Clinical trial NCT01107496
Conditions: Attention-Deficit/Hyperactivity Disorder (ADHD)
Keywords: ADHD Adults
Sponsor: Supernus Pharmaceuticals, Inc.
Start date: 2010-06-01; Completion date: 2010-12-01
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This will be a randomized, double-blind, placebo-controlled, parallel group, safety and tolerability study in adults with ADHD. The target subjects are healthy male or female adults aged 18 to 64 years, inclusive, with a diagnosis of ADHD.

Detailed description:
This will be a randomized, double-blind, multicenter, placebo-controlled, parallel group, safety and tolerability study in adults with ADHD. The target subjects are healthy male or female adults aged 18 to 64 years of age, inclusive, with a diagnosis of ADHD. Approximately 50 subjects will be enrolled at approximately 5 sites in the United States. Subjects will be randomized (1:1) to one of two treatment groups, immediate-release (IR) viloxazine or placebo. Primary objective is to determine the safety of IR viloxazine in adults with ADHD.

Arms: arm 1: Treatment A: immediate-release (IR) viloxazine capsules administered orally 3 times a day arm 2: Treatment B: Placebo capsules administered orally 3 times a day
Interventions: intervention 1: IR Viloxazine intervention 2: Placebo
Intervention descriptions: intervention 1: One 50mg immediate-release viloxazine capsule administered orally 3 times a day (150mg total daily dose) for Week 1.

Two 50mg immediate-release viloxazine capsules administered orally 3 times a day (300mg total daily dose) for Weeks 2 to 6. intervention 2: Placebo capsules administered orally 3 times a day

Protocol documents:
Prot_000.pdf: 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
30Jun2010 
812P201 
 
Version 2.0 
 
This document is confidential. It contains proprietary information of Supernus® Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited . 
Such information may be used solely for the purpose of reviewing or performing this study. 
COVER PAGE - PROTOCOL 
 
Protocol Number: 
812P201 
Title: 
A Phase I/IIa, Randomized, Double-Blind, Multicenter, Placebo-
Controlled, Parallel-Group Study of the Safety, and Efficacy of 
SPN-812V in Adults with Attention Deficit Hyperactivity Disorder 
(ADHD) 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
9715 Key West Avenue 
Rockville, MD 20850 
United States 
Phone: (301) 838-2500 
Fax: (240) 403-0065 
Protocol Version: 
2.0 
Date: 
30Jun2010 
NCT: 
NCT01107496 


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1.  TITLE PAGE 
Protocol Number: 
812P201 
 
 
Title: 
A Phase I/IIa, Randomized, Double-Blind, Multicenter, Placebo-Controlled, 
Parallel-Group Study of the Safety, and Efficacy of SPN-812V in Adults with 
Attention Deficit Hyperactivity Disorder (ADHD) 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
1550 East Gude Drive  
Rockville, MD 20850 
Phone: 301-838-2500 
Fax: 301-838-2504 
 
 
IND Number: 
106,729 
 
 
Test Drug: 
Viloxazine  
 
 
Indication: 
Attention Deficit Hyperactivity Disorder (ADHD) 
 
 
Phase: 
I/IIa 
 
 
Release Date: 
30 June 2010 / Version 2.0 
09 April 2010 / Version 1.0 
 
 
Good Clinical 
Practice (GCP) 
Statement 
This study is to be performed in full compliance with International Conference 
on Harmonization (ICH) GCP and all applicable local regulations.  All required 
study documentation will be archived as required by regulatory authorities. 
Confidentiality: 
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.   
 
 
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 and all 
applicable local GCP guidelines, including the Declaration of Helsinki and all its 
accepted amendments to date. 
 
 
 
 
 
 
Principal Investigator 
 
Signature 
 
Date 
 


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2.  CLINICAL PROTOCOL SYNOPSIS 
Name of Company: 
Supernus Pharmaceuticals, Inc.  
IND Number: 
106,729 
Name of Product: Viloxazine Capsules 50mg 
Na
 
me of Active Ingredient: Viloxazine HCl 
Full Title of the Study:  A Phase I/IIa, Randomized, Double-Blind, Multicenter, Placebo-Controlled, 
Parallel-Group Study of the Safety, and Efficacy of SPN-812V in Adults with Attention Deficit Hyperactivity 
Disorder (ADHD) 
Investigator(s)/Center(s):  Approximately 5 US centers 
Protocol Number: 812P201 
Pha
 
se of Development:  I/IIa 
Objectives:   
Primary Objective: 
• 
To determine the safety of SPN-812V in adults with ADHD  
Secondary  Objective: 
• 
To determine the efficacy of SPN-812V in adults with ADHD  
• 
To explore the single dose and steady state pharmacokinetics of SPN-812V in adults with ADHD 
Study Design (Methodology):  Randomized, double-blind, placebo-controlled, parallel-group 
Number of Subjects:  Approximately 50 subjects (25 per arm) 
Criteria for Inclusion/Exclusion:   
Inclusion criteria: 
1. Able to provide informed consent prior to any study procedure being conducted. 
2. Capable and willing to comply with study procedures. 
3. Male or female aged 18 to 64, inclusive.  
4. Subjects with a current diagnosis of ADHD as confirmed by the Conners’ Adult ADHD Diagnostic 
Interview for DSM-IV (CAADID)  
5. Clinical Global Impression – Severity (CGI-S) score of 4 or higher. 
6. On no treatment for ADHD or willing to be withdrawn from an ongoing treatment after a washout 
of at least 10 days. 
7. Body Mass Index (BMI) between 18.0 and 34.0 inclusive. 
8. Subject must be in general good health as determined by medical history, ECG, and other 
analysis that, in the judgment of the Investigator, would confirm the Subject's good health. 
9. Females of childbearing potential (FOCP) who, if sexually active, agree to use acceptable forms 
of contraception (including oral, transdermal, or implanted contraceptives; intrauterine device; 
female condom with spermicide; diaphragm with spermicide; cervical cap; abstinence; use of 
condom with spermicide by sexual partner or sterile [at least 6 months prior to SM administration] 
sexual partner) at least 14 days prior to start of study drug administration, throughout the study, 
and for 30 days following the last dose of SM. 
10. Postmenopausal females with amenorrhea for at least 2 years or females who are permanently 
sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy). 


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Exclusion Criteria
1. Current or past history of psychotic disorder or major depressive disorder with psychotic features. 
2. Presence of another primary DSM-IV-TR disorder. 
3. Suicidality, defined as either active suicidal plan/intent or active suicidal thoughts, in the 6 months 
before the Screening Visit or more than 1 lifetime suicide attempt. (The Columbia-Suicide 
Severity Rating Scales [C-SSRS] will be administered at each visit.) 
4. Substance or alcohol abuse/dependence within previous 6 months, or a positive urine drug 
screen at screening or baseline prior to first dose of study medication (SM). 
5. Any known or suspected significant medical or psychiatric illnesses that, in the judgment of the 
Investigator, may impair interpretation of study results or constitute a significant safety concern in 
the context of the clinical trial 
6. ECG abnormalities (clinically significant according to Investigator’s opinion) or vital sign 
abnormalities (systolic blood pressure [SBP] <90 or >140 millimeters of mercury [mmHg], diastolic 
blood pressure [DBP] <40 or >90mmHg, or heart rate [HR] <40 or >100 beats per minute [BPM]) at 
screening. 
7. Clinically significant laboratory abnormalities; including presence of potential hepatic function 
impairment as shown by, but not limited to alanine aminotransferase (ALT/SGPT) values >2 times 
upper limit of normal (ULN), aspartate aminotransferase (AST/SGOT) > 2 times ULN, gamma-glutamyl 
transpeptidase (GGT) >3 times ULN, or total bilirubin >1.5 ULN . 
8. Medications, including health food supplements judged by the Investigator to be likely to have 
central nervous system activity (for example, St John's Wort, gingko leaf, and melatonin), are not 
permitted during the study.  If the subject is taking the medication prior to study entry, there must 
be a 7 day washout period prior to first dose of SM. 
9. Lifetime history of tic disorder, Tourette’s Disease, or organic brain disorder; or family history of 
Tourette’s Disease. 
10. Current or lifetime history of hyperthyroidism unless treated and stable for at least 6 months. 
11. Participation in or plan to begin behavioral therapy during the study. 
12. Subject has a prior history of allergy or any significant adverse reaction (including rash) to 
viloxazine, or any of the product components. 
13. Females who are pregnant or lactating or are unwilling to use an acceptable form of 
contraception throughout the study. 
14. Difficulty swallowing whole capsules. 
15. History of seizures or risk factors for seizures (e.g., head trauma), not including febrile seizures. 
16. Use of an investigational drug or participation in an investigational study within 30 days prior to 
first dose of SM. 
17. Any reason which, in the opinion of the Investigator, would prevent the subject from participating 
in the study. 
Test Treatment, Dose, and Mode of Administration:   
50mg capsules containing either SPN-812V or placebo by mouth (PO) three times per day (TID) 


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Duration of Treatment and Study Duration:  There will be a total of 8 visits. 
 
Visit 1: Screening  
Visit 2: Baseline, randomization, and dispensation of SM 
Visit 3-8: Weekly assessment  
Visit 8: Final visit, Optional PK day, End of study assessments 
Total subject duration on study:  up to 8 weeks 
 
Enrollment is estimated to require approximately 4 months, and the study is expected to be completed 
approximately 6 months after enrollment begins. 
Treatment Schedule (Procedure):   
Screening (Visit 1):  Subjects will undergo initial screening evaluation after informed consent is obtained, 
including complete medical and psychiatric history, physical exam, serum pregnancy test (FOCP only), 
routine laboratory assessment and genetic testing for CYP2D6 enzyme activity, smoking status, and urine 
drug screen. Confirmation of ADHD will be performed with the CAADID and the CGI-S will be 
administered.  Study qualification requirements will be reviewed to confirm that the subject meets all 
inclusion and exclusion criteria.  
Baseline and Randomization and dispensation of SM (Visit 2): After a screening period of up to 14 days 
subjects will return to the investigational site and undergo their scheduled baseline assessment.  If their 
eligibility to participate in the trial is confirmed, subjects will be randomized (1:1) to receive a starting dose 
of 1x50 mg capsule TID (150 mg/day) of either SPN-812V or placebo.  Subjects will receive treatment at 
the 150 mg/day starting dose for one week.  Dosing is to start the morning after Visit 2.  Subjects who do 
not tolerate the starting dose will be discontinued from the study.  
Study Dose Treatment Phase (Visits 3 – 8): Subjects who tolerated the starting dose will then be titrated 
to receive a study dose of 2x50 mg TID (300mg/day) and continue this treatment regiment for five weeks.  
Subjects who, after titration to the study dose, do not tolerate treatment at 300 mg/day, will be allowed, at 
any time, to down-titrate the dose to the 150 mg/day starting dose and continue treatment at the same 
dose until completion of the study.  Subjects will return to the investigational site once a week to undergo 
safety and efficacy evaluations and to have SM compliance checked.  At the end of Visit 7, the subjects 
who have consented to participate in the optional PK sub study will receive a drug diary to record times of 
all weekly doses, will be instructed to fast the night before Visit 8, and will be instructed to not take SM 
that morning.  At Visit 8, subjects who agree to participate in the optional PK sub study will receive SM 
dose and will have blood drawn for PK assessments over approximately seven hours.  All rating scales 
will be administered prior to PK dosing and blood draws.  For subjects not participating in the optional PK 
sub study, their last dose will be taken the evening before the End of Study Visit (Visit 8).    
End of Study: At the end of the Visit 8 procedures or at early termination, subjects will complete end of 
study assessments. Subjects will return any unused capsules and undergo safety and efficacy 
evaluations if not already performed as part of that visit. 
Pharmacokinetic Sampling:  
Population PK data will be pooled across all subjects who participate in this optional portion of the study. 
On the final visit, there is an optional PK day.  All subjects who wish to participate will be dosed with 
active SM after an overnight fast and after all efficacy assessments are completed, Blood will be draw
for quantitative PK analysis according to the following schedule (all times +/- 30 minutes
n 
): 
Pre-dose and ½, 1, 2, 3, 4, 5, and 6 hours post-dose  
 
Although draw windows are given, efforts should be made to ensure that the time interval between any 
two sampling timepoints is not less than 30 minutes  




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Endpoints: 
Primary Endpoints: 
1. To establish the safety of SPN-812V after 6 weeks of treatment with either SPN-812V dose. 
Secondary Endpoints: 
1. To establish the efficacy of SPN-812V over a 5-week treatment period with SPN-812V 300 
mg/day 
2. To establish the initial efficacy of SPN-812V after a 1-week treatment period with SPN-812V 
150mg/day. 
3. To establish the effectiveness of SPN-812V over a 6-week treatment period with any SPN-812V 
dose. 
4. To establish the clinical utility of SPN-812V after a 5-week treatment period with SPN-812V 
300mg/day. 
5. To establish the study subject’s perception of clinical benefit of SPN-812V at endpoint after a 5-
week treatment with SPN-812V at 300mg/day. 
6. To explore in a population model the single dose and steady state pharmacokinetics of SPN-
812V in adults with ADHD 
Efficacy Measures 
• 
Investigator-rated Conners’ Adult ADHD Rating Scale (CAARS) Total ADHD Symptom Score  
• 
Clinical Global Impression – Improvement (CGI-I)  
• 
Self-rated Conners’ Adult ADHD Rating Scale (CAARS) Total ADHD Symptom Score 


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Statistical Methods:   
Safety Analyses
The incidence rate of AEs will be calculated by treatment group for each SOC and preferred term.  The 
severity of the AEs and the relationship to SM will be summarized by treatment group for each SOC and 
preferred term.  
Descriptive statistics will be presented for the results from the clinical laboratory tests, vital signs, weight, 
ECGs, and physical examinations.  Statistical testing will be performed for some of the safety endpoints, 
but the resulting p-values will be used for descriptive purposes only, i.e., not for inferential purposes. 
1. Incidence summary (> 2%) of AEs (SOC, Preferred Term, Relationship, Severity) when compared 
to placebo after 6-week treatment with any SPN-812V dose 
2. Changes from baseline in biochemistry, hematology, and urinalysis values from baseline after 6-
week treatment with any SPN-812V dose 
3. Percent of change from baseline in biochemistry, hematology, and urinalysis values from baseline 
after 6-week treatment with any SPN-812V dose when compared to placebo after 6-week 
treatment with any SPN-812V dose 
4. Changes from baseline in blood pressure, heart rate, respiratory rate, and body temperature after 
6-week treatment with any SPN-812V dose 
5. Percent of change from baseline in blood pressure, heart rate, respiratory rate, and body 
temperature when compared to placebo after 6-week treatment with any SPN-812V dose 
6. 12-lead ECGs changes from baseline after 6-week treatment with any SPN-812V dose 
7. 12-lead ECGs percent of change from baseline when compared to placebo after 6-week 
treatment with any SPN-812V dose 
8. Normal or abnormal findings on physical examinations after 6-week treatment with any SPN-812V 
dose   
9. Rate of abnormal findings on physical examinations after 6-week treatment with any SPN-812V 
dose  when compared to placebo after 6-week treatment with any SPN-812V dose 
 


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Efficacy Analyses
Descriptive statistics will be presented for all efficacy variables by visit and treatment group.  
All significance tests will be performed at the 0.05 level. 
As down titration from 300mg to 150mg is allowed for subjects who cannot tolerate the maintenance 
dose, those subjects will be treated as part of the 300mg arm while analyzing the data. 
Primary Efficacy Analyses
The primary efficacy measure is the investigator-rated CAARS Total ADHD Symptom Score which is the 
sum of the Inattention and Hyperactivity/Impulsivity subscales (18 items rated on 4-point scale). 
The changes from baseline to the endpoint in the investigator-rated CAARS Total ADHD Symptom 
Scores will be compared between the two treatment groups using the Wilcoxon rank-sum test or the two-
sample t-test.  To confirm the results (sensitivity analysis), a mixed model repeated measures (MMRM) 
analysis will be conducted.  MMRM analysis will contain fixed effect terms for treatment, investigative si
visit, and interaction between treatment and visit.  The model will include post-baseline values of
investigator-rated CAARS Total ADHD Symptom Score as the dependent variable with a random patient 
effect and baseline investigator-rated CAARS Total ADHD Symptom Score as a covariate and will use an 
unstructured covariance. 
te, 
 the 
 
Secondary Efficacy Analyses
1. Initial efficacy of SPN-812V starting dose (150 mg/day) when compared to placebo as measured 
by changes in the investigator-rated CAARS Total ADHD Symptom Score from baseline at week 
1 of treatment with starting dose will be analyzed with Wilcoxon rank-sum test or two-sample t-
test 
2. Effectiveness of any SPN-812V dose when compared to placebo as determined by the weekly 
changes in the Clinical Global Impression – Improvement (CGI-I) score from baseline severity for 
6-week treatment will be plotted as mean CGI-I change versus visit and analyzed using Wilcoxon 
rank-sum test or two-sample t-test 
3. Clinical utility of SPN-812V study dose (300 mg/day) when compared to placebo as determined 
by the investigator’s assessment of the changes in the CAARS score from baseline at week 2, 3, 
4, 5, and 6 of treatment will be analyzed with Wilcoxon rank-sum test or two-sample t-test 
4. Study subject’s perception of clinical benefit of SPN-812V study dose (300 mg/day) when 
compared to placebo as determined by changes in the self-rated CAARS score from baseline at 
endpoint after 5-week treatment will be analyzed with Wilcoxon rank-sum test or two-sample t-test
Subgroup Analyses for Efficacy
Subgroup analyses for efficacy will be performed on categories of the following measures: 
• 
Sex 
• 
Race 
for the ITT population for the investigator-rated CAARS Total ADHD Symptom Score.  Subgroup analyses 
will also be carried out for the following subscales 
• 
investigator-rated CAARS inattention subscale score 
• 
investigator-rated CAARS hyperactivity/impulsivity subscale score 
 
that together make up the CAARS Total ADHD Symptom Score 
Pharmacokinetic and/or Pharmacodynamic Analyses:  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. The objective of the population PK analyses is to derive individual-specific estimates 
of apparent oral clearance (CL/F) but not to fully characterize the PK of this formulation of Viloxazine.  
 


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3.  TABLE OF CONTENTS 
 
               Page 
1. TITLE PAGE ..........................................................................................................1 
2. CLINICAL PROTOCOL SYNOPSIS......................................................................2 
3. TABLE OF CONTENTS.........................................................................................9 
4. LIST OF ABBREVIATIONS.................................................................................14 
5. ETHICS................................................................................................................16 
5.1. Institutional Review Boards / Independent Ethics Committees..................16 
5.2. Ethical Conduct of the Study .........................................................................16 
5.3. Subject Information and Consent..................................................................16 
6. INVESTIGATORS AND STUDY PERSONNEL...................................................17 
7. INTRODUCTION..................................................................................................17 
8. STUDY OBJECTIVES .........................................................................................19 
9. INVESTIGATIONAL PLAN..................................................................................19 
9.1. Overall Study Design and Plan ......................................................................19 
9.1.1. Screening Period .........................................................................................20 
9.1.2. Dosing Period ..............................................................................................20 
9.1.3. End of Study Visit/Early Termination ...........................................................21 
9.2. Discussion of Study Design, Including Choice of Treatment Groups and 
Appropriateness of Measurements ......................................................................21 


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9.3. Selection of Study Population........................................................................22 
9.3.1 Inclusion Criteria...........................................................................................22 
9.3.2 Exclusion Criteria..........................................................................................23 
9.4. Study Methods.................................................................................................24 
9.4.1. Schedule of Visits and Procedures..............................................................24 
9.4.1.1. Screening Period ......................................................................................26 
9.4.1.2. Baseline and Randomization ....................................................................26 
9.4.1.3. Dose Treatment Period.............................................................................27 
9.4.1.3.1.  Visits 2-7..................................................................................................27 
9.4.1.3.2. Visit 8.....................................................................................................27 
9.4.1.4. Final Visit/Early Termination .....................................................................28 
9.4.2. Efficacy Assessments..................................................................................28 
9.4.3. Pharmacokinetic Measurements..................................................................29 
9.4.4. Safety Assessments ....................................................................................29 
9.4.4.1. Adverse Events.........................................................................................29 
9.4.4.1.1. Reporting of Adverse Events .................................................................30 
9.4.4.1.2. Criteria for Assessing Severity...............................................................30 
9.4.4.1.3. Criteria for Assessing Causality.............................................................31 
9.4.4.2. Serious Adverse Events ...........................................................................31 
9.4.4.2.1. Reporting of SAEs .................................................................................32 
9.4.4.2.2. Other Events Requiring Immediate Reporting .......................................32 
9.4.4.2.3. Expedited Reporting ..............................................................................33 
9.4.4.3. Laboratory Measurements........................................................................33 
9.4.4.4. Vital Signs, Height, and Weight Measurements........................................34 
9.4.4.5. Medical, Psychiatric History and Physical Examinations ..........................35 


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9.4.4.6. Electrocardiograms (ECGs)......................................................................35 
9.4.5. Completion/Discontinuation of Subjects ......................................................35 
9.5. Treatments.......................................................................................................36 
9.5.1. Treatments Administered.............................................................................36 
9.5.2. Identity of Study Medication.........................................................................36 
9.5.3. Handling of Study Medication ......................................................................36 
9.5.4. Study Medication Accountability ..................................................................36 
9.5.5. Method of Assigning Subjects to Treatment Groups....................................37 
9.5.6. Removal of Subjects from Therapy or Assessment.....................................38 
9.5.7. Dosing Schedule..........................................................................................38 
9.5.8. Method of Administration .............................................................................38 
9.5.9. Blinding........................................................................................................38 
9.5.10. Concomitant Medications ..........................................................................38 
9.5.11. Treatment Compliance ..............................................................................39 
9.5.10. Change of Study Medication Dose ............................................................39 
9.6. Data Quality Assurance ..................................................................................39 
9.6.1. Data Collection ............................................................................................39 
9.6.2. Clinical Data Management...........................................................................39 
9.6.3. Database Quality Assurance .......................................................................39 
9.6.4. Bioanalytical Data Management and Quality Control...................................40 
9.7. Statistical Methods..........................................................................................40 
9.7.1. Statistical and Analytical Plans ....................................................................40 
9.7.1.1. Analysis Populations.................................................................................40 
9.7.1.1.1. Demographic/Baseline Analyses ...........................................................41 


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9.7.1.1.2. Study Medication ...................................................................................41 
9.7.1.1.3. Concomitant Medications.......................................................................41 
9.7.1.2. Efficacy Analyses......................................................................................41 
9.7.1.2.1. Primary Efficacy Analysis.......................................................................41 
9.7.1.2.2. Secondary Efficacy Analyses.................................................................42 
9.7.1.2.3. Subgroup Analyses for Efficacy.............................................................42 
9.7.1.3. Pharmacokinetic Analyses........................................................................42 
9.7.1.4. Safety Analyses........................................................................................43 
9.7.1.4.1. Adverse Events......................................................................................43 
9.7.1.4.2. Laboratory Values..................................................................................43 
9.7.1.5. Vital Signs.................................................................................................44 
9.7.1.6. ECG Results.............................................................................................44 
9.7.1.7. Other Special Tests ..................................................................................44 
9.7.2. Sample Size and Power Considerations......................................................44 
10. PROCEDURES AND INSTRUCTIONS .............................................................44 
10.1. Ethics and Good Clinical Practice ...............................................................44 
10.2. Subject Information and Informed Consent................................................45 
10.3. Changes to the Protocol...............................................................................45 
10.4. Adherence to the Protocol............................................................................46 
10.5. Retention of Records....................................................................................46 
10.6. Auditing Procedures.....................................................................................47 
10.7. Publication of Results...................................................................................47 
10.8. Disclosure and Confidentiality.....................................................................47 


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10.9. Discontinuation of Study..............................................................................47 
11. REFERENCE LIST ............................................................................................48 
12. APPENDICES....................................................................................................56 
12.1. Conners’ Adult ADHD Rating Scale (CAARS).............................................56 
12.1.1.  Investigator-Report......................................................................................56 
12.1.2.  Self-Report ..................................................................................................57 
12.2. Clinical Global Impression (CGI) Scale .......................................................58 
12.3. Columbia-Suicide Severity Rating Scales (C-SSRS)..................................59 
12.3.1.  Baseline ......................................................................................................59 
12.3.2.  Since Last Visit............................................................................................63 
 
 
 
 
LIST OF TABLES 
                                                                                                                               Page 
Table 1. 
Schedule of Visits and Procedures ...................................................................... 24 
Table 2. 
Clinical Laboratory Assessments......................................................................... 34 
 
 
 
 
LIST OF FIGURES 
                                                                                                                               Page 
Figure 1. 
Study Schematic................................................................................................. 20 
 


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4.  LIST OF ABBREVIATIONS 
ADHD 
Attention Deficit Hyperactivity Disorder  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical  
AUC 
area under the plasma concentration versus time curve 
AUCss 
area under the concentration-time curve at steady state 
BUN 
blood urea nitrogen 
CAARS 
Conners’ Adult ADHD Rating Scale 
CAADID 
Conners’ Adult ADHD Diagnostic Interview for DSM-IV 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression 
CGI-S 
Clinical Global Impression – Severity of Illness 
CGI-I  
Clinical Global Impression – Global Improvement 
CL/F 
apparent oral clearance 
CRA 
Clinical Research Associate 
CRF  
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scales 
CRO 
Contract Research Organization 
Css avg 
average steady-state concentration 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders – Text Revision 
ECG 
electrocardiogram 
FOCP 
Females of Childbearing Potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
HR 
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
ITT 
intent to treat 
LNH 
Low, normal, high 
MedDRA 
Medical Dictionary for Regulatory Activities  
PK 
pharmacokinetic 
PK-PD  
pharmacokinetic-pharmacodynamic 
PO 
orally 
PR  
Interval from the P wave (atrial contraction or depolarization) to the onset of the Q 
wave in the measurement of electrical activity of the myocardium 
QRS 
QRS complex refers to ventricular depolarization in the measurement of electrical 
activity of the myocardium 
QT 
Interval from ventricular depolarization and repolarization in the measurement of 
electrical activity of the myocardium 
QTc 
QT, corrected 
QTcF 
QT corrected using Fridericia's method 
RBC 
red blood cell 


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SAE 
serious adverse event 
SM 
study medication 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
treatment-emergent adverse event 
TESS 
Treatment-emergent signs and symptoms 
TID 
three times per day 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WHO DD 
World Health Organization Drug Dictionary 


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5.  ETHICS 
5.1.  Institutional Review Boards / Independent Ethics Committees 
A list of the Institutional Review Board(s) (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 informed consent form (ICF) will be reviewed 
and approved by the IRB before subjects are screened for entry.  Verification of the IRB’s 
unconditional approval of the protocol will be transmitted to the Sponsor prior to the shipment of 
SM to the investigational site.  The Investigators or Sponsor will submit periodic reports and 
inform the IRB of any reportable adverse events (AEs) per International Conference on 
Harmonization (ICH) guidelines and IRB standards of practice. 
5.2.  Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating practices of the Sponsor (or 
designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines 
as required by the following: 
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 Good Clinical Practices (GCP) (CPMP/ICH/135/95) of the European Agency 
for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, ICH of 
Pharmaceuticals for Human Use. 
United States (US) Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR, 
including parts 50 and 56 concerning Informed Patient Consent and IRB regulations).  
5.3.  Subject Information and Consent 
The Investigator (or designee) will inform subjects of all aspects pertaining to the subject’s 
participation in the study.  All subjects will be provided with oral and written information 
describing the nature and duration of the study and the procedures to be performed. 
The process for obtaining informed consent will be in accordance with all applicable regulatory 
requirements.  The Investigator (or designee) and the subject must sign and date the ICF before 
the subject can participate in the study.  The subject will be given a copy of the signed and 
dated ICF and the original will be retained in the investigational site study records. 
The decision regarding subject participation in the study is entirely voluntary.  The Investigator 
(or designee) must emphasize to the subject that consent regarding study participation may be 
withdrawn at any time without penalty or loss of benefits to which the subject is otherwise 
entitled. 


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If the ICF is amended during the study, the Investigator must follow all applicable regulatory 
requirements pertaining to approval of the amended ICF by the IRB and use the amended 
informed consent form (including ongoing subjects). 
A separate ICF will be given for the optional PK portion of the study.  The above procedures will 
be followed in obtaining this consent. 
6.  INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified Investigators under the Sponsorship of Supernus 
Pharmaceuticals Inc. (Supernus) at approximately 5 investigational sites in the US. 
Contact persons at the Sponsor and the contract research organization(s) (CRO) are listed in 
the Regulatory Binder provided to each site. 
Contact information for the Safety Contact and Medical Monitor can be found listed in the 
Regulatory Binder provided to each site. 
The study will be monitored by qualified personnel identified by the Sponsor.  Data 
management, statistical analyses, safety, pharmacovigilance, and medical writing will be the 
responsibility of the CRO. 
7.  INTRODUCTION 
Viloxazine was previously marketed as an antidepressant in several European countries, since 
the 1970’s, and is currently under development by the Sponsor as SPN-812V, for its potential 
utility in treating adult attention deficit hyperactivity disorder (ADHD).  Viloxazine is a racemate 
and Supernus plans to develop the compound as such. Supernus intends to carry out this 
preliminary safety and proof of concept study in adult ADHD patients using an immediate 
release formulation that will support future development of a modified release formulation to 
facilitate compliance and possibly improve tolerability. 
 
Similar to tricyclic antidepressants and atomoxetine, viloxazine is an inhibitor of the reuptake of 
norepinephrine, but may also enhance the release of serotonin from neuronal stores. Clinical 
efficacy in Major Depressive Disorder has been shown at daily doses of 300 to 600 mg. 
Thorough published pharmacological and clinical summaries of the product are found in the 
reviews of Pinder et al., 1977 and Ban et al., 1980.  
 
Supernus development thesis is based on the current unmet medical need for effective long-
acting non-stimulant treatment for ADHD in adults.  Viloxazine can offer a compelling alternative 
to the use of scheduled substances to control ADHD thus limiting patients’ exposure to agents 
with potential for substance abuse.  


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This Phase I/IIa study seeks to evaluate the safety and tolerability of an immediate release 
formulation of viloxazine given three times per day (TID) at a dose of 150 or 300mg/day in 
adults.  A randomized, multicenter, parallel group, double-blind, placebo-controlled dose-ranging 
study design will be used.  50 subjects will be randomized; assuming a 20% dropout rate, it is 
anticipated that 40 subjects will complete the study.  Subjects will be monitored regularly for 
safety endpoints. 
Study Rationale 
Epidemiological data suggest that ADHD affects up to 8% of children in the USA while the 
estimated prevalence in the adult population is between 0.3 to 5%. (McCann, 2004). The 
increased recognition of ADHD as a disorder affecting adults has led investigators to focus on 
identifying 
pharmacological 
treatments 
for 
this 
age 
group. 
While 
stimulants, 
like 
methylphenidate, and amphetamine derivatives, are highly effective in ADHD with low risk of 
tolerance, they have significant adverse effects and a potential for abuse and illicit trafficking 
(Popper, 2000). Although stimulants are the mainstay of ADHD pharmacotherapy, atomoxetine 
is an FDA-approved non-stimulant selective noradrenergic re-uptake inhibitor considered a 
useful option for patients at risk of substance abuse, as well as for those who have co-morbid 
anxiety or tics, or who do not wish to take a controlled substance (Garnock-Jones, 2009-2010).  
Antidepressant drugs have also been shown to be effective in the treatment of ADHD (Slatkoff 
and Greenfield, 2006).  According to the literature, antidepressants with a wide range of receptor 
actions, efficacy, and side effects, including tricyclic antidepressants, noradrenergic, 
dopaminergic and 5-HT re-uptake inhibitors, can be helpful in controlling the ADHD symptoms.  
For instance reboxetine – an antidepressant registered in Europe with a mechanism of action 
supposedly very similar to viloxazine – has been claimed to have comparable efficacy to 
methylphenidate (Cohen-Yavin, 2009). Finally, the recently FDA-approved alpha-2 adrenergic 
agonist, guanfacine, has demonstrated efficacy in reducing hyperactivity and impulsivity in 
ADHD patients (Popper, 2000).  
 
After publishing fundamental research to clarify the mechanism of action of stimulants in ADHD, 
Arnsten, one of the key experts in this area, has summarized past and new results of 
neurobiological research on ADHD (Arnsten, 2006, 2009), suggesting an important role for 
prefrontal cortex (PFC) dysfunction. The PCF is critical for regulating so-called executive 
functions and for controlling attention and behavior.  Regulation of behavior is accomplished 
through networks of interconnected pyramidal cells which serve to store goals and rules guiding 
an individual’s actions.  The networks interact with each other and are highly dependent on their 
neurochemical 
environment. 
 
In 
particular, 
small 
changes 
in 
the 
catecholamines 
(norepinephrine) or dopamine can have marked effects on the PCF function.   It is not surprising 
that all drugs effective in ADHD, regardless of their mechanisms of action, modulate 
norepinephrine and dopamine release and optimize their concentrations at alpha (2A)-receptors 
and D (1) receptors respectively.  Serotonin has also been implicated in behavior modulation as 
suggested by some preclinical evidence generated in a rodent ADHD model.  Research 
conducted in young rats with neonatal hyperactivity induced by 6- hydroxydopamine (6-OHDA) 
lesioning indicates that behavioral effects of stimulants are mediated by release of both NE and 
serotonin (Davids, 2002).  These findings support the clinical testing of potential ADHD 
therapies that increase activity of the abovementioned neuromodulators.  
 


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The pharmacological similarity of viloxazine to other agents with proven efficacy in ADHD 
provides the rationale for a clinical trial to test preliminarily its effectiveness in this indication.  
While viloxazine inhibitory action on serotonin re-uptake appears to be weak, the drug does 
potentiate serotonin-mediated functions in mouse and rat (Ref: Lippman and Pugsley, 1976), 
and that feature might add interest to its pharmacological profile. 
 
Finally, the extensive human use of this product for depression has not generated any major 
safety concerns. Formulated as an extended-release product to overcome the molecule’s short 
half life, viloxazine may represent a novel approach to a polymorphic disease, for which more 
therapeutic options are still deemed necessary (Wigal, 2009).  
8.  STUDY OBJECTIVES 
Primary Objective 
The primary objective is to determine the safety of SPN-812V in adults with ADHD. 
Secondary Objectives 
The secondary objectives of this study are: 
• 
To determine the efficacy of SPN-812V in adults with ADHD  
• 
To explore the single dose and steady state pharmacokinetics of SPN-812V in adults 
with ADHD. 
9.  INVESTIGATIONAL PLAN 
9.1.  Overall Study Design and Plan 
This will be a multicenter, randomized, double-blind, placebo-controlled, parallel group study of 
the safety and efficacy in adults with ADHD.  The target subjects are healthy male or female 
adults aged 18 to 64 years, inclusive, with a diagnosis of ADHD.  A total of fifty subjects will be 
enrolled at approximately 5 sites in the US.  Subjects will be randomized (1:1) to one of two 
treatment groups, SPN-812V or placebo. 
The study will consist of a Screening Period (within 14 days prior to randomization) and a 
Dosing Period of 6 weeks,.  The total subject duration in the study will be up to 8 weeks as 
illustrated in Figure 1. 




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of vital signs and weight, PK blood sampling at Visit 8 (optional, if subjects wish to participate), 
and an ECG at Visit 4.  Assessments of concomitant medications, suicide risk, and SM 
compliance and dispensation will be performed.  Subjects who have consented to participate in 
the optional PK sub study will be given a diary at Visit 7 on which to record time of SM doses 
taken prior to Visit 8.  Subjects who are participating in the optional PK sub study will be given 
all efficacy assessments prior to blood draws or dosing on the PK day. For subjects not 
participating in the optional PK sub study, their last dose will be taken the evening before the 
End of Study Visit (Visit 8).    
9.1.3. End of Study Visit/Early Termination 
At the end of Visit 8, or prior to early discontinuation, subjects will undergo end of study 
assessments.  AEs will be monitored, and safety tests and efficacy scales will be administered 
unless assessments were performed earlier in the visit.  The procedures to be performed will 
include physical examination, collection of vital signs, weight, ECG, blood collection for 
hematology and chemistry, urine collection for urinalysis, drug screen, and pregnancy test (for 
FOCP).  Assessments of concomitant medications and SM compliance will be performed.   
9.2.  Discussion of Study Design, Including Choice of Treatment Groups and 
Appropriateness of Measurements 
This will be a randomized, double-blind, multicenter, parallel group, placebo-controlled safety 
and tolerability study in adults with ADHD.  The target subjects are healthy male and female 
adults aged 18 to 64 years, inclusive, with a diagnosis of ADHD.  50 subjects will be 
randomized; assuming a 20% dropout rate, it is anticipated that 40 subjects will complete the 
study.   
Blinding to treatment will be employed to reduce potential bias during data collection and 
evaluation of endpoints.  Randomization will be used in this trial to avoid bias in the assignment 
of subjects to treatment, to increase the likelihood that known and unknown subject attributes 
(e.g., demographics and baseline characteristics) are evenly balanced across treatment groups, 
and to enhance the validity of statistical comparisons across treatment groups.   
The primary objective of this Phase I/IIa study is to evaluate the safety of SPN-812V in these 
subjects.  Safety will be assessed by the monitoring of AEs, vital signs, clinical laboratory tests, 
physical examinations, and ECGs.   
The secondary endpoints of this study are: 
1. To establish the efficacy of SPN-812V over a 5-week treatment period with SPN-812V 
300 mg/day 
2. To establish the initial efficacy of SPN-812V after a 1-week treatment period with SPN-
812V 150mg/day. 
3. To establish the effectiveness of SPN-812V over a 6-week treatment period with either 
SPN-812V dose. 
4. To establish the clinical utility of SPN-812V after a 5-week treatment period with SPN-
812V 300mg/day. 
5. To establish the study subject’s perception of clinical benefit of SPN-812V at endpoint 
after a 5-week treatment with SPN-812V at 300mg/day. 


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6. To explore in a population model the single-dose and steady state pharmacokinetics of 
SPN-812V in adults with ADHD. 
 
To determine the drug effect on reducing ADHD symptoms, the CAARS will be utilized.  The 
CGI Scale will be administered to reflect drug effect on global functioning.  These efficacy 
assessments will be performed at all study visits.  Subjects who have agreed to participate in the 
optional PK sub study will have the efficacy assessments performed prior to blood being drawn 
and dosing for the PK sub study. 
Randomization will be used in this trial to avoid bias in the assignment of subjects to treatment, 
to increase the likelihood that known and unknown subject attributes (e.g., demographics and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the 
validity of statistical comparisons across treatment groups.   
9.3.  Selection of Study Population 
This study population was selected to evaluate SPN-812V safety and efficacy in adults, aged 18 
to 64 years old, inclusive, with ADHD.  In this study 50 subjects will be randomized at 
approximately 5 US sites. 
9.3.1 Inclusion Criteria 
Subjects meeting all of the following criteria may be included in the study: 
1. Able to provide informed consent prior to any study procedure being conducted. 
2. Capable and willing to comply with study procedures. 
3. Male or female aged 18 to 64, inclusive.  
4. Subjects with a current diagnosis of ADHD as confirmed by the Conners’ Adult ADHD 
Diagnostic Interview for DSM-IV (CAADID)  
5. Clinical Global Impression – Severity (CGI-S) score of 4 or higher. 
6. On no treatment for ADHD or willing to be withdrawn from an ongoing treatment after a 
washout of at least 10 days. 
7. Body Mass Index (BMI) between 18.0 and 34.0 inclusive 
8. Subject must be in general good health as determined by medical history, ECG, and 
other analysis that, in the judgment of the Investigator, would confirm the Subject's good 
health. 
9. Females of childbearing potential (FOCP) who, if sexually active, agree to use 
acceptable forms of contraception (including oral, transdermal, or implanted 
contraceptives; intrauterine device; female condom with spermicide; diaphragm with 
spermicide; cervical cap; abstinence; use of condom with spermicide by sexual partner 
or sterile [at least 6 months prior to SM administration] sexual partner) at least 14 days 
prior to start of study drug administration, throughout the study, and for 30 days following 
the last dose of SM. 
10. Postmenopausal females with amenorrhea for at least 2 years or females who are 
permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy). 


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9.3.2 Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria apply: 
1. Current or past history of psychotic disorder or major depressive disorder with psychotic 
features. 
2. Presence of another primary DSM-IV-TR disorder. 
3. Suicidality, defined as either active suicidal plan/intent or active suicidal thoughts in the 6 
months before the Screening Visit or more than 1 lifetime suicide attempt. (The 
Columbia-Suicide Severity Rating Scales [C-SSRS] will be administered at each visit.) 
4. Substance or alcohol abuse/dependence within previous 6 months, or a positive urine 
drug screen at screening or baseline prior to first dose of study medication (SM). 
5. Any known or suspected significant medical or psychiatric illnesses that, in the judgment 
of the Investigator, may impair interpretation of study results or constitute a significant 
safety concern in the context of the clinical trial 
6. ECG abnormalities (clinically significant according to Investigator’s opinion) or vital sign 
abnormalities (systolic blood pressure [SBP] <90 or >140 millimeters of mercury [mmHg], 
diastolic blood pressure [DBP] <40 or >90mmHg, or heart rate [HR] <40 or >100 beats 
per minute [BPM]) at screening. 
7. Clinically significant laboratory abnormalities; including presence of potential hepatic 
function impairment as shown by, but not limited to alanine aminotransferase (ALT) 
values >2 times upper limit of normal (ULN), aspartate aminotransferase (AST) > 2 times 
ULN, gamma-glutamyl transpeptidase (GGT) >3 times ULN, or total bilirubin >1.5 ULN . 
8. Medications, including health food supplements judged by the Investigator to be likely to 
have central nervous system activity (for example, St John's Wort, gingko leaf, and 
melatonin), are not permitted during the study.  If the subject is taking the medication 
prior to study entry, there must be a 7 day washout period prior to first dose of SM. 
9. Lifetime history of tic disorder, Tourette’s Disease, or organic brain disorder; or family 
history of Tourette’s Disease. 
10. Current or lifetime history of hyperthyroidism unless treated and stable for 6 months. 
11. Participation in or plan to begin behavioral therapy during the study. 
12. Subject has a prior history of allergy or any significant adverse reaction (including rash) 
to viloxazine, or any of the product components. 
13. Females who are pregnant or lactating or are unwilling to use an acceptable form of 
contraception throughout the study. 
14. Difficulty swallowing whole capsules. 
15. History of seizures or risk factors for seizures (e.g., head trauma), not including febrile 
seizures. 
16. Use of an investigational drug or participation in an investigational study within 30 days 
prior to first dose of SM. 
17. Any reason which, in the opinion of the Investigator, would prevent the subject from 
participating in the study. 




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g 
Dose to be administered on-site after the pre-dose draw and an overnight fast at Visit 8; subjects may eat 2 hours after dosing. 
h 
At Visit 8, subjects who wish to participate will be dosed after an overnight fast and have a series of PK samples drawn.  Samples will be taken 
pre-dose, and at Hours ½, 1, 2, 3, 4, 5, and 6.  
i 
Any subject who experiences an adverse event (whether serious or non-serious) or has a clinically significant abnormal laboratory test value(s) 
will be followed by the Investigator at appropriate intervals based on the severity and nature of the event, until resolved, or when the condition is 
assessed as stable, causality other than the SM has been found, or the subject is referred to another health care professional. 
 


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9.4.1.1. 
Screening Period 
A Screening Period will take place within 14 days prior to the first dose administration to 
determine subjects’ eligibility to participate in the study.  If needed, screening may take 
place over more than 1 visit.  Prior to conducting any screening procedures, written 
informed consent must be obtained from the subject.   
The procedures to be performed will include: 
• 
Informed consent process 
• 
Medical and psychiatric history, including smoking history 
• 
Demographics 
• 
Administration of CAADID for confirmation of ADHD diagnosis 
• 
Administration of CGI-S 
• 
Administration of C-SSRS 
• 
Assessment of inclusion/exclusion criteria  
• 
Physical examination 
• 
ECG (12-lead) 
• 
Vital signs, height, and weight 
• 
Laboratory tests (including hematology, clinical chemistry, and urinalysis) 
• 
Urine drug screen 
• 
Serum pregnancy test (for FOCP) 
• 
Assessment of prior and concomitant medications  
9.4.1.2. 
Baseline and Randomization  
Once subjects have been adequately screened and it is determined the subject is 
eligible for the study, the subject will return for the baseline and randomization visit.   
 
The procedures to be performed will include: 
• 
Changes in medical and psychiatric history since last visit (AE collection starts after 
first dose) 
• 
Administration of CGI-S 
• 
Administration of CAARS, both investigator-rated and self-rated versions 
• 
Administration of C-SSRS 
• 
Vital signs and weight 
• 
Urine pregnancy test (for FOCP) 
• 
Assessment of concomitant medications 
• 
Randomization 
 


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• 
SM dispensed 
9.4.1.3. 
Dose Treatment Period  
9.4.1.3.1.  Visits 2-7 
Dosing Schedule: 
• 
The first dose of SM should be taken the morning following the randomization visit.    
• 
Following dosing for a week at the starting dose of 150mg SPN-812V or placebo 
(1 capsule TID), subjects will be titrated to and maintained at the 300mg SPN812-V 
or placebo dose level (2 capsules TID) for 5 weeks.   
• 
Subjects in the highest dose group will be permitted to down titrate to the starting 
dose at the Investigator’s discretion in consultation with the Medical Monitor. 
Subjects who still cannot tolerate study medication after one down-titration should be 
removed from the study.  Visits will occur on a weekly basis (+/- 2 days). 
The following evaluations will be performed: 
• 
AEs assessed (monitoring begins after first dose of SM) 
• 
Administration of CGI-I 
• 
Administration of CAARS, investigator-rated version at each visit, self-rated version 
only at Visit 8 
• 
Administration of C-SSRS 
• 
Vital signs and weight 
• 
ECG (12-lead) (Visit 4 only) 
• 
Assessment of concomitant medications 
• 
SM returned and dispensed, assessment of compliance 
• 
SM time recordation diary dispensed to subjects who have consented to participate 
in the PK sub study (Visit 7) 
• 
Subjects who will participate in the optional PK sub study at Visit 8 will be reminded 
to not eat or take SM prior to coming to the clinic the morning of Visit 8 
9.4.1.3.2. Visit 8 
The following evaluations will be performed: 
• 
AEs assessed 
• 
Administration of CGI 
• 
Administration of CAARS, investigator-rated and self-rated versions 
• 
Administration of C-SSRS 
• 
Vital signs and weight 
 


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• 
Assessment of concomitant medications 
• 
SM returned, assessment of compliance 
• 
SM time recordation diary collected  
 
PK Sub study Procedures:  All efficacy assessments will be done first. 
• 
Subjects who agree to participate in the optional PK sub study will be given 2 x 50mg 
SPN-812V on-site in the morning, unless the subject had been down-titrated, in 
which case, the subject will receive 1 x 50mg SPN-812V on-site in the morning. 
• 
Subjects must arrive after an overnight fast and may eat two hours after dosing.  The 
subject will have a pre-dose PK draw taken, will be dosed, and will have PK draws 
taken at ½, 1, 2, 3, 4, 5, and 6 hours post-dose.  There is a 30 minute window on all 
draw times, but they may be used only so that there is at least one hour between 
each sampling time after the ½ hour post-dose draw. 
9.4.1.4. 
Final Visit/Early Termination 
The following evaluations will be performed during the final visit or at early 
discontinuation (assessments completed at Visit 8 will not be repeated): 
• 
Administration of CGI 
• 
Administration of CAARS, investigator-rated version at Visits 2-8, self-rated version 
at Visit 8 only 
• 
Administration of C-SSRS 
• 
Physical examination 
• 
ECG (12-lead) 
• 
Vital signs and weight 
• 
Laboratory tests (including hematology, clinical chemistry, and urinalysis) 
• 
Urine drug screen 
• 
Serum pregnancy test (for FOCP) 
• 
Assessment of concomitant medications 
• 
SM returned, assessment of compliance 
• 
AEs assessed 
 
9.4.2. Efficacy Assessments 
Investigator-rated Conners’ Adult ADHD Rating Scale (CAARS)  
This assessment will be administered at study visits 2 - 8. 
Clinical Global Impression (CGI)  
This assessment will be administered at all study visits. 
 
 


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Self-rated Conners’ Adult ADHD Rating Scale (CAARS)  
This assessment will be administered at study visits 2 and 8. 
 
9.4.3. Pharmacokinetic Measurements 
On the morning of Visit 8, all subjects who wish to participate in the optional PK day will 
arrive at the clinic after an overnight fast and will have all efficacy assessments 
administered first.  The subjects then will have a pre-dose PK sample taken, and be 
administered either 2 x 50mg SPN-812V capsules or will be administered 1 x 50mg 
SPN-812V capsule for subjects who underwent dose reduction. PK sampling will occur 
pre-dose and at 0.5, 1, 2, 3, 4, 5, and 6 hours post-dose.  Although there is a 30 minute 
window on draw times, efforts should be made to ensure that the time interval between 
any two sampling timepoints is not less than 30 minutes. Subjects may eat two hours 
after dosing.   
SPN-812V concentrations in plasma samples will be determined by the Sponsor using a 
validated chromatographic method.  The amount of blood to be drawn at each timepoint 
to determine the plasma concentrations of SPN-812V is 4mL.  Information regarding 
sample collection, handling, and shipping procedures will be detailed in a separate 
manual. 
Single dose administration of viloxazine hydrochloride (100mg) to ten healthy volunteers 
resulted in mean Cmax near 1800 ng/mL for viloxazine at a mean Tmax ~100 min post-
dose and with elimination half-life ~3 hr (Vandel B. et al., “Pharmacokinetics of viloxazine 
hydrochloride in man,” European Journal of Drug Metabolism and Pharmacokinetics, 
1982, Vol 7, pp. 65-68).  Timepoints were chosen on the basis of these data to inform 
both absorption and elimination phases of the viloxazine time course while minimizing 
the sampling burden on patients.  The design of the study provides both first-dose (in 
placebo group) and steady state (in active group) observations, albeit in parallel 
treatment groups. 
 
9.4.4. Safety Assessments 
Safety assessments during the study will consist of AE and SAE monitoring, weight, 
clinical laboratory tests, vital signs, physical examinations, and 12-lead ECGs, as 
detailed in section 9.4.1.   
9.4.4.1. 
Adverse Events 
As defined by the ICH Guideline for GCP, an AE is any untoward medical occurrence in 
a patient or clinical investigation subject administered a pharmaceutical product, which 
does not necessarily have to have a causal relationship with treatment. 
 


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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 or exacerbation of an existing disease. 
• 
Any deterioration in non-protocol-required measurements of laboratory value or other 
clinical test (e.g., ECG or X-ray) 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. 
AEs fall into the categories of “non-serious” and “serious”.  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.   
AEs or SAEs that are ongoing at the subject’s last study visit must be followed until 
resolution or if, in the medical judgment of the Investigator, the event has stabilized or is 
assessed as chronic.   
9.4.4.1.1. Reporting of Adverse Events 
All subjects will be closely questioned regarding the occurrence of AEs. 
For subjects who receive SM, all AEs (learned of through spontaneous reports or subject 
interview) will be collected starting from the first dose of SM until the end of the study.  
All AEs will be collected on the AE Case Report Form (CRF).  All SAEs will be reported 
to the Sponsor.   
A cluster of signs and symptoms that results from a single cause may be reported as a 
single AE (e.g., fever, elevated WBC, cough, abnormal chest X-ray, etc. can all be 
reported as “pneumonia”). 
9.4.4.1.2. Criteria for Assessing Severity 
The Investigator will evaluate the comments of the subject and the response to 
treatment in order that he/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 
 


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The criteria for assessing severity are different from those used for seriousness (see 
Section 9.4.4.2. for the definition of an SAE). 
9.4.4.1.3. Criteria for Assessing Causality 
The question of the relationship of an AE to SM should be determined by the 
Investigator or study physician after thorough consideration of all facts that are available.  
Assessment of causality is based on considering associative connections (time or 
place), pharmacological explanations, previous knowledge of the drug, presence of 
characteristic clinical or pathological phenomena, exclusion of other causes, and/or 
absence of alternative explanations.  The causal relationship of an AE to SM will be 
assessed according to the following criteria (based on World Health Organization [WHO] 
definitions): 
The Investigator is responsible for determining the relationship between the 
administration of SM and the occurrence of an AE as not suspected or suspected.  
• 
Not suspected: The temporal relationship of the AE to SM administration makes 
a causal relationship unlikely, or other drugs, therapeutic interventions, or 
underlying conditions provides a sufficient explanation for the observed event.  
• 
Not related:  Temporal relationship to SM administration is missing or 
implausible, or there is an evident other cause. 
• 
Unlikely related:  Temporal relationship to SM administration makes a causal 
relationship improbable; and other drugs, chemicals, or underlying disease 
provide plausible explanations 
• 
Suspected: The temporal relationship of the AE to SM administration makes a 
causal relationship possible, and other drugs, therapeutic interventions, or 
underlying conditions do not provide a sufficient explanation for the observed 
event.  
• 
Possibly related:  Reasonable time sequence to administration of SM, but event 
could also be explained by concurrent disease or other drugs or chemicals.  
Information on drug withdrawal may be lacking or unclear. 
• 
Definitely related: Plausible time relationship to SM administration; event cannot 
be explained by concurrent disease or other drugs or chemicals.  The response 
to withdrawal of the drug (dechallenge) should be clinically plausible.  The event 
must be definitive pharmacologically or phenomenological, using a satisfactory 
rechallenge procedure if necessary. 
9.4.4.2. 
Serious Adverse Events 
A SAE is any untoward medical occurrence that at any dose: 
• 
results in death; 
• 
is life-threatening (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.); 
 


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• 
requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
results in persistent or significant disability/incapacity; or 
• 
is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
SM) 
• 
is a medically important event or reaction (see below) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization, but when based on appropriate medical judgment, may 
jeopardize the subject or may require intervention to prevent one of the outcomes in the 
definition of SAE listed above should also be considered SAEs.  Examples of such 
events are intensive treatments in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or seizures that do not result in hospitalization, or 
development of drug dependency or drug abuse.  These events may be considered to 
need rapid reporting by the Sponsor to regulatory authorities (see Section 9.4.4.2.2.). 
Any new SAEs reported by the subject that occur after the first dose of SM and until the 
end of the study will be collected.  SAEs that are ongoing at the subject’s last study visit 
must be followed until resolution or if, in the medical judgment of the Investigator, the 
event has stabilized or is assessed as chronic.   
9.4.4.2.1. Reporting of SAEs 
All SAEs must be reported to the Safety Contact person(s) within 24 hours of first 
becoming aware of the SAE.  The Investigator must complete an SAE Form, including a 
detailed description of the SAE and all other information available (e.g., hospital records, 
autopsy reports and other relevant documents).  The Investigator must inform the IRB 
about such AEs in accord with ICH guidelines and the practices of the governing IRBs 
(Section 5.1.). 
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 
Form. 
Safety Contact persons and all contact information are listed in the Site Manual and/or 
Regulatory Binder provided to each investigational site. 
9.4.4.2.2. Other Events Requiring Immediate Reporting 
The Investigator must report a pregnancy that occurs in a subject during a clinical study 
to the Medical Monitor within 24 hours of first becoming aware of the event.  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. 
 
 
 


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9.4.4.2.3. Expedited Reporting 
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 investigational sites submit 
SAE information to the Sponsor (or designee) in the manner described above. 
9.4.4.3. 
Laboratory Measurements 
Clinical laboratory tests will be performed by a central laboratory.  Information regarding 
collecting, handling, and shipping samples will be detailed in a separate manual.  The 
Schedule of Visits and Procedures (Table 1.  Schedule of Visits and Procedures) shows 
the time points at which blood and urine will be collected for clinical laboratory tests.   
For subjects who participate in the optional PK portion of the study, a total of 
approximately 32mL (8 PK blood draws × 4mL) of blood/subject will be taken during the 
course of the study for the purpose of PK samples, in addition to 29mL (2 blood draws 
for clinical chemistry × 14.5mL) required for laboratory tests for all subjects.  A complete 
list of all clinical laboratory assessments is presented in Table 2.  Clinical Laboratory 
Assessments. 
Laboratory personnel contact information and laboratory sample shipment information 
and instructions are listed in the Site Manual and/or Regulatory Binder provided to each 
investigational site. 
 


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Table 2.  Clinical Laboratory Assessments 
Hematology 
Serum Chemistry  
Urinalysis 
Hematocrit 
Hemoglobin 
Red blood cell count (RBC) 
Platelet count 
White blood cell count (WBC) 
(with differential) 
 
Albumin 
Alkaline phosphatase 
Alanine transaminase (ALT) 
Aspartate transaminase (AST)
Bilirubin- Total and Direct 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Cholesterol- Total, HDL and 
LDL 
Creatinine 
Creatine phosphokinase 
(CPK) 
Gamma-glutamyl 
transpeptidase (GGT) 
Glucose 
Inorganic phosphorous 
Potassium 
Sodium 
Total protein 
Triglycerides 
Uric acid 
Ketones 
Protein 
Specific gravity 
Glucose 
pH 
 
Other tests 
Urine drug panel for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, 
marijuana/cannabinoids, methadone, opiates, phencyclidine, propoxyphene, and alcohol) 
Urine pregnancy test (for FOCP) 
CYP2D6 enzyme activity (poor, intermediate and ultra rapid metabolizers)  
 
Abnormal lab findings may be confirmed if necessary by one repeated testing at the 
discretion of the Investigator.  Any laboratory abnormality may qualify as an AE in the 
Investigator’s judgment. 
9.4.4.4. 
Vital Signs, Height, and Weight Measurements 
Vital sign measurements (HR, blood pressure, temperature, and respiratory rate) will be 
obtained at all visits as designated on the Schedule of Visits and Procedures (Table 1.  
Schedule of Visits and Procedures).  Blood pressure and pulse will be measured after 
the subject has been sitting for 5 minutes.  Height and weight will be obtained at the 
Screening Visit and weight will be collected at all visits as designated on the Schedule of 
Visits and Procedures (Table 1.  Schedule of Visits and Procedures). 
 


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9.4.4.5. 
Medical, Psychiatric History and Physical Examinations 
Medical and psychiatric history, including smoking history, will be taken at the screening 
visit.  Physical examinations will be performed at the Screening Visit and Final Visit as 
designated on the Schedule of Visits and Procedures (Table 1.  Schedule of Visits and 
Procedures). 
9.4.4.6. 
Electrocardiograms (ECGs) 
ECGs (12-lead) will be obtained at the Screening Visit, Visit 4, and the Final Visit as 
designated on the Schedule of Visits and Procedures (Table 1.  Schedule of Visits and 
Procedures).  Additional ECGs may be performed at other times if deemed necessary. 
The ECG will be recorded while the subject is resting in a supine position.  The ECG will 
electronically measure the PR, QRS, QT, and QTc intervals, and heart rate. 
All ECG tracings will be reviewed within 24 hours by the Investigator or qualified Sub-
Investigator.  PR intervals will be determined for each of these ECGs from a single 
reading.  Invalid measurements will be repeated.  QTc will be reported as QTcF (QT 
corrected using Fridericia's method). 
9.4.5. Completion/Discontinuation of Subjects 
Subjects will be permitted to leave the study at any time.  Subjects can be withdrawn 
from the study in any of the following circumstances: 
• 
SAE or an AE 
• 
Administrative reasons (e.g., sponsor decision) 
• 
Withdrawal of consent/assent 
• 
If the subject becomes pregnant  
• 
If it is in the best interest of the subject, in the opinion of the Investigator 
• 
Termination of the study 
When an event such as a family emergency, a transient illness (such as a cold) 
unrelated to SM, or a remediable act of non-compliance prevents a subject from 
participating in a scheduled visit, but the subject wishes to continue in the study, the 
Investigator will attempt to reschedule the visit and retain the subject in the study on a 
case by case basis, rather than discontinue the subject’s participation. 
If a subject is prematurely discontinued from participation in the study for any reason 
after SM administration, the Investigator must make every effort to perform the Final Visit 
assessments. 
 


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9.5.  Treatments 
9.5.1. Treatments Administered 
SM will be dispensed at each visit during the Randomization and Dose Treatment 
Periods.  Subjects will receive a bottle at each visit containing the correct number of 
50mg (or placebo) capsules, which is a sufficient number of capsules for dosing until the 
next visit. The SM will be taken by the subject orally, three times per day during waking 
hours, with at least 4 hours between doses (morning, noon, and evening).  
At Visit 8, subjects who agree to participate in the optional PK sub study will be given 2 x 
50mg SPN-812V capsules on-site in the morning, unless the subject had been down-
titrated, in which case, the subject will receive 1 x 50mg SPN-812V capsule on-site in 
the morning.  Note: all subjects who participate in the optional PK sub study will be given 
active SPN-812V capsule(s) in this portion. For subjects not participating in the optional 
PK sub study, their last dose will be taken the evening before the End of Study Visit 
(Visit 8).    
9.5.2. Identity of Study Medication 
SM are supplied as size 0 white opaque capsules by the Sponsor in labeled bottles.  
There will be 50 capsules per bottle.  Labels will bear the protocol number, product code, 
and batch number. SM will be repackaged each week into a weekly supply by the 
unblinded site staff member who will be dispensing the blinded medication.  The site 
number, subject number, subject initials, and the number of capsules to be taken at each 
dose per day, will be handwritten on the labels by the unblinded staff member who will 
be dispensing the blinded medication. 
9.5.3. Handling of Study Medication 
All SM will be supplied to the Investigator by the Sponsor.  SM supplies must be kept in 
an appropriate secure area (e.g., locked cabinet) and stored according to the conditions 
specified on the SM labels.  The Investigator must maintain an accurate record of the 
shipment and dispensing of the SM in an accountability log, a copy of which must be 
given to the Sponsor at the end of the study.  An accurate record of the date and amount 
of SM dispensed to each subject must be available for inspection at any time.  The 
assigned unblinded CRA will review these documents on one or more visits to the 
investigational site. 
All SM supplies are to be used only for this protocol and not for any other purpose.  The 
Investigator must not destroy any SM labels or any partly used or unused SM supply.  At 
the conclusion of the study and as appropriate during the course of the study, the 
Investigator will return all used and unused SM containers and a copy of the completed 
SM accountability log to the Sponsor.   
9.5.4. Study Medication Accountability 
The Investigator, who will be blinded, will delegate responsibility to a qualified unblinded 
study staff member who will be responsible for the accountability of all clinical supplies 
(receipt, dispensing, inventory, record keeping, and return) following Sponsor 
 


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instructions and must adhere to GCP guidelines as well as municipal, state, and federal 
regulations. 
Under no circumstances will the Investigator or the delegated unblinded staff member 
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 in the study. 
An accurate and timely record of the receipt of all clinical supplies, dispensing of SM to 
the subject, collection of unused supplies returned by the subject at each visit, and 
subsequent return of unused SM to the Sponsor must be maintained.  This includes, but 
may not be limited to: (a) documentation of receipt of clinical supplies, (b) SM 
dispensing/return reconciliation log, (c) SM accountability log, and (d) all shipping 
service receipts.  All forms will be provided by the Sponsor.  Any comparable forms that 
the investigational site wishes to use must be approved by the Sponsor.  Discrepancies 
on SM accountability must be documented and addressed by the delegated unblinded 
staff member.    
The supplies and inventory records must be made available, upon request, for 
inspection by the designated representative of the Sponsor or a representative of the 
Food and Drug Administration (FDA).  All unused SM, including empty containers, are to 
be returned to the Investigator by the subject or parent or LAR, and ultimately to the 
Sponsor at the conclusion of the study, unless provision is made by the Sponsor for 
destruction of supplies and containers at the investigational site.  Upon completion of SM 
accountability and reconciliation procedures by investigational site personnel and 
documentation procedures by Sponsor personnel, SM that is to be returned to the 
Sponsor must be shipped following all local regulatory and shipment laws.  Forms and 
information that could unblind the study must be maintained such that the Investigator 
and blinded study staff are not unblinded. 
9.5.5. Method of Assigning Subjects to Treatment Groups 
The randomization for this study will be managed centrally; specific instructions to 
conduct subject randomization will be provided in a separate document to all 
investigational sites. 
A randomization scheme will be generated using a pseudo-random number generator in 
a computer program.  The method avoids bias by use of a chance mechanism.  The 
randomization scheme assigns Treatment 1 or Treatment 2 to each randomization 
number in a 1:1 ratio. 
Upon admission to the study, subjects will be assigned a 4-digit screening number, in 
the order that they are entered.  Subjects who subsequently meet all eligibility criteria will 
be assigned a 6-digit randomization number.  The first 3 digits will refer to the site, and 
the last 3 will refer to the subject-specific number, which will be assigned according to 
the randomization scheme.  
Once a randomization number has been assigned, no attempt should be made to use 
that number again, if, for example, a subject is withdrawn.  All subjects are randomized 
only once. 
 


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Note:  all subjects who participate in the optional PK substudy will be given active SPN-
812V capsule(s) in this portion. 
9.5.6. Removal of Subjects from Therapy or Assessment 
The Investigator or subjects themselves may stop SM treatment at any time for safety or 
personal reasons.  If possible, a subject who discontinues treatment will be followed for 
end of study protocol-specified visits and procedures.  A subject removed from the study 
for any reason may not be replaced. 
9.5.7. Dosing Schedule 
At the Baseline and Randomization Visit, subjects will be randomized to 
Treatments 1 or 2 and will initiate dosing.  Once the target dose is reached, maintenance 
treatment will continue for 6 weeks.  Down titration to the starting dose is allowed for 
subjects who cannot tolerate the maintenance dose, at the discretion of the Investigator 
in consultation with the Medical Monitor.  Subjects who cannot tolerate study drug after 
dose-reduction should be removed from the study. 
At Visit 8, subjects who agree to participate in the optional PK sub study will be 
administered efficacy assessments prior to dosing.  Then, subjects will be given 
2 x 50mg SPN-812V on-site in the morning, unless the subject had been down-titrated, 
in which case, the subject will receive 1 x 50mg SPN-812V on-site in the morning. 
9.5.8. Method of Administration 
Capsules should be swallowed whole and not crushed or chewed.  The SM will be 
administered three times per day, with at least 4 hours between doses (morning, noon, 
and evening).  When possible, doses should be administered at the same times each 
day.  If a dose is missed, it should be taken as soon as possible unless it is within 
30 minutes of the next dose; in this case the subject should skip the missed dose and 
return to the regular schedule thereafter. 
9.5.9. Blinding 
The appropriate SM, according to randomization, will be placed into bottles to be 
dispensed to the subject by an unblinded staff member (e.g., coordinator or pharmacist).  
Identity of treatment arm must not be disclosed to the site’s blinded study staff or the 
Sponsor (or designee).  An unblinded Clinical Research Associate (CRA) will monitor the 
SM records. 
9.5.10. 
Concomitant Medications 
For subjects who receive SM, concomitant medications and therapies that are ongoing 
as of the date of informed consent will be recorded on the Concomitant Medication CRF.  
The Investigator will record all concomitant medications, including over-the-counter 
medications, on the Concomitant Medication CRF.  The Investigator will record the AE 
for which the concomitant medication was administered on the AE CRF. 
 


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9.5.11. 
Treatment Compliance 
Records of SM and doses administered will be kept during the study by unblinded site 
staff.  The unblinded CRA will review SM accountability during investigational site visits 
and at the completion of the study. 
9.5.10. 
Change of Study Medication Dose 
Subjects will be assigned to 1 of 2 treatment groups.  All subjects will titrate to the 
maintenance dose of SM and will remain on SM for 6 weeks during the Maintenance 
Period.  Down titration to the starting dose is allowed for subjects who cannot tolerate 
the maintenance dose, at the discretion of the Investigator in consultation with the 
Medical Monitor.  Subjects who cannot tolerate study drug after dose-reduction should 
be removed from the study. 
9.6.  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 or 
CRO’s qualified compliance auditing team, which is an independent function from the 
study conduct team. 
9.6.1. Data Collection 
The Investigator (or designee) will enter the information required by the protocol into the 
CRF in accordance with the CRF Completion Instructions that are provided with the 
CRF.  The CRA will visit each investigational site as frequently as documented in the 
monitoring plan to review the CRF for completeness and accuracy against the source 
documents.  The CRA will highlight any discrepancies found in the documentation of 
study conduct and ensure that appropriate site personnel address the discrepancies.  
Procedures for data collection and correction will be discussed at the site initiation visit, 
routine monitoring visits, and will be included in the completion instructions. 
9.6.2. Clinical Data Management 
Data from the CRF and other external data (e.g., laboratory data) will be entered into or 
transferred to a clinical database as specified in the data management plan for this 
study.  Quality control and data validation procedures will be applied to ensure the 
validity and accuracy of the clinical database. 
9.6.3. Database Quality Assurance 
The clinical database will be reviewed and checked for omissions, apparent errors, and 
values requiring further clarification using computerized and manual procedures.  Data 
queries requiring clarification will be documented and returned to the investigational site 
for resolution.  Only authorized personnel will make corrections to the clinical database, 
and all corrections will be documented in an audit trail.  A quality assurance audit will be 
performed prior to database lock. 
 


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9.6.4. Bioanalytical Data Management and Quality Control 
PK samples and requisition forms will be shipped by the Investigator to the central 
laboratory, and instructions will be detailed in the central laboratory manual.  Analysis 
will be performed by means of a validated chromatographic method.  Details on the 
analytical methodology, the method validation, and the analytical within-study quality 
control procedures will be included in the clinical study report for this protocol. 
9.7.  Statistical Methods 
9.7.1. Statistical and Analytical Plans 
Tabular summaries of the data collected during the study will be presented to provide a 
general description of the subjects studied and an overview of the safety, efficacy, and 
PK results.  Data from all investigational sites will be combined in the computation of 
these summaries, and summaries will be presented by treatment group.   
 
As down titration from 300mg to 150mg is allowed for subjects who cannot tolerate the 
maintenance dose, those subjects will be treated as part of the 300mg arm while 
analyzing the data. 
 
Continuous variables will be summarized using descriptive statistics (number of 
subjects, mean, standard deviation, median, and minimum and maximum values).  
Categorical (nominal) variables will be summarized using frequency tables (number and 
percentage of subjects in each category).  
 
In addition to tabular summaries, subject data listings, as specified in Sections 16.2 and 
16.4 of ICH E3, will be provided.  Additional subject data listings to be provided for this 
study are listed under the relevant subsections below. 
 
The full data analyses will be performed by the CRO after the study is completed and the 
database is locked.  Statistical programming and analyses will be performed using SAS® 
and/or other validated statistical software as required. 
 
The statistical analyses described in this section will be described in more detail in the 
Statistical Analysis Plan (SAP), which will be finalized prior to database lock and will be 
included in the clinical study report for this protocol.  The final SAP will take into account 
any amendment to the protocol. 
9.7.1.1. 
Analysis Populations 
The safety population consists of all randomized subjects who take at least one dose of 
SM. 
The intent-to-treat (ITT) population consists of all randomized subjects who took at least 
one dose of SM (i.e., the safety population), had baseline efficacy assessment, and had 
at least one post-baseline efficacy assessment.  
 The ITT population is the population for the efficacy analysis.  Subjects will be analyzed 
according to treatment assigned. 
 


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The restricted ITT population consists of all ITT population subjects with at least 1 
efficacy assessment after three weeks of treatment. 
The PK population consists of all Safety population subjects with an evaluable PK 
profile. 
9.7.1.1.1. Demographic/Baseline Analyses 
Demographic/baseline variables include age, sex, ethnicity, race, baseline height, 
baseline weight, and medical history.  Tabular summaries of the demographic/baseline 
variables will be presented for the safety, ITT, and restricted ITT populations, except for 
medical history, which will be summarized for the safety population only.   
9.7.1.1.2. Study Medication 
Tabular summaries of the treatment percent compliance rate and duration of treatment 
exposure to SM will be presented for the safety population.  The number and percentage 
of subjects maintained on the target dose versus those reduced in dose during the 
Maintenance Period will be provided. 
Analysis of treatment compliance and exposure will be performed separately for the 
Baseline and Randomization Period, Dose Treatment Period, and combined Baseline 
and Randomization and Dose Treatment Periods.  
9.7.1.1.3. Concomitant Medications 
Concomitant medications will be assigned an 11-digit code using the WHO 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. 
9.7.1.2. 
Efficacy Analyses 
Efficacy analyses will be conducted for the ITT population.  Where appropriate, a 
restricted ITT population may also be used.   
Descriptive statistics will be presented for all efficacy variables by visit and treatment 
group.  
All significance tests will be performed at the 0.05 level. 
9.7.1.2.1. Primary Efficacy Analysis 
The primary efficacy measure is the investigator-rated CAARS Total ADHD Symptom 
Score which is the sum of the Inattention and Hyperactivity/Impulsivity subscales (18 
items measured on 4-point scale: 0, 1, 2, and 3). 
The changes from baseline to the endpoint (visit 8) in the investigator-rated CAARS 
Total ADHD Symptom Scores will be compared between the two treatment groups using 
the Wilcoxon rank-sum test or the two-sample t-test.   
To confirm the results (sensitivity analysis), a mixed model repeated measures (MMRM) 
analysis will be conducted.  MMRM analysis will contain fixed effect terms for treatment, 
 


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investigative site, visit, and interaction between treatment and visit.  The model will 
include post-baseline values of the investigator-rated CAARS Total ADHD Symptom 
Score as the dependent variable with a random patient effect and baseline investigator-
rated CAARS Total ADHD Symptom Score as a covariate and will use an unstructured 
covariance. 
9.7.1.2.2. Secondary Efficacy Analyses 
The following secondary efficacy analyses will be performed: 
1. Initial efficacy of SPN-812V starting dose (150 mg/day) when compared to 
placebo as measured by changes in the investigator-rated CAARS Total ADHD 
Symptom Score from baseline at week 1 of treatment with starting dose will be 
analyzed with Wilcoxon rank-sum test or two-sample t-test 
2. Effectiveness of any SPN-812V dose when compared to placebo as determined 
by the weekly changes in the Clinical Global Impression – Improvement (CGI-I) 
score from baseline severity for 6-week treatment will be plotted as mean CGI-I 
change versus visit and analyzed using Wilcoxon rank-sum test or two-sample t-
test 
3. Clinical utility of SPN-812V study dose (300 mg/day) when compared to placebo 
as determined by the investigator’s assessment of the changes in the Conner’s 
Adult ADHD Rating Scale (CAARS) score from baseline at week 2, 3, 4, 5, and 6 
of treatment will be analyzed with Wilcoxon rank-sum test or two-sample t-test 
4. Study subject’s perception of clinical benefit of SPN-812V study dose (300 
mg/day) when compared to placebo as determined by changes in the self-rated 
Conner’s Adult ADHD Rating Scale (CAARS) score from baseline at endpoint 
after 5-week treatment will be analyzed with Wilcoxon rank-sum test or two-
sample t-test 
9.7.1.2.3. Subgroup Analyses for Efficacy 
Subgroup analyses for efficacy will be performed on categories of the following 
measures: 
• 
Sex 
• 
Race 
for the ITT population for the investigator-rated CAARS Total ADHD Symptom Score.  
Subgroup analyses will also be carried out for the following subscales 
• 
investigator-rated CAARS inattention subscale score 
• 
investigator-rated CAARS hyperactivity/impulsivity subscale score 
 
that together make up the CAARS Total ADHD Symptom Score 
9.7.1.3. 
Pharmacokinetic Analyses 
Population PK data will be pooled across all subjects and analyzed using nonlinear 
mixed-effects modeling methods.  The objective of the population PK analyses is to 
derive individual-specific estimates of apparent oral clearance (CL/F) but not to fully 
characterize the PK of this formulation of viloxazine.  
 


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9.7.1.4. 
Safety Analyses 
Evaluation of safety will be performed for the safety population.  Safety data that will be 
evaluated include AEs, clinical laboratory results, vital signs, ECGs, and physical 
examination findings.  
9.7.1.4.1. Adverse Events 
AEs will be classified into standardized medical terminology from the verbatim 
description (Investigator term) using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be presented in the summary tables by preferred term nested 
within System Organ Class (SOC).  Verbatim description and all MedDRA level terms, 
including the lower level terms, for all AEs will be contained in the subject data listings.   
Data for AEs will be analyzed using the treatment-emergent signs and symptoms 
(TESS) philosophy.  TESS are defined as AEs that: 
• 
emerge during treatment, having been absent at pretreatment, or  
• 
reemerge during treatment, having been present at pretreatment but stopped prior to 
treatment, or  
• 
worsen in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only treatment-emergent AEs (TEAEs) from the study will be summarized in tables.  
TEAEs will be summarized by presenting, for each treatment group, the incidence of 
AEs.  The incidence of TEAEs will be based on the numbers and percentages of 
subjects with TEAEs.  Although a MedDRA term may be reported more than once for a 
subject, that subject will be counted only once in the incidence count for that MedDRA 
term. 
Separate TEAE incidence tables will be presented for the Baseline and Randomization 
Period, Dose Treatment Period, and combined Baseline and Randomization and Dose 
Treatment Periods.  For the combined Baseline and Randomization and Dose Treatment 
Periods, the incidence of TEAEs will also be presented by highest severity reported, 
closest relationship to SM reported, and the dose of SM at first occurrence.  For 
treatment-related TEAEs only, i.e., those TEAEs classified as possibly or definitely 
related to SM, the incidence rates will also be summarized as described previously for all 
TEAEs.  Listings (and tabular summaries, if warranted) of deaths, other SAEs, and other 
significant AEs, including AEs resulting in treatment discontinuation, will be provided. 
9.7.1.4.2. Laboratory Values 
By-visit tabular summaries of the laboratory test results will be presented.  For 
quantitative laboratory tests, both actual values and change from screening values will 
be summarized. 
Laboratory test results will be assigned an LNH classification according to whether the 
value was below (L), within (N), or above (H) the laboratory parameter’s reference 
ranges provided by the central laboratory.  Within treatment comparisons will be based 
 


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on 3 by 3 tables (shift tables) that, for a particular laboratory test, compare the LNH 
classification at screening to the LNH classification and the Final Visit. 
9.7.1.5. 
Vital Signs 
By-visit tabular summaries of the actual vital sign, height, and weight measurements and 
the changes from baseline will be presented. 
9.7.1.6. 
ECG Results 
By-visit tabular summaries of the quantitative ECG parameters and the overall ECG 
findings (normal, abnormal not clinically significant, or abnormal clinically significant) will 
be presented.  For the quantitative ECG parameters, both actual values and change 
from screening values will be summarized. 
9.7.1.7. 
Other Special Tests 
Findings from the physical examinations will be summarized through 2 by 2 shift tables 
that, for each system or area examined, compare the normal/abnormal finding at 
screening to the normal/abnormal finding at the Final Visit. 
9.7.2. Sample Size and Power Considerations 
Approximately 50 subjects (approximately 25 per treatment group) will be randomized in 
the study.  The sample size is not based on any statistical considerations, but it was 
judged adequate to provide safety, PK, and efficacy information for a proof-of-concept 
study.     
10.  PROCEDURES AND INSTRUCTIONS 
10.1.  Ethics and Good Clinical Practice 
The Investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described in the protocol and to adhere to the principles of ICH GCP to 
which the protocol conforms as well as all governing local regulations and principles for 
medical research. 
The protocol, informed consent, and appropriate related documents must be reviewed 
and approved by an IRB constituted and functioning in accordance with ICH E6, Section 
3, and any local regulations, i.e. Federal Regulations, Title 21 CFR Part 56.  
Documentation of IRB compliance with the ICH and any local regulations regarding 
constitution and review conduct will be provided to the Sponsor. 
A signed letter of study approval from the IRB Chairman must be sent to the Investigator 
with a copy to the Sponsor prior to study start and the release of any SM to the site by 
the Sponsor (or 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. 
 


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Study progress is to be reported to IRB annually (or as required) by the Investigator or 
Sponsor, depending on local regulatory obligations.  If the Investigator is required to 
report to the IRB, he/she will forward a copy to the Sponsor at the time of each periodic 
report.  SAEs should be reported to the IRB in accord with local regulatory requirements. 
10.2.  Subject Information and Informed Consent 
As part of administering the informed consent documents, the Investigator (or designee) 
must explain to each subject the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved, and any 
potential discomfort.  Each subject must be informed that participation in the study is 
voluntary and that he/she may withdraw from the study at any time and that withdrawal 
of consent will not affect his/her subsequent medical treatment or relationship with the 
treating physician.   
This informed consent should be given by means of a standard written statement, written 
in non-technical language.  The subject should understand the statement before signing 
and dating it and will be given a copy of the signed document.  If written consent is not 
possible, oral consent may be obtained if witnessed by at least one person not involved 
in the study.  The verbal consent will be documented and signed by the Investigator and 
the witness(s).  No subject can enter the study before his/her informed consent has been 
obtained.   
A separate ICF will be given for the optional PK substudy.  The above procedures will be 
followed in obtaining this consent. 
10.3.  Changes to the Protocol 
There are to be no changes to the protocol without written approval from the Sponsor.  
The protocol will be followed as written. 
Any change to the protocol requires a written protocol amendment or administrative 
change that must be approved by the Sponsor before implementation.  Amendments 
specifically affecting the safety of subjects, the scope of the investigation, or the 
scientific quality of the study require additional approval by the applicable IRBs.  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 must be notified promptly and the 
IRB for the site must be informed promptly. 
Changes affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB approval, but the IRB must be kept informed of such changes.  In 
these cases, the Sponsor will send a letter to the IRB detailing such changes. 
 


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10.4.  Adherence to the Protocol 
The Investigator will conduct the study in strict accordance with the protocol, which has 
been written to enable the Investigator’s compliance with ICH E6, Section 4, 
“Investigator Guideline for Good Clinical Practices”. 
There are to be no Investigator-initiated deviations from the protocol.  Any subject whose 
treatment deviates from the protocol or who is not qualified for study participation may 
be ineligible for analysis and may compromise the study.  On occasion, a subject whose 
medical condition does not exactly conform to the specifications of the protocol but who 
could potentially benefit from study participation may be considered for enrollment by the 
Sponsor if the Investigator first reviews the situation with the Medical Monitor.  In these 
cases, the potential subject’s participation will be discussed with the Sponsor personnel 
prior to having the subject sign the informed consent, and the exemption for study 
enrollment will be sent in writing to the investigational site by the Sponsor.  The 
investigational site will retain a copy of this document.  If the Investigator learns at any 
time after informed consent that a subject does not meet protocol specifications for study 
participation, he/she will call the Medical Monitor immediately. 
Subjects who have not signed an IRB approved ICF cannot receive SM. 
The Investigator and research team must comply with ICH E6 principles and all 
applicable local regulatory laws and regulations. 
10.5.  Retention of Records 
In accordance with applicable regulatory requirements, following closure of the study, 
the Investigator will maintain a copy of all site study records in a safe and secure 
location in the original format until at least 2 years after the last approval of a marketing 
application or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the SM. 
Essential documents include: 
• 
Signed informed consent documents for all subjects 
• 
Subject identification code list, screening log (if applicable) and enrollment log 
• 
Record of all communications between the Investigator and the IRB 
• 
Copies of CRFs and of documentation of corrections for all subjects 
• 
SM accountability records 
• 
All other source documents (subject medical records, hospital records, laboratory 
records, etc.) 
• 
All other documents as listed in Section 8 of the ICH E6 Guideline for GCP (Essential 
Documents for the Conduct of a Clinical Trial) 
Normally, these records will be held in the Investigator’s archives.  If the Investigator is 
unable to meet this obligation, he or she must ask the sponsor for permission to make 
alternative arrangements.  Details of these arrangements should be documented. 
 


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10.6.  Auditing Procedures 
In addition to the routine monitoring procedures, the Sponsor’s Corporate Quality 
Assurance department may conduct audits of clinical research activities in accordance 
with the Sponsor’s 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 
immediately that this request has been made. 
10.7.  Publication of Results 
Any presentation or publication of data collected as a direct or indirect result of this trial 
will be considered as a joint publication by the Investigator(s) and the appropriate 
personnel at the Sponsor’s site.  Authorship will be determined by mutual agreement.  
The study is being conducted as part of a multicenter clinical trial.  As stipulated in the 
protocol, data from all such sites shall be pooled and analyzed.  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, at least ninety (90) days 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). 
10.8.  Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the 
course of this study will be kept confidential by the Investigator, the Investigator’s staff, 
and IRB and will not be disclosed in whole or in part to others or used for any purpose 
other than reviewing or performing the study without the written consent of the Sponsor.  
No data collected as part of this study will be utilized in any written work, including 
publications, without the written consent of Sponsor.  These obligations of confidentiality 
and non-use shall in no way diminish such obligations as set forth in the Confidentiality 
Agreement between the Sponsor and the Investigator. 
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 (provided by the Sponsor). 
10.9.  Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative 
reasons at any time.  Reimbursement for expenses covering subjects, laboratory tests, 
and other professional fees will be made.  The Investigator will refund the excess of 
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The Investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  In such an event, final settlement of the grant-in-aid will be adjusted pro rata, 
and the Investigator will refund the excess of payments made in advance.  The 
Investigator will notify the IRB in case of study discontinuation.  Study records must be 
retained as noted above. 
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Age-related differences in kinetics and side effects of viloxazine in man and their clinical 
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Psychopharmacology (Berl). 1983;81(4):281-5. 
 
Altamura AC, Mauri MC, Guercetti G.  
Age, therapeutic "milieu" and clinical outcome in depressive patients treated with 
viloxazine: a study with plasma levels. 
Prog Neuropsychopharmacol Biol Psychiatry. 1986;10(1):67-75. 
 
Amaducci, L 
Multicentre studies with viloxazine (Vicilan) 
J Int Med Res. 1975; 3 (supp 3): 95-6 
 
Amin MM, Ban TA, Lehmann HE, Khan P. 
Viloxazine in the treatment of depression: psychophysical measures and clinical 
response.  
Psychopharmacol Bull. 1978 Jan;14(1):33-5.  
 
Arnsten AF. 
Stimulants: Therapeutic actions in ADHD. 
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Arnsten AF. 
Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: 
an important role fro prefrontal cortex dysfunction. 
CNS Drugs 2009;23 Suppl 1:33-41. 
 
Ban TA, McEvoy JP, Wilson WH. 
Viloxazine: a review of the literature.  
Int Pharmacopsychiatry. 1980;15(2):118-23. 
 
Bayliss PFC, Dewsbury AR, Donald JF, Harcup JW, Mayer M, Million R, Mola AL, 
Murphy JE, Plant B, Shaoul E (i.e. Bayliss et al., 1974a) 
A Double-Blind Controlled Trial of 'Vivalan' (Viloxazine Hydrochloride) and Imipramine 
Hydrochloride in the Treatment of Depression in General Practice 
J Int Med Res. 1974; 2:260-4  
 


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Bayliss PFC, Harcup JW, Mayer M, Million R, Murphy JE, Plant B, Shaoul E (i.e. Bayliss 
et al., 1974b) 
An Open Study of Two Dose Levels of 'Vivalan' (Viloxazine Hydrochloride ICI 58 834) in 
Depression in General Practice 
J Int Med Res. 1974; 2: 253-9 
 
Bayliss PF, Case DE. 
Blood level studies with viloxazine hydrochloride in man.  
Br J Clin Pharmacol. 1975 Jun;2(3):209-14. 
 
Botter PA. 
A double blind comparison of viloxazine and amitriptyline in involutional and endogenous 
depression.  
Acta Psychiatr Belg. 1979 Mar-Apr;79(2):198-209. 
 
Brion S, Chevalier JF. 
Long-term tolerance of viloxazine. 
Encephale. 1982;8(4):511-21. 
 
Brion S. 
Open studies with viloxazine 
J Int Med Res. 1975; 3 (supp 3): 87-91 
 
Brosnan RD, Busby AM, Holland RP. 
Cases of overdosage with viloxazine hydrochloride (Vivalan).  
J Int Med Res. 1976;4(2):83-5. 
 
Case DE, Reeves PR. 
The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans.  
Xenobiotica. 1975 Feb;5(2):113-29. 
 
Cassidy S, Henry J. 
Fatal toxicity of antidepressant drugs in overdose.  
Br Med J (Clin Res Ed). 1987 Oct 24;295(6605):1021-4.  
 
Cohen-Yavin I, Yoran-Hegesh R, Strous RD, Kotler M, Weizman A and Spivak B 
Efficacy of Reboxetine in the Treatment of Attention-Deficit/Hyperactivity Disorder in 
Boys With Intolerance to Methylphenidate: An Open-Label, 8-Week, Methylphenidate-
Controlled Trial 
Clinical Neuropharmacology, 2009; 32(4):179-182. 
 
Davids E, Zhang K, Kula NS, Tarazi FI, Baldessarini RJ. 
Effects of Norepinephrine and Serotonin Transporter Inhibitor on Hyperactivity Induced 
by Neonatal 6-Hydroxydopamine Lesioning in Rats. 
The Journal of Pharmacology and Experimental Therapeutics, 2002;301(3):1097-1102. 
 
 
 
 
 


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Davies B, Joshua S, Burrows G, Poynton C. 
A sequential trial of viloxazine (Vivalan) and imipramine in moderately depressed 
patients.  
Med J Aust. 1977 Apr 9;1(15):521-2. 
 
Dostal T, Kabes J. 
Intraindividual comparison of the antidepressant effectivity of viloxazine and maprotiline.  
Act Nerv Super (Praha). 1978 Dec;20(4):252-3.  
 
Edwards JG. (i.e. Edwards, 1977a) 
Viloxazine: an assessment of its potential rapid antidepressant action and unwanted 
effects.  
Curr Med Res Opin. 1977;5(3):226-33.  
 
Edwards JG. (i.e. Edwards, 1977b) 
Convulsive seizures and viloxazine.  
Br Med J. 1977 Jul 9;2(6079):96-7. 
 
Edwards JG, Glen-Bott M. 
Does viloxazine have epileptogenic properties?  
J Neurol Neurosurg Psychiatry. 1984 Sep;47(9):960-4.  
 
Elwan O. 
A comparative study of viloxazine and imipramine in the treatment of depressive states.  
J Int Med Res. 1980;8(1):7-17.  
 
Elwan O, Adam HK. 
Relationship between blood and cerebrospinal levels of the antidepressant agent 
viloxazine.  
Eur J Clin Pharmacol. 1980;17(3):179-82. 
 
Floru L, Czarny G, Tegeler J. 
Doubleblind study with the novel antidepressant viloxazine versus imipramine in 50 in-
patients (author's transl) 
Arzneimittelforschung. 1976;26(6):1170-1. 
 
Garnock-Jones KP, Keating GM.  
Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and 
adolescents. 
Pediatr Drugs 11 (3), 2009: 203-26. 
 
Garnock-Jones KP, Keating GM. 
Spotlight on Atomoxetine in Attention-Deficit Hyperactivity Disorder in Children and 
Adolescents. 
CNS Drugs 2010;24(1):85-88. 
 
Guy W, Ban TA, McEvoy JP, Petrie WM, Wilson WH, Schaffer JD. 
A collaborative study of a new antidepressant, viloxazine, in neurotic and endogenous 
depressives.  
Int Pharmacopsychiatry. 1982;17(1):36-42. 
 


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Guz I. 
Clinical and therapeutic trial with viloxazine (ICI 58,834), a new antidepressive drug, in 
43 depressed patients. 
Revista Brasilera Clinica Terapeutica 1974; 3:417 (Copy of reference unobtainable. Data 
taken from Pinder et al., 1974). 
 
Guz I. 
Open studies with viloxazine (Vicilan). 
J Int Med Res 1975; 3(3): 92.  
 
Additional studies – Japan 
Ichimaru I. 
J Int Med Res. 1975; 3 (supp 3): 97 
 
Kabes J, Nahunek K, Molcan J, Hynek K, Dostal T, Svestka J, Faltus F, Caplova T. 
The therapeutic effect of viloxazine (Vivalan ICI) in hospitalized depressive patients -- a 
multicenter study.  
Act Nerv Super (Praha). 1978 Dec;20(4):251-2.  
 
Kabes J, Dostal T, Nahunek K, Svestka J, Molcan J, Caplova T, Hynek K, Faltus F, 
Holland RP. 
Multicentre study with viloxazine (Vivalan) in depressed patients.  
Int Pharmacopsychiatry. 1980;15(4):228-39.  
 
Kiloh LG, Bartrop RW, Franklin JA, Neilson MD. 
A double blind comparative trial of viloxazine and amitriptyline in patients suffering from 
endogenous depression.  
Aust N Z J Psychiatry. 1979 Dec;13(4):357-60.  
 
Kurland AA, Nagaraju A. 
Viloxazine and the depressed schizophrenic--methodological issues.  
J Clin Pharmacol. 1981 Jan;21(1):37-41.  
 
Lennox, IG et al 
Viloxazine and amitriptyline in depressive illness. A double blind controlled trial in 
general practice.  
Practitioner. 1978 Jan;220(1315):153-6.  
 
Lomas DM. 
A comparative study of maprotiline (Ludiomil) and viloxazine in the management of 
depressed patients in General Practice. 
J Int Med Res. 1977; 5 (supp 4): 39-50 
 
Lopez Zanon A. 
Additional studies – Spain 
J Int Med Res. 1975; 3 (supp 3): 98 
 
 
 
 
 


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Magnus RV. 
A placebo controlled trial of viloxazine with and without tranquillizers in depressive 
illness.  
J Int Med Res. 1975;3 (supp. 3):207-13. 
 
Mahapatra SB. 
Short term effects of viloxazine (Vivalan) compared with placebo in depression. 
J Int Med Res. 1975;3 (supp. 3):70 
 
McCann BS, Roy-Byrne P, 
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McEvoy JP, Sheridan WF, Stewart WR Jr, Ban TA, Wilson WH, Guy W, Schaffer JD. 
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Br J Psychiat. 1980 Nov;137:440-3. 
 
McEvoy JP, Libiger J, Wilson WH, Ban TA, Berney S, Guy W. 
Viloxazine HCl in the treatment of endogenous depression: a standard (imipramine) 
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Melgar R, Lazzari A. 
Ensayo doble ciego cruzado entre un nuevo antidepresiv (viloxina) ICI 58.834 versus 
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Sem Med. 1975; 147: 633-8 
 
MHRA, 2007. Viloxazine data provided by the UK’s Medicines and Healthcare products 
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Moizeszowicz J, Subira S. 
Controlled trial of nomifensin (HOE 984) and viloxazine in the treatment of depression in 
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Mukherjee PK, Holland RP. 
Study of 'Vivalan' in geriatric patients suffering from depression.  
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Murphy JE 
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Pichot P, Guelfi J, Dreyfus JF. 
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and elderly patients.  
Int J Clin Pharmacol Ther Toxicol. 1985 May;23(5):270-3. 
 
Tsegos IK, Ekdawi MY. 
A double-blind controlled study of viloxazine and imipramine in depression.  
Curr Med Res Opin. 1974;2(8):455-60.  
 
Vandel B, Vandel S, Allers G, Volmat R. 
Clinical pharmacology of viloxazine hydrochloride.  
Pharmacopsychiatria. 1981 Mar;14(2):66-70. 
 
Von Knorring L. 
A double-blind trial: Vivalan against placebo in depressed elderly patients.  
J Int Med Res. 1980;8(1):18-21. 
 
 
 


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Wheatley D 
Viloxazine – a new antidepressant 
Curr Ther Res. 1974; 16 (8): 821-8 
 
Wheatley D 
Viloxazine (Vivalan) – a new antidepressant 
J Int Med Res. 1975; 3 (supp 3): 105-10 
 
Wigal SB. 
Efficacy 
and 
Safety 
Limitations 
of 
Attention-Defict 
Hyperactivity 
Disorder 
Pharmacotherapy in Children and Adults. 
CNS Drugs, 2009: 23 Suppl. 1:21-31.  
 


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12.  APPENDICES 
12.1.  Conners’ Adult ADHD Rating Scale (CAARS) 
12.1.1.  Investigator-Report 
 


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12.1.2.  Self-Report 
 


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12.2.  Clinical Global Impression (CGI) Scale 
 


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12.3.  Columbia-Suicide Severity Rating Scales (C-SSRS) 
12.3.1.  Baseline 
 


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12.3.2.  Since Last Visit 
 
 


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SAP_001.pdf: 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
09Feb2011 
812P201 
 
Version 2.0 
 
This document is confidential. It contains proprietary information of Supernus® Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited . 
Such information may be used solely for the purpose of reviewing or performing this study. 
COVER PAGE – STATISTICAL ANALYSIS PLAN (SAP) 
 
Protocol Number: 
812P201 
Title: 
A Phase I/IIa, Randomized, Double-Blind, Multicenter, Placebo-
Controlled, Parallel-Group Study of the Safety, and Efficacy of 
SPN-812V in Adults with Attention Deficit Hyperactivity Disorder 
(ADHD) 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
9715 Key West Avenue 
Rockville, MD 20850 
United States 
Phone: (301) 838-2500 
Fax: (240) 403-0065 
SAP Version: 
2.0 
Date: 
09Feb2011 
NCT: 
NCT01107496 


CONFIDENTIAL MATERIAL 
This material is the property of Supernus® Pharmaceuticals, Inc. 
and must not be disclosed or used except as authorized in writing by Supernus® Pharmaceuticals, Inc. 
 
 
 
 
 
 
SUPERNUS® PHARMACEUTICALS, INC. 
STATISTICAL ANALYSIS PLAN 
 
 
 Protocol Number: 812P201 
 
 
A Phase I/IIa, Randomized, Double-Blind, Multicenter, Placebo-Controlled, 
Parallel-Group Study of the Safety, and Efficacy of a Single Dose of SPN-
812V in Adults with Attention Deficit Hyperactivity Disorder (ADHD) 
 
 
Version: FINAL 2.0 
Date:   09 FEB 2011 




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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN.............................................................................................................. 1 
1. 
INTRODUCTION .............................................................................................................................. 7 
2. 
STUDY OBJECTIVES...................................................................................................................... 7 
2.1 
PRIMARY OBJECTIVE................................................................................................................7 
2.2 
SECONDARY OBJECTIVES.........................................................................................................7 
3. 
DESIGN OF THE STUDY ................................................................................................................ 7 
3.1 
STUDY DESIGN.................................................................................................................................... 7 
3.1.1 
Screening...................................................................................................................................... 8 
3.1.2 
Dosing Period....................................................................................................................8 
3.1.3 
End of Study Visit/Early Termination .................................................................................9 
3.1.4 
Pharmacokinetic Sampling................................................................................................9 
3.2 
SAMPLE SIZE CONSIDERATION........................................................................................................... 9 
3.3 
RANDOMIZATION PROCEDURE............................................................................................................ 9 
3.4 
SCHEDULE OF VISITS AND PROCEDURE............................................................................................. 9 
3.5 
EFFICACY MEASURES ............................................................................................................11 
3.5.1 
Primary Efficacy Measure ...............................................................................................11 
3.5.2 
Secondary Efficacy Measures.........................................................................................11 
3.6 
SAFETY MEASURES................................................................................................................11 
3.6.1 
Adverse Events..........................................................................................................................11 
3.6.2 
Clinical Laboratory Values........................................................................................................11 
3.6.3 
Vital Signs, Height, and Weight Measurements..............................................................12 
3.6.4 
Medical, Psychiatric History and Physical Examinations................................................12 
3.6.5 
Electrocardiograms (ECGs) ............................................................................................12 
3.6.6 
Prior and Concomitant Medications ................................................................................13 
3.7 
COMPLETION/DISCONTINUATION OF SUBJECTS........................................................................13 
4. 
DATA ANALYSIS............................................................................................................................ 13 
4.1 
SUBJECT DISPOSITION......................................................................................................................13 
4.2 
ANALYSIS POPULATIONS...................................................................................................................14 
4.3 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .........................................................................14 
4.4 
MEDICAL AND PSYCHIATRIC HISTORY ..............................................................................................15 
4.5 
TREATMENT COMPLIANCE AND EXPOSURE...............................................................................15 
4.6 
POTENTIAL EXCLUSIONS FROM ITT POPULATION .....................................................................15 
4.7 
BLIND DATA REVIEW...............................................................................................................16 
5. 
EFFICACY ANALYSES.................................................................................................................. 16 
5.1 
GENERAL CONSIDERATIONS AND STATISTICAL/ANALYTICAL ISSUES...........................................16 
5.1.1 
Definition of Baseline.......................................................................................................16 
5.1.2 
Treatment Comparisons..................................................................................................16 
5.1.3 
Pooling of Centers...........................................................................................................16 
5.1.4 
Multiple Comparisons/Multiplicity....................................................................................17 
5.1.5 
Examination of Subgroups ..............................................................................................17 
5.1.6 
Methods for Handling Dropouts or Missing Data ............................................................17 
5.2 
PRIMARY EFFICACY ANALYSIS.................................................................................................17 
5.3 
SECONDARY EFFICACY ANALYSES ..........................................................................................18 
5.3.1 
Investigator-Rated CAARS Total ADHD Symptom Score (150mg)....................................18 
5.3.2 
Global Improvement (CGI-I).....................................................................................................18 


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5.3.3 
Investigator-Rated CAARS Total ADHD Symptom Score (300mg)....................................18 
5.3.4 
Self-Rated CAARS Total ADHD Symptom Score .................................................................19 
5.4 
SENSITIVITY ANALYSIS............................................................................................................19 
5.5 
SUBGROUP ANALYSES............................................................................................................19 
6. 
SAFETY ANALYSES...................................................................................................................... 20 
6.1 
ADVERSE EVENTS..................................................................................................................20 
6.1.1 
Overall Study...................................................................................................................20 
6.1.2 
By Demographic/Baseline Variables...............................................................................20 
6.1.3 
Deaths, Serious AEs, and Other Significant AEs............................................................21 
6.2 
CLINICAL LABORATORY VALUES ..............................................................................................21 
6.3 
VITAL SIGNS, HEIGHT, WEIGHT AND BMI .................................................................................21 
6.4 
ECG RESULTS.......................................................................................................................21 
6.5 
PHYSICAL EXAMINATION .........................................................................................................21 
6.6 
PRIOR AND CONCOMITANT MEDICATIONS.................................................................................22 
6.7 
COLUMBIA – SUICIDE SEVERITY RATING SCALE (C-SSRS) ......................................................22 
7. 
PHARMACOKINETIC ANALYSIS................................................................................................. 22 
8. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ..................... 22 
9. 
PROGRAMMING SPECIFICATIONS............................................................................................ 22 
9.1 
FORMAT OF TABLES AND LISTINGS ..........................................................................................23 
9.1.1 
Title of a Table/Listing ...............................................................................................................23 
9.1.2 
Footnotes to a Table/Listing .....................................................................................................24 
9.1.3 
Header and Footer .................................................................................................................... 25 
9.2 
DATA FORMAT.................................................................................................................................... 25 
9.3 
CODING LISTS........................................................................................................................25 
10. 
SUMMARY TABLES, DATA LISTINGS AND FIGURES (TLFS)............................................. 25 
11. 
REFERENCES........................................................................................................................... 26 
12. 
FINAL VERSION REVISION HISTORY.................................................................................... 26 
13. 
APPENDICES ............................................................................................................................ 26 
13.1 
APPENDIX I: DATA REVIEW MEETING MINUTES................................................................................ 26 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
ADHD 
Attention Deficit Hyperactivity Disorder  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical  
AUC 
area under the plasma concentration versus time curve 
BUN 
blood urea nitrogen 
CAARS 
Conners’ Adult ADHD Rating Scale 
CAADID 
Conners’ Adult ADHD Diagnostic Interview for DSM-IV 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression 
CGI-S 
Clinical Global Impression – Severity of Illness 
CGI-I  
Clinical Global Impression – Global Improvement 
CL/F 
apparent oral clearance 
CRA 
Clinical Research Associate 
CRF  
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scales 
CRO 
Contract Research Organization 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders – Text Revision 
ECG 
electrocardiogram 
FOCP 
Females of Childbearing Potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
HR 
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
ITT 
intent to treat 
LNH 
Low, normal, high 
MedDRA 
Medical Dictionary for Regulatory Activities  
PK 
pharmacokinetic 
PK-PD  
pharmacokinetic-pharmacodynamic 
PO 
orally 
PR  
Interval from the P wave (atrial contraction or depolarization) to the onset of 
the Q wave in the measurement of electrical activity of the myocardium 
QRS 
QRS complex refers to ventricular depolarization in the measurement of 
electrical activity of the myocardium 
QT 
Interval from ventricular depolarization and repolarization in the measurement 
of electrical activity of the myocardium 
QTc 
QT, corrected 
QTcF 
QT corrected using Fridericia's method 
RBC 
red blood cell 
SAE 
serious adverse event 
SM 
study medication 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 


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TEAE 
treatment-emergent adverse event 
TID 
three times per day 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WHO DD 
World Health Organization Drug Dictionary 
 
 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to reasonably ensure that the tables, 
data listings and figures which will be produced, and statistical methodologies that will be 
used, are complete and allow for the arrival at valid conclusions regarding the study 
objectives. In the development of this SAP, the following documents were used: 
 
• 
The Final Protocol 812P201, Version 2.0, 30 June 2010 
• 
eCRF Screen Shots – Phase 1 (Received from Emphusion on 22 June 2010) 
• 
eCRF Screen Shots – Phase 2 (Received from Emphusion on 08 July 2010) 
• 
eCRF and Database Specifications, Version 1.2 (24 August 2010). 
 
2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective is to evaluate the safety of SPN-812V in adults with ADHD. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are: 
• 
To determine the efficacy and of SPN-812V in adults with ADHD  
• 
To explore the single dose and steady state pharmacokinetics of SPN-812V in adults 
with ADHD. 
3. 
DESIGN OF THE STUDY  
3.1 
STUDY DESIGN 
This will be a multicenter, randomized, double-blind, placebo-controlled, parallel group study 
of the safety and efficacy of SPN-812V in adults with ADHD.  The target subjects are male 
or female adults aged 18 to 64 years, inclusive, with a diagnosis of ADHD.  A total of fifty 
subjects will be enrolled at approximately 5 sites in the US.  Subjects will be randomized 
(1:1) to one of two treatment groups, SPN-812V or placebo. 
The study will consist of a Screening Period (within 14 days prior to randomization) and a 
Dosing Period of 6 weeks.  The total subject duration in the study will be up to 8 weeks as 
illustrated in Figure 1. 
 
 




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3.1.3 
End of Study Visit/Early Termination 
At the end of Visit 8, or prior to early discontinuation, subjects will undergo end of study 
assessments.  AEs will be monitored, and safety tests and efficacy scales will be 
administered unless assessments were performed earlier in the visit.  Subjects will return 
any unused capsules and undergo safety and efficacy evaluations if not already performed 
as part of that visit. 
3.1.4 
Pharmacokinetic Sampling 
On the final visit, there is an optional PK day.  All subjects who wish to participate will be 
dosed with active SM after an overnight fast and after all efficacy assessments are 
completed, Blood will be drawn for quantitative PK analysis according to the following 
schedule (all times +/- 30 minutes):  Pre-dose and ½, 1, 2, 3, 4, 5, and 6 hours post-dose. 
3.2 
SAMPLE SIZE CONSIDERATION 
Approximately 50 subjects (approximately 25 per treatment group) will be randomized in the 
study.  The sample size is not based on any statistical considerations, but it was judged 
adequate to provide safety, PK, and efficacy information for a proof-of-concept study.     
3.3 
RANDOMIZATION PROCEDURE 
The randomization for this study will be managed centrally by an IVRS vendor; specific 
instructions to conduct subject randomization will be provided in a separate document to all 
investigational sites, along with site staff access to the system. 
Upon admission to the study, subjects will be assigned a 4-digit screening number, in the 
order that they are entered.  Subjects who subsequently meet all eligibility criteria will be 
assigned a 6-digit randomization number.  The first 3 digits will refer to the site, and the last 
3 will refer to the subject-specific number, which will be assigned according to the 
randomization scheme. 
 
3.4 
SCHEDULE OF VISITS AND PROCEDURE 
All subjects who are randomized and take any SM will be followed according to the protocol, 
unless consent for follow-up is withdrawn.  The Sponsor, or the Sponsor’s designee, must 
be notified of all deviations from the protocol visits or procedures and these procedures, if 
applicable, will be rescheduled or performed at the nearest possible time to the original 
schedule. 
The exhibit on the next page presents the schedule of visits and procedures for the study 
(Table 1). 
 




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3.5 
EFFICACY MEASURES 
3.5.1 
Primary Efficacy Measure 
The primary efficacy measure is the investigator-rated CAARS Total ADHD Symptom Score 
which is the sum of the Inattention and Hyperactivity/Impulsivity subscales (18 items rated 
on 4-point scale: 0, 1, 2 and 3). 
3.5.2 
Secondary Efficacy Measures 
The secondary efficacy measures are: 
• 
Clinical Global Impression – Improvement (CGI-I)  
• 
Self-rated Conners’ Adult ADHD Rating Scale (CAARS).  This assessment will be 
administered at study Visits 2 and 8. 
 
3.6 
SAFETY MEASURES 
Safety measures during the study will consist of AE and SAE monitoring, clinical laboratory 
tests, vital signs, physical examinations, and 12-lead ECGs.  
3.6.1 
Adverse Events 
For subjects who receive SM, all AEs will be collected starting from providing informed 
consent for study participation.  All AEs will be collected on the AE Case Report Form 
(CRF).  SAEs will be reported if the Investigator believes the event is at least possibly 
related to SM.  Investigator will assess the severity and the causality of AEs.  
A cluster of signs and symptoms that results from a single cause should be reported as a 
single AE (e.g., fever, elevated WBC, cough, abnormal chest X-ray, etc. can all be reported 
as “pneumonia”). 
3.6.2 
Clinical Laboratory Values 
The Schedule of Visits and Procedures shows the time points at which blood and urine will 
be collected for clinical laboratory tests.  Laboratory tests should be performed under fasting 
conditions.  Any laboratory abnormality may qualify as an AE in the Investigator’s judgment.  
A complete list of all clinical laboratory assessments is presented in Table 2. 
For subjects who participate in the optional PK portion of the study, a total of approximately 
32mL (8 PK blood draws × 4mL) of blood/subject will be taken during the course of the study 
for the purpose of PK samples, in addition to 30mL (2 blood draws for clinical chemistry × 
15mL) required for laboratory tests for all subjects.   
 
 
 
 
 


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Table 2. 
Clinical Laboratory Assessments 
Hematology 
Serum Chemistry  
Urinalysis 
Hematocrit 
Hemoglobin 
Red blood cell count (RBC) 
Platelet count 
White blood cell count (WBC) (with 
differential) 
 
Albumin 
Alkaline phosphatase 
Alanine transaminase (ALT) 
Aspartate transaminase (AST) 
Bilirubin- Total and Direct 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Cholesterol- Total, HDL and LDL 
Creatinine 
Creatine phosphokinase (CPK) 
Gamma-glutamyl transpeptidase (GGT) 
Glucose 
Inorganic phosphorous 
Potassium 
Sodium 
Total protein 
Triglycerides 
Uric acid 
Ketones 
Protein 
Specific gravity 
Glucose 
pH 
 
Other tests 
Urine drug panel for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, marijuana/cannabinoids, 
methadone, opiates, phencyclidine, propoxyphene, and alcohol) 
Urine pregnancy test (for FOCP) 
CYP2D6 enzyme activity (poor, intermediate and ultra rapid metabolizers)  
 
3.6.3 
Vital Signs, Height, and Weight Measurements 
Vital sign measurements (HR, blood pressure, temperature, and respiratory rate) will be 
obtained at all visits as designated on the Schedule of Visits and Procedures (Table 1).  
Blood pressure and pulse will be measured after the subject has been sitting for 5 minutes.  
Height and weight will be obtained at the Screening Visit and weight will be collected at all 
visits as designated on the Schedule of Visits and Procedures (Table 1). 
3.6.4 
Medical, Psychiatric History and Physical Examinations  
Medical and psychiatric history, including smoking history, will be taken at the Screening 
Visit.  Physical examinations will be performed at the Screening Visit and Final Visit as 
designated on the Schedule of Visits and Procedures (Table 1). 
3.6.5 
Electrocardiograms (ECGs)  
ECGs (12-lead) will be obtained at the Screening Visit, Visit 4, and the Final Visit as 
designated on the Schedule of Visits and Procedures (Table 1).  Additional ECGs may be 
performed at other times if deemed necessary. 
The ECG will be recorded while the subject is resting in a supine position.  The ECG will 
electronically measure the PR, QRS, QT, and QTc intervals, and heart rate.  QTc will be 
reported as QTcF (QT corrected using Fridericia's method). 


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3.6.6 
Prior and Concomitant Medications 
For subjects who receive SM, prior and concomitant medications and therapies that are 
ongoing as of the date of informed consent will be recorded on the Concomitant Medication 
CRF.  The Investigator will record all concomitant medications, including over-the-counter 
medications, on the Concomitant Medication CRF.  The Investigator will record the AE for 
which the concomitant medication was administered on the AE CRF. 
3.7 
COMPLETION/DISCONTINUATION OF SUBJECTS 
Subjects will be permitted to leave the study at any time.  Subjects can be withdrawn from 
the study in any of the following circumstances: 
• SAE or an AE 
• Administrative reasons (e.g., sponsor decision) 
• Withdrawal of consent/assent 
• If the subject becomes pregnant  
• If it is in the best interest of the subject, in the opinion of the Investigator 
• Termination of the study. 
If a subject is prematurely discontinued from participation in the study for any reason after 
SM administration, the Investigator must make every effort to perform the Final Visit 
assessments. 
4. 
DATA ANALYSIS 
Tabular summaries of the data collected during the study will be presented to provide a 
general description of the subjects studied and an overview of the efficacy and safety 
results.  Data from all sites will be combined in the computation of these summaries, and 
summaries will be presented by treatment group.  All subjects randomized to SPN-812V 
300mg/day group, whether they are maintained on 300mg or reduced to 150mg, will be 
analyzed under the SPN-812V 300mg/day group.  Continuous variables will be summarized 
using descriptive statistics (number of subjects, mean, standard deviation [SD], median, and 
minimum and maximum values).  Categorical (nominal) variables will be summarized using 
frequency tables (number and percentage of subjects in each category).  If some values are 
missing, the percentages will sum to less than 100%.  
 
In addition to tabular summaries, subject data listings will be provided.  All data collected on 
eCRF and from central laboratory will be presented in data listings.  Where appropriate, data 
will be summarized for each protocol-specified visit.  Unscheduled data will be listed and 
included in the Last Observation Carried Forward (LOCF) analysis. 
 
4.1 
SUBJECT DISPOSITION  
Subject disposition will be summarized by treatment group and by all randomized subjects.  
The summary will include 
• 
number of subjects randomized 


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• 
number of subjects completed the study 
• 
number of subjects discontinued from the study. 
Reasons for discontinuation will be summarized by randomized treatment group for all 
randomized subjects.  Table 14.1.1 provides the subject disposition for all screened subjects. 
Listing 16.2.1.1 provides screen failures for all screened subjects.  Listing 16.2.1.2 provides 
subject disposition for all randomized subjects.  
4.2 
ANALYSIS POPULATIONS 
The population of “All Screened Subjects” will contain all those subjects who entered the 
screening period to determine their eligibility to participate in the study. 
The population of “All Randomized Subjects” will contain all those screened subjects who 
meet the requirements for study participation and are randomized, using a centralized 
randomization system, to either SPN-812V or placebo.   
The “Intent-to-Treat (ITT) Population” consists of all randomized subjects who took at least 
one dose of SM, had baseline efficacy assessment and had at least one post-baseline 
efficacy assessment.  The ITT population is the primary population for the efficacy analysis.   
The “Restricted ITT Population” consists of all ITT population subjects with at least 1 efficacy 
assessment after three weeks of treatment. 
The ITT and Restricted ITT populations will be analyzed according to treatment assigned.  
All subjects randomized to SPN-812V 300mg/day group, whether they are maintained on 
300mg or reduced to 150mg, will be analyzed under the SPN-812V 300mg/day group. 
The “Safety Population” consists of all randomized subjects who receive at least 1 dose of 
SM. 
The PK population consists of all safety subjects who consented to participate in the optional 
PK sub study and had at least one evaluable (non-BLQ) PK sample drawn. 
The safety and PK populations are based on actual treatment received.   
Table 14.1.2 provides these analysis populations for all randomized subjects.   
Listing 16.2.2 provides inclusion and exclusion criteria violations for all randomized subjects.  
Listing 16.2.3 gives analysis populations.   
4.3 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Subject demographic and baseline characteristics data will be summarized by treatment 
group for the safety, ITT, and restricted ITT populations.  
Demographic information (Sex, Race, Ethnicity and Age) will be listed (Listing 16.2.4).  
Height, weight and BMI will be listed with vital signs (Listing 16.2.9) where height is 
measured at screening only.  Descriptive statistics will be obtained for the continuous 
variables: age, height, weight and BMI (Table 14.1.3.1.1 through 14.1.3.1.3).  Frequencies 
and percentage of subjects will be tabulated for the categorical variables: sex, race and 


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ethnicity (Table 14.1.3.2.1 through 14.1.3.2.3).   
To calculate age, the following formula will be used: 
Age (years) = INT { (date of screening – date of birth) / 365.25 }. 
 
4.4 
MEDICAL AND PSYCHIATRIC HISTORY 
Medical and psychiatric history data recorded prior to dosing will be listed by subject for the 
safety population. Only those body systems where a condition or abnormality has been 
reported will be listed (Listing 16.2.5.1 and 16.2.5.2). 
The diagnoses present in subjects’ medical history and the duration of those medical 
conditions will be presented by treatment group in Table 14.1.3.3.  If start date is incomplete 
or missing, date of informed consent will be used for imputing the duration. 
4.5 
TREATMENT COMPLIANCE AND EXPOSURE 
Tabular summaries of the compliance rate and duration of treatment exposure to SM will be 
presented for the safety population by treatment group.  Summary of treatment compliance 
and exposure will be provided separately for the first week of start-up dose (Baseline and 
Randomization Period), study maintenance dose period (Study Dose Treatment Phase), and 
combined Baseline and Randomization and Study Dose Treatment Phase (Table 14.1.4.1).  
Listing 16.2.5.3 provides the compliance data. 
The number and percentage of subjects maintained on the target dose (300mg) versus 
those reduced in dose (150mg) during the Study Dose Treatment Phase will be provided 
(Table 14.1.4.2). 
4.6 
POTENTIAL EXCLUSIONS FROM ITT POPULATION 
Study data will be examined during the Blind Data Review (described below in section 4.7) 
for potential exclusions from ITT population.  ICH E9 guideline outlines circumstances where 
it will usually be acceptable to omit subjects from the ITT population without causing bias.  
Some of the potential exclusions in this study are: 
 
• 
Subjects who violate the inclusion/exclusion criteria; 
• 
Subjects who fail to take at least one dose of study medication; 
• 
Subjects who do not provide any post-baseline data; 
• 
Enrollment of a subject who did not meet all inclusion/exclusion criteria which would 
affect subject safety or would negatively impact data integrity; 
• 
Use of any prohibited concomitant medication that may confound study results; 
• 
Subject dosing error that results in a serious adverse event; 
• 
Having any non-compliance issues raised by the investigator or sponsor prior to 
breaking the blind;  
• 
Study visit or procedure conducted outside of required time frame that may 
negatively affect subject safety; 
• 
Subject visit/procedure falls outside of the window of time indicated by the protocol 


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resulting in increased potential for risk to the subject or any damage to the integrity or 
completeness of the data. 
 
4.7 
BLIND DATA REVIEW  
The checking and assessment of data to revisit the proposed methods of statistical analysis 
for the purpose of finalizing the planned analysis prior to the database lock will be 
conducted.  The following lists some of the aspects of analysis that would be considered: 
 
• 
Checking of data for potential exclusions from ITT population; 
• 
Precise definitions of analysis populations, especially which subjects will be included 
and which will be excluded; 
• 
Handling of missing data; 
• 
Outlier identification and specific decisions taken on how these will be handled. 
 
The data review will be documented in agreed and signed meeting minutes, which will 
include a version of Listing 16.2.3 as appendix.  The blind data review meeting minutes will 
be included in Appendix 13.1. 
5. 
EFFICACY ANALYSES 
Efficacy analyses will be conducted for the ITT population.  Where appropriate, a restricted 
ITT population may also be used.   
Descriptive statistics will be presented for all efficacy variables by visit and treatment group.  
All significance tests will be performed at the 0.05 level. 
5.1 
GENERAL CONSIDERATIONS AND STATISTICAL/ANALYTICAL ISSUES 
5.1.1 
Definition of Baseline 
Unless stated otherwise, subject’s Visit 2 will be considered as Baseline for statistical 
analyses.  If subject’s Visit 2 assessment is missing, the last available value on or prior to 
the first study dose date will be used as baseline.  
 
5.1.2 
Treatment Comparisons 
Statistical testing to compare treatment groups will be performed for the ITT population only 
using appropriate statistical methods, as described in the efficacy subsections below.  Given 
the small per-treatment group sample size for the study, the resulting p-values from the 
statistical testing will be used for descriptive purposes only (i.e., not for inferential purposes), 
primarily as an aid in the clinical interpretation of the efficacy results.   
5.1.3 
Pooling of Centers 
As sample size per center will be small, all the centers will be pooled together for the 
analysis. 


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5.1.4 
Multiple Comparisons/Multiplicity 
Treatment comparisons will be performed at Visit 3 through Visit 8 but without adjustment for 
multiple comparisons as sample size is small and is not based on any power calculations.  
P-values will be used only for interpretation. 
5.1.5 
Examination of Subgroups 
Subgroup analyses for efficacy will be performed on categories of the following measures: 
• 
Sex 
• 
Race 
for the ITT population for the investigator-rated CAARS Total ADHD Symptom Score.  
Subgroup analyses will also be carried out for 
• 
investigator-rated CAARS inattention subscale score 
• 
investigator-rated CAARS hyperactivity/impulsivity subscale score. 
Investigator-rated CAARS inattention subscale score has 9 items (1, 9, 13, 14, 19, 21, 26, 
29 and 30) and investigator-rated CAARS hyperactivity/impulsivity subscale score has 9 
items (2, 4, 6, 8, 16, 18, 22, 25 and 27).  These two subscales together make up the CAARS 
Total ADHD Symptom Score. 
5.1.6 
Methods for Handling Dropouts or Missing Data 
Subjects who discontinue the study without post-randomization scores will not be included in 
the analysis of efficacy variables.  Last observation carried forward (LOCF) technique will be 
used in the efficacy analysis for subjects who discontinue the study with post-randomization 
scores where last observation carried forward will be the last non-missing observation on 
scheduled or unscheduled visits.  
If more than one item of a subscale is missing, the score for the subscale (and the total 
score) will also be considered missing.  If only a single item is missing, the mean score for 
all other items in the subscale will be imputed as the score for the missing item. 
5.2 
PRIMARY EFFICACY ANALYSIS 
The primary efficacy measure is the investigator-rated CAARS Total ADHD Symptom Score 
which is the sum of the Inattention and Hyperactivity/Impulsivity subscales (18 item 
measured on 4-point scale). 
The changes from baseline to endpoint (Visit 8) in the investigator-rated CAARS Total 
ADHD Symptom Scores will be compared between the SPN-812V 300mg/day group and 
placebo using the two-sample t-test if normality assumption is satisfied.   
In case of non-normality of scores, Wilcoxon rank-sum test will be used.  The Hodges-
Lehmann estimate and associated 95% confidence interval will be calculated for the median 
difference between treatments.   


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Tables 14.2.1.1 and 14.2.1.2 provide the primary efficacy results for ITT and restricted ITT 
populations respectively.  Figures 14.2.1.3 and 14.2.1.4 provide visit-wise mean change 
from baseline in investigator-rated CAARS Total ADHD Symptom Score for the two 
treatments for ITT and restricted ITT populations respectively.  Figures 14.2.1.5 and 14.2.1.6 
provide cumulative proportion of subjects against change from baseline to the end of study 
(Visit 8) in investigator-rated CAARS Total ADHD Symptom Score for the two treatments for 
ITT and restricted ITT populations respectively.  Listing 16.2.6.1 provides the investigator-
rated CAARS Total ADHD Symptom Score data for the ITT population.   
5.3 
SECONDARY EFFICACY ANALYSES 
For the analysis of secondary efficacy variables, no statistical adjustment to the level of 
significance will be made for multiple endpoints and/or multiple comparisons. 
The secondary efficacy analyses for various secondary efficacy measures are as follows. 
5.3.1 
Investigator-Rated CAARS Total ADHD Symptom Score (150mg) 
Initial efficacy of SPN-812V starting dose (150 mg/day) when compared to placebo as 
measured by changes in the investigator-rated CAARS Total ADHD Symptom Score from 
baseline at week 1 of treatment with starting dose will be analyzed with two-sample t-test if 
normality assumption is satisfied.   
In case of non-normality of scores, Wilcoxon rank-sum test will be used.  The Hodges-
Lehmann estimate and associated 95% confidence interval will be calculated for the median 
difference between treatments.   
Table 14.2.2.1 provides the secondary efficacy results for ITT population for the investigator-
rated CAARS Total ADHD Symptom Score at week 1. 
5.3.2 
Global Improvement (CGI-I) 
Actual CGI-I scores at each post-baseline visit and endpoint will be compared among 
treatment groups using two-sample t-test if normality assumption is satisfied.   
In case of non-normality of scores, Wilcoxon rank-sum test will be used.  The Hodges-
Lehmann estimate and associated 95% confidence interval will be calculated for the median 
difference between treatments.   
Tables 14.2.2.2.1 and 14.2.2.2.2 provide secondary efficacy results for CGI-I for the ITT and 
restricted ITT populations.  Tables 14.2.2.2.3 and 14.2.2.2.4 provide the number and 
percentage of subjects with CGI-I < 3 at the end of study (EOS) for the two treatment groups 
for the ITT and restricted ITT populations respectively.  Listing 16.2.6.2.1 provides CGI-S 
and CGI-I data for the ITT population.   
5.3.3 
Investigator-Rated CAARS Total ADHD Symptom Score (300mg) 
The changes from baseline in the investigator-rated CAARS Total ADHD Symptom Scores 
will be compared between the two treatment groups for the Visit 4, 5, 6, 7 and 8 using the 
two-sample t-test if normality assumption is satisfied.   


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In case of non-normality of scores, Wilcoxon rank-sum test will be used.  The Hodges-
Lehmann estimate and associated 95% confidence interval will be calculated for the median 
difference between treatments at Visits 4, 5, 6, 7 and 8.   
Tables14.2.2.3.1 and 14.2.2.3.2 provide the secondary efficacy results for ITT and restricted 
ITT populations for the investigator-rated CAARS Total ADHD Symptom Scores at Visits 4, 
5, 6, 7 and 8.  Listing 16.2.6.1 provides the investigator-rated CAARS Total ADHD Symptom 
Score data for the ITT population.   
5.3.4 
Self-Rated CAARS Total ADHD Symptom Score  
The changes from baseline at endpoint (Visit 8) in the self-rated CAARS Total ADHD 
Symptom Scores will be compared between the SPN-812V 300mg/day group and placebo 
using the two-sample t-test if normality assumption is satisfied.   
In case of non-normality of scores, Wilcoxon rank-sum test will be used.  The Hodges-
Lehmann estimate and associated 95% confidence interval will be calculated for the median 
difference between treatments.   
Table 14.2.2.4 provides the secondary efficacy results for ITT population for the self-rated 
CAARS Total ADHD Symptom Scores.  Listing 16.2.6.2.2 provides the self-rated CAARS 
Total ADHD Symptom Score data for the ITT population.   
 
5.4 
SENSITIVITY ANALYSIS 
To confirm the results (sensitivity analysis), a mixed model repeated measures (MMRM) 
analysis will be conducted.  MMRM analysis will contain fixed effect terms for treatment, 
investigative site, visit, and interaction between treatment and visit.  Visit will be used as 
repeated measure.  The model will include change from baseline of the investigator-rated 
CAARS Total ADHD Symptom Score as the dependent variable with a random patient effect 
and baseline investigator-rated CAARS Total ADHD Symptom Score as a covariate and will 
use an auto regressive (1) covariance. 
Table 14.2.3 provides the sensitivity analysis results for the investigator-rated CAARS Total 
ADHD Symptom Score for the ITT population. 
5.5 
SUBGROUP ANALYSES 
Subgroup analyses for efficacy will be performed on categories of the following measures: 
• 
Sex 
• 
Race 
for the ITT population for the investigator-rated CAARS Total ADHD Symptom Score.   
Subgroup analyses will also be carried out for 
• 
investigator-rated CAARS inattention subscale score 
• 
investigator-rated CAARS hyperactivity/impulsivity subscale score. 
Investigator-rated CAARS inattention subscale score has 9 items (1, 9, 13, 14, 19, 21, 26, 
29 and 30) and investigator-rated CAARS hyperactivity/impulsivity subscale score has 9 
items (2, 4, 6, 8, 16, 18, 22, 25 and 27). 


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Table 14.2.4.1 will have results for sex.  Table 14.2.4.2 will have results for race.  Table 
14.2.4.3 will have results for the components of the primary efficacy measure, namely, 
investigator-rated CAARS inattention and hyperactivity/impulsivity subscale scores. 
6. 
SAFETY ANALYSES 
The safety and tolerability endpoints will be summarized for the safety population according 
to the treatment actually received.  Statistical testing will be performed for some of the safety 
endpoints, but the resulting p-values will be used for descriptive purposes only. 
 
Safety will be assessed by the monitoring of AEs, vital signs, clinical laboratory tests, 
physical examinations, and electrocardiograms (ECG). 
6.1 
ADVERSE EVENTS 
 
AEs will be classified into standardized medical terminology from the verbatim description 
(Investigator term) using the Medical Dictionary for Regulatory Activities (MedDRA).  
Although a MedDRA term for a subject may be reported more than once, that subject will be 
counted only once in the incidence count for that MedDRA term.  AEs will be presented in 
the summary tables by preferred term nested within System Organ Class.   
Verbatim description and all MedDRA level terms, including the lower level terms, for all AEs 
will be contained in the subject data listings (Listing 16.2.7.1). 
6.1.1 
Overall Study 
Adverse events that occur or worsen after the first administration of study medication are 
considered treatment-emergent and will be summarized in tables. For missing information, 
the most conservative interpretation will be assumed.  For example, if AE onset time is not 
collected, the AE starts on the first study dose date. 
AEs will be summarized for each treatment group by presenting the incidence of AEs based 
on the number and percentage of subjects with AEs.   
Table 14.3.1.1.1 will provide overall incidence of AEs for the Safety population.  Table 
14.3.1.1.2 will provide an incidence summary of AEs by System Organ Class, and Preferred 
Term for the Safety population.   
Table 14.3.1.1.3 will provide an incidence summary of AEs by System Organ Class, 
Preferred Term, and Relationship to Study Drug for the Safety population.  If a subject had 
two or more adverse events in the same system organ class (or with the same preferred 
term) with different relationships to study drug, then the event with the closest relationship to 
study drug will be used for that subject. 
Table 14.3.1.1.4 will provide an incidence summary of AEs by System Organ Class, 
Preferred Term, and Severity for the Safety population.  If a subject had two or more adverse 
events in the same system organ class (or with the same preferred term) with different levels 
of severity, then the event with the worst severity will be used for that subject.   
6.1.2 
By Demographic/Baseline Variables 
Tables similar to those for the Overall Study (14.3.1.1.1 – 14.3.1.1.4) will be presented for 
the demographic/baseline variables:  Sex – Tables 14.3.1.2.1 – 14.3.1.2.4, Race – Tables 


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14.3.1.2.5 – 14.3.1.2.8, Ethnicity – Tables 14.3.1.2.9 – 14.3.1.2.12. 
6.1.3 
Deaths, Serious AEs, and Other Significant AEs 
Listings (and tabular summaries, if warranted) of deaths, SAEs, and other significant AEs, 
including AEs resulting in treatment discontinuation, study drug dose reduction, and study 
drug interruption will be provided (Listings 16.2.7.2.1 through 16.2.7.2.5). 
6.2 
CLINICAL LABORATORY VALUES 
Table summaries and by-patient listings of the laboratory test results will be presented.  
Laboratory testing will be broken down by Hematology, Serum Chemistry, and Urinalysis 
tests.  Tables 14.3.2.1 through 14.3.2.4 will provide summaries for Hematology and Serum 
Chemistry respectively and associated shift tables.  Listings 16.2.8.1 through 16.2.8.6 will 
provide by-patient listing for hematology, serum chemistry, urinalysis, CYP2D6 enzymes, 
urine drug test, and urine pregnancy tests respectively. 
6.3 
VITAL SIGNS, HEIGHT, WEIGHT AND BMI 
Summary table of vital signs (HR, blood pressure, temperature, respiratory rate) and height 
and weight will be presented by treatment and by visit. This summary table will also include 
change from baseline by treatment and visit.  Descriptive summary statistics (mean, SD, 
median, and range) for vital sign data and height and weight will be evaluated by treatment 
group.  Table 14.3.4 provides the summary table for vital signs, heights, weights and BMI. 
Individual listings will also be provided for these parameters (Listing 16.2.9).   
6.4 
ECG RESULTS 
Table 14.3.5.1 provides overall ECG findings (normal, abnormal not clinically significant, or 
abnormal clinically significant).  Table 14.3.5.2 summarizes ECG results (both actual values 
and change from baseline values) by visit by treatment group using descriptive statistics for 
quantitative ECG parameters: PR Interval (msec), QRS Duration (msec), QT Interval (msec), 
and QTcF Interval (msec).  Table 14.3.5.3 presents the ECG Shift Table from Baseline to 
Post-Baseline Visits for qualitative ECG parameters. 
Table 14.3.5.4 provides the number and percentage of subjects with any QTcF value 
including  >= 500 msec for all assessments made during the study as well as by scheduled 
collection and treatment group.   This table also provides the number and percentage of 
subjects with any change from baseline in the QTcF value including >= 60 msec over all 
assessments made during the study as well as by visit and treatment group.  This table is 
constructed to identify outliers. 
Listing 16.2.10 provides ECG Findings. 
6.5 
PHYSICAL EXAMINATION 
Findings from the physical examinations will be summarized through shift tables that, for 
each system or area examined, compare the normal/abnormal finding at Baseline to the 
normal/abnormal finding at the Final Visit. Table 14.3.6 gives the results of physical 
examination. Listing 16.2.11 provides physical examination findings.  


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6.6 
PRIOR AND CONCOMITANT MEDICATIONS 
A table (Table 14.3.7) summarizing frequencies of prior and current use of concomitant 
medications will be presented for the safety population and its treatment group subsets. 
Prior and Concomitant medications and therapies that are ongoing as of the date of 
informed consent and all medications taken since the time of dosing of SM until the end of 
the study (the last visit) will be listed (Listing 16.2.12).  If non-SM’s taken time is not 
collected, the medication taken on and after the first dose date of SM until the end of study 
will be listed.  Concomitant medications will be assigned an 11-digit code using the WHO 
Drug Dictionary (WHO DD) drug codes.  Concomitant medications will be further coded to 
the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating therapeutic 
classification.   
 
6.7 
COLUMBIA – SUICIDE SEVERITY RATING SCALE (C-SSRS) 
A table (Table 14.3.8) summarizing frequencies of Suicidal Ideation and Behavior at 
Baseline and During the Trial will be presented for the safety population and its treatment 
group subsets.  P-values will be calculated using Fisher’s Exact Test for interpretation 
purposes.  Listings 16.2.13.1 and 16.2.13.2 will provide C-SSRS Baseline values and During 
the Trial (Since Last Visit Version) values respectively for the Safety Population.  Histograms 
displaying highest level of Suicidal Ideation (Figure 16.2.13.3) and Suicidal Behavior (Figure 
16.2.13.4) respectively against their categories for the two treatment groups will be 
constructed. 
7. 
PHARMACOKINETIC ANALYSIS 
Population PK data will be pooled across the PK populations and analyzed using nonlinear 
mixed-effects modeling methods.  The objective of the population PK analyses is to derive 
individual-specific estimates of apparent oral clearance (CL/F) but not to fully characterize 
the PK of this formulation of SPN-812V.  
The methodology and results of this exploratory population PK analysis will be presented in 
a separate report and included as an addendum to the CSR. 
Listings 16.2.14.1 and 16.2.14.2 will provide PK fasting status and PK blood collection data 
for the PK population. 
8. 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL 
Any changes to the statistical analysis plan after database lock should be addressed in a 
separate document. That document will be approved separately and included as an 
addendum to the final SAP. 
9. 
PROGRAMMING SPECIFICATIONS 
All summary tables, data listings, figures and other statistical output will be produced with 
the SAS system (version 9.1 or above) and will be incorporated into a MS Word document 
for easy integration into the CSR production process. Summary tables, data listings, and 
figures will be produced in the order that they appear in the textual sections of the plan.  


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The SAS generated output will adhere to the following specifications.  
9.1 
FORMAT OF TABLES AND LISTINGS 
Tables and listings will be produced in landscape orientation.  To ensure the print window is 
usable for both A4 paper size (21 x 29.7 cm; 8.27 x 11.69 inches) and US letter paper size 
(21.59 x 27.94 cm; 8.5 x 11 inches), the following page size and margins will be used: 
 
• 
Print window: 15.88 x 22.61 cm (6.25 x 8.9 inches)  
• 
Top and bottom margins approximately:  
 
 
 
 
 
 
 
 
A4: 2.54 cm (1 inch);   
 
 
 
 
 
 
 
US: 2.85 cm (1.25 inches). 
• 
Left and right margins approximately:  
 
 
 
 
 
 
 
 
A4: 3.56 cm (1.4 inches);  
 
 
 
 
 
 
 
US: 2.54 cm (1 inch). 
 
A fixed space font (Courier New or SAS Monospace) with point size 9 will be used for all 
tables and listings.  Under very limited circumstances, reducing the point size to 8 or 7.5 for 
a listing may be considered if the reduction is absolutely necessary to fit all columns on one 
page, and splitting the listing into two or more pages is not a viable option. 
9.1.1 
Title of a Table/Listing 
The first line of the title will immediately follow the header line (i.e., no blank line in between).  
The title of a table/listing will be centered.  The first letter of each imperative word will be 
capitalized.  Up to 6 lines of the page are available to enter the title.   (Note:  There will be no 
blank title lines.)  
 
The title will state the table/listing number, describe the table/listing briefly, and describe the 
population that is included in the table/listing, i.e.: 
 
 
 
Line 1 of title:  Table xx.x. 
 
 
 
Line 2 of title:  Main title 
 
 
 
Line 3 of title (optional):  Subtitle 
 
 
 
Line 4 of title:  XXX Population 
If Line 3 is not utilized, then Line 4 will be moved up.   
The table/listing numbering will be consecutive, with no skipping of numbers.  Up to 5 levels 
of numbering (i.e., xx.x.x.x.x or xx.x.x.x.x) are allowed.  If the same table/listing is produced 
for multiple analysis populations (e.g., ITT Population and restricted ITT Population) or data 
imputations (e.g., Observed Data and LOCF Data), the resulting multiple tables/listings 
should share the same table/listing number, except for the last level, which will be 
consecutively numbered 1, 2, 3,…, t where t is the total number of tables/listings generated 
(e.g., 4.2.1 for ITT Population and 4.2.2 for restricted ITT Population). 
For numeric variables, the appropriate unit will be added to the column heading.  For 
frequency tables, only those categories for which there is at least one subject represented in 
one or more groups should be included.  Within data listings, subjects will be ordered by 
treatment, investigator number, subject number, randomization number, visit, visit date and 
time of collection (if available). 


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Verbose titles should be avoided.  In the case where a title line is too wide for the page, then 
the title line will wrap on to the next line, and all subsequent lines will increment by one. 
If there is stratification or subgrouping of the population (e.g., Sex) with summaries to be 
presented for each subgroup on a separate page, the subgrouping label on a page (e.g., 
Males) will appear, left-aligned with the body of the table/listing, on the line immediately 
below the last title line. 
There will be a solid horizontal line across the page immediately below the last title line (or 
the subgroup label, if present), as wide as the body of the table/listing. 
9.1.2 
Footnotes to a Table/Listing 
There will be a solid horizontal line across the page, as wide as the upper horizontal line, 
signifying the end of the body of the table/listing for that page.  Footnotes are immediately 
below this horizontal line, with the exception of the documentation line, which appears on the 
bottom line of the page.  Footnotes will be left-aligned with the body of the table/listing.  If the 
footnote is a complete sentence, then the usual sentence construction will be followed.  If 
the footnote is a single word or a phrase, then the first letter of the first word will be 
capitalized.  Up to 9 lines of the page are available to enter footnotes. 
For a table, the first footnote will name the listing(s) where the data used in the table came 
from, in the following format: 
 
 
 
Source:  Listing xx.x 
Footnotes that apply to the table/listing in general will precede footnotes that apply to a 
specific item (e.g., title line, row label, column header, specific count, descriptive statistic, p-
value, or data) on the table/listing.  An example of a general footnote is as follows:  “A 
subject who has the same TEAE more than once during the study was counted once in the 
total number of subjects per system organ class calculation.”  An example of an item-specific 
footnote is as follows:  “*Significant at the 0.050 level”.  
The use of superscripting in footnotes is not recommended.  If there is only one item-specific 
footnote on a table/listing, one of the symbols #, *, and @ will be used to tag the item, with a 
single blank space between the item and the symbol.  In general, the asterisk will be 
reserved for tagging items related to the presentation of p-values.  The footnote will begin 
with the symbol, followed by a single blank space, and then the footnote text, e.g.: 
# footnote text here   
If there are multiple item-specific footnotes on a table/listing, “(x)” will be used to tag each 
item, with the x’s being either all numbers (1, 2, 3, etc.) or all letters (a, b, c, etc.), and with a 
single blank space between the item and the corresponding “(x)”.  The footnote will begin 
with the “(x)”, followed by a single blank space, and then the footnote text, e.g.: 
 
 
 
(x) footnote text here 
The use of self-explanatory or commonly used abbreviations to tag an item for footnoting 
may supersede the conventions described in the two preceding paragraphs.  Examples of 
commonly used abbreviations include the following:  H=Above upper normal limit, W=Within 


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normal limits, and L=Below lower normal limit; ND=Not done; N/A=Not applicable; and 
NAV=Not available.  Note that in these examples, the letters are not in parentheses and 
have the equal sign connecting the letters with the footnote text. 
When a general footnote exceeds one line in length, the text will wrap on to the next line, 
with no indentation if there is only one general footnote (excluding the source footnote) and 
with two-space indentation if there are more than one general footnote.  When an item-
specific footnote exceeds one line in length, the lines after the first one will be left-aligned 
with the first line, minus the “(x)”, e.g.: 
(x) first line of footnote text here 
 
 
 
    second line of footnote text here 
 
9.1.3 
Header and Footer 
Although not depicted on the shell outputs, every output will have the following Header: 
Supernus Pharmaceuticals, Inc. 
 
 
 
 
 
Page x of xx                    
Protocol No.: 812P201   
and the following Footer:  
Program:  Programname.sas  DDMMMYYYY HH:MM      
Produced: DDMMMYYYY HH:MM   
9.2 
DATA FORMAT 
Unless otherwise specified, the estimated mean and median for a set of values will be 
printed out to one more decimal place than the individual units of measurement, and the 
standard deviation and coefficient of variation will be printed out to one additional place 
further.  P-values will be given with 3 decimals.   P-values < .001 will be shown as “<0.001”.  
All fractional numeric values will be printed with a zero to the left of the decimal point (e.g., 
0.12, 0.3 etc.).  Unless otherwise specified, percentage values will be printed with one digit 
to the right of the decimal point (e.g., 52.3%, 8.9% etc.).   Dates will be presented as 
YYYY/MM/DD and time values will be presented as HH:MM:SS or HH:MM in all listings. 
 
9.3 
CODING LISTS 
The coding of the data is performed with the following coding lists: 
 
Data 
Coding list  
Adverse events 
MedDRA  
Medication names 
WHO Drug Dictionary 
 
10. 
SUMMARY TABLES, DATA LISTINGS AND FIGURES (TLFS) 
Shells of summary tables, data listings and figures are presented as separate documents in 
order to provide a framework for the display of data and results of statistical analyses for this 
study.  These shells may change due to unforeseen circumstances.