Clinical trial NCT04016779
Conditions: Attention-Deficit/Hyperactivity Disorder (ADHD)
Keywords: Attention-Deficit/Hyperactivity Disorder (ADHD), Adult ADHD,
Sponsor: Supernus Pharmaceuticals, Inc.
Start date: 2019-11-20; Completion date: 2020-10-10
Enrollment: 374 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy and safety of SPN-812 (Viloxazine extended-release capsules; 200-600 mg) in adults 18-65 years of age with Attention-Deficit/Hyperactivity Disorder (ADHD).

Detailed description:
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, 2-arm, parallel-group, flexible dose trial assessing the efficacy and safety of SPN-812 (Viloxazine extended-release capsules; 200-600 mg) as monotherapy for the treatment of adults 18-65 years old with Attention-Deficit/Hyperactivity Disorder (ADHD).

Arms: arm 1: Placebo, qd, oral capsule arm 2: SPN-812, qd, oral capsule
Interventions: intervention 1: Placebo intervention 2: SPN-812
Intervention descriptions: intervention 1: Placebo will be administered once daily intervention 2: SPN-812 will be administered once daily and compared to Placebo

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE 
 
Protocol Number: 
812P306 
Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled,  
Multicenter, Parallel-Group Flexible-Dose Study of the Efficacy and 
Safety of SPN-812 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 
IND number: 
108,864 
Investigational 
Medicinal 
Product: 
Viloxazine extended-release capsule  
Indication: 
Attention-deficit/hyperactivity disorder (ADHD)  
Contract 
Research 
Organization 
(CRO): 
CRO Medical 
Monitor 
Supernus 
Medical Advisor 
Phase: 
3 
Protocol Version: 
4.0 
Date: 
06Mar2020 
Good Clinical 
Practice (GCP) 
Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonisation (ICH) Good Clinical Practices (GCP) 
and all applicable local regulations. All required study 
documentation will be archived as required by regulatory 
authorities. 
 
 
 


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


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


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CLINICAL PROTOCOL SYNOPSIS 
Sponsor: Supernus Pharmaceuticals, Inc. 
Name of Product:  SPN-812 
(viloxazine extended-release capsule)  
Name of Active Ingredient:  
Viloxazine hydrochloride 
Protocol Number: 812P306 
Phase of Development:  3 
Full Title of Study: A Phase 3, Randomized, Double-Blind, Placebo-Controlled,  
Multicenter, Parallel-Group Flexible-Dose Study of the Efficacy and Safety of SPN-812 
in Adults with Attention-Deficit/Hyperactivity Disorder (ADHD) 
Number of Study Sites:  Up to 40 study sites 
Number of Subjects: Approximately 366 subjects will be randomized to one of two 
treatment arms (1:1 ratio; 183 subjects per arm). 
Indication:  Attention-deficit/hyperactivity disorder (ADHD) 
Objectives:  
Primary Objective: 
 
To evaluate the efficacy of SPN-812 200 mg to 600 mg compared to placebo 
for the treatment of ADHD in adults as measured by the adult ADHD 
Investigator Symptom Rating Scale (AISRS) total score. 
Key Secondary Objective: 
 
To evaluate the efficacy of SPN-812 200 mg to 600 mg compared to placebo on 
the global assessment of severity for ADHD as measured by the Clinical Global 
Impression - Severity of Illness (CGI-S) scale. 
Additional Secondary Objectives: 
 
To evaluate the efficacy of SPN-812 200 mg to 600 mg compared to placebo 
on: 
1) Clinical response rate of severity of illness as measured by the 
categorical CGI-S Responder Rate (CGI-S score 1 or 2). 
2) Global assessment of improvement as measured by the Clinical Global 
Impression - Improvement scale (CGI-I) for ADHD. 
3) Clinical response rate of improvement as measured categorical CGI-I 
Responder Rate (CGI-I score 1 or 2). 
4) Anxiety symptoms as measured by the Generalized Anxiety Disorder 
7-Item scale (GAD-7). 
5) Clinician-rated ADHD symptoms as measured by the AISRS subscales 
of Inattention and Hyperactivity/Impulsivity. 
6) Clinician response rate of ADHD symptom reduction as measured by 
the 50% responder rate in AISRS total score. 
7) Clinician response rate of ADHD symptom reduction as measured by 
the 30% responder rate in AISRS total score. 
8) Executive functioning as measured by Behavior Rating Inventory of 
Executive Function–Adult Version (BRIEF-A; Self Report). 
9) Aspects of executive function and problems of self-regulation as 
measured by the BRIEF-A Summary Index Scales and BRIEF-A scales. 


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Safety Objective: 
 
To evaluate the safety and tolerability of SPN-812 200 mg to 600 mg in adult 
subjects with ADHD. 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Efficacy Endpoints: 
Primary Endpoint: 
 
The primary efficacy endpoint is the change from baseline (CFB) at end of 
study (EOS) in the AISRS total score. 
Key Secondary Endpoints: 
 
The key secondary efficacy endpoint is the CFB at EOS in the CGI-S score. 
Additional Secondary Endpoints: 
Additional secondary efficacy endpoints are: 
1) Percentage of subjects with a CGI-S score of 1 or 2 at EOS. 
2) CGI-I score at EOS.  
3) Percentage of subjects with a CGI-I score of 1 or 2 at EOS. 
4) CFB at EOS in the GAD-7 total score.  
5) CFB at EOS in the AISRS Inattention subscale score and the 
Hyperactivity/Impulsivity subscale score.  
6) AISRS 50% responder rate (defined as the percentage of subjects with a ≥ 50% 
reduction in the CFB AISRS total score) at EOS. 
7) AISRS 30% responder rate (defined as the percentage of subjects with a ≥ 30% 
reduction in the CFB AISRS total score) at EOS. 
8) CFB at EOS in the BRIEF-A Global Executive Composite (GEC) T-score. 
9) CFB at EOS in the BRIEF-A T-score by each Summary Index Scale and by 
individual BRIEF-A scale. 
 
ta Red


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Safety Endpoints: 
 
Safety endpoints are adverse events (AEs), clinical safety laboratory tests, vital 
signs, weight, electrocardiograms (ECGs), physical examination, and the 
Columbia Suicide Severity Rating Scale (C-SSRS). 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
Study Design:   
This is a randomized, double-blind, placebo-controlled, multicenter, parallel group, 
flexible dose study of SPN-812 in adults diagnosed with ADHD per Diagnostic and 
Statistical Manual of Mental Disorders – 5th Edition (DSM-5™) criteria. Approximately 
366 subjects will be randomized in a 1:1 ratio (183 subjects per arm): SPN-812 (200 
mg to 600 mg) or placebo. Following up to 5 weeks of screening, subjects will be 
treated with study medication (SM) for 6 weeks.  
At the Screening Visit (Visit 1), after informed consent is obtained, subjects will 
undergo initial screening evaluations/scales, and inclusion/exclusion criteria will be 
reviewed to confirm the subject’s eligibility. Subjects taking ADHD medication at 
screening will undergo a washout of at least 1 week (or 5 half-lives of the medication, 
whichever is longer) before the Baseline Visit (Visit 2; Day 1). At the Baseline Visit, 
subjects who meet inclusion/exclusion criteria will be randomized. The Treatment 
Period will consist of 6 weeks of treatment with dosing starting Day 2 (morning after 
Visit 2) until Day 43 (Visit 7; end of study, EOS) (Section 4.2). Subjects will undergo 
efficacy and safety evaluations, return the previous dosing card, and receive the next 
card.  
Subjects who complete the study may enroll in a separate open-label extension (OLE) 
safety study. Those subjects who do not enroll in OLE safety study will receive a phone 
call 1 week following EOS visit for safety.  
Duration of Subject’s Participation:  
Following up to 5 weeks of screening, subjects will be treated with SM for 6 weeks. The 
total study duration from the Screening Visit to the end of the treatment period is up to 
11 weeks. 
 
 


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Investigational Medicinal Products, Reference Therapy, Doses and Mode of 
Administration 
Study Medication: SPN-812 (viloxazine extended-release capsule) 
Dose levels: 200 mg to 600 mg once daily (QD) 
Reference Therapy: Matching placebo 
Mode of Administration: Orally as intact capsules, each containing 200 mg of SPN-812 
 
Treatment Arm 
Number and Identity of Capsules to be Taken QD 
During the Treatment Period 
Week 1 
Week 2 
Week 3 to Week 6 
A: Placebo 
2 Placebo 
2 Placebo 
       1-3 Placebo 
B: SPN-812  
1 Placebo 
1 SPN-812 
2 SPN-812 
 
1-3 SPN-812 
 
QD = once daily 
Each SPN-812 capsule contains 200 mg SPN-812. 
Statistical Methodology 
Sample Size: 
Assuming an effect size of 0.407, 128 subjects per treatment group (256 total subjects 
for 2 arms) in the Full Analysis Set (FAS) will yield 90% power at a significance level of 
0.05 (two-sided) to reject the equality of treatment means between the placebo and the 
SPN-812 treatment group. Assuming approximately 30% of subjects drop out before 
the completion of the study, an adjusted sample size of 366 subjects (183 per arm) will 
be randomized to obtain 128 subjects per arm in the FAS at the completion of the 
study. 
Analysis Populations: 
The Randomized Population is all subjects who complete the Baseline Period, meet 
the inclusion/exclusion criteria and are randomized. 
The Full Analysis Set (FAS) is a subset of subjects in the Randomized Population 
who took at least one dose of study medication, and had a Baseline and at least one 
post-Baseline assessment of AISRS. Subjects in the FAS will be analyzed according to 
the treatment to which they were randomized. The efficacy analyses will be conducted 
using the FAS. 
The Per Protocol (PP) Population is a subset of subjects in the FAS who complete all 
7 visits through EOS with no missing AISRS assessments and no major protocol 
violations. Subjects in the PP Population will be analyzed according to the treatment 
received. 
The Safety Population is all subjects randomized into the study who receive at least 
one dose of SM. Subjects in the Safety Population will be analyzed according to the 
treatment received. 
 
 
 


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Statistical Methods: 
Efficacy 
 
The primary efficacy variable, change from baseline in AISRS total score to 
Week 6 (EOS), will be analyzed using mixed model for repeated measures 
(MMRM), which assumes that missing data are missing at random (MAR). The 
model will include fixed effect terms for baseline AISRS total score, treatment, 
visit, and treatment-by-visit interaction as independent variables. The model 
parameters will be estimated using restricted maximum likelihood (REML) 
method with unstructured variance-covariance matrix and Kenward-Roger 
approximation to estimate denominator degrees of freedom. In case there is a 
convergence problem in the MMRM model with the unstructured variance-
covariance matrix, the first (co)variance structure that does not have 
convergence problem will be used for the analysis from the following ordered 
list: 1) Toeplitz, 2) Autoregressive of order 1, and 3) Compound symmetry. The 
adjusted mean (least square mean [LS mean]) of CFB at EOS for AISRS total 
score for each treatment arm (placebo and SPN-812) will be presented, along 
with the corresponding standard error. The SPN-812 treatment arm will be 
compared with placebo. The LS means of the treatment groups, differences 
between the LS treatment means and placebo, and 95% confidence intervals 
(CIs) for the treatment differences with p-values will be computed. 
 
 
The sensitivity analysis assumes that missing AISRS total scores are missing 
not at random (MNAR). Placebo-based multiple imputation will be used to fill-in 
missing values. This approach may be considered “worst-case” sensitivity 
analyses as it assumes that after discontinuation, subjects from the SPN-812 
treatment arm would adopt the outcome model estimated from the placebo arm. 
The placebo-based imputation will be implemented as described in the 
statistical analysis plan. 
 
 
The secondary analyses will be based on the FAS with missing values imputed 
using multiple imputation assuming MAR. All secondary analyses will use 
analysis of covariance (ANCOVA) (except categorical CGI, 50% responder and 
30% responder which uses Pearson’s Chi-squared test or Fisher exact test on 
the absolute value at Week 6 (EOS)) on the change from baseline at Week 6 
(EOS) (except CGI-I which uses the absolute value) with treatment and 
baseline (baseline CGI-S will be used for CGI-I) as fixed effect. The SPN-812 
treatment arm will be compared with the placebo arm. The LS means of the 
treatment groups, differences between the LS treatment mean and placebo 
(SPN-812 minus placebo), and 95% CIs for the treatment differences with p-
values will be computed. 
 
 
The primary and key secondary analyses will be repeated for the PP Population 
as supplemental analyses. 




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11. Males must: 
a. Use 2 methods of contraception in combination if his female partner is of 
childbearing potential; this combination of contraceptive methods must 
be used from the Baseline Visit to ≥ 1 month after the last dose of SM, or 
b. Have been surgically sterilized prior to the Screening Visit. 
Exclusion Criteria: 
1. Has previously enrolled in a SPN-812 study.  
2. Is currently participating in another clinical trial or has participated in a clinical trial 
within 60 days prior to the first Screening Visit. 
3. Is a member of the study personnel or of their immediate families, or is a 
subordinate (or immediate family member of a subordinate) to any of the study 
personnel. 
4. Female subjects who are pregnant, lactating and/or sexually active and not 
agreeing to use one of the acceptable birth control methods throughout the study. 
5. Has history of severe drug allergy or hypersensitivity, or known hypersensitivity, to 
the study medication or excipients. 
6. Has history of moderate or severe head trauma or other neurological disorder or 
systemic medical disease that, in the Investigator's opinion, is likely to affect central 
nervous system functioning. This would include subjects with: 
a. A current diagnosis of a major neurological disorder; or  
b. Seizures, seizure disorder or seizure-like events; or a history of seizure 
disorder within the immediate family (siblings, parents); or 
c. Encephalopathy 
7. Has any history of schizophrenia, schizoaffective disorder, bipolar disorder, 
borderline personality disorder, antisocial personality disorder, narcissistic 
personality disorder, autism, post-traumatic stress disorder or obsessive-
compulsive disorder. 
8. Has any current psychiatric disorder (per DSM-5 criteria) other than ADHD with the 
following exceptions: ADHD is primary diagnoses with comorbidity/secondary 
diagnoses of major depression disorder (MDD), nicotine dependence, social 
anxiety disorder, generalized anxiety disorder, or phobias, and subject is not 
receiving pharmacological treatment for the comorbidity/secondary diagnoses (e.g., 
antidepressant for MDD) at time of screening nor for the duration of study. 
9. Has a Symptoms of Depression Questionnaire (SDQ) mean score >3.0 at 
screening. 
10. Has a Hamilton Anxiety Rating Scale (HAM-A) score of > 21 at screening. 
11. Has organic mental disorders, or mental disorders due to a general medical 
condition (per DSM-5 criteria). 
12. Has a current diagnosis or history of substance use disorder including alcohol use 
disorder (excluding nicotine and caffeine) (per DSM-5 criteria) within the 12 months 
prior to screening; or is assessed by the Investigator as having regularly consumed 
alcohol exceeding 21 units for males and 14 units for females per week (1 unit 


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equals 340 mL of beer, 115 mL of wine, or 43 mL of spirits) within the 12 months 
prior to screening. 
13. Is currently using, or has a positive result on the drug screening at the Screening 
Visit for drugs of abuse (alcohol, opiates, methadone, cocaine, methamphetamine 
[including ecstasy], phencyclidine, propoxyphene, methylphenidate, barbiturates, 
and benzodiazepines). If subject’s serum drug screen for ethanol is positive at 
Screening (V1) and the investigator determines subject does not have alcohol use 
disorder, then the subject may have a repeat serum drug screen for ethanol 
performed before baseline within the allotted screening period (results must be 
received prior to V2 baseline). If second serum drug screen for ethanol is positive, 
subject is excluded from participating in the study, however, if second serum drug 
screen for ethanol is negative, subject may proceed to V2. 
14. Is a (known or self-identified) current habitual/chronic cannabis user (medicinal or 
recreational); or 
 
Has a positive urine drug screen for cannabis at the Screening Visit and is 
considered, per the Investigator’s judgement, to be a habitual/chronic 
cannabis user; or 
 
Has a positive urine drug screen for cannabis at both the screening and 
follow-up drug screen at the Baseline Visit, even though the subject is not 
considered, per the Investigator’s judgement, to be a habitual/chronic 
cannabis user. 
Note: Subjects who have a positive urine drug screen for cannabis at the Screening 
Visit but who are not considered to be a habitual/chronic cannabis user per the 
Investigator’s judgement may, with Sponsor approval, undergo an additional urine 
drug screen at least 4 weeks after the original urine drug screen at Baseline Visit, 
prior to randomization. Subjects must agree to refrain from cannabis use 
throughout study. 
15. Has treatment-resistant ADHD based on a history of receipt of >2 approved ADHD 
medications that failed to adequately improve the subject’s symptoms. A subject 
who is naïve to ADHD treatment is not excluded from study participation. 
16. Has any other disorder for which its treatment takes priority over treatment of 
ADHD or is likely to interfere with study treatment, impair treatment compliance, or 
interfere with interpretation of study results. 
17. Has history of cancer, other than basal cell or Stage 1 squamous cell carcinoma of 
the skin that has not been in remission for > 5 years prior to the first dose of SM. 
18. Has or has had one or more of the following conditions considered clinically 
significant/relevant by the Investigator in the context of the study:  
 cardiovascular disease 
 congestive heart failure 
 cardiac hypertrophy 
 arrhythmia 
 bradycardia (pulse < 50 bpm) 
 tachycardia (pulse > 100 bpm) 
 respiratory disease 


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 hepatic impairment or renal insufficiency 
 metabolic disorder 
 endocrine disorder 
 gastrointestinal disorder 
 hematological disorder 
 infectious disorder 
 any clinically significant immunological condition 
 dermatological disorder 
19. Exhibits clinically significant abnormal vital signs at screening (see Note below).  
20. Has one or more screening clinical laboratory test values outside the reference 
range that, in the opinion of the Investigator, are clinically significant, or any of the 
following (see Note below): 
 Serum creatinine > 1.5 times the upper limit of normal (ULN); 
 Serum total bilirubin > 1.5 times ULN; 
 Serum alanine aminotransferase or aspartate aminotransferase > 2 times 
ULN. 
21. Has any of the following cardiology findings at screening (see Note below): 
 Abnormal ECG that is, in the Investigator's opinion, clinically significant; 
 PR interval > 220 ms; 
 QRS interval > 130 ms; 
 QTcF interval > 450 ms (for men) or > 470 ms (for women) (QT corrected 
using Fridericia’s method); 
 Second- or third-degree atrioventricular block; 
 Any rhythm, other than sinus rhythm, that is interpreted by the Investigator to 
be clinically significant. 
22. Has any disease or medication that could, in the Investigator's opinion, interfere 
with the assessments of safety, tolerability, or efficacy, or interfere with study 
conduct or interpretation of results. 
23. Evidence of infection with hepatitis B or C, or human immunodeficiency virus (HIV)-
1 or HIV-2, as determined by results of testing at screening. 
24. Lost or donated more than 450 mL of blood during the 30 days prior to screening. 
25. Use of any investigational drug or prohibited concomitant medications including 
known CYP1A2 substrates (e.g., theophylline, melatonin) within 30 days or 5 half-
lives prior to Baseline Visit (Day 1) (whichever is longer) during the screening 
period or anticipated for the duration of the study. 
26. History of unexplained loss of consciousness, unexplained syncope, unexplained 
irregular heartbeats or palpitations or near drowning with hospital admission. 
27. Has attempted suicide within the 6 months prior to screening, or is at significant risk 
of suicide, either in the opinion of the Investigator or defined as a "yes" to suicidal 
ideation questions 4 or 5 or answering "yes" to suicidal behavior on the C-SSRS 
within the 6 months prior to screening. 
28. In the Investigator's opinion, is unlikely to comply with the protocol or is unsuitable 
for any other reason.  


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TABLE OF CONTENTS 
 
INVESTIGATOR’S SIGNATURE PAGE.............................................................................2 
SUPERNUS PHARMACEUTICALS, INC. PROTOCOL APPROVAL PAGE ...................3 
CLINICAL PROTOCOL SYNOPSIS ...................................................................................4 
LIST OF ABBREVIATIONS .............................................................................................. 18 
1 
INTRODUCTION ........................................................................................................ 20 
1.1 
Background ....................................................................................................... 20 
1.2 
Clinical Information ........................................................................................... 20 
1.3 
Study Rationale ................................................................................................. 25 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 26 
2.1 
Primary Objective .............................................................................................. 26 
2.2 
Key Secondary Objectives ............................................................................... 26 
2.3 
Additional Secondary Objectives .................................................................... 26 
2.4 
Safety Objective ................................................................................................ 26 
 
 
2.6 
Primary Endpoint .............................................................................................. 27 
2.7 
Key Secondary Endpoints ............................................................................... 27 
2.8 
Additional Secondary Endpoints .................................................................... 27 
2.9 
Safety Endpoints ............................................................................................... 27 
 
 
3 
INVESTIGATIONAL STUDY PLAN .......................................................................... 28 
3.1 
Overall Study Design and Plan ........................................................................ 28 
3.2 
Rationale for Study Design .............................................................................. 29 
3.3 
Study Population ............................................................................................... 30 
3.3.1 
Number of Subjects ............................................................................................ 30 
3.3.2 
Inclusion Criteria .................................................................................................. 30 
3.3.3 
Exclusion Criteria ................................................................................................ 31 
3.4 
Completion of Study and Discontinuation of Subjects ................................ 34 
4 
STUDY TREATMENT ................................................................................................ 36 
4.1 
Study Medication Identity, Packaging and Labeling .................................... 36 
4.2 
Study Medication Administration .................................................................... 36 
4.3 
Method of Assigning Subjects to Treatment Arm ......................................... 36 
4.4 
Blinding .............................................................................................................. 37 
4.5 
Study Medication Handling and Accountability ............................................ 37 
4.6 
Concomitant Medications ................................................................................ 38 
5 
STUDY METHODS .................................................................................................... 38 
5.1 
Study Visits and Procedures ........................................................................... 38 
5.1.1 
Visit 1 – Screening .............................................................................................. 41 
5.1.2 
Visit 2 – Baseline (Randomization) ................................................................... 41 
5.1.3 
Visits 3 to 7 – Treatment Period Including End of Study ............................... 42 
 
ed
 
dacted


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5.1.4 
FPC – Follow-up Phone Call (Not for Subjects Who Enter OLE Study) ..... 44 
5.1.5 
Unscheduled Visits .............................................................................................. 44 
 
 
5.1.7 
Future Research .................................................................................................. 45 
6 
STUDY VARIABLES AND ASSESSMENTS ............................................................ 46 
6.1 
Efficacy Assessments ...................................................................................... 46 
6.1.1 
Adult ADHD Investigator Symptom Rating Scale (AISRS) ........................... 46 
6.1.2 
Clinical Global Impression – Severity of Illness (CGI-S) ............................... 46 
6.1.3 
Generalized Anxiety Disorder 7-item Scale (GAD-7) .................................... 46 
6.1.4 
Clinical Global Impression – Improvement (CGI-I) ........................................ 47 
6.1.5 
Behavior Rating Inventory of Executive Function–Adult (BRIEF-A) ............ 47 
6.1.6 
Symptoms of Depression Questionnaire (SDQ) ............................................. 48 
 
 
6.2 
Safety Variables and Assessments ................................................................ 49 
6.2.1 
Adverse Events .................................................................................................... 49 
6.2.2 
Adverse Events of Special Interest (AESI) ...................................................... 50 
6.2.3 
Causality ............................................................................................................... 50 
6.2.4 
Recording and Evaluation of Adverse Events ................................................ 50 
6.2.5 
Criteria for Assessing Severity .......................................................................... 51 
6.2.6 
Criteria for Assessing Causality ........................................................................ 51 
6.2.7 
Serious Adverse Events ..................................................................................... 52 
6.2.8 
Investigator Responsibilities for Reporting SAEs ........................................... 52 
6.2.9 
Other Events Requiring Immediate Reporting ................................................ 53 
6.2.10 
Sponsor Responsibilities for Reporting SAEs ................................................. 53 
6.3 
Treatment-Emergent Suicidal Ideation ........................................................... 53 
6.3.1 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................... 53 
6.3.2 
Suicide Risk Management Plan ........................................................................ 54 
6.3.2.1 
Assessment of Suicide Risk ............................................................................... 54 
6.3.2.2 
Acute Suicidal Crisis .......................................................................................... 54 
6.3.2.3 
Non-acute Suicidal Risk ..................................................................................... 54 
6.4 
Clinical Measurements ..................................................................................... 54 
6.4.1 
Screening and Clinical Safety Laboratory Assessments .............................. 54 
6.4.2 
Vital Signs and Weight ....................................................................................... 55 
6.4.3 
Physical Examinations and Height ................................................................... 56 
6.4.4 
Electrocardiograms (ECGs) ............................................................................... 56 
 
 
6.6 
Screening Scales and Assessment Tools...................................................... 56 
6.6.1 
Structured Clinical Interview for DSM-5 - Clinical Trials (SCID-5-CT) ........ 56 
6.6.2 
Hamilton Anxiety Rating Scale (HAM-A) ......................................................... 56 
6.6.3 
Symptoms of Depression Questionnaire (SDQ) ............................................. 57 
6.7 
Subject training video module ........................................................................ 57 
7 
STATISTICAL METHODS ......................................................................................... 58 
 
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7.1 
General Considerations ................................................................................... 58 
7.2 
Handling of Missing Data ................................................................................. 58 
7.3 
Analysis Populations ........................................................................................ 59 
7.4 
Demographics and Baseline Analysis ............................................................ 59 
7.5 
Subject Disposition ........................................................................................... 59 
7.6 
Study Medication Exposure and Compliance ............................................... 60 
7.7 
Concomitant Medications ................................................................................ 60 
7.8 
Efficacy Analysis ............................................................................................... 60 
7.8.1 
Primary Efficacy Analysis ................................................................................... 60 
7.8.1.1 
Sensitivity Analysis ............................................................................................. 61 
7.8.2 
Secondary Efficacy Analyses ............................................................................ 61 
7.8.2.1 
Key Secondary Efficacy Analyses...................................................................... 61 
7.8.2.2 
Additional Secondary Analyses.......................................................................... 61 
 
 
7.9 
Sample Size and Power Considerations ........................................................ 63 
7.10 
Interim Analysis................................................................................................. 63 
 
 
7.12 
Safety Analysis .................................................................................................. 63 
8 
DOCUMENTATION .................................................................................................... 64 
8.1 
Adherence to the Protocol ............................................................................... 64 
8.2 
Changes to the Protocol .................................................................................. 64 
8.3 
Data Quality Assurance .................................................................................... 64 
8.3.1 
Data Collection .................................................................................................... 64 
8.3.2 
Clinical Data Management ................................................................................. 65 
8.3.3 
Database Quality Assurance ............................................................................. 65 
8.3.4 
Bioanalytical Sample Handling .......................................................................... 65 
8.4 
Retention of Records ........................................................................................ 65 
8.5 
Auditing Procedures ......................................................................................... 66 
8.6 
Publication of Results ...................................................................................... 66 
8.7 
Financing and Insurance .................................................................................. 66 
8.8 
Disclosure and Confidentiality ........................................................................ 66 
8.9 
Discontinuation of Study ................................................................................. 67 
9 
ETHICS ....................................................................................................................... 68 
9.1 
Institutional Review Boards ............................................................................. 68 
9.2 
Ethical Conduct of the Study ........................................................................... 68 
9.3 
Investigators and Study Personnel................................................................. 68 
9.4 
Subject Information and Consent ................................................................... 68 
10 REFERENCES ........................................................................................................... 70 
11 APPENDIX: ................................................................................................................ 73 
11.1 
Screening, Efficacy and Safety Scales and Questionnaires ........................ 73 
11.1.1 
AISRS: Adult ADHD Investigator Symptom Rating Scale ............................ 74 
11.1.2 
CGI-S:  Clinical Global Impression – Severity of Illness ............................... 78 
 
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11.1.3 
CGI-I:  Clinical Global Impression – Improvement ......................................... 79 
11.1.4 
GAD-7:  Adult ADHD Investigator Symptom Rating Scale ........................... 80 
11.1.5 
BRIEF-A:  Behavioral Rating Inventory of Executive Functioning-Adult..... 81 
11.1.6 
SDQ:  Symptoms of Depression Questionnaire ............................................. 84 
 
 
11.1.8 
SCID-5-CT:  Structured Clinical Interview for DSM-5; Clinical Trial ............ 94 
11.1.9 
HAM-A:  Hamilton Anxiety Scale .................................................................... 139 
11.1.10 
C-SSRS:  Columbia-Suicide Severity Rating Scale; Baseline ............... 151 
11.1.11 
C-SSRS: Columbia-Suicide Severity Rating Scale; Since Last Visit .... 154 
 


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LIST OF TABLES AND FIGURES 
Table 1 Study Medication Administration .............................................................................. 36 
Table 2 Schedule of Events and Assessments..................................................................... 39 
Table 3 Clinical Laboratory Tests ............................................................................................ 55 
 
Figure 1 
Study Schematic ...................................................................................................... 30 
 
 
 


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LIST OF ABBREVIATIONS 
 
 
ADHD 
Attention-deficit/hyperactivity disorder 
ADHD-RS-IV/5 
ADHD Rating Scale IV/5 
ADR 
adverse drug reaction 
AE 
adverse event 
AISRS 
ADHD Investigator Symptom Rating Scale 
ANCOVA 
analysis of covariance 
ATC 
Anatomical-Therapeutic-Chemical (code) 
BMI 
body mass index 
BRI 
Behavioral Regulation Index  
BRIEF-A 
Behavior Rating Inventory of Executive Function–Adult version 
CAARS 
Conners Adult ADHD Rating Scale 
CFB 
change from baseline 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity of Illness 
CI 
confidence interval 
CL/F 
apparent clearance 
CRA 
clinical research associate 
CRO 
clinical research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-IV/5 
Diagnostic and Statistical Manual of Mental Disorders – 4th/5th 
Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
ER 
extended release 
ET 
early termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FOCP 
females of childbearing potential 
FSH 
follicle stimulating hormone 
FPC 
follow-up phone call 
GAD-7 
Generalized Anxiety Disorder 7-Item scale 
GCP 
Good Clinical Practice 
GEC 
Global Executive Composite 
HAM-A 
Hamilton Anxiety Rating Scale 
HIV 
human immunodeficiency virus 
HRQL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IR 
immediate release 
IRB 
institutional review board 
 
 


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IWRS 
interactive web response system 
LS 
least square 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Metacognitive Index 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
OLE 
open-label extension 
PFC 
prefrontal cortex 
PGx 
pharmacogenomics 
PK 
pharmacokinetics 
PP 
Per Protocol 
PT 
preferred term 
QD 
once daily 
QTcF 
QT corrected using Fridericia’s method 
REML 
restricted maximum likelihood 
SADR 
suspected adverse drug reaction 
SCID-5-CT 
Structured Clinical Interview for DSM-5 Clinical Trials version 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDQ 
Symptoms of Depression Questionnaire 
SM 
study medication 
SNMA 
serotonin norepinephrine modulating agent 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
UDS 
urine drug screen 
Vd/F 
apparent volume of distribution 
WBC 
white blood cell 
WHO DD 
World Health Organization Drug Dictionary 
 
 


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1 
INTRODUCTION 
1.1 
Background 
Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric condition 
characterized by inattention, hyperactivity and impulsivity. Epidemiological data suggest 
that ADHD affects up to 8% of children in the United States, while the estimated 
prevalence in the adult population is between 0.3% and 5% (McCann and Roy-Byrne, 
2004). The standard pharmaceutical treatments for ADHD include psychostimulants, 
non-stimulants, and antidepressants. Stimulants (e.g., methylphenidate, amphetamine) 
are the first-line pharmacotherapies for the treatment of ADHD. However, 10% to 30% of 
patients do not adequately respond to stimulants or experience intolerable adverse 
events (AEs; e.g., decreased appetite, sleep problems, headaches) (Briars and Todd, 
2016).  
SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin 
Norepinephrine Modulating Agent (SNMA). The active substance in SPN-812 is 
viloxazine, whose mechanism of action is multimodal with antagonistic activity observed 
at 5-HT2B and agonistic activity at 5-HT2C receptors, as well as weaker antagonistic 
effects at ADRα1B, ADRβ2 and 5-HT7 receptors. Additionally, SPN-812 acts as a 
modulator with inhibitory effects at the norepinephrine reuptake transporter. Viloxazine 
was previously marketed in several European countries as an antidepressant as an 
immediate-release (IR) product. An extended-release (ER) formulation of viloxazine, 
SPN-812, has been developed by Supernus to prolong the release and absorption of 
viloxazine post-administration, thereby minimizing fluctuations in plasma drug levels and 
allowing longer dosing intervals for a drug with a relatively short half-life. SPN-812 was 
developed for potential use in the treatment of subjects with ADHD, based on the 
pharmacological properties and favorable safety profile and the current unmet medical 
need for effective long-acting, nonstimulant ADHD treatment in children and 
adolescents. SPN-812 is being evaluated in the current study for potential use in the 
treatment of ADHD in adults based on the pharmacological properties and favorable 
safety profile of viloxazine. 
1.2 
Clinical Information 
The safety, pharmacokinetics (PK) and drug-drug interactions for the IR and ER 
formulations of SPN-812 have been evaluated in multiple Phase 1 studies in healthy 
adults. As of April 2019, a number of studies evaluating the efficacy and safety of 
SPN-812 treatment for ADHD in pediatric and adult populations have been completed, 
including one Phase 2 study in adults (18 to 65 years of age; 812P201), one pediatric 
Phase 2 in children (6 to 12 years of age; 812P202), and four pediatric Phase 3 studies, 
two in children (6 to 11 years of age; 812P301 and 812P303) and two in adolescents 
(12 to 17 years of age; 812P302 and 812P304). In addition, there is an ongoing pediatric 
open-label extension (OLE) safety study in children and adolescents (6 to 17 years of 
age; 812P310). Key findings from the completed Phase 2 and Phase 3 studies are 
summarized below. Additional details are provided in the SPN-812 Investigator’s 
Brochure. 


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Phase 1 Studies 
Phase 1 studies include comparison of single and two-bead SPN-812 extended release 
(ER) formulations to an SPN-812 immediate release (IR) formulation at single and 
multiple doses (812P102 and 812P103, respectively), evaluation of food and sprinkling 
effects (812P105), drug-drug interactions (DDIs) on CYP1A2, 2D6, and 3A4 substrates 
with evaluation of SPN-812 ER metabolism in CYP2D6 poor metabolizers vs. CYP2D6 
extensive metabolizers (812P113.1), DDI with d-amphetamine (812P113.2), DDI with 
methylphenidate (812P113.3), evaluation of the effect of alcohol on SPN-812 
metabolism (812P115), evaluation of the effect of renal impairment on SPN-812 
metabolism (812P112.1), evaluation of multiple dose SPN-812 on QT Interval 
(812P117), evaluation of maximum tolerable doses and cardiac safety in a single and 
multiple-ascending dose study (812P120) have also been evaluated. In addition, a 
[14C]-labelled oral IR solution was used to examine human absorption, metabolism, and 
excretion (812P111). 
Results from these studies demonstrated that 200 mg single dose of an extended 
release SPN-812 formulation resulted in a mean maximum plasma concentration 
(Cmax) of 1.33 µg/mL, area under the plasma concentration-time curve extrapolated to 
infinity (AUCinf) of 27.3 hr*µg/mL, median time to maximum concentration (tmax) of 5 
hours, and a half-life of approximately 7 hours (812P103). Lower mean Cmax was 
observed for SPN-812 as compared to SPN-812 IR and by 48 hours overall viloxazine 
exposure was comparable between the two formulations. The rate of absorption of 
viloxazine was formulation dependent; SPN-812 exhibited a slower absorption rate than 
SPN-812 IR. Following multiple-dose administration of SPN-812 on consecutive days, 
steady-state was achieved by the second day of multiple dosing. Little systemic 
accumulation of viloxazine was observed as no major increase in pharmacokinetic (PK) 
parameters was observed following multiple administration of SPN-812 compared to 
single dose administration, during the same time interval.  
Food and sprinkling did not affect the relative bioavailability of viloxazine following 
administration of SPN-812 capsules (812P105). SPN-812 interacted as a strong inhibitor 
of CYP1A2, a weak inhibitor of CYP2D6, a weak inhibitor of CYP3A4; and displayed no 
significant differences in metabolism within CYP2D6 poor metabolizers and CYP2D6 
extensive metabolizers (812P113.1). There was no DDI between SPN-812 and d-
amphetamine (812P113.2) nor SPN-812 and methylphenidate (812P113.3). In addition, 
there was no dose dumping observed with co-administration of alcohol with SPN-812 
(812P115). Renal impairment resulted in a 1.09-fold, 1.3-fold, and 1.9-fold increase in 
AUC for mild, moderate, and severe renal impairment subjects receiving 400 mg SPN-
812 as compared to healthy subjects (812P112.1). Multiple doses of 1800 mg 
(supratherapeutic) SPN-812 did not affect cardiac repolarization as measured by QTcI 
and QTcF or other electrocardiographic parameters (812P117). In the single 
ascending/multiple ascending dose study, SPN-812 was well tolerated up to 2100 
mg/day as a single dose and up to 1800 mg/day as multiple doses given once daily for 5 
consecutive days. Intolerable adverse events (AEs) were not observed at doses of up to 


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1800 mg/day. SPN-812 at a single supratherapeutic dose had no effect on cardiac 
repolarization or other electrocardiographic parameters, other than slight increase in 
heart rate consistent with the known anticholinergic effect of viloxazine (812P120).  
In the human absorption, metabolism, and excretion study, absorption of the isomers, R- 
and S-viloxazine, was rapid with a median Tmax of 1.0 hour and showed a 2:1 
concentration ratio, respectively. Nearly 100% of the radioactive dose was recovered 
with approximately 90% being recovered within 24 hours of administration, 
demonstrating complete absorption of the drug followed by rapid elimination. The 
primary circulating form was SPN 812; the only metabolite found above 10% total 
radioactivity was de-activated hydroxylated glucuronide.   
The most common AEs in the Phase 1 studies in healthy adults were somnolence and 
headache. Most AEs were mild; none were severe or serious. No clinically significant, 
study medication-related findings were observed for laboratory or electrocardiogram 
(ECG) tests in any study. In general, SPN 812 is considered to be well tolerated with no 
safety events observed that would be unexpected for viloxazine. 
Phase 2 Studies 
The randomized, blinded, proof-of-concept Phase 1/2 study 812P201 compared an IR 
formulation of SPN-812 and placebo administered three times a daily in a dose range of 
150 to 300 mg/day in 52 adults (26 per treatment) with ADHD. In addition to assessing 
the safety and tolerability of SPN-812 IR, scores of both the Investigator-rated and 
patient-rated Conners Adult ADHD Rating Scale (CAARS) were collected at weekly 
intervals during the 6-week treatment period. Treatment with SPN-812 IR showed a 
statistically significant reduction in median CAARS total ADHD symptom score 
compared to placebo. Treatment-emergent AEs were reported in 23 (88.5%) subjects in 
the SPN-812 IR group and in 18 (72.0%) subjects in the placebo group. The most 
common AEs in SPN-812 IR group were nausea, decreased appetite, headache, and 
insomnia. There were no clinically significant ECGs, clinical laboratory test results, vital 
signs, or physical examination findings in either group during the study. No serious 
adverse events (SAEs) or deaths occurred during the study. 
The 812P202 study in children with ADHD assessed the effect of SPN-812 in reducing 
the symptoms of ADHD as measured by the ADHD Rating Scale IV (ADHD-RS-IV). 
Subjects aged 6 to 12 years were randomized in a 1:2:2:2:2 ratio of placebo or active 
treatment (SPN-812 100, 200, 300, or 400 mg) and received 3 weeks of titration at 
100 mg/week followed by 5 weeks of maintenance dosing for a total of 8 weeks of 
treatment. Mean ADHD-RS-IV Total Scores improved throughout treatment in all groups. 
Differences in change from baseline to end of study between SPN-812 and placebo 
were statistically significant at the three higher SPN-812 doses (p ≤ 0.0310) but not at 
the 100-mg dose. The treatment effect compared to placebo increased with the dose; 
however, pairwise comparisons among the four active treatment groups showed no 
statistically significant differences among the SPN-812 doses. All doses of SPN-812 
were well tolerated with no serious or severe AEs and no clinically significant effect on 


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laboratory values of common hematology and chemistry tests. The most common AEs 
were somnolence, decreased appetite, and headache. 
Phase 3 Studies 
Four pivotal Phase 3 studies of SPN-812 for the treatment of ADHD have been 
completed in the pediatric population: two studies in children 6 to 11 years of age 
(evaluating 100 mg, 200 mg, and 400 mg) and two studies in adolescents 12 to 17 years 
of age (evaluating 200 mg, 400 mg, and 600 mg). As of April 2019, preliminary results 
are available for all four studies.  
Children (6 to 11 years of age) 
Study 812P301 was a randomized, double-blind, placebo-controlled study of the efficacy 
and safety of SPN-812 at 100 mg/day and 200 mg/day for the treatment of ADHD in 
children 6 to 11 years of age. The primary endpoint of the study was the change from 
baseline in ADHD-RS-5 Total Score at end of study. Treatment for 6 weeks (1 week of 
titration followed by 5 weeks of maintenance at a fixed dose) with SPN-812 100 mg/day 
or 200 mg/day led to a statistically significant improvement in ADHD-RS-5 Total Score 
compared to placebo.  
Throughout treatment, AEs were reported in 47 (29.6%), 74 (48.1%), and 
77 (47.8%) subjects in the placebo, SPN-812 100 mg/day, and SPN-812 200 mg/day 
treatment groups, respectively. The most frequently reported AEs were somnolence, 
decreased appetite, and headache. AEs were considered to be at least possibly 
treatment related in 16 (10.1%), 41 (26.6%), and 56 (34.8%) subjects in the placebo, 
SPN-812 100 mg/day, and SPN-812 200 mg/day treatment groups, respectively. AEs 
led to permanent study medication discontinuation (and study withdrawal) in 2 (1.3%), 
5 (3.2%), and 2 (1.2%) subjects in the placebo, SPN-812 100 mg/day, and SPN-812 
200 mg/day treatment groups, respectively. SAEs were reported in 3 subjects: 2 in the 
SPN-812 100 mg/day treatment group and 1 in the SPN-812 200 mg/day treatment 
group. All SAEs were considered unlikely related or not related to study medication. No 
deaths occurred during the study. 
Study 812P303 was a randomized, double-blind, placebo-controlled study of the efficacy 
and safety of SPN-812 at 200 mg/day and 400 mg/day for the treatment of ADHD in 
children 6 to 11 years of age. The primary endpoint of the study was the change from 
baseline in ADHD-RS-5 Total Score at end of study. Treatment with SPN-812 
200 mg/day or 400 mg/day for 8 weeks (3 weeks of titration followed by 5 weeks of 
maintenance at a fixed dose) led to a statistically significant improvement in ADHD-RS-5 
Total Score compared to placebo. 
Throughout treatment, AEs were reported in 47 (45.6%), 56 (52.3%), and 
58 (58.0%) subjects in the placebo, SPN-812 200 mg/day, and SPN-812 400 mg/day 
treatment groups, respectively. The most frequently reported AEs were somnolence, 
headache, decreased appetite, and fatigue. AEs were considered to be at least possibly 
treatment related in 22 (21.4%), 42 (39.3%), and 51 (51.0%) subjects in the placebo, 
SPN-812 200 mg/day, and SPN-812 400 mg/day treatment groups, respectively. AEs 


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led to permanent study medication discontinuation (and study withdrawal) in 3 (2.9%), 
6 (5.6%), and 4 (4.0%) subjects in the placebo, SPN-812 200 mg/day, and SPN-812 
400 mg/day treatment groups, respectively. SAEs were reported in 3 subjects: 1 in the 
SPN-812 200 mg/day treatment group and 2 in the SPN-812 400 mg/day treatment 
group. No deaths occurred during the study. 
Adolescents (12 to 17 years of age) 
Study 812P302 was a randomized, double-blind, placebo-controlled study of the efficacy 
and safety of SPN-812 at 200 mg/day and 400 mg/day for the treatment of ADHD in 
adolescents 12 to 17 years of age. The primary endpoint of the study was the change 
from baseline in ADHD-RS-5 Total Score at end of study. Treatment with SPN-812 
200 mg/day or 400 mg/day for 6 weeks (1 week of titration followed by 5 weeks of 
maintenance at a fixed dose) led to a statistically significant improvement in ADHD-RS-5 
Total Score compared to placebo. 
Throughout treatment, AEs were reported in 38 (36.5%), 43 (43.4%), and 
56 (53.3%) subjects in the placebo, SPN-812 200 mg/day, and SPN-812 400 mg/day 
treatment groups, respectively. The most frequently reported AEs were somnolence, 
decreased appetite, headache, fatigue and nausea. AEs were considered to be at least 
possibly treatment related in 20 (19.2%), 32 (32.3%), and 41 (39.0%) subjects in the 
placebo, SPN-812 200 mg/day, and SPN-812 400 mg/day treatment groups, 
respectively. AEs led to permanent study medication discontinuation (and study 
withdrawal) in 0, 4 (4.0%), and 2 (1.9%) subjects in the placebo, SPN-812 200 mg/day, 
and SPN-812 400 mg/day treatment groups, respectively. SAEs were reported in 
2 subjects, both in the SPN-812 200 mg/day treatment group. No deaths occurred during 
the study. 
Study 812P304 was a randomized, double-blind, placebo-controlled study of the efficacy 
and safety of SPN-812 at 400 mg/day and 600 mg/day for the treatment of ADHD in 
adolescents 12 to 17 years of age. The primary endpoint of the study was the change 
from baseline in ADHD-RS-5 Total Score at end of study. Treatment with SPN-812 
400 mg/day for 7 weeks (2 weeks of titration followed by 5 weeks of maintenance at a 
fixed dose) led to a statistically significant improvement in ADHD-RS-5 Total Score 
compared to placebo; however, ADHD-RS-5 Total Score during treatment with SPN-812 
600 mg/day did not showed a statistically significant improvement compared to placebo. 
Throughout treatment, AEs were reported in 39 (40.2 %), 58 (58.0%), and 
55 (55.6%) subjects in the placebo, SPN-812 400 mg/day, and SPN-812 600 mg/day 
treatment groups, respectively. The most frequently reported AEs were somnolence, 
fatigue, headache, decreased appetite, and nausea. AEs were considered to be at least 
possibly treatment related in 18 (18.6%), 44 (44.0 %), and 45 (45.5%) subjects in the 
placebo, SPN-812 400 mg/day, and SPN-812 600 mg/day treatment groups, 
respectively. AEs led to permanent study medication discontinuation (and study 
withdrawal) in 1 (1.0%), 4 (4.0%), and 5 (5.1%) subjects in the placebo, SPN-812 
400 mg/day, and SPN-812 600 mg/day treatment groups, respectively. SAEs were 
reported in 2 subjects, both in the SPN-812 400 mg/day treatment group. No deaths 
occurred during the study. 


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1.3 
Study Rationale 
In the 812P201 study, the change from baseline in CAARS total score at end of study 
(EOS) was significantly reduced with SPN-812 IR 150 to 300 mg/day compared to 
placebo in adults (ages ≥ 18 years of age) with ADHD. The efficacy and safety of 
SPN-812 showed positive results in three separate trials assessing efficacy of 
200 mg/day and two separate trials assessing efficacy of 400 mg/day SPN-812. The 
proposed doses of SPN-812 200 to 600 mg/day in the current adult study are expected 
to provide similar exposure in adults compared to that provided by 200 to 400 mg/day in 
children and adolescents. These doses fall well within the range of doses where a low 
number of AEs to no AEs were observed in Phase 1 trials (single and multiple dose), 
and those AEs that were observed were mild to moderate in severity. In addition, the 
current study is intended to expand the indication of SPN-812 treatment of ADHD in 
children/adolescents (6 to 17 years of age) to also include treatment of ADHD in adults 
(18 to 65 years of age). 
In addition to assessing the effect of SPN-812 treatment on ADHD symptom in adults 
(AISRS), the study aims to explore treatment response within other domains of the 
disorder, including functional impairment and executive functioning (Becker et al., 2011; 
Wiener et al., 2016). The prefrontal cortex (PFC) 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. These networks interact with each other 
and are highly dependent on their neurochemical environment. A change in the 
neurochemical environment can affect these networks and result in PFC dysfunction 
(Arnsten, 2006; Arnsten, 2009). ADHD is a chronic, debilitating disorder that affects 
many aspects of daily life and has a substantial burden on personal and professional 
functioning. A person with ADHD can exhibit a number of functional impairments, and 
the motivation in seeking medical treatment typically stems from the need to address 
dysfunction in social, emotional, academic, and/or familial domains (Epstein and Weiss, 
2012). Optimal medical and behavioral management should ideally incorporate 
treatments that do not just improve symptoms of ADHD, but improve the broader 
functioning of a patient, especially in the areas of self-esteem, educational achievement, 
executive function and relationships with peers, teachers, and family. In addition, the 
impact of reducing ADHD symptoms and improving executive function may have an 
impact on the presence and severity of anxiety 
 in adults, 
 
Therefore, executive function (BRIEF-A), the presence and severity of anxiety symptoms 
(GAD-7), 
 
) will be also assessed during the current study. 
In summary, the rationale for studying adult ADHD with SPN-812 is the efficacy and 
tolerability observed in the results from the four Phase 3 pediatric studies and the 
encouraging results in the Phase 2 adult ADHD study. 
 
 
 
 
 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
 
To evaluate the efficacy of SPN-812 200 mg to 600 mg compared to placebo for 
the treatment of ADHD in adults as measured by the adult ADHD Investigator 
Symptom Rating Scale (AISRS) total score. 
2.2 
Key Secondary Objectives 
 
To evaluate the efficacy of SPN-812 200 mg to 600 mg compared to placebo on 
the global assessment of severity for ADHD as measured by the Clinical Global 
Impression - Severity of Illness (CGI-S) scale.  
2.3 
Additional Secondary Objectives 
 
To evaluate the efficacy of SPN-812 200 mg to 600 mg compared to placebo on: 
1) Clinical response rate of severity of illness as measured by the 
categorical CGI-S Responder Rate (CGI-S score 1 or 2). 
2) Global assessment of improvement as measured by the Clinical Global 
Impression - Improvement (CGI-I) scale for ADHD. 
3) Clinical response rate of improvement as measured by the categorical 
CGI-I Responder Rate (CGI-I score of 1 or 2). 
4) Anxiety symptoms as measured by the Generalized Anxiety Disorder 
7-Item scale (GAD-7). 
5) Clinician-rated ADHD symptoms as measured by the AISRS subscales of 
Inattention and Hyperactivity/Impulsivity. 
6) Clinician response rate of ADHD symptom reduction as measured by the 
50% responder rate in AISRS total score. 
7) Clinician response rate of ADHD symptom reduction as measured by the 
30% responder rate in AISRS total score.  
8) Executive functioning as measured by the Behavior Rating Inventory of 
Executive Function–Adult Version (BRIEF-A; Self Report). 
9) Aspects of executive function and problems with self-regulation as 
measured by the BRIEF-A Summary Index Scales and BRIEF-A scales. 
2.4 
Safety Objective 
 
To evaluate the safety and tolerability of SPN-812 200 mg to 600 mg in adult 
subjects with ADHD.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
dacted
a Reda


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2.6 
Primary Endpoint 
 
The primary efficacy endpoint is change from baseline (CFB) at end of study 
(EOS) in the AISRS total score. 
2.7 
Key Secondary Endpoints 
 
The key secondary efficacy endpoint is the CFB at EOS in the CGI-S score. 
2.8 
Additional Secondary Endpoints 
Additional secondary efficacy endpoints are: 
1) Percentage of subjects with a CGI-S score of 1 or 2 at EOS. 
2) CGI-I score at EOS. 
3) Percentage of subjects with a CGI-I score of 1 or 2 at EOS. 
4) CFB at EOS in the GAD-7 total score.  
5) CFB at EOS in the AISRS Inattention subscale score and the 
Hyperactivity/Impulsivity subscale score.  
6) AISRS 50% responder rate (defined as the percentage of subjects with a ≥ 50% 
reduction in the CFB AISRS total score) at EOS. 
7) AISRS 30% responder rate (defined as the percentage of subjects with a ≥ 30% 
reduction in the CFB AISRS total score) at EOS. 
8) CFB at EOS in the BRIEF-A Global Executive Composite (GEC) T-score. 
9) CFB at EOS in the T-score by each BRIEF-A Summary Index Scale and by 
individual BRIEF-A scale. 
2.9 
Safety Endpoints 
The safety endpoints are adverse events (AEs), clinical safety laboratory tests, vital 
signs, weight, electrocardiograms (ECGs), physical examination, and the Columbia 
Suicide Severity Rating Scale (C-SSRS). 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 
INVESTIGATIONAL STUDY PLAN 
3.1 
Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled, multicenter, parallel group, 
flexible dose study of SPN-812 in adults diagnosed with ADHD per Diagnostic and 
Statistical Manual of Mental Disorders – 5th Edition (DSM-5™) criteria. Approximately 
366 subjects will be randomized in a 1:1 ratio (183 subjects per arm): SPN-812 (200 mg 
to 600 mg) or placebo. Following up to 5 weeks of screening, subjects will be treated 
with study medication (SM) for 6 weeks. Upon completion of the 6-week treatment 
period, subjects will be either enrolled in a separate OLE study or followed for 1 week 
after EOS for safety. The total study duration from the screening visit to the end of the 
treatment period is up to 11 weeks.  
Screening Period (Visit 1): The screening period is a minimum of 7 days and a 
maximum of 35 days. After informed consent is obtained, subjects will undergo initial 
screening evaluations and be administered the screening scales, and inclusion/exclusion 
criteria will be reviewed to confirm the subject’s eligibility. Subjects taking ADHD 
medication at screening will undergo a washout of at least 1 week (or 5 half-lives of the 
medication, whichever is longer) before the Baseline Visit (Day 1). 
Baseline and Randomization (Visit 2): At the Baseline Visit, inclusion/exclusion criteria 
will be reviewed to confirm eligibility, including pregnancy testing for females of 
childbearing potential (FOCP) and urine drug screen. Subjects with positive drug screen 
will be excluded. Subjects will also be administered the AISRS scale and CGI-S. Those 
with a Visit 2 AISRS total score of ≥ 26 and a CGI-S score of ≥ 4 will be eligible for 
randomization, and those with an AISRS total score of < 26 or a CGI-S score of < 4 will 
be excluded from study participation. On Day 1, eligible subjects will be randomized 1:1 
to SPN-812 200 mg to 600 mg or matching placebo; initial dose should be taken Day 2.  
Treatment Period (Visits 3 to 7): This period of the study will consist of 6 weeks of 
treatment with dosing starting Day 2 (morning after Visit 2) until Day 43 (Visit 7/EOS). 
The subject’s SM compliance will be assessed throughout the Treatment Period, and 
subjects who are noncompliant may be discontinued. 
Study Medication Treatment (Visits 3 to 7):  
All subjects should dose for 6 weeks starting on Day 2 (morning after Visit 2) through 
Day 43 (Visit 7/EOS) (Section 4.2). All subjects will take 2 capsules (SPN-812 200 
mg/day and/or matching placebo) daily starting on Day 1 for the first week (Week 1) 
and 2 capsules (SPN-812 400 mg/day or matching placebo) daily for the second week 
(Week 2). From Week 3 through Week 6 per the discretion of the Investigator, the 
subject’s dose may be titrated up (maximum 600 mg/day) or tapered down (minimum 
of 200 mg/day) in increments of 200 mg based on the subject’s clinical response and 
tolerability to SM. Subjects will return to the clinical site for weekly visits during this 
period of the study (except between Visits 6 and 7) to undergo efficacy and safety 
evaluations, return the previous dosing card, and receive the next card. For AEs or 
risks that cannot be managed using permitted concomitant medications (Section 4.6) 


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or other protocol-specified management (Section 6.3), SM dosing should be 
discontinued (Section 3.4) and an Early Termination (ET) Visit conducted. SM dosing 
will otherwise continue until Visit 7 (Week 6).  
End of Study (Visit 7):  
Subjects will return for final study assessments. Subjects terminated from the study 
prior to Visit 7 will also undergo safety evaluations at the time of study withdrawal at 
ET visit, however, if subject’s Early Termination (ET) visit occurs: 
 
>7 days after the date of subject’s last dose, efficacy assessments should not 
be performed/collected at ET visit  
 
≤7 days after the date of subject’s last dose, efficacy assessments should be 
performed/collected at ET visit;  
 
Unscheduled visits may be conducted at the discretion of the Investigator throughout the 
study. AEs will be assessed at all scheduled and unscheduled visits. 
Follow-up/Open-label Extension Period: Subjects who complete the 6-week treatment 
period may be eligible for an OLE safety trial. Subjects who do not enter the OLE trial 
will be contacted by telephone for safety follow-up 1 week after the EOS Visit.  
3.2 
Rationale for Study Design 
A randomized, placebo-controlled trial is the gold standard for evaluating the efficacy of 
an investigational product.  
Dose levels of SPN-812 200 to 600 mg were selected based on the efficacy results from 
the Phase 3 pediatric trials, as well as the low number and low intensity (mild or 
moderate) of AEs observed at doses from 300 to 900 mg in Phase 1 single dose and 
multiple dose studies. 
The AISRS is a validated, robust tool that measures ADHD symptoms and demonstrates 
responsiveness to change with medication in adults (Spencer et al., 2010). Change in 
AISRS total score was selected as the primary outcome measure because AISRS is a 
clinician/investigator structured interview assessing the existence and severity of ADHD 
symptoms per the DSM-IV criteria. The CGI-S was selected as a key secondary 
outcome measure because it is commonly used as a reliable measure of severity of a 
disease/disorder in clinical research, as well as a measure of change in severity over 
time during an experimental treatment.  
 
 




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9. Has a CGI-S score of ≥ 4 (moderately ill or worse) at the Screening Visit (V1) and 
Baseline Visit (V2, Day 1). 
10. Females of childbearing potential (FOCP) must be either sexually inactive 
(abstinent) or, if sexually active, must agree to use one of the following 
acceptable birth control methods beginning at least 30 days prior to the first dose 
of SM and throughout the study:  
a. Simultaneous use of male condom and intra-uterine contraceptive device 
placed at least 4 weeks prior to first SM administration 
b. Surgically sterile male partner 
c. Simultaneous use of male condom and diaphragm with spermicide 
d. Established hormonal contraceptive 
Females are considered not to be of childbearing potential if they are either post-
menopausal (amenorrhea for at least 2 years and serum follicle stimulating 
hormone [FSH] level of >40 IU/L) or permanently sterilized (e.g., bilateral tubal 
ligation, hysterectomy, bilateral oophorectomy for 6 months minimum prior to 
screening). 
11. Males must: 
a. Use 2 methods of contraception in combination if his female partner is of 
childbearing potential; this combination of contraceptive methods must be 
used from the Baseline Visit to ≥ 1 month after the last dose of SM; or 
b. Have been surgically sterilized prior to the Screening Visit. 
3.3.3 Exclusion Criteria 
1. Has previously enrolled in a SPN-812 study.  
2. Is currently participating in another clinical trial or has participated in a clinical trial 
within 60 days prior to the first Screening Visit. 
3. Is a member of the study personnel or of their immediate families, or is a subordinate 
(or immediate family member of a subordinate) to any of the study personnel. 
4. Female subjects who are pregnant, lactating and/or sexually active and not agreeing 
to use one of the acceptable birth control methods throughout the study. 
5. Has a history of severe drug allergy or hypersensitivity, or known hypersensitivity, to 
the study medication or excipients. 
6. Has a history of moderate or severe head trauma or other neurological disorder or 
systemic medical disease that, in the Investigator's opinion, is likely to affect central 
nervous system functioning. This would include subjects with: 
a. A current diagnosis of a major neurological disorder; or  
b. Seizures, seizure disorder or seizure-like events; or a history of seizure 
disorder within the immediate family (siblings, parents); or 
c. Encephalopathy 


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7. Has any history of schizophrenia, schizoaffective disorder, bipolar disorder, 
borderline personality disorder, antisocial personality disorder, narcissistic 
personality disorder, autism, post-traumatic stress disorder or obsessive-compulsive 
disorder. 
8. Has any current psychiatric disorder (per DSM-5 criteria) other than ADHD with the 
following exceptions: ADHD is primary diagnoses with comorbidity/secondary 
diagnoses of major depression disorder (MDD), nicotine dependence, social anxiety 
disorder, generalized anxiety disorder, or phobias, and subject is not receiving 
pharmacological treatment for the comorbidity/secondary diagnoses (e.g., 
antidepressant for MDD) at time of screening nor for the duration of study. 
9. Has a Symptoms of Depression Questionnaire (SDQ) mean score of >3.0 at 
screening. 
10. Has a Hamilton Anxiety Rating Scale (HAM-A) score of >21 at screening. 
11. Has organic mental disorders, or mental disorders due to a general medical condition 
(per DSM-5 criteria). 
12. Has a current diagnosis or history of substance use disorder including alcohol use 
disorder (excluding nicotine and caffeine) (per DSM-5 criteria) within the 12 months 
prior to screening; or is assessed by the Investigator as having regularly consumed 
alcohol exceeding 21 units for males and 14 units for females per week (1 unit 
equals 340 mL of beer, 115 mL of wine, or 43 mL of spirits) within the 12 months 
prior to screening. 
13. Is currently using, or has a positive result on the drug screening at the Screening 
Visit for drugs of abuse (alcohol, opiates, methadone, cocaine, methamphetamine 
[including ecstasy], phencyclidine, propoxyphene, methylphenidate, barbiturates, and 
benzodiazepines). If subject’s serum drug screen for ethanol is positive at Screening 
(V1) and the investigator determines subject does not have alcohol use disorder, 
then the subject may have a repeat serum drug screen for ethanol performed before 
baseline within the allotted screening period (results must be received prior to V2 
baseline). If second serum drug screen for ethanol is positive, subject is excluded 
from participating in the study, however, if second serum drug screen for ethanol is 
negative, subject may proceed to V2. 
14. Is a (known or self-identified) current habitual/chronic cannabis user (medicinal or 
recreational); or 
 
Has a positive urine drug screen for cannabis at the Screening Visit and is 
considered, per the Investigator’s judgement, to be a habitual/chronic 
cannabis user; or 
 
Has a positive urine drug screen for cannabis at both the screening and 
follow-up drug screen at the Baseline Visit, even though the subject is not 
considered, per the Investigator’s judgement, to be a habitual/chronic 
cannabis user. 


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Note: Subjects who have a positive urine drug screen for cannabis at the 
Screening Visit but who are not considered, per the Investigator’s judgement, to 
be a habitual/chronic cannabis user may, with Sponsor approval, undergo an 
additional urine drug screen at least 4 weeks after the initial urine drug screen at 
Baseline Visit, prior to randomization. Subjects must agree to refrain from 
cannabis use throughout study. 
15. Has treatment-resistant ADHD based on a history of receipt of >2 approved ADHD 
medications that failed to adequately improve the subject’s symptoms. A subject who 
is naïve to ADHD treatment is not excluded from study participation. 
16. Has any other disorder for which its treatment takes priority over treatment of ADHD 
or is likely to interfere with study treatment, impair treatment compliance, or interfere 
with interpretation of study results. 
17. Has a history of cancer, other than basal cell or Stage 1 squamous cell carcinoma of 
the skin that has not been in remission for > 5 years prior to the first dose of SM. 
18. Has or has had one or more of the following conditions considered clinically 
significant/relevant by the Investigator in the context of the study:  
 cardiovascular disease 
 congestive heart failure 
 cardiac hypertrophy 
 arrhythmia 
 bradycardia (pulse < 50 bpm) 
 tachycardia (pulse > 100 bpm) 
 respiratory disease 
 hepatic impairment or renal insufficiency 
 metabolic disorder 
 endocrine disorder 
 gastrointestinal disorder 
 hematological disorder 
 infectious disorder 
 any clinically significant immunological condition 
 dermatological disorder 
19. Exhibits clinically significant abnormal vital signs at screening (see Note below).  
20. Has one or more screening clinical laboratory test values outside the reference range 
that, in the opinion of the Investigator, are clinically significant, or any of the following 
(see Note below): 
 Serum creatinine > 1.5 × the upper limit of normal (ULN); 
 Serum total bilirubin > 1.5 × ULN; 
 Serum alanine aminotransferase or aspartate aminotransferase > 2 × ULN. 
21. Has any of the following cardiology findings at screening (see Note below): 
 Abnormal ECG that is, in the Investigator's opinion, clinically significant; 
 PR interval > 220 ms; 


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 QRS interval > 130 ms; 
 QTcF interval > 450 ms (for men) or > 470 ms (for women) (QT corrected 
using Fridericia’s method); 
 Second- or third-degree atrioventricular block; 
 Any rhythm, other than sinus rhythm, that is interpreted by the Investigator to 
be clinically significant. 
22. Has any disease or medication that could, in the Investigator's opinion, interfere with 
the assessments of safety, tolerability, or efficacy, or interfere with study conduct or 
interpretation of results. 
23. Evidence of infection with hepatitis B or C, or human immunodeficiency virus (HIV)-1 
or HIV-2, as determined by results of testing at screening. 
24. Lost or donated more than 450 mL of blood during the 30 days prior to screening. 
25. Use of any investigational drug or prohibited concomitant medications including 
known CYP1A2 substrates (e.g., theophylline, melatonin) within 30 days or 5 half-
lives prior to Baseline Visit (Day 1) (whichever is longer) during the screening period 
or anticipated for the duration of the study. 
26. History of unexplained loss of consciousness, unexplained syncope, unexplained 
irregular heartbeats or palpitations or near drowning with hospital admission. 
27. Has attempted suicide within the 6 months prior to screening, or is at significant risk 
of suicide, either in the opinion of the Investigator or defined as a "yes" to suicidal 
ideation questions 4 or 5 or answering "yes" to suicidal behavior on the Columbia-
Suicide Severity Rating Scale (C-SSRS) within the 6 months prior to screening. 
28. In the Investigator's opinion, is unlikely to comply with the protocol or is unsuitable for 
any other reason.  
Note: Repeat testing for clinical laboratory tests, vital signs, and ECG parameters is 
permitted one time for each test, at the discretion of the Investigator, as long as the 
repeat test result is available within the 35-day screening period to determine eligibility. 
3.4 
Completion of Study and Discontinuation of Subjects 
Subjects will be considered to have completed the study if they complete all visits up to 
and including Visit 7. 
Subjects who are randomized and dosed with SM, but who withdraw or are withdrawn 
from participation in the study by the Investigator before he/she finishes the study (i.e., 
after Visit 2 but to prior Visit 7), should complete an ET Visit. Procedures listed for Visit 7 
(see Table 2) should be completed at ET visit, with the following exception: 
If subject’s Early Termination (ET) visit occurs: 
 
>7 days after the date of subject’s last dose, efficacy assessments should not 
be performed/collected at ET visit. 
 
≤7 days after the date of subject’s last dose, efficacy assessments should be 
performed/collected at ET visit;  


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All reasons for screening failure will be recorded. If the subject passes screening but 
fails eligibility at Visit 2 (Baseline Visit), the reason(s) will also be recorded. 
The Site Investigator(s) or subjects themselves may stop SM treatment at any time for 
safety or personal reasons. A subject is free to withdraw from the study at any time for 
any reason without prejudice to their future medical care by the physician or at the 
institution. The Sponsor may also withdraw the subject at any time in the interest of 
subject safety. The withdrawal of a subject from the study should be discussed where 
possible with the Medical Monitor and Clinical Research Associate (CRA) before the 
subject stops SM. Subjects removed from the study for any reason will not be replaced. 
Reasons for a subject’s early discontinuation may include: 
 
Withdrawal of consent  
 
Noncompliance 
 
Occurrence of unmanageable AEs 
 
Lost to follow-up 
 
Other 
The primary reason for the subject’s early discontinuation, including specific reason why 
subject withdrew consent or PI ended subject’s study, must be recorded in the subject’s 
medical record and on the electronic case report form (eCRF). If the subject withdraws 
consent or the Investigator discontinues the subject’s participation in the study, the 
reason for the subject’s withdrawal or Investigator’s discontinuation of the subject should 
also be documented and captured on the eCRF. If a subject is withdrawn for more than 
one reason, each reason should be documented in the source document and the most 
medically significant reason should be entered on the eCRF. 
If a subject misses doses of SM during this study, the Investigator shall counsel the 
subject on the importance of compliance. If the subject has consistently missed doses, 
he or she may be discontinued from the study at the discretion of the Investigator and in 
consultation with the Medical Monitor; all procedures for discontinuation will be followed. 
 
 


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4 
STUDY TREATMENT 
4.1 
Study Medication Identity, Packaging and Labeling 
Study medication is supplied as capsules packaged in a double-blind configuration and 
supplied by the Sponsor in labeled blister cards. Each SM blister card will include 
identical-looking capsules that contain 200 mg of SPN-812 or matching placebo to 
provide daily dose levels of 0 mg, 200 mg, 400 mg, or 600 mg of SPN-812.  
Each blister card will supply a subject with 7 days of dosing plus 2 extra days if needed. 
Each card will be labeled with the protocol number, at a minimum. 
4.2 
Study Medication Administration 
Study medication will be administered orally once daily (QD) as intact capsules, with or 
without food. Daily dosing should occur in the morning. Splitting the daily dose (e.g., 
taking part of the daily dose in the morning and the remainder of the daily dose in the 
evening) is not permitted. Study medication will be dispensed to subject following 
randomization on Day 1 (Visit 2), however, subject should take initial dose of study 
medication the next morning on Day 2. During the first 2 weeks of the Treatment Period, 
regardless of treatment arm, subjects will take 2 capsules QD. During the remaining 4 
weeks of the Treatment Period, subjects may take a minimum of 1 capsule daily up to a 
maximum of 3 capsules QD as follows: per the Investigator’s discretion based on the 
subject’s clinical response and tolerability, the dose of SPN-812 can be titrated up or 
tapered down in increments of 200 mg/day per week to a target dose within the range 
between 200 and 600 mg/day (Table 1). However, it is recommended that subjects 
continue to take 2 capsules during Week 3.  
Table 1 
Study Medication Administration 
Treatment Arm 
Number and Identity of Capsules to be Taken QD 
During the Treatment Period 
Week 1 
Week 2 
Week 3 to Week 6 
A: Placebo 
2 Placebo 
2 Placebo 
1 to 3 Placebo 
B: SPN-812 
1 Placebo 
1 SPN-812 
2 SPN-812 
1 to 3 SPN-812 
QD = once daily 
Each SPN-812 capsule contains 200 mg SPN-812. 
4.3 
Method of Assigning Subjects to Treatment Arm 
Eligible subjects will be randomized in a 1:1 ratio at Visit 2 (Baseline) to receive placebo 
or active SPN-812.  
Treatment A: Placebo 
Treatment B: SPN-812 (200 mg to 600 mg) 


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Allocation of study treatment will occur centrally via an interactive web response system 
(IWRS) using a randomization schedule to determine the SM assignment for each 
subject being randomized. A dosing card(s) will be given to the subject at each study 
visit starting at Visit 2. 
4.4 
Blinding 
The subject and all personnel involved with the conduct and interpretation of the study, 
including the Investigators, study site personnel, the Sponsor and contract research 
organization (CRO) clinical staff, including the Medical Monitor, will be blinded to study 
medication. 
 
 
 
 
 Randomization schedule data will be kept 
strictly confidential, filed securely by the IWRS vendor, and accessible only to authorized 
persons until the time of unblinding. 
4.5 
Study Medication Handling and Accountability 
All SM will be supplied by the Sponsor to the Investigator. SM supplies must be stored in 
an appropriate secure area (e.g., locked cabinet) and stored according to the conditions 
specified on the SM label. 
Following Sponsor instructions and in compliance with International Conference on 
Harmonisation (ICH) E6 as well as local, state, and federal regulations, the Investigator 
and study staff will be responsible for the accountability of all clinical supplies (receiving, 
shipment, dispensing, inventory, and record keeping) in a SM accountability log, a copy 
of which will be collected by the Sponsor at the end of the study. 
Under no circumstances will the Investigator allow the SM to be used other than as 
directed by this protocol. Clinical supplies will not be dispensed to any individual who is 
not enrolled into the study. 
An accurate and timely record of the receipt of all clinical supplies; dispensing of SM to 
the subject; collection of unused supplies; and subsequent return of unused SM to the 
Sponsor must be maintained with dates. This SM accountability log includes, but may 
not be limited to: (a) documentation of receipt of clinical supplies, (b) SM inventory log, 
(c) SM accountability log, and (d) all shipping service receipts. Forms may be provided 
by the Sponsor. Any comparable forms that the study site wishes to use must be 
approved by the Sponsor. 
The supplies and inventory records must be made available, upon request, for 
inspection by the designated representative of the Sponsor, or a representative of the 
Food and Drug Administration (FDA). The assigned CRA will review these documents 
along with all other study conduct documents at specified intervals once SM has been 
received by the study site. All used, partly used, and unused clinical supplies, including 
 


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empty containers, are to be returned to the Sponsor at the conclusion of the study, 
unless provision is made by the Sponsor for destruction of supplies and containers at the 
study site. Upon completion of SM accountability and reconciliation procedures by study 
site personnel and documentation procedures by Sponsor personnel, SM is to be 
returned to the Sponsor with a copy of the completed SM disposition form. 
4.6 
Concomitant Medications  
Subjects may not be on any prohibited medication as indicated in the inclusion/exclusion 
criteria. SPN-812 is a strong CYP1A2 inhibitor. Substrates with a narrow therapeutic 
window are prohibited during the study. Specific prohibited concomitant medications for 
this study include known CYP1A2 substrates (e.g., theophylline, melatonin). Subjects 
receiving prior ADHD medication at screening will undergo a washout period of at least 
1 week (or 5 half-lives of the medication, whichever is longer) before the Baseline Visit 
(Day 1).  
No concomitant medications are allowed during the study, with the following exceptions: 
 
Nutritional supplements (e.g., multivitamins, fish oil) (herbal supplements are 
prohibited) 
 
EMLA® or other numbing cream for venipuncture 
 
Common over-the-counter therapies for minor transient ailments (e.g., 
acetaminophen for headache, ibuprofen for fever). 
Additional concomitant medications are allowable on a case-by-case basis at the 
discretion of the Investigator and sponsor approval. 
All concomitant medications will be recorded in the eCRF. 
Caffeine use is permitted during the study and will be recorded in the eCRF.  
5 
STUDY METHODS 
5.1 
Study Visits and Procedures 
All subjects who are randomized and take the initial dose of SM will be followed 
according to the protocol regardless of the number of doses of SM taken, unless consent 
for follow-up is withdrawn. The Sponsor or Sponsor’s designee must be notified of all 
deviations from the protocol visit or procedures, except as noted, and these procedures, 
if applicable, will be rescheduled or performed at the nearest possible time to the original 
schedule. Subjects will be instructed to call study personnel to report any abnormalities 
during the intervals in between study visits and to come to the study site if medical 
evaluation is needed and as the urgency of the situation indicates. For emergency and 
other unscheduled visits to a medical facility other than the study site, medical records 
will be obtained by the Investigator or qualified designee as source data for study 
follow-up. 
The Schedule of Events and Assessments for the study is shown in Table 2. 


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Table 2 
Schedule of Events and Assessments 
Study Period 
Screening 
Baseline 
Treatment 
EOS/ET 
Follow-upa 
(phone call) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
FPCa 
Day of Study 
-35 to -1 
1 
8 
15 
22 
29 
43 
50 
Week of Study  
-5 to -1 
̶ 
1 
2 
3 
4 
6 
̶ 
Study Visit Window 
̶ 
̶ 
 2 
 2 
 2 
 2 
 2 
 2 
Signed informed consent 
 
 
 
 
 
 
 
 
SCID-5-CT 
 
 
 
 
 
 
 
 
HAM-A 
 
 
 
 
 
 
 
 
Relevant histories (social, 
medical, psychiatric, family 
psychiatric, neurological) 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
Smoking, alcohol 
consumption use/history 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
Height 
 
 
 
 
 
 
 
 
Blood sample for FSH     
(Post-menopausal females 
only) 
 
 
 
 
 
 
 
 
Serum pregnancy test  
(FOCP only) 
 
 
 
 
 
 
 
 
Serology 
 
 
 
 
 
 
 
 
Subject training video module 
 
 
 
 
 
 
 
 
Review eligibility criteria 
 
 
 
 
 
 
 
 
Randomize 
 
 
 
 
 
 
 
 
Review adverse events 
 
 
 
 
 
 
 
 
Review concomitant 
medications and caffeine use 
 
 
 
 
 
 
 
 
Hematology/serum chemistry 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
 
 
Serum drug screen 
 
 
 
 
 
 
 
 
Urine drug screen c, g  
       c, g      h 
  h 
  h 
  h 
  h 
  h 
 
Urine pregnancy test (FOCP) 
 
 
 
 
 
 
 
 
Orthostatic BP/HR b 
 
 
 
 
 
 
 
 
Vital signs d and weight 
 
 
 
 
 
 
 
 
C-SSRS 
 
 
 
 
 
 
 
 


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Study Period 
Screening 
Baseline 
Treatment 
EOS/ET 
Follow-upa 
(phone call) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
FPCa 
Day of Study 
-35 to -1 
1 
8 
15 
22 
29 
43 
50 
Week of Study  
-5 to -1 
̶ 
1 
2 
3 
4 
6 
̶ 
Study Visit Window 
̶ 
̶ 
 2 
 2 
 2 
 2 
 2 
 2 
AISRS f 
 
 
 
 
 
 
 e 
 
CGI-S f 
 
 
 
 
 
 
 e 
 
CGI-I f 
 
 
 
 
 
 
 e 
 
GAD-7 
 
 
 
 
 
 
 e 
 
BRIEF-A  
 
 
 
 
 
 
 e 
 
SDQ 
 
Blood sample for PGx 
(optional) 
 
 
 
 
 
 
 
 
SM dispensed 
 
 
 
 
 
 
 
 
SM returned and 
accountability  
 
 
 
 
 
 
 
 
 
 ADHD = attention deficit/hyperactivity disorder; AISRS = Adult 
ADHD Investigator Symptom Rating Scale; BP = blood pressure; BRIEF-A = Behavior Rating Inventory of 
Executive Function–Adult Version (Self)=; CGI-I = Clinical Global Impression – Improvement scale; CGI-S 
= Clinical Global Impression – Severity of Illness scale; C-SSRS = Columbia Suicide Severity Rating Scale; 
ECG = electrocardiogram; EOS = end of study; ET = early termination; FOCP = females of childbearing 
potential; FPC = follow-up phone call; FSH = follicle stimulating hormone; GAD-7 = Generalized Anxiety 
Disorder 7-item scale; HAM-A = Hamilton Anxiety Rating Scale; HR = heart rate; PGx = 
pharmacogenomics; 
; POC = “Point of Care’; SCID-5-CT = Structured Clinical 
Interview for DSM-5 Clinical Trials version; SDQ = Symptoms of Depression Questionnaire; SM = study 
medication; UDS = urine drug screen. 
a. 
Follow-up assessments (via phone calls) are only required for subjects who do not enroll in the open-
label extension study. 
b. 
Orthostatic blood pressure and heart rate should be measured after the subject has been seated for at 
least 5 minutes and within 3 minutes of standing. 
c. 
With sponsor approval, subjects who exhibit a positive urine drug screen for cannabis at the Screening 
Visit and, per Investigator judgement, are not considered a habitual/chronic cannabis user, may 
undergo an additional urine drug screen at the Baseline Visit to determine eligibility; see Exclusion 
Criterion 14 in Section 3.3.3 for details.  
d. 
Blood pressure, heart rate, respiratory rate, and oral temperature. 
e. 
If subject’s ET visit is conducted >7 days after the date of subject's last dose, do not perform/collect 
efficacy assessments at ET visit
 
f. 
Investigator-rated efficacy assessments should be performed/conducted/collected prior to 
administering any self-report efficacy assessments to subjects. 
g. 
Perform Standard UDS and Point of Care UDS Test 2 only (V1; Table 3).  
h. 
Perform Point of Care UDS both Test 1 and Test 2 (V2-V7; Table 3). 
 
 
 
 
 
 
 
 
  


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5.1.1 Visit 1 – Screening  
The following assessments will be conducted: 
 
ICF signed 
 
SCID-5-CT, HAM-A and SDQ 
 
Social, medical, psychiatric, family psychiatric, and neurological histories 
 
Demographics 
 
Smoking and alcohol consumption use/history 
 
Physical examination and height 
 
Blood sample for: 
o FSH (post-menopausal females only) 
o Serum pregnancy test (FOCP only) 
o Hematology and serum chemistry (non-fasted sample allowed) 
o Serology (HIV, Hepatitis B and Hepatitis C)  
o Serum drug screen (ethanol) 
 
Urine sample for: 
o Urinalysis 
o ‘Standard’ UDS and Point of Care UDS Test 2 (Table 3) 
 
Orthostatic blood pressure/heart rate 
 
Vital signs and weight 
 
ECG 
 
C-SSRS 
 
Subject training video module 
 
AISRS and CGI-S 
 
Eligibility criteria 
 
Concomitant medications and caffeine use 
5.1.2 Visit 2 – Baseline (Randomization) 
The following assessments will be conducted: 
 
Blood sample for hematology and serum chemistry (non-fasted sample allowed) 
 
Urine sample for:  
o Urinalysis 
o Point of Care UDS Test 1 and Test 2 (Table 3)* 
o Urine pregnancy test (FOCP only) 
 
Orthostatic blood pressure/heart rate 
 
Vital signs and weight 
 
ECG 
 
C-SSRS 
 
Subject training video module 
 
AISRS, CGI-S, GAD-7, BRIEF-A, 
 
 
Eligibility criteria 
 
Concomitant medications and caffeine use 
 
Blood sample for pharmacogenomics (PGx; optional) 
 
Randomization 
 
SM dispensed 
 


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5.1.3 Visits 3 to 7 – Treatment Period Including End of Study 
Visit 3 – Week 1 
The following assessments will be conducted: 
 
Urine sample for: 
o Point of Care UDS Test 1 and Test 2 (Table 3)** 
o Urine pregnancy test (FOCP only) 
 
Orthostatic blood pressure/heart rate 
 
Vital signs and weight  
 
C-SSRS 
 
AISRS, CGI-S, and CGI-I 
 
AEs 
 
Concomitant medications and caffeine use 
 
SM dispensed 
 
SM return and accountability 
Visit 4 – Week 2 
The following assessments will be conducted: 
 
Urine sample for: 
o Point of Care UDS Test 1 and Test 2 (Table 3)** 
o Urine pregnancy test (FOCP only) 
 
Orthostatic blood pressure/heart rate 
 
Vital signs and weight 
 
C-SSRS 
 
Subject training video module 
 
AISRS, CGI-S, CGI-I, and GAD-7 
 
AEs 
 
Concomitant medications and caffeine use 
 
SM dispensed 
 
SM return and accountability 
Visit 5 – Week 3 
The following assessments will be conducted: 
 
Urine sample for: 
o Point of Care UDS Test 1 and Test 2 (Table 3)** 
o Urine pregnancy test (FOCP only) 
 
Orthostatic blood pressure/heart rate 
 
Vital signs and weight 
 
C-SSRS 
 
AISRS, CGI-S, and CGI-I 
 
AEs 
 
Concomitant medications and caffeine use 
 
 
 
SM dispensed 
 
SM return and accountability 
 


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Visit 6 – Week 4 
The following assessments will be conducted: 
 
Urine sample for: 
o Point of Care UDS Test 1 and Test 2 (Table 3)** 
o Urine pregnancy test (FOCP only) 
 
Orthostatic blood pressure/heart rate 
 
Vital signs and weight 
 
C-SSRS 
 
Subject training video module 
 
AISRS, CGI-S, CGI-I, and GAD-7 
 
AEs 
 
Concomitant medications and caffeine use 
 
 
 
SM dispensed 
 
SM return and accountability 
Visit 7 – Week 6/EOS 
The following assessments will be conducted: 
 
Physical examination  
 
Blood sample for hematology and serum chemistry (non-fasted sample allowed) 
 
Urine sample for: 
o Urinalysis  
o Point of Care UDS Test 1 and Test 2 (Table 3)** 
o Urine pregnancy test (FOCP only) 
 
Orthostatic blood pressure/heart rate 
 
Vital signs and weight 
 
ECG 
 
C-SSRS 
 
AISRS, CGI-S, CGI-I, GAD-7, BRIEF-A, 
 
 
AEs 
 
Concomitant medications and caffeine use 
 
 
 
SM return and accountability 
*  At the baseline visit (Visit 2), the Point of Care urine drug screen should be 
completed and results known first before randomizing subject or performing any 
efficacy assessments. If a subject has a positive drug screen at the baseline visit, 
he/she is excluded from participating in the study.   
**  At all post-baseline study visits (Visit 3-7/EOS), the Point of Care urine drug screen 
should be completed and results known first before any efficacy assessments are 
conducted. If a subject has a positive drug screen at any post-baseline visit (V3-V7), 
then the subject’s participation in the study should be ended/terminated and no 
efficacy assessments (AISRS, CG-S, CGI-I, GAD-7, BRIEF-A, 
) 
should be performed at that visit (ET); all safety assessments should still be 
 
 
 
 


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performed/completed at the visit. A follow-up phone call with the subject should also 
be performed 1 week following discontinuation of SM/study. 
NOTE: At each study visit, Investigator-rated efficacy assessments (AISRS, CGI-S, 
CGI-I) should be performed/conducted/collected prior to administering any self-report 
efficacy assessments to subjects.  
NOTE: When training video module is scheduled, the subject must view the training 
video module prior to administering any efficacy assessments (AISRS, CGI-S, CGI-I, 
GAD-7, BRIEF-A, 
). 
NOTE: For subjects who discontinue/terminate early (ET Visit), EOS assessments 
will be performed at ET visit, however, efficacy assessments (AISRS, CGI-S, CGI-I, 
GAD-7, BRIEF-A
 should not be 
collected if the ET visit occurs >7 days after date of subject’s last dose of SM. 
5.1.4 FPC – Follow-up Phone Call (Not for Subjects Who Enter OLE Study) 
Those subjects who do not enter the OLE study will be contacted via telephone for the 
following assessments approximately 1 week after the EOS Visit: 
 
AEs 
 
Concomitant medications and caffeine use  
5.1.5 Unscheduled Visits 
At the discretion of the investigator throughout the study, unscheduled visits may be 
conducted to perform or repeat assessments, including record ECG, measure vital signs 
and weight (orthostatic blood pressure/heart rate), draw blood sample for hematology 
and/or serum chemistry or serum pregnancy test (FOCP) or ethanol drug screen, obtain 
urine sample for urine pregnancy test and/or drug screen, administer C-SSRS, perform 
physical examination. AEs and concomitant medications should also be assessed at all 
unscheduled visits. SM may also be dispensed and/or returned at unscheduled visits if 
needed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
d
 
 
  


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5.1.7 Future Research 
If the subject consents to have samples used for future research, including but not 
limited to PGx testing, this additional research may not start immediately and may start 
at any time during the sample storage period.  
Subjects who have provided consent for PGx testing will have a blood sample taken at 
baseline. If PGx testing is performed, results from individual tests will be used for 
research purposes only, and a report separate from the clinical study report will be 
generated. Samples will be identified only by the study subject number to maintain 
confidentiality. If a given subject’s 
 safety data warrant evaluation of PGx, DNA will 
be extracted from that subject’s PGx blood sample and tested for any genetic variations 
associated with CYP2D6 enzyme. This enzyme is involved in the metabolism of 
viloxazine and genetic variation may affect the PK of SPN-812. Samples will be stored 
for up to 10 years for potential future research purposes such as possible testing of 
genes involved in the efficacy of the drug and possible association with particular 
adverse events of the drug (i.e., to facilitate an understanding of non-responders to 
treatment and/or individuals who show an unusual safety profile). The DNA analysis will 
not be used for individual genetic characterization, and the subject’s identity will be kept 
confidential.  
Data from samples will not have diagnostic value and will not be used for individual 
genetic characterization or development of a commercial product. At the end of testing 
or 10 years, any remaining samples will be destroyed. The subject may withdraw 
consent for PGx testing at any time; if consent is withdrawn, the subject’s sample will be 
destroyed.   
 
 
 
a Reda
 


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6 
STUDY VARIABLES AND ASSESSMENTS 
6.1 
Efficacy Assessments 
6.1.1 Adult ADHD Investigator Symptom Rating Scale (AISRS) 
The adult ADHD Investigator Symptom Rating Scale (AISRS) was developed to better 
measure the presence and severity of ADHD symptoms based on DSM-IV diagnostic 
criteria in adult patients (Spencer et al., 2010; Appendix 11.1.1). It is a semi-structured 
clinical interview with suggested prompts for each item to improve interrater reliability. 
The scale consists of 18 items that directly correspond to the 18 symptoms of ADHD and 
are further subdivided into two subscales: Inattention (9 items) and 
Hyperactivity/Impulsivity (9 items). During the interview with the subject, the 
clinician/investigator rates the frequency and severity of each symptom on a 4-point 
Likert-type scale, where 0 = None, 1 = Mild, 2 = Moderate, and 3 = Severe, with a 
maximum total score of 54 points and maximum subscale score of 27 points. The scale 
allows the assessment of functional impairments linked to each symptom dimension. 
The AISRS total score is the sum of the Inattention and Hyperactivity/Impulsivity 
subscale scores.  
The AISRS is used to assess drug efficacy in the treatment of ADHD in adults, and the 
AISRS total score is the primary outcome measure for this study.  
6.1.2 Clinical Global Impression – Severity of Illness (CGI-S)  
The CGI scale was developed to provide a brief, stand-alone assessment of the 
clinician’s view of a subject’s global functioning prior to and after administration of SM 
(Guy, 1976). The Clinical Global Impression – Severity of Illness scale (CGI-S; Appendix 
11.1.2) is a single item clinician rating of the clinician’s assessment of the severity of the 
ADHD symptoms in relation to the clinician’s total experience with patients with ADHD. 
The CGI-S is evaluated on a 7-point scale, where 1 = Normal, not at all ill, 
asymptomatic, 2 = Borderline Ill, 3 = Mildly Ill, 4 = Moderately Ill, 5 = Markedly Ill, 6 = 
Severely Ill, and 7 = Extremely Ill. Successful therapy is indicated by a lower overall 
score in subsequent testing. 
6.1.3 Generalized Anxiety Disorder 7-item Scale (GAD-7)  
Generalized Anxiety Disorder 7 scale (GAD-7) is a self-reported 7-item questionnaire for 
screening and measuring the severity of generalized anxiety disorder (Spitzer et al., 
2006; Appendix 11.1.4). The GAD-7 measures the severity of various symptoms of 
generalized anxiety disorder over the past 2 weeks according to reported response 
categories with assigned points. The patient scores each GAD-7 item on 4-point Likert 
scale, where 0 = Not at all, 1 = Several days, 2 = Over half the days, and 3 = Nearly 
every day. The clinician/investigator can obtain the total score by summating all 7 items. 
GAD-7 total scores range from 0 to 21, where a total score of 1 to 4 = None/Minimal 
anxiety, 5 to 9 = Mild anxiety, 10 to 14 = Moderate anxiety, and ≥ 15 = Severe anxiety. It 
takes less than 5 minutes to complete the GAD-7.  


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6.1.4 Clinical Global Impression – Improvement (CGI-I)  
The CGI scale was developed to provide a brief, stand-alone assessment of the 
clinician’s view of a subject’s global functioning prior to and after administration of SM 
(Guy, 1976). The Clinical Global Impression – Improvement scale (CGI-I; Appendix 
11.1.3) is an assessment of how much the patient’s illness has improved or worsened 
relative to a baseline state at the beginning of treatment. The CGI-I is evaluated by the 
investigator at each post-baseline study visit during treatment relative to the subject’s 
condition at baseline on a 7-point scale where 1 = Very much improved, 2 = Much 
improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much 
worse, and 7 = Very much worse. Successful therapy is indicated by a lower overall 
score in subsequent testing. The CGI-S assessment obtained at the baseline visit should 
serve as a basis for the investigator’s CGI-I assessment of improvement in the subject’s 
conditions at each post-baseline study visit during the treatment period. 
6.1.5 Behavior Rating Inventory of Executive Function–Adult (BRIEF-A) 
The Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A; Self 
report) is a standardized rating scale that captures views of an individual’s executive 
functions into everyday behaviors in adults ages 18 to 90 years (Roth et al., 2005; Roth 
et al., 2013; Appendix 11.1.5). It has been utilized in clinical trials to assess changes in 
executive function with treatment for neurological and psychiatric disorders, including 
ADHD (Adler et al 2014). The BRIEF-A is 75-item in nine non overlapping scales and 
two summary index scales that assesses aspects of executive function and problems 
with self-regulation from the perspective of the individual. The subject rates each item on 
a 3-point Likert scale (Never, Sometimes, or Often) based on their experienced within 
the last month. Higher scores indicate poorer executive function. The BRIEF-A takes 15-
20 minutes to complete. The self-report provides the insight of the individual’s viewpoint 
of their own difficulties in self-regulation.  
Description of the nine BRIEF-A scales (Roth et al., 2013) by summary index scale: 
1. 
The Behavioral Regulation Index (BRI) captures the ability to maintain 
appropriate regulatory control of one’s own behavior and emotional responses. 
The BRI is broken down into the following four scales within the BRIEF-A: 
 
Inhibit: Control impulses; appropriately stop verbal, attentional, physical 
behavior at the proper time 
 
Shift: Move freely from one situation, activity, or aspect of a problem to 
another as the situation demands; think flexibly to aid problem-solving 
 
Emotional control: Modulate one’s emotional responses appropriately 
 
Self-Monitor: Recognize the effect of one’s own behavior on others  
2. 
The Metacognitive Index (MI) reflects the individual’s ability to initiate activity and 
generate problem-solving ideas, to sustain working memory, to plan and 
organize problem-solving approaches, to monitor success and failure in problem 


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solving, and to organize one’s materials and environment. The MI is broken down 
into the following four scales within the BRIEF-A: 
 
Initiate: Begin a task or activity without external prompting; independently 
generate ideas 
 
Working memory: Hold information in mind in order to complete a task; stay 
with, or stick to, an activity 
 
Plan/organize: Anticipate future events; set goals; develop steps ahead of 
time to carry out a task; organize information and behavior to achieve and 
objective; carry out tasks in a systematic manner 
 
Task Monitor: Assess performance during or after finishing a task for 
mistakes 
 
Organization of Materials: Keep workspace and living areas in an orderly 
manner; keep track of materials needed for tasks 
6.1.6 Symptoms of Depression Questionnaire (SDQ) 
The Symptoms of Depression Questionnaire (SDQ) is designed to measure the severity 
of symptoms across several subtypes of depression and was developed (items chosen) 
on the basis of the most current knowledge of depressive symptoms and Major 
Depressive Disorder (MDD) subtypes (Pedrelli et al., 2014; Appendix 11.1.6). The SDQ 
is a 44-item self-report depression scale that inquires about an extensive number of 
depressive symptoms. Items reflect a broad and heterogeneous collection of depression 
related symptom features, and it includes several items that inquire about anxiety 
symptoms. The SDQ has been utilized in clinical trials along with other commonly used 
scales like the Montogmery Asberg Depression Rating Scale (MADRS) assessing 
potential treatments in patients with depression (Fava et al., 2016; Papakostas et al., 
2019).  The subject self-rates/scores each item on a 6-point scale (1-6) as it pertains to 
the past month. Each item is rated based on a subject’s perception of what is normal for 
the individual (score = 2), what is better than normal (score = 1), and what is worse than 
normal (scores = 3–6). A SDQ average (mean) score greater than 3.5, which is 
equivalent to a Montgomery-Asberg Depression Rating Scale (MADRS) score of 25, is 
consistent with severe depression (Fava et al., 2016). The clinician/investigator 
generates a total score (SDQ-T) by summated all 44 scores. SDQ total scores can range 
from 44-264. SDQ-T refers to the total score of the SDQ. SDQ-1 subscale includes items 
related to lassitude, mood, and cognitive functioning; SDQ-2 subscale includes items 
related to anxiety, agitation, irritability, and anger; SDQ-3 subscale includes items 
related to suicidal ideation. SDQ-4 subscale assesses disruptions in sleep quality. SDQ-
5 subscale includes items on changes in appetite and weight. The SDQ takes less than 
10 minutes to complete. 
 
  
 
 
 
 
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6.2 
Safety Variables and Assessments  
Safety assessments include monitoring, evaluation, and recording of all concomitant 
medications, and the evaluation of AEs, clinical laboratory test results, vital signs and 
12-lead ECGs, C-SSRS, and the performance of physical examinations as detailed in 
the Schedule of Events and Assessments. 
Investigators are responsible for monitoring the safety of subjects who have entered this 
study and for alerting Supernus or its designee to any event that seems unusual, even if 
this event may be considered an unanticipated benefit to the subjects.  
6.2.1 Adverse Events  
As defined by the ICH Guideline for Good Clinical Practice (GCP), an adverse event 
(AE) is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with treatment. 
An AE can be, for example: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• 
Any new disease, intercurrent injuries, or exacerbation of an existing disease. 
 


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• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG) that results in 
symptoms, a change in treatment, or discontinuation from SM. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 
Surgical procedures are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period.  
6.2.2 Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) are defined as seizure or AEs that might 
represent a seizure. This includes, but is not limited to syncope/syncopal episode, 
pseudoseizure, myoclonus, and severe muscle spasms. 
6.2.3 Causality 
Adverse events may be categorized as either Adverse Drug Reactions or Suspected 
Adverse Drug Reactions based on their relationship to SM and the degree of certainty 
about causality. 
Suspected adverse drug reactions (SADRs) are a subset of adverse events for which 
there is evidence to suggest a causal relationship between the drug and the AE, i.e., 
there is a reasonable possibility that the drug caused the adverse event.  
Adverse drug reactions (ADRs) are a subset of all SADRs for which there is reason to 
conclude that the drug caused the event. 
6.2.4 Recording and Evaluation of Adverse Events 
All subjects who are screened (Visit 1) will be questioned regarding any current and prior 
medical health status or diagnoses, which will be documented as medical history. At 
each contact with the subject following first dose of SM (post-Visit 2), the Investigator 
must seek information on AEs by specific questioning and, as appropriate, by 
examination. Information on all AEs should be recorded immediately in the source 
document, and also in the appropriate adverse event module of the eCRF. All clearly 
related signs, symptoms, and abnormal diagnostic procedures results should be 
recorded in the source document, though they may be grouped under one diagnosis. For 
example, fever, elevated WBC, cough, abnormal chest X-ray, etc., can all be reported as 
“pneumonia”. 
All AEs occurring after Visit 2 and throughout the study period must be recorded. A 
treatment-emergent adverse event (TEAE) is defined as an AE with a start date on or 
after the first dose of study medication is taken, or that worsened following first 
administration of study medication. All AEs in this study will be recorded after 
administration of SM, therefore all will be treatment-emergent. The clinical course of 
each AE should be followed for at least 30 days following the date of last dose of SM 
(either due to EOS or ET) or until resolution, or until, in the medical judgment of the 
Investigator, the event has stabilized or is assessed as chronic. 


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The Investigator is responsible for evaluating AEs and determining the following: 
• 
Serious vs. Non-serious: Is the event a Serious Adverse Event (SAE)? 
• 
Causality: Was AE related or possibly related to the SM? 
• 
Severity: How pronounced is the incapacity/discomfort caused by an AE? 
6.2.5 Criteria for Assessing Severity 
The Investigator will evaluate the comments of the subject and the response to 
treatment in order that he or she may judge the true nature and severity of the AE. 
Severity refers to the accumulated intensity of discomfort/impairment of health since the 
last recording of AEs and will be assessed according to the following criteria: 
• Mild: 
Awareness of sign, symptom, or event, but easily tolerated 
• Moderate: 
Discomfort enough to interfere with usual activity and may 
warrant intervention 
• Severe: 
Incapacitating with inability to do usual activities or significantly 
affects clinical status and warrants intervention 
The criteria for assessing severity are different from those used for seriousness. 
6.2.6 Criteria for Assessing Causality 
The Investigator is responsible for determining the relationship between the 
administration of SM and the occurrence of an AE as not suspected or as a suspected 
reaction to SM. These are defined as follows: 
Not suspected: The temporal relationship of the AE to SM administration makes a 
causal relationship unlikely, or other drugs, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed event.  
• Not related:  Temporal relationship to SM administration is missing or 
implausible, or there is an evident other cause. 
• Unlikely related:  Temporal relationship to SM administration makes a causal 
relationship improbable; and other drugs, chemicals, or underlying disease 
provide plausible explanations. 
Suspected: The temporal relationship of the AE to SM administration makes a causal 
relationship possible, and other drugs, therapeutic interventions, or underlying 
conditions do not provide a sufficient explanation for the observed event.  
• Possibly related:  Temporal relationship to SM administration is plausible, but 
concurrent disease or other drugs or chemicals could also explain event. 
Information on drug withdrawal may be lacking or unclear. This will be 
reported as a Suspected Adverse Drug Reaction (SADR). 
• Definitely related: Temporal relationship to SM administration is plausible, 
and concurrent disease or other drugs or chemicals cannot explain event. The 
response to withdrawal of the medication (dechallenge) should be clinically 
plausible. The event must be definitive pharmacologically or 
phenomenologically, using a satisfactory rechallenge procedure if necessary. 
This will be reported as an Adverse Drug Reaction (ADR). 


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6.2.7 Serious Adverse Events 
Adverse events are classified as serious or non-serious. An AE or ADR is considered 
“serious” if, in the view of either the Investigator or Sponsor, it results in one of the 
following outcomes:  
 
death 
 
life-threatening AE (i.e., the subject was at immediate risk of death from the AE 
as it occurred. This does not include an event that, had it occurred in a more 
severe form or was allowed to continue, might have caused death.) 
 
in-patient hospitalization or prolongation of existing hospitalization 
 
persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions 
 
a congenital anomaly or birth defect 
 
an important medical event 
Important medical events are those that may not be immediately life threatening or result 
in death or hospitalization, but are clearly of major clinical significance. They may 
jeopardize the subject, and may require intervention to prevent one of the other serious 
outcomes noted above. For example, drug overdose or abuse, blood dyscrasias, a 
seizure that did not result in in-patient hospitalization or intensive treatment for allergic 
bronchospasm in an emergency department would typically be considered serious. 
6.2.8 Investigator Responsibilities for Reporting SAEs 
The Investigator must immediately report to the Sponsor all SAEs, regardless of whether 
the Investigator believes they are drug related. 
All SAEs must be reported to the Drug Safety Contact within 24 hours of first becoming 
aware of the SAE. The Investigator must complete an SAE Form and include a detailed 
description of the SAE, as well as other available information pertinent to the case (e.g., 
hospital records, autopsy reports and other relevant documents). The Investigator will 
keep a copy of this SAE Report form on file at the study site. 
The Investigator or study physician, after thorough consideration of all facts that are 
available, must include an assessment of causality of an AE to SM in the report to the 
Sponsor. 
SAEs should be followed until resolution or until no further/additional information can be 
obtained regarding the event. Follow-up information, or new information available after 
the initial report, should be actively sought and reported to the Sponsor, as it becomes 
available, using the SAE Report Form. 
The Drug Safety Contact for SAE reporting is: 
 


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6.2.9 Other Events Requiring Immediate Reporting 
The Investigator must report a pregnancy that occurs in a subject during a clinical study 
to the Drug Safety Contact within 24 hours of first becoming aware of the event. 
Subjects who become pregnant during the study should be discontinued from study 
medication immediately. Pregnancy should be reported on a Pregnancy Report Form. 
The Investigator should discuss the case with the Medical Monitor; the Investigator must 
follow any pregnant subject for 3 months after the child is born. Any AEs concerning the 
pregnancy of the subject during pregnancy or the child after birth must be documented 
and reported to the Sponsor. 
Acute suicidal crisis or clinically significant suicidal behavior or ideation should be 
reported to the Drug Safety Contact within 24 hours of first becoming aware of the event. 
6.2.10 Sponsor Responsibilities for Reporting SAEs 
The Sponsor will inform Investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (i.e., within 
specific timeframes). For this reason, it is imperative that study sites submit SAE 
information to the Sponsor in the manner described above. 
Investigators must comply with the applicable regulatory requirements related to the 
reporting of SAEs to the Institutional Review Board (IRB). Investigators must also submit 
the safety information provided by the Sponsor to the IRB unless the country legal 
regulation requires that the Sponsor should be responsible for the safety reporting to the 
IRB. 
It is the responsibility of the Sponsor to notify all participating Investigators, in a written 
IND safety report, of any SADR that is both serious and unexpected. The Sponsor will 
also notify participating Investigators of any findings from other sources (other studies, 
animal and in vitro testing, etc.) that suggest a significant risk for human subjects. Such 
findings will typically lead to safety-related changes in the study protocol, Informed 
Consent, and/or Investigator’s Brochure. 
6.3 
Treatment-Emergent Suicidal Ideation 
Prospective assessment of suicidal ideation and suicidal behavior is a mandatory part of 
the safety evaluations for any drug developed for a psychiatric indication (FDA, 2012). In 
this study, the initial evaluation of subjects will be conducted prior to enrollment to 
assess lifetime suicidal ideation and to identify subjects who must not participate in the 
trial due to pre-existing suicidality risk. The assessment will then be repeated at each 
subsequent study visit to monitor the occurrence of new suicidal and self-injurious 
tendencies. 
6.3.1 Columbia Suicide Severity Rating Scale (C-SSRS) 
Assessment of suicidal ideation and behavior will be conducted using the Columbia-
Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2011; [Baseline] Appendix 
11.1.10; [Since Last Visit] Appendix 11.1.11). The C-SSRS is an FDA-recommended 
prospective assessment instrument that directly classifies suicidal ideation and behavior 


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events into 11 preferred categories, including 5 levels of suicidal ideation, 5 levels of 
suicidal behavior, and the category of self-injurious behaviors with no suicidal intent.  
The instrument has been validated used successfully in adult patients with various 
psychiatric disorders that do not involve cognitive impairment. The C-SSRS outcomes 
that can be used for clinical management and safety monitoring are suicidal lethality 
rating, suicidal ideation score, and suicidal ideation intensity rating. 
6.3.2 Suicide Risk Management Plan 
The protocol procedures related to clinical care of patients with treatment-emergent 
suicidal ideation and behavior must be implemented to ensure proper management of 
the event and protection of subject’s safety. If a disclosure of suicidal ideation is 
revealed as part of the C-SSRS questionnaire or when a subject spontaneously 
expresses that he/she may be a threat to him/herself, the study team should be 
prepared to quickly evaluate the event and to determine the appropriate course of 
action. 
6.3.2.1 Assessment of Suicide Risk 
Any indication of suicidal ideation should be evaluated as soon as possible by 
appropriately trained staff. The Investigator is responsible for making the final judgment 
regarding potential suicide risk and need subsequent action.  
6.3.2.2 Acute Suicidal Crisis 
A person evaluated as being at high risk should be transferred to an immediate care 
facility. The Investigator will guide intervention as clinically indicated and follow up with 
the subject within 1 week and/or refer him/her to a qualified mental health professional. 
6.3.2.3 Non-acute Suicidal Risk 
The Investigator will conduct safety planning with the subject and will follow up within 
1 week. 
Reference materials for subjects and caregivers should include lists of mental health 
organizations and professionals, outpatient behavioral services, local crisis and peer 
support groups and Suicide/Crisis Hotlines. 
6.4 
Clinical Measurements 
6.4.1 Screening and Clinical Safety Laboratory Assessments 
All clinical laboratory tests will be performed by a central laboratory as specified in the 
reference binder. 
Details for collecting, handling, and shipping samples (including shipment addresses) 
will be detailed in a separate clinical laboratory manual. The Schedule of Events and 
Assessments (Table 2) shows the time points at which blood and urine samples will be 
collected. Table 3 presents the clinical laboratory tests to be performed. At Screening 


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(Visit 1) perform the serum drug screen (ethanol), the ‘Standard’ urine drug screen 
(UDS) and ‘Point of Care’ UDS (Test 2 only). Perform the ‘Point of Care’ drug screen 
(Test 1 and Test 2) at baseline (Visit 2) and at every subsequent study visit during 
treatment period (Visit 3-7). 
Table 3 
Clinical Laboratory Tests 
Category 
Parameters 
Serology 
Human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B, 
hepatitis C 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, and 
WBC count with differential  
Chemistry 
Electrolytes: Chloride, phosphate, potassium, sodium 
Liver function tests: Alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, total bilirubin, direct 
bilirubin  
Renal function parameters: Blood urea nitrogen, creatinine 
Other: Glucose, Ca+2, albumin, total protein, bicarbonate 
FSH: Post-menopausal females only 
Urinalysis 
Macroscopic examinationa, pH, specific gravity, protein, glucose, 
ketone, occult blood, WBC, nitrites, bilirubin, urobilinogen 
Serum Drug Screen  
Ethanol 
‘Standard’  
Urine Drug Screen (UDS) 
amphetamines, barbiturates, benzodiazepines, buprenorphine, 
cocaine, ecstasy, methadone, methamphetamine, opiates, 
oxycodone, phencyclidine, propoxyphene, tricyclic 
antidepressant, THC (cannabinoids) 
‘Point of Care’  
Urine Drug Screen (UDS) 
Test 1: amphetamines, barbiturates, benzodiazepines, 
buprenorphine, cocaine, ecstasy, methadone, 
methamphetamine, opiates, oxycodone, phencyclidine, 
propoxyphene, tricyclic antidepressant, THC (cannabinoids). 
 
Test 2: methylphenidate 
Pregnancy test (blood 
sample at screening, urine 
sample at other time 
points) 
FOCP only 
FOCP = females of childbearing potential; FSH = follicle stimulating hormone; WBC = white blood cell 
a A microscopic examination will be performed on abnormal findings unless otherwise specified. 
6.4.2 Vital Signs and Weight 
Vital signs measurements (includes orthostatic blood pressure/heart rate, respiratory 
rate and body [oral] temperature) and body weight will be obtained at the time points 
shown in the Schedule of Events and Assessments (Table 2). Orthostatic blood pressure 
and heart rate should be measured after the subject has been sitting for 5 minutes and 
again within 3 minutes of subject standing. Vital signs may be taken at any other time, as 
deemed necessary by the Site Investigator. 


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6.4.3 Physical Examinations and Height 
Physical examinations and measurement of height will be obtained at the time points 
shown in the Schedule of Events and Assessments (Table 2). The physical examination 
conducted at screening will include assessments of all body systems except 
genitourinary. Any findings during screening will be recorded as medical history and any 
clinically significant abnormal findings during treatment will be recorded as an AE. At the 
EOS physical examination, only changes from baseline (Screening Visit) will be noted.  
6.4.4 Electrocardiograms (ECGs) 
A 12-lead ECG will be obtained at the time points shown in the Schedule of Events and 
Assessments (Table 2). Additional ECGs may be performed at other times if deemed 
necessary by the Investigator. 
The ECG will be recorded while the subject is resting in a supine position for at least 
10 minutes. The ECG will electronically measure the PR, QRS, QT, and QTc intervals, 
and heart rate. All ECG tracings will be reviewed within 24 hours by the Investigator or 
qualified Sub-investigator. PR intervals will be determined for each of these ECGs from 
a single reading. Invalid measurements will be repeated. QTc will be reported as QTcF 
(QT corrected using Fridericia's method). 
 
 
 
 
 
6.6 
Screening Scales and Assessment Tools 
6.6.1 Structured Clinical Interview for DSM-5 - Clinical Trials (SCID-5-CT) 
The Structured Clinical Interview for DSM-5 (SCID-5) is a semi-structured interview 
guide for making the major DSM-5 diagnoses (Spitzer et al., 1992; First et al., 2015; 
Appendix 11.1.8). It is administered by a clinician or trained mental health professional 
who is familiar with the DSM-5 classification and diagnostic criteria. The Clinical Trials 
version (SCID-5-CT) is an adaptation of the Research version (SCID-5-RV) that has 
been reformatted, streamlined, and optimized for use in clinical trials that incorporate 
typical inclusion and exclusion criteria. The SCID is broken down into separate modules 
corresponding to categories of diagnoses, including ADHD. Most sections begin with an 
entry question that would allow the interviewer to "skip" the associated questions if not 
met. For all diagnoses, symptoms are coded as present, subthreshold, or absent. A 
diagnosis of ADHD is made following the post-traumatic stress disorder diagnostic 
algorithm.  
6.6.2 Hamilton Anxiety Rating Scale (HAM-A) 
The Hamilton Anxiety Rating Scale (HAM-A) is a rating scale developed to 
assess/measure the severity of an individual’s anxiety (Hamilton, 1959; Appendix 
11.1.9). The HAM-A is used to assess severity of anxiety in children, adolescents and 
 
dacted


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adults in both clinical and research settings (Hamilton, 1959; Maier et al., 1988; 
Borkovec et al., 1993). The HAM-A consists of 14 items or parameters, each defined by 
a series of symptoms. It measures both psychic anxiety (mental agitation and 
psychological distress) and somatic anxiety (physical complaints related to anxiety). The 
HAM-A does not provide any standardized probe questions. The HAM-A is a clinician-
rated evaluation. Each item on the HAM-A is rated/scored on a 5-point Likert scale, 
where 0 = Not present, 1 = Mild, 2 = Moderate, 3 = Severe, and 4 = Very severe. The 
ratings/scores of all 14 items are summated to yield a total score (ranging from 0 to 56), 
where ≤ 17 indicates “mild anxiety severity,” 18 to 24 indicates “moderate anxiety 
severity,” 25 to 30 indicates “moderate to severe anxiety severity,” and ≥ 31 indicates 
“severe anxiety.” It take 5 to 10 minutes to complete the HAM-A.  
6.6.3 Symptoms of Depression Questionnaire (SDQ) 
See Section 6.1.6; Appendix 11.1.6 
6.7 
Subject training video module  
Study subject perceptions of clinical research can affect response to study treatments, 
including placebo (Leuchter et al., 2014).  In order to provide education and thereby 
reduce aspects of placebo response which may be associated with expectation of 
therapeutic benefit, all participants will view a brief training module which reviews key 
topics including (a) their role in the trial, (b) the difference between medical care and 
research, (c) the use of placebo and (d) the importance of accurate reporting of 
symptoms throughout the trial. These will be organized into short segments of ~2-3 
minutes each and will be delivered in non-technical language to help encourage 
comprehension. Site personnel will help facilitate viewing throughout the trial at the 
screening and baseline visits and predetermined study visits thereafter (see Schedule of 
Events; Table 2) in an appropriate location and be available to answer any questions 
that the study participant may have.  
 
 


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7 
STATISTICAL METHODS 
7.1 
General Considerations 
All statistical analysis will be performed using SAS version 9.2 or higher either by 
Supernus or a designated CRO. A unique program will be developed for each created TLF 
report. All corresponding programs will be delivered to Supernus at the completion of the 
study if a designated CRO is used. 
All tabulations of analysis results will include summaries for treatment arms of SPN-812 
and placebo. 
In this study, estimands will be estimated using appropriate statistical methods 
appropriate model (MMRM, ANCOVA, etc.) as described Section 7.8 for the efficacy 
analyses.  
Where appropriate, variables will be summarized descriptively (frequency count and 
percentage for categorical variables; number of subjects (n), mean, standard deviation 
(SD), median, minimum, and maximum for continuous variables).  
Categorical variables will be analyzed using categorical response methods such as 
Pearson’s Chi-square test.  If expected frequencies are too small for asymptotic 
assumptions, exact testing techniques will be used. 
The data summaries will be accompanied by individual subject data listings, as specified 
in Sections 16.2 and 16.4 of ICH Guidance E3, sorted by unique subject identifier. All 
data available from the eCRFs will be listed. Unscheduled measurements will be 
excluded from the descriptive statistics and statistical analysis but will be included in 
listings. 
Complete details of the statistical analysis will be provided in a separate statistical 
analysis plan (SAP). The statistical analysis methods described in the SAP will 
supersede the statistical methods described in this protocol. 
7.2 
Handling of Missing Data 
With respect to the primary analysis, missing AISRS Total Scores will be assumed to be 
missing at random (MAR), that is, given the observed data, the reason for the missing 
data does not depend on the unseen data. The mixed model for repeated measures 
(MMRM) method, implemented via SAS® PROC MIXED (SAS/STAT Software), will be 
used for handling missing AISRS Total Scores under MAR assumption. Under MAR, the 
propensity for a data point to be missing is not related to the missing data, but is related 
to some of the observed data.  
The sensitivity analysis for the primary endpoint will be performed by assuming that 
missing AISRS Total Scores are missing not at random (MNAR) meaning that the 
probability that an observation is missing may depend on its underlying unobserved 
value.  
For analysis of secondary endpoints, missing values will be assumed as MAR. 


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For safety analyses, missing dates for AEs and non-study medication use will be 
imputed as described in the SAP. Missing data for all other safety endpoints will not be 
imputed. 
7.3 
Analysis Populations 
The Randomized Population is all subjects who complete the Baseline Period, meet 
the inclusion/exclusion criteria and are randomized. 
The Full Analysis Set (FAS) is a subset of subjects in the Randomized Population who 
took at least one dose of study medication, and had a Baseline and at least one post-
Baseline assessment of AISRS. Subjects in the FAS will be analyzed according to the 
treatment to which they were randomized. The efficacy analyses will be conducted using 
the FAS. 
The Per Protocol (PP) Population is a subset of subjects in the FAS who complete all 
7 visits through EOS with no missing AISRS assessments and no major protocol 
violations. Subjects in the PP Population will be analyzed according to the treatment 
received. 
The Safety Population is all subjects randomized into the study who receive at least 
one dose of SM. Subjects in the Safety Population will be analyzed according to the 
treatment received. 
 
 
7.4 
Demographics and Baseline Analysis 
Demographic/baseline variables including age, age group, sex, ethnicity, race, height 
and weight at screening, and BMI will be summarized using descriptive statistics for 
continuous variables and using counts and percentages for categorical variables. The 
descriptive summary will be presented by treatment group for the Randomized 
Population, FAS, and Safety Population.  
Baseline comparability among the treatment groups will be summarized using a chi-
square test for categorical variables and F-test for continuous variables. P-values will be 
used for descriptive purposes only. 
7.5 
Subject Disposition 
A disposition of subjects will include the number and percentage of subjects in each of 
the following categories: 
 
Subjects in the Randomized Population 
 
Subjects in the FAS 
 
Subjects in the PP Population 
 
Subjects in the Safety Population 
Within each of the previous categories, the number and percentage of subjects who 
completed and discontinued from the study and primary reason for early discontinuation 
will be summarized. The reason for early discontinuation may include any of the 
following: 
 
Withdrawal of consent  
 


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 
Noncompliance 
 
Occurrence of unmanageable AEs 
 
Lost to follow-up 
 
Other 
7.6 
Study Medication Exposure and Compliance 
Duration of exposure is defined as the total number of days a subject is exposed to any 
SM. This will be calculated for each subject by taking the difference between the date of 
last dose minus the date of the first dose, plus 1 (date of last dose minus date of first 
dose +1). 
Duration of treatment exposure will be summarized by duration category and will also be 
summarized using descriptive statistics (n, mean, SD, median, minimum, and 
maximum). 
Percent of SM compliance is defined as {(number of capsules dispensed minus number 
of capsules returned) / X × (date of last dose minus date of first dose + 1)}* 100%, where 
‘X’ is equal to 1 (200 mg) or 2 (2X200 mg), or 3 (3x 200 mg) (the number of capsules 
that the subject was instructed to take daily during the treatment period (i.e, between 
visits)). 
% 𝑆𝑀 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒= [(no. of capsules dispensed) −(no. of capsules returned)
X × [(date of last dose) −(date of first dose) + 1]
] × 100  
For each treatment, SM compliance will be summarized by compliance category (<80%, 
80-120%, and >120%) and number of subjects in each compliance category. Study 
medication compliance will also be summarized as a continuous variable using 
descriptive statistics (n, mean, SD, median, minimum, and maximum) for each 
treatment. 
7.7 
Concomitant Medications 
Concomitant medications will be assigned an 11-digit code using the World Health 
Organization Drug Dictionary (WHODD) drug codes. Concomitant medications will be 
further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating 
therapeutic classification. A tabular summary of concomitant medications by drug class 
will be presented for the Safety Population. 
7.8 
Efficacy Analysis 
7.8.1 Primary Efficacy Analysis 
The primary efficacy variable, change from baseline in AISRS total score to Week 6 
(EOS), will be analyzed using MMRM, which assumes that missing data are MAR. The 
model will include fixed effect terms for baseline AISRS total score, treatment, visit, and 
treatment-by-visit interaction as independent variables. The model parameters will be 
estimated using restricted maximum likelihood (REML) method with unstructured 
variance-covariance matrix and Kenward-Roger approximation to estimate denominator 


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degrees of freedom. In case there is a convergence problem in the MMRM model with 
the unstructured variance-covariance matrix, the first (co)variance structure that does 
not have convergence problem will be used for the analysis from the following ordered 
list: 1) Toeplitz, 2) Autoregressive of order 1, and 3) Compound symmetry. The adjusted 
mean (least square mean [LS mean]) of change from baseline to EOS for AISRS total 
score for each treatment arm (placebo and SPN-812) will be presented, along with the 
corresponding standard error. The SPN-812 treatment arm will be compared with 
placebo. The LS means of the treatment groups, differences between the LS treatment 
mean and placebo, and 95% confidence intervals (CIs) for the treatment differences with 
p-values will be computed. 
7.8.1.1 Sensitivity Analysis 
The sensitivity analysis assumes that missing AISRS total scores are MNAR. Placebo-
based multiple imputation will be used to fill-in missing values. This approach may be 
considered “worst-case” sensitivity analyses as it assumes that after discontinuation, 
subjects from the SPN-812 treatment arm would adopt the outcome model estimated 
from the placebo arm. The placebo-based imputation will be implemented, which will be 
described in the SAP. 
7.8.2 Secondary Efficacy Analyses 
The secondary analyses will be based on the FAS with missing values imputed using 
multiple imputation assuming MAR. 
All secondary analyses will use analysis of covariance (ANCOVA) [except categorical 
CGI, 50% responder and 30% responder, which use Pearson’s Chi-squared test or 
Fisher exact test on the absolute value at Week 6 (EOS)] on the change from baseline at 
Week 6 (EOS) (except CGI-I, which uses the absolute value) with treatment and 
baseline (baseline CGI-S will be used for CGI-I) as fixed effect. The SPN-812 treatment 
arm will be compared with the placebo arm. The LS means of the treatment groups, 
differences between the LS treatment means and placebo (SPN-812 minus placebo), 
and 95% CIs for the treatment differences with p-values will be computed. 
7.8.2.1 Key Secondary Efficacy Analyses 
The analysis of the key secondary objective will be conducted on the CFB at EOS in the 
CGI-S score  
To preserve the overall type I error rate at 0.05 for the key secondary endpoint, a 
sequential testing procedure will be used with the following features. The key secondary 
endpoint will only be tested if SPN-812 treatment is significantly different from placebo 
for the primary endpoint.   
7.8.2.2 Additional Secondary Analyses 
Additional secondary analyses of the secondary efficacy variables will include: 
1. 
Percentage of subjects with a CGI-S score of 1 or 2 weekly and at EOS.  


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 The proportion (%) of responders (CGI-S score of 1 or 2) will be presented for 
each treatment group. The 2-sided 95% CI around the difference in 
proportions (SPN-812 minus placebo) and the p-value from Pearson’s Chi 
squared Test or Fisher’s Exact Test will be presented.  
2. 
CGI-I score at EOS    
 The absolute value of CGI-I weekly and at EOS (Week 6) will be analyzed 
using ANCOVA with treatment as a fixed classification variable and baseline 
CGI-S as a covariate. To compare the treatment groups, the difference in LS 
means (SPN-812 minus placebo) will be presented along with the 95% CI 
around the difference and p-value. 
3. 
Percentage of subjects with a CGI-I score of 1 or 2 weekly and at EOS  
 The proportion (%) of responders (CGI-I score of 1 or 2) will be presented for 
each treatment group. The 2-sided 95% CI around the difference in 
proportions (SPN-812 minus placebo) and the p-value from Pearson’s 
Chi-squared Test or Fisher’s Exact Test will be presented.  
4. 
CFB biweekly and at EOS (Week 6) in the GAD-7 total score 
5. 
CFB weekly (Week 6) in the AISRS Inattention subscale score and the 
Hyperactivity/Impulsivity subscale score at EOS  
6. 
AISRS 50% Responder (defined a subject with a ≥ 50% reduction in the CFB 
AISRS total score) weekly and at EOS 
 The proportion (%) of responders will be presented for each treatment group. 
The 2-sided 95% CI around the difference in proportions (SPN-812 minus 
placebo) and the p-value from Pearson’s Chi-squared Test or Fisher’s Exact 
Test will be presented.  
7. 
AISRS 30% Responder (defined as a subject with a ≥ 30% reduction in the CFB 
AISRS total score) weekly and at EOS 
 The proportion (%) of responders will be presented for each treatment group. 
The 2-sided 95% CI around the difference in proportions (SPN-812 minus 
placebo) and the p-value from Pearson’s Chi-squared Test or Fisher’s Exact 
Test will be presented. 
8. 
CFB at EOS in the BRIEF-A Global Executive Composite (GEC) T-score. 
9. 
CFB at EOS in the BRIEF-A T-score by each Summary Index Scale and by each 
individual BRIEF-A scale. 
 
 
 
 
 
 
 
 
 
d
 


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7.9 
Sample Size and Power Considerations 
Assuming an effect size of 0.407, 128 subjects per treatment arm (256 total subjects for 
2 arms) in the FAS will yield 90% power at a significance level of 0.05 (two-sided) to 
reject the equality of treatment means between the placebo and the SPN-812 treatment 
group.  
Assuming approximately 30% of subjects drop out before the completion of the study, an 
adjusted sample size of 366 subjects (183 per arm) will be randomized to obtain 
128 subjects per arm in the FAS at the completion of the study. 
7.10 Interim Analysis 
No interim analysis will be performed. 
 
 
 
 
7.12 Safety Analysis 
Safety analyses will be performed by treatment arm based on the Safety Population.  
The incidence rate of AEs will be calculated by treatment arm for each system organ 
class (SOC) and preferred term (PT). The severity of the AEs and the relationship to SM 
will be summarized by treatment arm for each SOC and PT. 
AEs will be summarized using discrete summaries at the subject and event level by SOC 
and PT, and by severity and relationship separately for each treatment arm. Verbatim 
description and Medical Dictionary for Regulatory Activities (MedDRA) SOCs and PTs 
for all AEs will be contained in the subject data listings. 
Clinical laboratory values will be summarized by visit by treatment arm using descriptive 
statistics. For quantitative laboratory parameters, both actual values and change from 
screening values will be summarized. 
Vital signs will be summarized by visit by treatment arm using descriptive statistics. Both 
actual values and change from baseline will be summarized. 
ECG results will be summarized by visit by treatment arm using descriptive statistics (for 
quantitative ECG parameters) and frequency tables (for qualitative ECG parameters, 
including the overall ECG finding). 
C-SSRS outcomes will be summarized using number and percent of subjects by 
categories for suicidal ideation only, suicidal behavior only and suicidality (ideation and 
behavior combined). The summary will be presented by treatment arm. 
 
 Reda


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8 
DOCUMENTATION 
8.1 
Adherence to the Protocol 
The Investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described within and to the principles of ICH GCP as well as all governing 
local regulations and principles for medical research. 
The protocol, ICF, and appropriate related documents must be reviewed and approved 
by an IRB constituted and functioning in accordance with ICH E6 and any local 
regulations. Documentation of IRB compliance with the ICH and any local regulations 
regarding constitution and review conduct will be provided to the Sponsor. 
A signed letter of study approval from the IRB must be sent to the Investigator with a 
copy to the Sponsor prior to study start and the release of SM to the site by the Sponsor 
or its designee. If the IRB decides to suspend or terminate the study, the Investigator will 
immediately send the notice of study suspension or termination by the IRB to the 
Sponsor. 
8.2 
Changes to the Protocol 
Changes to the protocol will not be made without written approval from the Sponsor. 
Any change to the protocol requires a written protocol amendment or administrative 
change that must be approved by the Sponsor before implementation. Amendments 
specifically affecting the safety of subjects, the scope of the investigation, or the 
scientific quality of the study require additional approval by the applicable IRB, and in 
some cases, filings to the regulatory authority. These requirements should in no way 
prevent any immediate action from being taken by the Investigator, or by the Sponsor, in 
the interest of preserving the safety of all subjects included in the study. If an immediate 
change to the protocol is felt by the Investigator to be necessary for safety reasons, the 
Medical Monitor, and IRB must be notified promptly. 
Changes to the protocol which are administrative in nature do not require formal protocol 
amendments or IRB approval, but the IRB must be kept informed of such changes. In 
these cases, the Sponsor or CRO will send a letter to the IRB detailing such changes. 
8.3 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures (SOPs), working practice documents, and applicable 
regulations and guidelines. Site visit audits may be made periodically by the Sponsor’s 
Quality Assurance team or qualified designee, which is an independent function from the 
study conduct team. 
8.3.1 Data Collection 
The primary source document will be the subject’s medical record. If separate research 
records are maintained by the Investigator(s), both the medical record and the research 


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record will be considered the source documents for the purposes of monitoring and 
auditing the study. 
Electronic data collection techniques will be used to collect data directly from the study 
sites using eCRFs. The electronic data will be stored centrally in a fully validated clinical 
database. 
Data recorded on source documents will be transcribed into the eCRFs in accordance 
with the eCRF Completion Instructions that are provided to the study sites. The 
Investigator is responsible for ensuring that all sections of each eCRF are completed 
correctly, and that entries can be verified against source documents. The eCRFs will be 
monitored for completeness and accuracy against the source documents by the CRA(s) 
on a regular basis. Inconsistencies between the eCRFs and source documents will be 
resolved in accordance with the principles of GCP. 
8.3.2 Clinical Data Management 
Data from eCRFs and other external data (e.g., laboratory data) will be entered into or 
merged with a clinical database as specified in the data management plan. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy 
of the clinical database.  
8.3.3 Database Quality Assurance 
In accordance with the vendor’s procedures, the clinical database will be reviewed and 
checked for omissions, apparent errors, and values requiring further clarification using 
computerized and manual procedures. The procedure for handling missing data will be 
addressed in the Statistical Analysis Plan (SAP). Data queries requiring clarification will 
be documented and returned to the study site for resolution. Only authorized personnel 
will make corrections to the clinical database, and all corrections will be documented in 
an audit trail.  
8.3.4 Bioanalytical Sample Handling 
Viloxazine and 5-hydroxy-viloxazine glucuronide concentrations in plasma samples will 
be determined using a validated chromatographic method. Viloxazine concentrations will 
be reported as viloxazine free base. Details on the analytical methodology, the method 
of validation, and the analytical within-study quality control procedures will be included in 
the clinical study report.  
8.4 
Retention of Records 
The Investigator has the responsibility to retain all study “essential documents”, as 
described in ICH E6 for at least two years after approval of a marketing application or 
after formal discontinuation of the clinical program. Essential documents include but not 
limited to the protocol, eCRFs, source documents, laboratory test results, SM inventory 
records, Investigator's Brochure, regulatory agency registration documents (e.g., FDA 
form 1572, ICFs, and IRB correspondence). The Investigator must obtain written 
permission from Supernus prior to the destruction of any study document.  


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Such information may be used solely for the purpose of reviewing or performing this study. 
8.5 
Auditing Procedures 
In addition to the routine monitoring procedures, the Sponsor’s Corporate Quality 
Assurance department or qualified designee may conduct audits of clinical research 
activities in accordance with the Sponsor’s written SOPs to evaluate compliance with the 
principles of ICH GCP and all applicable local regulations. A government regulatory 
authority may also wish to conduct an inspection (during the study or after its 
completion). If an inspection is requested by a regulatory authority, the Investigator must 
inform the Sponsor and the CRO immediately that this request has been made. 
These records must be made available at reasonable times for inspection and 
duplication, if required, by a properly authorized representative of the US FDA in 
accordance with the US 21 Code of Federal Regulation (CFR) 312.68 or other national 
or foreign regulatory authorities in accordance with regulatory requirements. 
8.6 
Publication of Results 
Any presentation or publication of data collected as a direct or indirect result of this trial 
will be considered as a joint publication by the Investigator(s) and the appropriate 
personnel at the Sponsor’s site. Authorship will be determined by mutual agreement. All 
manuscripts, abstracts or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the Sponsor, prior to submission for 
publication or presentation. No publication or presentation with respect to the study shall 
be made until all Sponsor comments on the proposed publication or presentation have 
been addressed to the Sponsor’s satisfaction. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be outlined in the 
agreement between each Investigator and the Sponsor or designee. 
8.7 
Financing and Insurance 
Financing and Insurance information will be set forth in a separate document between 
the Investigator and Sponsor (provided by the Sponsor or designee). 
8.8 
Disclosure and Confidentiality 
The contents of this protocol, any amendments, and results obtained during the course 
of this study will be kept confidential by the Investigator, the Investigator’s staff, and the 
IRB and will not be disclosed in whole or in part to others or used for any purpose other 
than reviewing or performing the study without the written consent of the Sponsor. No 
data collected as part of this study will appear in any written work, including publications, 
without the written consent of Sponsor. 
All persons assisting in the performance of this study must be bound by the obligations 
of confidentiality and non-use set forth in the Confidentiality Agreement between the 
Investigator and Sponsor. 


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Such information may be used solely for the purpose of reviewing or performing this study. 
8.9 
Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative 
reasons at any time. The Investigator will be reimbursed for reasonable expenses 
covering subjects, use of live-in facilities, laboratory tests, and other professional fees. 
The Investigator will refund the excess of payments made in advance. 
The Investigator reserves the right to discontinue the study should his/her judgment so 
dictate. The Investigator will notify the IRB in case of study discontinuation. Study 
records must be retained as noted above. 
 
 


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9 
ETHICS 
9.1 
Institutional Review Boards 
The IRB that approved this study and the approval letters will be included in the clinical 
study report for this protocol. 
The protocol, any protocol amendments, and the ICF will be reviewed and approved by 
the appropriate IRB before subjects are enrolled. The Investigators or Sponsor will 
submit, depending on local regulations, periodic reports and inform the IRB of any 
reportable AEs per ICH guidelines and local IRB standards of practice. 
9.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with SOPs from both the Sponsor and the 
CRO. These SOPs are designed to ensure adherence to GCP guidelines as required by: 
 
Declaration of Helsinki, 1964 (“Recommendations Guiding Physicians in 
Biomedical Research Involving Human Patients”), and all its accepted 
amendments to date concerning medical research in humans. 
 
ICH Guideline for GCP (Committee for Proprietary Medicinal 
Products/ICH/135/95) of the European Agency for the Evaluation of Medicinal 
Products, Committee for Proprietary Medicinal Products, ICH of Pharmaceuticals 
for Human Use. 
 
United States (US) CFR dealing with clinical studies (21 CFR, including parts 50 
and 56 concerning Patient Informed Consent/Assent and IRB regulations). 
 
Local, national legal guidelines. 
9.3 
Investigators and Study Personnel 
This study will be conducted by qualified Investigators under the sponsorship of 
Supernus Pharmaceuticals, Inc. (Sponsor). 
Contact persons at the Sponsor and the CROs are listed in the reference binder 
provided to each investigational site. The study will be monitored by qualified personnel 
from the Sponsor or their designees, such as the CROs, for their respective sites. 
Medical writing, data management, and statistical analyses will be performed by the 
CROs. Laboratory tests will be conducted by a central laboratory as designated in the 
reference binder.  
The study will be monitored by qualified personnel from Supernus. Data management 
and statistical analyses will be the responsibility of the CRO data management and 
biostatistics groups.  
9.4 
Subject Information and Consent 
The Investigator (or designee) will inform the subject of all aspects pertaining to the 
subject’s participation in the study and will provide oral and written information 
describing the nature and duration of the study, the procedures involved, the expected 
duration, the potential risks and benefits involved, and any potential discomfort. 


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Such information may be used solely for the purpose of reviewing or performing this study. 
The process for obtaining informed consent will be in accordance with all applicable 
regulatory requirements. The Investigator (or designee) and 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. 
If the ICF is amended during the study, the Investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICF by the IRB and use 
the amended ICF (including ongoing subjects). 
 
 


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10 REFERENCES 
Adler LA, Clemow DB, Williams DW, Durell TM. Atomoxetine effects on executive 
function as measured by the BRIEF-A in young adults with ADHD: a randomized, 
double-blind, placebo-controlled study. PLoS One. 2014 Aug 22; 9(8):e104175. 
Arnsten AF. Stimulants: Therapeutic actions in ADHD. Neuropsychopharmacology. 
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Arnsten AF. Toward a new understanding of attention-deficit hyperactivity disorder 
pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs. 
2009;23 Suppl 1:33-41. 
Becker A, Roessner V, Breuer D, Dopfner M, Rothenberger A. Relationship between 
quality of life and psychopathological profile: data from an observational study in children 
with ADHD. Eur Child Adolesc Psychiatry. 2011;20(2):267-275. 
Borkovec T and Costello E. Efficacy of applied relaxation and cognitive behavioral 
therapy in the treatment of generalized anxiety disorder. J Clin Consult Psychol. 
1993;61(4):611-619. 
Briars L and Todd T. A review of pharmacological management of attention-
deficit/hyperactivity disorder. J Pediatr Pharmacol Ther. 2016;21(3):192-206. 
 
 
 
 
Epstein JN and Weiss MD. Assessing Treatment Outcomes in Attention-
Deficit/Hyperactivity Disorder: A Narrative Review. Prim Care Companion CNS Disord. 
2012;14(6):PCC.11r01336. 
Fava M, Johe K, Ereshefsky L, Gertsik LG, English BA, Bilello JA, Thurmond LM, 
Johnstone J, Dickerson BC, Makris N, Hoeppner BB, Flynn M, Mischoulon D, Kinrys G, 
Freeman MP. A Phase 1B, randomized, double blind, placebo controlled, multiple-dose 
escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients. 
Mol Psychiatry. 2016 Oct;21(10):1372-1380. 
FDA Guidance for Industry: Suicidal Ideation and Behavior: Prospective Assessment of 
Occurrence in Clinical Trials. U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER), 2012.  
First MB, Williams JBW, Karg RS, Spitzer RL: Structured Clinical Interview for DSM-5 
Disorders, Clinical Trials Version (SCID-5-CT). Arlington, VA, American Psychiatric 
Association, 2015. 
 
 


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Guy W. Clinical global impressions. ECDEU Assessment manual for 
Psychopharmacology, Rockville, MD: US National Institutes of Health, 
Psychopharmacology Research Branch, 1976. 
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50-
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Leuchter AF, Hunter AM, Tartter M, Cook IA. Role of pill-taking, expectation and 
therapeutic alliance in the placebo response in clinical trials for major depression. Br J 
Psychiatry. 2014;205(6):443-449. 
Maier W, Buller R, Philipp M, Heuser I. The Hamilton Anxiety Scale: reliability, validity 
and sensitivity to change in anxiety and depressive disorders. J Affect Disord. 
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McCann BS and Roy-Byrne P. Screening and diagnostic utility of self-report attention 
deficit hyperactivity disorder scales in adults. Compr Psychiat 2004;45(3):175-183. 
Papakostas GI, Johe K, Hand H, Drouillard A, Russo P, Kay G, Kashambwa R, 
Hoeppner B, Flynn M, Yeung A, Martinson MA, Fava M. A phase 2, double-blind, 
placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among 
outpatients with major depressive disorder. Mol Psychiatry. 2019 Jan 9. 
Pedrelli P, Blais MA, Alpert JE, Shelton RC, Walker RS, Fava M. Reliability and validity 
of the Symptoms of Depression Questionnaire (SDQ). CNS Spectr. 2014 Dec;19(6):535-
546. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, 
Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry. 2011;168(12):1266-1277. 
Roth R, Isquith P, Gioia G. Behavior Rating Inventory of Executive Function - Adult 
Version (BRIEF-A).  Psychological Assessment Resources, Inc.: Lutz, FL; 2005. 
Roth RM, Lance CE, Isquith PK, Fischer AS, Giancola PR. Confirmatory factor analysis 
of the Behavior Rating Inventory of Executive Function-Adult version in healthy adults 
and application to attention-deficit/hyperactivity disorder. Arch Clin Neuropsychol. 2013 
Aug; 28(5):425-434. 
Spencer TJ, Adler LA, Meihua Q, Saylor KE, Brown TE, Holdnack JA, Schuh KJ, 
Trzepacz PT, Kelsey DK. Validation of the adult ADHD investigator symptom rating 
scale (AISRS). J Atten Disord. 2010;14(1):57-68. 
Spitzer RL, Williams JB, Gibbon M, First MB. The Structured Clinical Interview for DSM-
III-R (SCID). I: History, rationale, and description. Arch Gen Psychiatry.1992;49(8):624-
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viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 
Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized 
anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092-1097. 
Wiener J, Biondic D, Grimbos T, Herbert M. Parenting Stress of Parents of Adolescents 
with Attention-Deficit Hyperactivity Disorder. J Abnormal Child Psych. 2016;44(3):561-
574.  
 
 


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Such information may be used solely for the purpose of reviewing or performing this study. 
11 APPENDIX:   
11.1 Screening, Efficacy and Safety Scales and Questionnaires 
 
 







































































































































































SAP_001.pdf: 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc   
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33 05  Effective date: 22-Jan-2018 
    |    Date 21-Sep-2020    |    AD-PR-109 01  Effective date: 26-Jun-2017 
 Page 2 of 41 
 
Signature Page 
 
 
 


















 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
05  Effective date: 22-Jan-2018 
        Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 11 of 43 
 
1. 
Introduction 
This document describes the statistical analyses and data presentations to be performed on Study 
812P306, (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel-
Group Flexible-Dose Study of the Efficacy and Safety of SPN-812 in Adults with Attention-
Deficit/Hyperactivity Disorder (ADHD)), protocol version 4.0, dated 06Mar2020). 
The purpose of this SAP is to ensure the credibility of the study findings by specifying detailed 
statistical approaches to the analysis of the data prior to database lock. This SAP covers the 
planned analyses of all data collected on the eCRFs and diary pages, and will describe handling 
of data issues. It describes the efficacy and safety variables, anticipated data manipulations, and 
other details of the analyses not provided in the study protocol. The analysis methods presented 
in this document will supersede the statistical analysis methods described in the clinical protocol. 
Any deviations/changes from the planned analyses described in this SAP will be identified, with 
justification, in the appropriate section of the clinical study report. 
2. 
Study Objectives  
2.1. 
Primary Objective 
The primary objective is to evaluate the efficacy of SPN-812 200 mg to 600 mg compared to 
placebo for the treatment of ADHD in adults as measured by the adult ADHD Investigator 
Symptom Rating Scale (AISRS) total score. 
2.2. 
Key Secondary Objective 
The key secondary objective is to evaluate the efficacy of SPN-812 200 mg to 600 mg compared 
to placebo on the global assessment of severity for ADHD as measured by the Clinical Global 
Impression – Severity of Illness (CGI-S) scale. 
 
 


 
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2.3. 
Additional Secondary Objectives 
The additional secondary objectives are to evaluate the efficacy of SPN-812 200 mg to 600 mg 
compared to placebo on: 
1. Clinical response rate of severity of illness as measured by the categorical CGI-S 
Responder Rate (CGI-S score 1 or 2)  
2. Global assessment of improvement as measured by the Clinical Global Impression – 
Improvement scale (CGI-I) for ADHD 
3. Clinical response rate of improvement as measured by the categorical CGI-I Responder 
Rate (CGI-I score 1 or 2) 
4. Anxiety symptoms as measured by the Generalized Anxiety Disorder 7-Item scale 
(GAD-7) 
5. Clinician-rated ADHD symptoms as measured by the AISRS subscales of Inattention and 
Hyperactivity/Impulsivity 
6. Clinician response rate of ADHD symptom reduction as measured by the 50% Responder 
rate in AISRS total score 
7. Clinician response rate of ADHD symptom reduction as measured by the 30% Responder 
rate in AISRS total score  
8. Executive functioning as measured by Behavior Rating Inventory of Executive Function 
– Adult Version (BRIEF-A; Self Report)  
9. Aspects of executive function and problems of self-regulation as measured by the 
BRIEF-A Summary Index Scales and BRIEF-A scales 
2.4. 
Safety Objective 
The safety objective is to evaluate the safety and tolerability of SPN-812 200 mg to 600 mg in 
adult subjects with ADHD. 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
2.6. 
Estimand 
Consistent with the ICH E9 Addendum, definition of the attributes of the estimand (target of 
estimation) is provided in this section. 
1. Population: The population targeted for the scientific question is defined via the inclusion 
and exclusion criteria in adults diagnosed with ADHD per Diagnostic and Statistical 
 
cted
 
 
 


 
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Manual of Mental Disorders – 5th Edition (DSM-5™) criteria. 
2. Variable (or endpoint): Change from baseline to Week 6 of the double-blind study period 
in AISRS 18-item, each item scored on a scale of 0 to 4, where 0 = none and 3 = severe, 
total score ranging from 0 to 54. 
 
3. Intercurrent Events: A treatment policy estimand will be followed. All observed values 
will be used regardless of occurrence of an intercurrent event. If a subject is discontinued 
due to AE or lack of efficacy, missing data will be handled as stated in item 4 below. i 
 
4. Population level summary: The change from baseline in AISRS Total Score to Week 6 
(EOS), will be analyzed using a Mixed Model for Repeated Measures (MMRM), which 
assumes that missing data are missing at random (MAR). The model will include fixed 
effect terms for baseline AISRS total score, treatment, study visit, and treatment-by-study 
visit interaction as independent variables. Missing data will be accounted for by the 
MMRM model except for subjects discontinued due to AE or lack of efficacy, which will 
be explicitly imputed using multiple imputation under Missing not at Random 
assumption.   
3. 
Study Description 
3.1. 
Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter, parallel group, flexible dose 
study of SPN-812 in adults diagnosed with ADHD per Diagnostic and Statistical Manual of 
Mental Disorders – 5th Edition (DSM-5™) criteria. Approximately 366 subjects will be 
randomized in a 1:1 ratio (183 subjects per arm): SPN-812 (200 mg to 600 mg) or placebo. 
Following up to 5 weeks of screening, subjects will be treated with study medication (SM) for 6 
weeks.  
At the Screening Visit (Visit 1), after informed consent is obtained, subjects will undergo initial 
screening evaluations/scales, and inclusion/exclusion criteria will be reviewed to confirm the 
subject’s eligibility. Subjects taking ADHD medication at screening will undergo a washout of at 
least 1 week (or 5 half-lives of the medication, whichever is longer) before the Baseline Visit 
(Visit 2; Day 1). At the Baseline Visit, subjects who meet inclusion/exclusion criteria will be 
randomized. The Treatment Period will consist of 6 weeks of treatment starting Day 2 (morning 
after Visit 2) until Day 43 (Visit 7; Week 6, EOS). At study visits, subjects will undergo efficacy 
and safety evaluations, compliance evaluations, return the previous dosing card, and receive the 
next card. The total study duration from the Screening Visit to the end of the Treatment Period is 
up to 11 weeks. 
Subjects who complete the study may enroll in a separate open-label extension (OLE) safety 
study, 812P311. Those subjects who do not enroll in the OLE safety study will receive a phone 
call 1 week after their EOS visit for safety.  
A study schematic is provided in Figure 1 below. 
 
 












 
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Allocation of study treatment will occur centrally via an interactive web response system 
(IWRS) using a randomization schedule to determine the SM assignment for each subject being 
randomized. A dosing card(s) will be given to the subject at each study visit starting at Visit 2. 
3.5.4. Blinding and Unblinding 
The subject and all personnel involved with the conduct and interpretation of the study, including 
the Investigators, study site personnel, the sponsor and contract research organization (CRO) 
clinical staff, including the Medical Monitor, will be blinded to SM. 
 
 
 
 
 Randomization schedule data 
will be kept strictly confidential, filed securely, and accessible only to authorized persons until 
the time of unblinding. 
3.5.5. Concomitant Medications 
Subjects may not be on any prohibited medication as indicated in the inclusion/exclusion criteria. 
SPN-812 is a strong CYP1A2 inhibitor. Substrates with a narrow therapeutic window are 
prohibited during the study. Specific prohibited concomitant medications for this study include 
known CYP1A2 substrates (e.g., theophylline, melatonin). Subjects receiving prior ADHD 
medication at screening will undergo a washout period of at least 1 week (or 5 half-lives of the 
medication, whichever is longer) before the Baseline Visit (Day 1).  
No concomitant medications are allowed during the study, with the following exceptions: 
 Nutritional supplements (e.g., multivitamins, fish oil) (herbal supplements are prohibited) 
 EMLA® or other numbing cream for venipuncture 
 Common over-the-counter therapies for minor transient ailments (e.g., acetaminophen for 
headache, ibuprofen for fever). 
Additional concomitant medications are allowable on a case-by-case basis at the discretion of the 
Investigator and sponsor approval. 
All concomitant medications will be recorded in the eCRF. 
Caffeine use is permitted during the study and will be recorded in the eCRF. 
3.6. 
Sample Size and Power 
Assuming an effect size of 0.407, 128 subjects per treatment group (256 total subjects for 2 
arms) in the Full Analysis Set (FAS) will yield 90% power at a significance level of 0.05 
(2-sided) to reject the equality of treatment means between the placebo and the SPN-812 
treatment group. Assuming approximately 30% of subjects drop out before the completion of the 
study, an adjusted sample size of 366 subjects (183 per arm) will be randomized to obtain 128 
subjects per arm in the FAS at the completion of the study. 
 
 


 
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4. 
Definitions and Derivations 
 Baseline is the last non-missing assessment recorded before receiving the first dose of 
study medication, will be used as the baseline observation for all calculations of change 
from baseline. 
 AISRS Total Score = sum of the 18 individual items. Each individual item is scored on a 
scale of 0 to 4, where 0 = none and 3 = severe, so the total score ranges from 0 to 54. Higher 
scores indicate more severe symptoms. If more than 3 items of AISRS are missing then the 
total score will be set to missing. If ≤3 items are missing then the values for the missing 
items will be imputed using the mean of the non-missing items rounded to the nearest 
integer. 
 AISRS Inattention Subscale Score = sum of the odd numbered individual items. Each 
individual item is scored on a scale of 0 to 3, where 0 = none and 3 = severe, so the total 
score ranges from 0 to 27. Higher scores indicate more severe symptoms. If more than 3 
items of AISRS are missing then the subscale score will be set to missing. If ≤3 items are 
missing then the values for the missing items will be imputed using the mean of the non-
missing items rounded to the nearest integer. 
 AISRS Hyperactivity/Impulsivity Subscale Score = sum of the even numbered 
individual items. Each individual item is scored on a scale of 0 to 3, where 0 = none and 3 
= severe, so the total score ranges from 0 to 27. Higher scores indicate more severe 
symptoms. If more than 3 items of AISRS are missing then the subscale score will be set 
to missing. If ≤3 items are missing then the values for the missing items will be imputed 
using the mean of the non-missing items rounded to the nearest integer. 
 Percent Reduction in AISRS Total Score = 100 * (AISRS Total Score at Week 6 (EOS) 
- Baseline AISRS Total Score) / Baseline AISRS Total Score.   
 GAD-7 Total Score = sum of the 7 individual items. Each individual item is scored on a 
scale of 0 to 3, where 0 = not at all and 3 = nearly every day, so the total score ranges from 
0 to 21. Higher scores indicate worse anxiety. If 1 of the individual item scores is missing, 
the total score will be set to missing. 
 BRIEF-A Global Executive Composite (GEC) Total Raw Score = sum of the BRI and 
MI, with a range of 70 to 210. Higher scores indicate poorer executive function. If the BRI 
or MI is missing, the total score will be set to missing. 
 BRIEF-A Behavioral Regulation Index (BRI) Raw Score = sum of the Inhibit, Shift, 
Emotional Control, and Self-Monitor Scale Scores, with a range of 30 to 90. Higher scores 
indicate poorer executive function. If 1 of the scale scores is missing, the BRI will be set 
to missing. 
 BRIEF-A Metacognitive Index (MI) Raw Score = sum of the Initiate, Working Memory, 
Plan/Organize, Task Monitor, and Organization of Materials Scale Scores with a range of 
 


 
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40 to 120. Higher scores indicate poorer executive function. If 1 of the scale scores is 
missing, the MI will be set to missing. 
 BRIEF-A Inhibit Scale Score = sum of items 5, 16, 29, 36, 43, 55, 58, and 73. Each 
individual item is scored on a scale of 1 to 3, where 1 = never and 3 = often, so the total 
score ranges from 8 to 24. Higher scores indicate poorer executive function. If 1 of the 
individual item scores is missing, the scale score will be set to missing. 
 BRIEF-A Self-Monitor Scale Score = sum of items 13, 23, 37, 50, 64, and 70. Each 
individual item is scored on a scale of 1 to 3, where 1 = never and 3 = often, so the scale 
score ranges from 6 to 18. Higher scores indicate poorer executive function. If 1 of the 
individual item scores is missing, the scale score will be set to missing. 
 BRIEF-A Plan/Organize Scale Score = sum of items 9, 15, 21, 34, 39, 47, 54, 63, 66, and 
71. Each individual item is scored on a scale of 1 to 3, where 1 = never and 3 = often, so 
the scale score ranges from 10 to 30. Higher scores indicate poorer executive function. If 
1 of the individual item scores is missing, the scale score will be set to missing. 
 BRIEF-A Shift Scale Score = sum of items 8, 22, 32, 44, 61, and 67. Each individual item 
is scored on a scale of 1 to 3, where 1 = never and 3 = often, so the scale score ranges from 
6 to 18. Higher scores indicate poorer executive function. If 1 of the individual item scores 
is missing, the scale score will be set to missing. 
 BRIEF-A Initiate Scale Score = sum of items 6, 14, 20, 25, 45, 49, 53, and 62. Each 
individual item is scored on a scale of 1 to 3, where 1 = never and 3 = often, so the scale 
score ranges from 8 to 24. Higher scores indicate poorer executive function. If 1 of the 
individual item scores is missing, the scale score will be set to missing. 
 BRIEF-A Task Monitor Scale Score = sum of items 2, 18, 24, 41, 52, and 75. Each 
individual item is scored on a scale of 1 to 3, where 1 = never and 3 = often, so the scale 
score ranges from 6 to 18. Higher scores indicate poorer executive function. If 1 of the 
individual item scores is missing, the scale score will be set to missing. 
 BRIEF-A Emotional Control Scale Score = sum of items 1, 12, 19, 28, 33, 42, 51, 57, 
69, and 72. Each individual item is scored on a scale of 1 to 3, where 1 = never and 3 = 
often, so the scale score ranges from 10 to 30. Higher scores indicate poorer executive 
function. If 1 of the individual item scores is missing, the scale score will be set to missing. 
 BRIEF-A Working Memory Scale Score = sum of items 4, 11, 17, 26, 35, 46, 56, and 
68. Each individual item is scored on a scale of 1 to 3, where 1 = never and 3 = often, so 
the scale score ranges from 8 to 24. Higher scores indicate poorer executive function. If 1 
of the individual item scores is missing, the scale score will be set to missing. 
 BRIEF-A Organization of Materials Scale Score = sum of items 3, 7, 30, 31, 40, 60, 65, 
and 74. Each individual item is scored on a scale of 1 to 3, where 1 = never and 3 = often, 
 


 
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so the scale score ranges from 8 to 24. Higher scores indicate poorer executive function. If 
1 of the individual item scores is missing, the scale score will be set to missing. 
 
 
 
 
 
 SDQ Average (Mean) Score = average of the 44 individual item scores. Each individual 
item is scored on a scale of 1 to 6, so the average score ranges from 1 to 6. Higher scores 
indicate worse depression. If 1 of the individual item scores is missing, the average (mean) 
score will be set to missing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
a 
a 
 
a Reda
a Reda
a Reda


 
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 HAM-A Total Score = sum of the 14 individual items. Each individual item is scored on 
a 5-point Likert scale, where 0 = Not present, 1 = Mild, 2 = Moderate, 3 = Severe, and 4 = 
Very severe. The total score ranges from 0 to 56, where ≤17 indicates “mild anxiety 
severity”, 18 to 24 indicates “moderate anxiety severity”, 25 to 30 indicates “moderate to 
severe anxiety severity”, and ≥31 indicates “severe anxiety”. If 1 of the individual item 
scores is missing, the total score will be set to missing. 
 Change from Baseline = value at current time point – value at baseline.  
 Percent Change from Baseline = (change from baseline / value at baseline) * 100.  
 Body Mass Index (BMI) kg/m2 =  
(
𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚)
100
∗ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚)
100
) 
 
 
 
 
a 
a 
a 
 


 
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Protocol Number 812P306  
 
PCN Number SUPE9582 
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 Page 24 of 43 
 
 Treatment Emergent Adverse Event (TEAE) = any adverse event with an onset 
date/time after first dose of study medication. 
 Duration of Adverse Event = AE end date – AE start date + 1 
 Duration of Treatment Exposure = date of last dose – date of first dose + 1 
 Percent of Study Medication Compliance =  
∑(𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑 𝑎𝑡 𝑣𝑖𝑠𝑖𝑡 (𝑖−1) −𝑁𝑢𝑚𝑏𝑒𝑟𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑 𝑎𝑡 𝑣𝑖𝑠𝑖𝑡 𝑖 
𝑋∗(𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠 𝑓𝑟𝑜𝑚 𝑉𝑖𝑠𝑖𝑡 𝑖−1 𝑡𝑜  𝑉𝑖𝑠𝑖𝑡 𝑖)
)
𝑖=7
𝑖=2
∗100 
Where X is equal to the number of capsules that the subject was instructed to take daily 
during the treatment period (between visits) i.e. 1 (200 mg) or 2 (2 x 200 mg), or 3 (3 x 
200 mg).  
5. 
Study Variables 
5.1. 
Primary Efficacy Variable 
The primary efficacy endpoint of this study is the change from baseline (CFB) at end of study 
(EOS) in the AISRS total score.  
The adult ADHD Investigator Symptom Rating Scale (AISRS) was developed to better measure 
the presence and severity of ADHD symptoms based on DSM-IV diagnostic criteria in adult 
patients4. It is a semi-structured clinical interview with suggested prompts for each item to improve 
interrater reliability. The scale consists of 18 items that directly correspond to the 18 symptoms of 
ADHD and are further subdivided into two subscales: Inattention (9 items) and 
Hyperactivity/Impulsivity 
(9 
items). 
During 
the 
interview 
with 
the 
subject, 
the 
clinician/investigator rates the frequency and severity of each symptom on a 4-point Likert-type 
scale, where 0 = None, 1 = Mild, 2 = Moderate, and 3 = Severe, with a maximum total score of 54 
points and maximum subscale score of 27 points. Derivations for scores are described in Section 
4. 
The scale allows the assessment of functional impairments linked to each symptom dimension. 
The AISRS total score is the sum of the Inattention and Hyperactivity/Impulsivity subscale 
scores.  
The AISRS is used to assess drug efficacy in the treatment of ADHD in adults, and the AISRS 
total score is the primary outcome measure for this study.  
5.2. 
Key Secondary Efficacy Variable 
The key secondary efficacy endpoint is the CFB at EOS in the CGI-S score. 
The CGI-S scale is a single item clinician rating of the clinician’s assessment of the severity of 
the ADHD symptoms in relation to the clinician’s total experience with patients with ADHD. 
 


 
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The CGI-S is evaluated on a 7-point scale, where 1 = Normal, not at ill, asymptomatic, 2 = 
Borderline Ill, 3 = Mildly Ill, 4 = Moderately Ill, 5 = Markedly Ill, 6 = Severely Ill, and 7 = 
Extremely Ill. Successful therapy is indicated by a lower overall score in subsequent testing. 
The CGI-S scale was developed to provide a brief, stand-alone assessment of the clinician’s view 
of a subject’s global functioning prior to and after administration of SM5. 
5.3. 
Additional Secondary Efficacy Variables 
The additional secondary efficacy endpoints of this study include the following:  
1. Percentage of subjects with a CGI-S score of 1 or 2 at EOS 
2. CGI-I score at EOS 
3. Percentage of subjects with a CGI-I score of 1 or 2 at EOS 
The CGI scale was developed to provide a brief, stand-alone assessment of the clinician’s view 
of a subject’s global functioning prior to and after administration of SM5. The CGI-I scale is an 
assessment of how much the patient’s illness has improved or worsened relative to a baseline 
state at the beginning of treatment. The CGI-I is evaluated by the investigator at each post-
baseline study visit during treatment relative to the subject’s condition at baseline on a 7-point 
scale where 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No 
change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. Successful therapy is 
indicated by a lower overall score in subsequent testing. The CGI-S assessment obtained at the 
baseline visit should serve as a basis for the investigator’s CGI-I assessment of improvement in 
the subject’s conditions at each post-baseline study visit during the treatment period.  
4. CFB at EOS in the GAD-7 total score 
Generalized Anxiety Disorder 7 scale (GAD-7) is a self-reported 7-item questionnaire for 
screening and measuring the severity of generalized anxiety disorder6. The GAD-7 measures the 
severity of various symptoms of generalized anxiety disorder over the past 2 weeks according to 
reported response categories with assigned points. The patient scores each GAD-7 item on 4-
point Likert scale, where 0 = Not at all, 1 = Several days, 2 = More than half the days, and 3 = 
Nearly every day. GAD-7 total scores range from 0 to 21, where a total score of 1 to 4 = 
None/Minimal anxiety, 5 to 9 = Mild anxiety, 10 to 14 = Moderate anxiety, and ≥15 = Severe 
anxiety. Derivations for scores are described in Section 4. 
5. CFB at EOS in the AISRS Inattention subscale score and the Hyperactivity/Impulsivity 
subscale score 
6. AISRS 50% Responder rate (defined as the percentage of subjects with a ≥50% reduction 
in the CFB AISRS total score) at EOS  
7. AISRS 30% Responder rate (defined as the percentage of subjects with a ≥30% reduction 
in the CFB AISRS total score) at EOS 
 
8. CFB at EOS in the BRIEF-A Global Executive Composite (GEC) T-score 
9. CFB at EOS in the BRIEF-A T-score by each Summary Index Scale and by individual 
BRIEF-A scale. 
The BRIEF-A is a standardized 75-item rating scale in 9 scales and 2 summary index scales that 
assesses aspects of executive function and problems with self-regulation from the perspective of 
 


 
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 Page 26 of 43 
 
the individual. The subject rates each item on a 3-point Likert scale (Never, Sometimes, or 
Often) based on their experiences within the last month. Higher scores indicate poorer executive 
function.  
The Global Executive composite (GEC) raw score is the sum the Behavioral Regulation Index 
(BRI) raw score and Metacognition Index (Ml) raw score. The BRI raw score is the sum of raw 
scores of subscales Inhibit, Shift, Emotional Control, and Self-Monitor scales. To calculate the 
Metacognition Index (Ml) raw score, sum the raw scores obtained for the Initiate, Working 
Memory, Plan/Organize, Task Monitor; and Organization of Materials scales. Raw GEC scores, 
BRI, MI, and their component subscale (individual scales) will be converted to T-scores and the 
CFB in T-scores will be calculated. Derivations for raw scores are described in Section 4. The 
raw GEC, BRI, MI and individual subscale scores will be converted to T-scores using Appendix 
A of the BRIEF-A Professional Manual. 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.5. 
Safety Variables 
The safety endpoints of this study include the following: 
 Adverse events (AEs) 
 Clinical safety laboratory tests 
 Vital signs 
 Weight 
 
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 Electrocardiograms (ECGs) 
 Physical examination 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 
 
  
6. 
Statistical Methods 
6.1. 
General Principles 
All statistical analysis, data processing, tabulation of descriptive statistics, calculation of 
inferential statistics, and graphical representations will be performed using SAS version 9.4 or 
higher by Premier research, which is the designated CRO. Premier will be responsible for 
creating table, listing, and figure (TLF) reports via SAS programming. The reports and SAS 
programs will be delivered to Supernus at the completion of the study.   
All tabulations of analysis results will include summaries for the two treatments: SPN-812 and 
placebo. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, mean, standard deviation (SD), median, minimum, and maximum. 
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the study 
population for the treatment groups, unless otherwise specified. The denominator for by-visit 
displays will be the number of subjects in the relevant study population with non-missing data at 
each study visit. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified and with the 
following exceptions: a percentage of 0% will not be displayed (i.e., only the count of 0 will be 
displayed), and a percentage of 100% will be displayed with 0 decimal places. 
Derived analysis datasets will be produced from the SDTM data. Specifications for derived 
datasets will be developed. Analysis datasets to be created will include ADQS (Questionnaire 
analysis dataset), ADEF1 (Primary analysis efficacy dataset), ADEF2 (Sensitivity analysis 
efficacy dataset), ADSL (subject-level analysis dataset), ADAE (Adverse event analysis dataset) 
and others, as appropriate. 
 
Data collected at unscheduled time points will not be summarized but will be presented in 
subject listings. 
 
 
cted
 


 
Statistical Analysis Plan,  
 
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Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 28 of 43 
 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests, where applicable.  
A P value of 0.10 but >0.05 will be considered evidence of a trend.  
All P values will be displayed in four decimals and rounded using standard scientific notation 
(e.g., 0.XXXX). If a P value less than 0.0001 occurs it will be shown in tables as <0.0001 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings 
6.2. 
Analysis Populations 
The following analysis populations are planned for this study:  
 Randomized Population: The Randomized Population includes all subjects who 
complete the Baseline Period, meet inclusion/exclusion criteria, and are randomized. 
 Full Analysis Set: The FAS is a subset of subjects in the Randomized Population who 
took at least 1 dose of SM, and had a Baseline and at least one post-Baseline assessment 
of AISRS. Subjects in the FAS will be analyzed according to the treatment to which they 
were randomized. The efficacy analyses will be conducted using the FAS. 
 Per Protocol (PP) Population: The PP Population is a subset of subjects in the FAS who 
complete all 7 visits through EOS with no missing AISRS assessments and no major 
protocol violations. Subjects in the PP Population will be analyzed according to the 
treatment received. 
 Safety Population: The Safety Population includes all subjects randomized into the 
study who receive at least one dose of study medication. Subjects in the Safety 
Population will be analyzed according to the treatment received. The safety analyses will 
be conducted using the Safety Population. 
6.3. 
Interim Analysis and Data Monitoring 
No interim analyses are planned. 
6.4. 
Adjustments for Covariates 
If there is a statistical difference among treatment groups with respect to baseline characteristics, 
that variable may be added to the statistical models as a blocking factor or covariate to determine 
the effect on treatment. Baseline efficacy scale scores are planned for inclusion in statistical 
models, unless otherwise indicated. See Section 6.12 for more details. 
6.5. 
Hypotheses 
The primary objective of this study is to test the null hypothesis (H0) is that there is no difference 
between SPN-812 and placebo groups with respect to LS means. The alternative hypothesis (Ha) 
is that the LS mean of SPN-812 is greater than the LS Mean of Placebo in absolute value. In 
other words, 1 daily dose of SPN-812 is superior to placebo in the treatment of Adults with 
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 29 of 43 
 
Attention-Deficit/Hyperactivity Disorder (ADHD) in adult patients. 
6.6. 
Multiple Comparisons 
The type I error rate for the study will be preserved at the 5% significance level by using 
sequential (hierarchical) testing for the primary and key secondary endpoints. The key secondary 
endpoint will only be tested if SPN-812 treatment is significantly different from placebo for the 
primary endpoint. 
The testing will be done in the following order: 
1. Primary: change from baseline in AISRS total score at EOS (Week 6). 
2. Key Secondary: change from baseline in CGI-S score at EOS (Week 6). 
Because the testing is sequential, the type I error rate of α = 0.05 is maintained. Failure at any 
stage in the sequence implies automatic failure at all subsequent stages. All P values for each 
comparison without adjustments will be provided in the summary tables for informational 
purposes. 
No adjustments will be made for multiple comparisons for other endpoints. 
6.7. 
Handling of Dropouts or Missing Data 
6.7.1. Missing Efficacy Data 
All possible efforts will be made to ensure that subjects stay in the study and all data are collected 
as scheduled. Any subject who has received at least 1 dose of study medication who discontinues 
from the study for any reason will be encouraged to complete the end of study (EOS) visit. 
If more than 3 items of AISRS are missing then the total score will be set to missing. 
If ≤3 items are missing then the values for the missing items will be imputed using the mean of 
the non-missing items rounded to the nearest integer. 
1. Missing endpoint values in this study may result from subjects discontinuing from the study 
prematurely or missing intermediate assessments while remaining on study. The primary 
efficacy analysis method will be based on a mixed model with repeated measures (MMRM) 
which utilizes all available data (complete and partial) from subjects included in an analysis set. 
The MMRM-based approach assumes that missing AISRS total scores are missing at random 
(MAR). MAR refers to a missingness mechanism that is independent of missing responses, 
conditionally on observed response history and covariates, that is, given the observed data, the 
reason for the missing data does not depend on the unseen data. This assumption inherently 
implies that the treatment effect is similar for those who discontinue prematurely and for those 
who complete the study in their respective treatment groups. Under MAR, the propensity for a 
data point to be missing is not related to the missing data, but is related to some of the 
observed data. Missing data for subjects discontinued due to AE or lack of efficacy will be 
explicitly imputed using multiple imputation under Missing not at Random assumption.   . 
. 
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 30 of 43 
 
Sensitivity analyses to investigate robustness to missing primary endpoint data will be performed 
by assuming that missing AISRS total scores are missing not at random (MNAR), meaning that 
the probability that an observation is missing may depend on its underlying unobserved value. 
See Section 6.12.2 for more details. 
For analysis of secondary endpoints, missing values will be assumed to be MAR. 
6.7.2. Missing Safety Variables 
Missing dates for AEs and non-study concomitant medications will be imputed as described in 
using the following rules:  
If partial AE or medication dates occur, the convention for replacing missing dates for the 
purpose of statistical analysis is as follows.  
For partial AE and medication start dates: 
 If the year is unknown, then do not impute the date but assign a missing value. 
 If the year is known, but the month or month and day is/are unknown, then: 
o If the year matches the year of first dose date and the end date (if present) is after 
first dose date, then impute as the month and day of the first dose date. 
o Otherwise, assign 01 January. 
 If the year and month are known, but the day is unknown, then: 
o If the month and year match the month and year of the first dose date, then impute 
as the day of the first dose date. 
o Otherwise, assign 01. 
For partial AE and medication end dates: 
 If the year is unknown, then do not impute the date but assign as missing value. 
 If the year is known, but the month or month and day is/are unknown, then: 
o If the year matches the year of the last date of the study (date of last contact if 
subject lost to follow-up; date of completion or early termination), then impute as 
the month and day of the last date of the study. 
o Otherwise, assign 31 December. 
 If the year and month are known, but the day is unknown, then: 
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 31 of 43 
 
o If the month and year match the month and year of the last date of the study, then 
impute as the day of the last date of the study. 
o Otherwise, assign the last day of the month. 
If partial times occur, the convention is as follows:  
 if the missing time occurs on the day of the first dose and both the hour and minute are 
missing, then the time assigned is the time of the first dose, otherwise if both the hour and 
minute are missing and the date is not the date of first dose the time assigned is 12:00;  
 if the date is the same as the date of the first dose and  
o only hour is missing, the hour assigned is 12 or the hour of first dose, whichever 
is later; 
o only the minute is missing, the minute assigned is 30 or the minute of first dose, 
whichever is later;  
 Otherwise if the date is not the same as the date of first dose, the hour assigned is 12 if 
the hour is missing and the minute assigned is 30 if the minute is missing. 
Missing data for all other safety endpoints will not be imputed. 
6.8. 
Analysis Visit Windows 
Data from scheduled visits will be analyzed. Visits will be analyzed as scheduled. Unscheduled 
measurements will be excluded from the descriptive statistics and statistical analyses but will be 
included in listings.  
6.9. 
Pooling of Sites 
This is a multicenter study. The primary analysis will be performed without site as a factor. 
However, if applicable, for certain 
 analyses small sites (defined as those with sample 
size <12 FAS subjects per site with uneven distribution of treatment groups) will be pooled based 
on geographic proximity. 
6.10. Study Subjects and Demographics 
6.10.1. Disposition of Subjects and Withdrawals 
Subject disposition summary will presented for the randomized population. Disposition will 
include tabulations of the number and percentage of subjects in each of the following categories 
by treatment group and overall: 
 Subjects in the Randomized Population 
 Subjects in the FAS 
 Subjects in the PP Population 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 32 of 43 
 
 Subjects in the Safety Population 
Within each of the previous categories, the number and percentage of subjects who completed 
and discontinued from the study and primary reason for early discontinuation will be 
summarized. The reason for early discontinuation may include any of the following: 
 Withdrawal of consent 
 Noncompliance 
 Occurrence of unmanageable AEs  
 Lost to follow-up  
 Other 
The number of subjects in each of the above analysis populations who will be continuing in the 
311 OLE safety study will also be tabulated. 
All disposition information as well as inclusion and exclusion criteria met/not met and reasons 
for screen failures will be listed. 
6.10.2. Protocol Violations and Deviations 
Protocol deviations will be listed and major protocol deviations will be summarized. 
6.10.3. Demographics and Other Baseline Characteristics 
Summary statistics for age, age group, sex, ethnicity, race, height and weight at screening, BMI, 
HAM-A score, AISRS Total score at screening, SDQ 
 mean score at Screening and 
CGI-S score at screening will be presented by treatment group and overall. 
Age will be broken up into quartiles to determine age group. If the distribution of age is such that 
the use of quartiles does not lead to distinct intervals of values, other cut-off points will be 
examined (e.g. tertiles, above/below median). 
Baseline comparability among the treatment groups will be summarized using a Chi-square test 
for categorical variables and one-way ANOVA (F-test) for continuous variables. P-values will 
be used for descriptive purposes only.   
These analyses will be conducted for the FAS. 
The number and percent of subjects reporting various medical histories, grouped by MedDRA 
system organ class (SOC) and preferred term (PT), will be tabulated by treatment group and 
overall. This analysis will be conducted for the Safety Population. 
Prior medications will be summarized by treatment group, by the number and percentage of 
subjects taking each medication, classified using WHO-DDE ATC Class Level 4 and preferred 
term (ATC Class Level 5) and will be presented by treatment group and overall. This analysis 
will be conducted for the Safety Population. Prior medications are defined in Section 7.7. 
The Structured Clinical Interview for DSM-5 Clinical (SCID) and the Hamilton Anxiety Rating 
Scale (HAM-A), as well as the alcohol, tobacco, and substance use collected at screening will be 
listed. Subject training module data will also be listed. See Section 4 for the derivation of the 
HAM-A total score. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 33 of 43 
 
6.11. Exposure and Compliance 
Duration of treatment exposure will be summarized by treatment group and overall using 
descriptive statistics. Additionally, duration of treatment exposure will be summarized by 
duration category.  
Duration of treatment exposure will be categorized as follows: 1-7 days, 8-14 days, 15-21 days, 
22-35 days, 36-42 days, and >42 days 
Subject exposure will be summarized categorically by study week, dose (200 mg, 400 mg and 
600 mg), and treatment group. The number and percent of subjects in each dose group will be 
presented for each treatment.  
For each treatment, SM compliance will be summarized by compliance category (<80%, 80 to 
120%, and >120%) and number of subjects in each compliance category. Study medication 
compliance will also be summarized as a continuous variable using descriptive statistics. 
This analysis will be conducted for the Safety Population. Derivations of duration of treatment 
exposure and compliance are defined in Section 4. All study medication administration, exposure, 
and accountability data collected will be listed. 
6.12. Efficacy Analysis 
All efficacy endpoints will be summarized using the FAS. All efficacy data will be presented in data 
listings. The mean profiles of AISRS Total Score, CGI-S score, and CGI-I score will be presented 
graphically by treatment group and scheduled study visit. In addition, plots of the Cumulative 
Distribution Functions of Change from Baseline in AISRS Total score will be presented. Bar charts 
of CGI-S and CGI-I response by treatment group and study visit will also be presented. Furthermore, 
bar charts for the absolute mean of GAD-7, BRIEF-A, 
 total scores by treatment 
group and study visit be presented. 
To ensure the overall type I error rate of α = 0.05 will be maintained for the study, hierarchical 
testing, based on a fixed sequence procedure, will be used for the primary endpoint and continuing 
for the key secondary endpoints. The MMRM primary analysis, as described in Section 6.12.1 will 
start the hierarchical testing. If statistical significance is declared for the primary MMRM analysis, 
formal hypothesis testing will be done for the key secondary endpoint (see Section 6.6 for sequence 
of testing) until a non-significant result is reached. The key secondary endpoint will only be tested if 
SPN-812 treatment is significantly different from placebo for the primary endpoint. All other P 
values, after a non-significant P value is reached, will be considered nominal. 
6.12.1. Primary Efficacy Analysis 
The primary efficacy endpoint, change from baseline in AISRS total score to Week 6, will be 
analyzed using MMRM, which assumes that missing data are MAR. The model will include 
change from baseline in AISRS score as the dependent variable, fixed effect terms for baseline 
AISRS total score, treatment, study visit, and treatment-by-study visit interaction as independent 
variables. All post-baseline study visits will be included in the model; however, the primary 
comparison will be between SPN-812 and placebo at Week 6. The model parameters will be 
estimated using the restricted maximum likelihood (REML) method with unstructured variance-
covariance matrix and Kenward-Roger approximation to estimate denominator degrees of 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 34 of 43 
 
freedom. If the unstructured covariance model fails to converge, the first (co)variance structure 
that does not have convergence problem will be used for the analysis from the following ordered 
list: 1) Toeplitz, 2) Autoregressive of order 1, and 3) Compound Symmetry.  
The adjusted mean (LS Mean) of CFB to EOS of SPN-812 treatment group and placebo for 
AISRS Total Score will be presented, along with the corresponding standard error. The SPN-812 
treatment group will be compared with the placebo by presenting the difference between the LS 
Means of SPN-812 and placebo (SPN-812 minus placebo), and 95% confidence intervals for the 
treatment difference and the p-value.   
The observed value and change from baseline in AISRS score will also be summarized 
descriptively by study visit and treatment group using descriptive statistics in addition to the 
above noted model. Results from the MMRM primary analysis, described above, will be used to 
determine study success.  
6.12.2. Sensitivity Analysis  
The sensitivity analysis assumes that missing AISRS Total Scores are missing not at random 
(MNAR), that is, the probability that an observation is missing may depend on its underlying 
unobserved value. For example, the probability of missing AISRS Total Score at Week 4 is not 
related to the observed AISRS Total Score at Visit 5. Placebo-based multiple imputation will be 
used to fill in missing values. This approach may be considered “worst-case” sensitivity analysis 
as it assumes that after discontinuation, subjects from the SPN-812 treatment group would adopt 
the outcome model estimated from the placebo arm.  The placebo-based imputation will be 
implemented by adopting the following three steps. 
1. SAS PROC MI (SEED=220877) is applied to the input dataset containing all by-visit 
AISRS Total Score during the baseline and treatment period.  Multivariate imputation will 
be carried out by the fully conditional specification (FCS) method. One hundred (100) 
multiply-imputed datasets will be created. SAS® PROC MI with the MNAR statement will 
be implemented by using the following SAS code. 
 
 
  
  
 
  
 
  
 
 
 
 
 
 
 
  
  
   
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
     
 
 
RUN; 
 
In the above SAS code, EFF denotes the input efficacy analysis dataset, MNAROUT 
denotes the output dataset, Baseline, Week1, Week 2, Week 3, Week 4, and Week 6 are 
analysis values of AISRS total scores at baseline and at each of the treatment weeks from 
Week 1 to Week 6, where modelobs=(treatment=(“placebo”))) means model observations 
will be from the placebo arm only.  
 
 
d


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 35 of 43 
 
Imputed values will be rounded to the closest integer. In case imputed values are below 
or above the range of the AISRS scale, values will be imputed to respectively the 
minimum or maximum value of the scale. 
2. For each of the imputations from Step #1, CFB to study visit will be computed on the 
completed dataset.  
For each imputation the CFB will be analyzed using an MMRM ANCOVA model, which 
will include change from baseline in AISRS total score as the dependent variable, 
treatment, study visit, study visit-by-treatment interaction as fixed effect factors, and 
baseline AISRS total score as a covariate.  
3. Finally, to combine estimates (LS means, LS mean treatment differences, 95% CI around 
the difference and P value) from the 100 datasets, SAS®  PROC MIANALYZE will be 
used as in the following. 
 
 
    
 
 
 
    
 
 
    
 
 
    
 
 
 
run; 
The adjusted mean (LS Mean) of CFB to EOS of SPN-812 treatment group and placebo, along 
with the corresponding standard error, difference between the LS Means of SPN-812 and 
placebo (SPN-812 minus placebo), 95% confidence intervals for the treatment difference and the 
p-value will be presented from the combined estimates.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
6.13. Analysis of Secondary Endpoints 
6.13.1. Key Secondary Analysis 
The key secondary efficacy endpoint, change from baseline in CGI-S score to Week 6 (EOS), 
will be analyzed using a MMRM. The model will include change from baseline in CGI-S score 
to Week 6 (EOS), as the dependent variable, baseline in CGI-S score as a covariate, and 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 36 of 43 
 
treatment, study visit, and treatment-by-study visit interaction as independent fixed effect 
variables. 
The adjusted mean (LS Mean) of CFB to EOS of SPN-812 treatment group and placebo, along 
with the corresponding standard error, difference between the LS Means of SPN-812 and 
placebo (SPN-812 minus placebo), 95% confidence intervals for the treatment difference and the 
p-value will be presented.  
 
The null hypothesis is that the difference in change from baseline in SPN-812 minus placebo is 0 
with a 2-sided alternative considering a difference in either direction. 
The observed value and change from baseline in CGI-S score will also be summarized 
descriptively by study visit and treatment group using descriptive statistics in addition to the 
above noted model. 
6.13.2. Additional Secondary Analyses 
1) A CGI-S “responder” is defined as having a CGI-S score of 1 or 2. The number and 
percentage of CGI-S responders along with 95% CIs will be summarized by treatment 
group and study visit. A 2-sided Pearson’s Chi-Square Test, or Fisher’s Exact Test, as 
appropriate, will be performed at the 5% significance level to determine whether there is 
a significant difference between treatment groups. The null hypothesis is that there is no 
difference in proportion of CGI-S responders between SPN-812 and placebo, with a 2-
sided alternative considering a difference in either direction. The difference in proportions 
between SPN-812 and placebo (SPN-812 minus placebo), 95% CIs for the differences, and 
P-values for the differences in treatment will also be presented. 
 
2) The absolute value of in CGI-I score at each study visit including Week 6, will be 
analyzed using a MMRM with absolute CGI-I score as the dependent variable, baseline 
CGI-S score as a covariate, and treatment, study visit, treatment-by-study visit interaction 
as independent fixed effect factors. SPN-812 and placebo will be compared; the LS 
Means and the LS mean differences in CGI-I score will be presented along with 
associated 95% CIs of the treatment difference and P-values will be computed. The null 
hypothesis is that the difference in CGI-I score in SPN-812 minus placebo is 0 with a 2-
sided alternative considering a difference in either direction. Additionally, Absolute CGI-
I scores will be summarized by treatment group and study visit using descriptive 
statistics. CGI-I scores are collected at Week 1 through Week 6.  
 
3) A CGI-I “responder” is defined as having a CGI-I score of 1 or 2. The analysis in number 
1 above will be repeated for this endpoint.  
 
4) Change from baseline in GAD-7 score to Week 6 will be analyzed using the same 
MMRM in number 2 above.  
 
5) Change from baseline in AISRS Inattention and Hyperactivity/Impulsivity subscale score 
to Week 6, will be analyzed using the same MMRM in number 2 above.  
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 37 of 43 
 
 
6) A 50% AISRS “responder” is defined as having at least a 50% reduction from baseline 
AISRS total score. For each subject, the percent reduction will be calculated as defined in 
Section 4. The number and percentage of 50% AISRS responders along with 95% CIs 
will be summarized by treatment group and study visit. A 2-sided Pearson’s Chi-Square 
Test, or Fisher’s Exact Test, as appropriate, will be performed at the 5% significance 
level to determine whether there is a significant difference between treatment groups. The 
null hypothesis is that there is no difference in proportion of 50% AISRS responders 
between SPN-812 and placebo, with a 2-sided alternative considering a difference in 
either direction. The difference in proportions between SPN-812 and placebo (SPN-812 
minus placebo), 95% CIs for the differences, and P-values for the differences in treatment 
will also be presented. 
 
7) Analysis of 30% AISRS responder rates, defined as having at least a 30% reduction from 
baseline AISRS total score, will mimic that in number 6 above. 
 
8) With respect to BRIEF-A GEC T-score, data are collected at baseline and Week 6. 
Hence, MMRM is not applicable since there is only one post randomization value to be 
analyzed.  The change from baseline in BRIEF-A GEC T-score to Week 6 will be 
analyzed using ANCOVA model with change from baseline in BRIEF-A GEC T-score as 
dependent variable and baseline BRIEF-A GEC T-score and treatment as fixed 
independent variables. 
 
9) The change from baseline in the BRIEF-A BRI, MI, and each individual BRIEF-A 
subscale (BRIEF-A -Inhibit, BRIEF-A -Self-Monitor, BRIEF-A -Plan/Organize, BRIEF-
A -Shift, BRIEF-A -Initiate, BRIEF-A -Task Monitor, BRIEF-A -Emotional Control, 
BRIEF-A -Working Memory, and BRIEF-A -Organization of Materials) will be analyzed 
using the same ANCOVA model in number 8 above. 
 
 
 
 
 
 
 
 
 
 
 
6.15. Supplementary Analyses 
The primary and key secondary analyses will be repeated in the PP Population. 
 
d
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 38 of 43 
 
 
 
   
7. 
Safety and Tolerability Analysis 
Safety assessments include monitoring, evaluation, and recording of all concomitant medications, 
and the evaluation of AEs, clinical laboratory test results, vital signs, weight, 12-lead ECGs, 
C-SSRS, and the performance of physical examinations. 
All safety analyses will be performed on the Safety population. No inferential statistical tests will 
be performed. 
7.1. 
Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA Version 22.0.   
A treatment-emergent adverse event (TEAE) is defined as an AE with a start date on or after the 
date of the first dose of study medication, or that worsened in severity following the first dose of 
study medication. All AEs in this study will be recorded after administration of study 
medication, therefore all will be considered treatment-emergent.  
The causal relationship of the AE to the study medication is determined by the investigator as 
Not Related, Unlikely Related, Possibly Related, and Definitely Related. These will be mapped 
to Unrelated (Not Related or Unlikely Related) and Related (Possibly Related or Definitely 
Related).  
Adverse event severity grades are reported as mild, moderate, or severe. 
Summaries of incidence rates (frequencies and percentages) of individual TEAEs will be 
presented by SOC, PT, and treatment group. Such summaries will be displayed for all TEAEs, 
TEAEs by maximum severity, and TEAEs by relationship.  
Each subject will be counted only once within each summation level (SOC and PT). If a subject 
experiences more than 1 TEAE within each summation level, the TEAE with the strongest 
relationship or the maximum severity, as appropriate, will be included in the summaries of 
relationship and severity. If a particular event is missing the severity and/or relationship, then the 
strongest possible severity or relationship will be assumed for analysis (severity = severe, 
relationship = definitely related). 
Incidences will be presented by descending frequency of SOC and PT within SOC, and then 
alphabetically within PT where the incidence is the same; this is based on overall subjects then 
alphabetically in case of a tie. 
In addition, number and percent of patients reporting common AEs (≥5% in any treatment 
group) will be presented by PT. 
Missing and partially missing AE start and/or stop dates and times will be imputed, for the 
purpose of statistical analysis, according to the specifications described in Section 6.7.2. 
 
d
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 39 of 43 
 
In the AE data listings, all AEs will be displayed. AEs that are treatment emergent will be 
flagged. 
7.1.1. Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study medication, by treatment group, SOC, and PT will be prepared for the Safety Population.  
A data listing of AEs leading to withdrawal of study medication will also be provided, displaying 
details of the event(s) captured on the CRF. 
7.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
Serious adverse events will be listed and also tabulated by SOC and PT and presented by 
treatment. 
7.2. 
Clinical Laboratory Evaluations 
Laboratory tests (clinical chemistry, hematology, and urinalysis) will be performed at Screening, 
Baseline, and Week 6 and results will be summarized descriptively by treatment group and study 
visit as both observed values and change from baseline values. See Section 4 for the definition of 
baseline. Number and percentage of subjects with abnormal qualitative urinalysis results will be 
provided by treatment group and study visit. 
Laboratory values for clinical chemistry and hematology will be presented at Week 6 using 
descriptive statistics (n, mean, SD, median, minimum, and maximum) by treatment group for the 
actual and change from baseline values will be presented in Tables.  
 
Laboratory values for clinical chemistry and hematology will be flagged as abnormally low (L) if 
the value < lower limit of the normal range, normal (N) if the value is within normal range or 
abnormally high (H) if the value > upper limit of the normal range. In addition, shift tables for 
the change from baseline to Week 6 (EOS) will be presented. 
 
Laboratory values will be displayed in the data listings and those that are outside the normal 
range will be flagged and presented along with corresponding normal ranges (if available). A 
separate listing of abnormal laboratory values will be provided. All study visits within a 
parameter for a subject will be presented if at least 1 study visit within that parameter has an 
abnormal result.  
Serology, follicle stimulating hormone (FSH), serum drug screen results, standard urine drug 
screen results, point of care urine drug screen results, and pregnancy test results will be listed 
separately. 
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 40 of 43 
 
7.3. 
Vital Signs 
Vital signs will be collected at all study visits. Descriptive summaries of actual values and 
changes from baseline will be calculated for weight (kg), BMI (kg/m2), oral body temperature 
(ºC), respiration rate (breaths per minute), sitting heart rate (bpm), standing heart rate (bpm), 
sitting systolic blood pressure (mmHg), standing systolic blood pressure (mmHg), sitting 
diastolic blood pressure (mmHg), and standing diastolic blood pressure (mmHg). These 
summaries will be presented by study visit and treatment group. See Section 4 for the definition 
of baseline. 
The number of subjects with vital signs below, within, or above normal ranges, by study visit 
will be tabulated (shift tables) for each parameter by treatment group.  
The number of subjects with vital signs values below, within, or above normal ranges, by study 
visit will be tabulated (shift tables) for each vital sign parameter by treatment group. Normal 
ranges are presented in Table 3. 
Table 3: Vital Sign Normal Ranges 
Measurement 
Normal Range 
Body Mass Index 
18 – 35 kg/m2 
Temperature 
95-100 ℉ (35-37.8 ℃) 
Diastolic blood pressure 
60 – 90 mmHg 
Systolic blood pressure 
90 – 140 mmHg 
Heart rate 
50 – 100 bpm 
Respiration rate 
10 – 25 breaths per minute 
7.4. 
Electrocardiograms 
12-Lead ECGs will be collected at Screening, Baseline, and Week 6. Descriptive summaries will 
be presented for heart rate (bpm), PR interval (msec), QRS duration (msec), uncorrected QT 
interval (msec), and QTcF (msec). These summaries will be presented by study visit and 
treatment group. 
The number of subjects with ECG results below, within, or above normal ranges, by study visit 
will be tabulated (shift tables) for each parameter by treatment group.  
Normal, abnormal but not clinically significant, and abnormal and clinically significant ECG 
investigator interpretation results will flagged in the listings. 
Additionally, the number and percentage of subjects with actual QT and QTcF values ≤450 
msec, 450 msec to ≤480 msec, 480 to ≤ 500 msec, >500 msec and with changes from baseline 
<= 30 msec, 30 msec to ≤ 60 msec, and  >60 msec will be presented. 
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 41 of 43 
 
7.5. 
Physical Examination 
The physical examination conducted at screening will include assessments of all body systems 
except genitourinary. Any findings during screening will be recorded as medical history and any 
clinically significant abnormal findings during treatment will be recorded as an AE. At the EOS 
physical examination, only changes from the screening visit will be noted. 
All physical examination results will be listed. 
7.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Assessment of suicidal ideation and behavior will be conducted using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) which classifies suicidal ideation and behavior events into 11 
preferred categories including 5 levels of suicidal ideation, 5 levels of suicidal behavior, and the 
category of self-injurious behaviors with no suicidal intent. The C-SSRS will be performed at all 
study visits. At the Screening visit, the “baseline” version of the C-SSRS will be administered. 
This version assesses Suicidal Ideation and Suicidal Behavior during the subject’s lifetime and 
during the past 6 months. At the subsequent study visits, the “since last visit” version will be 
administered. 
 
The number and percentages of subjects with a response of “Yes” at any point on the suicidal 
ideation only, suicidal behavior only, and suicidality (ideation and behavior combined) items will 
be summarized by treatment group. 
7.7. 
Concomitant Medications 
Prior and concomitant medications, coded using World Health Organization-Drug Dictionary 
Enhanced (WHO-DDE) (March 2019), will be summarized descriptively by Anatomical 
Therapeutic Chemical (ATC) classification Level 4 and PT (i.e., ATC classification Level 5), if 
applicable, using counts and percentages for the Safety Population.  
If a medication starts prior to the first dose and continues after the first dose it will be considered 
both prior and concomitant. Prior and concomitant medications will also be listed. Prior and 
concomitant medications will be summarized descriptively by treatment using counts and 
percentages. 
7.8. 
Caffeine Consumption 
Caffeine consumption will be assessed at all study visits and listed.  
7.9. 
Other Safety Assessments 
Follow-up phone call data and subject training video module data will be listed. 
8. 
Changes from Planned Analysis 
A Mixed Model for Repeated Measure (MMRM) will be used instead of an ANCOVA model for 
the multiply imputed data using SAS PROC MI for primary, secondary, 
 efficacy 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 42 of 43 
 
endpoints except for BRIEF-A, 
. Since BRIEF-A, 
 data are 
only collected at baseline and Week 6 or ANCOVA analysis will be used as per the protocol.  
9. 
Validation of Analysis Reports 
Supernus seeks to ensure the quality of the reports provided by Premier in the form of TLFs and 
derived datasets must pass a rigorous validation process involving the following processes.  
 
Derived datasets must be independently reprogrammed by a second programmer based 
on analysis data specifications. The separate datasets produced by the 2 programmers 
must match 100% or in case of any differences, an explanation should be given and 
documented.   
 Figures must be checked for consistency against corresponding tables and listings, or 
independently reprogrammed if there are no corresponding tables or listings.  
 Listings must be checked for consistency against corresponding tables, figures, and 
derived datasets.  
The above validation process must be repeated any time TLFs are redelivered using updated or 
different data. Execution of this validation process must be documented through the study in a 
tracking sheet which contains TLF number and title, name of the production programmer, name 
of the QC programmer and comments. The validation tracking sheet must be submitted at each 
delivery of TFLs. 
10. 
References 
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food 
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, 
pages 49583-49598. September 16, 1998. 
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm 
3. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
4. Spencer TJ, Adler LA, Meihua Q, Saylor KE, Brown TE, Holdnack JA, Schuh KJ, Trzepacz 
PT, Kelsey DK. Validation of the adult ADHD investigator symptom rating scale (AISRS). J 
Atten Disord. 2010;14(1):57-68. 
5. Guy W. Clinical global impressions. ECDEU Assessment manual for Psychopharmacology, 
Rockville, MD: US National Institutes of Health, Psychopharmacology Research Branch, 
1976. 
6. Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized 
anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092-1097. 
7. Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences (2nd ed.). Hillsdale, 
NJ: Lawrence Erlbaum Associates, Publishers. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Supernus Pharmaceuticals, Inc.  
 
Protocol Number 812P306  
 
PCN Number SUPE9582 
AD-ST-33.05  Effective date: 22-Jan-2018 
    |    Date 20-Oct-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 43 of 43 
 
8. Glass GV, McGaw B, Smith ML (1981). Meta-Analysis in Social Research. Sage: Beverly Hills. 
11. 
Planned Table, Figure, and Listing Descriptions 
The planned summary tables, figures, and listings for protocol number 812P306 are contained in 
a separate appendix to this SAP.