Clinical trial NCT03247556
Conditions: ADHD
Sponsor: Supernus Pharmaceuticals, Inc.
Start date: 2017-11-20; Completion date: 2019-02-14
Enrollment: 297 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy and safety of high doses of SPN-812 in adolescents (12-17 years old) 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 a monotherapy for the treatment of adolescents 12-17 years old with ADHD.

Arms: arm 1: Placebo, qd, oral capsule arm 2: 400mg SPN-812, qd, oral capsule arm 3: 600mg SPN-812, qd, oral capsule
Interventions: intervention 1: Placebo intervention 2: 400mg SPN-812 intervention 3: 600mg SPN-812
Intervention descriptions: intervention 1: Placebo was administered once daily intervention 2: 400mg SPN-812 was administered once daily and compared to Placebo intervention 3: 600mg SPN-812 was administered once daily and compared to Placebo

Protocol documents:
Prot_000.pdf: 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
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812P304 
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TITLE PAGE 
Protocol Number: 
812P304 
Title: 
Evaluation of SPN-812 ER 400 and 600 mg Efficacy and Safety 
in Adolescents with ADHD - A Double-Blind, Placebo-
Controlled, Pivotal Trial 
Sponsor: 
 
  
 
 
 
 
IND number: 
108,864 
Investigational 
Medicinal Product: 
Viloxazine hydrochloride 
Indication: 
Attention Deficit Hyperactivity Disorder (ADHD) 
Contract Research 
Organization (CRO): 
 
 
 
CRO Medical 
Monitor 
 
 
 
 
 
 
 
Phase: 
3 
Protocol Version: 
4.0 
Date: 
12 October 2018 
Good Clinical 
Practice (GCP) 
Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonization (ICH) Good Clinical Practices 
(GCP) and all applicable local regulations.  All required study 
documentation will be archived as required by regulatory 
authorities. 
 
 
 
 


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






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Study Design:  Randomized, double-blind, placebo-controlled, multicenter, 3-arm, parallel-
group, efficacy and safety pivotal study  
Number of Subjects:  Approximately 300 subjects (100 subjects per treatment) 
Criteria for Inclusion: 
Male and female subjects, 12-17 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 200 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 200 mg/week to the final randomized dose (1:1:1) as follows:  
Treatment A: Placebo  
Treatment B: SPN 812 ER 400 mg/day (2 x 200 mg SPN-812 ER) 
Treatment C: SPN-812 ER 600 mg/day (3 x 200 mg SPN-812 ER) 
Duration of Treatment and Study Duration:  
Screening window: within 28 days prior to Visit 2 (Baseline Visit) 
Titration period: 2 weeks  
Maintenance treatment period: 5 weeks  
Total subject duration on study: approximately 11 weeks (including up to 28 days of Screening) 
Total number of visits: 9  
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. 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 – 9): This phase will consist of two weeks of Titration 
followed by five weeks of Maintenance phase until end of study (EOS)/Visit 9. 
Baseline, Randomization, and Dispensation of SM (Visit 2):  Approximately 300 eligible subjects 
will be randomized.  Within 28 days of the 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]), subjects will be randomized and receive blinded SM.  
Study Dose Treatment: Titration (Visits 2-3): Subjects will return to the clinical site for weekly 
visits to undergo efficacy and safety evaluations and to pick up the next dosing card. 
Study Dose Treatment: Maintenance (Visits 4-9): 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 9/EOS. 
End of Study (Visit 9): Subjects will return for final evaluation (the same evaluation will be done 
if the subject terminated early). 
Optional Substudy: Pharmacokinetic Sampling (Visit 3-9):  The following PK samples will be 
collected: pre-dose and 1, 2, 4, and 6 hours post-dose. 


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Endpoints: 
Primary Endpoint: The primary endpoint in this study is the change from baseline (CFB) to EOS 
in the ADHD-RS-5 total score. 
Key Secondary Efficacy Endpoints: a) CGI-I, b) Conners 3 - Parent composite T-score, and 
c) WFIRS-P average score 
Additional Secondary Efficacy Endpoints: a) Proportion of responders with 50% improvement in 
ADHD-RS-5 Total score, b) SIPA, c) ADHD-RS-5 Inattention and Hyperactivity/Impulsivity 
subscale scores, and d) Conners 3 - Self composite T-score  
  
 
 
 
 
Safety Assessments: Safety will be assessed using Adverse Events (AEs), clinical laboratory 
tests, vital signs, physical examinations, ECGs and the Columbia Suicide Severity Rating Scale 
(C-SSRS). 
Sample Size: 
Seventy-two subjects per treatment group in the Intent-To-Treat (ITT) population will yield 90% 
power at a significance level of 0.05 (two-sided) using a two-sample t-test with equal allocation to 
the treatment groups. This assumes an effect size of 0.547, which was observed in the 
comparison of SPN-812 200 mg and placebo in the SPN 812 Phase IIb study (based on 
the CFB to endpoint in the ADHD-RS-IV total score) and will maintain consistency in the 
sample size assumption used between this clinical trial and the SPN-812 P302 study 
(e.g., across the SPN-812 clinical trials in the adolescent population).  A total of 300 
subjects (100 subjects in each of the three treatment groups) will be randomized to account for 
an anticipated 27.9% of randomized subjects not completing the study. 
Analysis Populations: 
 
The Randomized population will include all enrolled subjects who had a baseline visit and 
are randomized via the IWRS. 
 
The ITT population for efficacy will include all randomized subjects who took at least one 
dose of study medication, and had a Baseline and at least one 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 9 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. 
 
The PK population will include all subjects in the safety population with ≥1 PK sample 
that is not below the Lower Limit of Quantitation (LLOQ). 
Handling of Missing Data:  
With respect to the primary analysis, missing ADHD-RS-5 Total scores will be assumed to be 
missing at random (MAR) and will be handled using a Mixed Model for Repeated Measures 
(MMRM) method in SAS. The sensitivity analysis for the primary endpoint will be performed by 
assuming that missing ADHD-RS-5 Total Scores are missing not at random (MNAR). For analysis 
of secondary endpoints, missing values will be assumed as MAR. 
Statistical Methods: 
 


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All tabulations of analysis results will include summaries for the following three treatments: 
SPN-812 ER 600 mg, SPN-812 ER 400 mg, and placebo. 
Where appropriate, variables will be summarized descriptively (frequency count and percent for 
categorical variables, and number of subjects (n), mean, standard deviation (SD), median, 
minimum, and maximum for continuous variables).  
Categorical variables will be analyzed using categorical response methods such as Pearson’s 
Chi-square test. If expected frequencies are less than 5 in a given cell, then 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 7 (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, 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 400 mg and SPN-812 ER 600 mg) will be presented, along with the 
corresponding standard error. Each of the active treatment groups (SPN-812 ER 400 and 
600 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 at Week 7 (EOS) on the change from baseline at Week 7 (EOS) with treatment and 
baseline as fixed effect. 
Analyses of key secondary endpoints will 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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Pharmacokinetic and Pharmacogenomic Methods: 
Sampling:  For PK analysis, a maximum of five blood samples will be collected at one or more of 
Visits 3-9. For PGx analysis, a single blood sample will be collected at screening. 
Bioanalytical Analysis: 
Viloxazine concentrations and 5-hydroxy-viloxazine glucuronide concentrations in plasma will be 
determined for all treatments using a validated achiral chromatographic method. Viloxazine 
concentrations will be reported as viloxazine free base. 
Pharmacokinetic Analysis: 
Plasma concentrations for viloxazine (and 5-hydroxy-viloxazine glucuronide, if applicable) will be 
provided. Population PK data will be pooled across all subjects who participate in this optional 
portion of the study and analyzed using nonlinear mixed-effects modeling methods. 
 
 
 
 Population PK analyses will be reported separately from the clinical study 
report. 
 
Pharmacogenomics Analysis: 
A blood sample will be collected from each individual at screening for PGx analysis. 
 
 
 
 
 
 
 
 
 
 
 
 


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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 ....................................................................................... 18 
2.3 
Exploratory Objectives ..................................................................................... 18 
3 
INVESTIGATIONAL STUDY PLAN ............................................................. 18 
3.1 
Overall Study Design and Plan ........................................................................ 18 
3.2 
RATIONALE FOR STUDY DESIGN .................................................................. 20 
3.3 
STUDY POPULATION........................................................................................ 20 
3.3.1 
Number of Subjects ...................................................................................... 20 
3.3.2 
Inclusion Criteria ........................................................................................... 20 
3.3.3 
Exclusion Criteria .......................................................................................... 21 
3.4 
Completion of Study and Discontinuation of Subjects ................................ 21 
4 
STUDY TREATMENT................................................................................... 22 
4.1 
Study Medication Identity, Packaging and Labeling..................................... 22 
4.2 
Study Medication Administration .................................................................... 22 
4.3 
Method of Assigning Subjects to Treatment Group ..................................... 22 
4.4 
Blinding .............................................................................................................. 23 
4.5 
Study Medication Handling and Accountability ............................................ 23 
4.6 
Concomitant Medications ................................................................................ 24 
5 
Study Methods ............................................................................................ 24 
5.1 
Study Visits and Procedures ........................................................................... 24 
5.1.1 
Visit 1 - Screening (Day -28 to -1) ................................................................ 26 
5.1.2 
Visit 2 - Baseline Visit (Day 1) ...................................................................... 26 
5.1.3 
Visit 3 – 8 - Titration (Days 7, 14 [±2 days]) and Maintenance (Days 21, 28, 
35, 42 [±2 days]) ........................................................................................... 26 
5.1.4 
Visit 9 - End-of Study (Day 49 [±2 days]) ..................................................... 27 
5.1.5 
Pharmacogenomic Sample Collection ......................................................... 27 


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5.1.6 
Pharmacokinetic Sub-study-Sample Collection ........................................... 27 
6 
STUDY VARIABLES .................................................................................... 28 
6.1 
Primary Efficacy Variable ................................................................................. 28 
6.1.1 
ADHD-RS-5................................................................................................... 28 
6.2 
Secondary Efficacy Variables .......................................................................... 28 
6.2.1 
Clinical Global Impression – Improvement ................................................... 29 
6.2.2 
Conners 3...................................................................................................... 29 
6.2.3 
WFIRS-P ....................................................................................................... 29 
6.2.4 
SIPA .............................................................................................................. 30 
6.3 
Safety Variables................................................................................................. 30 
6.4 
Adverse Events ................................................................................................. 30 
6.4.1 
Causality........................................................................................................ 30 
6.4.2 
Recording and Evaluation of Adverse Events .............................................. 31 
6.4.3 
Criteria for Assessing Severity...................................................................... 31 
6.4.4 
Criteria for Assessing Causality.................................................................... 31 
6.4.5 
Serious Adverse Events ............................................................................... 32 
6.4.6 
Investigator Responsibilities for Reporting SAEs ......................................... 32 
6.4.7 
Other Events Requiring Immediate Reporting ............................................. 33 
6.4.8 
Sponsor Responsibilities for Reporting SAEs .............................................. 33 
6.5 
Treatment-Emergent Suicidal Ideation ........................................................... 33 
6.5.1 
Columbia Suicide Severity Rating Scale (C-SSRS) ..................................... 34 
6.5.2 
Suicide Risk Management Plan.................................................................... 34 
6.5.2.1 
Assessment of Suicide Risk ......................................................................... 34 
6.5.2.2 
Acute Suicidal Crisis.................................................................................... 34 
6.5.2.3 
Non-acute Suicidal Risk............................................................................... 34 
6.6 
Clinical Measurements ..................................................................................... 34 
6.6.1 
Laboratory Tests ........................................................................................... 34 
6.6.2 
Vital Signs ..................................................................................................... 35 
6.6.3 
Physical Examinations .................................................................................. 35 
6.6.4 
Electrocardiograms (ECGs) .......................................................................... 35 
6.7 
Exploratory Variables ....................................................................................... 35 
7 
STATISTICAL METHODS ........................................................................... 36 
7.1 
General Considerations.................................................................................... 36 
7.2 
Handling of Missing Data ................................................................................. 36 
7.3 
Analysis Populations ........................................................................................ 36 
7.4 
Demographics and Baseline Analysis ............................................................ 37 
7.5 
Subject Disposition ........................................................................................... 37 
7.6 
Study Medication Exposure and Compliance................................................ 37 
7.7 
Concomitant Medications ................................................................................ 38 
7.8 
Efficacy Analysis ............................................................................................... 38 
7.8.1 
Primary Efficacy Analysis ............................................................................. 38 


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7.8.1.1 
Primary analysis.......................................................................................... 38 
7.8.1.2 
Sensitivity Analyses..................................................................................... 39 
7.8.2 
Secondary Efficacy Analyses ....................................................................... 39 
7.8.2.1 
Key secondary efficacy analyses.................................................................. 39 
7.8.2.2 
Additional secondary analyses ..................................................................... 40 
7.8.3 
Subgroup Analyses ....................................................................................... 40 
7.8.4 
Exploratory Analyses .................................................................................... 41 
7.9 
Sample Size and Power Considerations ........................................................ 41 
7.10 
Interim Analysis................................................................................................. 41 
7.11 
Pharmacokinetic Analyses............................................................................... 41 
7.12 
Pharmacogenomic Analysis ............................................................................ 41 
7.13 
Safety Analysis .................................................................................................. 41 
8 
DOCUMENTATION ...................................................................................... 42 
8.1 
Adherence to the Protocol ............................................................................... 42 
8.2 
Changes to the Protocol................................................................................... 42 
8.3 
Data Quality Assurance .................................................................................... 43 
8.3.1 
Data Collection .............................................................................................. 43 
8.3.2 
Clinical Data Management............................................................................ 43 
8.3.3 
Database Quality Assurance ........................................................................ 43 
8.3.4 
Bioanalytical Sample Handling ..................................................................... 43 
8.4 
Retention of Records ........................................................................................ 44 
8.5 
Auditing Procedures ......................................................................................... 44 
8.6 
Publication of Results....................................................................................... 44 
8.7 
Financing and Insurance .................................................................................. 44 
8.8 
Disclosure and Confidentiality ........................................................................ 44 
8.9 
Discontinuation of Study.................................................................................. 45 
9 
ETHICS ......................................................................................................... 45 
9.1 
Institutional Review Boards ............................................................................. 45 
9.2 
Ethical Conduct of the Study ........................................................................... 45 
9.3 
Investigators and Study Personnel ................................................................. 45 
9.4 
Subject Information and Consent/Assent ...................................................... 45 
10 
REFERENCES.............................................................................................. 46 


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LIST OF TABLES AND FIGURES 
Table 1: Dosing Schedule.................................................................................................. 23 
Table 2:  Schedule of Events and Assessments ............................................................... 25 
Table 3: Clinical Laboratory Tests ..................................................................................... 35 
 
Figure 1: Study Schematic................................................................................................. 20 
 
 
 


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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 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression-Severity of Illness 
CGI-I 
Clinical Global Impression - Improvement 
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 
ICF 
Informed Consent Form 
IAF 
Informed Assent Form 
ICH 
International Conference on Harmonization 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IWRS 
Interactive Web Response System 
LLOQ 
Lower Limit of Quantitation 
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 
Missing Not At Random 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PT 
Preferred Term 
QD 
Once a day 
REML 
Restricted Maximum Likelihood 


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SADR 
Suspected Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIPA 
Stress Index for Parents of Adolescents 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
SM 
Study Medication 
WFIRS-P 
Weiss Functional Impairment Rating Scale – Parent Version 
WHO-DD 
World Health Organization Drug Dictionary  
 
 


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1 
INTRODUCTION 
1.1 
Background 
Viloxazine hydrochloride (2-[(2-ethoxyphenoxy) methyl] morpholine hydrochloride) is a 
structurally distinct bicyclic norepinephrine reuptake inhibitor (NRI) with antagonistic activity 
observed at 5-HT7 and 5-HT1B receptors and agonistic activity at 5-HT2B and 5-HT2C 
receptors. Viloxazine was previously marketed in several European countries as an 
antidepressant. Supernus is currently developing viloxazine (SPN-812) for potential use 
in the treatment of subjects with attention deficit hyperactivity disorder (ADHD), based on 
the compelling pharmacological properties and favorable safety profile of viloxazine, as 
well as on the current unmet medical need for effective long-acting non-stimulant ADHD 
treatment in children and adolescents. 
Compared to other bicyclic antidepressants, viloxazine has generally been found to be 
well tolerated, with no reports of major toxicity during short or long-term research studies.  
Anticholinergic-like effects and sedation have been less marked and less frequent than 
those of the tricyclic antidepressants, but nausea and vomiting have been common 
complaints with the immediate-release (IR) formulation and may be dose-related. 
Viloxazine is similar in structure to reboxetine and atomoxetine and is a racemic mixture 
of two stereoisomers of similar affinities for many important neurotransmitter receptors.  It 
is an inhibitor of the reuptake of norepinephrine and affects norepinephrine-related 
functional activities, and although its inhibitory action on serotonin re-uptake appears to 
be weak, viloxazine may facilitate serotonin activity pre- or post-synaptically.  Furthermore, 
viloxazine is known to upregulate GABAB binding sites. These neurotransmitters have 
been implicated in pathophysiology of ADHD, and drugs that are effective in the treatment 
of ADHD act in noradrenergic and dopaminergic systems. 
Viloxazine is rapidly and almost completely absorbed following oral administration to man. 
Unchanged drug is the major component in blood at all times in man and is probably the 
pharmacologically active moiety. Viloxazine is metabolized and rapidly excreted in the 
urine; there are no known active metabolites. 
1.2 
Clinical Information 
Two Phase 2 studies in ADHD patients, one in adults and one in children, and four Phase 
1 studies in healthy adults have been conducted with SPN-812 IR or ER. An additional 
open label extension study in children is ongoing. 
Phase 1 Studies 
Phase 1 studies included comparison of SPN-812 ER formulation to an immediate-release 
(IR) formulation at single and multiple doses (812P103), evaluation of maximum tolerable 
doses and cardiac safety in a single- and multiple-ascending dose study (812P120), and 
assessment of the effects of food and sprinkling on the relative bioavailability of viloxazine 
(812P105).  In addition, a [14C]-labelled oral IR solution was used to examine absorption, 
metabolism, and excretion of viloxazine in healthy males (812P111).  
 
 
 
 
 
 
 
 
 


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Phase 2 Studies 
The proof-of-concept Phase 1/2 study (812P201), compared an IR formulation of SPN-812 
and placebo in a randomized, blinded study, administered three times a day in a dose 
range of 150 to 300 mg/d in 52 adults (26 per treatment) with ADHD.  In addition to 
assessing the safety and tolerability of SPN-812 IR, scores of both the investigator-rated 
and patient-rated Conner’s’ Adult ADHD Rating Scale (CAARS) were collected at weekly 
intervals during the 6-week treatment period.  
 
 
  
The 812P202 study in children with ADHD assessed the effect of SPN-812 ER in reducing 
the symptoms of ADHD as measured by the ADHD Rating Scale-IV (ADHD-RS-IV).  
Subjects aged 6-12 years were randomized in a 1:2:2:2:2 ratio of placebo or active 
treatment (SPN 812 ER 100, 200, 300, or 400 mg) and received three weeks of titration 
at 100 mg/week followed by five weeks of maintenance treatment for a total of eight weeks 
of therapy.  Mean ADHD-RS-IV Total Scores improved throughout treatment, in all groups.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Information and data from clinical studies are available in detail in the SPN-812 ER 
Investigator’s Brochure, version 6.0. 
 
 
 
 
 
a


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1.3 
Study Rationale 
An initial Phase 2 study demonstrated a 300 mg dose of an immediate-release formulation 
of SPN-812 was able to significantly lower the CAARS total score in adults with ADHD. 
 
 
  
 
 
 
 
 
When used for over 20 years as an anti-depressant, the IR form of viloxazine was 
approved at dosages of 200-600 mg/day.  Although higher doses were occasionally used 
and reported, no clear advantage in efficacy was demonstrated and a modest decrease 
in tolerability could occur (often related to nausea). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
In addition to assessing the effect of SPN-812 ER treatment on ADHD symptom reduction, 
the study aims to explore treatment response within other domains of the disorder, 
including functional impairment and parental stress (Becker, 2011; Wiener, 2016).  ADHD 
is a chronic, debilitating disorder that affects many aspects of daily life and has a 
substantial burden on family functioning.  Children with ADHD exhibit a number of 
functional impairments, and the motivation in seeking medical treatment typically stems 
from the need to address dysfunction in social, emotional, academic, and familial domains 
(Epstein and Weiss, 2012).  Therefore, optimal medical and behavioral management 
should ideally incorporate treatments that do not just improve symptoms of ADHD, but 
improve broader functioning of a patient, especially in the areas of self-esteem, 
educational achievement, and relationships with peers, teachers, and family. 
2 
STUDY OBJECTIVES  
2.1 
Primary Objective 
 
To evaluate the efficacy of SPN-812 ER compared to placebo as monotherapy for the 
treatment of ADHD in adolescents (12-17 years). 
 
 
 
 
 


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2.2 
Secondary Objectives 
Key Secondary 
 
To evaluate the effect of SPN-812 ER compared to placebo as assessed by: 
o Clinical Global Impression – Improvement (CGI-I) scale 
o Conners 3rd edition (Conners 3) – parent, composite T-score 
o Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) 
Additional Secondary 
 
To evaluate the effect of SPN-812 ER compared to placebo as assessed by: 
o 50% Responder rate based on the ADHD-RS-5 Total score 
o Stress Index for Parents of Adolescents (SIPA) 
o ADHD-RS-5 Inattention and Hyperactivity/Impulsivity subscale scores 
Conners 3 – Self, composite T-score 
Safety 
 
To evaluate the safety and tolerability of SPN-812 ER in adolescents with ADHD.  
2.3 
Exploratory Objectives 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
) 
 
3 
INVESTIGATIONAL STUDY PLAN 
3.1 
Overall Study Design and Plan 
This is a multicenter, randomized, double-blind, placebo-controlled, 3-arm, parallel-group 
study, to evaluate the efficacy and safety of SPN-812 ER as monotherapy for the 
treatment of adolescents (12-17 years old) with ADHD. Approximately 300 subjects will 
be randomized in a 1:1:1 ratio of placebo or one of the two active treatment arms 
(SPN-812 ER 400 or 600 mg). Following up to four weeks of screening, subjects will be 
randomized and undergo two weeks of titration followed by five weeks of maintenance for 
a total of seven weeks of treatment and total study duration of up to 9-11 weeks.  The 
study schematic appears in Figure 1. 
Screening (Visit 1):  After administering the informed consent form (ICF; and informed 
assent form [IAF], if applicable), subjects will undergo initial screening evaluation including 
medical and psychiatric history, ECG, vital signs, physical examination, routine laboratory 
assessment, PGx sample collection, and urine drug screen.  Data from testing may also 
be used for future research but will not be used for individual genetic characterization. 
ADHD diagnosis will be confirmed, as will all study inclusion/exclusion criteria.  Eligible 
subjects will be scheduled for a Baseline Visit within  28 days.  Subjects receiving ADHD 
 


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medication at Screening will undergo a washout of at least one week before the Baseline 
Visit. 
Study Dose Treatment Phase (Visits 2 – 9): This phase will consist of two weeks of 
Titration followed by five weeks of Maintenance phase until end of study/Visit 9. 
Baseline, Randomization, and Dispensation of Study Medication (SM) (Visit 2):  At the 
Baseline Visit, inclusion/exclusion criteria will be reviewed to confirm continued eligibility, 
including urine pregnancy test for Females of Childbearing Potential (FOCP).  Eligible 
subjects will be randomized and assigned the corresponding blinded dosing kit. The 
titration card of the blinded SM will be dispensed and the first study dose taken. 
Study Dose Treatment: Titration (Visits 2-3): Subjects will return to the clinical site for 
weekly visits to undergo efficacy and safety evaluations, pick up the next dosing card 
and return the previous card. 
Study Dose Treatment: Maintenance (Visits 4-9): Subjects will return to the clinical site 
for weekly visits to undergo efficacy and safety evaluations, pick up the next dosing card 
(except at Visit 9, the last visit) and return the previous card. 
End of Study (Visit 9): Subjects will return for final evaluation (subjects terminated prior 
to Visit 9 will also undergo EOS evaluations). 
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 during Visits 3-9, inclusive, will be conducted to assess the PK 
characteristics of viloxazine (and its metabolite 5-hydroxy-viloxazine glucuronide, if 
applicable) 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. 
 


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Figure 1: Study Schematic 
 
 
3.2 
RATIONALE FOR STUDY DESIGN 
812P304 is a randomized, double-blind, placebo-controlled, multicenter, 3-arm, parallel-
group, pivotal study of SPN-812 ER as monotherapy for the treatment of adolescents ages 
12-17 years with ADHD. This study is designed to demonstrate efficacy of either 400 or 
600 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 300 subjects will be randomized (100 subjects per treatment) in this clinical 
study. 
3.3.2 Inclusion Criteria 
1. Healthy male or female subjects, 12-17 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: 
Adolescent, 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 35 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. 


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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). 
 
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 9 (EOS). 
All subjects who discontinue early will complete the procedures listed for Visit 9 (EOS). 
All reasons for screening failure or for failure to continue study eligibility at Baseline after 
successful screening will 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 


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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 and/or 200 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 
(subject study 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.  
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 400 mg/day, or SPN-812 ER 600 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 eight 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 200 mg/week to the final dose 
(1:1:1) as follows: 
Treatment A: Placebo 
Treatment B: SPN-812 ER 400 mg/day (2  200 mg SPN-812 ER) 
Treatment C: SPN-812 ER 600 mg/day (3  200 mg SPN-812 ER) 
 


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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. 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 


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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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5.1.1 Visit 1 - Screening (Day -28 to -1) 
Prior to conducting screening procedures, written Informed Consent 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 sample for pregnancy test for FOCP 
3. Randomize (via IWRS) 
4. Administer efficacy and safety scales: ADHD-RS-5, Conners 3 (parent, self), 
WFIRS-P, SIPA, 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 – 8 - Titration (Days 7, 14 [±2 days]) and Maintenance (Days 21, 28, 
35, 42 [±2 days]) 
1. Record vital signs (HR, BP, temperature, and RR)  


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2. Administer efficacy and safety scales: ADHD-RS-5, CGI-I and C-SSRS 
3. Record concomitant medications 
4. Record AEs 
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 9 - End-of Study (Day 49 [±2 days]) 
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), 
WFIRS-P, SIPA, 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. 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). The DNA analysis will not be used for individual genetic characterization and the 
subject’s identity will be kept confidential. 
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 3-9. 
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: Adolescent 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) SIPA 
c) ADHD-RS-5 Inattention and Hyperactivity/Impulsivity subscale scores 
d) Conners 3 – Self, composite T-score 


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Such information may be used solely for the purpose of reviewing or performing this study. 
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 
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 8-18 year-olds) 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 – Parent: Short, and Conners 3 – Self-Report: Short assessments will be 
performed at Visit 2 (Baseline) and at Visit 9 (EOS). 
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 SIPA 
The Stress Index for Parents of Adolescents (SIPA) is a screening and diagnostic 
instrument that identifies areas of stress in parent-adolescent interactions and is 
appropriate for parents of adolescents aged 11-19 years (Sheras, 1998).  The SIPA scale 
is a 112-item questionnaire that yields scores across three domains (Adolescent Domain, 
Parent Domain, and Adolescent-Parent Domain) and the Life Stressors Scale.  The 
Adolescent and Parent Domains are further subdivided into four subscales that focus on 
the parent‘s perception of their child’s personality and on the parent’s characteristics and 
behaviors.  The Life Stressor Scale assesses external life factors contributing to stress 
experienced by a parent. The Index of Total Parenting Stress (TS) is the composite score 
of all items across all domains and reflects the total stress experienced as a function of 
parenting a particular adolescent.   
The SIPA questionnaire 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 Practice (GCP), an adverse event (AE) 
is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with treatment. 
An AE can be: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• Any new disease, intercurrent injuries, or exacerbation of an existing disease. 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG) that results in 
symptoms, a change in treatment, or discontinuation from SM. 
• Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 
Surgical procedures are not AEs; they are therapeutic measures for conditions that require 
surgery.  The condition for which the surgery is required is an AE, if it occurs or is detected 
during the study period. 
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. 


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Suspected adverse drug reactions (SADRs) are a subset of adverse events for which 
there is evidence to suggest a causal relationship between the drug and the AE, i.e., there 
is a reasonable possibility that the drug caused the adverse event.   
Adverse drug reactions (ADRs) are a subset of all SADRs for which there is reason to 
conclude that the drug caused the event. 
6.4.2 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 Adverse Event (SAE)? 
• 
Causality: Was AE related or possibly related to the SM? 
• 
Severity: How pronounced is the incapacity/discomfort caused by an AE? 
6.4.3 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.  


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• Not related:  Temporal relationship to SM administration is missing or 
implausible, or there is an evident other cause. 
• Unlikely related:  Temporal relationship to SM administration makes a causal 
relationship improbable; and other drugs, chemicals, or underlying disease 
provide plausible explanations. 
Suspected: The temporal relationship of the AE to SM administration makes a causal 
relationship possible, and other drugs, therapeutic interventions, or underlying 
conditions do not provide a sufficient explanation for the observed event.  
• Possibly related:  Temporal relationship to SM administration is plausible, but 
concurrent disease or other drugs or chemicals could also explain event.  
Information on drug withdrawal may be lacking or unclear.  This will be reported 
as a Suspected Adverse Drug Reaction (SADR). 
• Definitely related: Temporal relationship to SM administration is plausible, and 
concurrent disease or other drugs or chemicals cannot explain event.  The 
response to withdrawal of the medication (dechallenge) should be clinically 
plausible. 
The 
event 
must 
be 
definitive 
pharmacologically 
or 
phenomenologically, using a satisfactory rechallenge procedure if necessary.  
This will be reported as an Adverse Drug Reaction (ADR). 
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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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 Tests  
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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7 
STATISTICAL METHODS 
7.1 
General Considerations 
All statistical analysis will be performed using SAS version 9.2 or higher by 
, which is 
the designated CRO. 
 will be responsible for developing a unique program for each 
TLF to create a TLF report and deliver to Supernus at the completion of the study. 
All tabulations of analysis results will include summaries for the following three treatments: 
SPN-812 ER 600 mg, SPN-812 ER 400 mg, and placebo. 
Where appropriate, variables will be summarized descriptively (frequency count and 
percent for categorical variables, and number of subjects (n), mean, standard deviation 
(SD), median, minimum, and maximum for continuous variables).  
Categorical variables will be analyzed using categorical response methods such as 
Pearson’s Chi-square test. If expected frequencies are less than 5 in a given cell, then 
exact testing techniques will be used. 
The data summaries will be accompanied by individual subject data listings, as specified 
in Sections 16.2 and 16.4 of ICH Guidance E3, sorted by unique subject identifier.  All 
data available from the electronic case report forms (eCRFs) will be listed. Unscheduled 
measurements will be excluded from the descriptive statistics and statistical analysis but 
will be included in listings. 
Complete details of the statistical analysis will be provided in a separate statistical analysis 
plan (SAP). The statistical analysis methods described in the SAP will supersede the 
statistical methods described in this protocol. 
7.2 
Handling of Missing Data 
With respect to the primary analysis, missing ADHD-RS-5 Total Scores will be assumed 
to be missing at random (MAR), that is, given the observed data, the reason for the missing 
data does not depend on the unseen data. The Mixed Model for Repeated Measures 
(MMRM) method, implemented via SAS® PROC MIXED (SAS/STAT Software), will be 
used for handling missing ADHD-RS-5 Total Scores under MAR assumption. Under MAR, 
the propensity for a data point to be missing is not related to the missing data, but is related 
to some of the observed data.  
The sensitivity analysis for the primary endpoint will be performed by assuming that 
missing ADHD-RS-5 Total Scores are missing not at random (MNAR) meaning that the 
probability that an observation is missing may depend on its underlying unobserved value.  
For analysis of secondary endpoints, missing values will be assumed as MAR. 
For safety analyses, missing dates for AEs and non-study medication use will be imputed 
as described in the SAP. Missing data for all other safety endpoints will not be imputed. 
7.3 
Analysis Populations 
 
The Randomized population will include all enrolled subjects who had a baseline 
visit and are randomized via the IWRS. 
 
e
 
e
 Reda


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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 
complete all 9 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. 
 
The PK population will include all subjects in the safety population who had at 
≥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) /3 × (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 7 
(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 400 mg and SPN-812 ER 600 mg) will be 
presented, along with the corresponding standard error. Each of the treatment groups 
(SPN-812 ER 400 and 600 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. 
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 600 mg 
group and placebo group and H02: No treatment mean difference between SPN-812 ER 
400 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 600 mg and SPN-812 ER 400 mg are superior to placebo. If H01 is rejected and 
H02 is not rejected then it will be concluded that only SPN-812 ER 600 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 at Week 7 (EOS) on the change 
from baseline at Week 7 (EOS) with treatment and baseline as fixed effect. Each of the 
treatment groups (SPN-812 ER 400 mg and 600 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 400 mg minus Placebo and SPN-812 ER 600 
mg minus Placebo), and 95% confidence intervals for the treatment differences will be 
computed. 
7.8.2.1 Key secondary efficacy analyses 
The analyses of key secondary objectives will be conducted on the following sequentially 
ordered endpoints for testing: 1) CGI-I, 2) Conners 3 - Parent composite T-score, and 
3) WFIRS-P. 
To preserve the overall type I error rate at 0.05 for the key secondary endpoints, a 
sequential testing procedure will be used. 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 does not reject H01 (i.e., the 600 mg is not superior to 
placebo) or the primary endpoint analysis rejects only H01, then no multiplicity adjustment 
is required. Otherwise, multiplicity adjustment will be performed with the following features. 
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 600 mg group and placebo group and H02: No treatment 
mean difference between SPN-812 ER 400 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 600 mg and SPN-812 ER 400 mg 
are superior to Placebo. If H02 is not rejected, then it will be concluded that only SPN-812 
ER 600 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. 
a) CGI-I – The absolute value of CGI-I at Week 7 (EOS) will be analyzed using 
ANCOVA with treatment as a fixed classification variable and baseline CGI-S as a 
covariate. To compare the treatment groups, the difference in LS means (SPN-
812 ER 400 mg minus Placebo and SPN-812 ER 600 mg minus Placebo) will be 


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Such information may be used solely for the purpose of reviewing or performing this study. 
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 Week 7 (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 400 mg and 
600 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 Week 7 (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 400 mg and 600 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. 
 
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 Week 7 (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 400 mg minus Placebo, SPN-812 ER 
600 mg minus Placebo) and the p-value from Pearson’s Chi-squared Test or 
Fisher’s Exact Test  will be presented.  
b) SIPA - The change from baseline in SIPA total score to Week 7 (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 400 mg and 600 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 Week 7 (EOS) 
in Hyperactivity/Impulsivity subscales.  
d) Conners 3 - Self – The analysis for Conners 3 - Parent will be repeated for Self 
scores. 
 
The key secondary analyses will be repeated for the per protocol population for 
supplementary analyses. 
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: 
a) Gender (male, female) 
b) Age (12-14 years, 15-17 years) 
c) Race (white, non-white) 


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7.8.4 Exploratory Analyses 
Exploratory analyses of the key exploratory efficacy variables will include: 
 
 
 
 
 
 
 
 
 
 
 
7.9 
Sample Size and Power Considerations 
Seventy-two subjects per treatment group in the ITT population will yield 90% power at a 
significance level of 0.05 (two-sided) using a two-sample t-test with equal allocation to the 
treatment groups. This assumes an effect size of 0.547, which was observed in the 
comparison of SPN-812 200 mg and placebo in the SPN 812 Phase IIb study (based on 
the CFB to endpoint in the ADHD-RS-IV total score) and will maintain consistency in the 
sample size assumption used between this clinical trial and the SPN-812 P302 study (e.g., 
across the SPN-812 clinical trials in the adolescent population). A total of 300 subjects 
(100 subjects in each of the three treatment groups) will be randomized to account for an 
anticipated 27.9% of randomized subjects not completing the study. 
7.10 Interim Analysis 
No interim analysis will be performed. 
7.11 Pharmacokinetic Analyses 
Plasma concentrations for viloxazine (and 5-hydroxy-viloxazine glucuronide, If applicable) 
will be provided. 
 
  Population PK data analysis will be performed using 
nonlinear mixed-effects modeling program (NONMEM). The structural model for 
viloxazine (and 5-hydroxy-viloxazine glucuronide, if applicable) may include data from 
studies in which sampling was more intensive than in the present study.  Inclusion of 
covariates in the pharmacokinetic model will be accomplished through a systematic 
process.  For each NONMEM run, covariate graphics will be examined for relationships 
between covariates and the post hoc etas.  Covariates of interest will include (but not be 
limited to) age, gender, body size, etc. Population PK analyses will be reported separately 
from the clinical study report. 
7.12 Pharmacogenomic Analysis 
If PGx testing is performed, individual data will be presented as a listing and summaries 
will be tabulated using descriptive statistics. 
7.13 Safety Analysis 
Safety analysis as described below will be conducted on the Safety Population. Safety 
data that will be evaluated include concomitant medications, AEs, clinical laboratory 
results, vital signs, ECGs, and findings from the physical examinations.  Suicidal ideation 
and suicidal behavior will be measured by C-SSRS. 
 Reda
 


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The incidence rate of AEs will be calculated by treatment group for each System Organ 
Class (SOC) and Preferred Term (PT). The severity of the AEs and the relationship to SM 
will be summarized by treatment group for each SOC and PT. 
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. 


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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. 
Changes to the protocol which are administrative in nature do not require formal protocol 
amendments or IRB approval, but the IRB must be kept informed of such changes.  In 
these cases, the Sponsor or CRO will send a letter to the IRB detailing such changes. 
8.3 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures (SOPs), working practice documents, and applicable 
regulations and guidelines.  Site visit audits may be made periodically by the Sponsor’s 
Quality Assurance team or qualified designee, which is an independent function from the 
study conduct team. 
8.3.1 Data Collection 
The primary source document will be the subject’s medical record.  If separate research 
records are maintained by the Investigator(s), both the medical record and the research 
record will be considered the source documents for the purposes of monitoring and 
auditing the study. 
Electronic data collection techniques will be used to collect data directly from the study 
sites using eCRFs.  The electronic data will be stored centrally in a fully validated clinical 
database. 
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 protocol.  


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Such information may be used solely for the purpose of reviewing or performing 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, copies of paper CRFs or eCRFs, source documents, laboratory test 
results, SM inventory records, Investigator's Brochure, regulatory agency registration 
documents (e.g., FDA form 1572, ICFs, and IRB 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. 


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Such information may be used solely for the purpose of reviewing or performing this study. 
8.9 
Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative 
reasons at any time.  The Investigator will be reimbursed for reasonable expenses 
covering subjects, use of live-in facilities, laboratory tests, and other professional fees.  
The Investigator will refund the excess of payments made in advance. 
The Investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  The Investigator will notify the IRB in case of study discontinuation.  Study records 
must be retained as noted above. 
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 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 25 study sites in the US. 
Contact persons at the Sponsor and the CROs are listed in the reference binder provided 
to each investigational site.  The study will be monitored by qualified personnel from the 
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/Assent 
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 


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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. 
information describing the nature and duration of the study, the procedures involved, the 
expected duration, the potential risks and benefits involved, and any potential discomfort. 
The process for obtaining informed consent/assent will be in accordance with all 
applicable regulatory requirements.  The Investigator (or designee) and caregiver/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/IAF 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/IAF (including ongoing subjects). 
 
10 REFERENCES 
Becker A, Roessner V, Breuer D, Dopfner M, Rothenberger A.  Relationship between 
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. 
Sheras PL, Abidin RR, Konold TR. (1998) Stress Index for Parents of Adolescents: 
Professional Manual.  Lutz, FL: Psychological Assessment Resources. 
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 
Scale-Parent Form for assessing ADHD: evaluating diagnostic accuracy and determining 
optimal thresholds using ROC analysis. Qual Life Res. (2017); Feb 20. doi: 
10.1007/s11136-017-1514-8. [Epub ahead of print].  


Supernus Pharmaceuticals, Inc. 
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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. 
Westfall, Peter H., Tobias, Randall D., and Wolfinger, Russell D., (1999). Multiple 
Comparisons and Multiples Tests Using SAS®, Cary, NC: SAS Institute Inc. 
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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Protocol 812P304 
 
Page 1 of 29 
 
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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
 
SUMMARY OF CHANGES 
INCLUDED IN THE PROTOCOL AMENDMENT OF: 
 
812P304 
Evaluation of SPN-812 ER 400 and 600 mg Efficacy and Safety in Adolescents with ADHD - A 
Double-Blind, Placebo-Controlled, Pivotal Trial 
 
Current Protocol 
Version 3.0 
07 September 2017 
Amended Protocol 
Version 4.0 
12 October 2018 
 
IND # 108,864 
SUMMARY OF REVISIONS 
This amendment incorporates the following protocol revisions: 
 
Updates and clarifications to the secondary and exploratory objectives and endpoints  
 
Increase in sample size 
 
Revisions and clarifications to the Statistical Methods sections (based on the revised Statistical 
Analysis Plan) 
 
  
 
Expanded concomitant medications prohibitions to include CYP1A2 substrates 
 
Other minor editorial and administrative changes to improve clarity and correct errors 
 
RATIONALE 
1. The 812P304 Statistical Analysis Plan (SAP) was revised and updated based on FDA review 
comments (FDA Advice Letter dated 19 July 2018, Ref ID 4294123).  The protocol was amended to 
reflect the changes in the revised SAP, including the following updates: 
 The secondary objectives and endpoints were updated and clarified to identify those considered 
“key” for data analysis and interpretation purposes. The exploratory objectives and endpoints 
were updated accordingly. 
 To maintain consistency across similar study protocols and to increase the probability of 
success, the same effect size from the SPN-812 ER 200 mg and placebo in the SPN-812 ER Phase 
IIb study was used for the power calculation for 812P304, and the sample size was increased 
accordingly.  
 Methods for handling missing data and for conducting the sensitivity analyses were revised (e.g., 
the LOCF method will no longer be used).  
 


 
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for the purpose of reviewing or performing this study. 
 
 Clarifications were made to the definitions of the analysis populations and to the subject 
disposition categories. 
 The section on the primary endpoint analysis was updated to include a fixed effect of age group 
and to provide new details with respect to the analysis of covariance (per FDA suggestion).  
 The Secondary Efficacy Analyses Sections were expanded to include descriptions of the key 
secondary analyses, additional secondary analyses, and subgroup analyses.  The Exploratory 
Analyses section was also added for the newly identified exploratory efficacy variables. 
2. 
 
 
 
3. 
 
 
 
 
 
    
4. Some information was reorganized or slightly revised to provide clarifications, describe study 
procedures in a greater detail, and for consistency with the SAP.  Section numbers have been 
reformatted throughout the protocol as needed to clarify the content and to incorporate new 
information. 
 
Detailed Listing of Revisions 
Detailed modifications of the protocol text are indicated by strikethrough (for deletions) and bold (for 
additions). 
# 
Global Changes 
1 
Throughout the amended protocol, the protocol version and version date are updated to Version 4.0 and 
12 October 2018, respectively. 
2 
The Table of Contents is updated to reflect current document pagination. 
3 
Section numbers have been reformatted to reflect information that was added, deleted, or relocated. 
4 
ADHD-RS-V and DSM-V have been replaced with ADHD-RS-5 and DSM-5, respectively, to reflect the DSM-5 
nomenclature 
 
 
 


 
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for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
5 
Protocol Approval Page, p.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approver: 
 
 
 
 
 
 
Protocol Approval Page, p.3 
Authors: 
 
 
 
 
 
 
 
Reviewers: 
 
 
 
  
 
Approvers: 
 
 
 
 
 
 
 
Administrative 
change 
6 
Clinical Protocol Synopsis, Objective, p.4 
Secondary 
 To assess the effect of SPN-812 ER as 
assessed by: 
o Conners 3rd edition (Conners 3) – 
parent, self 
o 30% Responder rate (Attention 
Deficit/Hyperactivity Disorder Rating 
Scale V [ADHD-RS-V] Total Score) 
o Hyperactivity/Impulsivity and 
Inattention subscales of ADHD-RS-V 
o Weiss Functional Impairment Rating 
Scale – Parent report (WFIRS-P) 
o Stress Index for Parents of 
Adolescents (SIPA) 
o Clinical Global Impression – Severity 
of Illness and Improvement (CGI-S/I) 
Scale  
 
 
Clinical Protocol Synopsis, Objectives, p.4 
Key Secondary 
• To assess evaluate the effect of SPN-812 
ER compared to placebo as assessed by: 
o Clinical Global Impression – 
Improvement (CGI-I) scale 
o Conners 3rd edition (Conners 3) – 
parent, self composite T-score 
o 30% Responder rate (Attention 
Deficit/Hyperactivity Disorder Rating 
Scale V [ADHD RS V] Total Score) 
o Hyperactivity/Impulsivity and 
Inattention subscales of ADHD-RS-V 
o Weiss Functional Impairment Rating 
Scale – Parent report (WFIRS-P) 
o Stress Index for Parents of Adolescents 
(SIPA)  
Update to 
secondary 
objectives and 
endpoints 
 
 
 
 
 


 
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for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 To evaluate the safety and tolerability of 
SPN-812 ER in adolescents with ADHD 
 
o Clinical Global Impression  Severity of 
Illness and Improvement (CGI S/I) Scale  
Additional Secondary 
• To evaluate the effect of SPN-812 ER 
compared to placebo as assessed by: 
o 50% Responder rate based on the 
ADHD-RS-5 Total score 
o Stress Index for Parents of Adolescents 
(SIPA) 
o ADHD-RS-5 Inattention and 
Hyperactivity/Impulsivity subscale 
scores 
o Conners 3 – Self, composite T-score 
 
Safety 
• To evaluate the safety and tolerability of 
SPN-812 ER in adolescents with ADHD 
7 
Clinical Protocol Synopsis, Objective, 
Exploratory, p.4 
n/a 
Clinical Protocol Synopsis, Objectives, 
Exploratory, p.4 
(Added) 
• To evaluate the effect of SPN-812 ER 
compared to placebo as assessed by: 
o Conners 3 – Parent, individual domain 
scores 
o Conners 3 – Self, individual domain 
scores 
o WFIRS-P individual domain scores 
o SIPA individual domain scores 
Update to 
exploratory 
objectives and 
endpoints 
8 
Clinical Protocol Synopsis, Objective, 
Exploratory, p.4 
 
 
 
 
Clinical Protocol Synopsis, Objectives, 
Exploratory, p.4 
• 
  
 
 
 
 
 
 
 
Assessment of 
viloxazine 
metabolite 
 
 


 
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Protocol 812P304 
 
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for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
9 
Clinical Protocol Synopsis, Number of 
Subjects, p.4 
Approximately 234 subjects (78 subjects 
per treatment) 
Clinical Protocol Synopsis, Number of 
Subjects, p. 5 
Approximately 234 300 subjects (78 100 
subjects per treatment) 
Increased 
sample size 
10 
Clinical Protocol Synopsis, Treatment 
Schedule, Study Dose Treatment Phase 
(Visits 2-9), p.5 
Baseline, Randomization, and 
Dispensation of SM (Visit 2): 
Approximately 234 eligible subjects will be 
randomized. 
Clinical Protocol Synopsis, Treatment 
Schedule, Study Dose Treatment Phase 
(Visits 2-9), p.5 
Baseline, Randomization, and Dispensation 
of SM (Visit 2): Approximately 234 300 
eligible subjects will be randomized. 
Increased 
sample size 
11 
Clinical Protocol Synopsis, Endpoints, p.5 
Key Secondary Endpoints: a) Conners 3, b) 
30% Responder Rate, and 
c) Hyperactivity/Impulsivity and Inattention 
subscales of ADHD-RS-V 
 
 
 
 
Additional Secondary Endpoints will 
include: a) WFIRS-P, b) SIPA, and c) CGI-S/I  
 
 
 
Clinical Protocol Synopsis, Endpoints, p.6 
Key Secondary Efficacy Endpoints: CFB to 
EOS in scores for a) CGI-I, b) Conners 3 – 
Parent, composite T-score self, teacher 
(optional), b) 30% Responder Rate (ADHD
RS V total score), and c) WFIRS-P average 
score Inattentive and Hyperactive 
subscales of ADHD RS V 
 
Additional Secondary Efficacy Endpoints 
will include: a) WFIRS P, Proportion of 
responders with 50% improvement in 
ADHD-RS-5 Total score, b) SIPA,  and c) 
CGI S/I ADHD-RS-5 Inattention and 
Hyperactivity/Impulsivity subscale scores, 
and d) Conners 3 – Self composite T-score 
Update to 
secondary 
objectives and 
endpoints 
12 
Clinical Protocol Synopsis, Endpoints, p.5 
Exploratory Endpoints:  
 
 
Clinical Protocol Synopsis, Endpoints, p.6 
Exploratory Endpoints:  
 
 
 
 
 
 
 
Update to 
exploratory 
objectives and 
endpoints 
13 
Clinical Protocol Synopsis, Sample Size, p.5 
Fifty-six per treatment group in the Intent-
To-Treat (ITT) population will yield 90% 
power at a significance level of 0.05 (two-
sided) using a two-sample t-test with 
equal allocation to the treatment groups. 
This assumes an effect size of 0.623, 
observed in the comparison of SPN-812 ER 
400 mg and placebo in the SPN-812 ER 
Clinical Protocol Synopsis, Sample Size, p. 6 
Fifty six Seventy-two subjects per 
treatment group in the Intent-To-Treat 
(ITT) population will yield 90% power at a 
significance level of 0.05 (two-sided) using 
a two-sample t-test with equal allocation to 
the treatment groups. This assumes an 
effect size of 0.623 0.547, observed in the 
comparison of SPN-812 ER 400 200 mg and 
Increased 
sample size 
 
 


 
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12 Oct 2018 
Protocol 812P304 
 
Page 6 of 29 
 
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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
Phase IIb study (based on the CFB to 
endpoint in the ADHD-RS-IV total score). A 
total of 234 subjects (78 subjects in each 
of the three treatment groups) will be 
randomized to account for an anticipated 
27.9% of randomized subjects not 
completing the study. 
placebo in the SPN-812 ER Phase IIb study 
(based on the CFB to endpoint in the 
ADHD-RS-IV total score). To keep 
consistency with the sample size 
assumption used in the SPN-812 P302 
study (adolescent population), a total of 
234 300 subjects (78 100 subjects in each 
of the three treatment groups) will be 
randomized to account for an anticipated 
27.9% of randomized subjects not 
completing the study. 
14 
Clinical Protocol Synopsis, Analysis 
Populations, p.6 
 
 
 
 The ITT population for efficacy will 
include all randomized subjects who 
took at least one dose of study 
medication, and had a Baseline and at 
least one post-Baseline assessment of 
ADHD-RS-V. 
 
 The Per Protocol (PP) population 
consists of all subjects in the ITT 
population with no missing visits or 
ADHD-RS-V assessments and no major 
protocol violations. 
 
 
 The Safety Population consists of all 
subjects who receive at least one dose 
of SM. 
 
 
 The PK population will include all 
subjects in the safety population with ≥1 
non-below-the limit-of-quantitation PK 
sample drawn. 
Clinical Protocol Synopsis, Analysis 
Populations, p.6 
• The Randomized population will include 
all enrolled subjects who had a baseline 
visit and are randomized via the IWRS. 
• The ITT population for efficacy will 
include all randomized subjects who took 
at least one dose of study medication, and 
had a Baseline and at least one post-
Baseline randomization ADHD-RS-5 
assessment of ADHD RS V. 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 9 visits with no missing visits 
or ADHD-RS-V5 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. 
• The PK population will include all subjects 
in the safety population with ≥1 non below 
the limit of quantitation PK sample drawn  
that is not below the Lower Limit of 
Quantitation (LLOQ). 
Updated for 
consistency 
with revised 
SAP 
15 
Clinical Protocol Synopsis, Handling of 
Missing Data, p.6 
For primary efficacy analysis, missing data 
will be assumed as missing at random 
Clinical Protocol Synopsis, Handling of 
Missing Data, p.6 
For With respect to the primary efficacy 
analysis, missing data ADHD-RS-5 Total 
LOCF method 
no longer used 


 
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12 Oct 2018 
Protocol 812P304 
 
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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
(MAR) and will be handled using a Mixed 
Models Repeated Measures (MMRM) 
technique according to the MMRM 
paradigm. For secondary and first 
sensitivity analyses, missing data will be 
imputed using the last observation carried 
forward (LOCF) method. 
scores will be assumed as to be Mmissing 
at Rrandom (MAR) and will be handled 
using a Mixed Models for Repeated 
Measures (MMRM) technique according to 
the MMRM paradigm method in SAS.  For 
secondary and first sensitivity analyses, 
missing data will be imputed using the last 
observation carried forward (LOCF) 
method. The sensitivity analysis for the 
primary endpoint will be performed by 
assuming that missing ADHD-RS-5 Total 
Scores are missing not at random (MNAR). 
For analysis of secondary endpoints, 
missing values will be assumed as MAR. 
16 
Clinical Protocol Synopsis, Statistical 
Methods, p.6 
In general, continuous variables will be 
summarized with standard descriptive 
statistics including number of subjects (n), 
means, standard deviations, medians, 
minimum, and maximum. Categorical 
variables will be summarized with 
frequencies and percentages. 
 
Clinical Protocol Synopsis, Statistical 
Methods, p.6 
In general, continuous variables will be 
summarized with standard descriptive 
statistics including number of subjects (n), 
means, standard deviations, medians, 
minimum, and maximum. Categorical 
variables will be summarized with 
frequencies and percentages. All 
tabulations of analysis results will include 
summaries for the following three 
treatments: SPN-812 ER 600 mg, SPN-812 
ER 400 mg, and placebo. 
Where appropriate, variables will be 
summarized descriptively (frequency 
count and percent for categorical 
variables, and number of subjects (n), 
mean, standard deviation (SD), median, 
minimum, and maximum for continuous 
variables). 
Categorical variables will be analyzed 
using categorical response methods such 
as Pearson’s Chi-square test.  If expected 
frequencies are less than 5 in a given cell, 
then 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. 
Updated for 
consistency 
with revised 
SAP 


 
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12 Oct 2018 
Protocol 812P304 
 
Page 8 of 29 
 
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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
17 
Clinical Protocol Synopsis, Statistical 
Methods, Efficacy Analyses, p.6 
The primary analysis, based on the ITT 
population, will be performed using a 
longitudinal MMRM and a restricted 
maximum likelihood (REML) approach. An 
unstructured (co)variance structure will be 
used to model the within-subject errors. 
Primary:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Each of the active treatment groups 
(SPN-812 ER 400 and 600 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. 
 
Clinical Protocol Synopsis, Statistical 
Methods, Efficacy Analyses, p.7 
The primary analysis, based on the ITT 
population, will be performed using a 
longitudinal MMRM and a restricted 
maximum likelihood (REML) approach. An 
unstructured (co)variance structure will be 
used to model the within subject errors. 
Primary: The primary efficacy variable, 
change from baseline in ADHD-RS-5 Total 
Score to Week 7 (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, 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 400 
mg and SPN-812 ER 600 mg) will be 
presented, along with the corresponding 
standard error. Each of the active 
treatment groups (SPN-812 ER 400 and 600 
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 
Updated for 
consistency 
with revised 
SAP, and LOCF 
no longer used 


 
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12 Oct 2018 
Protocol 812P304 
 
Page 9 of 29 
 
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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
 
 
 
Secondary: The CFB to EOS for continuous 
key secondary and additional endpoints 
will be analyzed using ANCOVA or ANOVA 
as appropriate based on the ITT 
population with LOCF.  The mean of each 
treatment group will be compared with 
the mean of the placebo group.  For 
responder analyses, the proportion each 
active treatment group will be compared 
with the proportion of the placebo group 
 
Scores are missing not at random (MNAR). 
Placebo-based multiple imputation will be 
used to fill in missing values. 
Secondary: The CFB to EOS for continuous 
key secondary and additional endpoints will 
be analyzed using ANCOVA or ANOVA as 
appropriate based on the ITT population 
with LOCF.  The mean of each treatment 
group will be compared with the mean of 
the placebo group.  For responder analyses, 
the proportion each active treatment group 
will be compared with the proportion of 
the placebo group 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 at 
Week 7 (EOS) on the change from baseline 
at Week 7 (EOS) with treatment and 
baseline as fixed effect.  
Analyses of key secondary endpoints will 
be repeated for the PP population. 
18 
Clinical Protocol Synopsis, Statistical 
Methods, Safety Analyses, p.6 
Descriptive statistics will be presented for 
demographics, data from the clinical 
laboratory tests, vital signs, weight, ECGs, 
and physical examinations.   
Clinical Protocol Synopsis, Statistical 
Methods, Safety Analyses, p.7 
(Deleted) Descriptive statistics will be 
presented for demographics, data from the 
clinical laboratory tests, vital signs, weight, 
ECGs, and physical examinations. 
Statement 
moved for 
clarification 
purposes 
19 
Clinical Protocol Synopsis, 
Pharmacokinetic and Pharmacogenomic 
Methods, Sampling, p.6  
A maximum of five blood samples will be 
collected at one or more of Visits 3-9. 
Clinical Protocol Synopsis, Pharmacokinetic 
and Pharmacogenomic Methods, Sampling, 
p.8  
For PK analysis, aA maximum of five blood 
samples will be collected at one or more of 
Visits 3-9. For PGx analysis, a single blood 
sample will be collected at screening. 
Clarification 
20 
Clinical Protocol Synopsis Pharmacokinetic 
and Pharmacogenomic Methods, 
Bioanalytical Analysis, p.6  
Viloxazine concentrations in plasma will 
be determined for all treatments using a 
validated achiral chromatographic 
method. Concentrations will be reported 
as viloxazine free base. 
Clinical Protocol Synopsis Pharmacokinetic 
and Pharmacogenomic Methods, 
Bioanalytical Analysis, p.8  
Viloxazine concentrations and 5-hydroxy-
viloxazine glucuronide concentrations in 
plasma will be determined for all 
treatments using a validated achiral 
chromatographic method.  Viloxazine 
concentrations will be reported as 
viloxazine free base. 
Assessment of 
viloxazine 
metabolite 


 
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12 Oct 2018 
Protocol 812P304 
 
Page 10 of 29 
 
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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
21 
Clinical Protocol Synopsis, 
Pharmacokinetic and Pharmacogenomic 
Methods, Pharmacokinetic Analysis, p.6  
n/a 
Clinical Protocol Synopsis, Pharmacokinetic 
and Pharmacogenomic Methods, 
Pharmacokinetic Analysis, p.8  
 
 
 
  
Assessment of 
viloxazine 
metabolite 
22 
Clinical Protocol Synopsis, 
Pharmacokinetic and Pharmacogenomic 
Methods, Pharmacokinetic Analysis, p.6  
The analyses’ report will be a stand-alone 
document. 
Clinical Protocol Synopsis, Pharmacokinetic 
and Pharmacogenomic Methods, 
Pharmacokinetic Analysis, p.8  
The analyses’ report will be a stand alone 
document. Population PK analyses will be 
reported separately from the clinical study 
report. 
Clarification 
23 
Clinical Protocol Synopsis, 
Pharmacokinetic and Pharmacogenomic 
Methods, Pharmacogenomics Analysis, p.7 
The DNA will be extracted and tested for 
any genetic variations associated with 
CYP2D6 enzyme. 
Clinical Protocol Synopsis, Pharmacokinetic 
and Pharmacogenomic Methods, 
Pharmacogenomics Analysis, p.8 
The If a given subject’s PK data warrant 
evaluation of PGx, 
 
 
 
  
Clarification 
24 
Clinical Protocol Synopsis, Parmacokinetic 
and Pharmacogenomic Methods, 
Pharmacogenomics Analysis, p.7 
The PGx report may be a stand-alone 
document. 
Clinical Protocol Synopsis, Pharmacokinetic 
and Pharmacogenomic Methods, 
Pharmacogenomics Analysis, p.8 
The PGx report may be a stand alone 
document. If PGx testing is performed, 
individual data will be presented as a 
listing and summaries will be tabulated 
using descriptive statistics. 
Clarification 
25 
List of Abbreviations, p.12 
ADHD-RS-IV/V   ADHD Rating Scale- IV/V 
ANOVA   Analysis of Variance 
DSM-V  Diagnostic and Statistical Manual 
of Mental Disorders-V 
ET          Early Termination 
 
LOCF     Last Observation Carried Forward 
MMRM  Mixed Models Repeated 
Measures 
List of Abbreviations, p.13 
ADHD-RS-IV/V5   ADHD Rating Scale- IV/V5 
ANOVA    Analysis of Variance 
DSM-V5   Diagnostic and Statistical Manual 
of Mental Disorders-V5 
ET              Early Termination 
LLOQ        Lower Limit of Quantitation 
LOCF        Last Observation Carried Forward 
MMRM   Mixed Models for Repeated 
Measures 
MNAR     Missing Not At Random 
Editorial 
change 
 
 


 
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Protocol 812P304 
 
Page 11 of 29 
 
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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
26 
1.2 Clinical Information, Phase 2 Studies, 
p.15 
Information and data from clinical studies 
are available in detail in the SPN-812 ER 
Investigator’s Brochure, version 5.0. 
1.2 Clinical Information, Phase 2 Studies, 
p.16 
Information and data from clinical studies 
are available in detail in the SPN-812 ER 
Investigator’s Brochure, version 5.0 6.0. 
Correction 
27 
2.2 Secondary Objectives, p.16 
 
 To assess the effect of SPN-812 ER 
compared to placebo as assessed by: 
o Conners 3rd edition – parent, self 
o 30% Responder rate (ADHD-RS-V) 
o Hyperactivity/Impulsivity and 
Inattention subscales of ADHD-RS-V 
o Weiss Functional Impairment Rating 
Scale-Parent Report (WFIRS-P) 
o Stress Index for Parents of 
Adolescents (SIPA) 
o Clinical Global Impression - Severity of 
Illness and Improvement (CGI-S/I) 
Scale  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 To evaluate the safety and tolerability of 
SPN-812 ER in 12-17 year-olds.  
2.2 Secondary Objectives, p.18 
Key Secondary 
 To assess evaluate the effect of SPN-812 
ER compared to placebo as assessed by: 
o 
Clinical Global Impression - 
Improvement (CGI-I) scale 
o 
Conners 3rd edition (Conners 3)  – 
parent, self composite T-score 
o 
30% Responder rate (ADHD RS V) 
o 
Hyperactivity/Impulsivity and 
Inattention subscales of ADHD RS
V 
o 
Weiss Functional Impairment 
Rating Scale-Parent Report 
(WFIRS-P) 
o 
Stress Index for Parents of 
Adolescents (SIPA) 
o 
Clinical Global Impression  
Severity of illness and 
Improvement (CGI S/I) Scale 
(Added) Additional Secondary 
 To evaluate the effect of SPN-812 ER 
compared to placebo as assessed by: 
o 
50% Responder rate based on the 
ADHD-RS-5 Total score 
o 
Stress Index for Parents of 
Adolescents (SIPA) 
o 
ADHD-RS-5 Inattention and 
Hyperactivity/Impulsivity 
subscale scores 
o 
Conners 3 – Self, composite T-
score 
Safety 
 To evaluate the safety and tolerability of 
SPN-812 ER in 12 17 year olds 
adolescents with ADHD. 
Update to 
secondary 
objectives and 
endpoints 
28 
2.3 Exploratory, p.17 
n/a 
2.3 Exploratory Objectives, p.18 
(Added) 
Update to 
exploratory 
objectives and 
endpoints 


 
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12 Oct 2018 
Protocol 812P304 
 
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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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
 To evaluate the effect of SPN-812 ER 
compared to placebo as assessed by: 
o 
 
 
 
 
 
 
 
 
 
29 
2.3 Exploratory, p.16 
 
 
 
2.3 Exploratory Objectives, p.18 
 To gain information about viloxazine:  
o 
 
 
  
 
 
 
 
 
Assessment of 
viloxazine 
metabolite 
30 
3.1 Overall Study Design and Plan, p.17 
This is a multicenter, randomized, double-
blind, placebo-controlled, 3-arm, parallel-
group study, to assess the efficacy and 
safety of SPN-812 ER as monotherapy for 
the treatment of adolescents (12-17 years 
old) with ADHD. Approximately 234 
subjects will be randomized in a 1:1:1 
ratio of placebo or one of the two active 
treatment arms (SPN-812 ER 400 or 
600 mg). 
 
Screening (Visit 1):  After administering 
the informed consent form (ICF; and 
informed assent form [IAF], if applicable), 
subjects will undergo initial screening 
evaluation including medical and 
psychiatric history, ECG, vital signs, 
physical examination, routine laboratory 
assessment, PGx testing, and urine drug 
screen.   
3.1 Overall Study Design and Plan, p.18 
This is a multicenter, randomized, double-
blind, placebo-controlled, 3-arm, parallel-
group study, to assess evaluate the efficacy 
and safety of SPN-812 ER as monotherapy 
for the treatment of adolescents (12-17 
years old) with ADHD. Approximately 234 
300 subjects will be randomized in a 1:1:1 
ratio of placebo or one of the two active 
treatment arms (SPN-812 ER 400 or 
600 mg). 
 
Screening (Visit 1):  After administering the 
informed consent form (ICF; and informed 
assent form [IAF], if applicable), subjects 
will undergo initial screening evaluation 
including medical and psychiatric history, 
ECG, vital signs, physical examination, 
routine laboratory assessment, PGx testing 
sample collection, and urine drug screen. 
Editorial 
change 
and 
Increased 
sample size 
 
 
 


 
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12 Oct 2018 
Protocol 812P304 
 
Page 13 of 29 
 
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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
31 
3.1 Overall Study Design and Plan, p.18 
An optional PK substudy during Visits 3-9, 
inclusive will be conducted to assess 
viloxazine PK characteristics in this 
pediatric population. 
3.1 Overall Study Design and Plan, p.19 
An optional PK substudy during Visits 3-9, 
inclusive, will be conducted to assess 
viloxazine the PK characteristics of 
viloxazine (and its metabolite 5-hydroxy-
viloxazine glucuronide, if applicable) in this 
pediatric population. 
Assessment of 
viloxazine 
metabolite 
32 
3.3.1 Number of Subjects, p.18 
Approximately 234 subjects will be 
randomized (78 subjects per treatment) in 
this clinical study. 
3.3.1 Number of Subjects, p.20 
Approximately 234 300 subjects will be 
randomized (78 100 subjects per 
treatment) in this clinical study. 
Increased 
sample size 
33 
3.3.3 Exclusion Criteria, p.19 
1. Current diagnosis of major 
psychological disorders.  
3.3.3 Exclusion Criteria, p.21 
1. Current diagnosis of major psychological 
psychiatric disorders.  
Clarification 
34 
4.6 Concomitant Medications, p.22 
n/a 
4.6 Concomitant Medications, p.24 
(Added) Specific concomitant medication 
prohibitions include known CYP1A2 
substrates (e.g., theophylline, melatonin, 
olanzapine, duloxetine).   
New restriction 
on 
concomitant 
medications 
metabolized by 
CYP1A2 
35 
5.1.1 Visit 1 Screening (Day -28 to -1), p.24 
8. Collect blood samples for hematology, 
chemistry and pharmacogenomic testing 
5.1.1 Visit 1 Screening (Day -28 to -1), p.26 
8. Collect blood samples for hematology, 
chemistry and pharmacogenomic testing 
PGx 
Clarification 
36 
5.1.5 Pharmacogenomic Sample 
Collection, p.25 
The DNA will be extracted and tested for 
any genetic variations associated with 
CYP2D6 enzyme. 
5.1.5 Pharmacogenomic Sample Collection, 
p.27 
The If a given subject’s PK data warrant 
evaluation of PGx, 
 
 
 
  
Clarification 
37 
5.1.5 Pharmacogenomic Sample 
Collection, p.25 
n/a 
5.1.5 Pharmacogenomic Sample Collection, 
p.27 
(Added) The DNA analysis will not be used 
for individual genetic characterization and 
the subject’s identity will be kept 
confidential. 
Clarification 
38 
6.1 Primary Efficacy  Variable, p.26 
 
The scale consists of 18 items that directly 
correspond to the 18 DSM-V symptoms 
and are further subdivided into two 
6.1 Primary Efficacy  Variable, p.28 
6.1.1 ADHD-RS-5 
The scale consists of 18 items that directly 
correspond to the 18 DSM-V5 symptoms 
and are further subdivided into two 
Editorial 
change 
 


 
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Protocol 812P304 
 
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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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
subscales: Hyperactivity/Impulsivity and 
Inattentiveness (DuPaul, 2016). 
subscales: Hyperactivity/Impulsivity and 
Inattentiveness Inattention (DuPaul, 2016). 
 
39 
6.2 Key Secondary Efficacy Variables: , 
p.26 
 
a) Conners 3 
b) 30% Responder Rate  
c) Hyperactivity/Impulsivity and 
Inattention subscales of ADHD-RS-V 
6.2 Key Secondary Efficacy Variables:, p.28 
The key secondary efficacy variables 
include: 
a) Conners 3 CGI-I 
b) 30% Responder Rate (ADHD RS V Total 
Score) Conners 3 – Parent, composite T-
score 
c) Hyperactivity/Impulsivity and Inattention 
subscales of ADHD-RS-V WFIRS-P average 
score 
Update to 
secondary 
objectives and 
endpoints 
40 
6.3 Additional Secondary Efficacy 
Variables:, p. 26 
d) WFIRS-P 
e) SIPA 
f) CGI-S/I 
6.3 Additional secondary Efficacy variables 
will include:, p.28 
a) WFIRS P Proportion of responders with 
50% improvement in the ADHD-RS-5 
Total score (50% Responder rate) 
b) SIPA 
c) CGI S/I ADHD-RS-5 Inattention and 
Hyperactivity/Impulsivity subscale 
scores 
d) Conners 3 – Self, composite T-score 
Update to 
secondary 
objectives and 
endpoints 
41 
Version 4.0, (Added) 6.2.1 Clinical Global Impression - Improvement, p.29 
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 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. 
Editorial 
change 
(section moved 
with no change 
to content) 


 
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CONFIDENTIAL 
12 Oct 2018 
Protocol 812P304 
 
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for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
42 
6.4.3 WFIRS-P, p.27 
The WFIRS instrument evaluates ADHD-
related functional impairment (Gajria, 
2014 Thompson, 2017). 
 
 
The parent-based version 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.   
6.2.3 WFIRS-P, p.29 
The Weiss Functional Impairment Rating 
Scale (WFIRS) instrument evaluates ADHD-
related functional impairment (Gajria, 2014 
2015; Thompson, 2017). 
 
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.   
Editorial 
change 
43 
Version 3.0, (Deleted) 6.4.5 CGI-S/I, p.27 
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 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. 
Editorial 
change 
(section moved 
with no change 
to content) 
44 
6.5 Safety Variables and Assessments, 
p.28 
 
 
 
 
Safety assessments will consist of 
monitoring of and recording of all 
concomitant medications and AEs, clinical 
laboratory tests, measurement of vital 
signs and 12-lead ECGs, suicidality 
monitoring, and the performance of 
6.3 Safety Variables and Assessments, p.30 
(Added) The safety variables for the study 
are AEs, clinical laboratory test results, 
vital signs, ECG results, and treatment-
emergent suicidal ideation. 
 
Safety assessments include will consist of 
monitoring, evaluation,  of and recording 
of all concomitant medications, and the 
evaluation of AEs, clinical laboratory test 
results, measurement of vital signs and 12-
lead ECGs, suicidality monitoring C-SSRS, 
and the performance of physical 
Clarification 


 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
12 Oct 2018 
Protocol 812P304 
 
Page 16 of 29 
 
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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
physical examinations as detailed in the 
Schedule of Events and Assessments. 
examinations as detailed in the Schedule of 
Events and Assessments. 
45 
Version 4.0 (Added) 6.7 Exploratory Variables, p.35 
Exploratory variables include: 
 
 
 
 
 
 
  
Update to 
secondary 
objectives and 
endpoints 
and 
Assessment of 
viloxazine 
metabolite 
46 
7.1 General Considerations, p.34 
All data analyses will be performed by the 
designated CRO after the study is 
completed and the database is released.  
Statistical programming and analyses will 
be performed All data will be analyzed 
using SAS (SAS Institute, Inc., Version 9.2 
or later). 
 
 
 
 
 
In general, continuous variables will be 
summarized with standard descriptive 
statistics including number of subjects (n), 
means, standard deviations, medians, 
minimum, and maximum. Categorical 
variables will be summarized with 
frequencies and percentages. 
 
 
 
 
 
 
 
 
 
 
7.1 General Considerations, p.36 
All data analyses will be performed by the 
designated CRO after the study is 
completed and the database is released.  
Statistical programming and analyses will 
be performed. All data will be analyzed 
using SAS (SAS Institute, Inc., Version 9.2 or 
later). All statistical analysis will be 
performed using SAS version 9.2 or higher 
by 
, which is the designated CRO. 
 
will be responsible for developing a 
unique program for each TLF to create a 
TLF report and deliver to Supernus at the 
completion of the study. 
In general, continuous variables will be 
summarized with standard descriptive 
statistics including number of subjects (n), 
means, standard deviations, medians, 
minimum, and maximum. Categorical 
variables will be summarized with 
frequencies and percentages. 
All tabulations of analysis results will 
include summaries for the following three 
treatments: SPN-812 ER 600 mg, SPN-812 
ER 400 mg, and placebo. 
Where appropriate, variables will be 
summarized descriptively (frequency 
count and percent for categorical 
variables, and number of subjects (n), 
mean, standard deviation (SD), median, 
minimum, and maximum for continuous 
variables).  
Updated for 
consistency 
with revised 
SAP 
 
 
 


 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
12 Oct 2018 
Protocol 812P304 
 
Page 17 of 29 
 
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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
If expected frequencies are too small for 
asymptotic assumptions, exact testing 
techniques will be used. 
If expected frequencies are too small for 
asymptotic assumptions, less than 5 in a 
given cell, then exact testing techniques 
will be used. 
47 
7.1 General Considerations, p.34 
When inferential analyses are conducted 
for continuous variables, they will 
primarily be based on parametric general 
linear models such as analysis of 
covariance or analysis of variance. 
For variables that do not meet the 
normality assumptions, nonparametric 
methods, such as the Wilcoxon rank-sum 
method, will be used. 
Treatment effects for all efficacy variables 
will be evaluated based on a two- sided 
significance level of 0.05 and the 
interaction effects at 0.10. 
Subject characteristics are assumed to be 
comparable at the start of the study, as 
randomization is designed to ensure 
balance between the groups on the 
baseline characteristics, so no formal 
statistical group comparisons will be 
conducted on the subject characteristics. 
7.1 General Considerations, p.36 
(Deleted) When inferential analyses are 
conducted for continuous variables, they 
will primarily be based on parametric 
general linear models such as analysis of 
covariance or analysis of variance. 
(Deleted) For variables that do not meet 
the normality assumptions, nonparametric 
methods, such as the Wilcoxon rank-sum 
method, will be used. 
(Deleted) Treatment effects for all efficacy 
variables will be evaluated based on a two  
sided significance level of 0.05 and the 
interaction effects at 0.10. 
(Deleted) Subject characteristics are 
assumed to be comparable at the start of 
the study, as randomization is designed to 
ensure balance between the groups on the 
baseline characteristics, so no formal 
statistical group comparisons will be 
conducted on the subject characteristics. 
Updated for 
consistency 
with revised 
SAP 
48 
7.2 Handling of Missing Data, p.34 
For primary efficacy analysis, missing data 
will be assumed as Missing at Random 
(MAR) and will be handled using Mixed 
Models Repeated Measures (MMRM) 
technique according to the MMRM 
paradigm. Under MAR, the propensity for 
a data point to be missing is not related to 
the missing data, but is related to some of 
the observed data. For secondary and first 
sensitivity analyses, the last observation 
carried forward (LOCF) method of 
imputation will be used. The underlying 
assumption for using the LOCF method is 
based on the fact that 35% of subjects 
early terminated (ET) before completion 
of the Phase II 202 study as lost-to-follow-
up. It is assumed that majority of subject 
dropout in the Phase III trial will follow the 
same pattern and hence, the assumption 
of Missing Completely at Random (MCAR) 
7.2 Handling of Missing Data, p.36 
For With respect to the primary efficacy 
analysis, missing data ADHD-RS-5 Total 
Scores will be assumed as to be Mmissing 
at Rrandom (MAR), that is, given the 
observed data, the reason for the missing 
data does not depend on the unseen data. 
and will be handled using The Mixed 
Models for Repeated Measures (MMRM) 
technique according to the MMRM 
paradigm method, implemented via SAS® 
PROC MIXED (SAS/STAT Software), will be 
used for handling missing ADHD-RS-5 Total 
Scores under MAR assumption. Under 
MAR, the propensity for a data point to be 
missing is not related to the missing data, 
but is related to some of the observed 
data. For secondary and first sensitivity 
analyses, the last observation carried 
forward (LOCF) method of imputation will 
be used. The underlying assumption for 
LOCF method 
no longer used 


 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
12 Oct 2018 
Protocol 812P304 
 
Page 18 of 29 
 
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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
can be applied and the LOCF imputation 
for missing data can be used. 
using the LOCF method is based on the fact 
that 35% of subjects early terminated (ET) 
before completion of the Phase II 202 study 
as lost to follow up. It is assumed that 
majority of subject dropout in the Phase III 
trial will follow the same pattern and 
hence, the assumption of Missing 
Completely at Random (MCAR) can be 
applied and the LOCF imputation for 
missing data can be used.  
 
 
(Added) 
The sensitivity analysis for the primary 
endpoint will be performed by assuming 
that missing ADHD-RS-5 Total Scores are 
missing not at random (MNAR) meaning 
that the probability that an observation is 
missing may depend on its underlying 
unobserved value.  
For analysis of secondary endpoints, 
missing values will be assumed as MAR.  
For safety analyses, missing dates for AEs 
and non-study medication use will be 
imputed as described in the SAP. Missing 
data for all other safety endpoints will not 
be imputed. 
49 
7.3 Analysis Populations, p.35 
 
 
 
 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-Baseline ADHD-RS-V 
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 with missing visits or 
ADHD-RS-V assessments and no major 
protocol violations. Subjects will be 
7.3 Analysis Populations, p.36 
 The Randomized population will include 
all enrolled subjects who had a baseline 
visit and are randomized via the IWRS. 
 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-Baseline randomization ADHD-
RS-V5 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 
complete all 9 visits with no missing 
visits or ADHD-RS-V5 assessments and no 
major protocol violations. Subjects will be 
Updated for 
consistency 
with revised 
SAP 


 
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12 Oct 2018 
Protocol 812P304 
 
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of such information that is not authorized in writing by the Sponsor is strictly prohibited.  Such information may be used solely 
for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
analyzed according to the treatment 
they actually received. 
 The Safety Population consists of all 
subjects who receive at least one dose 
of SM. 
 
 
 PK population will include all subjects in 
the safety population who had at ≤1 
non-below-the-limit-of-quantitation PK 
sample drawn. 
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.  
 The PK population will include all 
subjects in the safety population who 
had ≤ ≥ 1 non-below-the-limit-of-
quantitation PK sample drawn that is not 
below the LLOQ. 
50 
7.4 Demographics and Baseline Analysis, 
p.35 
Demographic/baseline variables include 
age, sex, ethnicity, race, height and weight 
at screening, and medical history will be 
summarized using descriptive statistics for 
continuous variables and using counts and 
percentages for categorical variables.   
7.4 Demographics and Baseline Analysis, 
p.37 
Demographic/baseline variables includeing 
age, age group, sex, ethnicity, race, height 
and weight at screening, and medical 
history BMI will be summarized using 
descriptive statistics for continuous 
variables and using counts and percentages 
for categorical variables.  
Updated for 
consistency 
with revised 
SAP 
51 
7.4 Demographics and Baseline Analysis, 
p.35 
n/a 
 
 
7.4 Demographics and Baseline Analysis, 
p.37 
(Added)  
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. 
Updated for 
consistency 
with revised 
SAP 
52 
7.5 Subject Disposition, p.35 
• Subjects in the randomized population 
• Subjects in the ITT population 
 
• Subjects treated (safety population) 
 
 
7.5 Subject Disposition, p.37 
• Subjects in the randomized population 
• Subjects in the ITT population 
• Subjects in the PP population 
• Subjects treated (in the safety 
population) 
 
Within each of the previous categories, the 
number and percentage of subjects who 
Updated for 
consistency 
with revised 
SAP 


 
Supernus Pharmaceuticals, Inc. 
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12 Oct 2018 
Protocol 812P304 
 
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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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
Within each of the previous categories, 
the number and percentage of subjects 
who completed and discontinued from 
the study and the primary reason for 
discontinuation will be summarized.  The 
reason for discontinuation may include 
any of the following: 
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: 
53 
7.6 Study Medication Exposure and 
Compliance, p.35 
Duration of Treatment exposure will also 
be summarized using descriptive statistics 
(n, mean, SD, median, minimum, and 
maximum). 
 
Percent of study drug compliance is 
defined as {(number of capsules dispensed 
minus number of capsules returned) / 
(date of last dose minus date of first dose 
+ 1)}* 100%. 
7.6 Study Medication Exposure and 
Compliance, p.37 
Duration of Ttreatment 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) /3 × (date of 
last dose minus date of first dose + 1)}* 
100%. 
Updated for 
consistency 
with revised 
SAP 
54 
7.8.1.1 Primary analyses, p.35 
The primary endpoint is change from 
baseline in ADHD-RS-V Total Score and the 
primary analysis, based on the ITT 
population, will be performed using a 
longitudinal MMRM and a restricted 
maximum likelihood (REML) approach. 
The model will include the fixed, 
categorical effects of treatment, 
investigative site, visit, and treatment-by-
visit interaction, as well as the continuous, 
fixed covariates of baseline score and 
baseline score-by-visit interaction.  
An unstructured (co)variance structure 
will be used to model the within-subject 
errors. If this analysis fails to converge, the 
Compound Symmetry and Toeplitz 
structures will be tested. The covariance 
structure converging to the best fit as 
determined by Akaike’s information 
criterion will be used. The Kenward-Roger 
approximation will be used to estimate 
denominator degrees of freedom. 
 
 
7.8.1.1 Primary analysis, p.38 
(Deleted) The primary endpoint is change 
from baseline in ADHD RS V Total Score 
and the primary analysis, based on the ITT 
population, will be performed using a 
longitudinal MMRM and a restricted 
maximum likelihood (REML) approach. The 
model will include the fixed, categorical 
effects of treatment, investigative site, 
visit, and treatment by visit interaction, as 
well as the continuous, fixed covariates of 
baseline score and baseline score by visit 
interaction.  
(Deleted) An unstructured (co)variance 
structure will be used to model the within-
subject errors. If this analysis fails to 
converge, the Compound Symmetry and 
Toeplitz structures will be tested. The 
covariance structure converging to the best 
fit as determined by Akaike’s information 
criterion will be used. The Kenward Roger 
approximation will be used to estimate 
denominator degrees of freedom.  
(Added) The primary efficacy variable, 
change from baseline in ADHD-RS-5 Total 
Updated for 
consistency 
with revised 
SAP 


 
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12 Oct 2018 
Protocol 812P304 
 
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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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Each of the treatment groups (SPN-812 ER 
200 and 400 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. 
 
To maintain the Type I error rate at 5% 
level, a sequential testing of hypotheses 
will be performed. 
 
 
 
 
 
 
 
 
Score to Week 7 (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 400 
mg and SPN-812 ER 600 mg) will be 
presented, along with the corresponding 
standard error. Each of the treatment 
groups (SPN-812 ER 200 400 mg and 400 
600 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. 
To maintain the Type I error rate at 5% 
level, a sequential testing of (Westfall et al, 
1999) of the null hypotheses H01: No 
treatment mean difference between SPN-
812 ER 600 mg group and placebo group 
and H02: No treatment mean difference 
between SPN-812 ER 400 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 600 mg and SPN-812 ER 


 
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12 Oct 2018 
Protocol 812P304 
 
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for the purpose of reviewing or performing this study. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
 
 
 
Let µ1, µ2, and µ3 be the LS Means of 
SPN-812 ER 600 mg, SPN-812 ER 400 mg 
and Placebo, respectively, for CFB to EOS 
in the ADHD-RS-V Total Score. 
The first step will be to test H0:µ1 =µ3 vs. 
H1: µ1 < µ3, a comparison of the LS mean 
of SPN-812 ER 600 mg dose group and 
with the LS mean of Placebo group, at the 
5% significance level.  If H0 is not rejected, 
then formal testing stops and the 
conclusion will be that there is insufficient 
evidence to conclude that both the LS 
mean of SPN-812 ER 600 mg dose and the 
LS mean of SPN-812 ER 400 mg are less 
than the LS mean of the Placebo group.  In 
other words, neither dose group is 
efficacious. 
If H0 is rejected, then formal testing will be 
performed at step two with a test of H0: µ2 
= µ3 vs. H1: µ2 <  µ3, a comparison of the LS 
mean of SPN-812 ER 400 mg and with the 
LS mean of Placebo group at the 5% 
significance level.  If the null hypothesis is 
not rejected, then formal testing stops 
and the conclusion is that there is only 
sufficient evidence to conclude that the LS 
mean of SPN-812 ER 600 mg is less than 
the LS mean of the Placebo group.  If H0 is 
rejected, then it will be concluded that 
both the LS means of SPN-812 ER 600 mg 
and SPN-812 ER 400 mg doses are less 
than the LS mean of the placebo group. In 
other words, the superiority of both arms 
to placebo will be claimed. 
400 mg are superior to placebo. If H01 is 
rejected and H02 is not rejected then it will 
be concluded that only SPN-812 ER 600 mg 
is superior to placebo. 
Let µ1, µ2, and µ3 be the LS Means of SPN
812 ER 4600 mg SPN 812 ER 400 mg and 
Placebo, respectively, for CFB to EOS in the 
ADHD RS V Total Score. 
The first step will be to test H0:µ1 =µ3 vs. 
H1: µ1 < µ3, a comparison of the LS mean of 
SPN 812 ER 600 mg dose group and with 
the LS mean of Placebo group, at the 5% 
significance level.  If H0 is not rejected, then 
formal testing stops and the conclusion will 
be that there is insufficient evidence to 
conclude that both the LS mean of SPN-812 
ER 600 mg dose and the LS mean of SPN
812 ER 400 mg are less than the LS mean of 
the Placebo group.  In other words, neither 
dose group is efficacious. 
If H0 is rejected, then formal testing will be 
performed at step two with a test of H0: µ2 
= µ3 vs. H1: µ2 < µ3, a comparison of the LS 
mean of SPN 812 ER 400 mg and with the 
LS mean of Placebo group at the 5% 
significance level.  If the null hypothesis is 
not rejected, then formal testing stops and 
the conclusion is that there is only 
sufficient evidence to conclude that the LS 
mean of SPN 812 ER 600 mg is less than the 
LS mean of the Placebo group.  If H0 is 
rejected, then it will be concluded that 
both the LS means of SPN 812 ER 600 mg 
and SPN 812 ER 400 mg doses are less than 
the LS mean of the placebo group.  In other 
words, the superiority of both arms to 
placebo will be claimed. 
55 
7.8.1.2 Sensitivity Analyses, p.37 
To confirm the results of the primary 
analysis, two sensitivity analyses will be 
performed. 
First Sensitivity Analysis - the CFB to EOS 
will be analyzed using an analysis 
covariance (ANCOVA) model with 
treatment as fixed effect and baseline 
7.8.1.2 Sensitivity Analyses, p.39 
To confirm the results of the primary 
analysis, two sensitivity analyses will be 
performed. 
First Sensitivity Analysis  the CFB to EOS 
will be analyzed using an analysis 
covariance (ANCOVA) model with 
treatment as fixed effect and baseline 
LOCF method 
no longer used 


 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
12 Oct 2018 
Protocol 812P304 
 
Page 23 of 29 
 
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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
ADHD-RS-V Total Score as a covariate 
based on the ITT population. The last 
observation carried forward (LOCF) 
method of imputation will be used for 
handling missing data. The assumption for 
using LOCF is described in Section 7.2-
Handling Missing Data. 
Second Sensitivity Analysis - The first 
sensitivity analysis will be repeated for the 
PP population. 
ADHD RS V Total Score as a covariate 
based on the ITT population. The last 
observation carried forward (LOCF) method 
of imputation will be used for handling 
missing data. The assumption for using 
LOCF is described in Section 7.2 Handling 
Missing Data. 
Second Sensitivity Analysis  The first 
sensitivity analysis will be repeated for the 
PP population. 
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. 
56 
7.8.2 Secondary Analyses, p.37 
n/a 
7.8.2 Secondary Efficacy Analyses, p.39 
(Added)  
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 at Week 7 on the change 
from baseline at Week 7 (EOS) with 
treatment and baseline as fixed effect. 
Each of the treatment groups (SPN-812 ER 
400 mg and 600 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 400 mg 
minus Placebo and SPN-812 ER 600 mg 
minus Placebo), and 95% confidence 
intervals for the treatment differences will 
be computed. 
Updated for 
consistency 
with revised 
SAP 


 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
12 Oct 2018 
Protocol 812P304 
 
Page 24 of 29 
 
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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
57 
7.8.2.1 Key secondary analyses, p.37 
 
Key secondary analyses will include: 
a) Conners 3 - Treatment comparisons 
will be performed using ANCOVA or 
ANOVA on CFB to EOS, as appropriate. 
b) 30% Responder Rate - The proportion 
of subjects with ≥30% improvement 
(decrease) from baseline to EOS in 
ADHD-RS-V Total Score  will be 
calculated for each treatment group. 
The 2-sided 95% CI around the 
difference in proportions (SPN-812 ER 
dose minus Placebo) and the p-value 
from Pearson’s chi-squared test will be 
presented. 
c) Hyperactivity/Impulsivity and 
Inattention subscales of ADHD-RS-V – 
analyzed as for Conners 3 
 
7.8.2.1 Key secondary efficacy analyses, 
p.39 
Key secondary analyses will include: 
The analyses of key secondary objectives 
will be conducted on the following 
sequentially ordered endpoints for testing: 
1) CGI-I, 2) Conners 3 - Parent composite 
T-score, and 3) WFIRS-P. 
To preserve the overall type I error rate at 
0.05 for the key secondary endpoints, a 
sequential testing procedure will be used. 
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 does not reject H01 (i.e., 
the 600 mg is not superior to placebo) or 
the primary endpoint analysis rejects only 
H01, then no multiplicity adjustment is 
required. Otherwise, multiplicity 
adjustment will be performed with the 
following features. 
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 600 mg group and placebo group 
and H02: No treatment mean difference 
between SPN-812 ER 400 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 600 mg and SPN-812 ER 
400 mg are superior to Placebo. If H02 is 
not rejected, then it will be concluded that 
only SPN-812 ER 600 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) 
Updated for 
consistency 
with revised 
SAP 


 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
12 Oct 2018 
Protocol 812P304 
 
Page 25 of 29 
 
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. 
 
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. 
a) CGI-I – The absolute value of CGI-I at 
Week 7 (EOS) will be analyzed using 
ANCOVA with treatment as a fixed 
classification variable and baseline CGI-S 
as a covariate. To compare the treatment 
groups, the difference in LS means (SPN-
812 ER 400 mg minus Placebo and SPN-812 
ER 600 mg minus Placebo) will be 
presented along with the 95% confidence 
interval (CI) around the difference and p-
value. 
b) Conners 3 - Parent - Treatment 
comparisons will be performed using 
ANCOVA or ANOVA on CFB to EOS as 
appropriate. A composite T-score will be 
calculated by averaging over the six 
domains, and the change from baseline to 
Week 7 (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 400 mg and 600 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. 
b) 30% Responder Rate  The proportion of 
subjects with ≥30% improvement 
(decrease) from baseline to EOS in ADHD
RS V Total Score  will be calculated for each 
treatment group. The 2 sided 95% CI 
around the difference in proportions (SPN
812 ER dose minus Placebo) and the p-
value from Pearson’s chi-squared test will 
be presented. c) WFIRS-P - The change 
from baseline in WFIRS-P to Week 7 (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 400 


 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
12 Oct 2018 
Protocol 812P304 
 
Page 26 of 29 
 
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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
mg and 600 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. 
c) Hyperactivity/Impulsivity and Inattention 
subscales of ADHD RS V  analyzed as for 
Conners 3 
58 
7.8.2.2 Additional secondary analyses, 
p.37 
Additional secondary analyses include 
treatment comparisons using ANCOVA or 
ANOVA on CFB to EOS, as appropriate.: 
a) WFIRS-P  
b) SIPA 
c) CGI-S/I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.8.2.2 Additional secondary analyses, p.40 
 
Additional secondary analyses of the 
secondary efficacy variables will include: 
treatment comparisons using ANCOVA or 
ANOVA on CFB to EOS, as appropriate. 
a) WFIRS P 50% Responder rate for ADHD-
RS-5 - Percent reduction will be calculated 
as: % reduction = 100*(ADHD-RS-5 Total 
Score at Week 7 (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 400 mg minus 
Placebo, SPN-812 ER 600 mg minus 
Placebo) and the p-value from Pearson’s 
Chi-squared Test or Fisher’s Exact Test  will 
be presented. 
b) SIPA - The change from baseline in SIPA 
total score to Week 7 (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 400 mg and 600 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) CGI S/I 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 Week 7 
Updated for 
consistency 
with revised 
SAP 


 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
12 Oct 2018 
Protocol 812P304 
 
Page 27 of 29 
 
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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
 
 
 
The primary and secondary analyses will 
be repeated for the per protocol 
population. 
(EOS) in Hyperactivity/Impulsivity 
subscales. 
d) Conners 3 - Self – The analysis for 
Conners 3 - Parent will be repeated for 
Self scores. 
The primary and key secondary analyses 
will be repeated for the per protocol 
population for supplementary analyses. 
59 
Version 4.0, (Added) 7.8.3 Subgroup Analyses, p.40 
The primary and key secondary efficacy variable analyses may be repeated by the 
following subgroups to explore the heterogeneity of treatment effect: 
a) Gender (male, female) 
b) Age (12-14 years, 15-17 years) 
c) Race (white, non-white) 
Updated for 
consistency 
with revised 
SAP 
60 
Version 4.0 (Added) 7.8.4 Exploratory Analyses, p.41 
Exploratory analyses of the key exploratory efficacy variables will include: 
 
 
 
 
 
 
Updated for 
consistency 
with revised 
SAP 
61 
7.9 Sample Size and Power 
Considerations, p.37 
Fifty-six subjects per treatment group in 
the ITT population will yield 90% power at 
a significance level of 0.05 (two-sided) 
using a two-sample t-test with equal 
allocation to the treatment groups. This 
assumes an effect size of 0.623, observed 
in the comparison of SPN-812 400 mg and 
placebo in the SPN-812 ER Phase IIb study 
(based on the CFB to endpoint in the 
ADHD-RS-IV total score). A total of 234 
subjects (78 subjects in each of the three 
treatment groups) will be randomized to 
account for an anticipated 27.9% of 
randomized subjects not completing the 
study. 
7.9 Sample Size and Power Considerations, 
p.41 
Fifty six Seventy-two subjects per 
treatment group in the ITT population will 
yield 90% power at a significance level of 
0.05 (two-sided) using a two-sample t-test 
with equal allocation to the treatment 
groups. This assumes an effect size of 0.623 
0.547, observed in the comparison of 
SPN-812 400 200 mg and placebo in the 
SPN-812 ER Phase IIb study (based on the 
CFB to endpoint in the ADHD-RS-IV total 
score). A total of 234 300 subjects (78 100 
subjects in each of the three treatment 
groups) will be randomized to account for 
an anticipated 27.9% of randomized 
subjects not completing the study. 
Increased 
sample size 
 


 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
12 Oct 2018 
Protocol 812P304 
 
Page 28 of 29 
 
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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
62 
7.11 Pharmacokinetic Analyses, p.38 
n/a 
 
 
 
 
 
   
 
 
 
 
   
7.11 Pharmacokinetic Analyses, p.41 
 
 
 
 
 
 
   
 
 
 
 
in the present study.   
Assessment of 
viloxazine 
metabolite 
63 
7.11 Pharmacokinetic Analyses, p.38 
n/a 
7.11 Pharmacokinetic Analyses, p.41 
(Added) Population PK analyses will be 
reported separately from the clinical study 
report. 
Clarification 
64 
7.12 Pharmacogenomic Analysis, p.38 
Individual data will be presented as a 
listing and summaries will be tabulated 
using descriptive statistics. 
7.12 Pharmacogenomic Analysis, p.41 
If PGx testing is performed, Iindividual data 
will be presented as a listing and 
summaries will be tabulated using 
descriptive statistics. 
Clarification 
65 
7.13 Safety Analysis, p.38 
Verbatim description and all Medical 
Dictionary for Regulatory Activities 
(MedDRA) level terms, including the 
Lower Level Terms, for all AEs will be 
contained in the subject data listings. 
 
 
For quantitative laboratory parameters, 
both actual values an change from Visit 2 
will be summarized. 
 
Both actual values and change from Visit 2 
to Visit 9 will be summarized. 
7.13 Safety Analysis, p.42 
Verbatim description and all Medical 
Dictionary for Regulatory Activities 
(MedDRA) SOCs and PTs level terms, 
including the Lower Level Terms, for all AEs 
will be contained in the subject data 
listings. 
 
For quantitative laboratory parameters, 
both actual values an change from Visit 2 
Screening will be summarized. 
 
Both actual values and change from Visit 2 
to Visit 9 baseline will be summarized. 
Clarification 
66 
8.3.4 Bioanalytical Sample Handling, p.40 
Viloxazine concentrations in plasma 
samples will be determined using a 
validated chromatographic method.   
8.3.4 Bioanalytical Sample Handling, p.43 
Viloxazine and 5-hydroxy-viloxazine 
glucuronide concentrations in plasma 
samples will be determined using a 
validated chromatographic method.   
Assessment of 
viloxazine 
metabolite 
 
 


 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
12 Oct 2018 
Protocol 812P304 
 
Page 29 of 29 
 
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. 
 
# 
812P304 Protocol Version 3.0 
dated 07 September 2017 
812P304 Protocol Version 4.0 
dated 12 October 2018 
Rationale 
(Added) Viloxazine concentrations will be 
reported as viloxazine free base.  
67 
10 References, p.43 
Gajria K, Kivote V, Sikirica V, Reilly K, 
Kosinski M, Erder MH. Validation of the 
Weiss Functional Impairment Rating Scale 
– Parent Report Form in attention 
deficit/hyperactivity disorder. European 
Neuropsychopharmacology, Volume 24, 
S711 - S712. 
10 References, p.46 
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. 
(Added) Westfall, Peter H., Tobias, Randall 
D., and Wolfinger, Russell D., (1999). 
Multiple Comparisons and Multiples Tests 
Using SAS®, Cary, NC: SAS Institute Inc. 
Editorial 
change 
 

SAP_001.pdf: 
Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
    Protocol 812P304 
Page 1 of 39 
CONFIDENTIAL AND PROPRIETARY 
          18 October 2018 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol Title 
Evaluation of SPN-812 ER 400 and 600 mg Efficacy and Safety in 
Adolescents with ADHD - A Double-Blind, Placebo-Controlled, 
Pivotal Trial 
Protocol Number  
812P304 
Protocol Version 
V4.0 
Protocol Date: 
12OCT2018 
Study Drug 
Viloxazine Extended-Release Capsules (SPN-812 ER)  
Study Phase 
III 
IND Number 
108,864 
Sponsor  
Supernus Pharmaceuticals, Inc.  
 
 
 
SAP Version 
Final 
Date 
18Oct2018  
 number: 
 
 
 
 
 
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
    Protocol 812P304 
Page 2 of 39 
CONFIDENTIAL AND PROPRIETARY 
          18 October 2018 
 
 
 
SIGNATURE PAGE 
Prepared at Supernus Pharmaceuticals, Inc 
 
 
 
 
Reviewed at Supernus Pharmaceuticals, Inc 
 
 
 
 
Reviewed at
 
   
 
  
  
 
 
 
 
 
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
    Protocol 812P304 
Page 3 of 39 
CONFIDENTIAL AND PROPRIETARY 
          18 October 2018 
 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ............................................................................................. 1 
LIST OF ABBREVIATIONS ....................................................................................................... 7 
1 
INTRODUCTION .................................................................................................................. 9 
2 
STUDY OBJECTIVES......................................................................................................... 9 
2.1 Primary Objective ........................................................................................................................................ 9 
2.2 Secondary Objectives ................................................................................................................................ 9 
2.2.1 Key Secondary Objectives: ......................................................................................................................... 9 
2.2.2 Additional Secondary Objectives: .............................................................................................................. 9 
2.2.3 Exploratory Objectives............................................................................................................................... 10 
2.2.4 Safety Evaluation ....................................................................................................................................... 10 
2.2.5 Additional Exploratory Objective .............................................................................................................. 10 
3 
STUDY DESCRIPTION..................................................................................................... 10 
3.1 Study Design .............................................................................................................................................. 10 
3.2 Schedule of Visits and Procedures Study ............................................................................................ 12 
3.3 Procedures for Discontinuing Treatment and Removal of Subjects from Study .......................... 15 
3.4 Study Treatments ...................................................................................................................................... 15 
3.4.1 Methods of Assigning Subjects to Treatment Group ............................................................................ 15 
3.4.2 Treatment, Dose, and Mode of Administration ...................................................................................... 16 
3.4.3 Duration of Treatment and Study Duration ............................................................................................. 16 
3.4.4 Blinding ........................................................................................................................................................ 16 
3.5 Sample Size and Power Considerations ............................................................................................... 16 
4 
DEFINITIONS AND DERIVATIONS ............................................................................... 17 
5 
STUDY VARIABLES ......................................................................................................... 17 
5.1 Primary Efficacy Variable ........................................................................................................................ 17 
5.2 Secondary Efficacy Variables ................................................................................................................. 18 
5.2.1 Clinical Global Impression-Improvement ................................................................................................ 18 


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Statistical Analysis Plan 
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5.2.2 Conners 3 .................................................................................................................................................... 18 
5.2.3 WFIRS-P...................................................................................................................................................... 19 
5.2.4 SIPA ............................................................................................................................................................. 19 
5.3 Pharmacokinetic Variables ...................................................................................................................... 19 
5.4 Safety Assessments ................................................................................................................................. 19 
6 
STATISTICAL METHODS ............................................................................................... 19 
6.1 General Principles ..................................................................................................................................... 19 
6.2 Visit Windows ............................................................................................................................................ 20 
6.3 Analysis populations ................................................................................................................................ 21 
6.3.1 Randomized population ............................................................................................................................. 21 
6.3.2 Safety population ........................................................................................................................................ 21 
6.3.3 Intent-to-treat (ITT) population ................................................................................................................. 21 
6.3.4 Per-Protocol (PP) population .................................................................................................................... 21 
6.4 Subject Disposition ................................................................................................................................... 22 
6.5 Protocol Deviations .................................................................................................................................. 22 
6.6 Handling Missing Data ............................................................................................................................. 23 
6.6.1 Missing Efficacy Variables ........................................................................................................................ 23 
6.6.2 Missing Safety Variables ........................................................................................................................... 24 
6.7 Demographic and Baseline Characteristics ......................................................................................... 24 
6.8 Medical and Psychiatric History ............................................................................................................. 25 
6.9 Concomitant Medications ........................................................................................................................ 25 
6.10 Study Medication Exposure and Compliance .................................................................................... 25 
6.11 Site Pooling .............................................................................................................................................. 26 
6.12 Multiple Comparisons/Multiplicity ....................................................................................................... 26 
6.13 Efficacy Analyses .................................................................................................................................... 26 
6.13.1 Analysis of Primary Endpoint ................................................................................................................. 27 
6.13.2 Sensitivity Analysis .................................................................................................................................. 28 
6.14 Analysis of Secondary Endpoints ........................................................................................................ 29 
6.14.1 Analyses of Key Secondary Endpoints ................................................................................................. 29 
6.14.1.1 Clinical Global Impression – Improvement (CGI-I) ..................................................................... 29 


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6.14.1.2 Conners 3-Parental Short Form ..................................................................................................... 30 
6.14.1.3 Weiss Functional Impairment Rating Scale – Parent Version (WFIRS-P) .............................. 30 
6.14.2 Analysis of Additional Secondary endpoints ........................................................................................ 31 
6.14.2.1 Responder Analysis (50% responder rate) .................................................................................. 31 
6.14.2.2 Stress Index for Parents of Adolescents (SIPA) ......................................................................... 31 
6.14.2.3 ADHD-RS-5 Hyperactivity/Impulsivity and Inattention Subscales ............................................ 32 
6.14.2.4 Conners 3– Self-report Short Form ............................................................................................... 32 
6.14.2.5 Categorical Analysis of CGI-I ......................................................................................................... 32 
6.14.3 Exploratory Analyses ............................................................................................................................... 33 
6.14.3.1 
............................................................... 33 
6.14.3.2 
 ........................................................ 33 
6.14.3.3 
 ..................................................................................................... 33 
6.14.3.4
 ................................................................................................ 33 
6.14.4 Supplementary Analyses ........................................................................................................................ 33 
6.15 Examination of Subgroups .................................................................................................................... 33 
6.16 Pharmacokinetic (PK) Data Analysis ................................................................................................... 34 
6.17 Safety Analyses ....................................................................................................................................... 34 
6.17.1 Adverse Events ........................................................................................................................................ 34 
6.17.1.1 Treatment Emergent Adverse Events ........................................................................................... 34 
6.17.1.2 Severity of TEAEs ............................................................................................................................ 35 
6.17.1.3 Relatedness of TEAEs to SM ......................................................................................................... 35 
6.17.1.4 Serious Adverse Events .................................................................................................................. 35 
6.17.2 Laboratory Data ........................................................................................................................................ 36 
6.17.3 Vital Signs ................................................................................................................................................. 36 
6.17.4 Twelve (12)-Lead ECG ........................................................................................................................... 37 
6.17.5 Physical examinations ............................................................................................................................. 37 
6.17.6 C-SSRS ..................................................................................................................................................... 38 
7 
VALIDATION ...................................................................................................................... 38 
8 
REFERENCES ................................................................................................................... 38 
 
 
 
 
 
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
    Protocol 812P304 
Page 6 of 39 
CONFIDENTIAL AND PROPRIETARY 
          18 October 2018 
 
 
List of Tables 
FIGURE 1: DESIGN SCHEMATIC 
11 
TABLE 1: SCHEDULE OF VISITS AND PROCEDURE 
13 
TABLE 2: VISIT WINDOWS AND STUDY DAY RANGES 
21 
TABLE 3: VITAL SIGNS NORMAL RANGES 
36 
TABLE 4: NORMAL ECG RANGES 
37 
 
 
 
List of Figures 
FIGURE 1: DESIGN SCHEMATIC ......................................................................................................................... 11 
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
    Protocol 812P304 
Page 7 of 39 
CONFIDENTIAL AND PROPRIETARY 
          18 October 2018 
 
 
LIST OF ABBREVIATIONS  
AE  
Adverse event 
ADHD-RS-5 
Attention Deficit Hyperactivity Disorder Rating Scale 
QD  
Once daily 
CFB 
Change from Baseline 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global impression – Severity of illness 
Conners 3-PS 
Conners 3-Parent Short Form 
Conners 3-SRS Conners 3 – Self-Report Short Form 
CRO 
Contract Research Organization 
CRF  
Case report form 
EOS 
Visit 9 date or date of last visit for dropout subjects  
ECG  
Electrocardiogram 
ITT 
Intent-to-treat 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonization  
IWRS  
Interactive web-based randomization system 
LS Mean 
Least Square Mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
msec 
Millisecond 
PK  
Pharmacokinetic(s) 
PP 
Per Protocol 
PT 
Preferred term in MedDRA and WHODD 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SIPA 
Stress Index for Parents of Adolescents 
SM 
Study Medication 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
    Protocol 812P304 
Page 8 of 39 
CONFIDENTIAL AND PROPRIETARY 
          18 October 2018 
 
 
SOC 
System Organ Class in MedDRA 
TEAE  
Treatment-emergent adverse event 
TLF 
Tables, Listings and Figures 
WFIRS-P 
Weiss Functional Impairment Rating Scale – Parent Version 
WHODD 
WHO Drug Dictionary 
 
 
 
 
 


Supernus Pharmaceuticals, Inc. 
Statistical Analysis Plan 
    Protocol 812P304 
Page 9 of 39 
CONFIDENTIAL AND PROPRIETARY 
          18 October 2018 
 
 
 
1 Introduction 
This document describes the statistical analyses and data presentations to be performed on Study 
812P304.  This Phase III, randomized, multicenter, double-blind, 3-arm, parallel-group, and 
placebo controlled pivotal study of SPN-812 ER is titled “Evaluation of SPN-812 ER 400 and 600 
mg Efficacy and Safety in Adolescents with ADHD - A Double-Blind, Placebo-Controlled, Pivotal 
Trial.” 
The purpose of this statistical analysis plan (SAP) is to ensure the credibility of the study findings 
by specifying the statistical approaches to the analysis of the data prior to database lock. This SAP 
covers the planned analyses of all data collected on the eCRFs and diary pages, and will identify 
handling of data issues. It describes the efficacy and safety variables, anticipated data 
manipulations, and other details of the analyses not provided in the study protocol. Any 
deviations/changes from the planned analyses described in this SAP will be identified, with 
justification, in the appropriate section of the clinical study report. The statistical analysis plan 
presented in this document will supersede the statistical analysis methods described in the clinical 
protocol. This SAP is based on the protocol 812P304, Version 4.0, dated 12Oct2018. 
2 Study Objectives 
2.1 Primary Objective 
 To evaluate the efficacy of SPN-812 extended-release (ER) compared to placebo as 
monotherapy for the treatment of ADHD in adolescents (12 -17 years). 
2.2 Secondary Objectives 
2.2.1 Key Secondary Objectives:  
To assess the effect of SPN-812 ER as assessed by: 
1. Clinical Global Impression-Improvement (CGI-I) 
2. Conners 3rd edition (Conners 3) – Parent, composite T-score 
3. Weiss Functional Impairment Rating Scale – Parent report (WFIRS-P) 
2.2.2 Additional Secondary Objectives:  
1. 50% Responder rate in ADHD-RS-5 Total score  
2. Stress Index for Parents of Adolescents (SIPA)  
3. ADHD RS-5 Inattention and Hyperactivity/Impulsivity subscale scores  


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4. Conners 3 – Self, Composite T-score 
2.2.3 Exploratory Objectives  
 
  
 
 
 
 
 
 
2.2.4 Safety Evaluation 
 To evaluate the safety and tolerability of SPN-812 ER in adolescents with ADHD 
2.2.5 Additional Exploratory Objective 
 
 
 
 
 
 
3 Study Description 
3.1 Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, 3-arm, parallel-group study, 
to assess the efficacy and safety of SPN-812 ER as monotherapy for the treatment of adolescents 
(12-17 years old) with ADHD.  Approximately 300 subjects will be randomized in a 1:1:1 ratio of 
placebo or one of the two active treatment arms (SPN-812 ER 400 or 600 mg). Following up to 
four weeks of screening, subjects will be randomized and undergo two weeks of titration followed 
by five weeks of maintenance for a total of seven weeks of treatment and total study duration of 
up to 9-11 weeks.  The study schematic appears in Figure 1. 
 Reda
a Reda


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Figure 1: Design Schematic 
 
 
Screening 
R 
 
Double-blind Treatment Period 
a 
n 
Titration 
Maintenance 
d 
 
 
SPN-812 ER 600 mg/day (N=100) 
o 
400mg 
z 
200 mg 
 
 
 
 
 
a 
 
 
 
 
 
 
t 
 
SPN-812 ER 400 mg/day (N=100) 
i 
200 mg 
o 
n 
Placebo (N=100) 
 
 
Week 0 
Week 1 
Week 2 Week 3 
Week 4 Week 5 Week 6 Week 7 
Day -28 to -1 1 
7 
14 
21 
28 
35 
42 
49 
Visit 
1 2 
3 
4 
5 
6 
7 
8 
9 
Titration to SPN-812 ER 400 mg dose from baseline (Day 1) in the week 1 visit for subjects randomized to SPN-
812 ER 400 mg dose by 200 mg. Titration to SPN-812 ER 600 mg dose from baseline (Day 1) in the week 1 and 
week 2 visits for subjects randomized to SPN-812 ER 600 mg dose by 200 mg each week. 
 


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3.2 Schedule of Visits and Procedures Study   
All subjects who are randomized and take any SM will be followed according to the protocol 
regardless of the number of doses of SM taken, unless consent for follow-up is withdrawn. Table 
1 below presents the Schedule of Visits and Procedures for the study. 
 


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Table 1: Schedule of Visits and Procedure 
 
Treatment Phaseg 
Period 
Screening 
Titration 
Maintenance 
 
 
Baseline 
Randomization 
 
 
End of Studyh  
Visit # 
1 
2 
3 
4-8 
9 
Visit Day 
 
1 
7 
14, 21, 28, 35, 42 
49 
Visit Window (days) 
28d before V2 
 
±2 
±2 
±2 
Informed Consent/Assenta 
X 
 
 
 
 
Medical and Psychiatric History 
X 
 
 
 
 
Mini-KID 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
Physical Examb 
X 
 
 
 
   X c 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
ECG (12-lead) 
X 
 
 
 
X 
Vital Signsd  
X 
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 
X 
C-SSRS 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
ADHD-RS-5 
X  
X 
X 
X 
X 
WIFRS-P, SIPA 
 
X 
 
 
X 
Conners 3- parent, self 
 
X 
 
 
X 
Concomitant Medication 
 X 
X 
X 
X 
X 
Adverse Events 
 
X e 
X 
X 
Xe 
Drug Dispensed 
 
Xf 
X 
X 
 
Drug Return, Compliance 
 
 
X 
X 
X 
Optional PK Blood Samplingg 
 
 
X 
X 
X 
a 
To be obtained prior to performing any study procedures. 
b 
Includes height and weight, excludes genitourinary system 


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c 
Changes from Screening only 
d 
Seated (5 min) heart rate and blood pressure, temperature, respiratory rate 
e 
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. 
f 
Titration will begin after the first dose of SM is administered 
g 
An optional PK substudy will take place between Visits 3 and 9 inclusive. Samples will be taken pre-dose and post-dose at hours 1, 
2, 4, and 6.  
h 
EOS or last visit in the case of early discontinuation.  
 


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3.3 Procedures for Discontinuing Treatment and Removal of Subjects from Study 
Subjects will be considered to have completed the study if they complete all visits up to and 
including Week 7 (EOS). 
All subjects who discontinue early will complete the procedures listed for Week 7 (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. 
3.4 Study Treatments 
3.4.1 Methods 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 400 mg/day, or SPN-812 ER 600 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 


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3.4.2 Treatment, Dose, and Mode of Administration 
SPN-812 (Viloxazine hydrochloride extended-release tablet) or matching placebo tablets will be 
administered orally (PO) once daily (QD). 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 200 
mg/week to the final dose (1:1:1) as follows: 
Treatment A: Placebo 
Treatment B: SPN-812 ER 400 mg/day (2  200 mg SPN-812 ER) 
Treatment C: SPN-812 ER 600 mg/day (3 200 mg SPN-812 ER) 
3.4.3 Duration of Treatment and Study Duration 
Total subject duration on study is approximately 11 weeks. 
 Pre-treatment phase: 4 weeks  
 Treatment phase: 7 weeks  
o Titration period: 2 weeks  
o Maintenance period: 5 weeks  
3.4.4 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. 
3.5 Sample Size and Power Considerations  
Seventy-two subjects per treatment group in the ITT population will yield 90% power at a 
significance level of 0.05 (two-sided) using a two-sample t-test with equal allocation to the 
treatment groups.   This assumes an effect size of 0.547, which was observed in the comparison of 
SPN-812 200 mg and placebo in the SPN 812 Phase IIb study (based on the CFB to endpoint in 
the ADHD-RS-IV total score) and will maintain consistency in the sample size assumption used 
between this clinical trial and the SPN-812 P302 study in the adolescent population. A total of 300 
subjects (100 subjects in each of the three treatment groups) will be randomized to account for an 
anticipated 27.9% of randomized subjects not completing the study 


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4 Definitions and Derivations 
1. Baseline: Unless specified otherwise, baseline is defined as the non-missing value collected 
most recent to and before the time of the very first dose of the SM. 
2. The study day (DY) is calculated as Visit date minus Reference date + 1 day if the visit 
date occurs on or after the reference date or Visit date minus Reference date if  the visit 
date occurs before the Reference date, where the Reference date is defined as the first dose 
date (DY=1) 
3. The change from baseline at  a given Visit = observed value at that Visit minus observed 
value at baseline  
4. ADHD-RS-5 total score =sum of scores for the 18 behaviors 
5. ADHD-RS-5 Inattention subscale score = sum of scores for the first 9 behaviors 
6. ADHD-RS-5 Hyperactivity/Impulsivity Subscale score = sum of scores for the last 9 
behaviors  
7. Conners 3-Parent Reported score: Composite T-score calculated by averaging over the 6 
domains 
8. Conners 3-Parent Reported score: T-score for individual domain: inattention, 
hyperactivity/impulsivity, aggression, executive functioning, learning problems, and 
relationships 
9. Conners 3-Self Reported score domains: Composite T-score over the 5 domains 
10. Conners 3-Self Reported score domains: inattention, hyperactivity/impulsivity, aggression, 
learning problems, and relationships  
11. WFIRS-P score=average of all 50 items 
12. WFIRS-P subscale scores: average of items of following 6 subdomains: Family, School 
(learning and behavior), Life Skills, Child’s Self-Concept, Social Activities, and Risky 
Activities 
13. SIPA: total score=sum of the 3 domain scores: Adolescent (AD), Parent (PD), Adolescent-
Parent Relationship (APRD)  
14. SIPA: domain scores: sum of subscale scores for Adolescent and Parent domains, sum of 
items for the Adolescent-Parent Relationship domain and the Life Stressor Scale (LS).  
15. SIPA subscale scores: sum of items of the subscale 
5 Study Variables  
5.1 Primary Efficacy Variable  
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-V).  The scale consists of 18 items that directly correspond to the 18 
DSM-V symptoms and are further subdivided into two subscales: Hyperactivity/Impulsivity and 
Inattentiveness (DuPaul, 2016). The ADHD-RS-5 scale rates the frequency and severity of each 


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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: Adolescent instrument will be 
administered and scored by Investigator at each weekly visit from Baseline through EOS. 
5.2 Secondary Efficacy Variables 
5.2.1 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 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-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.   
5.2.2 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 – Parent: Short and Conners 3 – Self-Report: Short assessments will be 
administered at Visit 2 (Baseline) and at Week 7 (EOS). 


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5.2.3 WFIRS-P 
The 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 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. 
5.2.4 SIPA 
The Stress Index for Parents of Adolescents (SIPA) is a screening and diagnostic instrument that 
identifies areas of stress in parent-adolescent interactions and is appropriate for parents of 
adolescents aged 11-19 years (Sheras, 1998).  The SIPA scale is a 112-item questionnaire that 
yields scores across three domains (Adolescent Domain (AD), Parent Domain (PD), and 
Adolescent-Parent Domain (APRD)) and the Life Stressors Scale (LS). The Adolescent and Parent 
Domains are further subdivided into four subscales that focus on the parent‘s perception of their 
child’s personality and on the parent’s characteristics and behaviors. The Life Stressor Scale 
assesses external life factors contributing to stress experienced by a parent. The Index of Total 
Parenting Stress (TS) is the composite score of all items across all domains and reflects the total 
stress experienced as a function of parenting a particular adolescent.  The SIPA questionnaire will 
be completed at Baseline and at EOS by the parent/caregiver. 
5.3 Pharmacokinetic Variables  
The PK variables are the apparent clearance (CL/F) and apparent volume of distribution (Vd/F) of 
viloxazine and 5-hydroxy-viloxazine glucuronide. 
5.4 Safety Assessments  
Safety assessments include adverse events (AEs), clinical laboratory tests, vital signs, physical 
examinations, ECGs, and the Columbia Suicide Severity Rating Scale (C-SSRS).  
6 Statistical Methods 
6.1 General Principles 
All statistical analysis will be performed using SAS version 9.2 or higher by 
 which is the 
designated CRO. 
 will be responsible for creating TLF reports by SAS programming and 
delivering the reports as well as the programs to Supernus at the completion of the study.   
 
 
e


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All tabulations of analysis results will include summaries for the following three treatments: SPN-
812 ER 600 mg, SPN-812 ER 400 mg and placebo. 
Where appropriate, variables will be summarized descriptively (frequency count and percentage 
for categorical variables, and number of subjects (n), mean, standard deviation (SD), median, 
minimum, and maximum for continuous variables).  
Means, least-squares (LS) means and medians will be presented to 1 more decimal place than the 
recorded data. Standard deviations and standard errors will be presented to two (2) more decimal 
places than the recorded data. Minimum and maximum values will be presented using the same 
number of decimal places as the recorded data. Confidence intervals will be presented using the 
same number of decimal places as the parameters (e.g., mean). Percentages will be presented to 
one (1) decimal place. P-values will use four decimal places. 
Categorical variables will be analyzed using categorical response methods such as Pearson’s Chi-
square test. If expected frequencies are too small for asymptotic assumptions, exact testing 
techniques will be used. 
The data summaries will be accompanied by individual subject data listings, as specified in 
Sections 16.2 and 16.4 of ICH Guidance E3, sorted by unique subject identifier. All data available 
from the electronic case report forms (eCRFs) will be listed. Unscheduled measurements will be 
excluded from the descriptive statistics and statistical analysis but will be included in listings. The 
“EARLY_TERMINATION VISIT” for early discontinued subjects will be assumed to correspond 
to Visit 9 for statistical summaries but displayed as is in listings. 
Derived analysis datasets will be produced from the SDTM data.  Specifications for derived 
datasets will be developed. Analysis datasets to be created will include ADQS (Questionnaire 
analysis dataset), ADEFF1 and ADEFF2 (efficacy analysis dataset2), ADSL (subject-level 
analysis dataset), ADAE (Adverse event analysis dataset) and other as appropriate.  
The ADEFF1 analysis dataset will be used for programing the primary analysis table and will 
contain variables for Subject ID, BASE (Baseline (Visit 2)), AVAL (values at Visit 3 –Visit 9), 
CHG (for CFB), ITT Flag variable, Treatment, and other necessary variables to be created. For 
each subject there will be eight records associated with eight visits: Baseline and Visit 3 - Visit 9. 
The ADEFF2 analysis dataset will be created based on MI assuming MNAR for sensitivity 
analysis and MI assuming MAR for secondary analyses. The ADEFF2 will contain 100 
imputations of each record of each visit for the variables in ADEF1 with IMPUTNR variable.  
6.2 Visit Windows 
The Visit windows depicted in the table below will be used to evaluate subject compliance with 
scheduled visits with respect to protocol deviation. However, no visit windows will be used for 
statistical analysis; data will be analyzed according to the scheduled visit they are associated with 
in the CRF. 


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Table 2: Visit Windows and Study Day Ranges 
 
Week 
Day 
Visit Window 
0 (Visit 1-2) 
1 
<= Day 1 
1 (Visit 2-3) 
7 
Day 2 - Day 9 
2 (Visit 3-4) 
14 
Day 10 - Day 16 
3 (Visit 4-5) 
21 
Day 17 - Day 23 
4 (Visit 5-6) 
28 
Day 24 - Day 30 
5 (Visit 6-7) 
35 
Day 31 - Day 37 
6 (Visit 7-8) 
42 
Day 38 - Day 44 
7 (Visit 8-9) 
49 
Day 45 - Day 51 
For analysis by titration and maintenance period, the periods will be defined as follows: Titration 
period:  First dose date ≤ to ≤ v4 date; Maintenance period: V4 date < to ≤ V9 date. 
6.3 Analysis populations 
6.3.1 Randomized population 
All enrolled subjects that had a Baseline Visit scheduled and are randomized via the IWRS.  
6.3.2 Safety population 
All subjects randomized into the study, who received at least 1 dose of SM. Subjects will be 
analyzed according to the treatment they received. 
6.3.3 Intent-to-treat (ITT) population 
All randomized subjects who received at least 1 dose of study drug and have a baseline and at least 
one post-randomization ADHD-RS-5 assessment. Subjects will be analyzed according to the 
treatment to which they were randomized. 
6.3.4 Per-Protocol (PP) population 
The Per Protocol (PP) population consists of all subjects in the ITT population who have completed 
all 9 visits with no missing ADHD-RS-5 assessments and no major protocol violations. Subjects 
will be analyzed according to the treatment they received. 
The analysis population will be indicated as a subtitle in each table, listing and figure. 


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6.4 Subject Disposition  
A disposition of subjects will include the number and percentage of subjects in each of the 
following categories:  
 Subjects in the randomized population 
 Subjects in the safety population  
 Subjects in the ITT population  
 Subjects in the PP population  
Within each of the previous categories, the number and percentage of subjects who completed, 
early discontinued and the reason for early discontinuation from the study will be summarized in 
Table 14.1.1.1. The reason for early discontinuation may include any of the following:  
 Subject withdrew consent  
 Lost to follow-up  
 Administrative reason  
 Adverse event  
 Investigator decision  
 Failure to follow required study procedures  
 Other  
Subject randomization schedule will be listed.  Subjects whose randomization codes are unblinded 
during the conduct of the study will be listed along with the reason for un-blinding (Listing 16.1.7). 
Subject disposition for screened subjects will be presented in Table 14.1.1.2. Subject enrollment 
distribution by site will be presented for the ITT population in Tables 14.1.1.3.  
Data listing will be presented for subject disposition among all randomized subjects (Listing 
16.2.1.1), screen failure among screened subjects (Listing 16.2.1.2), subject visit status at each 
visit (Listing 16.2.1.3), and visit dates (Listing 16.2.1.4) among all randomized subjects. Subject’s 
inclusion and exclusion criteria response will be listed (Listings 16.2.2.1 - 16.2.2.2). 
6.5 Protocol Deviations 
The date of and reason for protocol deviations will be documented in all cases. Major protocol 
deviations will include the following but not limited to:  
1) Subjects enrolled in the study but did not meet the inclusion/exclusion criteria.  
2) Subjects who missed doses as per the treatment he was randomized to.  
3) Subjects who received non-randomized medication.  
4) Subject’s treatment compliance < 80% or > 120%. 


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Major protocol violations will be finalized before the database lock and will be added to the above 
list. 
Protocol violations will be summarized in Table 14.1.1.4. 
Subjects with major protocol deviations will be listed based on all randomized subjects.  The listing 
will include a brief description of the deviation, deviation category, and if applicable, study day 
when deviation occurred along with other pertinent information (Listing 16.2.2.3). 
6.6 Handling Missing Data 
 6.6.1 Missing Efficacy Variables 
Missing items in ADHD-RS-5 scale 
1. If more than 3 items of ADHD-RS-5 have missing or invalid data, the total score will be 
set to missing. If the total score is missing then both subscales (inattention or 
Hyperactivity/ Impulsivity) will be set to missing.  
 
2. If 3 items of ADHD-RS-5 or less have missing or invalid data, the values for the missing 
items will be imputed using the mean of the non-missing items rounded to the nearest 
integer. 
With respect to the primary analysis, missing ADHD-RS-5 Total Scores will be assumed to be 
missing at random (MAR) (See Panel on Handling Missing Data in Clinical Trials, (2010) National 
Research Council: The Prevention and Treatment of Missing Data in Clinical Trials) that is, given 
the observed data, the reason for the missing data does not depend on the unseen data. The Mixed 
Model for Repeated Measures (MMRM) method, implemented via SAS® PROC MIXED 
(SAS/STAT Software), will be used for handling missing ADHD-RS-5 Total Scores under MAR 
assumption.  The motivation behind MMRM is to solve the issue of addressing an on-treatment 
question, i.e. what happens if a typical subject completes their assigned treatment. MMRM does 
this by conditioning on the previous observations and other covariates that may inform on both 
missingness and outcome.  
A sensitivity analysis will be performed by assuming missing ADHD-RS-5 Total Scores are not 
missing at random (MNAR) (Yang, 2014), that is, the probability that an observation is missing 
may depend on its underlying unobserved value. This will be implemented using SAS® PROC MI 
and SAS® PROC MIANALYZE (SAS/STAT Software). 
For secondary endpoints, missing values will be assumed as missing at random (MAR). Missing 
data will be imputed using SAS® PROC MI (SAS/STAT Software).   


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6.6.2 Missing Safety Variables 
Missing dates for occurrence of adverse events and non-study medication use will be imputed 
using the following rules:  
1. Start dates with both missing day and month will be set to the 1st of January of that year, 
except as noted in rule 4 below. End dates with both missing day and month will be set to 
the 31st of December of that year.  
2. Start dates with missing day only will be imputed with the first day of the month, except 
as noted in rule 4 below. End dates with missing day only will be imputed with the last day 
of the month.  
3. Start dates with missing month only will be imputed by setting the month to January of the 
year. End dates with missing month only will be imputed to December of the year.  
4. If a start date has missing day only with month and year the same as the month and year of 
the first dose date, then the start date will be set to the first dose date. If a start date has 
missing day and month with the year the same as the year of the first dose date, then the 
start date will be set to the first dose date. 
If a start or end date are completely missing, then the date will be imputed with the dates of the 
first or last date of treatment, respectively. If an AE is ongoing (AEENRTPT= ONGOING) or a 
non-study medication is ongoing (CMENRTPT= ONGOING), the end date will be imputed by the 
end of study date (ADSL.EOSDT). 
Missing data for all other safety endpoints will not be imputed. 
6.7 Demographic and Baseline Characteristics  
Demographic/baseline variables include age, age group, sex, ethnicity, race, height and weight at 
screening, and BMI. Baseline disease characteristics include ADHD-RS-5 total score, inattention 
subscale score and hyperactivity/impulsivity subscale score. Both will be summarized for the ITT 
population in Table 14.1.2.1 using descriptive statistics for continuous variables and using counts 
and percentages for categorical variables. 
All demographic and baseline characteristics will be included in the subject data listing among all 
randomized subjects (Listing 16.2.4.1). The analysis populations will be listed in Listing 16.2.4.2. 
Baseline comparability among the treatment groups will be presented in Table 14.1.2.2 using a 
chi-square test for the categorical variables, and using an F-test for the continuous variables. These 
p-values will be used for descriptive purposes, and will not be considered as the formal basis for 
determining factors to be included in statistical analysis model. 
Mini-KID data will only be listed (Listings 16.2.4.3.1 and 16.2.4.3.2). 
Smoking history data will only be listed (Listing 16.2.4.9) 


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6.8 Medical and Psychiatric History 
Medical history will be coded using MedDRA version 20.1. All medical and psychiatric history 
will be listed. Medical and psychiatric history will be summarized by body system for each 
treatment group in Table 14.1.2.3 for the safety population.  The table will be sorted in alphabetic 
order by system organ class and the statistics n and % will be presented by treatment where: n is 
the number of subjects who present at least one occurrence of the medical history, and % is the 
percentage of subjects.  The denominator used for calculating the percentages will be the total 
number of subjects included in the safety population in each treatment group. The tables will 
include two (2) parts: is the condition still active at screening (part a) or not (part b).  
The pregnancy test results and urine drug screen will be listed in Listings 16.2.4.4.1 and 16.2.4.4.2. 
The medical history will be listed in Listings 16.2.4.5 - 16.2.4.7. 
6.9 Concomitant Medications  
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary (WHODD version 20170901 (Classic) Format B3) drug codes. Concomitant 
medications will be further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) 
code indicating therapeutic classification. Concomitant medications will be presented for each 
treatment period during which the medication was taken (Titration period, Maintenance period, 
and combined Titration and Maintenance period). A tabular summary of concomitant medications 
by drug class will be presented for the safety population in Table 14.1.2.4. 
A subject data listing will be provided to include the reported medication name, the WHODD drug 
codes, ATC codes, study day and pertinent subject information (Listing 16.2.4.8). 
6.10 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).  
Treatment duration will be categorized in days as: Day 1 to ≤ Day 9, Day 10 to ≤ Day 16, Day 17 
to ≤ Day 23, Day 24 to ≤ Day 30, Day 31 to ≤ Day 37, Day 38 to ≤ Day 44, Day 45 to ≤ Day 51 
and ≥ Day 52. The number and percentage of subjects in each duration group will be summarized 
by treatment group for the Safety population. 
Duration of Treatment exposure will also be summarized using descriptive statistics (n, mean, SD, 
median, minimum, and maximum).   
Percent of study drug compliance is defined as {(number of capsules dispensed minus number of 
capsules returned) /(3*(date of last dose minus date of first dose + 1))}* 100%. If for a certain 


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period no capsules are returned, the data is considered missing and not accounted for, and therefore 
this period will also not accounted for in the denominator (=number of planned doses).  
For each treatment, SM compliance will be summarized by compliance category (<80%, 80-120%, 
and >120%) using number and percent of subjects in each compliance category for the safety 
population. 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.  
The summary of duration of exposure to study medication and compliance will be presented for 
each treatment period (Titration period, Maintenance period, and combined Titration and 
Maintenance period) in Table 14.1.2.5 and Listings 16.2.5.1.1 - 16.2.5.1.3.  
6.11 Site Pooling  
This is a multicenter study. The primary analysis will be performed without site as a factor. 
However, for certain exploratory analyses small sites (defined as those with sample size <12 ITT 
subjects/site with uneven distribution of treatment groups) will be pooled to a group based on the 
geographic proximity. The purpose of pooling is to ensure that each site contains a sufficient 
number of subjects for statistical analyses that consider site as a factor. 
6.12 Multiple Comparisons/Multiplicity 
 This is a 3-arm parallel group design. To account for the potential Type I error rate inflation due 
to multiple dose group comparisons to placebo, a sequential testing procedure with a fixed testing 
method will be used. The details of this multiplicity adjustment are defined in Sections 6.13.1 and 
6.14.1. 
6.13 Efficacy Analyses 
The efficacy analyses will be based on the ITT population and will be performed on ADHD-RS-5 
total score, Conners 3-PS composite T score, Conners 3-SRS composite T score, WFIRS-P total 
score and SIPA total score.  
All confidence intervals, statistical tests, and resulting p-values will be reported as two-sided and 
will be assessed at the 5% significance level and interactions at 10%. 
With respect to Analysis of Covariance, the Gamma regression will be used on the original scale, 
if the normality assumption for the standard ANCOVA model is not met based on diagnostic 
residual plots based on the data before imputation. 
Multiplicity will be adjusted for the primary endpoint and key secondary endpoints. 
The mean profiles of ADHD-RS-5 total score, Conners 3-PS composite T score, Conners 3-SRS 
composite T score, WFIRS-P total score, SIPA score and CGI-I score will be presented graphically 


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by treatment group and scheduled study visit. In addition, plots of the Cumulative Distribution 
Functions of Change from Baseline in ADHD-RS-5 will be presented (Figures 14.2.1.1 - 14.2.6.2) 
For supportive analysis, the absolute value and change from baseline to Week 7 (EOS) of all 
efficacy variables will be summarized using descriptive statistics by treatment group and visit 
(Tables 14.2.5.1- 14.2.5.6).  
6.13.1 Analysis of Primary Endpoint 
The primary efficacy variable, change from baseline in ADHD-RS-5 Total Score to Week 7 (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 400 mg and SPN-812 ER 600 mg) will be presented, along with the 
corresponding standard error. Each of the treatment groups (SPN-812 ER 400 mg and 600 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 600 mg group and placebo 
group and H02: No treatment mean difference between SPN-812 ER 400 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 600 mg and SPN-812 ER 400 mg are 
superior to placebo. If H01 is rejected and H02 is not rejected then it will be concluded that only 
SPN-812 ER 600 mg is superior to placebo. 
The summary of primary analysis will be presented in Table 14.2.1.1.  
The corresponding MMRM SAS output will be presented in Listing 16.1.9.1. The ADHD-RS-5 
questionnaire, total, subscale scores, and derived ADHD rating scale - 5 (behaviors and scores) 
and binary variables will be listed in Listings 16.2.6.1 and 16. 2.6.2 and 16.2.6.3.1 and 16.2.6.3.2.  


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6.13.2 Sensitivity Analysis 
The sensitivity analysis assumes that missing ADHD-RS-5 Total Scores are missing not at random 
(MNAR), that is, the probability that an observation is missing may depend on its underlying 
unobserved value. (For example, the probability of missing ADHD-RS-5 Total Score at Week 7 
is not related to the observed ADHD-RS-5 Total Score at visit 9). 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 by adopting the following three steps. 
1) SAS PROC MI (SEED=220877) is applied to the input dataset containing all by-visit 
ADHD-RS-5 Total Score during the baseline, titration, and maintenance period.  
Multivariate imputation will be carried out by the fully conditional specification (FCS) 
method. One hundred (100) multiply-imputed datasets will be created. SAS® PROC MI 
with the MNAR statement will be implemented by using the following SAS code. 
PROC MI DATA= EFF NIMPUTE=100 SEED=220877 OUT=MNAROUT 
CLASS TREATMENT;  
VAR BASE WK1– WK7(EOS); 
FCS REG; 
MNAR MODEL (BASE WK1– WK7 (EOS))/MODELOBS= (TREATMENT='A'));  
RUN; 
In the above SAS code, EFF denotes the efficacy data set, Base, WK1– WK7  are analysis 
values of ADHD-RS-5 total at baseline and each of treatment weeks from Week 1 (at Visit 3) to 
Week 7 (at Visit 9), and treatment = ‘A ’denotes Placebo.  
2. For each of the multiply-imputed data sets, CFB to EOS will be computed.  For each 
imputation, the CFB will be analyzed using ANCOVA model, which will include fixed 
effect terms for treatment and baseline ADHD-RS-5 Total Score as a covariate. Each of 
the treatment groups (SPN-812 ER 400 mg and 600 mg) will be compared with the Placebo. 
The LS means of treatment groups, differences between the LS means of treatment groups 
and placebo, 95% confidence intervals around the differences and p-value will be 
computed.   
3. Finally, to combine estimates (LS means, treatment LS mean differences, 95% CI around 
the difference and p-value) from the 100 datasets, SAS® PROC MIANALYZE will be 
used. 
The summary of sensitivity analysis will be presented in Table 14.2.1.2. The corresponding full 
SAS output will be presented in Listing 16.1.9.2. 


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6.14 Analysis of Secondary Endpoints 
All secondary analyses are based on the ITT population with missing values imputed at Week 7 
(WK7) using multiple imputation (MI) assuming MAR using SEED=2460650. In case imputed 
values are below or above the range of the applicable scale, values will be imputed to respectively 
the minimum or maximum value of the scale.  The following SAS code will be used MI.  
PROC MI DATA=EFF NIMPUTE=100 SEED=2460650 OUT=MIOUT; 
 
CLASS TREATMENT; 
 
VAR TREATMENT BASELINE WK7(EOS);  
 
FCS  REG; 
RUN ; 
6.14.1 Analyses of Key Secondary Endpoints  
The analyses of key secondary objectives will be conducted on the following sequentially ordered 
endpoints for testing: 1) CGI-I, 2) Conners-3, 3) WFIRS-P.  
To preserve the overall type I error rate at 0.05 for the key secondary endpoints, a sequential testing 
procedure will be used. 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 does 
not reject H01 (i.e. the 600 mg is not superior to placebo) or the primary endpoint analysis rejects 
only H01, then no multiplicity adjustment is required. Otherwise, multiplicity adjustment will be 
performed with the following features. 
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 600 mg group and placebo group and H02: No treatment mean difference between SPN-
812 ER 400 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 600 mg 
and SPN-812 ER 400 mg are superior to Placebo. If H02 is not rejected, then it will be concluded 
that only SPN-812 ER 600 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 endpoint. 
6.14.1.1 Clinical Global Impression – Improvement (CGI-I)   
The absolute value of CGI-I at week 7 (EOS) will be analyzed using ANCOVA with treatment as 
a fixed classification variable and baseline CGI-S as a covariate. Each of the treatment groups 


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(SPN-812 ER 400 mg and 600 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 400 mg minus Placebo and SPN-812 ER 600 mg minus Placebo), 95% confidence 
intervals for the treatment differences will be computed. The summary of this analysis will be 
presented in Table 14.2.2.1.1 and listed in Listings 16.2.6.3.2, 16.2.6.4, and 16.2.6.5.  
6.14.1.2 Conners 3-Parental Short Form   
The Conners 3-PS will include 6 domains (subscales): inattention, hyperactivity/impulsivity, 
aggression, executive functioning, learning problems, and relationships.  
The data for Conners 3-PS comprise derived T-scores for each domain rounded to the nearest 
integer.  If a T-score ≤ 40 then the T-score will be set to 40 and if a T-score ≥ 90 then the T-score 
will be set to 90. If 1 of the subdomains is missing then the total score will be missing and the 
missing value will be handled using multiple imputation under MAR. A composite T-score will 
be calculated by averaging over the six domains (rounded to the nearest integer) and the change 
from baseline to Week 7 (EOS) in the composite T-score will be calculated and analyzed using 
ANCOVA model with fixed classification variable for treatment and baseline as a covariate. 
Each of the treatment groups (SPN-812 ER 400 mg and 600 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.  The 
summary of this analysis will be presented in Table 14.2.2.1.2 and Listings 16.2.6.6, 16.2.6.7 and 
16.2.6.8. 
6.14.1.3 Weiss Functional Impairment Rating Scale – Parent Version (WFIRS-P) 
WFIRS-P 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 (0, 1, 2 and 3) Likert scale. Higher WFIRS-P scores 
indicate more severe functional impairment. Missing items do not include omitted responses in 
the scoring (i.e., treat as “not applicable”). Each of the six domains is scored omitting items with 
a missing or ‘not applicable’ response. The WFIRS-P average score will be calculated over the 
50 items as sum of all items with a response divided by total number of items that have been 
endorsed (e.g., do not include ‘not applicable’ items in the total). The same approach will be 
used for the subscores.  The change from baseline in WFIRS-P to Week 7 (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 400 mg and 600 
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.  The summary of this analysis will be presented in Table 14.2.2.1.3 and 
Listings 16.2.6.9, 16.2.6.10 and 16.2.6.11. 


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6.14.2 Analysis of Additional Secondary endpoints  
6.14.2.1 Responder Analysis (50% responder rate) 
For each subject, the response indicator variable will be set equal to 'YES' if a subject’s % 
reduction ≥ 50% or ‘NO’ otherwise. Percent reduction will be calculated as: % reduction 
=100*(ADHD-RS-5 Total Score at Week 7 (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-812 400 mg ER minus Placebo, 
SPN-812 600 mg ER minus Placebo) and the p-value from Pearson’s Chi-squared Test or Fisher’s 
Exact Test will be presented. The summary of this analysis will be presented in Table 14.2.2.2.1. 
6.14.2.2 Stress Index for Parents of Adolescents (SIPA) 
The raw scores will be calculated as below: 
(1) Index of Total Parenting Stress (TS): TS is the sum of all three domains (AD, PD, and APRD) 
consisting of Items from 1 to 90 with responses of 1=SD (Strongly Disagree), 2=DA 
(Disagree), 3=NS (Not Sure), 4=A (Agree), and 5=SA (Strongly Agree). Note that Items 2-5, 
9-10, 15, 25, 28, 34, 40, 45, 49, 54, 66, 69, 74, 81, 83, 85, 87, and 88 have to be reversed (15, 
24, 33, 42, and 51) prior to calculating subscales and domains. 
a. Adolescent Domain (AD): summation of four subscales MEL, ISO, DEL, ACH:  
Moodiness/Emotional Lability (MEL): sum of 10 items (1, 6, 11, 16, 21, 26, 31, 36, 41, 
46); 
Social Isolation/ Withdrawal (ISO): sum of 10 items (2, 7, 12, 17, 22, 27, 32, 37, 42, 47); 
Delinquency/Antisocial (DEL): sum of 10 items (3, 8, 13, 18, 23, 28, 33, 38, 43, 48); and  
Failure to Achieve or Persevere (ACH): sum of 10 items (4, 9, 14, 19, 24, 29, 34, 39, 44, 
49).  
b. Parent Domain (PD): sum of four subscales LFR, REL, SOC, INC:  
Life Restrictions (LFR): sum of 10 items (51, 52, 55, 56, 59, 63, 67, 71, 75, 79); 
Relationship with Spouse/Partner (REL): sum of 9 items (60, 64, 68, 72, 73, 76, 77, 80, 81);  
Social Alienation (SOC): sum of 7 items (53, 54, 57, 58, 61, 65, 69); and  
Incompetence/Guilt (INC): sum of 8 items (62, 66, 70, 74, 78, 82, 86, 90).  
c. Adolescent-Parent Relationship Domain (APRD): sum of 16 items (5, 10, 15, 20, 25, 30, 
35, 40, 45, 50, 83, 84, 85, 87, 88, and 89). 
2) Life Stressors (LS) Scale: LS is to sum 22 items (Items 91-112) with responses of 1=Yes and 
0=No, sum of Items 91-112. 
 
Scores will be calculated if: 
1. No more than 3 items are missing from any domain;  
2. No more than 1 item is missing from any subscale; AND  


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3. No more than 6 items are missing from the entire SIPA (excluding the LS scale) 
 
If the above criteria are met, then the missing data convention is: 
1. Identify the subscale  from which the item response is missing 
2. Compute the average raw score for the completed items within that subscale, and round 
the average to the nearest whole number. 
3. Assign the rounded whole number score to the missing item and then sum all the items to 
obtain the subscale score 
Domains and Subscales: 
a. AD = MEL + ISO + DEL+ACH 
b. PD = LFR + REL + SOC + INC 
c. APRD 
Index of Total Parenting Stress (TS) = AD + PD + APRD  
The change from baseline in SIPA total score to Week 7 (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 400 mg and 600 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. The 
summary of this analysis will be presented in Table 14.2.2.2.2 and Listings 16.2.6.12 - 16.2.6.14. 
6.14.2.3 ADHD-RS-5 Hyperactivity/Impulsivity and Inattention Subscales 
The change from baseline to EOS in ADHD-RS-5 Inattention and the change from baseline to 
Week 7 (EOS) in Hyperactivity/Impulsivity subscales will be analyzed using ANCOVA model 
with fixed effects for treatment, age group and baseline as a covariate. Each of the treatment groups 
(SPN-812 ER 400 mg and 600 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. The 
summary of this analysis will be presented in Table 14.2.2.2.3. 
6.14.2.4 Conners 3– Self-report Short Form 
The Conners 3-SRS will include 5 domains (subscales): inattention, hyperactivity/impulsivity, 
aggression, learning problems, and relationships. 
The Conners 3-PS analysis from Section 6.14.1.2 will be repeated here. The summary of this 
analysis will be presented in 14.2.2.2.4. 
6.14.2.5 Categorical Analysis of CGI-I  
Categorical analysis will be performed using Pearson’s Chi-square test by dichotomizing the CGI-I score 
as ‘Improved’ if the score is ‘very much improved’ or ‘much improved’ and ‘Not Improved’, otherwise, 
and will be presented for each visit in Table 14.2.2.2.5. 


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6.14.3 Exploratory Analyses  
6.14.3.1 
 
 
 
 
6.14.3.2 
 
 
 
 
6.14.3.3 
 
 
 
6.14.3.4 
 
 
 
 
 
6.14.4 Supplementary Analyses  
Supplementary analyses, based on the per protocol population, will be performed as in the 
following.   
1. The primary endpoint (change from baseline in ADHD-RS-5 Total Score to Week 7 
(EOS)) will be analyzed using ANCOVA model using treatment and baseline as fixed 
effect independent variables. This analysis will be summarized in Table 14.2.4.1. 
2. The above analysis will be repeated for the Key secondary endpoints (Tables 14.2.4.2 – 
14.2.4.4).   
6.15 Examination of Subgroups 
The primary and key secondary efficacy variables may be repeated by subgroup to explore the 
heterogeneity of the treatment effect across subgroups.  Subgroups are defined as follows: 
1. Gender (Male, Female) 
2. Ages (12-14 years, 15-17 years) 
3. Race (White, non-white) 
 
 
 
 


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This analyses will be summarized in Tables 14.2.3.1.1 to 14.2.3.1.3 for ADHD-RS-5 total score, 
Tables 14.2.3.2.1 to 14.2.3.2.3 for CGI-I, Tables 14.2.3.3.1 to 14.2.3.3.3 for Conners 3-PS 
composite T-score, and Tables 14.2.3.4.1 to 14.2.3.4.3 for WFIRS-P total score. 
6.16 Pharmacokinetic (PK) Data Analysis 
Plasma concentrations will be provided at the end of the study in SAS format to an external PK 
Scientist. This SAS data set will include subject number, visit, nominal timepoint, actual draw 
date, actual draw time, deviation from nominal timepoint, and concentration. Blood collection time 
and SM administration will be presented in Listing 16.2.13.  
The Population PK model will be created separately and the analyses are not included in this SAP.  
6.17 Safety Analyses 
The assessment of overall safety will be based on adverse events, laboratory values, vital signs, 
ECGs and C-SSRS.  Unless specified otherwise, comparison will be made to baseline as defined 
in Section 4 of the SAP. 
All summary tables related to safety analyses will use the safety population. All subjects in the 
safety analysis set will be analyzed according to the treatment received.  
6.17.1 Adverse Events 
Adverse events (AEs) are described in Section 6.4 of Protocol 812P304. AEs will be classified 
into standardized medical terminology from the Verbatim description (Investigator term) using the 
Medical Dictionary for Regulatory Activities (MedDRA version 20.1).  
AEs will be summarized for each treatment period separately (Titration period, Maintenance 
period, and combined Titration and Maintenance period). 
The overall incidence of AEs will be presented in Table 14.3.1.1. Subject data listing will be 
provided for all adverse events (Listing 16.2.7.1). Included in the listing are the reported term, PT, 
SOC, TEAE flag, study day when AE starts, duration, relationship, severity, action taken, outcome, 
and seriousness category. Data listings will be provided for subjects who experienced SAEs, have 
TEAEs leading to study drug discontinuation, or death (Listing 16.2.7.2, Listing 16.2.7.3, and 
Listing 16.2.7.4). 
6.17.1.1 Treatment Emergent Adverse Events 
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. 
TEAEs will be analyzed separately from those AEs that were not treatment-related. Only TEAE 


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tables will be summarized. If a subject experiences more than 1 episode of a particular AE, the 
subject will be counted only once for that event.  If a subject has more than 1 AE that codes to the 
same preferred term, the subject will be counted only once for that preferred term.  Similarly, if a 
subject has more than 1 AE within a system organ class, the subject will be counted only once in 
that system organ class. 
TEAEs will be summarized at the subject level by system organ class and preferred term for each 
treatment group in Table 14.3.1.2. 
6.17.1.2 Severity of TEAEs 
Based on the investigators determination, the severity of TEAEs will be classified as mild, 
moderate or severe. 
If a subject experiences more than one episode of a coded TEAE, the subject will be counted only 
once by the maximum severity of the episode (preferred term).  Similarly, if a subject has more 
than one TEAE within a system organ class, the subject will be counted only once by the maximum 
severity among TEAEs in that system organ class.  TEAEs with missing severity will be considered 
as severe. The severity of TEAEs will be presented in Table 14.3.1.3. 
6.17.1.3 Relatedness of TEAEs to SM  
Based on the investigators determination, the relationship between the SM and a TEAE will be 
classified as not suspected (not related or unlikely related) or suspected (possibly related or 
definitely related). TEAE relatedness to SM will be summarized based on derived binary values 
as: “Drug Related” if the relationship to SM is probably or definitely related or “Not Related” if 
the relationship to SM is not related or unlikely related. 
If a subject experiences more than one episode of a coded AE, the subject will be counted only 
once by the maximum relatedness of these episodes (preferred term).  Similarly, if a subject has 
more than one AE within a system organ class, the subject will be counted only once by the 
maximum relatedness among AEs in that system organ class.  AEs with missing relatedness will 
be counted as definitely related.   
The summary of TEAE relatedness to SM will be presented in Table 14.3.1.4 
In addition, number and percent of patients reporting common AEs (≥5% in any group) will be 
presented by PT in Table 14.3.1.5 and AEs leading to study drug discontinuation will be presented 
by SOC and PT in Table 14.3.1.6. 
6.17.1.4 Serious Adverse Events  
Serious adverse events (SAEs) are described in Section 6.4.5 of Protocol 812P304. A listing of 
SAEs and AEs leading to discontinuation will be presented. All subject deaths during this study 


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will be collected and presented in a listing. The information presented will include date of death, 
days on study, cause of death, and relationship of death to study drug 
Adverse event data will be presented in Listings 16.2.7.1, 16.2.7.2, 16.2.7.3 and 16.2.7.4. 
6.17.2 Laboratory Data 
The change from baseline will be calculated as post-baseline value minus baseline value. 
For each laboratory parameter, the following will be displayed for baseline and Week 7 (EOS). 
 Summary statistics (n, mean, SD, median, minimum, and maximum) by treatment group 
for the actual and change from baseline values will be presented in Tables 14.3.2.1.1 and 
14.3.2.2.1.  
 Laboratory values will be flagged as abnormally low (L) if the value < lower limit of the 
normal range, normal (N) if the value is within normal range or abnormally high (H) if the 
value > upper limit of the normal range. Shift tables for the change from baseline to 
endpoint Week 7 (EOS) will be presented in Tables 14.3.2.1.2 and 14.3.2.2.2. Laboratory 
data will be presented in Listings 16.2.8.1 and 16.2.8.2. 
6.17.3 Vital Signs 
Vital signs parameters include: heart rate, diastolic and systolic blood pressure, respiratory rate, 
and temperature. 
The change from baseline will be calculated as post-baseline value– baseline value. 
Table 3: Vital Signs Normal ranges 
Parameter, unit 
Normal range 
Lower limit 
Upper limit 
Pulse, bpm 
60 
100 
DBP, mmHg 
64 
83 
SBP, mmHg 
90 
135 
Temperature, °C 
35.5 
37.8 
Respiratory rate, bpm 
12 
20 
 
Values equal to the boundaries are still considered normal (N).  
A value is classified as abnormally low (L) when the value < lower limit of the normal range.  
A value is classified as abnormally high (H) when the value > upper limit of the normal range. 


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Vital signs will be summarized by treatment group using descriptive statistics (for quantitative 
parameters) in Table 14.3.3.1 and frequency tables (categorical variables) in Table 14.3.3.2.   
Subject Listing of Vital Signs will be presented in Listings16.2.9.1 and 16.2.9.2. 
6.17.4 Twelve (12)-Lead ECG 
ECG parameters include HR, QRS, PR, and QTc. 
If there is no original QTc in the database, then the QTc will be calculated using the following 
formulae: 
Fridericia’s cube-root corrected QT : QTcF (ms) = QT (ms)  3
60
)
(bpm
HR
 
Table 4: Normal ECG ranges 
Parameter, unit 
Normal range 
Lower limit 
Upper limit 
HR, bpm 
50 
130 
PR, ms 
90 
200 
QRS, ms 
40 
100 
 
Values within boundaries and equal to the boundaries are still considered normal (N).  
A value is classified as abnormally low (L) when the value < lower limit of the normal range.  
A value is classified as abnormally high (H) when the value > upper limit of the normal range. 
For the QT and QTc parameters, the following categorizations  will be done: 
 of the actual values: ≤ 450 ms, 450 ms < to ≤ 480 ms, 480 < to ≤ 500 ms, >500 ms 
 of the changes from baseline: ≤ 30 ms (including all decreases in QT), 30 < to ≤60 ms, 
>60 ms. 
ECG parameters will be summarized by treatment group using descriptive statistics (for 
quantitative ECG parameters) in Table 14.3.4.1 and frequency tables (for categorical parameters) 
in Table 14.3.4.2, Table 14.3.4.3, and Table 14.3.4.4. 
Subject Listing of ECG: Parameters for actual and derived variables will be presented Listings 
16.2.10.1 and 16.2.10.2. 
6.17.5 Physical examinations 
All physical examination findings will be presented in Listing 16.2.11.1. 


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Actual values and changes from baseline will be calculated at EOS for weight, height and BMI 
and presented in Listing 16.2.11.2.  
6.17.6 C-SSRS 
C-SSRS outcomes will be summarized using number and percent of subjects by categories for 
suicidal ideation only, suicidal behavior only and suicidality (ideation and behavior combined). 
The summary will be presented by treatment groups (Table 14.3.5). 
Suicidal ideation and Suicidal behavior will be presented in Listings 16.2.12.1 - 16.2.12.2. 
7 Validation  
Supernus seeks to ensure the quality of the reports provided by 
 in the form of TLFs and 
derived datasets must pass a rigorous validation process involving the following processes.  
 
Derived datasets for AEs and the primary efficacy parameter must be independently 
reprogrammed by a second programmer based on analysis data specifications. The 
separate datasets produced by the 2 programmers must match 100% or in case of any 
differences, an explanation should be given and documented.   
 Furthermore, all derived datasets will be independently programmed by BAIM institute 
based on analysis data specifications.  
 Tables for AEs and the primary efficacy endpoint must be independently reprogrammed 
by a second programmer and the results from both programs must match 100% or in case 
of any differences, an explanation should be given and documented. Furthermore, all 
tables (efficacy, AEs, an all other summary tables) will be validated by BAIM institute. 
 Figures must be checked for consistency against corresponding tables and listings, or 
independently reprogrammed if there are no corresponding tables or listings.  
 Listings must be checked for consistency against corresponding tables, figures, and 
derived datasets.  
The entire set of TLF must be checked for completeness and consistency prior to its delivery to 
Supernus.  
The above validation process must be repeated any time TLFs are redelivered using different data. 
Execution of this validation process must be documented through the study in a tracking sheet 
which containing TFL names, name of the primary programmer, name of the QC programmer and 
comment. The validation tracking sheet must be submitted at each delivery of TFLs.  
8 References 
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. 
 


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Gajria K et al (2015) Psychometric validation of the Weiss Functional Impairment Rating Scale-
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Protocol 812P304: Evaluation of SPN-812 ER 400 and 600 mg Efficacy and Safety in 
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