Conditions: ADHD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 477
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of low doses of SPN-812 in children 6-11 years of age diagnosed with ADHD.

Detailed description:
This is a multicenter, randomized, double-blind, placebo-controlled, 3-arm, parallel-group study, to assess the efficacy and safety of SPN-812 as monotherapy for the treatment of children 6-11 years old with ADHD.

Arms:
arm 1: Placebo, qd, oral capsule arm 2: 100mg SPN-812, qd, oral capsule arm 3: 200mg SPN-812, qd, oral capsule

Interventions: intervention 1: Placebo intervention 2: 100mg SPN-812 intervention 3: 200mg SPN-812
Intervention descriptions: intervention 1: Placebo was administered once daily intervention 2: 100mg SPN-812 was administered once daily and compared to placebo intervention 3: 200mg SPN-812 was administered once daily and compared to placebo

Protocol document:
Prot_000.pdf: 


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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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Criteria for Inclusion: 
Male and female subjects, 6-11 years of age, diagnosed with ADHD, parents/caregivers and 
subjects able to give consent/assent and to follow the protocol requirements of the study. 
Criteria for Exclusion: 
History or presence of significant diseases, evidence of suicidality, allergy to viloxazine, or any 
other reason that could interfere with the subject’s participation in the study as determined by the 
Investigator. 
Treatment, Dose, and Mode of Administration: 
Study medication (SM): capsules containing either SPN-812 ER 100 mg or placebo  
Mode of administration: Each treatment will be administered once daily (QD) as a single oral dose. 
Dose: Subjects will be titrated up at 100 mg/week to the final randomized dose (1:1:1) as follows:  
Treatment A: Placebo  
Treatment B: SPN-812 ER 100 mg/day (1 x 100 mg SPN-812 ER) 
Treatment C: SPN-812 ER 200 mg/day (2 x 100 mg SPN-812 ER) 
Duration of Treatment and Study Duration:  
Screening window: within 28 days prior to Visit 2 (Baseline Visit) 
Titration period: 1 week  
Maintenance treatment period: 5 weeks  
Total subject duration on study: approximately 10 weeks (including up to 28 days of Screening) 
Total number of visits: 8  
Total duration of study: Approximately 12 months (9 months of enrollment). At the end of the 
study, eligible subjects will have the option to enroll in a separate, open-label extension study. 
Treatment Schedule: 
Screening (Visit 1):  After informed consent and informed assent (if applicable) is obtained, 
subjects will undergo initial screening evaluation including medical and psychiatric history, ECG, 
vital signs, physical examination, hematology and chemistry laboratory tests, and urine drug 
screen. A blood sample will also be drawn for PGx testing. The subjects will be administered 
ADHD-RS-5, CGI-S, and the C-SSRS scales. ADHD diagnosis and severity will be confirmed and 
inclusion/exclusion criteria will be reviewed to confirm eligibility of the subject. 
Study Dose Treatment Phase (Visits 2 – 8): This phase will consist of one week of Titration 
followed by five weeks of Maintenance phase until end of study (EOS)/Visit 8. 
Baseline, Randomization, and Dispensation of SM (Visit 2):  Approximately 432 eligible subjects 
will be randomized.  Within 28 days of Screening Visit, eligible subjects will return for the 
Baseline Visit. After confirmation of eligibility (including a urine pregnancy test for Females of 
Childbearing Potential [FOCP] only), subjects will be randomized and receive blinded study 
medication (SM). Blind titration to the target dose will occur during the first week of dosing. 
Maintenance (Visits 3-8): Subjects will return to the clinical site for weekly visits to undergo 
efficacy and safety evaluations and to pick up the next dosing card until Visit 8/ (EOS).  
End of Study (Visit 8): Subjects will return for final evaluation (the same evaluation will be done 
if the subject terminated early). 
Optional Substudy: Pharmacokinetic Sampling (Visit 3-8): The following PK samples will be 
collected: pre-dose; and 1, 2, 4, and 6 hours post-dose. 
Endpoints: 
Primary Endpoint: The primary endpoint in this study is the change from baseline (CFB) to EOS 
in the ADHD-RS-5 total score. 




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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. 
Descriptive statistics will be presented for demographics, data from the clinical laboratory tests, 
vital signs, weight, ECGs, and C-SSRS. 
 
Efficacy Analyses 
Primary: The primary efficacy variable, change from baseline in ADHD-RS-5 Total Score to Week 
6 (EOS), will be analyzed using a Mixed Model for Repeated Measures (MMRM), which assumes 
that missing data are missing at random (MAR). The model will include fixed effect terms for 
baseline ADHD-RS-5 Total Score, age group, treatment, visit, and treatment-by-visit interaction 
as independent variables. The model parameters will be estimated using restricted maximum 
likelihood method with unstructured variance-covariance matrix and Kenward-Roger 
approximation to estimate denominator degrees of freedom. In case there is a convergence 
problem in the MMRM model with the unstructured variance covariance matrix, the first 
(co)variance structure which does not have convergence problem will be used for the analysis 
from the following ordered list: 1) Toeplitz, 2) Autoregressive of order 1, 3) Compound symmetry. 
The adjusted mean (LS Mean) of CFB to EOS for ADHD-RS-5 Total Score for each treatment 
group (Placebo, SPN-812 ER 100 mg and SPN-812 ER 200 mg) will be presented, along with the 
corresponding standard error. Each of the active treatment groups (SPN-812 ER 100 and 200 mg) 
will be compared with placebo. The p-values, Least Squares (LS) of treatment means, differences 
between the LS treatment means and placebo, and 95% confidence intervals for the treatment 
differences will be computed. 
Sensitivity analysis: The sensitivity analysis assumes that missing ADHD-RS-5 Total Scores are 
missing not at random (MNAR). Placebo-based multiple imputation will be used to fill in missing 
values.  
Secondary: The secondary analyses will be based on the ITT population with missing values 
imputed using multiple imputation assuming MAR. All secondary analyses will be analyzed using 
ANCOVA (except CGI which uses ANOVA on the absolute value of CGI-I at week 6 (EOS) on the 
change from baseline at Week 6 (EOS) with treatment and baseline as fixed effect. Each of the 
treatment groups (SPN-812 ER 100 mg and 200 mg) will be compared with the Placebo. The p-
values, Least Squares means of the treatment groups, differences between the LS treatment 
means and placebo (SPN-812 ER 100 mg minus Placebo and SPN-812 ER 200 mg minus 
Placebo), and 95% confidence intervals for the treatment differences will be computed. 
To preserve the overall type I error rate at 0.05 for the key secondary endpoints, a sequential 
testing procedure will be used with the following features. First, only the dose or doses that are 
significantly different from placebo for the primary endpoint will be tested for secondary endpoints. 
If the primary endpoint analysis indicates that only one dose is significant, no multiplicity 
adjustment is required. Otherwise, multiplicity adjustment will be performed as described in the 
SAP. 
Secondary analyses will also be repeated for the PP population. 
 
Safety Analyses 
Safety analyses will be performed by treatment group based on the safety population. The 
incidence rate, severity, and relationship to SM for all AEs will be summarized by treatment group 
for each System Organ Class and preferred term. 
  




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TABLE OF CONTENTS 
 
TITLE PAGE .......................................................................................................................... 1 
INVESTIGATOR’S SIGNATURE PAGE ............................................................................. 2 
SUPERNUS PHARMACEUTICALS, INC. PROTOCOL APPROVAL PAGE ................... 3 
CLINICAL PROTOCOL SYNOPSIS .................................................................................... 4 
LIST OF ABBREVIATIONS ............................................................................................... 13 
1 
INTRODUCTION .......................................................................................................... 15 
1.1 
Background ......................................................................................................... 15 
1.2 
Clinical Information ............................................................................................ 15 
1.3 
Study Rationale ................................................................................................... 17 
2 
STUDY OBJECTIVES ................................................................................................. 17 
2.1 
Primary Objective ............................................................................................... 17 
2.2 
Secondary Objectives ........................................................................................ 17 
2.3 
Exploratory Objectives ...................................................................................... 18 
3 
INVESTIGATIONAL STUDY PLAN ........................................................................... 18 
3.1 
Overall Study Design and Plan ......................................................................... 18 
3.2 
RATIONALE FOR STUDY DESIGN ................................................................... 19 
3.3 
STUDY POPULATION ......................................................................................... 19 
3.3.1 
Number of Subjects ............................................................................................ 19 
3.3.2 
Inclusion Criteria .................................................................................................. 20 
3.3.3 
Exclusion Criteria ................................................................................................ 20 
3.4 
Completion of Study and Discontinuation of Subjects ................................ 21 
4 
STUDY TREATMENT ................................................................................................. 21 
4.1 
Study Medication Identity, Packaging and Labeling ..................................... 21 
4.2 
Study Medication Administration .................................................................... 21 
4.3 
Method of Assigning Subjects to Treatment Group ..................................... 22 
4.4 
Blinding ................................................................................................................ 22 
4.5 
Study Medication Handling and Accountability ............................................ 22 
4.6 
Concomitant Medications ................................................................................. 23 
5 
Study Methods ........................................................................................................... 23 
5.1 
Study Visits and Procedures ............................................................................ 23 
5.1.1 
Visit 1-Screening (Day -28 to -1) ....................................................................... 25 
5.1.2 
Visit 2- Baseline Visit (Day 1) ............................................................................ 25 
5.1.3 
Visit 3 through 7- Maintenance (Days 7, 14, 21, 28, 35 [±2 days]) ............. 25 
5.1.4 
Visit 8- End-of Study (Day 42) ........................................................................... 26 
5.1.5 
Pharmacogenomic Sample Collection ............................................................. 26 
5.1.6 
Pharmacokinetic Sub-study-Sample Collection.............................................. 26 


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6 
STUDY VARIABLES ................................................................................................... 27 
6.1 
Primary Efficacy Variable .................................................................................. 27 
6.1.1 
ADHD-RS-5 .......................................................................................................... 27 
6.2 
Secondary Efficacy Variables ........................................................................... 27 
6.2.1 
Clinical Global Impression - Improvement ....................................................... 27 
6.2.2 
Conners 3 ............................................................................................................. 28 
6.2.3 
WFIRS-P ............................................................................................................... 28 
6.2.4 
PSI-4-SF ............................................................................................................... 29 
6.3 
Safety Variables .................................................................................................. 29 
6.4 
Adverse Events ................................................................................................... 29 
6.4.1 
Causality ............................................................................................................... 29 
6.4.2 
Recording and Evaluation of Adverse Events ................................................ 30 
6.4.3 
Criteria for Assessing Severity .......................................................................... 30 
6.4.4 
Criteria for Assessing Causality ........................................................................ 30 
6.4.5 
Serious Adverse Events ..................................................................................... 31 
6.4.6 
Investigator Responsibilities for Reporting SAEs ........................................... 31 
6.4.7 
Other Events Requiring Immediate Reporting ................................................ 32 
6.4.8 
Sponsor Responsibilities for Reporting SAEs ................................................. 32 
6.5 
Treatment-Emergent Suicidal Ideation ........................................................... 32 
6.5.1 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................... 33 
6.5.2 
Suicide Risk Management Plan ........................................................................ 33 
6.5.2.1 
Assessment of Suicide Risk ............................................................................... 33 
6.5.2.2 
Acute Suicidal Crisis .......................................................................................... 33 
6.5.2.3 
Non-acute Suicidal Risk ..................................................................................... 33 
6.6 
Clinical Measurements ...................................................................................... 33 
6.6.1 
Laboratory ............................................................................................................ 33 
6.6.2 
Vital Signs ............................................................................................................. 34 
6.6.3 
Physical Examinations ........................................................................................ 34 
6.6.4 
Electrocardiograms (ECGs) ............................................................................... 34 
6.7 
Exploratory Variables ........................................................................................ 34 
7 
STATISTICAL METHODS .......................................................................................... 35 
7.1 
General Considerations ..................................................................................... 35 
7.2 
Handling of Missing Data .................................................................................. 35 
7.3 
Analysis Populations ......................................................................................... 35 
7.4 
Demographics and Baseline Analysis ............................................................ 36 
7.5 
Subject Disposition ............................................................................................ 36 
7.6 
Study Medication Exposure and Compliance ................................................ 36 
7.7 
Concomitant Medications ................................................................................. 37 
7.8 
Efficacy Analysis ................................................................................................ 37 
7.8.1 
Primary Efficacy Analysis ................................................................................... 37 
7.8.1.1 
Primary analysis ................................................................................................. 37 
7.8.1.2 
Sensitivity analyses ............................................................................................ 38 


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7.8.2 
Secondary Efficacy Analyses ............................................................................ 38 
7.8.2.1 
Key secondary analyses .................................................................................... 38 
7.8.2.2 
Additional secondary analyses ........................................................................... 39 
7.8.3 
Subgroup Analyses ............................................................................................. 39 
7.8.4 
Exploratory Analyses .......................................................................................... 40 
7.9 
Sample Size and Power Considerations ......................................................... 40 
7.10 
Interim Analysis .................................................................................................. 40 
7.11 
Pharmacokinetic Analyses ............................................................................... 40 
7.12 
Pharmacogenomic Analysis ............................................................................. 40 
7.13 
Safety Analysis ................................................................................................... 40 
8 
DOCUMENTATION ..................................................................................................... 41 
8.1 
Adherence to the Protocol ................................................................................ 41 
8.2 
Changes to the Protocol .................................................................................... 41 
8.3 
Data Quality Assurance ..................................................................................... 42 
8.3.1 
Data Collection .................................................................................................... 42 
8.3.2 
Clinical Data Management ................................................................................. 42 
8.3.3 
Database Quality Assurance ............................................................................. 42 
8.3.4 
Bioanalytical Sample Handling .......................................................................... 42 
8.4 
Retention of Records ......................................................................................... 42 
8.5 
Auditing Procedures .......................................................................................... 43 
8.6 
Publication of Results ........................................................................................ 43 
8.7 
Financing and Insurance ................................................................................... 43 
8.8 
Disclosure and Confidentiality ......................................................................... 43 
8.9 
Discontinuation of Study ................................................................................... 43 
9 
ETHICS ......................................................................................................................... 44 
9.1 
Institutional Review Boards .............................................................................. 44 
9.2 
Ethical Conduct of the Study ............................................................................ 44 
9.3 
Investigators and Study Personnel ................................................................. 44 
9.4 
Subject Information and Consent .................................................................... 44 
10 
REFERENCES ......................................................................................................... 45 


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LIST OF TABLES AND FIGURES 
Table 1: Dosing Schedule .......................................................................................................... 22 
Table 2:  Schedule of Events and Assessments .................................................................... 24 
Table 3: Clinical Laboratory Tests ............................................................................................ 34 
 
Figure 1: Study Schematic ......................................................................................................... 19 
 
 
 


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LIST OF ABBREVIATIONS 
ADHD 
Attention Deficit Hyperactivity Disorder 
ADHD-RS-IV/5 
ADHD Rating Scale- IV/5 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ANCOVA 
Analysis of Covariance 
CFR 
CGI-I 
Code of Federal Regulations 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity of Illness 
CI 
Confidence interval 
CL/F 
Apparent clearance 
Conners 3 
Conners 3rd edition Rating Scale 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders-5 
EOS 
End of Study 
ER 
Extended Release 
FDA 
Food and Drug Administration 
FOCP 
Females of Childbearing Potential 
GCP 
Good Clinical Practice 
IAF 
Informed Assent Form 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IWRS 
Interactive Web Response System 
LS 
Least square 
MAR 
Missing at Random 
MCAR 
Missing Completely at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI-KID 
Mini International Neuropsychiatric Interview for Children and 
Adolescents 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
PP 
Missing Not At Random 
Per Protocol 
PSI-4-SF 
Parenting Stress Index, Fourth Edition, Short Form 
PGx 
PK 
Pharmacogenomics 
Pharmacokinetics 
PT 
Preferred Term 
QD 
Once a day 
REML 
Restricted Maximum Likelihood 
SADR 
Suspected Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 


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SM 
Study Medication 
WFIRS-P 
Weiss Functional Impairment Rating Scale – Parent Version 
WHO DD 
World Health Organization Drug Dictionary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 










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Unscheduled visits may be conducted at the discretion of the investigator throughout the 
study. AEs will be assessed at all unscheduled visits. 
An optional PK substudy will be conducted between Visits 3 and 8, inclusive, to assess 
the PK characteristics of viloxazine and its metabolite, 5-hydroxy-viloxazine glucuronide, 
in this pediatric population.  A total of five blood samples will be taken: pre-dose and 1, 2, 
4, and 6 hours post dose. On the day the pre-dose sample is taken, SM must be 
administered at the site visit. Post-dose samples may be drawn on the same day or 
alternative visit days.  If drawn on alternate visit days, the time the SM was taken that day 
must be consistent with the dose time for the previous two days and the time of dose 
administration must be recorded for all three days. 
Subjects that have successfully completed this study will have the option of enrolling in a 
separate, open-label extension study. 
Figure 1: Study Schematic 
 
 
3.2 
RATIONALE FOR STUDY DESIGN 
812P301 is a randomized, double-blind, placebo-controlled, multicenter, 3-arm, parallel-
group, pivotal study of SPN-812 ER as monotherapy for the treatment of children ages 
6-11 years with ADHD.  This study is designed to demonstrate efficacy of either 100 or 
200 mg/day SPN-812 ER compared to placebo using change from baseline to the end of 
the study of the ADHD-RS-5 Total Score, the measure most commonly used to assess 
efficacy of drug treatment of ADHD.  Study structure and analysis are typical for a Phase 3 
pivotal trial. 
3.3 
STUDY POPULATION 
3.3.1  Number of Subjects 
Approximately 432 subjects will be randomized (144 subjects per treatment) in this study. 


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3.3.2 Inclusion Criteria   
1. Healthy male or female subjects, 6-11 years of age, inclusive. 
2. Diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental 
Disorders-5 (DSM-5), confirmed with the Mini International Neuropsychiatric 
Interview for Children and Adolescents (MINI-KID). 
3. Attention Deficit/Hyperactivity Disorder Rating Scale-5, Home Version: Child, 
Investigator Administered and Scored (ADHD-RS-5) score of at least 28. 
4. CGI-S score of at least 4 at screening. 
5. Weight of at least 20 kg. 
6. Free of medication for the treatment of ADHD for at least one week prior to 
randomization and agreement to remain so throughout the study.  
7. Considered medically healthy by the Investigator via assessment of physical 
examination, medical history, clinical laboratory tests, vital signs, and 
electrocardiogram. 
8. Written informed consent obtained from the subject’s parent or legal representative 
and informed assent from the subject, if applicable. 
9. Females of childbearing potential (FOCP) must be either sexually inactive 
(abstinent) or, if sexually active, must agree to use one of the following acceptable 
birth control methods beginning 30 days prior to the first dose, throughout the 
study: 
a. simultaneous use of male condom and intra-uterine contraceptive device 
placed at least four weeks prior to the first study drug administration 
b. surgically sterile male partner 
c. simultaneous use of male condom and diaphragm with spermicide 
d. established hormonal contraceptive 
3.3.3 Exclusion Criteria 
1. Current diagnosis of major psychiatric disorders. Subjects with Major Depressive 
Disorder are allowed in the study if the subject is free of episodes both currently 
and for the last six months. 
2. Current diagnosis of major neurological disorders.  Subjects with seizures or a 
history of seizure disorder within the immediate family (siblings, parents), or a 
history of seizure-like events are excluded from the study. 
3. Current diagnosis of significant systemic disease. 
4. 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. 
5. BMI greater than 95th percentile for the appropriate age and gender. 
6. History of an allergic reaction to viloxazine or related drugs. 
7. Any food allergy, intolerance, restriction or special diet that, in the opinion of the 
Investigator, could contraindicate the subject’s participation in this study.  
8. Subjects who received any investigational drug within the longer of 30 days or 5 
half-lives prior to Day 1 dosing of SM. 
9. Any reason, which, in the opinion of the Investigator, would prevent the subject 
from participating in the study. 
10. Positive drug screen at the Screening Visit. A positive test for amphetamines is 
allowed for subjects receiving a stimulant ADHD medication at Screening; the 
subject will be required to discontinue the stimulant for the study, beginning at least 
one week prior to the Baseline Visit. 
11. Pregnancy, breastfeeding, or refusal to practice abstinence or acceptable birth 
control during the study (for female subjects of childbearing potential). 


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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 8 (EOS). 
All subjects who discontinue early will complete the procedures listed for Visit 8 (EOS). 
All reasons for screening failure will be recorded. If the subject passes screening but fails 
eligibility at Baseline, the reason(s) will also be recorded. 
The Investigator(s) or subjects themselves may stop SM treatment at any time for safety 
or personal reasons.  A subject is free to withdraw from the study at any time for any 
reason without prejudice to their future medical care by the physician or at the institution.  
The 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 SM.  
Subjects removed from the study for any reason will not be replaced. 
Reasons for subject discontinuation may include: 
• 
Withdrawal of consent  
• 
Noncompliance  
• 
Occurrence of unmanageable AEs 
• 
Lost to follow-up 
• 
Other 
 
The primary reason for subject discontinuation must be recorded in the subject’s medical 
record and on the eCRF.  If a subject is withdrawn for more than one reason, each reason 
should be documented in the source document and the most medically significant reason 
should be entered on the eCRF. 
If a subject misses doses of SM during this study, the Investigator shall counsel the 
subject/caregiver on the importance of compliance.  If the subject has consistently missed 
doses, he or she may be discontinued from the study at the discretion of the Investigator 
and in consultation with the Medical Monitor; all procedures for discontinuation will be 
followed. 
4 
STUDY TREATMENT 
4.1 
Study Medication Identity, Packaging and Labeling 
Test and reference (matching placebo) products are capsules packaged in a double-blind 
configuration and supplied in labeled blister cards by the Sponsor. 
Each SM blister card will include identical capsules containing placebo or 100 mg of 
SPN-812  ER, and will supply a subject with seven days of dosing plus two extra days if 
needed.  Each card will be labeled with identification specific to the study and subject 
(protocol number, subject number and initials). 
4.2 
Study Medication Administration 
Each treatment will be administered as a single oral dose, once-a-day (QD), with or without 
food as either intact capsule, or as capsule content sprinkled on soft food. 


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4.3 
Method of Assigning Subjects to Treatment Group 
Eligible subjects will be randomized in a 1:1:1 ratio at Visit 2 (Baseline) and will receive 
either placebo, SPN-812 ER 100 mg/day, or SPN-812 ER 200 mg/day. 
Allocation of study treatment will occur centrally via an interactive web response system 
(IWRS) using a randomization schedule to determine the kit assignment for each subject 
being randomized.  Each SM kit contains six dosing cards.  One dosing card will be given 
to the subject at each weekly visit.  
The initial dose may be taken at the clinic during the Baseline Visit, with the next dose 
taken the next morning. Subjects will be titrated up at 100 mg/week to the final dose (1:1:1) 
as follows: 
Treatment A: Placebo 
Treatment B: SPN-812 ER100 mg/day (1  100 mg SPN-812 ER) 
Treatment C: SPN-812 ER 200 mg/day (2 100 mg SPN-812 ER) 
Table 1 below presents the details of the dosing schedule for each treatment group. 
Table 1: Dosing Schedule 
 
4.4 
Blinding 
The subject and all personnel involved with the conduct and the interpretation of the study, 
including the Investigators, study site personnel, the Sponsor and Contract Research 
Organization (CRO) clinical staff, including the Medical Monitor, will be blinded to the 
medication codes.  A limited number of Supernus personnel will perform and interpret the 
plasma assays for the population PK analysis and will be aware of these plasma data 
during the study.  These personnel will not have access to the randomization schedule, 
are not associated with the clinical conduct of the study, and will not reveal to any clinical 
personnel involved in the study the treatment to which a subject will be assigned.  
Randomization schedule data will be kept strictly confidential, filed securely by the IWRS 
vendor, and accessible only to authorized persons until the time of unblinding. 
4.5 
Study Medication Handling and Accountability 
All SM are supplied to the Investigator by the Sponsor. SM supplies must be kept in an 
appropriate secure area (e.g., locked cabinet) and stored according to the conditions 
specified on the SM label. 
Following Sponsor instructions and in compliance with International Conference on 
Harmonization (ICH) E6 as well as local, state, and federal regulations. The Investigator 
and study staff will be responsible for the accountability of all clinical supplies (receiving, 
shipment, dispensing, inventory, and record keeping) in a SM accountability log, a copy 
of which will be collected by Sponsor at the end of the study. 


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Under no circumstances will the Investigator allow the SM to be used other than as 
directed by this protocol.  Clinical supplies will not be dispensed to any individual who is 
not enrolled into the study. 
An accurate and timely record of the receipt of all clinical supplies; dispensing of SM to 
the subject; collection of unused supplies; and subsequent return of unused SM to the 
Sponsor must be maintained with dates.  This SM accountability log includes, but may not 
be limited to: (a) documentation of receipt of clinical supplies, (b) SM inventory log, (c) SM 
accountability log, and (d) all shipping service receipts.  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 FDA.  The 
assigned Clinical Research Associate (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. 
4.6 
Concomitant Medications  
Subjects may not be on any prohibited medication as indicated in the Inclusion/Exclusion 
Criteria.  Specific concomitant medication prohibitions include known CYP1A2 substrates 
(e.g., theophylline, melatonin, olanzapine, duloxetine). No additional concomitant 
medications are allowed during the study, with the following exceptions: 
• 
Nutritional supplements (e.g. multivitamins, fish oil) 
• 
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) 
All concomitant medications will be recorded in the eCRF. 
5 
Study Methods 
5.1 
Study Visits and Procedures 
All subjects who are randomized and take the initial dose of SM will be followed according 
to the protocol regardless of the number of doses of SM taken, unless consent for follow-
up is withdrawn.  The Sponsor or the Sponsor’s designee must be notified of all deviations 
from the protocol 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.  
Subjects will be instructed to call study personnel to report any abnormalities during the 
intervals in between study visits and to come to the study site if medical evaluation is 
needed and as the urgency of the situation indicates.  For emergency and other 
unscheduled visits to a medical facility other than the study site, medical records will be 
obtained by the Investigator or qualified designee as source data for study follow-up. 
Table 2 represents the Schedule of Events and Assessments for the study. 


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Table 2:  Schedule of Events and Assessments 
 
 
Treatment Phaseg 
 
Screening 
Baseline, 
Randomization 
Maintenance 
End of 
Studyi 
Visit # 
1 
2 
3-7 
8 
Visit Day 
 
1 
7, 14, 21, 28, 35 
42 
Visit Window (days) 
≤28d before 
V2 
 
±2 
±2 
Informed 
Consent/Assenta 
X 
 
 
 
Medical and 
Psychiatric History 
X 
 
 
 
Mini-KID 
X 
 
 
 
Demographics 
X 
 
 
 
Urine Drug Screen 
X 
 
 
 
Randomization 
 
X 
 
 
Physical Examb 
X 
 
 
 Xc 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
ECG (12-lead) 
X 
 
 
X 
Vital Signsd  
X 
X  
X 
X 
Hematology 
X 
 
 
X 
Serum Chemistry 
X 
 
 
X 
Pharmacogenomic 
sample 
X 
 
 
 
Urine Pregnancy Test, 
FOCP only 
 
X 
 
X 
CGI-S 
X 
X 
 
 
CGI-I 
 
 
X 
X 
C-SSRS 
X 
X 
X 
X 
ADHD-RS-5 
X  
X 
X 
X 
WFIRS-P, PSI-4-SF 
 
X 
 
X 
Conners 3e – parent, 
self 
 
X 
 
X 
Concomitant 
Medication 
X 
X 
X 
X 
Adverse Events 
 
Xf 
X 
 X 
Drug Dispensed 
 
Xg 
X 
 
Drug Return, 
Compliance 
 
 
X 
X 
Optional PK Blood 
Samplingh 
 
 
 
 
a 
To be obtained prior to performing any study procedures.  
b 
Includes height and weight, excludes genitourinary system 
c 
Changes from Screening only 
d 
Seated (5 min) heart rate and blood pressure, temperature, respiratory rate 
e 
Self report = 8-11 year olds only 
f 
At Baseline, AEs are recorded only after SM is administered. Subjects with serious adverse events at 
EOS will be followed until the event has resolved or considered stable. 
g 
Titration will begin after first dose of SM is administered 
h 
An optional PK substudy will take place between Visits 3 and 8, inclusive. Samples will be taken pre-dose 
and post-dose at hours 1, 2, 4, and 6. 
i 
EOS or last visit in the case of early discontinuation  


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5.1.1 Visit 1-Screening (Day -28 to -1) 
Prior to conducting screening procedures, written Informed Consent/Assent must be 
obtained from the parent or legal representative; written Informed Assent must also be 
obtained from the subject, if applicable according to local requirements.  Subject screening 
procedures will be performed within 28 days prior to Baseline Visit and may be done on 
more than one day.  Abnormal results on screening laboratory tests may be repeated at 
the discretion of the Investigator.  Subjects receiving ADHD drug therapy at Screening 
must discontinue that therapy for at least one week prior to Visit 2 (Baseline) and must 
remain off the ADHD drug for the duration of the study. 
The following procedures will be performed at Visit 1: 
1. Obtain written informed consent/assent. 
2. Obtain demographic information, medical and psychiatric history 
3. Administer MINI-KID for confirmation of ADHD diagnosis 
4. Perform limited (excluding genitourinary system) physical examination, record 
height and weight 
5. Assess Inclusion/Exclusion criteria 
6. Perform 12-lead ECG 
7. Record vital signs (HR, BP, temperature, and RR) 
8. Collect blood samples for hematology, chemistry, and PGx 
9. Collect urine sample for drug screen 
10. Administer ADHD-RS-5, CGI-S, and C-SSRS 
11. Assess and record concomitant medications 
12. For subjects eligible for study participation based on the above parameters, 
schedule the Baseline Visit, allowing for at least a one-week washout of any ADHD 
drug therapy the subject was receiving at Screening. 
A positive test for amphetamine is allowed for subjects receiving a stimulant ADHD 
medication.  However, the subject must discontinue the stimulant for the duration of the 
study starting at least one week prior to the Baseline Visit.  
5.1.2 Visit 2- Baseline Visit (Day 1) 
1. Confirm eligibility for the study (Inclusion/Exclusion criteria) 
2. Collect urine and perform pregnancy test (FOCP only) 
3. Randomize (via IWRS) 
4. Administer efficacy and safety scales: ADHD-RS-5, Conners 3 (parent, self [ages 
8-11]), WFIRS-P, PSI-4-SF, CGI-S, and C-SSRS  
5. Record vital signs (HR, BP, temperature, and RR) 
6. Record concomitant medications 
7. Record AEs after SM dosing only 
8. Dispense SM dosing card, observe administration of initial dose (titration starts 
when the first dose of SM is taken). 
 
Study Visits after Visit 2 will have a visit window of ±2 days.  Deviations from this window 
will be recorded in the eCRF but will not require separate notification of the Sponsor. 
5.1.3 Visit 3 through 7- Maintenance (Days 7, 14, 21, 28, 35 [±2 days]) 
1. Record vital signs (HR, BP, temperature, and RR)  
2. Administer efficacy and safety scales: ADHD-RS-5, CGI-I, and C-SSRS  
3. Record concomitant medications 
4. Record AEs 


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5. Collect returned SM and assess treatment compliance 
6. Dispense SM dosing card 
7. Optional - blood collection for PK substudy, if applicable 
5.1.4 Visit 8- End-of Study (Day 42) 
1. Perform limited (excluding genitourinary system) PE (record only changes from 
baseline), record height and weight 
2. Perform 12-lead ECG 
3. Record vital signs (HR, BP, temperature, and RR) 
4. Collect blood samples for hematology and chemistry 
5. Administer efficacy and safety scales: ADHD-RS-5, Conners 3 (parent, self [ages 
8-11]), WFIRS-P, PSI-4-SF, CGI-I, and C-SSRS  
6. Collect urine and perform pregnancy test (FOCP only) 
7. Record concomitant medications 
8. Record AEs 
9. Collect returned SM and assess treatment compliance 
10. Optional - blood collection for PK substudy, if applicable 
11. Determine if subject wants to participate in the open-label extension study 
5.1.5 Pharmacogenomic Sample Collection 
All subjects will have a blood sample taken at Screening for CYP2D6 pharmacogenomic 
testing. Results from individual tests will be used for research purposes only and will not 
be distributed. 
Samples will be identified only by the study subject number to maintain confidentiality. If 
a given subject’s PK data warrant evaluation of PGx, DNA will be extracted from that 
subject’s PGx blood sample and tested for any genetic variations associated with CYP2D6 
enzyme. This enzyme is involved in the metabolism of viloxazine and genetic variation 
may affect the pharmacokinetics of the drug. The residual DNA will be stored for possible 
testing of genes involved in the efficacy and possible association with particular adverse 
events of the drug (e.g., understand the non-responders to treatment and/or individuals 
who show unusual safety profile). The DNA analysis will not be used for individual genetic 
characterization and the subject’s identity will be kept confidential. Samples will be stored 
for up to 10 years for potential future research purposes such as possible testing of genes 
involved in the efficacy and possible association with particular adverse events of the drug 
(e.g., understand the non-responders to treatment and/or individuals who show unusual 
safety profile). 
Data from samples will not have diagnostic value and will not be used for individual genetic 
characterization or development of a commercial product. At the end of testing or 10 years, 
any remaining samples will be destroyed. The subject may withdraw consent for 
pharmacogenomic testing at any time; if consent is withdrawn, the subject’s sample will 
be destroyed. 
5.1.6 Pharmacokinetic Sub-study-Sample Collection 
Participation in the PK Sub-study is optional.  All blood samples for PK analysis will be 
drawn at the clinical site.  A maximum of five blood samples (4 mL each) will be taken for 
PK analysis over the course of the study.  Blood may be drawn for quantitative PK analysis 
during Visits 3-8. 
At one of these visits, subjects will arrive at the clinic in the morning prior to taking their 
morning dose.  A PK sample will be drawn pre-dose, after which the dose will be 


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administered in the clinic.  Post-dose PK samples will be taken at approximately 1, 2, 4, 
and 6 hours after the administered dose.  Collection of the post-dose samples may be on 
the same visit or an alternate visit (dosing at home) if the previous two doses were taken 
at approximately the same time and the times for that day and the previous two days were 
recorded. 
Blood samples will be collected and processed as per instructions in the Laboratory 
Manual.  The following excursion windows are permitted: 
• 
Pre-dose: 
up to 30 minutes before dose 
• 
1-2 hours: 
± 15 minutes 
• 
4 and 6 hours: 
± 30 minutes 
 
6 
STUDY VARIABLES 
6.1 
 Primary Efficacy Variable 
6.1.1 ADHD-RS-5 
The primary endpoint in this study is the CFB to EOS in the ADHD-RS-5 Total Score.  
The ADHD-RS-5 is an ADHD-specific rating scale designed and validated to assess 
current ADHD symptomatology as described in the fifth 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 and Inattention (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 the primary outcome 
measure for this study.  The ADHD-RS-5 Home Version: Child instrument will be 
administered and scored by Investigator at each weekly visit from Baseline through EOS. 
6.2 
Secondary Efficacy Variables 
The key secondary efficacy variables include: 
a) CGI-I 
b) Conners 3 –Parent, composite T-score 
c) WFIRS-P average score 
 
Additional secondary variables include: 
a) Proportion of responders with 50% improvement in the ADHD-RS-5 Total score (50% 
Responder rate) 
b) PSI-4-SF  
c) ADHD-RS-5 Inattention and Hyperactivity/Impulsivity subscale scores 
d) Conners 3 –Self, composite T-score (for ages 8-11 years) 
 
6.2.1 Clinical Global Impression - Improvement 
The CGI scale was developed to provide a brief, stand-alone assessment of the clinician’s 
view of a subject’s global functioning prior to and after administration of a SM (Guy 1976).  
The Clinical Global Impression – Severity of Illness (CGI-S) is a single item clinician rating 


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of clinician’s assessment of the severity of the ADHD symptoms in relation to the clinician’s 
total experience with patients with ADHD.  The Clinical Global Impression – Improvement 
Scale (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. Both CGI-S and CGI-I 
are rated on a 7-point scale of 1 to 7 with 7 being “extremely ill” or “very much worse”, 
respectively.  Successful therapy is indicated by a lower overall score in subsequent 
testing.   
• 
CGI-S will be evaluated by the Investigator at Screening and Baseline on a 7-point 
scale with 1=Normal,    2=Borderline ill, 3=Mildly ill, 4=Moderately ill, 5=Markedly 
ill, 6=Severely ill, and 7=Extremely ill.    
• 
CGI-I, relative to the condition at baseline, will be evaluated by the Investigator at 
each post-baseline visit on a 7-point scale with 1=Very much improved, 2=Much 
improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much 
worse, and 7=Very much worse.   
6.2.2 Conners 3 
The Conners 3rd Edition™ (Conners 3) is a focused diagnostic tool for assessment of 
ADHD and associated learning, behavior, and emotional problems in children ages 6 to 
18 years (Sparrow, 2010). The scale is based on the solid findings and key elements of 
its predecessor, the Conners' Rating Scales–Revised (CRS–R™), but offers a more 
refined assessment of ADHD and comorbid disorders (e.g., oppositional defiant disorder 
and conduct disorder). The Conners 3 instrument includes items related to inattention, 
hyperactivity, and impulsivity, as well as assessments of executive functioning, learning 
problems, and relationships. Like previous versions, the Conners 3 combines teacher, 
parent, and student reports to provide a particularly detailed and comprehensive 
evaluation of student behavior as observed in different settings. Teacher, parent, and self-
report (for 8-18y.o.) rating scales are all available in long and short versions.  The short 
forms of Parent, Teacher, and Self Reports of Conners 3 are comprised (respectively) of 
45, 41, and 41 items.  All Conners 3 scale versions are scored on a 4-point scale (0-3), 
where a higher score indicates more severe symptom presentation.   
The Conners 3 scales will be administered at Visit 2 (Baseline) and at Visit 8 (EOS) 
according to subjects’ age as follows: 
• 
Age 6-11:  
Conners 3 – Parent: Short (Conners 3-PS) 
• 
Age 8-11 only:  Conners 3 – Self-Report; Short (Conners 3-SRS) 
 
6.2.3 WFIRS-P 
The Weiss Functional Impairment Rating Scale (WFIRS) instrument evaluates ADHD-
related functional impairment (Gajria, 2015 Thompson, 2017).  This scale allows the 
clinician to assess to what degree a patient’s behavior and emotional problems affect 
his/her ability to accomplish daily tasks and interactions and helps to identify specific areas 
of difficulty.  The scale has been validated in the ADHD population; the parent-based 
version (WFIRS-P) completed by the parent/guardian of a child is used in this study and 
comprises 50 items grouped into six domains: Family, School (learning and behavior), Life 
Skills, Child’s Self-Concept, Social Activities, and Risky Activities.  The items relate to the 
past month and are scored using a 4-point Likert scale. Higher WFIRS-P scores indicate 
more severe functional impairment.   
This instrument will be completed at Baseline and EOS by the parent/caregiver. 


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6.2.4 PSI-4-SF 
The Parenting Stress Index, Fourth Edition (PSI-4) questionnaire evaluates the magnitude 
of stress in the parent-child relationship based on the parent’s perception of the child’s 
characteristics, the personal characteristics of the parent, and the interaction between the 
parent and the child (Abidin, 1995).  The short form of the PSI-4 (PSI-4-SF) consists of 36 
items divided into three domains: parental distress, parent-child dysfunctional interaction, 
and difficult child.  The PSI-4-SF scale was developed for parents of children ages 1 month 
to 12 years.   
This scale will be completed at Baseline and at EOS by the parent/caregiver. 
6.3 
Safety Variables 
The safety variables for the study are AEs, clinical laboratory test results, vital signs, ECG 
results, and treatment-emergent suicidal ideation. 
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. 
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, C-SSRS, and the performance of physical examinations as detailed in the 
Schedule of Events and Assessments. 
6.4 
Adverse Events 
As defined by the ICH Guideline for Good Clinical Practices (GCP), an adverse event (AE) 
is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with treatment. 
An AE can be: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• 
Any new disease, intercurrent injuries, or exacerbation of an existing disease. 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG) that results in 
symptoms, a change in treatment, or discontinuation from SM. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 
Surgical procedures are not AEs; they are therapeutic measures for conditions that require 
surgery.  The condition for which the surgery is required is an AE, if it occurs or is detected 
during the study period. 
6.4.1 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. 


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Adverse drug reactions (ADRs) are a subset of all SADRs for which there is reason to 
conclude that the drug caused the event. 
6.4.2 Recording and Evaluation of Adverse Events 
All subjects who are screened (Visit 1) will be questioned regarding the occurrence of AEs.  
At each contact with the subject, the investigator must seek information on AEs by specific 
questioning and, as appropriate, by examination.  Information on all AEs should be 
recorded immediately in the source document, and also in the appropriate adverse event 
module of the eCRF.  All clearly related 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 screening and throughout the study period must be recorded.  A 
treatment-emergent adverse event (TEAE) is defined as an AE with a start date on or after 
the first dose of study drug is taken, or that worsened following first administration of study 
drug.  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 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 Averse Event (SAE)? 
• 
Causality: Was AE related or possibly related to the SM? 
• 
Severity: How pronounced is the incapacity/discomfort caused by an AE. 
6.4.3 Criteria for Assessing Severity 
The Investigator will evaluate the comments of the subject and the response to treatment 
in order that he or she may judge the true nature and severity of the AE.  Severity refers 
to the accumulated intensity of discomfort/impairment of health since the last recording of 
AEs and will be assessed according to the following criteria: 
• Mild: 
Awareness of sign, symptom, or event, but easily tolerated 
• Moderate: Discomfort enough to interfere with usual activity and may warrant 
intervention 
• Severe:    Incapacitating with inability to do usual activities or significantly 
affects clinical status and warrants intervention 
The criteria for assessing severity are different from those used for seriousness. 
6.4.4 Criteria for Assessing Causality 
The Investigator is responsible for determining the relationship between the administration 
of SM and the occurrence of an AE as not suspected or as a suspected reaction to SM.  
These are defined as follows: 
Not suspected: The temporal relationship of the AE to SM administration makes a causal 
relationship unlikely, or other drugs, therapeutic interventions, or underlying conditions 
provide a sufficient explanation for the observed event.  
• Not related:  Temporal relationship to SM administration is missing or 
implausible, or there is an evident other cause. 


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• Unlikely related:  Temporal relationship to SM administration makes a causal 
relationship improbable; and other drugs, chemicals, or underlying disease 
provide plausible explanations. 
Suspected: The temporal relationship of the AE to SM administration makes a causal 
relationship possible, and other drugs, therapeutic interventions, or underlying 
conditions do not provide a sufficient explanation for the observed event.  
• Possibly related:  Temporal relationship to SM administration is plausible, but 
concurrent disease or other drugs or chemicals could also explain event.  
Information on drug withdrawal may be lacking or unclear.  This will be reported 
as a Suspected Adverse Drug Reaction (SADR). 
• Definitely related: Temporal relationship to SM administration is plausible, and 
concurrent disease or other drugs or chemicals cannot explain event.  The 
response to withdrawal of the medication (dechallenge) should be clinically 
plausible. 
 
The 
event 
must 
be 
definitive 
pharmacologically 
or 
phenomenologically, using a satisfactory rechallenge procedure if necessary.  
This will be reported as an Adverse Drug Reaction (ADR). 
6.4.5 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. 
6.4.6 Investigator Responsibilities for Reporting SAEs 
The Investigator must immediately report to the Sponsor all SAEs, regardless of whether 
the Investigator believes they are drug related. 
All SAEs must be reported to the Drug Safety Contact within 24 hours of first becoming 
aware of the SAE.  The Investigator must complete an SAE Form and include a detailed 
description of the SAE, as well as other available information pertinent to the case (e.g., 
hospital records, autopsy reports and other relevant documents).  The investigator will 
keep a copy of this SAE Report form on file at the study site. 


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viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or performing this study. 
The Investigator or study physician, after thorough consideration of all facts that are 
available, must include an assessment of causality of an AE to SM in the report to the 
Sponsor. 
Follow-up information, or new information available after the initial report, should be 
actively sought and reported to the Sponsor, as it becomes available, using the SAE 
Report Form. 
 
 
  
6.4.7 Other Events Requiring Immediate Reporting 
The Investigator must report a pregnancy that occurs in a subject during a clinical study 
to the Drug Safety Contact within 24 hours of first becoming aware of the event.  
Pregnancy should be reported on a Pregnancy Report Form.  The Investigator should 
discuss the case with the Medical Monitor; the Investigator must follow any pregnant 
subject for 3 months after the child is born.  Any AEs concerning the pregnancy of the 
subject during pregnancy or the child after birth must be documented and reported to the 
Sponsor. 
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. 
6.4.8 Sponsor Responsibilities for Reporting SAEs 
The Sponsor will inform Investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (i.e., within 
specific timeframes).  For this reason, it is imperative that study sites submit SAE 
information to the Sponsor in the manner described above. 
Investigators must comply with the applicable regulatory requirements related to the 
reporting of SAEs to the 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. 
6.5 
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. 
 


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6.5.1 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).  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. 
6.5.2 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. 
6.5.2.1 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.  
6.5.2.2 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 one week and/or refer him/her to a qualified mental health professional. 
6.5.2.3 Non-acute Suicidal Risk 
The Investigator will conduct safety planning with the subject and will follow up within one 
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. 
6.6 
 Clinical Measurements 
6.6.1 Laboratory 
All clinical laboratory tests will be performed by a central laboratory as specified in the 
reference binder. 
Details for collecting, handling, and shipping samples (including shipment addresses) will 
be detailed in a separate clinical laboratory manual.  The Schedule of Events and 
Assessments (Table 2) shows the time points at which blood and urine samples will be 
collected for clinical laboratory tests (and plasma concentration levels for those subjects 
that choose to participate in the PK substudy). 
Table 3 presents the clinical laboratory tests to be performed. 






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• 
The Intent-to-Treat (ITT) population for efficacy will include all randomized subjects 
who took at least one dose of study medication and had a Baseline and ≥1 post-
randomization ADHD-RS-5 assessment. Subjects will be analyzed according to 
the treatment to which they were randomized. 
• 
The Per Protocol (PP) population consists of all subjects in the ITT population who 
completed all 8 visits with no missing ADHD-RS-5 assessments and no major 
protocol violations. Subjects will be analyzed according to the treatment they 
actually received. 
• The Safety Population consists of all subjects randomized into the study who 
receive at least one dose of SM. Subjects will be analyzed according to the 
treatment they actually received. 
• 
PK population will include all subjects in the safety population who had ≤1 PK 
sample that is not below the LLOQ. 
7.4 
Demographics and Baseline Analysis 
Demographic/baseline variables including age, age group, sex, ethnicity, race, height and 
weight at screening, and BMI will be summarized using descriptive statistics for continuous 
variables and using counts and percentages for categorical variables.  The descriptive 
summary will be presented by treatment group for the randomized population and ITT 
population. 
Baseline disease characteristics will include ADHD-RS-5 Total score, subscale scores, 
and hyperactivity/impulsivity score. These will be summarized for the ITT population. 
Baseline comparability among the treatment groups will be summarized using a chi-
square test for categorical variables and F-test for continuous variables. P-values will be 
used for descriptive purposes only. 
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 ITT population 
• 
Subjects in the PP 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 the 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 any 
study treatment. This will be calculated for each subject by taking the difference between 
the date of last dose minus the date of the first dose, plus 1 (date of last dose minus date 
of first dose +1). 


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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 study drug compliance is defined as {(number of capsules dispensed minus 
number of capsules returned) / (date of last dose minus date of first dose + 1)}* 100%. 
For each treatment, SM compliance will be summarized by compliance category (<80%, 
80-120%, and >120%) and number of subjects in each compliance category.  Study 
medication compliance will also be summarized as a continuous variable using descriptive 
statistics (n, mean, standard deviation, median, minimum, and maximum) for each 
treatment. 
Summaries of treatment compliance and exposure will be presented separately for the 
Titration Period, Maintenance Period, and combined Titration and Maintenance Periods. 
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 
Efficacy Analysis 
7.8.1 Primary Efficacy Analysis 
7.8.1.1 Primary analysis 
The primary efficacy variable, change from baseline in ADHD-RS-5 Total Score to Week 6 
(EOS), will be analyzed using MMRM, which assumes that missing data are MAR. The 
model will include fixed effect terms for baseline ADHD-RS-5 Total Score, age group, 
treatment, visit, and treatment-by-visit interaction as independent variables. The model 
parameters will be estimated using restricted maximum likelihood method with 
unstructured variance-covariance matrix and Kenward-Roger approximation to estimate 
denominator degrees of freedom. In case there is a convergence problem in the MMRM 
model with the unstructured variance-covariance matrix, the first (co)variance structure 
which does not have convergence problem will be used for the analysis from the following 
ordered list: 1) Toeplitz, 2) Autoregressive of order 1, and  3) Compound symmetry. 
The adjusted mean (LS Mean) of CFB to EOS for ADHD-RS-5 Total Score for each 
treatment group (Placebo, SPN-812 ER 100 mg and SPN-812 ER 200 mg) will be 
presented, along with the corresponding standard error. Each of the treatment groups 
(SPN-812 ER 100 mg and 200 mg) will be compared with the Placebo. The p-values, 
Least Squares (LS) of treatment means, differences between the LS treatment means and 
placebo, and 95% confidence intervals for the treatment differences will be computed. 
To maintain the Type I error rate at 5% level, a sequential testing (Westfall et al ,1999) of 
the null hypotheses H01: No treatment mean difference between SPN-812 ER 200 mg 
group and placebo group and H02: No treatment mean difference between SPN-812 ER 
100 mg group and placebo group will be performed. If H01 is not rejected, then H02 will not 
be tested and the conclusion will be that neither dose groups are efficacious. If H01 is 
rejected, then H02 will be tested. If H02 is rejected then it will be concluded that both SPN-
812 ER 200 mg and SPN-812 ER 100 mg are superior to placebo. If H01 is rejected and 
H02 is not rejected then it will be concluded that only SPN-812 ER 200 mg is superior to 
placebo. 


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7.8.1.2 Sensitivity analyses 
The sensitivity analysis assumes that missing ADHD-RS-5 Total Scores are MNAR. 
Placebo-based multiple imputation will be used to fill in missing values. This approach 
may be considered “worst-case” sensitivity analyses as it assumes that after 
discontinuation, subjects from the active treatment arms would adopt the outcome model 
estimated from the placebo arm. The placebo-based imputation will be implemented as 
described in the SAP. 
7.8.2 Secondary Efficacy Analyses 
The secondary analyses will be based on the ITT population with missing values imputed 
using multiple imputation assuming MAR.  
All secondary analyses will be analyzed using ANCOVA (except CGI which uses ANOVA 
on the absolute value of CGI-I at Week 6 (EOS) on the change from baseline at Week 6 
(EOS) with treatment and baseline as fixed effect. Each of the treatment groups (SPN-
812 ER 100 mg and 200 mg) will be compared with the Placebo. The p-values, Least 
Squares means of the treatment groups, differences between the LS treatment means 
and placebo (SPN-812 ER 100 mg minus Placebo and SPN-812 ER 200 mg minus 
Placebo), and 95% confidence intervals for the treatment differences will be computed.  
7.8.2.1 Key secondary analyses 
Key secondary analyses of the secondary efficacy variables will include: 
a) CGI-I – The absolute value of CGI-I at EOS will be analyzed using ANCOVA with 
fixed effects for treatment and baseline as a covariate. To compare the treatment 
groups, the difference in LS means (SPN-812 ER 100 mg minus Placebo and 
SPN-812 ER 200 mg minus Placebo) will be presented along with the 95% 
confidence interval (CI) around the difference and p-value. 
b) Conners 3 Parent - A composite T-score will be calculated by averaging over the 
six domains, and the change from baseline to Visit 8 (EOS) in the composite T-
score will be analyzed using ANCOVA model with fixed effects for treatment and 
baseline as a covariate. Each of the treatment groups (SPN-812 ER 100 mg and 
200 mg) will be compared with the Placebo. The p-values, Least Squares means, 
differences between the LS treatment means and placebo, and 95% confidence 
intervals for the treatment differences will be computed. 
c) WFIRS-P - The change from baseline in WFIRS-P to Visit 8 (EOS) will be analyzed 
using ANCOVA model with fixed effects for treatment and baseline as a covariate. 
Missing Subscale scores and Total Score will be handled using multiple imputation 
under MAR assumption for inferential analyses. Each of the treatment groups 
(SPN-812 ER 100 mg and 200 mg) will be compared with the Placebo. The p-
values, LS means of treatment groups, differences between the LS means and 
placebo, and 95% confidence intervals for the treatment differences will be 
computed. 
 
To preserve the overall type I error rate at 0.05 for the key secondary endpoints, a 
sequential testing procedure will be used with the following features. First, only dose or 
doses that are significantly different from placebo for the primary endpoint will be tested 
for secondary endpoints. If the primary endpoint analysis indicates only one dose is 
significant, no multiplicity adjustment is required. Otherwise, multiplicity adjustment will be 
performed as in the following. 


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The first of the secondary endpoints (CGI-I) will be used to test each treatment group to 
placebo using a sequential testing of the null hypotheses H01: No treatment mean 
difference between SPN-812 ER 200 mg group and placebo group and H02: No treatment 
mean difference between SPN-812 ER 100 mg group and placebo group will be 
performed. If H01 is not rejected, then H02 will not be tested and the conclusion will be that 
neither dose groups are efficacious. If H01 is rejected, then H02 will be tested. If H02 is 
rejected, then it will be concluded that both SPN-812 ER 200 mg and SPN-812 ER 100 mg 
are superior to Placebo. If H02 is not rejected, then it will be concluded that only SPN-812 
ER 200 mg is superior to placebo. Then, the second secondary endpoint (Conners-3) will 
be tested in the same manner but only using those doses that were retained from the 
primary and the first secondary endpoint. Finally, the third key secondary endpoint 
(WFIRS-P) will be tested in the same manner but only using those doses that were 
retained from the primary, the first key secondary endpoint, and the second key secondary 
endpoints. 
7.8.2.2 Additional secondary analyses 
Additional secondary analyses of the secondary efficacy variables will include: 
a) 50% Responder rate for ADHD-RS-5 - Percent reduction will be calculated as: % 
reduction =100*(ADHD-RS-5 Total Score at Visit 8 (EOS) - Baseline ADHD-RS-5 
Total Score)/ Baseline ADHD-RS-5 Total Score. The proportion of responders will 
be presented for each treatment group. The 2-sided 95% CI around the difference 
in proportions (SPN-812 ER 100 mg minus Placebo, SPN-812 ER 200 mg minus 
Placebo) and the p-value from Pearson’s Chi-squared Test or Fisher’s Exact Test  
will be presented. 
b) PSI-4-SF - The change from baseline in PSI-4 total score to Visit 8 (EOS) will be 
analyzed using ANCOVA model with fixed effects for treatment and baseline as a 
covariate. Each of the treatment groups (SPN-812 ER 100 mg and 200 mg) will be 
compared with the Placebo. The p-values, LS means of treatment groups, 
differences between the LS means and placebo will be presented.   
c) ADHD-RS-5 Inattention and Hyperactivity/Impulsivity subscales - The primary 
analysis for ADHD-RS-5 Total score will be repeated for the change from baseline 
to EOS in ADHD-RS-5 Inattention and the change from baseline to Visit 8 (EOS) 
in Hyperactivity/Impulsivity subscales.  
d) Conners 3 -Self – The analysis for Conners 3 -Parent will be repeated for self 
scores. 
The secondary analyses will be repeated for the per protocol population. 
7.8.3 Subgroup Analyses 
The primary and key secondary efficacy variable analyses may be repeated by the 
following subgroups to explore the heterogeneity of treatment effect: 
• 
Gender (male, female) 
• 
Age (6-9 years, 10-11 years) 
• 
Race (white, non-white) 




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AEs will be summarized using discrete summaries at the subject and event level by 
System Organ Class and Preferred Term, and by severity and relationship separately for 
each treatment group.  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 group using descriptive 
statistics for hematology and biochemistry.  For quantitative laboratory parameters, both 
actual values and change from Screening values will be summarized. 
Vital signs will be summarized by visit by treatment group using descriptive statistics.  Both 
actual values and change from baseline will be summarized. 
ECG results will be summarized by visit by treatment group using descriptive statistics (for 
quantitative ECG parameters) and frequency tables (for qualitative ECG parameters, 
including the overall ECG finding). 
C-SSRS outcomes will be summarized using number and percent of subjects by 
categories for suicidal ideation only, suicidal behavior only, and suicidality (ideation and 
behavior combined). The summary will be presented by treatment groups. 
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/IAF, 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. 


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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. 
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 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 
Viloxazine and 5-hydroxy-viloxazine glucuronide concentrations in plasma samples will be 
determined using a validated chromatographic method.  Viloxazine concentrations will be 
reported as viloxazine free base. Details on the analytical methodology, the method of 
validation, and the analytical within-study quality control procedures will be included in the 
clinical study report for this study.  
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, 


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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 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 any Sponsor comments on the proposed publication or presentation have 
been addressed to the Sponsor’s satisfaction. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be outlined in the agreement 
between each Investigator and the Sponsor or designee. 
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 


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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. 
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/IAF 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) at approximately 32 study sites in the US. 
Contact persons at the Sponsor and the CROs are listed in the reference binder provided 
to each investigational site.  The study will be monitored by qualified personnel from the 
Sponsor or their designees, such as the CROs, for their respective sites.  Medical writing, 
data management, and statistical analyses will be performed by the CROs.  Laboratory 
tests will be conducted by a central laboratory as designated in the reference binder.  
The study will be monitored by qualified personnel from Supernus.  Data management 
and statistical analyses will be the responsibility of the CRO data management and 
biostatistics groups.  
9.4 
Subject Information and Consent 
The Investigator (or designee) will inform the caregiver and subject 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. 


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This document is confidential.  It contains proprietary information of Supernus® Pharmaceuticals, Inc.  Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or performing this study. 
The process for obtaining informed consent/assent will be in accordance with all 
applicable regulatory requirements.  The Investigator (or designee) and subject must sign 
and date the ICF/IAF before the subject can participate in the study.  The caregiver/subject 
will be given a copy of the signed and dated ICF/IAF and the original will be retained in 
the investigational site study records. 
The decision regarding subject participation in the study is entirely voluntary.  The 
Investigator (or designee) must emphasize to the subject 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/IAF by the IRB and 
use the amended ICF (including ongoing subjects). 
10 REFERENCES 
Abidin, R. R. (1995). Parenting Stress Index, Third Edition: Professional Manual. Odessa, 
FL: Psychological Assessment Resources, Inc. 
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quality of life and psychopathological profile: data from an observational study in children 
with ADHD. Eur Child Adolesc Psychiatry (2011); 20(2):267-275. 
DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD Rating Scale-5 for Children and 
Adolescents: Checklists, Norms, and Clinical Interpretation. New York, NY: The Guilford 
Press. 2016. 
Epstein JN, Weiss MD.  Assessing Treatment Outcomes in Attention-Deficit/Hyperactivity 
Disorder: A Narrative Review. Prim Care Companion CNS Disord. 2012; 14(6): 
PCC.11r01336. 
Gajria K, Kivote V, Sikirica V, Reilly K, Kosinski M, Erder MH. (2015) Validation of the 
Weiss Functional Impairment Rating Scale – Parent Report Form in attention 
deficit/hyperactivity disorder. European Neuropsychopharmacology, Volume 24, S711 - 
S712. 
Guy, W. (1976). “Clinical Global Impression (CGI). Early Clinical Drug Evaluation Unit 
(ECDEU) Assessment Manual for Psychopharmacology”.  Rockville, MD: U.S. 
Department of Health, Education, and Welfare; Public Health Service, Alcohol, Drug 
Abuse, and Mental Health Administration; National Institute of Mental Health; 
Psychopharmacology Research Branch; Division of Extramural Research Programs. pp. 
218–222. 
Sparrow EP Essentials of Conners Behavior Assessments. Hoboken, NJ: John Wiley & 
Sons, Inc. 2010 
SPN-812V-ER Investigator's Brochure v5.0, 2017. 
Thompson T, Lloyd A, Joseph A, Weiss M. The Weiss Functional Impairment Rating 
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optimal thresholds using ROC analysis. Qual Life Res. (2017); Feb 20. doi: 
10.1007/s11136-017-1514-8. [Epub ahead of print].   
Westfall, Peter H., Tobias, Randall D., and Wolfinger, Russell D., (1999). Multiple 
Comparisons and Multiples Tests Using SAS®, Cary, NC: SAS Institute Inc. 


Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
22 Aug 2018 
812P301 
Version 4.0 
Page 46 of 46 
 
This document is confidential.  It contains proprietary information of Supernus® Pharmaceuticals, Inc.  Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or performing this study. 
Wiener J, Biondic D, Grimbos T, Herbert M. Parenting Stress of Parents of Adolescents 
with Attention-Deficit Hyperactivity Disorder. Journal of Abnormal Child Psychology 
(2016); 44(3):561-574. 
 

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