................... 70 
11.1.1.1 
IR-ADHD-RS-5 Child Version [6-11 years old] ....................................... 71 
11.1.1.2 
IR-ADHD-RS-5 Home Version: Adolescent [12-17 years old] ............. 73 
11.1.2 
‘MORNING Parent-rated ADHD-RS-5 Home Version ................................... 75 
11.1.2.1 
‘Morning’ PR-ADHD-RS-5 Child [6-11 years old] ................................... 75 
11.1.2.2 
‘Morning’ PR-ADHD-RS-5 Adolescent [12-17 years old] ...................... 77 
11.1.3 
‘EVENING’ Parent-rated ADHD-RS-5 Home Version ................................... 79 
11.1.3.1 
‘Evening’ PR-ADHD-RS-5 Child [6-11 years old] ................................... 79 
11.1.3.2 
‘Evening’ PR-ADHD-RS-5 Adolescent [12-17 years old] ...................... 81 
11.2 
Clinical Global Impression – Severity of Illness (CGI-S) ....................................... 83 
11.3 
Clinical Global Impression – Improvement (CGI-I) ................................................ 84 
11.4 
Sleep Disturbance Scale for Children (SDSC) ....................................................... 85 
11.5 
Weekly Parent Rating of Evening and Morning Behavior-Revised (WPREMB-R)
 
86 
11.6 
C-SSRS: 6-11 years old ............................................................................................. 88 
11.6.1 
C-SSRS; Children’s “Baseline/Screening” Version ........................................ 88 
11.6.2 
C-SSRS; Children’s “Since Last Visit” Version ............................................... 91 
11.7 
C-SSRS: 12-17 years old ........................................................................................... 94 
11.7.1 
C-SSRS; “Baseline” Version .............................................................................. 94 
11.7.2 
C-SSRS; “Since Last Visit” Version .................................................................. 97 
11.8 
MINI-KID ..................................................................................................................... 100 


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LIST OF TABLES AND FIGURES 
Table 1 
Study Medication Administration ............................................................ 37 
Table 2 
Schedule of Events and Assessments ................................................... 40 
Table 3 
Clinical Laboratory Tests ......................................................................... 56 
 
Figure 1 
Study Schematic ....................................................................................... 30 
 
 
 


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LIST OF ABBREVIATIONS 
ADHD 
Attention-deficit/hyperactivity disorder 
ADHD-RS-IV/5 
ADHD Rating Scale 4th Edition/5th Edition 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical-Therapeutic-Chemical (code) 
AUC0-tau 
Area under the concentration-time curve 
BMI 
Body mass index 
CAARS 
Conners Adult ADHD Rating Scale 
CFB 
Change from Baseline 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression-Severity of Illness 
CGI-I 
Clinical Global Impression-Improvement 
CI 
Confidence interval 
CL/F 
Oral clearance 
Cmax 
Maximum observed concentration 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DDI 
Drug-drug interaction 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 
(Text Revision) 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition  
ECG 
Electrocardiogram 
ECI-4 
Early Childhood Inventory-4 
eCRF 
Electronic case report form 
EOS 
End of study 
ER 
Extended-release 
ET 
Early termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IR-ADHD-RS-5 
Investigator-rated ADHD-RS-5 version 
IR 
Immediate release 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
LLOQ 
Lower limit of quantitation 
LS 
Least square 


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MedDRA 
Medical Dictionary for Regulatory Activities 
MINI KID 
Mini International Neuropsychiatric Interview for Children and 
Adolescents 
OLE 
Open-label extension 
PK 
Pharmacokinetics 
PPK   
Population pharmacokinetics 
PP 
Per protocol 
PR-ADHD-RS-5 Parent-rated ADHD-RS-5 version 
PT 
Preferred Term 
QD 
Once a day 
QTcF 
QT interval corrected using Fridericia’s method 
SADR 
Suspected adverse drug reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDSC 
Sleep Disturbance Scale for Children 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
SM 
Study medication 
SNMA 
Serotonin norepinephrine modulating agent 
TEAE 
Treatment-emergent adverse event 
USA 
United States of America 
Vd/F 
Apparent volume of distribution 
VLX 
Viloxazine 
WHO-DD 
World Health Organization Drug Dictionary 
WPREMB-R 
Weekly Parent Rating of Evening/Morning Behavior-Revised 
5HVLX-gluc 
5-hydroxy-viloxazine glucuronide 
 
 


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1 
INTRODUCTION 
1.1 
Background 
Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric condition 
characterized by the existence of persistent (≥ 6 months) behavioral symptom(s) of 
inattention and/or hyperactivity/impulsivity that is (are) not consistent with expected level 
of developmental and that have an adverse impact on multiple aspects of an individual’s 
daily life and functioning, including, but not limited to relationships with family members 
and others, social interactions and academic/occupational performance. ADHD is mostly 
identified/diagnosed in children and adolescent. As such, it has been recommended that 
any child between 4 and 18 years of age who exhibits symptoms of ADHD be 
administered a thorough, systematic assessment (and those diagnosed in childhood 
may likely exhibit some significant ADHD symptoms (inattention) into adulthood. 
Symptoms of ADHD may first be observed in younger, preschool-age children (>3 to < 6 
years of age). Epidemiological data suggest that ADHD affects up to 8% of children in 
the United States of America (USA), while the estimated prevalence in the adult 
population is between 0.3% and 5% (McCann and Roy-Byrne, 2004). The standard 
pharmaceutical treatments for ADHD include psychostimulants, non-stimulants, and 
antidepressants. Stimulants (e.g., methylphenidate, amphetamine) are the first-line 
pharmacotherapies for the treatment of ADHD. However, 10% to 30% of patients (i.e., 
children and adults) do not adequately respond to stimulants or experience intolerable 
adverse events (e.g., decreased appetite, sleep problems, headaches) (Briars and Todd, 
2016). 
SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, norepinephrine 
reuptake inhibitor. The active substance in SPN-812 is viloxazine, whose mechanism of 
action is multimodal with antagonistic activity observed at 5-HT2B and agonistic activity 
at 5-HT2C receptors, as well as weaker antagonistic effects at ADRα1B, ADRβ2 and 5-
HT7 receptors. Additionally, SPN-812 acts as a modulator with inhibitory effects at the 
norepinephrine reuptake transporter. Viloxazine was previously marketed in several 
European countries as an antidepressant as an immediate-release (IR) product. An 
extended-release (ER) formulation of viloxazine, SPN-812, has been developed by 
Supernus to prolong the release and absorption of viloxazine post-administration, 
thereby minimizing fluctuations in plasma drug levels and allowing longer dosing 
intervals for a drug with a relatively short half-life. SPN-812 was developed for potential 
use in the treatment of subjects with ADHD, based on the pharmacological properties 
and favorable safety profile and the current unmet medical need for effective long-acting, 
nonstimulant ADHD treatment in children and adolescents. SPN-812 is being evaluated 
in the current study for potential use in the treatment of ADHD in adults based on the 
pharmacological properties and favorable safety profile of viloxazine. 


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1.2 
Clinical Information 
The safety, pharmacokinetics (PK) and drug-drug interactions for the IR and ER 
formulations of SPN-812 have been evaluated in multiple Phase 1 studies in healthy 
adults. As of April 2019, a number of studies evaluating the efficacy and safety of SPN-
812 treatment for ADHD in pediatric and adult populations have been completed, 
including one Phase 2 study in adults (18 to 65 years of age; 812P201), one pediatric 
Phase 2 in children (6 to 12 years of age; 812P202), and four pediatric Phase 3 studies, 
two in children (6 to 11 years of age; 812P301 and 812P303) and two in adolescents 
(12 to 17 years of age; 812P302 and 812P304). In addition, there is an ongoing pediatric 
open-label extension (OLE) safety study in children and adolescents (6 to 17 years of 
age; 812P310). Key findings from the completed Phase 2 and Phase 3 studies are 
summarized below. Additional details are provided in the SPN-812 Investigator’s 
Brochure. 
1.2.1 Phase 1 Studies 
Phase 1 studies include comparison of single and two-bead SPN-812 extended release 
(ER) formulations to an SPN-812 immediate release (IR) formulation at single and 
multiple doses (812P102 and 812P103, respectively), evaluation of food and sprinkling 
effects (812P105), drug-drug interactions (DDIs) on CYP1A2, 2D6, and 3A4 substrates 
with evaluation of SPN-812 ER metabolism in CYP2D6 poor metabolizers vs. CYP2D6 
extensive metabolizers (812P113.1), DDI with d-amphetamine (812P113.2), DDI with 
methylphenidate (812P113.3), evaluation of the effect of alcohol on SPN-812 
metabolism (812P115), evaluation of the effect of renal impairment on SPN-812 
metabolism (812P112.1), evaluation of multiple dose SPN-812 on QT Interval 
(812P117), evaluation of maximum tolerable doses and cardiac safety in a single and 
multiple-ascending dose study (812P120) have also been evaluated. In addition, a 
[14C]-labelled oral IR solution was used to examine human absorption, metabolism, and 
excretion (812P111). 
Results from these studies demonstrated that 200 mg single dose of an extended 
release SPN-812 formulation resulted in a mean maximum plasma concentration 
(Cmax) of 1.33 µg/mL, area under the plasma concentration-time curve extrapolated to 
infinity (AUCinf) of 27.3 hr*µg/mL, median time to maximum concentration (tmax) of 5 
hours, and a half-life of approximately 7 hours (812P103). Lower mean Cmax was 
observed for SPN-812 as compared to SPN-812 IR and by 48 hours overall viloxazine 
exposure was comparable between the two formulations. The rate of absorption of 
viloxazine was formulation dependent; SPN-812 exhibited a slower absorption rate than 
SPN-812 IR. Following multiple-dose administration of SPN-812 on consecutive days, 
steady-state was achieved by the second day of multiple dosing. Little systemic 
accumulation of viloxazine was observed as no major increase in pharmacokinetic (PK) 
parameters was observed following multiple administration of SPN-812 compared to 
single dose administration, during the same time interval.  
Food and sprinkling did not affect the relative bioavailability of viloxazine following 
administration of SPN-812 capsules (812P105). SPN-812 interacted as a strong inhibitor 


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of CYP1A2, a weak inhibitor of CYP2D6, a weak inhibitor of CYP3A4; and displayed no 
significant differences in metabolism within CYP2D6 poor metabolizers and CYP2D6 
extensive metabolizers (812P113.1). There was no DDI between SPN-812 and d-
amphetamine (812P113.2) nor between SPN-812 and methylphenidate (812P113.3) In 
addition, there was no dose dumping observed with co-administration of alcohol with 
SPN-812 (812P115). Renal impairment resulted in a 1.09-fold, 1.3-fold, and 1.9-fold 
increase in AUC for mild, moderate, and severe renal impairment subjects receiving 400 
mg SPN-812 as compared to healthy subjects (812P112.1). Multiple doses of 1800 mg 
(supra-therapeutic) SPN-812 did not affect cardiac repolarization as measured by QTcI 
and QTcF or other electrocardiographic parameters (812P117). In the single 
ascending/multiple ascending dose study, SPN-812 was well tolerated up to 2100 
mg/day as a single dose and up to 1800 mg/day as multiple doses given once daily for 5 
consecutive days. Intolerable adverse events (AEs) were not observed at doses of up to 
1800 mg/day. SPN-812 at a single supratherapeutic dose had no effect on cardiac 
repolarization or other electrocardiographic parameters, other than slight increase in 
heart rate consistent with the known anticholinergic effect of viloxazine (812P120).  
In the human absorption, metabolism, and excretion study, absorption of the isomers, R- 
and S-viloxazine, was rapid with a median Tmax of 1.0 hour and showed a 2:1 
concentration ratio, respectively. Nearly 100% of the radioactive dose was recovered 
with approximately 90% being recovered within 24 hours of administration, 
demonstrating complete absorption of the drug followed by rapid elimination. The 
primary circulating form was SPN-812; the only metabolite found above 10% total 
radioactivity was de-activated hydroxylated glucuronide.   
The most common AEs in the Phase 1 studies in healthy adults were somnolence and 
headache. Most AEs were mild; none were severe or serious. No clinically significant, 
study medication-related findings were observed for laboratory or electrocardiogram 
(ECG) tests in any study. In general, SPN-812 is considered to be well-tolerated with no 
safety events observed that would be unexpected for viloxazine. 
1.2.2 Phase 2 Studies 
The randomized, blinded, proof-of-concept Phase 1/2 study 812P201 compared an IR 
formulation of SPN-812 and placebo administered three times a daily in a dose range of 
150 to 300 mg/day in 52 adults (26 per treatment) with ADHD. In addition to assessing 
the safety and tolerability of SPN-812 IR, scores of both the Investigator-rated and 
patient-rated Conners Adult ADHD Rating Scale (CAARS) were collected at weekly 
intervals during the 6-week treatment period. Treatment with SPN-812 IR showed a 
statistically significant reduction in median CAARS total ADHD symptom score 
compared to placebo. Treatment-emergent AEs were reported in 23 (88.5%) subjects in 
the SPN-812 IR group and in 18 (72.0%) subjects in the placebo group. The most 
common AEs in SPN-812 IR group were nausea, decreased appetite, headache, and 
insomnia. There were no clinically significant ECGs, clinical laboratory test results, vital 
signs, or physical examination findings in either group during the study. No serious 
adverse events (SAEs) or deaths occurred during the study. 


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The 812P202 study in children with ADHD assessed the effect of SPN-812 in reducing 
the symptoms of ADHD as measured by the ADHD Rating Scale IV (ADHD-RS-IV) 
(Johnson et al., 2020). Subjects aged 6 to 12 years were randomized in a 1:2:2:2:2 ratio 
of placebo or active treatment (SPN-812 100, 200, 300, or 400 mg) and received 
3 weeks of titration at 100 mg/week followed by 5 weeks of maintenance dosing for a 
total of 8 weeks of treatment. Mean ADHD-RS-IV Total Scores improved throughout 
treatment in all groups. Differences in change from baseline to end of study between 
SPN-812 and placebo were statistically significant at the three higher SPN-812 doses 
(p ≤ 0.0310) but not at the 100-mg dose. The treatment effect compared to placebo 
increased with the dose; however, pairwise comparisons among the four active 
treatment groups showed no statistically significant differences among the SPN-812 
doses. All doses of SPN-812 were well tolerated with no serious or severe AEs and no 
clinically significant effect on laboratory values of common hematology and chemistry 
tests. The most common AEs were somnolence, decreased appetite, and headache. 
1.2.3 Pediatric Phase 3 Studies 
Four pivotal Phase 3 studies of SPN-812 for the treatment of ADHD have been 
completed in the pediatric population: two studies in children 6 to 11 years of age 
(evaluating 100 mg, 200 mg, and 400 mg) and two studies in adolescents 12 to 17 years 
of age (evaluating 200 mg, 400 mg, and 600 mg). As of April 2019, preliminary results 
are available for all four studies.  
1.2.3.1 Children (6 to 11 years of age) 
Study 812P301 was a randomized, double-blind, placebo-controlled study of the efficacy 
and safety of SPN-812 at 100 mg/day and 200 mg/day for the treatment of ADHD in 
children 6 to 11 years of age (Nasser et al., 2020). The primary endpoint of the study 
was the change from baseline in ADHD-RS-5 Total Score at end of study. Treatment for 
6 weeks (1 week of titration followed by 5 weeks of maintenance at a fixed dose) with 
SPN-812 100 mg/day or 200 mg/day led to a statistically significant improvement in 
ADHD-RS-5 Total Score compared to placebo.  
Throughout treatment, AEs were reported in 47 (29.6%), 74 (48.1%), and 
77 (47.8%) subjects in the placebo, SPN-812, 100 mg/day, and SPN-812, 200 mg/day 
treatment groups, respectively. The most frequently reported AEs were somnolence, 
decreased appetite, and headache. AEs were considered to be at least possibly 
treatment related in 16 (10.1%), 41 (26.6%), and 56 (34.8%) subjects in the placebo, 
SPN-812, 100 mg/day, and SPN-812, 200 mg/day treatment groups, respectively. AEs 
led to permanent study medication discontinuation (and study withdrawal) in 2 (1.3%), 
5 (3.2%), and 2 (1.2%) subjects in the placebo, SPN-812 100 mg/day, and SPN-812 
200 mg/day treatment groups, respectively. SAEs were reported in 3 subjects: 2 in the 
SPN-812, 100 mg/day treatment group and 1 in the SPN-812, 200 mg/day treatment 
group. All SAEs were considered unlikely related or not related to study medication. No 
deaths occurred during the study. 


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Study 812P303 was a randomized, double-blind, placebo-controlled study of the efficacy 
and safety of SPN-812 at 200 mg/day and 400 mg/day for the treatment of ADHD in 
children 6 to 11 years of age. The primary endpoint of the study was the change from 
baseline in ADHD-RS-5 Total Score at end of study. Treatment with SPN-812 
200 mg/day or 400 mg/day for 8 weeks (3 weeks of titration followed by 5 weeks of 
maintenance at a fixed dose) led to a statistically significant improvement in ADHD-RS-5 
Total Score compared to placebo. 
Throughout treatment, AEs were reported in 47 (45.6%), 56 (52.3%), and 
58 (58.0%) subjects in the placebo, SPN-812, 200 mg/day, and SPN-812, 400 mg/day 
treatment groups, respectively. The most frequently reported AEs were somnolence, 
headache, decreased appetite, and fatigue. AEs were considered to be at least possibly 
treatment related in 22 (21.4%), 42 (39.3%), and 51 (51.0%) subjects in the placebo, 
SPN-812, 200 mg/day, and SPN-812, 400 mg/day treatment groups, respectively. AEs 
led to permanent study medication discontinuation (and study withdrawal) in 3 (2.9%), 
6 (5.6%), and 4 (4.0%) subjects in the placebo, SPN-812 200 mg/day, and SPN-812 
400 mg/day treatment groups, respectively. SAEs were reported in 3 subjects: 1 in the 
SPN-812, 200 mg/day treatment group and 2 in the SPN-812, 400 mg/day treatment 
group. No deaths occurred during the study. 
1.2.3.2 Adolescents (12 to 17 years of age) 
Study 812P302 was a randomized, double-blind, placebo-controlled study of the efficacy 
and safety of SPN-812 at 200 mg/day and 400 mg/day for the treatment of ADHD in 
adolescents 12 to 17 years of age. The primary endpoint of the study was the change 
from baseline in ADHD-RS-5 Total Score at end of study. Treatment with SPN-812 
200 mg/day or 400 mg/day for 6 weeks (1 week of titration followed by 5 weeks of 
maintenance at a fixed dose) led to a statistically significant improvement in ADHD-RS-5 
Total Score compared to placebo. 
Throughout treatment, AEs were reported in 38 (36.5%), 43 (43.4%), and 
56 (53.3%) subjects in the placebo, SPN-812 200 mg/day, and SPN-812 400 mg/day 
treatment groups, respectively. The most frequently reported AEs were somnolence, 
decreased appetite, headache, fatigue and nausea. AEs were considered to be at least 
possibly treatment related in 20 (19.2%), 32 (32.3%), and 41 (39.0%) subjects in the 
placebo, SPN-812, 200 mg/day, and SPN-812, 400 mg/day treatment groups, 
respectively. AEs led to permanent study medication discontinuation (and study 
withdrawal) in 0, 4 (4.0%), and 2 (1.9%) subjects in the placebo, SPN-812 200 mg/day, 
and SPN-812, 400 mg/day treatment groups, respectively. SAEs were reported in 
2 subjects, both in the SPN-812, 200 mg/day treatment group. No deaths occurred 
during the study. 
Study 812P304 was a randomized, double-blind, placebo-controlled study of the efficacy 
and safety of SPN-812 at 400 mg/day and 600 mg/day for the treatment of ADHD in 
adolescents 12 to 17 years of age. The primary endpoint of the study was the change 
from baseline in ADHD-RS-5 Total Score at end of study. Treatment with SPN-812, 
400 mg/day for 7 weeks (2 weeks of titration followed by 5 weeks of maintenance at a 


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fixed dose) led to a statistically significant improvement in ADHD-RS-5 Total Score 
compared to placebo; however, ADHD-RS-5 Total Score during treatment with SPN-812 
600 mg/day did not showed a statistically significant improvement compared to placebo. 
Throughout treatment, AEs were reported in 39 (40.2 %), 58 (58.0%), and 
55 (55.6%) subjects in the placebo, SPN-812, 400 mg/day, and SPN-812, 600 mg/day 
treatment groups, respectively. The most frequently reported AEs were somnolence, 
fatigue, headache, decreased appetite, and nausea. AEs were considered to be at least 
possibly treatment related in 18 (18.6%), 44 (44.0 %), and 45 (45.5%) subjects in the 
placebo, SPN-812, 400 mg/day, and SPN-812, 600 mg/day treatment groups, 
respectively. AEs led to permanent study medication discontinuation (and study 
withdrawal) in 1 (1.0%), 4 (4.0%), and 5 (5.1%) subjects in the placebo, SPN-812 
400, mg/day, and SPN-812, 600 mg/day treatment groups, respectively. SAEs were 
reported in 2 subjects, both in the SPN-812, 400 mg/day treatment group. No deaths 
occurred during the study. 
1.2.3.3 Pediatric Open-Label Extension Safety Trial (6 to 17 years of age) 
Study 812P310 is an ongoing open-label extension safety study assessing the long-term 
safety of SPN-812 in children (6-11 years of age) at dose of 100 to 400 mg/day and in 
adolescents (12-11 years of age) at dose of 100 to 600 mg/day for the treatment of 
ADHD. Subjects enrolled in Study 812P310 were studied in either the Phase 2 trial 
(812P202) or one of the four Phase 3 trials (812P301-812P304). The primary safety 
endpoints of the study include adverse events (AEs), clinical safety laboratory tests, vital 
signs, weight, height, BMI, electrocardiograms (ECGs), physical examination, and the 
Columbia Suicide Severity Rating Scale (C-SSRS). The secondary efficacy endpoints 
include the ADHD-RS-IV/5 Total Score and CGI-I score by visit. SPN-812 treatment 
during Study 812P310 are at doses between 100 to 400 mg/day (100 mg capsule) in 
children and at doses of 100 to 600 mg/day (100 or 200 mg capsule) in adolescents for 
up to 72 months. As of 31Jul2019, 1,116 pediatric subjects enrolled and 1,097 took at 
least one dose of open-label SPN-812 in the Study 812P310. Of the 1097 subjects with 
at least one dose of SM, 6 (0.5%) subjects completed the study, 411 (37.5%) subjects 
were ongoing, and 680 (62.0%) subjects discontinued their participation in the study. 
The most common reasons for study discontinuation were withdrawal by parent/guardian 
(19.4%), lost to follow-up, (17.7%), and withdrawal by subject (10.4%). SAEs were 
reported for 2.3% of subjects, and the majority of SAEs were considered as unlikely or 
not related to the SPN-812. AEs were mostly mild or moderate in severity, with a low 
discontinuation rate due to AEs. AEs that led to discontinuation of SPN-812 were 
reported in 6.7% of the subjects. The most common AEs that were reported in >5% of 
subjects included somnolence, headache, nasopharyngitis, decreased appetite, and 
fatigue. Nearly all subjects (98.4%) had no report of any suicidal ideation or behavior. 
Overall, subjects maintained normal growth in weight and height during the study. The 
clinical laboratory abnormalities trends were not clinically significant. Low neutrophil 
counts were observed in 13.5% of subjects, but were not considered clinically 
meaningful because they were not frequently reported as AEs; the race of the majority of 
these subjects was Black or African-American who had a neutrophil count that was 


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<1500/μL at baseline (Benign Ethnic Neutropenia). There have been no notable trends 
in liver function tests in this study. There were only 3 subjects with ALT >3×ULN and 2 
subjects with Bilirubin >2×ULN. There were no subjects with elevated Albumin, AST, and 
ALP values after treatment with SPN-812. The abnormalities observed in vital signs 
were not considered clinically meaningful because they were not frequently reported as 
AEs. ECG abnormalities were not considered clinically meaningful, because they were 
not reported as AEs. In summary, long-term use of SPN-812 has been well-tolerated 
with a generally safe profile.  
1.3 
Study Rationale 
The efficacy and safety of SPN-812 (100-600 mg/day) as a treatment for ADHD has 
been assessed in four pivotal pediatric Phase 3 clinical trials, including two trials in 
children 6-11 years of age (812P301 and 812P303) and two trials in adolescents 12-17 
years of age (812P302 and 812P304). SPN-812 (100-400 mg/day) has been shown to 
be effective, safe and well tolerated. Of the over 1300 subjects who participated in a 
pivotal Phase 3 trial, there have been 1,097 pediatric subjects (6 years and older) dosed 
with SPN-812 (100-600 mg/day) in a long-term safety study (812P310).  In addition, 
Supernus conducted two Drug-Drug Interaction (DDI) clinical trials in healthy adult 
subjects to assess the safety/tolerability of two FDA approved and most prescribed 
psychostimulants for the treatment of ADHD individually when co-administered with 
SPN-812. In Study 812P113.2, Vyvanse® (lisdexamfetamine dimesylate, 36 mg) was 
co-administered with SPN-812. In Study 812P113.3, Concerta® (methylphenidate, 50 
mg) was co-administered with SPN-812 (viloxazine, 700 mg). The results of these two 
trials showed no effect of either psychostimulant on the pharmacokinetics (PK) of SPN-
812 and no effect of SPN-812 on the PK of either psychostimulants. A single dose of 
d-amphetamine or methylphenidate co-administrated with viloxazine did not impact on 
the exposure of viloxazine. A single-dose administration of viloxazine co-administrated- 
with d-amphetamine or methylphenidate did not impact on the exposure either d-
amphetamine or methylphenidate. As no relevant interactions were observed, no dose 
adjustment is recommended when taking either Vyvanse® or Concerta® in combination 
with SPN-812. All adverse events were mild in severity, and no Serious Adverse Events 
were reported. Altogether, SPN-812 was safe and generally well-tolerated in healthy 
adults when co-administered with either Vyvanse® or Concerta®. 
While there have been no DDI clinical trials conducted in children/adolescents, the data 
from the adult clinical trials indicate that co-administered of SPN-812 with either 
psychostimulant (Vyvanse® or Concerta®) in children and adolescents is safe and 
should be well-tolerated. In summary, the rationale for this study is to assess the safety 
and tolerability of SPN-812 administered with a psychostimulant therapy for ADHD. 
 
 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
• 
To evaluate the safety and tolerability of AM and PM dosing of SPN-812 
administered with psychostimulants (methylphenidate or amphetamine) for 
ADHD in children and adolescents (6-17 years of age) 
 
2.1.1 Primary Endpoints 
• 
Safety endpoints for Weeks 1-4 (AM dosing) and Weeks 5-8 (PM dosing) are 
adverse events (AEs), clinical safety laboratory tests, vital signs, weight, height, 
BMI, electrocardiograms (ECGs), physical examination, and the Columbia 
Suicide Severity Rating Scale (C-SSRS). 
2.2 
Secondary Objectives 
1. 
To evaluate the safety and tolerability of AM versus PM dosing of SPN-812 
administered with psychostimulants (methylphenidate or amphetamine) for 
ADHD in children and adolescents (6-17 years of age). 
2. 
 To evaluate the efficacy of AM and PM dosing of SPN-812 administered with 
psychostimulants (methylphenidate or amphetamine) for ADHD in children and 
adolescents (6-17 years of age) on:  
i. ADHD symptoms as measured by the investigator-rated ADHD-RS-5 (IR-
ADHD-RS-5). 
ii. the global assessment of severity for ADHD as measured by the Clinical 
Global Impression - Severity of Illness (CGI-S) scale. 
iii. the global assessment of improvement for ADHD as measured by the Clinical 
Global Impression - Improvement (CGI-I) scale.  
iv. sleep as measured by the Sleep Disturbance Scale for Children (SDSC). 
v. home functioning in the morning and evening as measured by the Weekly 
Parent Rating of Evening and Morning Behavior-Revised (WPREMB-R). 
3. 
To evaluate the efficacy of AM versus PM dosing of SPN-812 administered with 
psychostimulants (methylphenidate or amphetamine) for ADHD in children and 
adolescents (6-17 years of age) on:  
i. ADHD symptoms as measured by the IR-ADHD-RS-5. 
ii. the global assessment of severity as measured by the CGI-S scale. 
iii. the global assessment of improvement for ADHD as measured by the CGI-I 
scale. 
iv. sleep as measured by the SDSC. 
v. home functioning in morning and evening as measured by the WPREMB-R. 
4. 
To evaluate efficacy in the morning for AM and PM dosing of SPN-812 
administered with psychostimulants (methylphenidate or amphetamine) for 
ADHD in children and adolescents (6-17 years of age) on ADHD symptoms as 
measured by the Morning Parent-Rated-ADHD-RS-5 (PR-ADHD-RS-5). 


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5. 
To evaluate efficacy in the evening for AM and PM dosing of SPN-812 
administered with psychostimulants (methylphenidate or amphetamine) for 
ADHD in children and adolescents (6-17 years of age) on ADHD symptoms as 
measured by the Evening PR-ADHD-RS-5. 
6. 
To evaluate duration of efficacy within day (morning versus evening) for AM and 
PM dosing of SPN-812 administered with psychostimulants (methylphenidate or 
amphetamine) for ADHD in children and adolescents (6-17 years of age) on 
ADHD symptoms as measured by the Morning and Evening PR-ADHD-RS-5. 
2.2.1 Secondary Endpoints 
1. 
Safety endpoints for Weeks 1-4 (AM dosing) versus Weeks 5-8 (PM dosing) are 
AEs, clinical safety laboratory tests, vital signs, weight, height, BMI, ECGs, 
physical examination, and the C-SSRS. 
2. 
Secondary endpoints for evaluating the efficacy of SPN-812 at Week 4 (AM 
dosing) and Week 8 (PM dosing) are: 
i. Change from baseline (CFB) in the IR-ADHD-RS-5 Total Score at Week 4 and 
Week 8.  
ii. CFB in CGI-S score at Week 4 and Week 8. 
iii. CGI-I score at Week 4 and Week 8. 
iv. CFB in SDSC total score and subscale scores at Week 4 and Week 8. 
v. CFB in WPREMB-R total score and subscale scores at Week 4 and Week 8. 
3. 
Secondary endpoints for evaluating the efficacy of SPN-812 Week 4 (AM dosing) 
versus Week 8 (PM dosing) are: 
i. CFB in the IR-ADHD-RS-5 Total Score at Week 4 versus Week 8.  
ii. CFB in CGI-S score at Week 4 versus Week 8. 
iii. CGI-I score at Week 4 versus Week 8. 
iv. CFB in SDSC total score and subscale scores at Week 4 versus Week 8. 
v. CFB in WPREMB-R total score and subscale scores at Week 4 versus Week 8. 
4. 
 CFB in the Moring PR-ADHD-RS-5 Total Score at Week 4 (AM dosing) and  
Week 8 (PM dosing). 
5. 
CFB in the Evening PR-ADHD-RS-5 Total Score at Week 4 (AM dosing) and 
Week 8 (PM dosing). 
6. 
The CFB in the Morning PR-ADHD-RS-5 Total Score versus the CFB in the 
Evening PR-ADHD-RS-5 Total Score at Week 4 (AM dosing) and Week 8 (PM 
dosing). 
 


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3 
INVESTIGATIONAL STUDY PLAN 
3.1 
Overall Study Design and Plan 
This is an open-label, flexible-dose, safety study of SPN-812 in pediatric patients 
diagnosed with ADHD per Diagnostic and Statistical Manual of Mental Disorders – 5th 
Edition (DSM-5™) criteria who are experiencing an inadequate efficacy response to 
psychostimulant therapy (dosed at least 5 days per week). Up to 60 subjects will enroll, 
and up to 50 subjects will complete this study (Figure 1).  
During screening period (up to 4 weeks), subjects will continue their psychostimulant 
ADHD treatment (dosed at least 5 days per week). Following the screening period, 
eligible subjects will receive SPN-812 with their current psychostimulant treatment for 
ADHD for 8 weeks. The subject’s psychostimulant medication dose (mg) cannot be 
increased during the 8-week SPN-812 treatment, however, the investigator may 
decrease the dose of subject’s psychostimulant medication once during 8-week SPN-
812 treatment; if an additional dose adjustment is needed (e.g., due to worsening of AE 
or start of new AE), the investigator should inform the medical monitor and study 
sponsor. A urine drug screen will be performed at every study visit (V1-V10) to confirm 
use of psychostimulant medication at visit, and (in addition to clinical laboratory testing) 
a single confirmatory blood sample will be collected at every study visit (V1-V10) to 
determine psychostimulant and/or viloxazine/its metabolite concentrations (see Section 
6.6). The total duration of the study between the screening visit and the end of the 
treatment period/end of study (EOS) visit is up to 12 weeks.  
3.1.1 Screening Period (Visit 1)  
The screening period is a minimum of 7 days and a maximum of 28 days. After informed 
consent/assent is obtained, subjects will undergo initial screening evaluations (Section 
5.1.1). Subjects with an IR-ADHD-RS-5 total score <24 or CGI-S score <3 will be 
excluded from study participation. Subjects with an IR-ADHD-RS-5 total score ≥24 and a 
CGI-S score ≥3 will be eligible to enroll if meet all other eligibility criteria. 
Inclusion/exclusion criteria will be reviewed to confirm the subject’s eligibility. Subjects 
must washout of any prohibited medications at least 7 days prior to Visit 2. Subjects 
must continue taking stable dose of psychostimulant medication at least 5 days per 
week throughout the screening period, and subject’s parent/guardian must record 
whether it was taken and date/time of each psychostimulant dose taken in a daily diary. 
3.1.2 Baseline (Visit 2) 
At Visit 2, a urine drug screen will be performed for all subjects and a pregnancy testing 
will be performed for females of childbearing potential (FOCP). If both are negative, the 
IR-ADHD-RS-5 scale and the CGI-S will be administered. Subjects with an IR-ADHD-
RS-5 total score of <24 or CGI-S <3 will be excluded from study participation. Subjects 
with an IR-ADHD-RS-5 total score of ≥24 and a CGI-S score ≥3 will enroll. Safety 
evaluations will be performed and the IR-ADHD-RS-5 scale, CGI-S, SDSC, and 
WPREMB-R will be administered and inclusion/exclusion criteria will be reviewed to 


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confirm eligibility. Subjects who are eligible to participate will begin dosing SPN-812 
dosing at Visit 2 (Day 1).  
3.1.3 Treatment Period (Visits 3 to 10) 
The treatment period of the study will consist of 8 weeks of adjunct SPN-812 treatment 
with the subject’s current psychostimulant ADHD treatment. Subjects must continue 
taking stable dose of psychostimulant medication at least 5 days per week during the 8-
week SPN-812 treatment period, and subject’s parent/guardian must record whether it 
was taken and date/time of each psychostimulant dose taken in a daily diary (Figure 1).  
Subjects will dose SPN-812 daily between Visit 2 (Day 1) and Visit 10/EOS (Day 57). 
Subjects will dose SPN-812 daily in the morning (AM) during Weeks 1-4, and then dose 
SPN-812 daily in the evening (PM) during Weeks 5-8 (Figure 1). The timing of the PM 
dose during Weeks 5-8 should occur approximately 12 hours (± 60 minutes) after the 
timing of AM dose during Weeks 1-4 (e.g., if subject dosed at 7:00AM during Weeks 1-4, 
they should take SPN-812 dose at or around 7:00PM). Subject’s parent/guardian will 
record SPN-812 dosing each day in a daily diary, including date/time dose taken, SPN-
812 dose (mg) and method (swallow capsule whole or sprinkle capsule contents on 
apple sauce) or reason dose not taken, if applicable. Children (6 to 11 years of age) will 
begin SPN-812 dosing at 100 mg/day during Week 1 of Treatment and may be titrated 
up or tapered down in increments/decrements of 100 mg/day per week between 100 and 
400 mg/day. Adolescents (12 to 17 years of age) will begin SPN812 dosing at 200 
mg/day during Week 1 of Treatment and may be titrated up or tapered down in 
increments/decrements of 100-200 mg/day per week between 100 and 600 mg/day-.  
Following Baseline (Visit 2), subjects will complete weekly post-baseline study visits 
during the 8-week Treatment Period (Visits 3-10). At each study visit, safety evaluations 
(including review of AEs/concomitant medications, clinical safety laboratory tests, vital 
signs, weight, ECGs, and the C-SSRS) will be conducted, efficacy assessments (IR-
ADHD-RS-5, CGI-S, CGI-I) will be administered, drug compliance will be evaluated, and 
subject will return bottle of study medication and receive next bottle of study medication, 
if necessary. SDSC and WPREMB-R will only be administered at Visits 6 and 10 during 
Treatment Period. In addition, parent/guardian/caregiver must complete a “Morning” PR-
ADHD-RS-5 and “Evening” PR-ADHD-RS-5 one or two days prior to Study Visits 2, 6, 
and 10. Parent will rate their child’s behavior based upon interactions with their child 
during the morning hours in the past week and then rate their child’s behavior based 
upon interactions with their child during the evening hours in the past week.  
Subjects who are non-compliant (e.g., with study procedures, dosing study medication, 
study visits, etc.) may be discontinued. For AEs or risks that cannot be managed using 
permitted concomitant medications or other protocol-specified management, SM dosing 
should be discontinued and an Early Termination (ET) visit conducted. Study medication 
dosing will otherwise continue until Week 8 (Visit 10/EOS), at which time subjects will 
return for final study assessments. Subjects who discontinue early from the study will 
undergo safety evaluations. 


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3.1.4 Follow-up Period 
Subjects will receive a safety follow-up phone call approximately 1 week after the date of 
EOS Visit (or last dose of SPN-812) for final safety assessments (i.e. AEs, concomitant 
medications). 
Figure 1 Study Schematic 
 
3.2 
Rationale for Study Design 
Psychostimulants are usually first line treatment for ADHD in children and adolescents. 
However, a small proportion of patients may not receive an adequate response to 
psychostimulant treatment, particularly if adverse events preclude an increase to a 
higher, effective dose. In such cases, an FDA-approved non-stimulant ADHD treatment 
may be administered with psychostimulant. In Phase 3 trials, SPN-812 has 
demonstrated efficacy by significantly reducing (improving) ADHD symptoms, and it has 
been shown to be generally safe and well tolerated when taken as a monotherapy in 
children and adolescents with ADHD. In addition, in Phase 1 trials in healthy adults, PK 
parameters (Cmax, Tmax, AUC) for either viloxazine or psychostimulant 
(methylphenidate or amphetamine) were not affected when a single-dose of SPN-812 
was co-administered with a psychostimulant (methylphenidate or amphetamine). 
Therefore, in the current study, the aim is to assess the safety and efficacy of once daily 
SPN-812 treatment when administered with a psychostimulant in children and 
adolescents. 


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3.3 
Study Population 
3.3.1 Number of Subjects 
Approximately 60 subjects will be enrolled, and approximately 50 subjects are expected 
to completed study. 
3.3.2 Inclusion Criteria  
1. Is male or female, 6 to ≤17 years and 9 months of age at screening.  
2. Parent(s)/legal guardian(s) is able to read and understand the Informed Consent 
Form (ICF). 
3. Written informed consent obtained by parent(s)/legal guardian(s) and informed 
assent obtained from the subject, if applicable. 
4. Subject and parent(s)/legal guardian(s) are willing and able to comply with all of the 
procedures and requirements defined in the protocol, including parents(s)/legal 
guardian(s) oversight of morning and evening dosing of the SPN-812 and recording 
a daily medication/dosing diary for psychostimulant and/or SPN-812 during the 
study. 
5. Has lived with the same parent(s)/legal guardian(s) at same residence for at least 
the last 6 months prior to screening. 
6. Has a primary diagnosis of ADHD (inattentive, hyperactive, or combined 
presentation) confirmed with the Mini International Neuropsychiatric Interview for 
Children and Adolescents (MINI-KID) at screening. 
7. Is currently on a stable psychostimulant regimen (see Inclusion Criterion 8 for 
definition) for treatment of ADHD with a partial, but inadequate efficacy response to 
at least 2 weeks of treatment with a psychostimulant (methylphenidate or 
amphetamine) prior to screening. An inadequate response is defined as an 
investigator-rated ADHD-RS-5 Total score ≥24 and a CGI-S score ≥3 (mildly ill or 
worse) at Screening and Baseline. Subjects taking additional medication for ADHD 
(e.g., nonstimulant) are excluded 
8. Is currently and expecting to continue and remain on a stable psychostimulant 
regimen throughout the study. A stable stimulant regimen is defined as taking dose 
at least 5 days per week (morning), no significant change in dose or dosing 
frequency at least 2 weeks prior to baseline (Visit 2), and the investigator believes 
the subject’s psychostimulant dose is optimized. 
9. Is functioning at an age-appropriate level intellectually, as judged by the 
Investigator.  
10. Is a child (6-11 years of age) with a body weight of at least 20 kg at screening or is 
an adolescent (12-17 years of age) with a body weight of at least 35 kg at 
screening. 
11. Has a resting (sitting) blood pressure (BP) and pulse rate measurement within the 
95th percentile for age, sex, and height. 


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12. Is considered medically healthy by the Investigator via assessment of physical 
examination, medical and psychiatric histories, clinical laboratory tests, vital signs, 
and electrocardiogram (ECG). 
13. Females of childbearing potential (FOCP) must be either sexually inactive 
(abstinent) or, if sexually active, must agree to use/practice one of the following 
acceptable, highly effective contraceptive methods beginning during screening 
period prior to the first dose of SM and throughout the study:  
a. Simultaneous use of male condom and intra-uterine contraceptive device 
placed during screening period to first dose of SM  
b. Surgically sterile male partner (e.g., vasectomized partner is sole partner) 
c. Barrier method: condom with spermicidal foam/gel/film/cream/suppository or 
occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository 
d. Established use of oral, injected, or implanted hormonal methods of 
contraception 
With approval by the Investigator, subjects’ parents or legal guardians may select 
abstinence as a form of birth control if deemed more appropriate. For the purposes 
of this study, all females are considered to be of childbearing potential unless they 
are confirmed by the Investigator to be premenarchal, biologically sterile, or 
surgically sterile (e.g., hysterectomy with bilateral oophorectomy, tubal ligation). 
14. Adolescent males, if sexually active, must: 
a. Use 2 methods of contraception in combination if his female partner is of 
childbearing potential; this combination of contraceptive methods must be 
used from the Baseline Visit to ≥ 1 month after the last dose of SM, or 
b. Have been surgically sterilized prior to the Screening Visit. 
3.3.3 Exclusion Criteria 
1. Is currently participating in another clinical trial or has participated in a clinical trial 
within 60 days prior to screening. 
2. Is a member of the study personnel or of their immediate families, or is a subordinate 
(or immediate family member of a subordinate) to any of the study personnel. 
3. Is a female subject who is pregnant, lactating and/or sexually active and not agreeing 
to use one of the acceptable contraceptive methods throughout the study. 
4. Has history of severe drug allergy or hypersensitivity, or known hypersensitivity, to 
the study medication (SPN-812). 
5. Has history of moderate or severe head trauma or other neurological disorder or 
systemic medical disease that, in the Investigator's opinion, is likely to affect central 
nervous system functioning. This would include subjects with: 
a. a current diagnosis of a major neurological disorder;   
b. seizures, seizure disorder or seizure-like events;  
c. history of seizure disorder within the immediate family (siblings, parents); or 
d. encephalopathy 


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Note: Febrile seizures are not exclusionary and will be assessed on a case-by-case 
basis. If for any reason the subject received medication for a febrile seizure or has a 
history of complex febrile seizures, this will be exclusionary.   
6. Has current diagnosis or history of major psychiatric disorders or intellectual 
disabilities other than ADHD per DSM-5 criteria (including schizophrenia, 
schizoaffective disorder, bipolar disorder, borderline personality disorder, antisocial 
personality disorder, narcissistic personality disorder, post-traumatic stress disorder, 
obsessive-compulsive disorder, severe oppositional defiant disorder, conduct 
disorder, disruptive mood dysregulation disorder (DMDD), and autism spectrum 
disorders). The following is not exclusionary:  
a. a history of mild social anxiety disorder or generalized anxiety disorder 
according to DSM-5 criteria; 
b. a history of mild to moderate ODD according to DSM-5 criteria;  
c. a history of Major Depressive Disorder, if he/she has not experienced a major 
depressive disorder episode or required psychiatric counselling; or 
pharmacotherapy within the 6 months prior to screening 
7. Has a known history of physical, sexual, or emotional abuse in the last year prior to 
screening. 
8. Has any other disorder for which its treatment takes priority over treatment of ADHD 
or is likely to interfere with study treatment, impair treatment compliance, or interfere 
with interpretation of study results. 
9. Has a current diagnosis of drug abuse or dependence disorder within the 12 months 
prior to screening, has a history of drug abuse or dependence disorder or has an 
immediate family member living at study participant's' home who has current 
diagnosis drug abuse or dependence disorder (per DSM-5 criteria). 
10. Evidence of suicidality (defined as either active suicidal plan/intent or active suicidal 
thoughts, or more than one lifetime suicide attempt) within the six months before 
Screening or at Screening.  
11. Has positive findings on C-SSRS for suicidal ideation or behaviors at screening. Has 
attempted suicide within the 6 months prior to screening, or is at significant risk of 
suicide, either in the opinion of the Investigator or defined as a "yes" to suicidal 
ideation questions 4 or 5 or answering "yes" to suicidal behavior on the C-SSRS 
within the 6 months prior to screening. 
12. Is currently using, or has a positive result on the urine drug screening for, drugs of 
abuse (alcohol, amphetamine, barbiturates, benzodiazepines, cannabis [THC], 
cocaine, cotinine, methadone, methamphetamine [including ecstasy], 
methylphenidate, phencyclidine, propoxyphene, and opiates) with the exception of 
the psychostimulant stimulant prescribed for the treatment of ADHD.  
13. Is unable to discontinue all prohibited medication at least 7 days prior to baseline. 


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14. Has body mass index (BMI) greater than 95th percentile for her/his appropriate age 
and gender (per CDC’s gender specific “BMI-for-age percentiles” charts). 
15. Has a current diagnosis of significant systemic disease. 
16. Has uncontrolled thyroid disorder defined as thyroid stimulating hormone ≤ 0.8 x the 
lower limit of normal or ≥ 1.25 x the upper limit of normal for the reference laboratory 
range. 
17. Has resting (sitting) blood pressure and pulse rate greater than the 95th percentile 
for age and gender. 
18. Has a known personal history, or presence, of structural cardiac abnormalities, 
cardiovascular or cerebrovascular disease, serious heart rhythm abnormalities, 
syncope, tachycardia, cardiac conduction problems (e.g., clinically significant heart 
block or QT interval prolongation: QTc >0.44 seconds), exercise-related cardiac 
events including syncope and pre-syncope, or clinically significant bradycardia. 
19. Has any clinically significant abnormal clinical laboratory test, urine test, 
electrocardiogram (ECG) result, vital signs or physical examination finding at 
screening that, in the opinion of the Investigator, would interfere with the safety of the 
subject (see Note below). 
20. Has a concurrent chronic or acute illness (such as severe allergic rhinitis or an 
infectious process requiring antibiotics), disability, or other condition that might 
confound the results of safety assessments. 
21. Has or has had one or more medical conditions considered clinically 
significant/relevant by the Investigator in the context of the study (e.g., 
cardiovascular disease, congestive heart failure, cardiac hypertrophy, arrhythmia, 
bradycardia [pulse < 70 bpm (6-11 years), pulse < 60 bpm (12-17 years)], 
tachycardia [pulse > 120 bpm (6-11 years); pulse > 100 bpm (12-17 years)], 
respiratory disease, hepatic impairment or renal insufficiency, metabolic disorder, 
endocrine disorder, gastrointestinal disorder, hematological disorder, infectious 
disorder, any clinically significant immunological condition, dermatological disorder. 
22. Has any disease or medication that could, in the Investigator's opinion, interfere with 
the assessments of safety, tolerability, or efficacy, or interfere with study conduct or 
interpretation of results. 
23. Lost or donated more than 450 mL of blood during the 30 days prior to screening. 
24. Use of any investigational drug or prohibited concomitant medications including 
known CYP1A2 substrates (e.g., theophylline, melatonin) within 28 days or 5 half-
lives prior to Baseline Visit (Day 1) (whichever is longer) or anticipated for the 
duration of the study. 
25. History of unexplained loss of consciousness, unexplained syncope, unexplained 
irregular heartbeats or palpitations or near drowning with hospital admission. 


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26. Has an allergy to applesauce and cannot swallow capsules whole. 
27. In the Investigator's opinion, is unlikely to comply with the protocol or is unsuitable for 
any other reason.  
Note: Repeat testing for clinical laboratory tests, vital signs, and ECG parameters is 
permitted one time for each test during screening period, at the discretion of the 
Investigator, as long as the repeat test result is available within the 28-day screening 
period to determine eligibility. 
3.4 
Completion of Study and Discontinuation of Subjects 
Subjects will be considered to have completed the study if they complete all visits up to 
and including Visit 10. Subjects who dose SPN-812, but who withdraw or are withdrawn 
from participation in the study by the Investigator before he/she finishes the study (i.e., 
after Visit 2 but prior to Visit 10), should complete an early termination (ET) visit. 
Procedures listed for Visit 10 should be completed at the ET visit. 
All reasons for screening failure will be recorded. If the subject passes screening but 
fails eligibility at Visit 2 (Baseline), the reason(s) will also be recorded. 
The Investigator(s) or subjects themselves may stop SPN-812 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 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 Clinical Research Associate (CRA) before the 
subject stops SPN-812 treatment. Subjects removed from the study for any reason will 
not be replaced. 
Reasons for subject’s early discontinuation may include: 
• 
Withdrawal of consent (parent/guardian) 
• 
Withdrawal of assent (subject) 
• 
Inclusion/Exclusion criteria 
• 
Noncompliance  
• 
Lack of Efficacy 
• 
Occurrence of unmanageable AEs 
• 
Lost to follow-up 
• 
Other 
The primary reason for subject’s early discontinuation must be recorded in the subject’s 
medical record and on the electronic case report form (eCRF). If subject withdraws 
assent or parent withdraws consent, the specific reason for withdrawal (e.g., 
relocating/moving [change of residence/address], personal time constraint(s) [e.g., 
changes in social/family/employment/health changes], loss of Interest, etc.] should be 
captured.  
 


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4 
STUDY TREATMENT 
4.1 
Study Medication Identity, Packaging and Labeling 
Study medication (SPN-812) are capsules supplied in labeled bottles by the Sponsor. 
Each bottle of SM will include capsules that contain either 100 mg or 200 mg of 
SPN-812 in 90-count bottles. Each bottle will be labeled with the protocol number, at a 
minimum. 
4.2 
Study Medication Administration 
Study medication (SPN-812) will be administered orally once daily (QD), with or without 
food, as an intact capsule or by sprinkling the content of the capsule on one tablespoon 
of applesauce followed by drinking water after having ingested the SM/applesauce mix. 
The subject’s parent/guardian will record a daily diary (e.g., paper or electronic source) 
to capture daily SPN-812 dose information, including total daily dose (mg), dosing 
date/time (MM/DD/YYYY, 00:00 AM/PM), administration method [e.g., subject swallowed 
total daily dose as intact capsule(s) or subject swallowed total daily dose as a 
SM/applesauce mix] and reason why no SPN-812 dose was taken or why a partial SPN-
812 dose was taken, if applicable.  
4.2.1 AM Dosing; Weeks 1-4 of Treatment Period 
Subject will take daily SPN-812 dose in the MORNING (AM) hours during Weeks 1-4 of 
the Treatment period. Splitting the daily dose (e.g., taking part of the daily dose in the 
morning and the remainder of the daily dose in the evening) is not permitted.  A daily 
diary (e.g., paper or electronic source) will be used to confirm whether subject takes 
SPN-812 dose in the morning each day during the first 4 weeks of treatment; if it is 
discovered that subject has been taking daily SPN-812 dose much later in the day than 
expected/planned (e.g., evening) without prior Site Investigator or Sponsor approval, the 
medical monitor and sponsor must be informed immediately. Subject will take first AM 
dose of SPN-812 at Visit 2 and last AM dose of SPN-812 the morning of Visit 6. 
4.2.2 PM Dosing; Weeks 5-8 of Treatment Period 
Subject will take daily SPN-812 dose in the EVENING (PM) hours during Weeks 5-8 of 
the Treatment period. The timing of the PM dose during Weeks 5-8 should occur 
approximately 12 hours (± 60 minutes) after the timing of AM dose during Weeks 1-4 
(e.g., if subject dosed at 7:00AM during Weeks 1-4, they should take SPN-812 dose at 
or around 7:00PM. Splitting the daily dose (e.g., taking part of the daily dose in the 
morning and the remainder of the daily dose in the evening) is not permitted. A daily 
diary (e.g., paper or electronic source) will be used to confirm whether subject takes 
SPN-812 dose in the evening each day during the last 4 weeks of treatment; if it is 
discovered that subject has been taking daily SPN-812 dose much earlier in the day 
than expected/planned (e.g., morning/afternoon) without prior Site Investigator or 
Sponsor approval, the medical monitor and sponsor must be informed immediately. 
Subject will take first PM dose of SPN-812 the night after Visit 6 (e.g., subject will take 
last AM dose morning of Visit 6, Day 29, and then subject will take first PM evening of 
Day 30). Subject will take last PM dose of SPN-812 the night before Visit 10. Subject 
should continue dosing SPN-812 either at planned dose of previous week or at an 




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Such information may be used solely for the purpose of reviewing or performing this study. 
not be limited to: (a) documentation of receipt of clinical supplies, (b) SM inventory log, 
(c) SM accountability log, and (d) all shipping service receipts. Forms may be provided 
by the Sponsor. Any comparable forms that the study site wishes to use must be 
approved by the Sponsor. 
The supplies and inventory records must be made available, upon request, for 
inspection by the designated representative of the Sponsor, or a representative of the 
Food and Drug Administration (FDA). The assigned CRA will review these documents 
along with all other study conduct documents at specified intervals once SM has been 
received by the study site. All used, partly used, and unused clinical supplies, including 
empty containers, are to be returned to the 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. 
4.5 
Blinding 
This is an open-label study. 
4.6 
Concomitant Medications  
At screening, the subject’s prior history of concomitant medication(s) (lifetime) and 
current concomitant medication(s) will be obtained. Subjects must continue taking stable 
dose of psychostimulant medication at least 5 days per week in the morning throughout 
study, including the screening period and 8-week SPN-812 treatment period. Every day 
between Visit 1 and Visit 10, the subject’s parent/guardian will complete a daily 
medication diary (e.g., Paper or electronic) to confirm whether the prescribed 
psychostimulant medication dose was taken in the morning. The total daily dose (mg) of 
subject’s psychostimulant medication cannot be increased during 8-week SPN-812 
treatment, but it may be decreased once. 
Subjects may not be on any prohibited medication as indicated in the inclusion/exclusion 
criteria. SPN-812 is a strong CYP1A2 inhibitor. Substrates with a narrow therapeutic 
window are prohibited during the study. Specific prohibited concomitant medications for 
this study include known CYP1A2 substrates (e.g., theophylline, melatonin). Subjects 
will undergo a washout period of prohibited medication at least 1 week (or 5 half-lives of 
the medication, whichever is longer) before the Baseline Visit (Day 1).  
No concomitant medications are allowed during the study, with the following exceptions: 
• 
Nutritional supplements (e.g., multivitamins, fish oil) (however, herbal 
supplements are prohibited) 
• 
EMLA® or other numbing cream for venipuncture 
• 
Common over-the-counter (OTC) therapies for minor transient ailments (e.g., 
acetaminophen for headache, ibuprofen for fever). 
• 
Over-the-counter, non-sedating allergy medications and antibiotics. 
All concomitant medications will be recorded in the eCRF. 
Caffeine use is not prohibited during the study, however, caffeine intake will be assessed 
at screening, baseline and at all post-baseline study visits and recorded in the eCRF. 


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5 
STUDY METHODS 
5.1 
Study Visits and Procedures 
All subjects who are eligible, enroll and take the initial dose of SPN-812 will be followed 
according to the protocol regardless of the number of doses of SPN-812 taken, unless 
consent for follow-up is withdrawn. The Sponsor or the Sponsor’s designee must be 
notified of all deviations from the protocol visit or procedures, except as noted, and these 
procedures, if applicable, will be rescheduled or performed at the nearest possible time 
to the original schedule. The subject’s parent, legal guardian/representative or caregiver 
will be instructed to call study personnel to report any abnormalities during the intervals 
in between study visits and to come to the study site if medical evaluation is needed and 
as the urgency of the situation indicates. 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. 
The Schedule of Events and Assessments for the study is shown in Table 2.






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5.1.1 Visit 1 – Screening  
The following assessments will be conducted at this visit: 
• 
Informed consent/assent form signed 
• 
Investigator complete MINI-KID to confirm ADHD diagnosis per DSM-5  
• 
Complete social, medical, psychiatric, neurological, and family psychiatric histories 
• 
Demographics 
• 
Smoking, alcohol consumption use/history 
• 
Physical examination and height 
• 
Blood sample for: 
o clinical safety laboratory tests (Hematology/chemistry) 
o confirmatory analyses of psychostimulant and viloxazine and its metabolite 
o Serum Pregnancy Test (FOCP only) 
• 
Urine sample for: 
o ‘Standard’ Urine drug screen (Table 3) 
o POC Urine Drug Screen Test 2 and Test 3 only (Table 3) 
o Urinalysis 
• 
Measure/record vital signs and weight 
• 
Perform 12-lead ECG 
• 
Investigator complete the IR-ADHD-RS-5 and CGI-S 
• 
C-SSRS (age-appropriate “Children’s Baseline/Screening’ or ‘Baseline’ version) 
• 
Review eligibility criteria 
• 
Review concomitant medications and caffeine intake 
• 
Provide parent/guardian with paper or electronic PR-ADHD-RS-5 and psychostimulant 
dosing diary and instruct them on how to complete  
• 
Remind parent/guardian to stop prohibited medications 7 days prior to next visit.  
5.1.2 Visit 2 – Baseline 
The following assessments will be conducted at this visit: 
• 
Reminder Call 2-3 days prior to visit: Parent should complete the Morning & Evening 
PR-ADHD-RS-5 at home, 1-2 day(s) before Baseline  
• 
Review eligibility criteria 
• 
Blood sample for: 
o clinical safety laboratory tests (Hematology/Chemistry) 
o confirmatory analyses of psychostimulant and viloxazine and its metabolite 
• 
Urine sample for: 
o POC Urine Drug Screens (Test 1, Test 2, and Test 3) 
o Urine Pregnancy Test (FOCP only) 
• 
Measure/record vital signs and weight 
• 
Perform 12-lead ECG 
• 
Administer the SDSC and WPREMB-R 
• 
Investigator complete the IR-ADHD-RS-5 and CGI-S 
• 
C-SSRS; Since Last Visit (if “Children’s” version used at screening, use “Children’s”) 
• 
Review/collect dosing diary and both PR-ADHD-RS-5 (Morning & Evening)     


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• 
Review concomitant medications and caffeine intake 
• 
Review adverse events (events occurring before first SPN-812 dose, recorded as 
medical history; events occurring after first SPN-812 dose record as an AE). 
• 
Instruct parent/guardian on how to record dosing diary for study medication (SPN-812) 
AM daily to V3; remind them to record psychostimulant dosing diary AM daily to V3 
• 
Dispense SM; subject should take first dose of SPN-812 and record 1st dose in diary. 
5.1.3 Visit 3 – Treatment Period  
The following assessments will be conducted at this visit: 
• 
Blood sample for:  
o clinical safety laboratory tests (Hematology/Chemistry) 
o confirmatory analyses of psychostimulant and viloxazine and its metabolite 
• 
Urine sample for:  
o POC Urine Drug Screen (Test 1, Test 2, and Test 3) 
o Urine Pregnancy Test (FOCP only)  
• 
Measure/record vital signs and weight 
• 
Perform 12-lead ECG 
• 
Investigator complete the IR-ADHD-RS-5, CGI-S, and CGI-I 
• 
C-SSRS; Since Last Visit (if “Children’s” version used at screening, use “Children’s”) 
• 
Review concomitant medications and caffeine intake 
• 
Review adverse events 
• 
SM return and accountability 
• 
Dispense SM  
• 
Review/collect dosing diary; remind parent to record dosing diary AM daily to V4 
5.1.4 Visit 4 – Treatment Period 
The following assessments will be conducted at this visit: 
• 
Blood sample for:  
o clinical safety laboratory tests (Hematology/Chemistry) 
o confirmatory analyses of psychostimulant and viloxazine and its metabolite 
• 
Urine sample for: :  
o POC Urine Drug Screen (Test 1, Test 2, and Test 3) 
o Urine Pregnancy Test (FOCP only)  
• 
Measure/record vital signs and weight 
• 
Perform 12-lead ECG 
• 
Investigator complete the IR-ADHD-RS-5, CGI-S and CGI-I 
• 
C-SSRS; Since Last Visit (if “Children’s” version used at screening, use “Children’s”) 
• 
Review concomitant medications and caffeine intake 
• 
Review adverse events 
• 
SM return and accountability 
• 
Dispense SM  
• 
Review/collect dosing diary; remind parent to record dosing diary AM daily to V5 


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5.1.5 Visit 5 – Treatment Period 
The following assessments will be conducted at this visit: 
• 
Blood sample for: 
o clinical safety laboratory tests (Hematology/Chemistry) 
o confirmatory analyses of psychostimulant and viloxazine and its metabolite 
• 
Urine sample for:  
o POC Urine Drug Screen (Test 1, Test 2, and Test 3) 
o Urine Pregnancy Test (FOCP only)  
• 
Measure/record vital signs and weight 
• 
Perform 12-lead ECG 
• 
Investigator complete the IR-ADHD-RS-5, CGI-S and CGI-I 
• 
C-SSRS; Since Last Visit (if “Children’s” version used at screening, use “Children’s”) 
• 
Review concomitant medications and caffeine intake 
• 
Review adverse events 
• 
Remind parent/guardian to complete Morning/Evening PR-ADHD-RS-5 before Visit 6 
• 
SM return and accountability 
• 
Dispense SM  
• 
Review/collect dosing diary; remind parent to record dosing diary daily AM to V6  
5.1.6 Visit 6 – Treatment Period 
The following assessments will be conducted at this visit: 
o Reminder Call 2-3 days prior to visit: Parent should complete the Morning & Evening 
PR-ADHD-RS-5 at home, 1-2 day(s) before Visit 6 
• 
Blood sample for:  
o clinical safety laboratory tests (Hematology/Chemistry) 
o confirmatory analyses of psychostimulant and viloxazine and its metabolite 
• 
Urine sample for:  
o POC Urine Drug Screen (Test 1, Test 2, and Test 3) 
o Urine Pregnancy Test (FOCP only)  
• 
Measure/record vital signs and weight 
• 
Perform 12-lead ECG 
• 
Administer SDSC and WPREMB-R 
• 
Investigator complete the IR-ADHD-RS-5, CGI-S, and CGI-I 
• 
C-SSRS; Since Last Visit (if “Children’s” version used at screening, use “Children’s”) 
• 
Review concomitant medications and caffeine intake 
• 
Review adverse events 
• 
SM return and accountability 
• 
Dispense SM  
• 
Review/collect dosing diary and both PR-ADHD-RS-5 (Morning & Evening) 
• 
Remind parent/guardian to start PM dosing next day and record date and time in diary 
(no AM dose tomorrow morning; first PM dose tomorrow night) 
• 
Remind parent to record dosing diary daily until V7 (AM: Psychostimulant; PM: SPN-812) 


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5.1.7 Visit 7 – Treatment Period 
The following assessments will be conducted at this visit: 
• 
Blood sample for:  
o clinical safety laboratory tests (Hematology/Chemistry) 
o confirmatory analyses of psychostimulant and viloxazine and its metabolite 
• 
Urine sample for:  
o POC Urine Drug Screen (Test 1, Test 2, and Test 3) 
o Urine Pregnancy Test (FOCP only)  
• 
Measure/record vital signs and weight 
• 
Perform 12-lead ECG 
• 
Investigator complete the IR-ADHD-RS-5, CGI-S and CGI-I 
• 
C-SSRS; Since Last Visit (if “Children’s” version used at screening, use “Children’s”) 
• 
Review concomitant medications and caffeine intake 
• 
Review adverse events 
• 
SM return and accountability 
• 
Dispense SM  
• 
Review/collect subject’s dosing diary 
• 
Remind parent to record dosing diary daily until V8 (AM: Psychostimulant; PM: SPN-812) 
5.1.8 Visit 8 – Treatment Period 
The following assessments will be conducted at this visit: 
• 
Blood sample for:  
o clinical safety laboratory tests (Hematology/Chemistry) 
o confirmatory analyses of psychostimulant and viloxazine and its metabolite 
• 
Urine sample for:  
o POC Urine Drug Screen (Test 1, Test 2, and Test 3) 
o Urine Pregnancy Test (FOCP only) 
• 
Measure/record vital signs and weight 
• 
Perform 12-lead ECG 
• 
Investigator complete the IR-ADHD-RS-5, CGI-S and CGI-I  
• 
C-SSRS; Since Last Visit (if “Children’s” version used at screening, use “Children’s”) 
• 
Review concomitant medications and caffeine intake 
• 
Review adverse events 
• 
SM return and accountability 
• 
Dispense SM  
• 
Review/collect subject’s dosing diary 
• 
Remind parent to record dosing diary daily until V9 (AM: Psychostimulant; PM: SPN-812) 


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5.1.9 Visit 9 – Treatment Period 
The following assessments will be conducted at this visit: 
• 
Blood sample for:  
o clinical safety laboratory tests (Hematology/Chemistry) 
o confirmatory analyses of psychostimulant and viloxazine and its metabolite 
• 
Urine sample for:  
o POC Urine Drug Screen (Test 1, Test 2, and Test 3) 
o Urine Pregnancy Test (FOCP only) 
• 
Measure/record vital signs and weight 
• 
Perform 12-lead ECG 
• 
Investigator complete the IR-ADHD-RS-5, CGI-S and CGI-I 
• 
C-SSRS; Since Last Visit (if “Children’s” version used at screening, use “Children’s”) 
• 
Review concomitant medications and caffeine intake 
• 
Review adverse events 
• 
Remind parent/guardian to complete Morning/Evening PR-ADHD-RS-5 before Visit 10 
• 
SM return and accountability 
• 
Dispense SM  
• 
Review/collect subject’s dosing diary 
• 
Remind parent to record dosing diary daily until V10 (AM: Psychostimulant; PM: SPN-812) 
5.1.10 Visit 10 – End of Study 
The following assessments will be conducted at this visit: 
• 
Reminder Call 2-3 days prior to visit: Parent should complete the Morning & Evening 
PR-ADHD-RS-5 at home, 1-2 day(s) before Visit 10 
• 
Physical examination and height 
• 
Blood sample for:  
o clinical safety laboratory tests (Hematology/Chemistry) 
o confirmatory analyses of psychostimulant and viloxazine and its metabolite 
• 
Urine sample for:  
o POC Urine Drug Screen (Test 1, Test 2, and Test 3) 
o Urine Pregnancy Test (FOCP only) 
o Urinalysis 
• 
Measure/record vital signs and weight  
• 
Perform 12-lead ECG 
• 
Administer SDSC and WPREMB-R  
• 
Investigator complete the IR-ADHD-RS-5, CGI-S, and CGI-I 
• 
C-SSRS (age-appropriate ‘Since Last Visit’ version) 
• 
Review concomitant medications and caffeine intake 
• 
Review adverse events 
• 
SM return and accountability 
• 
Review/collect dosing diary and both PR-ADHD-RS-5 (Morning & Evening) 


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5.1.11 Follow-up Phone Call (FPC) 
Subjects will be contacted via telephone 1 week after EOS (or last dose of SPN-812) for the 
following assessments: 
• 
Review AEs 
• 
Review concomitant medications and caffeine intake 
For subjects who discontinue/terminate early (ET Visit), EOS assessments will be performed at 
the ET Visit; however, efficacy assessments (IR-ADHD-RS-5, CGI-S, CGI-I, SDSC and 
WPREMB-R) should not be performed/collected if the ET Visit occurs > 7 days after the date of 
the subject’s last dose of SM. 
5.1.12 Unscheduled Visits 
At the discretion of the investigator throughout the study, unscheduled visits may be conducted 
to perform or repeat assessments, including 12-lead ECG, measure vital signs (including 
orthostatic blood pressure/pulse rate, respiratory rate, and temperature) and weight, draw blood 
sample for hematology and/or serum chemistry and/or urine drug screen, administer age-
appropriate C-SSRS (“Since Last Visit”; if “Children’s” version used at screening, use 
“Children’s”), perform physical examination or efficacy assessments. AEs, concomitant 
medications, and caffeine intake should also be assessed at all unscheduled visits. SM may 
also be dispensed and/or returned at unscheduled visits, if needed. 
 
 


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6 
STUDY VARIABLES AND ASSESSMENTS 
6.1 
Efficacy Assessments 
6.1.1 ADHD Rating Scale-5 (ADHD-RS-5)  
The ADHD Rating Scale has been one of the most commonly used measures of drug efficacy in 
the treatment of ADHD in children, adolescents and adults. The ADHD-RS-5 is an ADHD-
specific rating scale designed and validated to assess current ADHD symptomatology as 
described in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-
5).  The scale consists of 18 items that directly correspond to the 18 DSM-5 symptoms and are 
further subdivided into two subscales: Hyperactivity/Impulsivity (9 items) and Inattention (9-
items) (DuPaul et al., 1998a; DuPaul et al., 1998b; DuPaul, 2016). The ADHD-RS-5 scale rates 
the frequency and severity of each symptom on a 4-point Likert-type scale from 0 (none) to 3 
(severe) and allows assessment of functional impairments linked to each symptom dimension.  
The ADHD-RS-5 rating scale is one of the most commonly used measures of drug efficacy in 
the treatment of ADHD and is a secondary outcome measure for this study.   
6.1.1.1 Investigator-Rated ADHD-RS-5 (IR-ADHD-RS-5) 
The ADHD-RS-5 Home Version will be administered and scored by a trained investigator (IR-
ADHD-RS-5) at each weekly visit from Screening through EOS. The IR-ADHD-RS-5 Home 
Version: Child (Appendix 11.1.1.1) will be administered to subjects who are 6 to 11 years of 
age. The IR-ADHD-RS-5 Home Version: Adolescent (Appendix 11.1.1.2) will be administered 
to subjects who are 12 years of age and older. If an 11-year-old subject turns 12 years of age 
after screening, continue to administer the IR-ADHD-RS-5 Home Version: Child throughout the 
trial, regardless. 
6.1.1.2 Parent-Rated ADHD-RS-5 (PR-ADHD-RS-5) 
In addition, 1-2 days prior to Study Visits 2, 6, and 10 the subject’s parent/guardian will 
complete two PR-ADHD-RS-5, one in the morning and another in the evening, as follows:  
Morning Assessment: Parent will rate their child’s behavior based upon interactions with their 
child during the morning hours in the past week. If the subject is 6 to 11 years of age, parent 
will use the ‘Morning’ PR-ADHD-RS-5 Home Version: Child (Appendix 11.1.2.1). If the subject 
is 12 years of age and older, parent will use the ‘Morning’ PR-ADHD-RS-5 Home Version: 
Adolescent (Appendix 11.1.2.2). If an 11-year-old subject turns 12 years of age after screening, 
continue to administer the ‘Morning’ PR-ADHD-RS-5 Home Version: Child throughout the trial, 
regardless. This can be completed on electronically diary or paper version. 
Evening Assessment: Parent will then rate their child’s behavior based upon interactions with 
their child during the evening hours in the past week. If the subject is 6 to 11 years of age, 
parent will use the ‘Evening’ PR-ADHD-RS-5 Home Version: Child (Appendix 11.1.3.1). If the 
subject is 12 years of age and older, parent will use the ‘Evening’ PR-ADHD-RS-5 Home 
Version: Adolescent (Appendix 11.1.3.2). If an 11-year-old subject turns 12 years of age after 
screening, continue to administer the ‘Evening’ PR-ADHD-RS-5 Home Version: Child 
throughout the trial, regardless. This can be completed on electronic diary or paper version. 


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6.1.2 Clinical Global Impression – Severity of Illness Scale (CGI-S)  
The Clinical Global Impression scale was developed to provide a brief, stand-alone assessment 
of the clinician’s view of a subject’s global functioning prior to and after administration of SM 
(Guy, 1976; Appendix 11.2). The CGI-S is a single item clinician rating of clinician’s assessment 
of the severity of the ADHD symptoms in relation to the clinician’s total experience with patients 
with ADHD. The CGI-S is evaluated on a 7-point scale with 1 = Normal, not at all ill, 2 = 
Borderline Ill, 3 = Mildly Ill, 4 = Moderately Ill, 5 = Markedly Ill, 6 = Severely Ill, and 
7 = Extremely Ill. Successful therapy is indicated by a lower overall score in subsequent testing. 
6.1.3 Clinical Global Impression – Improvement Scale (CGI-I)  
The Clinical Global Impression scale was developed to provide a brief, stand-alone assessment 
of the clinician’s view of a subject’s global functioning prior to and after administration of SM 
(Guy, 1976; Appendix 11.3). The CGI-I is an assessment of how much the patient’s illness has 
improved or worsened relative to a baseline state at the beginning of treatment. The CGI-I is 
evaluated 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. 
Successful therapy is indicated by a lower overall score in subsequent testing.  
6.1.4 Sleep Disturbance Scale for Children (SDSC) 
The Sleep Disturbance Scale for Children (SDSC) is an instrument originally developed and 
validated as a parent-report measure to screen for sleep disturbances in children and adolescents 
6-15 years of age (Bruni et al., 1996; Appendix 11.4). It has since been validated in broader 
pediatric populations, 5-18 years of age (Marriner et al., 2017), including in an ADHD population 
(Vincent et al., 2019) The SDSC is a 26-item questionnaire from which six factor/subscale scores 
are generated: (1) disorders of initiating and maintaining sleep, (2) sleep breathing disorders, (3) 
disorders of arousal, (4) sleep-wake transition disorders, (5) disorders of excessive somnolence, 
and (6) sleep hyperhidrosis (or excessive sweating that's not necessarily related to heat or 
exercise). For item 1, the parent indicates the average sleep duration most nights on a 5-point 
Likert scale, where 1=9-11 hours, 2=8-9 hours, 3=7-8 hours, 4=5-7 hours, and 5=less than 5 
hours. For item 2, the parent indicates the average sleep latency (duration of time it takes their 
child to fall asleep after going to bed) on a 5-point Likert scale, where 1=less than 15 minutes, 
2=15-30 minutes, 3=30-45 minutes, 4=45-60 minutes, and 5=more than 60 minutes. Items 
(sleep/sleep-related problems) 3 to 26, the parent rates their child indicating the frequency with 
which their child has experienced any of these sleep/sleep-related problems in the past week; 
ratings are on a 5-point Likert scale (1 to 5), where 1=Never, 2=Occasionally (once or twice per 
month or less), 3=Sometimes (once or twice per week), 4=Often (3 or 5 times per week), and 
5=Always (daily). The sum of scores for these six factors/subscales yields one Total score (score 
ranges from 26 to 130). Raw scores can be converted to T-scores, where a T-score >70 (>95th 
percentile) is indicative of a clinically significant sleep problem. The parent will rate their child for 
each item based on the past week (7 days). It takes 5-10 minutes to complete the SDSC. 
6.1.5 Weekly Parent Rating of Evening and Morning Behavior-Revised (WPREMB-R) 
The Parent Rating of Evening and Morning Behavior-Revised (PREMB-R) is a validated, 11-
item scale validated for assessment of ADHD-related morning and evening behaviors (Sutton et 
al., 2003; Faraone et al., 2018; Appendix 11.5) that assesses at-home functioning (i.e., 


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behaviors that impact activities of daily living, such as getting up and out of bed, doing or 
completing homework, and falling asleep) during the early morning (PREMB-R AM) and late 
afternoon/evening (PREMB-R PM) in children with ADHD (Sutton et al., 2003; Faraone et al. 
2018). It includes surrogate measure of ADHD-related severity of impairment (“Difficult with…”) 
rather than frequency of ADHD symptoms. It primarily focuses on Evening Behaviors, but 
includes assessment of Morning Behaviors (e.g., getting out of bed, getting ready and 
arguing/struggling). PREMB-R has been administered as clinician-rated (by interview) or parent 
rated, and it has been administered for daily (DPREMB-R) or weekly (WPREMB-R) 
assessments (Carlson et al 2007; Faraone et al., 2018; Wehmeier et al. 2009). For this trial, the 
WPREMB-R will be administered as a parent-rated to measure both morning- and evening-
related functional impairment in children and adolescents in past week. Each item is rated from 
0 (no difficulty) to 3 (a lot of difficulty), with the three-item WPREMB-R AM having a maximum 
score of 9, and the eight-item WPREMB-R PM having a maximum score of 24. It takes ~5 
minutes to complete. 
6.2 
Safety Variables and Assessments  
Safety assessments include monitoring, evaluation, and recording of all concomitant 
medications, and the evaluation of AEs, clinical laboratory test results, vital signs and 12-lead 
ECGs, and the performance of physical examinations as detailed in the Schedule of Events and 
Assessments (Table 2). 
Site Investigators are responsible for monitoring the safety of subjects who have entered this 
study and for alerting Supernus or its designee to any event that seems unusual, even if this 
event may be considered an unanticipated benefit to the subjects. 
6.3 
Adverse Events 
As defined by the ICH Guideline for Good Clinical Practice (GCP), an adverse event (AE) is any 
untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
treatment. 
An AE can be: 
• 
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. 


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6.3.1 Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) are defined as seizure or AEs that might represent a 
seizure. This includes, but is not limited to syncope/syncopal episode, pseudoseizure, 
myoclonus, and severe muscle spasms. 
6.3.2 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 drug and the AE, i.e., there is a 
reasonable possibility that the drug caused the adverse event.  
Adverse drug reactions (ADRs) are a subset of all SADRs for which there is reason to conclude 
that the drug caused the event. 
6.3.3 Recording and Evaluation of Adverse Events 
All subjects who are screened (Visit 1) will be questioned regarding the occurrence of AEs, 
which will be documented as medical history. At each contact with the subject, and beginning 
after first dose, the Investigator must seek information on AEs by specific questioning and, as 
appropriate, by examination. Information on all AEs should be recorded immediately in the 
source document, and also in the appropriate adverse event module of the eCRF. All clearly 
related 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 Visit 2 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 is taken, or that worsened following first administration of study medication 
(SPN-812). All AEs in this study will be recorded after administration of SM, therefore all will be 
treatment-emergent. The clinical course of each AE should be followed for at least 30 days 
following the date of last dose of SM (either due to EOS or ET) or until resolution or until, in the 
medical judgment of the Investigator, the event has stabilized or is assessed as chronic. 
The Investigator is responsible for evaluating AEs and determining the following: 
• 
Serious vs. Non-serious: Is the event a Serious Adverse Event (SAE)? 
• 
Causality: Was AE related or possibly related to the SM? 
• 
Severity: How pronounced is the incapacity/discomfort caused by an AE? 
6.3.4 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 


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accumulated intensity of discomfort/impairment of health since the last recording of AEs and will 
be assessed according to the following criteria: 
• 
Mild: 
Awareness of sign, symptom, or event, but easily tolerated 
• 
Moderate: Discomfort enough to interfere with usual activity and may warrant 
intervention 
• 
Severe: 
Incapacitating with inability to do usual activities or significantly affects 
clinical status and warrants intervention 
The criteria for assessing severity are different from those used for seriousness. 
6.3.5 Criteria for Assessing Causality 
The Investigator is responsible for determining the relationship between the administration of 
SM and the occurrence of an AE as not suspected or as a suspected reaction to SM. These are 
defined as follows: 
Not suspected: The temporal relationship of the AE to SM administration makes a causal 
relationship unlikely, or other drugs, therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event.  
• Not related: Temporal relationship to SM administration is missing or implausible, or 
there is an evident other cause. 
• Unlikely related: Temporal relationship to SM administration makes a causal 
relationship improbable; and other drugs, chemicals, or underlying disease provide 
plausible explanations. 
Suspected: The temporal relationship of the AE to SM administration makes a causal 
relationship possible, and other drugs, therapeutic interventions, or underlying conditions do 
not provide a sufficient explanation for the observed event.  
• Possibly related:  Temporal relationship to SM administration is plausible, but 
concurrent disease or other drugs or chemicals could also explain event. Information 
on drug withdrawal may be lacking or unclear. This will be reported as a Suspected 
Adverse Drug Reaction (SADR). 
• Definitely related: Temporal relationship to SM administration is plausible, and 
concurrent disease or other drugs or chemicals cannot explain event. The response 
to withdrawal of the medication (dechallenge) should be clinically plausible. The event 
must be definitive pharmacologically or phenomenologically, using a satisfactory 
rechallenge procedure if necessary. This will be reported as an Adverse Drug 
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6.3.6 Serious Adverse Events 
Adverse events 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 overdose or abuse, blood dyscrasias, a seizure that did not result in 
in-patient hospitalization or intensive treatment for allergic bronchospasm in an emergency 
department would typically be considered serious. 
6.3.7 Investigator Responsibilities for Reporting SAEs/AESIs 
The Site Investigator must immediately report to the Sponsor all SAEs/AESIs, regardless of 
whether the Investigator believes they are drug related. 
All SAEs/AESIs must be reported to the Drug Safety Contact within 24 hours of first becoming 
aware of the SAE/AESIs. The Investigator must complete an SAE/AESIs Form and include a 
detailed description of the SAE, as well as other available information pertinent to the case (e.g., 
hospital records, autopsy reports and other relevant documents). The investigator will keep a 
copy of this SAE/AESIs Report form on file at the study site. 
The Site 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/AESIs Report 
Form.  
The Drug Safety Contact for SAE/AESI reporting is: 
 
 
 
6.3.8 Other Events Requiring Immediate Reporting 
Acute suicidal crisis or clinically significant suicidal behavior or ideation should be reported to 
the Drug Safety Contact within 24 hours of first becoming aware of the event. Pregnancy should 
also be reported to the Sponsor’s Drug Safety Contact within 24 hours of confirmation. 


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6.3.9 Sponsor Responsibilities for Reporting SAEs 
The Sponsor will inform Site Investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (i.e., within specific 
timeframes). For this reason, it is imperative that study sites submit SAE information to the 
Sponsor in the manner described above. 
Site Investigators must comply with the applicable regulatory requirements related to the 
reporting of SAEs to the Institutional Review Board (IRB). Investigators must also submit the 
safety information provided by the Sponsor to the IRB unless the country legal regulation 
requires that the Sponsor should be responsible for the safety reporting to the IRB. 
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. 
6.4 
Treatment-Emergent Suicidal Ideation 
Prospective assessment of suicidal ideation and suicidal behavior is a mandatory part of the 
safety evaluations for any drug developed for a psychiatric indication (FDA Guidance for 
Industry: Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical 
Trials, 2012). In this study, the initial evaluation of subjects will be conducted prior to enrollment 
to assess lifetime suicidal ideation and to identify subjects who must not participate in the trial 
due to pre-existing suicidality risk. The assessment will then be repeated at each subsequent 
study visit to monitor the occurrence of new suicidal and self-injurious tendencies. 
6.4.1 Columbia Suicide Severity Rating Scale (C-SSRS) 
Assessment of suicidal ideation and behavior will be conducted using the C-SSRS. The 
C-SSRS is an FDA-recommended prospective assessment instrument that directly classifies 
suicidal ideation and behavior events into 11 preferred categories, including 5 levels of suicidal 
ideation, 5 levels of suicidal behavior, and the category of self-injurious behaviors with no 
suicidal intent. The instrument has been validated and used successfully in both children and 
adolescent patients with various psychiatric disorders that do not involve cognitive impairment.  
The C-SSRS outcomes that can be used for clinical management and safety monitoring are 
suicidal lethality rating, suicidal ideation score, and suicidal ideation intensity rating. 
For subjects who are 6 to 11 years of age, use the:  
a. Children’s “Baseline/Screening” version at Study Visit 1/Screening (Appendix 11.6.1) 
b. Children’s “Since Last Visit” version at Study Visits 2-10 (Appendix 11.6.2)  
NOTE: If child is 11 yrs old at screening, please use the Children’s “Since Last Visit” 
version throughout their study, even at visits occurring on or after their 12th birthday. 
For subjects who are 12 years of age and older, use the: 
a. “Baseline” version at Study Visit 1/Screening (Appendix 11.7.1) 
b. “Since Last Visit” version at Study Visits 2-10 (Appendix 11.7.2). 


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6.4.2 Suicide Risk Management Plan 
The protocol procedures related to clinical care of patients with treatment-emergent suicidal 
ideation and behavior must be implemented to ensure proper management of the event and 
protection of subject’s safety. If a disclosure of suicidal ideation is revealed as part of the 
C-SSRS questionnaire or when a subject spontaneously expresses that he/she may be a threat 
to him/herself, the study team should be prepared to quickly evaluate the event and to 
determine the appropriate course of action. 
6.4.2.1 Assessment of Suicide Risk 
Any indication of suicidal ideation should be evaluated as soon as possible by appropriately 
trained staff. The Investigator is responsible for making the final judgment regarding potential 
suicide risk and need subsequent action.  
6.4.2.2 Acute Suicidal Crisis 
A person evaluated as being at high risk should be transferred to an immediate care facility. The 
Investigator will guide intervention as clinically indicated and follow up with the subject within 1 
week and/or refer him/her to a qualified mental health professional. 
6.4.2.3 Non-acute Suicidal Risk 
The Investigator will conduct safety planning with the subject and will follow up within 1 week. 
Reference materials for subjects and caregivers should include lists of mental health 
organizations and professionals, outpatient behavioral services, local crisis and peer support 
groups and Suicide/Crisis Hotlines. 
6.5 
Clinical Measurements 
6.5.1 Physical Examinations and Height 
Physical examinations and measurement of height will be obtained at the time points shown in 
the Schedule of Events and Assessments (Table 2). The physical examination conducted at 
Screening will include assessments of all body systems, except genitourinary. Any findings 
during screening will be recorded as medical history and any clinically significant abnormal 
findings during treatment will be recorded as an AE. At the EOS physical examination, only 
changes from baseline (Screening Visit) will be noted.  
6.5.2 Vital Signs and Weight 
Vital signs measurements (e.g., orthostatic blood pressure/pulse rate, oral temperature, and 
respiratory rate) and body weight will be obtained at every study visit as shown in the Schedule 
of Events and Assessments (Table 2). Orthostatic blood pressure and pulse rate will be 
measured after the subject has been sitting for at least 5 minutes and again within 3 minutes of 
subject standing. Vital signs may be taken at any other time, as deemed necessary by the 
Investigator, but must be measured as described above. 




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6.5.4 Electrocardiograms (ECGs) 
A 12-lead ECG will be obtained at every study visits as shown in the Schedule of Events and 
Assessments (Table 2). 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 for at least 
10 minutes. 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 interval corrected 
using Fridericia's method). 
6.6 
Confirmatory Blood Sample Assessment 
An additional confirmatory blood sample will be collected at each study visit (1-10) to assess 
concentrations of psychostimulant and viloxazine and its metabolite. Confirmatory blood 
samples for measurement of plasma concentrations of viloxazine (and 5-hydroxy-viloxazine 
glucuronide, if applicable) and of psychostimulant will be collected at any time during the Visit, 
shown in the Schedule of Events and Assessments (Table 2).  
6.7 
Screening Scales and Assessment Tools 
6.7.1 Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI-
KID)  
The Mini-International Neuropsychiatric Interview for Children and Adolescents is a semi-
structured interview designed to determine early diagnosis of affective childhood mental 
disorders and/or current and past episodes of psychopathology in children and adolescents 6 to 
18 years of age according to DSM-5 criteria (Sheehan et al., 2010; APA, 2013; Duncan et al., 
2018; Appendix 11.8). 
 
 


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7 
STATISTICAL METHODS 
7.1 
General Considerations 
All statistical analysis will be performed using SAS version 9.2 or higher either by Supernus or a 
designated CRO.  
All tabulations of analysis results will include summaries for treatment arms of SPN-812 100 mg 
and placebo. 
Where appropriate, variables will be summarized descriptively: frequency count and percentage 
for categorical variables; and number of subjects (n), mean, standard deviation (SD), median, 
minimum, and maximum for continuous variables.  
Categorical variables will be analyzed using categorical response methods such as Pearson’s 
Chi-square test. If expected frequencies are too small for asymptotic assumptions, exact testing 
techniques will be used. 
The data summaries will be accompanied by individual subject data listings, as specified in 
Sections 16.2 and 16.4 of ICH Guidance E3, sorted by unique subject identifier. All data 
available from the eCRFs will be listed. Unscheduled measurements will be excluded from the 
descriptive statistics and statistical analysis but will be included in listings. 
Baseline is defined as the last non-missing assessment recorded before receiving the first dose 
of study medication. 
Complete details of the statistical analysis will be provided in a separate statistical analysis plan 
(SAP). The statistical analysis methods described in the SAP will supersede the statistical 
methods described in this protocol. 
7.2 
Handling of Missing Data 
Missing dates for occurrence of adverse events and non-study medication use will be imputed. 
The details will be presented in the SAP. 
7.3 
Analysis Populations 
The Enrolled Population consists of all subjects who have signed Informed Consent/Assent 
and have fulfilled all Inclusion/Exclusion Criteria. 
The Safety Population consists of all subjects who enrolled in the study and receive at least 
one dose of SM. Subjects in the Safety Population may be analyzed according to the 
psychostimulant treatment that they received. The Safety population will be used for all safety 
and efficacy variables. 
7.4 
Demographics and Baseline Analysis 
Demographic/baseline variables [including age, sex, ethnicity, race, height and weight, and BMI 
at screening, baseline IR-ADHD-RS-5 scores (Total score, Inattention subscale score, 
Hyperactivity/Impulsivity subscale score), the “Morning” PR-ADHD-RS-5 scores (Total score, 


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Inattention subscale score, “Hyperactivity/Impulsivity subscale score), the “Evening” 
PR-ADHD-RS-5 scores (Total score, Inattention subscale score, Hyperactivity/Impulsivity 
subscale score), CGI-S score, SDSC total score and subscale scores, and WPREMB-R total 
score and morning/evening scores] will be summarized using descriptive statistics for 
continuous variables and using counts and percentages for categorical variables. The 
descriptive summary will be presented by optimized dose group for Safety Population.  
7.5 
Subject Disposition 
A disposition of subjects will include the number and percentage of subjects in each of the 
following categories: 
• 
Subjects in the Enrolled Population 
• 
Subjects in the Safety Population 
Within each of the previous categories, the number and percentage of subjects who completed 
and discontinued from the study and primary reason for early discontinuation will be 
summarized.  
The reason for early discontinuation may include any of the following: 
• 
Withdrawal of consent  
• 
Noncompliance 
• 
Occurrence of unmanageable AEs 
• 
Lost to follow-up 
• 
Other 
7.6 
Study Medication Exposure and Compliance 
Duration of exposure is defined as the total number of days a subject is exposed to SM. This will 
be calculated for each subject by taking the difference between the date of last dose minus the 
date of the first dose, plus 1 (date of last dose minus date of first dose +1) and multiply that by 
the number of capsules that the subject was instructed to take daily during the treatment period 
(i.e, between visits) for total daily dose planned dose (‘X’).  
Duration of treatment exposure will be summarized by duration category and will also be 
summarized using descriptive statistics (n, mean, SD, median, minimum, and maximum). 
Percent of SM compliance is defined as {(number of capsules dispensed minus number of 
capsules returned) / X × (date of last dose minus date of first dose + 1)}* 100%.  
For subjects 6 to 11 years of age, ‘X’ may be equal to: 
o 1 (1 × 100mg); or  
o 2 (2 × 100mg); or  
o 3 (3 × 100mg); or 
o 4 (4 × 100mg) 
For subjects 12 to 17 years of age, ‘X’ may be equal to:  
o 1 (1 × 100mg) or (1 × 200mg); or 
o 2 (2 × 200mg) or ([1 × 200mg] + [1 × 100mg]); or 
o 3 (3 × 200mg) or ([2 × 200mg] + [1 × 100mg]) 


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% 𝑆𝑀 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒= 100 x [(no. of capsules dispensed) −(no. of capsules returned) 
X × [(date of last dose) −(date of first dose) + 1]
] 
For each treatment, SM compliance will be summarized by compliance category (<80%, 80-
120%, and >120%) and number of subjects in each compliance category. Study medication 
compliance will also be summarized as a continuous variable using descriptive statistics (n, 
mean, SD, median, minimum, and maximum) for each treatment. 
7.7 
Concomitant Medications 
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary (WHO-DD) drug codes. Concomitant medications will be further coded to the 
appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating therapeutic classification. 
A tabular summary of concomitant medications by drug class will be presented for the Safety 
Population. 
7.8 
Primary Analysis 
All primary and secondary analyses will be based on the Safety Population. 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. Suicidal ideation and suicidal behavior will be measured by C-SSRS. 
All summary tables related to safety analyses will use the safety population. 
7.8.1 Primary Safety Analysis 
Safety analyses will be performed by optimized dose group based on the Safety Population.  
The incidence rate of AEs will be calculated by treatment arm for each System Organ Class 
(SOC) and Preferred Term (PT). The severity of the AEs and the relationship to SM will be 
summarized by treatment arm for each SOC and PT. 
AEs will be summarized using discrete summaries at the subject and event level by SOC and 
PT, and by severity and relationship separately for each treatment arm. Verbatim description 
and Medical Dictionary for Regulatory Activities (MedDRA) SOCs and PTs for all AEs will be 
contained in the subject data listings. 
Clinical laboratory values will be summarized by visit by treatment arm using descriptive 
statistics. For quantitative laboratory parameters, both actual values and change from Screening 
values will be summarized. 
Vital signs will be summarized by visit by treatment arm using descriptive statistics. Both actual 
values and CFB will be summarized. 
ECG results will be summarized by visit by treatment arm using descriptive statistics (for 
quantitative ECG parameters) and frequency tables (for qualitative ECG parameters, including 
the overall ECG finding). 


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7.8.2 Adverse Events 
AEs will be classified into standardized medical terminology from the verbatim description 
(Investigator term) using the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be 
summarized using discrete summaries at the subject and event level by system organ class and 
preferred term for each group of doses. Similarly, treatment-emergent AEs will be summarized 
by severity and relationship separately. Verbatim description and all MedDRA level terms, 
including the lower level terms, for all AEs will be contained in the subject data listings. 
All AEs occurring throughout the study period will be recorded. Treatment-emergent AEs 
(TEAEs) will be collected starting after the first dose of 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, if applicable, of optimized 
dose (100, 200, 300, 400, 500 or 600 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. 
7.8.3 Clinical Laboratory Values 
Clinical laboratory values for hematology and chemistry will be summarized by visit and by 
group of optimized dose (100, 200, 300, 400, 500, 600 mg/day) received using descriptive 
statistics.  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.  
7.8.4 Vital Signs, Height, Weight and BMI  
Vital signs will be summarized by the group, if applicable, of the optimized doses (100, 200, 
300, 400, 500, 600 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 signs’ data, height, weight, and BMI will be evaluated.  
7.8.5 Electrocardiogram (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 by group 
of the optimized doses (100, 200, 300, 400, 500, 600 mg/day).  The QT will be corrected using 
Fridericia’s method. 
ECG results will be summarized by visit and by group, if applicable, of optimized doses using 
descriptive statistics (for quantitative ECG parameters) and frequency tables (for qualitative 


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ECG parameters, including the overall ECG finding).  For quantitative ECG parameters, both 
actual values and change from Baseline values will be summarized  
7.8.6 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 Anatomical-Therapeutic-Chemical (ATC) code indicating therapeutic classification.  
A tabular summary of concomitant medications by drug class will be presented  
7.8.7 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 “Non-suicidal Self-injurious Behaviors” category will be captured separately. The summary 
will be presented by group of optimized dose (100, 200, 300, 400, 500, 600 mg/day) the subject 
received and if applicable by visit. 
7.9 
Efficacy Analysis 
Where applicable, each of the efficacy assessments/scales variable (IR-ADHD-RS-5, CGI-S, 
CGI-I, ‘Morning’ and ‘Evening’ PR-ADHD-RS-5, SDSC, and WPREMB-R) will be listed and 
summarized by group, if applicable, of optimized dose.  Total score for the ADHD-RS-5, as well 
as the Hyperactivity/Impulsivity and Inattention subscale score, will be summarized by optimized 
dose and visit and will be examined for trends. 
7.10 Sample Size and Power Considerations 
There is no consideration for power or sample size determination in this open-label study. There 
are approximately 50 subjects expected to complete this study. Based on an early 
discontinuation rate of 20%, approximately 60 subjects would need to be enrolled. Based on a 
screen failure rate of 40%, approximately 100 subjects will be screened to enroll approximately 
60 subjects. 
7.11 Interim Analysis 
No interim analysis will be performed. 
7.12 Pharmacokinetic Analyses 
No pharmacokinetic analyses other than summary statistics of plasma concentrations of 
psychostimulant (methylphenidate and amphetamine) and viloxazine and its metabolite 
obtained from confirmatory blood sampling (Section 6.6). 
 
 


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8 
DOCUMENTATION 
8.1 
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. 
8.2 
Changes to the Protocol 
Changes to the protocol will not be made without written approval from the Sponsor. 
Any change to the protocol requires a written protocol amendment or administrative change that 
must be approved by the Sponsor before implementation. Amendments specifically affecting the 
safety of subjects, the scope of the investigation, or the scientific quality of the study require 
additional approval by the applicable IRB, and in some cases, filings to 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 or CRO will send a letter to the IRB detailing such changes. 
8.3 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures (SOPs), working practice documents, and applicable regulations and 
guidelines. Site visit audits may be made periodically by the Sponsor’s Quality Assurance team 
or qualified designee, which is an independent function from the study conduct team. 
8.3.1 Data Collection 
The primary source document will be the subject’s medical record. If separate research records 
are maintained by the Investigator(s), both the medical record and the research record will be 
considered the source documents for the purposes of monitoring and auditing the study. 
Electronic data collection techniques will be used to collect data directly from the study sites 
using eCRFs. The electronic data will be stored centrally in a fully validated clinical database. 


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Data recorded on source documents will be transcribed into the eCRFs in accordance with the 
eCRF completion instructions that are provided to the study sites. The Investigator is 
responsible for ensuring that all sections of each eCRF are completed correctly, and that entries 
can be verified against source documents. The eCRFs will be monitored for completeness and 
accuracy against the source documents by the CRA(s) on a regular basis. Inconsistencies 
between the eCRFs and source documents will be resolved in accordance with the principles of 
GCP. 
8.3.2 Clinical Data Management 
Data from eCRFs and other external data (e.g., laboratory data) will be entered into or merged 
with a clinical database as specified in the data management plan. Quality control and data 
validation procedures will be applied to ensure the validity and accuracy of the clinical database.  
8.3.3 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. The procedure for handling missing data will be addressed in the Statistical 
Analysis Plan (SAP). 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.  
8.3.4 Bioanalytical Sample Handling 
The concentrations of amphetamine, methylphenidate, viloxazine and 5-HVLX-gluc in plasma 
will be determined using validated achiral chromatographic tandem mass spectrometry 
methods. The analytical range for plasma concentrations are reported as free base. Details on 
the analytical methodology, the method of validation, and the analytical within-study quality 
control procedures may be included in the clinical study report. Bioanalytical sample analysis 
may be performed by the Bioanalytical group at Supernus Pharmaceuticals (Rockville, MD). 
8.4 
Retention of Records 
The Investigator has the responsibility to retain all study “essential documents”, as described in 
ICH E6 for at least two years after approval of a marketing application or after formal 
discontinuation of the clinical program. Essential documents include but not limited to the 
protocol, eCRFs, source documents, laboratory test results, SM inventory records, Investigator's 
Brochure, regulatory agency registration documents (e.g., FDA form 1572, ICFs, and IRB 
correspondence). The Investigator must obtain written permission from Supernus prior to the 
destruction of any study document.  
8.5 
Auditing Procedures 
In addition to the routine monitoring procedures, the Sponsor’s Corporate Quality Assurance 
department or qualified designee may conduct audits of clinical research activities in 
accordance with the Sponsor’s written SOPs to evaluate compliance with the principles of ICH 
GCP and all applicable local regulations. A government regulatory authority may also wish to 
conduct an inspection (during the study or after its completion). If an inspection is requested by 


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a regulatory authority, the Investigator must inform the Sponsor and the CRO immediately that 
this request has been made. 
These records must be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the US FDA in accordance with the US 21 
Code of Federal Regulation (CFR) 312.68 or other national or foreign regulatory authorities in 
accordance with regulatory requirements. 
8.6 
Publication of Results 
Any presentation or publication of data collected as a direct or indirect result of this trial will be 
considered as a joint publication by the Investigator(s) and the appropriate personnel at the 
Sponsor’s site. Authorship will be determined by mutual agreement. All manuscripts, abstracts 
or other modes of presentation arising from the results of the study must be reviewed and 
approved in writing by the Sponsor, prior to submission for publication or presentation. No 
publication or presentation with respect to the study shall be made until all Sponsor comments 
on the proposed publication or presentation have been addressed to the Sponsor’s satisfaction. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be outlined in the agreement 
between each Investigator and the Sponsor or designee. 
8.7 
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). 
8.8 
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. 
8.9 
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. 
 


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9 
ETHICS 
9.1 
Institutional Review Boards 
The IRB 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 ICF will be reviewed and approved by the 
appropriate IRB before subjects are enrolled. The Investigators or Sponsor will submit, 
depending on local regulations, periodic reports and inform the IRB of any reportable AEs per 
ICH guidelines and local IRB standards of practice. 
9.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with SOPs from both the Sponsor and the CRO. 
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) CFR dealing with clinical studies (21 CFR, including parts 50 and 56 
concerning Patient Informed Consent/Assent and IRB regulations). 
• 
Local, national legal guidelines. 
9.3 
Investigators and Study Personnel 
This study will be conducted by qualified Investigators under the sponsorship of Supernus 
Pharmaceuticals, Inc. (Sponsor). 
Contact persons at the Sponsor and the CROs are listed in the reference binder provided to 
each investigational site. The study will be monitored by qualified personnel from the Sponsor or 
their designees, such as the CROs, for their respective sites. Medical writing, data 
management, and statistical analyses may be performed by the CROs. Laboratory tests will be 
conducted by a central laboratory as designated in the reference binder.  
9.4 
Subject Information and Consent 
The Investigator (or designee) will inform the subject (and the subject’s parent or legal 
guardian/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 will be in accordance with all applicable regulatory 
requirements. The Investigator (or designee) and subject’s parent or legal 
guardian/representative must sign and date the ICF before the subject can participate in the 


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study. The subject’s parent or legal guardian/representative will be given a copy of the signed 
and dated ICF 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’s parent or legal guardian/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. 
If the ICF is amended during the study, the Investigator must follow all applicable regulatory 
requirements pertaining to approval of the amended ICF by the IRB and use the amended ICF 
(including ongoing subjects). 
 
 


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10 REFERENCES 
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DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. AD/HD Rating Scale IV: Checklists, norms, 
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DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD Rating Scale-5 for children and 
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Faraone SV, Childress A, Wigal SB, Kollins SH, McDonnell MA, DeSousa NJ, Sallee FR. 
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McCann BS, Roy-Byrne P. Screening and diagnostic utility of self-report attention deficit 
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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. 
Johnson JK, Liranso T, Saylor K, Tulloch G, Adewole T, Schwabe S, Nasser A, Findling RL, 
Newcorn JH. A Phase II Double-Blind, Placebo-Controlled, Efficacy and Safety Study of SPN-
812 (Extended-Release Viloxazine) in Children With ADHD. J Atten Disord. 2020 Jan;24(2):348-
358. 
Nasser A, Liranso T, Adewole T, Fry N, Hull JT, Chowdhry F, Busse GD, Cutler AJ, Jones NJ, 
Findling RL, Schwabe S. A Phase III, Randomized, Placebo-controlled Trial to Assess the 
Efficacy and Safety of Once-daily SPN-812 (Viloxazine Extended-release) in the Treatment of 
Attention-deficit/Hyperactivity Disorder in School-age Children. Clin Ther. 2020 Aug;42(8):1452-
1466. 
Sheehan DV, Sheehan KH, Shytle RD, Janavs J, Bannon Y, Rogers JE, Milo KM, Stock SL, 
Wilkinson B. Reliability and validity of the Mini International Neuropsychiatric Interview for 
Children and Adolescents (MINI-KID). J Clin Psychiatry. 2010 Mar;71(3):313-326. 
Sutton VK, Sumner C, Allen A, Feng W, Schuh K, Michelson D. Validity, Reliability, and 
Responsiveness of the DPREMB-R Scale for ADHD. Scientific Proceedings of the 50th 
Anniversary Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP). 
2003, pp. 169-170. 
Vincent O. Mancini, Daniel Rudaizky, Benjamin T.D. Pearcy, Angela Marriner, Carmela F. 
Pestell, Rapson Gomez, Romola S. Bucks, Wai Chen. Factor structure of the Sleep Disturbance 
Scale for Children (SDSC) in those with Attention Deficit and Hyperactivity Disorder (ADHD)/ 
Sleep Medicine: X, Volume 1, 2019, 100006. 
Wehmeier PM, Dittmann RW, Schacht A, Helsberg K, Lehmkuhl G. Morning and evening 
behavior in children and adolescents treated with atomoxetine once daily for attention-
deficit/hyperactivity disorder (ADHD): findings from two 24-week, open-label studies. Child 
Adolesc Psychiatry Ment Health. 2009 Feb 9;3(1):5. 
 
 


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11 APPENDIX:   
11.1 ADHD-RS-5 
11.1.1 Investigator-rated ADHD-RS-5 Home Version 
 
 
 
 
 
 










































































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SAP_003.pdf: 
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CONFIDENTIAL 
10Jul2023 
812P412 
 
Version 2.0 
 
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Such information may be used solely for the purpose of reviewing or performing this study. 
COVER PAGE – STATISTICAL ANALYSIS PLAN (SAP) 
 
Protocol Number: 
812P412 
Title: 
A Phase IV, Open-Label, Flexible-Dose Safety Trial Evaluating 
SPN-812 Administered with Psychostimulants in Children and 
Adolescents (6 to 17 years of age) with Attention-
Deficit/Hyperactivity Disorder (ADHD) 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
9715 Key West Avenue 
Rockville, MD 20850 
United States 
Phone: (301) 838-2500 
Fax: (240) 403-0065 
SAP Version: 
2.0 
Date: 
10Jul2023 
NCT: 
NCT04786990 




Supernus Pharmaceuticals, Inc.  
Protocol 812P412 
 
 Statistical Analysis Plan  
CONFIDENTIAL 
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SIGNATURE PAGE 
  
 
 


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Protocol 812P412 
 
 Statistical Analysis Plan  
CONFIDENTIAL 
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Document Version History 
Version Number 
Date 
Section 
Description of Change 
1.0 
14 June 2023 
NA 
First Approval 
2.0 
10 July 2023 
Section 2.1: Study 
Objectives 
Administrative changes, 
duplication of primary objective 
removed. 
Section 4.1: 
Definitions and 
derivations 
Removal of AM and PM 
derivations since analysis will be 
performed using period weeks 
(Week 1-4 and Week 5-8) 
Section 6: Statistical 
Methods 
Clarification that data will be 
summarized by week 1-4 and 
week 5-8 instead of AM/PM 
dosing. 
Section 7.2: Protocol 
Deviation 
Protocol deviation as well as 
major protocol deviation 
definitions were inserted. 
Section 11: Changes 
of planned analyses 
from Protocol 
Clarification on compliance 
derivations 
 
General 
Administrative changes to correct 
typos, and other minor updates 
throughout the document. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Statistical Analysis Plan  
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Table of Contents 
1. 
Introduction ......................................................................................................................... 7 
2. 
Study Objectives and Endpoints ......................................................................................... 7 
2.1. 
Study Objectives ........................................................................................................... 7 
2.1.1. Primary Objective ......................................................................................................... 7 
2.1.2. Secondary Objectives .................................................................................................... 7 
2.2. 
Study Endpoints ............................................................................................................ 8 
2.2.1. Primary Endpoints ........................................................................................................ 8 
2.2.2. Secondary Endpoints .................................................................................................... 8 
3. 
Study Description................................................................................................................ 9 
3.1. 
Study Design ................................................................................................................. 9 
3.2. 
Schedule of Study Visits and Procedures ................................................................... 10 
3.3. 
Study Population ......................................................................................................... 13 
3.4. 
Completion and Discontinuation of Subjects ............................................................. 13 
3.5. 
Study Treatments ........................................................................................................ 14 
3.5.1. Study Medication Identity, Packaging, and Labeling ................................................. 14 
3.5.2. Study Medication Administration ............................................................................... 14 
3.5.3. Method of Assigning Subjects to Treatment Groups .................................................. 14 
3.5.4. Blinding and Unblinding............................................................................................. 14 
3.5.5. Concomitant Medications ........................................................................................... 14 
3.6. 
Sample Size and Power ............................................................................................... 15 
4. 
Definitions and Derivations .............................................................................................. 15 
4.1. 
General study level definitions ................................................................................... 15 
5. 
Study Variables ................................................................................................................. 16 
5.1. 
Safety Variables .......................................................................................................... 16 
5.2. 
Efficacy Variables ....................................................................................................... 16 
5.3. 
Confirmatory Blood Sample ....................................................................................... 17 
6. 
Statistical Methods ............................................................................................................ 17 
6.1. 
General Principles ....................................................................................................... 17 
6.2. 
Analysis Populations ................................................................................................... 18 
6.3. 
Interim Analysis and Data Monitoring ....................................................................... 18 
6.4. 
Handling of Dropouts or Missing Data ....................................................................... 18 
6.4.1. Missing Efficacy variables .......................................................................................... 18 
6.4.2. Missing Safety Variables ............................................................................................ 19 
6.5. 
Analysis Visit Windows ............................................................................................. 20 
7. 
Study Subjects and Demographics.................................................................................... 20 
7.1. 
Disposition of Subjects and Withdrawals ................................................................... 20 
7.2. 
Protocol Deviations ..................................................................................................... 21 


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7.3. 
Demographics and Other Baseline Characteristics ..................................................... 21 
7.4. 
Exposure and Compliance .......................................................................................... 21 
8. 
Efficacy Analysis .............................................................................................................. 22 
9. 
Safety and Tolerability Analysis ....................................................................................... 23 
9.1. 
Adverse Events ........................................................................................................... 23 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................... 23 
9.1.2. Deaths, Adverse Events of Special Interest, and Serious Adverse Events ................. 24 
9.2. 
Laboratory Data .......................................................................................................... 24 
9.3. 
Vital Signs ................................................................................................................... 24 
9.4. 
Electrocardiograms ..................................................................................................... 25 
9.5. 
Physical Examination.................................................................................................. 26 
9.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................... 26 
9.7. 
Concomitant Medications ........................................................................................... 26 
9.8. 
Other Safety Assessments ........................................................................................... 26 
10. 
Confirmatory Blood Sample ............................................................................................. 26 
11. 
Changes of planned analyses from the Protocol ............................................................... 26 
 


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LIST OF ABBREVIATIONS  
ADHD 
Attention-deficit/hyperactivity disorder 
ADHD-RS-5 
ADHD Rating Scale, 5th Edition 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical Classification 
BMI 
Body Mass Index 
BPM 
Beats per minute 
CFB 
Change from Baseline 
CGI-S 
Clinical Global Impression-Severity of Illness 
CGI-I 
Clinical Global Impression-Improvement 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-5TM 
ADHD per Diagnostic and Statistical Manual of Mental Disorders, 5th Edition  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
ER 
Extended-Release 
ET 
Early Termination 
IR-ADHD-RS-5 
Investigator Rated ADHD Rating Scale, 5th edition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI KID 
Mini International Neuropsychiatric Interview for Children and Adolescents 
PK 
Pharmacokinetics 
PR-ADHD-RS-5 
Parent Rated ADHD Rating Scale, 5th edition 
PT 
Preferred Term 
QD 
Once a day 
QTcF 
QT interval corrected using Fridericia’s method 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDSC 
Sleep Disturbance Scale for Children 
SOC 
System Organ Class 
SM 
Study Medication 
TEAE 
Treatment-Emergent Adverse Event 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
WPREMB-R 
Weekly Parent Rating of Evening and Morning Behavior-Revised 
 
 


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 Statistical Analysis Plan  
CONFIDENTIAL 
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1. 
Introduction 
This document describes the statistical analyses and data presentations to be performed on safety 
and efficacy data collected during the conduct of Study 812P412, titled, “A Phase IV, Open-
Label, Flexible-Dose Safety Trial Evaluating SPN-812 Administered with Psychostimulants in 
Children and Adolescents (6 to 17 years of age) with Attention-Deficit/Hyperactivity Disorder 
(ADHD)” (Protocol Version 3.0, 01Feb2022). 
The purpose of this SAP is to ensure the credibility of the study findings by specifying detailed 
statistical approaches to the analysis of the data prior to database lock. This SAP covers the 
planned analyses of all data collected on the electronic case report forms (eCRFs) and electronic 
diary and will describe handling of data issues. It describes the efficacy and safety variables, 
anticipated data manipulations, and other details of the analyses not provided in the study 
protocol. The analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. Any deviations/changes from the planned analyses 
described in this SAP will be identified, with justification, in the appropriate section of the 
clinical study report. 
2. 
Study Objectives and Endpoints 
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The primary objective is to evaluate the safety and tolerability of AM and PM dosing of SPN-
812 administered with a psychostimulant (methylphenidate or amphetamine) for the treatment of 
ADHD in children and adolescents (6-17 years of age). 
2.1.2. Secondary Objectives 
The following are the secondary objectives: 
1. Evaluate the safety and tolerability of AM versus PM dosing of SPN-812 administered with a 
psychostimulant (methylphenidate or amphetamine) for ADHD in children and adolescents 
(6-17 years of age). 
2. Evaluate the efficacy of AM and PM dosing of SPN 812 administered with psychostimulants 
(methylphenidate or amphetamine) for ADHD in children and adolescents (6-17 years of age) 
on: 
i. 
ADHD symptoms as measured by the Investigator-rated ADHD-RS-5 (IR-
ADHD-RS-5). 
ii. 
the global assessment of severity for ADHD as measured by the Clinical Global 
Impression-Severity of Illness (CGI-S) scale. 
iii. 
the global assessment of improvement for ADHD as measured by the Clinical 
Global Impression-Improvement (CGI-I) scale. 
iv. 
sleep as measured by the Sleep Disturbance Scale for Children (SDSC). 


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v. 
home functioning in the morning and evening as measured by the Weekly Parent 
Rating of Evening and Morning Behavior-Revised (WPREMB-R). 
3. Evaluate the efficacy of AM versus PM dosing of SPN 812 administered with 
psychostimulants (methylphenidate or amphetamine) for ADHD in children and adolescents 
(6-17 years of age). 
i. 
ADHD symptoms as measured by the Investigator-rated ADHD-RS-5 (IR-
ADHD-RS-5). 
ii. 
the global assessment of severity for ADHD as measured by the Clinical Global 
Impression-Severity of Illness (CGI-S) scale. 
iii. 
the global assessment of improvement for ADHD as measured by the Clinical 
Global Impression-Improvement (CGI-I) scale. 
iv. 
sleep as measured by the Sleep Disturbance Scale for Children (SDSC). 
v. 
home functioning in the morning and evening as measured by the Weekly Parent 
Rating of Evening and Morning Behavior-Revised (WPREMB-R). 
4. Evaluate efficacy in the morning for AM and PM dosing of SPN-812 administered with 
psychostimulants (methylphenidate or amphetamine) for ADHD in children and adolescents 
(6-17 years of age) on ADHD symptoms as measured by the Morning Parent-Rated-ADHD-
RS-5 (PR-ADHD-RS-5).  
5. Evaluate efficacy in the evening for AM and PM dosing of SPN-812 administered with 
psychostimulants (methylphenidate or amphetamine) for ADHD in children and adolescents 
(6-17 years of age) on ADHD symptoms as measured by the Evening PR-ADHD-RS-5. 
6. Evaluate duration of efficacy within day (morning versus evening) for AM and PM dosing of 
SPN-812 administered with psychostimulants (methylphenidate or amphetamine) for ADHD 
in children and adolescents (6-17 years of age) on ADHD symptoms as measured by the 
Morning and Evening PR-ADHD-RS-5. 
2.2. 
Study Endpoints 
2.2.1. Primary Endpoints 
• Safety endpoints for Weeks 1-4 (AM dosing) and Weeks 5-8 (PM dosing) are adverse 
events (AEs), clinical safety laboratory tests results, vital signs, weight, height, body 
mass index (BMI), electrocardiograms (ECGs), physical examination, and the Columbia 
Suicide Severity Rating Scale (C-SSRS) assessment. 
2.2.2. Secondary Endpoints 
• Safety endpoints for Weeks 1-4 (AM dosing) versus Weeks 5-8 (PM dosing) are AEs, 
clinical safety laboratory tests results, vital signs, weight, height, BMI, ECGs, physical 
examination, and the C-SSRS assessment. 
7. Secondary endpoints for evaluating the efficacy of SPN-812 at Week 4 (AM dosing) and 
Week 8 (PM dosing) are: 


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i. Change from baseline (CFB) in the IR-ADHD-RS-5 Total Score at Week 4 and Week 8.  
ii. CFB in CGI-S score at Week 4 and Week 8. 
iii. CGI-I score at Week 4 and Week 8. 
iv. CFB in SDSC total score and subscale scores at Week 4 and Week 8 
v. CFB in WPREMB-R total score and subscale scores at Week 4 and Week 8. 
8. Secondary endpoints for evaluating the efficacy of SPN-812 Week 4 (AM dosing) versus 
Week 8 (PM dosing) are: 
i. CFB in the IR-ADHD-RS-5 Total Score at Week 4 versus Week 8.  
ii. CFB in CGI-S score at Week 4 versus Week 8. 
iii. CGI-I score at Week 4 versus Week 8. 
iv. CFB in SDSC total score and subscale scores at Week 4 versus Week 8 
v. CFB in WPREMB-R total score and subscale scores at Week 4 versus Week 8. 
9. The CFB in the Morning PR-ADHD-RS-5 Total Score at Week 4 (AM dosing) and Week 8 
(PM dosing). 
10. The CFB in the Evening PR-ADHD-RS-5 Total Score at Week 4 (AM dosing) and Week 8 
(PM dosing).  
11. The CFB in the Morning PR-ADHD-RS-5 Total Score versus the CFB in the Evening PR-
ADHD-RS-5 Total Score at Week 4 (AM dosing) and Week 8 (PM dosing). 
3. 
Study Description 
3.1. 
Study Design 
This is an open-label, flexible-dose, safety study of SPN-812 in pediatric patients diagnosed with 
ADHD per Diagnostic and Statistical Manual of Mental Disorders – 5th Edition (DSM-5™) 
criteria who are experiencing an inadequate efficacy response to psychostimulant therapy. 
Approximately 60 subjects will enroll, and approximately 50 subjects are expected to complete 
this study.  During screening period (up to 4 weeks), subjects will continue their psychostimulant 
ADHD treatment. During Weeks 1-4 of the Treatment period, eligible subjects will take daily 
SPN-812 dose in the combination with their current psychostimulant therapy in the morning 
(AM) hours but during Weeks 5-8, subjects will take daily SPN-812 dose in the EVENING (PM) 
hours in combination with their current psychostimulant. The total duration of treatment period is 
8 weeks. Total duration of the study between screening visit and end of study (EOS) visit is up to 
12 weeks.  
During the Treatment period, subjects will complete weekly study visits (Visits 3-10) during the 
Treatment Period (Days 2-57). At each post-baseline study visit, safety evaluations will be 
conducted, efficacy assessments (IR-ADHD-RS-5, CGI-S, CGI-I) will be administered, drug 
compliance will be evaluated, and subject will return bottle of study medication and receive next 
bottle of study medication, if required. SDSC and WPREMB-R will only be administered at 
Visits 6 and 10 during Treatment Period. In addition, parent/guardian must complete a ‘Morning’ 
PR-ADHD-RS-5 and ‘Evening’ PR-ADHD-RS-5 one or two days prior to Study Visits 2, 6, and 
10. Parent will rate their child’s behavior based upon interactions with their child during the 
morning hours in the past week and then rate their child’s behavior based upon interactions with 








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 Statistical Analysis Plan  
CONFIDENTIAL 
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    n. Review subject’s prior lifetime history of concomitant medication(s) and current concomitant medication(s). 
3.3. 
Study Population 
The study population will comprise children and adolescent who are 6 to ≤17 years and 9 months 
of age diagnosed with ADHD and on a stable psychostimulant regimen for treatment of ADHD 
with a partial but inadequate efficacy response (IR-ADHD-RS-5 total score of ≥24 and a CGI-S 
score of ≥3 at Screening and Baseline) to psychostimulant therapy. 
3.4. 
Completion and Discontinuation of Subjects 
Subjects will be considered to have completed the study if they complete all visits up to and 
including Visit 10 or complete 8 weeks (56 days ±2 days) of treatment. Subjects who dose SPN-
812 but withdraw or are withdrawn from participation in the study by the Investigator before 
he/she finishes the study (i.e., after Visit 2 but prior to Visit 10 or less than 54 days of treatment 
exposure), should complete an early termination (ET) visit. Procedures listed for Visit 10 should 
be completed at the ET visit. 
All reasons for screening failure will be recorded. If the subject passes screening but fails 
eligibility at Visit 2 (Baseline), the reason(s) will also be recorded. 
The Investigator(s) or subjects themselves may stop SPN-812 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 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 Clinical 
Research Associate (CRA) before the subject stops SPN-812 treatment. Subjects removed from 
the study for any reason will not be replaced. 
Reasons for subject’s early discontinuation/termination may include: 
• Withdrawal of consent (parent/guardian) 
• Withdrawal of assent (subject) 
• Inclusion/Exclusion criteria 
• Noncompliance  
• Lack of Efficacy 
• Occurrence of unmanageable AEs 
• Lost to follow-up 
• Other 
 
 
 
 
 
 
 




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CONFIDENTIAL 
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known CYP1A2 substrates (e.g., theophylline, melatonin, etc.). Subjects will undergo a washout 
period of prohibited medication for at least 1 week (or 5 half-lives of the medication, whichever 
is longer) before the Baseline Visit (Day 1).  
No concomitant medications are allowed during the study, with the following exceptions: 
• Nutritional supplements (e.g., multivitamins, fish oil) (however, herbal supplements are 
prohibited) 
• EMLA® or other numbing cream for venipuncture 
• Common over-the-counter (OTC) therapies for minor transient ailments (e.g., 
acetaminophen for headache, ibuprofen for fever). 
• Over-the-counter, non-sedating allergy medications and antibiotics. 
All concomitant medications will be recorded in the eCRF. 
Caffeine use is not prohibited during the study, however, caffeine intake will be assessed at 
screening, baseline and at all post-baseline study visits and recorded in the eCRF. 
3.6. 
Sample Size and Power 
There is no consideration for power or sample size determination in this open-label study. There 
are approximately 50 subjects expected to complete this study. Based on an early discontinuation 
rate of 20%, approximately 60 subjects would need to be enrolled. Based on a screen failure rate 
of 40%, approximately 100 subjects will be screened to enroll approximately 60 subjects. 
4. 
Definitions and Derivations 
4.1. 
General study level definitions 
• Baseline is the last non-missing assessment recorded before receiving the first dose of 
study medication and will be used as the baseline observation for all calculations of 
change from baseline. 
• Change from Baseline = value at current time point – value at baseline.  
• Percent Change from Baseline = (change from baseline / value at baseline) * 100.  
• Body Mass Index (BMI) kg/m2 =  
 
• Treatment Emergent Adverse Event (TEAE) = an AE with a start date on or after the 
first dose of study medication is taken, or that worsened following first administration of 
study medication (SPN-812). 
• Duration of Adverse Event = AE end date – AE start date + 1 
• Duration of Treatment Exposure = date of last dose – date of first dose + 1 (overall and 
by dose timing [Section 4.2.1]) 


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• Total Dose (mg) Taken Based on Drug Accountability= total dispensed dosage – total 
returned dosage. 
• Average Daily Dose Based on Drug Accountability= (total dispensed dosage – total 
returned dosage)/duration of exposure  
• Total planned Dose Based on Drug Accountability= total planned dose for each day 
shown in the dispensed section for the subject. 
• SM Compliance Based on Drug Accountability= [(total dispensed dosage – total 
returned dosage)/total planned dose based on drug accountability]×100%. 
• Total Dose (mg) Taken Based on Drug Administration= total dispensed dosage – total 
missed dosage. 
• Average Daily Dose Based on Drug Administration=(total dispensed dosage – total 
missed dosage)/duration of exposure. 
• Total Expected Dosed based on Drug Administration= Total dose expected based on 
the number of days for each administration record. 
• SM Compliance Based on Drug Administration= [(total dispensed dosage – total 
missed dosage)/total expected dose based on drug administration] ×100%. 
 
5. 
Study Variables 
5.1. 
Safety Variables 
The safety endpoints of this study include the following: 
• Adverse events (AEs) 
• Clinical safety laboratory tests results 
• Vital signs (orthostatic blood pressure and pulse rate, respiratory rate, temperature) 
• Weight/Height/BMI 
• 12-Lead Electrocardiogram (ECG) 
• Physical examination 
• Suicidality (C-SSRS) 
 
5.2. 
Efficacy Variables 
The efficacy endpoints of this study include the following: 
• Investigator-rated (IR) ADHD-RS-5  
• Morning Parent-rated (PR) ADHD-RS-5  
• Evening Parent-rated (PR) ADHD-RS-5 


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• CGI-S scale 
• CGI-I scale 
• SDSC and subscales 
• WPREMB-R and subscales 
5.3. 
 Confirmatory Blood Sample 
 A confirmatory blood sample will be collected at each study visit (1-10) to assess concentrations 
of psychostimulant, viloxazine, and viloxazine’s metabolite. 
6. 
Statistical Methods 
6.1. 
General Principles 
All statistical analysis, data processing, tabulation of descriptive statistics and graphical 
representations will be performed using SAS version 9.4 or higher.  
Continuous (quantitative) variable summaries will include the number of subjects (n) with non-
-missing values, mean, standard deviation (SD), median, interquartile (Q1 and Q3), minimum, 
and maximum. If warranted, standard error (SE) will be displayed for some efficacy figures. 
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the safety 
population, unless otherwise specified. The denominator for by-visit displays will be the number 
of subjects in the relevant study population with non-missing data at each study visit. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean, Q1, Q3, and 
median) will be reported to 1 degree of precision more than the observed data and measures of 
spread (SD) will be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified and with the 
following exceptions: a percentage of 0% will not be displayed (i.e., only the count of 0 will be 
displayed), and a percentage of 100% will be displayed with 0 decimal places. 
Data collected at unscheduled time points will not be summarized but will be presented in 
subject listings. 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
Data will be summarized by periods for weeks 1-4 and weeks 5-8 and overall depending on the 
endpoint. In the case that the data supporting the endpoint is collected only at study visits, 
summary will be presented by  scheduled visits. In the case that the data supporting the endpoint 
is collected at times other than study visits (e.g., Adverse Events), the data will be presented with 


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the columns of Weeks 1-4 and Weeks 5-8 in addition to the overall participation in the trial. 
6.2. 
Analysis Populations 
The following analysis populations are planned for this study:  
The Safety Population consists of all subjects who enrolled in the study and receive at least one 
dose of SM. The Safety population will be used for all analyses including both safety and 
efficacy analyses. 
6.3. 
Interim Analysis and Data Monitoring 
No interim analyses are planned. 
6.4. 
Handling of Dropouts or Missing Data 
6.4.1. Missing Efficacy variables 
Missing efficacy variables will be handled using the following rules: 
• ADHD-RS-5 Total Score = sum of the 18 individual items. Each individual item is 
scored on a scale of 0 to 3, where 0 = none and 3 = severe, so the total score ranges from 
0 to 54. Higher scores indicate more severe symptoms. If more than 3 items of ADHD-
RS-5 are missing, then the total score will be set to missing. If ≤3 items are missing, then 
the values for the missing items will be imputed using the mean of the non-missing items 
rounded to the nearest integer. It will be applied for both the investigator-rated ADHD-
RS-5 and the parent-rated ADHD-RS-5. 
• ADHD-RS-5 Inattention Subscale Score = sum of the first 9 individual items. Each 
individual item is scored on a scale of 0 to 3, where 0 = none and 3 = severe, so the total 
score ranges from 0 to 27. Higher scores indicate more severe symptoms. If the total 
score is missing, then both subscales (inattention or Hyperactivity/ Impulsivity) will be 
set to missing.  It will be applied for both the investigator-rated ADHD-RS-5 and the 
parent-rated ADHD-RS-5. 
• ADHD-RS-5 Hyperactivity/Impulsivity Subscale Score = sum of 16 to 24 individual 
items. Each individual item is scored on a scale of 0 to 3, where 0 = none and 3 = severe, 
so the total score ranges from 0 to 27. Higher scores indicate more severe symptoms. If 
the total score is missing, then both subscales (inattention or Hyperactivity/ Impulsivity) 
will be set to missing. It will be applied for both the investigator-rated ADHD-RS-5 and 
the parent-rated ADHD-RS-5. 
• SDSC Total Score = sum of the 26 individual items. Each individual item is scored on a 
scale of 1 to 5, so the total score ranges from 26 to 130. Raw scores can be converted to 
T-scores, where a T-score >70 (>95th percentile) is indicative of a clinically significant 
sleep problem. The parent will rate their child for each item based on the past week (7 
days). Higher scores indicate worse sleep disturbances. If one item has no rating/score 
(missing), the total score will be set to missing. 
• SDSC Disorders of Initiating and Maintaining Sleep (DIMS) Scale Score = sum the 
score of the items 1, 2, 3, 4, 5, 10, and 11. If one item has no rating/score (missing), the 


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scale score will be set to missing. 
• SDSC Sleep Breathing Disorders (SBD) Scale Score = sum the score of the items 
13,14,15. If one item has no rating/score (missing), the scale score will be set to missing. 
• SDSC Disorders of Arousal Scale (DA) Score = sum the score of the items 17, 20, 21. 
If one item has no rating/score (missing), the scale score will be set to missing. 
• SDSC Sleep-wake Transition Disorders (STD) Scale Score = sum the score of the 
items 6,7,8,12,18,19. If one item has no rating/score (missing), the scale score will be set 
to missing. 
• SDSC Disorders of Excessive Somnolence (DES) Scale Score = sum the score of the 
items 22,23,24,25,26. If one item has no rating/score (missing), the scale score will be set 
to missing. 
• SDSC Sleep Hyperhidrosis (SH) Scale Score = sum the score of the items 9,16. If one 
item has no rating/score (missing), the scale score will be set to missing. 
• WPREMB-R Total Score = sum of the 11 individual items. Each individual item is 
scored on a scale of 0 (no difficulty) to 3 (a lot of difficulty), so the total score ranges 
from 0 to 33.  If one item has no rating/score (missing), the total score will be set to 
missing. 
• WPREMB-R Morning Subscale Score = sum of items 1, 2 and 3 1. Each individual 
item is scored on a scale of 0 to 3, so the subscale score ranges from 0 to 9. If one item 
has no rating/score (missing), the subscale score will be set to missing. 
• WPREMB-R Evening Subscale Score = sum of items 4, 5, 6, 7, 8 9, 10 and 11. Each 
individual item is scored on a scale of 0 to 3, so the subscale score ranges from 0 to 24. If 
one item has no rating/score (missing), the subscale score will be set to missing. 
6.4.2. Missing Safety Variables 
Missing dates for AEs and non-study concomitant medications will be imputed using the 
following rules:  
If partial AE or medication dates occur, the convention for replacing missing dates for the 
purpose of statistical analysis is as follows.  
For partial AE and medication start dates: 
• If the year is unknown, then do not impute the date but assign a missing value. 
• If the year is known, but the month or month and day is/are unknown, then: 
o If the year matches the year of first dose date and the end date (if present) is after 
first dose date, then impute as the month and day of the first dose date. 
o Otherwise, assign 01 January. 
• If the year and month are known, but the day is unknown, then: 
o If the month and year match the month and year of the first dose date, then impute 
as the day of the first dose date. 
o Otherwise, assign 01. 


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For partial AE and medication end dates: 
• If the year is unknown, then do not impute the date, but assign as missing value. 
• If the year is known, but the month or month and day is/are unknown, then: 
o If the year matches the year of the last date of the study (date of last contact if 
subject lost to follow-up; date of completion or early termination), then impute as 
the month and day of the last date of the study. 
o Otherwise, assign 31 December. 
• If the year and month are known, but the day is unknown, then: 
o If the month and year match the month and year of the last date of the study, then 
impute as the day of the last date of the study. 
o Otherwise, assign the last day of the month. 
Missing data for all other safety endpoints will not be imputed. 
6.5. 
Analysis 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 (except if 
the unscheduled visit used for baseline) but will be included in listings.  
7. 
Study Subjects and Demographics  
7.1. 
Disposition of Subjects and Withdrawals 
Disposition will include tabulations of the number and percentage of subjects in each of the 
following categories: 
• Screened Subjects 
• Subjects in the Safety Population 
The number and percentage of subjects who completed and discontinued from the study and 
primary reason for early discontinuation will be summarized. The reason for early 
discontinuation may include any of the following: 
• Withdrawal of consent (parent) 
• Withdrawal of assent (subject) 
• Inclusion/Exclusion criteria 
• Noncompliance 
• Occurrence of unmanageable AEs 
• Lack of Efficacy  
• Lost to follow-up  
• Other 
All disposition information as well as inclusion and exclusion criteria met/not met and reasons 
for screen failures will be listed. 


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7.2. 
Protocol Deviations 
A protocol deviation is defined as any change, divergence, or departure from the study design or 
procedures defined in the protocol. A major protocol deviation 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.  
 
Protocol deviations will be listed, and major protocol deviations will be summarized. 
7.3. 
Demographics and Other Baseline Characteristics 
Summary statistics for age, age group, sex, ethnicity, race (White vs Non-white which including 
other races besides White), smoking, alcohol consumption use/history, height/ weight/BMI at 
screening and IR-ADHD-RS-5 Total score and subscale scores, CGI-S score at baseline will be 
presented. 
Age will be broken up into two age groups (children: 6-11, adolescent: 12-17).  
The number and percent of subjects reporting various medical histories, grouped by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and preferred term 
(PT), will be tabulated. This analysis will be conducted for the Safety Population. 
Prior medications and psychostimulant (methylphenidate or amphetamine) will be summarized 
by the number and percentage of subjects taking each medication, classified using World Health 
Organization-Drug Dictionary Enhanced (WHO-DDE) Anatomical –Therapeutic Chemical 
Classification (ATC) Class Level 4 and preferred name (ATC Class Level 5). This analysis will 
be conducted for the Safety Population.  
7.4. 
Exposure and Compliance 
Duration of treatment exposure will be summarized using descriptive statistics. Additionally, 
duration of treatment exposure will be summarized by duration category.  
Duration of treatment exposure will be categorized as follows: 1-7 days, 8-14 days, 15-21 days, 
22-28 days, 39-35 days, 36-42 days, 43-49 days, and >=50 days.  
Subject exposure for planned daily dose will be summarized by study visit, dose (100 mg, 200 
mg, 300 mg, 400 mg, 500 mg and 600 mg).  
For each treatment, SM compliance based on drug accountability and administration will be 
summarized by compliance category (<80%, 80 to 120%, and >120%) and number of subjects in 
each compliance category. Study medication compliance based on drug accountability and 
administration will also be summarized as a continuous variable using descriptive statistics. 
Average daily dosing based on drug accountability and administration for each subject will be 
summarized using descriptive statistics (N, Mean(SD), Median, Q1, Q3, Min and Max) for 
weeks 1- 4 and Weeks 5-8. Distribution of SPN-812 doses at Week 4 and Week 8 will be 
summarized using descriptive statistics. 


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8. 
Efficacy Analysis 
All efficacy endpoints will be summarized descriptively using the safety population. All efficacy 
data will be presented in data listings.  
The descriptive statistics including N, mean, standard deviation, median, Q1, Q3, minimum and 
maximum of observed value and change from baseline will be presented by visit.  
 
For IR-ADHD-RS-5 Total Score and subscale scores, CGI-S, SDSC (total and subscale scores) 
and WPREMB (total and subscale scores), the following CFB analyses will be provided: 
• A comparison of week 4 vs week 8 difference in CFB a nominal p-value from paired t-
test will be presented. 
• Change from baseline by visit.  
For CGI-I: 
• A comparison of week 4 vs week 8 difference in CGI-I score will be provided: nominal 
p-value from paired t-test will be presented. 
• CGI-I score by visit will be provided.  
For Morning PR-ADHD-RS-5 Total Score and Evening PR-ADHD-RS-5 Total Score: 
• A comparison of week 4 vs week 8 difference in CFB will be provided. 
The following will be provided for PR-ADHD-RS-5 Total Score and subscale scores: 
• CFB in the Morning PR-ADHD-RS-5 versus the Evening PR-ADHD-RS-5 at Week 4. 
• CFB in the Morning PR-ADHD-RS-5 versus the Evening PR-ADHD-RS-5 at Week 8. 
Analysis of 30% and 50% IR-ADHD-RS-5 Total score responder rates, defined as having at least 
a 30% and 50% reduction respectively from baseline IR-ADHD-RS-5 Total score will be 
presented. 
For each subject, the percent reduction will be calculated as 100*(IR-ADHD-RS-5 Total Score at 
week Y-Baseline IR-ADHD-RS-5 Total Score)/ Baseline ADHD-RS-5 Total Score.  
• The number and percentage of IR-ADHD-RS-5 responders will be summarized and 
presented, the odds ratio between week 4 and week 8 will be presented along with the 
associated 95% CI. 
• The responder 30% and 50% rates for IR-ADHD-RS-5 will be presented by visit. 
A CGI-S and CGI-I “responder” is defined as having a CGI-S score of 1 or 2. 
• The number and percentage of CGI-S/I responders will be summarized and presented. 
The odds ratio between week 4 and week 8 will be presented along with the associated 
95% CI. 
• The responder rates for CGI-S/I will be presented at by visit. 


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9. 
Safety and Tolerability Analysis 
Safety assessments include monitoring, evaluation, and recording of all concomitant 
medications, and the evaluation of AEs, clinical laboratory test results, vital signs, weight, 
height, BMI, 12-lead ECGs, C-SSRS, and physical examinations. 
All safety analyses will be performed on the Safety population. No inferential statistics will be 
performed. 
9.1. 
Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA Version 23.1.   
A treatment-emergent adverse event (TEAE) is defined as an AE with a start date on or after the 
date of the first dose of study medication, or that worsened in severity following the first dose of 
study medication. All AEs in this study will be recorded after administration of study 
medication, therefore all will be considered treatment-emergent.  
The causal relationship of the AE to the study medication is determined by the investigator as 
“Not Related”, “Unlikely Related”, “Possibly Related”, and “Definitely Related”. These will be 
mapped to “Unrelated (Not Related or Unlikely Related)” and “Related (Possibly Related or 
Definitely Related)”.  
Adverse event severity grades are reported as “mild”, “moderate”, or “severe”. 
Summaries of incidence rates (frequencies and percentages) of individual TEAEs will be 
presented by SOC, PT, and (Week 1 - 4, Week 5 - 8 and overall duration [i.e., Week1-Week8]). 
Such summaries will be displayed for all TEAEs, TEAEs by maximum severity, and TEAEs by 
relationship.  
Each subject will be counted only once within each summation level (SOC and PT). If a subject 
experiences more than 1 TEAE within each summation level, the TEAE with the strongest 
relationship or the maximum severity, as appropriate, will be included in the summaries of 
relationship and severity. If a particular event is missing severity and/or causal relationship to 
study medication, then the strongest possible severity or causal relationship will be assumed for 
analysis (severity = severe, relationship = definitely related). 
Incidences will be presented by descending frequency of SOC and PT within SOC, and then 
alphabetically within PT where the incidence is the same; this is based on overall subjects then 
alphabetically in case of a tie. 
In addition, number and percent of patients reporting common AEs (≥5% in any treatment 
group) will be presented by SOC and PT. 
Missing and partially missing AE start and/or stop dates will be imputed, for the purpose of 
statistical analysis, according to the specifications described in Section 6.4.2. 
In the AE data listings, all AEs will be displayed. AEs that are treatment emergent will be 
flagged. 
9.1.1. Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study medication, SOC, and PT will be prepared for the Safety Population.  


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A data listing of AEs leading to withdrawal of study medication will also be provided, displaying 
details of the event(s) captured on the CRF. 
9.1.2. Deaths, Adverse Events of Special Interest, and Serious Adverse Events 
Any deaths, adverse events of special interest, and serious adverse events that occur during the 
study will be listed. 
Adverse events of special interest (AESI) are defined as seizure or AEs that might represent a 
seizure. This includes, but is not limited to syncope/syncopal episode, pseudoseizure, myoclonus, 
and severe muscle spasms.  
9.2. 
Laboratory Data 
Laboratory tests (clinical chemistry, hematology) will be performed at all study visits and results 
will be summarized descriptively by study visit (week 1 to 4 with AM dosing, week 5 to 8 with 
PM dosing) as both observed values and change from baseline values. Urinalysis will be 
performed at screening and EOS. Number and percentage of subjects with abnormal qualitative 
urinalysis results will be provided by study visit. 
Laboratory values for clinical chemistry and hematology will be presented at each visit using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for the actual and 
change from baseline values will be presented in Tables. Laboratory assessment values of the 
form of “< x” or “<= x” (i.e., below or at/below the lower limit of quantification) or “> x” or “>= 
x” (i.e., above or at/above the upper limit of quantification) will be imputed as “x” in the 
calculation of summary statistics. For listings however, the original ranges (e.g., “< x”, “<= x”, 
“> x”, “>= x”) as stated in the database will be presented. 
Laboratory values for clinical chemistry and hematology will be flagged as abnormally low (L) if 
the value < lower limit of the normal range, normal (N) if the value is within normal range or 
abnormally high (H) if the value > upper limit of the normal range. In addition, shift tables for 
the change from baseline by study visit will be presented. 
Laboratory values will be displayed in the data listings and those that are outside the normal 
range will be flagged and presented along with corresponding normal ranges (if available). A 
separate listing of abnormal laboratory values will be provided. All study visits within a 
parameter for a subject will be presented if at least 1 study visit within that parameter has an 
abnormal result.  
Standard urine drug screen results, and pregnancy test results will be listed separately. 
9.3. 
Vital Signs 
Vital signs will be collected at all study visits. Descriptive summaries of actual values and 
changes from baseline will be calculated for height (cm), weight (kg), BMI (kg/m2), oral body 
temperature (ºC), respiration rate (breaths per minute), sitting pulse rate (beats per minute 
[bpm]), standing pulse rate (bpm), sitting systolic blood pressure (mmHg), standing systolic 
blood pressure (mmHg), sitting diastolic blood pressure (mmHg), and standing diastolic blood 
pressure (mmHg). These summaries will be presented by study visit.  
The number of subjects with vital signs below, within, or above normal ranges, by study visit 
will be tabulated (shift tables) for each parameter.  




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9.5. 
Physical Examination 
The physical examination conducted at screening will include assessments of all body systems 
except genitourinary. Any findings during screening will be recorded as medical history and any 
clinically significant abnormal findings during treatment will be recorded as an AE. At the EOS 
physical examination, only changes from the screening visit will be noted. 
All physical examination results will be listed. 
9.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Assessment of suicidal ideation and behavior will be conducted using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) which classifies suicidal ideation and behavior events into 11 
preferred categories including 5 levels of suicidal ideation, 5 levels of suicidal behavior, and the 
category of self-injurious behaviors with no suicidal intent. The C-SSRS will be performed at all 
study visits. At the Screening visit, the “baseline” version of the C-SSRS will be administered. 
This version assesses Suicidal Ideation and Suicidal Behavior during the subject’s lifetime and 
during the past 6 months. At the subsequent study visits, the “since last visit” version will be 
administered. 
The number and percentages of subjects with a response of “Yes” at any point on the suicidal 
ideation only, suicidal behavior only, and suicidality (ideation and behavior combined) items will 
be summarized by study visit. 
9.7. 
Concomitant Medications 
Prior and concomitant medications coded using World Health Organization-Drug Dictionary 
Enhanced (WHO-DDE) (version Sep, 2020), will be summarized descriptively by Anatomical 
Therapeutic Chemical (ATC) classification Level 4 and PN (i.e., ATC classification Level 5), if 
applicable, using counts and percentages for the Safety Population.  
If a medication starts prior to the first dose and continues after the first dose, it will be considered 
both prior and concomitant. Prior and concomitant medications will also be listed. 
9.8. 
Other Safety Assessments 
Follow-up phone call data will be listed. 
10. 
Confirmatory Blood Sample 
Concentration for viloxazine and Psychostimulant will be summarized using descriptive statistics 
(N, Mean/SD, Median, Q1, Q3, Min/Max) by visit.    
11. 
Changes of planned analyses from the Protocol 
For SM compliance, the derivation based on retuned capsules as defined in the study protocol 
could not be used because of the following: 
• 
Subjects did not consistently return bottles on the visit following the visit on which they 
were dispensed. As such, the derivation of the number of capsules intended to be taken cannot be 
completely followed.  


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• 
Dosage requires capsules of multiple dose levels to be taken. In those cases, the number 
of capsules missed may reflect greater or lesser compliance with the intended dose depending 
upon the dose level of capsule that was missing. In the case where capsules of multiple dosage 
strength were taken, the average dose/capsule was assumed for the capsules (e.g., 300 mg dosage 
for Adolescents was 1 capsule of 100 mg and 1 capsule of 200 mg, each capsule is calculated to 
be 150 mg). 
Hence the derivations provided in Section 4.1 will be used to derive SM compliance, that is: 
• SM Compliance Based on Drug Accountability= [(total dispensed dosage – total 
returned dosage)/total planned dose based on drug accountability] ×100%. 
In addition, compliance based on drug administration will be added to provide a full compliance 
based on both drug accountability and drug administration. 
• SM Compliance Based on Drug Administration= [(total dispensed dosage – total 
missed dosage)/total expected dose based on drug administration] ×100%.