Clinical trial NCT04143217
Conditions: Attention-Deficit/Hyperactivity Disorder
Sponsor: Supernus Pharmaceuticals, Inc.
Start date: 2020-01-23; Completion date: 2022-12-14
Enrollment: 159 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Open label, flexible dose, long-term multicenter study of safety and efficacy of SPN-812 in adult ADHD patients

Detailed description:
This is a multicenter, open-label extension study aimed to assess long-term safety and efficacy of SPN-812 when administered alone or in conjunction with an Food and Drug Administration (FDA)-approved Attention-Deficit Hyperactivity Disorder (ADHD) medication in the treatment of ADHD in adult subjects who completed a blinded study of SPN-812 (812P306). Subjects initiate SPN-812 dosing at 200 mg/day once daily (QD) during first 2 weeks. At or after Visit 2 (Week 2), per the Investigator's discretion and based on Investigator's assessment of subject's clinical response and tolerability, the dose of SPN-812 can be titrated up or tapered down in increments of 50 mg/day, 100 mg/day, 150 mg/day, or 200 mg/day per week to a target dose within the ranges between 200 and 600 mg/day. Additionally, after 12 weeks of dosing (after Visit 4), at the discretion of the Investigator and based on subject's clinical response, the optimized dose of SPN-812 may be supplemented with an adjunctive FDA-approved stimulant treatment. Total treatment duration per subject from Visit 1 to Visit 22 (end of study) is approximately 3 years (156 weeks ± 1 week) or until SPN-812 becomes commercially available.

Arms: arm 1: SPN-812 Open-Label Treatment 200mg to 600mg SPN-812 once daily for up to 156 weeks
Interventions: intervention 1: SPN-812
Intervention descriptions: intervention 1: SPN-812 200 to 600 mg/day

Protocol documents:
Prot_002.pdf: 
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812P311 
 
Version 5.0 
 
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COVER PAGE - PROTOCOL 
 
Protocol Number: 
812P311 
Title: 
An Open-Label Extension Study to Evaluate the Long-Term 
Safety and Efficacy of SPN-812 in Adults with Attention-
Deficit/Hyperactivity Disorder 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
9715 Key West Avenue 
Rockville, MD 20850 
United States 
Phone: (301) 838-2500 
Fax: (240) 403-0065 
Protocol Version: 
5.0 
Date: 
15Dec2020 
NCT: 
NCT04143217 


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TITLE PAGE 
 
 
Protocol Number: 
812P311 
Title: 
An Open-Label Extension Study to Evaluate the Long-Term 
Safety and Efficacy of SPN-812 in Adults with Attention-
Deficit/Hyperactivity Disorder 
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: 
5.0 
Date: 
15Dec2020 
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. 
Data Redacted
Data Redacted
Data Redacted


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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: 
 
 
 
 
Data Redacted
Data Redacted
Data Redacted


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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: 812P311 
Phase of Development: 3 
Full Title of Study: An Open-Label Extension Study to Evaluate the Long-Term Safety 
and Efficacy of SPN-812 in Adults with Attention-Deficit/Hyperactivity Disorder 
Number of Study Sites:  Up to 40 study sites in the US 
Number of Subjects:  Up to 366 subjects 
Indication: Attention-deficit/hyperactivity disorder (ADHD) 
Objectives:  
Primary Safety Objective:  To monitor and collect long-term safety data on the use of 
SPN-812 as monotherapy for the treatment of ADHD in the adult population. 
Secondary Efficacy Objective:  To evaluate the efficacy of SPN-812 as monotherapy for 
the treatment of ADHD in the adult population. 
Endpoints: 
Primary Safety Endpoints: 
The primary safety endpoints are adverse events (AEs), clinical safety laboratory tests’ 
results, vital signs, weight, electrocardiograms (ECGs), physical examination, and the 
Columbia Suicide Severity Rating Scale (C-SSRS). 
Secondary Efficacy Endpoints: 
The secondary efficacy endpoints are: 
1) Change from baseline (CFB) in the AISRS total score by visit. 
2) CFB in the CGI-S score by visit  
3) Percentage of subjects with a CGI-S score of 1 or 2 by visit. 
4) CGI-I score by visit.  
5) Percentage of subjects with a CGI-I score of 1 or 2 by visit. 
6) CFB in the GAD-7 total score by visit.  
7) CFB in the AISRS Inattention subscale score and the Hyperactivity/Impulsivity 
subscale score by visit.  
8) AISRS 50% Responder rate (defined as the percentage of subjects with a ≥ 50% 
reduction in the CFB AISRS total score) by visit. 
9) AISRS 30% Responder rate (defined as the percentage of subjects with a ≥ 30% 
reduction in the CFB AISRS total score) by visit. 
10) CFB in the BRIEF-A Global Executive Composite (GEC) T-score by visit. 
11) CFB in the BRIEF-A T-score by each Summary Index Scale and subscale by visit. 
12) CFB in SDQ total score by visit  
13) CFB in SDQ  subscale scores by visit 
14) CFB in AAQoL total score by visit 
15) CFB in AAQoL subscale scores by visit 


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Study Design:   
This is an open-label, long-term, multicenter, flexible-dose study of SPN-812 in adults 
diagnosed with ADHD. Up to 366 subjects will be enrolled. Subjects who have completed 
Study 812P306 (a randomized, double-blind, placebo-controlled study of SPN-812 for the 
treatment of ADHD) will be eligible for enrollment into Study 812P311. Interest and 
suitability will be ascertained at the last 1 to 2 visits of 812P306 to allow immediate 
enrollment into Study 812P311 for subjects who complete Study 812P306. 
For subjects who complete Study 812P306 and rollover into Study 812P311 on the same 
day as or ≤7 days after their 812P306 EOS visit, use INCLUSION/EXCLUSION 
CRITERIA ‘A’ (Section 3.3.2. ) and follow SCHEDULE ‘A’ (Table 1; Figure 1). All 
efficacy and safety assessments collected at the subject’s end of study (EOS) Visit 
(812P306) will serve as their efficacy and safety assessments for Visit 1 (812P311). 
For subjects who complete Study 812P306, but who rollover into Study 812P311 more 
than 7 days after their EOS Visit (812P306), use INCLUSION/EXCLUSION CRITERIA 
‘B’ (Section 3.3.3. ) and follow SCHEDULE ‘B’ (Table 2; Figure 2). Efficacy and safety 
assessments will be collected at a screening visit (Visit ‘S’) to determine eligibility, and 
subjects will return to the clinical site for Visit 1 within 28 days of screening to make final 
eligibility determination and complete baseline efficacy and safety assessments at Visit 1.  
De novo subjects (individuals who did not screen/enroll in Study 812P306) may screen 
and, if eligible, enroll in Study 812P311, but only after a “Note To File” has been 
submitted by the Sponsor to the IRB and approved. The clinical sites will be notified 
when the approval is granted. For these subjects, use INCLUSION/EXCLUSION 
CRITERIA ‘B’ (Section 3.3.3. ) and follow SCHEDULE ‘B’ (Table 2; Figure 2). 
On a case-by-case basis, a subject who did not complete Study 812P306 (e.g., 
randomized, dosed SM and had at least one post-baseline AISRS assessment and then 
early terminated) may be allowed to screen and, if eligible, enroll in Study 812P311, but 
only after receiving approval from the Site Investigator, Medical Monitor, and the 
Sponsor. For these subjects, use INCLUSION/EXCLUSION CRITERIA ‘B’ (Section 
3.3.3. ) and follow SCHEDULE ‘B’ (Table 2; Figure 2). 
All subjects will initiate SPN-812 dosing at 200 mg once daily (QD) during the first 2 
weeks of the study. At Visit 2 (Week 2) and all subsequent study visits, 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 50 mg/day, 100 mg/day, 
150 mg/day, or 200 mg/day per week to a target dose within the ranges between 200 
and 600 mg/day. Additionally, after the first 12 weeks of dosing (after Visit 4), at the 
discretion of the Investigator and based on the subject’s clinical response, the optimized 
dose of SPN-812 may be supplemented with an adjunctive FDA-approved stimulant 
treatment (see Section 4.3. ).  
Following the day that the subject takes first dose of SPN-812 (Day 1), the subject will 
have a study visit every 2 weeks for the first 4 weeks of the study (Visit 2 and Visit 3). 
After Visit 3, study visits (Visits 4-22) will occur 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 
100, 108, 116, 124, 132, 140, 148 and 156 weeks after first dose of SPN-812 
(approximately every 8 weeks). In addition, the site should conduct a follow-up phone call 
(FPC) to each subject 4 weeks after Study Visits 3-21 to assess adverse events, 
changes in concomitant medications, obtain results of home pregnancy test (FOCP only). 
The timing of each study visit (V2-V22) and each FPCs should occur per the Schedule of 
Events and Assessments (Table 1 [SCHEDULE ‘A’] or Table 2 [SCHEDULE ‘B’]) 
relative to the date of subject’s first dose of SPN-812.  


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Subjects will be contacted for a final safety follow-up (FPC) approximately 1 week after 
the EOS visit. The clinical course of each AE should be followed for at least 30 days 
following the date of last dose of SM (due to either EOS or ET) or until resolution, or until, 
in the medical judgment of the Investigator, the event has stabilized or is assessed as 
chronic. 
Duration of Subject’s Participation:  
For subjects who follow SCHEDULE ‘A’, the total study duration per subject, from Visit 1 
to Visit 22/EOS will be up to ~156 weeks (3 years) or until SPN-812 becomes approved 
and commercially available for Adults.  
For subjects who follow SCHEDULE ‘B’, the total study duration per subject is up to 160 
weeks, including screening (up to 4 weeks) and from Visit 1 to Visit 22/EOS (up to 
~156 weeks [3 years]), or until SPN-812 becomes approved and commercially available 
for Adults.  
Investigational Medicinal Products, Reference Therapy, Doses and Mode of 
Administration 
Study Medication: SPN-812: 100 mg, 150 mg and 200 mg capsules. 
Reference Therapy: None 
Dose levels: Daily target dose of SPN-812 should be between 200 and 600 mg/day (QD). 
Mode of Administration: Orally as intact capsules 
Statistical Methodology 
All subjects who are enrolled and receive at least one dose of SPN-812 during the OLE 
study will be in the Safety Population. 
All statistical analyses will be based on the Safety Population. Summary statistics for 
continuous variables will include sample size (N), mean, median, standard deviation, 
minimum, and maximum. Summary statistics for discrete variables will be presented in 
terms of frequencies and percentages. 
Each efficacy endpoint will be listed and summarized by group of the optimized dose as 
applicable. Total and subscale scores/points for AISRS, CGI-S, CGI-I, GAD-7, BRIEF-A, 
SDQ and AAQoL will be summarized by dose and visit and will be examined for trends. 
More details will be provided in the Statistical Analysis Plan (SAP). 
INCLUSION/EXCLUSION CRITERIA ‘A’ 
Inclusion Criteria ‘A’: 
1. Is a male or female who completed Study 812P306 and opts/consents to participate 
in the study if approved by PI.  
2. Continues to be medically healthy and with clinically normal laboratory profiles, vital 
signs, and electrocardiograms (ECGs), in the opinion of the Investigator, as 
assessed at Visit 1. 
3. Is able to read and understand the Informed Consent Form (ICF). 


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4. Has signed the ICF. 
5. Is willing and able to attend study appointments within specified time windows. 
6. Is a female of childbearing potential (FOCP) who is either sexually inactive 
(abstinent) or, if sexually active, agrees to use one of the following acceptable birth 
control methods beginning 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 their Visit 1). 
7. Is a male who: 
a. Agrees to use 2 methods of contraception in combination if his female 
partner is of childbearing potential; this combination of contraceptive 
methods must be used from Visit 1 to ≥ 1 month after the last dose of SM, 
OR 
b. Has been surgically sterilized prior to Visit 1. 
Exclusion Criteria ‘A’: 
1. Is currently participating in another clinical trial other than Study 812P306. 
2. Has any current psychiatric disorder per Diagnostic and Statistical Manual of Mental 
Disorders - 5th Edition (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. 
3. Current diagnosis of significant systemic disease and/or of a major psychiatric or 
neurological disorder, including history or family history of seizures or seizure-like 
disorders. 
4. Current evidence of suicidality (suicidal thoughts or behaviors). 
5. 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. 
6. Has a positive result on urine drug screen at Visit 1. 
7. Use of prohibited concomitant medications including known CYP1A2 substrates 
(e.g., theophylline, melatonin) at the Visit 1 and for the duration of the study. 


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8. Has a clinical laboratory value, vital sign value or ECG result at Visit 1 that is 
considered to be clinically significant in the opinion of the Investigator. 
9. Has one or more clinical laboratory test values outside the reference range at Visit 1 
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. 
10. Has any of the following cardiology findings at Visit 1 (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. 
11. Any reason that, in the opinion of the Investigator, would prevent the subject from 
participating in the study. 
Note: For subjects who follow SCHEDULE ‘A’, with the approval from the investigator, 
medical monitor and the sponsor, repeat testing for clinical laboratory tests, vital signs, 
and ECG parameters is permitted one time within 1 week following Visit 1 prior to first 
dose for each test to determine eligibility. 
INCLUSION/EXCLUSION CRITERIA ‘B’ 
Inclusion Criteria ‘B’: 
1. Is male or female, aged 18 to ≤ 65 years at screening.  
2. Is able to read and understand the Informed Consent Form (ICF). 
3. Written informed consent obtained from the subject (a signed ICF).  
4. Weight within the normal or overweight ranges according to accepted values of the 
Body Mass Index (BMI) Chart (18.0 to 35.0 kg/m2). 
5. Is able to swallow capsules whole, without crushing, chewing or cutting. 
6. Is willing and able to attend study appointments within the specified time windows. 
7. Has a primary diagnosis of ADHD according to the DSM-5 classification, with 
diagnosis made at least 6 months prior to screening and confirmed with Structured 
Clinical Interview for DSM-5 Clinical Trials version (SCID-5-CT; de novo subjects). 
8. Has an AISRS total score of ≥ 24 at the screening (Visit ‘S’). 
9. Has a CGI-S score of ≥ 4 (mildly ill or worse) at the screening (Visit ‘S’). 


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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 28 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 Visit 1 (baseline) to ≥ 1 month after the last dose of SM; or 
b. Have been surgically sterilized prior to the Screening Visit. 
Exclusion Criteria ‘B’ 
1. Is currently participating in another clinical trial or has participated in a clinical trial 
within 60 days prior screening, with the exception of Study 812P306. 
2. Is a member of the study personnel or of their immediate families, or is a 
subordinate (or immediate family member of a subordinate) to any of the study 
personnel. 
3. 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. 
4. Has a history of severe drug allergy or hypersensitivity, or known hypersensitivity, to 
the study medication. 
5. 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 Encephalopathy 
6. 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. 


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7. 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. 
8. Has organic mental disorders, or mental disorders due to a general medical 
condition (per DSM-5 criteria). 
9. 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. 
10. 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 (Visit ‘S’) 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 Visit 1 within the allotted screening period (results must be 
received prior to Visit 1). 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 Visit 1. 
11. Is a (known or self-identified) current habitual/chronic cannabis user (medicinal or 
recreational); or 
 
Has a positive urine drug screen for cannabis at screening (Visit ‘S’) 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 (Visit ‘S’) 
and follow-up drug screen (Visit 1), 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 screening 
(Visit ‘S’) 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 Visit 1 prior to 
randomization. Subjects must agree to refrain from cannabis use throughout study. 
12. Has treatment-resistant ADHD based on a history of receipt of >2 approved ADHD 
medications that failed to adequately improve the subject’s symptoms, with the 


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exception of subjects who completed Study 812P306. A subject who is naïve to 
ADHD treatment is not excluded from study participation. 
13. 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. 
14. 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. 
15. 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 
16. Exhibits clinically significant abnormal vital signs at screening (see Note below).  
17. 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. 
18. 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. 


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19. 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. 
20. 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. 
21. Lost or donated more than 450 mL of blood during the 30 days prior to screening. 
22. 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 Visit 1 (baseline) (whichever is longer) during the screening period or 
anticipated for the duration of the study. 
23. History of unexplained loss of consciousness, unexplained syncope, unexplained 
irregular heartbeats or palpitations or near drowning with hospital admission. 
24. 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. 
25. In the Investigator's opinion, is unlikely to comply with the protocol or is unsuitable 
for any other reason.  
Note:  For subjects who follow SCHEDULE ‘B’, with the approval from the investigator, 
medical monitor and the sponsor, 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 28-day screening 
period (prior to first study dose) to determine eligibility. 


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TABLE OF CONTENTS 
 
INVESTIGATOR’S SIGNATURE PAGE.............................................................................2 
SUPERNUS PHARMACEUTICALS, INC. PROTOCOL APPROVAL PAGE ...................3 
CLINICAL PROTOCOL SYNOPSIS ...................................................................................4 
TABLE OF CONTENTS .................................................................................................... 13 
LIST OF TABLES AND FIGURES.................................................................................... 16 
LIST OF ABBREVIATIONS .............................................................................................. 17 
1. INTRODUCTION ........................................................................................................... 19 
1.1. Background ........................................................................................................... 19 
1.2. Clinical Information .............................................................................................. 19 
1.2.1. Phase 1 Studies ....................................................................................................... 20 
1.2.2. Phase 2 Studies ....................................................................................................... 21 
1.2.3. Phase 3 Studies ....................................................................................................... 22 
1.3. Study Rationale ..................................................................................................... 24 
2. STUDY OBJECTIVES AND ENDPOINTS ................................................................... 25 
2.1. Primary Safety Objective: .................................................................................... 25 
2.2. Secondary Efficacy Objective ............................................................................. 25 
2.3. Primary Safety Endpoints .................................................................................... 25 
2.4. Secondary Efficacy Endpoints ............................................................................ 25 
3. INVESTIGATIONAL STUDY PLAN .............................................................................. 26 
3.1. Overall Study Design and Plan............................................................................ 26 
3.2. Rationale for Study Design .................................................................................. 30 
3.3. Study Population ................................................................................................... 30 
3.3.1. Number of Subjects ................................................................................................. 30 
3.3.2. INCLUSION/EXCLUSION CRITERIA ‘A’ ............................................................. 30 
3.3.2.1. Inclusion Criteria ‘A’ .............................................................................................. 30 
3.3.2.2. Exclusion Criteria ‘A’ ............................................................................................. 31 
3.3.3. INCLUSION/EXCLUSION CRITERIA ‘B’ ............................................................. 32 
3.3.3.1. Inclusion Criteria ‘B’: ............................................................................................. 32 
3.3.3.2. Exclusion Criteria ‘B’ ............................................................................................. 33 
3.4. Completion of Study and Discontinuation of Subjects .................................... 36 
4. Study Treatment........................................................................................................... 38 
4.1. Study Medication Identity, Packaging and Labeling ........................................ 38 
4.2. Study Medication Administration ....................................................................... 38 
4.3. Adjunctive Stimulant Therapy ............................................................................. 38 
4.4. Method of Assigning Subjects to Treatment Arm ............................................. 39 
4.5. Blinding .................................................................................................................. 39 


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4.6. Study Medication Handling and Accountability ................................................ 39 
4.7. Concomitant Medications .................................................................................... 40 
5. STUDY METHODS ........................................................................................................ 41 
5.1. Study Visits and Procedures ............................................................................... 41 
5.1.1. Study Initiation .......................................................................................................... 47 
5.1.1.1. SCHEDULE ‘A’ [‘Same day/Short Delayed (≤7 day)’ Rollover Subjects]: ............ 47 
5.1.1.1.1. Visit 1 – Initial Study Visit ............................................................................... 47 
5.1.1.2. SCHEDULE ‘B’ [‘Long Delayed’ (>7days) Rollover & De Novo Subjects] ............ 48 
5.1.1.2.1. Visit ‘S’ – Screening Visit [SCHEDULE ‘B’] ................................................... 48 
5.1.1.2.2. Visit 1 – Baseline [SCHEDULE ‘B’] ................................................................ 48 
5.1.2. Visit 2 – Treatment Period ...................................................................................... 49 
5.1.3. Visit 3 – Treatment Period ...................................................................................... 49 
5.1.4. Visit 4 to Visit 21 – Treatment Period .................................................................... 50 
5.1.5. Visit 22 – End of Study / Early Termination ......................................................... 50 
5.1.6. Safety Follow-up Phone Call (FPC) ...................................................................... 51 
5.1.7. Unscheduled Visits .................................................................................................. 51 
6. STUDY VARIABLES AND ASSESSMENTS ............................................................... 52 
6.1. Efficacy Assessments .......................................................................................... 52 
6.1.1. Adult ADHD Investigator Symptom Rating Scale (AISRS) ................................ 52 
6.1.2. Clinical Global Impression – Severity of Illness (CGI-S) .................................... 52 
6.1.3. Generalized Anxiety Disorder 7-item Scale (GAD-7) ......................................... 52 
6.1.4. Clinical Global Impression – Improvement (CGI-I) ............................................. 53 
6.1.5. Behavior Rating Inventory of Executive Function–Adult (BRIEF-A) ................ 53 
6.1.6. Symptoms of Depression Questionnaire (SDQ).................................................. 54 
6.1.7. Adult ADHD Quality of Life Scale (AAQoL) .......................................................... 55 
6.2. Safety Variables and Assessments .................................................................... 55 
6.3. Adverse Events ..................................................................................................... 55 
6.3.1. Adverse Events of Special Interest (AESI) ........................................................... 56 
6.3.2. Causality .................................................................................................................... 56 
6.3.3. Recording and Evaluation of Adverse Events ..................................................... 56 
6.3.4. Criteria for Assessing Severity ............................................................................... 57 
6.3.5. Criteria for Assessing Causality ............................................................................. 57 
6.3.6. Serious Adverse Events .......................................................................................... 58 
6.3.7. Investigator Responsibilities for Reporting SAEs ................................................ 58 
6.3.8. Other Events Requiring Immediate Reporting ..................................................... 59 
6.3.9. Sponsor Responsibilities for Reporting SAEs ..................................................... 59 
6.4. Treatment-Emergent Suicidal Ideation ............................................................... 59 
6.4.1. Columbia Suicide Severity Rating Scale (C-SSRS) ........................................... 60 
6.4.2. Suicide Risk Management Plan ............................................................................. 60 
6.4.2.1. Assessment of Suicide Risk .................................................................................. 60 
6.4.2.2. Acute Suicidal Crisis ............................................................................................. 60 
6.4.2.3. Non-acute Suicidal Risk ........................................................................................ 60 


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6.5. Clinical Measurements ......................................................................................... 61 
6.5.1. Clinical Safety Laboratory Assessments .............................................................. 61 
6.5.2. Vital Signs and Weight ............................................................................................ 62 
6.5.3. Physical Examinations and Height ........................................................................ 62 
6.5.4. Electrocardiograms (ECGs) .................................................................................... 62 
6.6. Screening Scales and Assessment Tools ......................................................... 62 
6.6.1. Structured Clinical Interview for DSM-5, Clinical Trials (SCID-5-CT) .............. 62 
7. STATISTICAL METHODS ............................................................................................ 63 
7.1. General Considerations ....................................................................................... 63 
7.2. Handling of Missing Data ..................................................................................... 63 
7.3. Analysis Populations ............................................................................................ 63 
7.4. Demographics and Baseline Analysis ............................................................... 63 
7.5. Subject Disposition .............................................................................................. 64 
7.6. Study Medication Exposure and Compliance ................................................... 64 
7.7. Concomitant Medications .................................................................................... 64 
7.8. Efficacy Analysis................................................................................................... 65 
7.9. Safety Analysis ...................................................................................................... 65 
7.10. Sample Size and Power Considerations .......................................................... 65 
8. DOCUMENTATION ....................................................................................................... 66 
8.1. Adherence to the Protocol ................................................................................... 66 
8.2. Changes to the Protocol ...................................................................................... 66 
8.3. Data Quality Assurance........................................................................................ 66 
8.3.1. Data Collection ......................................................................................................... 66 
8.3.2. Clinical Data Management ...................................................................................... 67 
8.3.3. Database Quality Assurance .................................................................................. 67 
8.4. Retention of Records ............................................................................................ 67 
8.5. Auditing Procedures ............................................................................................. 67 
8.6. Publication of Results .......................................................................................... 68 
8.7. Financing and Insurance ..................................................................................... 68 
8.8. Disclosure and Confidentiality ............................................................................ 68 
8.9. Discontinuation of Study ..................................................................................... 68 
9. ETHICS .......................................................................................................................... 69 
9.1. Institutional Review Boards ................................................................................. 69 
9.2. Ethical Conduct of the Study ............................................................................... 69 
9.3. Investigators and Study Personnel .................................................................... 69 
9.4. Subject Information and Consent ....................................................................... 69 
10. REFERENCES ............................................................................................................ 71 
 
 
 
Data Redacted


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LIST OF TABLES AND FIGURES 
Table 1 SCHEDULE ‘A’:  Schedule of Events and Assessments ...................................... 42 
Table 2 SCHEDULE ‘B’:  Schedule of Events and Assessments ...................................... 44 
Table 3 Clinical Laboratory Tests ............................................................................................ 61 
 
Figure 1 
SCHEDULE ‘A’ Study Schematic ......................................................................... 28 
Figure 2 
SCHEDULE ‘B’ Study Schematic ......................................................................... 29 
 
 
 
Data Redacted


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LIST OF ABBREVIATIONS 
AAQoL 
Adult ADHD Quality of Life scale 
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) 
BRIEF-A 
Behavior Rating Inventory of Executive Function–Adult Version 
BMI 
Body mass index 
CAARS 
Conners Adult ADHD Rating Scale 
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 
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 
IWRS 
Interactive web response system 
LS 
Least square 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MMRM 
Mixed model for repeated measures 
MNAR 
Missing not at random 
OLE 
Open-label extension 
PFC 
Prefrontal cortex 
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 
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 
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 the 5-HT2B receptor and agonistic activity at the 5-HT2C receptor, 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, non-stimulant 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 1, Phase 2 and Phase 3 studies 


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are summarized below. Additional details are provided in the SPN-812 Investigator’s 
Brochure. 
1.2.1.  Phase 1 Studies 
Phase 1 studies include comparison of single and two-bead SPN-812 extended release 
(ER) formulations to an SPN-812 immediate release (IR) formulation at single and 
multiple doses (812P102 and 812P103, respectively), evaluation of food and sprinkling 
effects (812P105), drug-drug interactions (DDIs) on CYP1A2, 2D6, and 3A4 substrates 
with evaluation of SPN-812 ER metabolism in CYP2D6 poor metabolizers vs. CYP2D6 
extensive metabolizers (812P113.1), DDI with d-amphetamine (812P113.2), DDI with 
methylphenidate (812P113.3), evaluation of the effect of alcohol on SPN-812 
metabolism (812P115), evaluation of the effect of renal impairment on SPN-812 
metabolism (812P112.1), evaluation of multiple dose SPN-812 on QT Interval 
(812P117), and 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.  
The relative bioavailability of viloxazine was not affected when SPN-812 was 
administered via sprinkle over food. 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 


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mg/day as a single dose and up to 1800 mg/day as multiple doses given once daily for 5 
consecutive days. Intolerable adverse events (AEs) were not observed at doses of up to 
1800 mg/day. SPN-812 at a single supra-therapeutic dose had no effect on cardiac 
repolarization or other electrocardiographic parameters, other than a slight increase in 
heart rate consistent with the known anticholinergic effect of viloxazine (812P120).  
In the human absorption, metabolism, and excretion study, absorption of the isomers, 
R- and S-viloxazine, was rapid with a median Tmax of 1.0 hour and showed a 2:1 
concentration ratio, respectively. Nearly 100% of the radioactive dose was recovered 
with approximately 90% being recovered within 24 hours of administration, 
demonstrating complete absorption of the drug followed by rapid elimination. The 
primary circulating form was SPN 812; the only metabolite found above 10% total 
radioactivity was de-activated hydroxylated glucuronide.   
The most common AEs in the Phase 1 studies in healthy adults were somnolence and 
headache. Most AEs were mild; none were severe or serious. No clinically significant, 
study medication-related findings were observed for laboratory or electrocardiogram 
(ECG) tests in any study. In general, SPN 812 is considered to be well tolerated with no 
safety events observed that would be unexpected for viloxazine. 
1.2.2.  Phase 2 Studies 
The randomized, blinded, proof-of-concept Phase 1/2 study 812P201 compared an IR 
formulation of SPN-812 and placebo administered three times a daily in a dose range of 
150 to 300 mg/day in 52 adults (26 per treatment) with ADHD. In addition to assessing 
the safety and tolerability of SPN-812 IR, scores of both the Investigator-rated and 
patient-rated Conners Adult ADHD Rating Scale (CAARS) were collected at weekly 
intervals during the 6-week treatment period. Treatment with SPN-812 IR showed a 
statistically significant reduction in median CAARS total ADHD symptom score 
compared to placebo. Treatment-emergent AEs were reported in 23 (88.5%) subjects in 
the SPN-812 IR group and in 18 (72.0%) subjects in the placebo group. The most 
common AEs in SPN-812 IR group were nausea, decreased appetite, headache, and 
insomnia. There were no clinically significant ECGs, clinical laboratory test results, vital 
signs, or physical examination findings in either group during the study. No serious 
adverse events (SAEs) or deaths occurred during the study. 
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 (ADHDRSIV). 
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 


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were well tolerated with no serious or severe AEs and no clinically significant effect on 
laboratory values of common hematology and chemistry tests. The most common AEs 
were somnolence, decreased appetite, and headache. 
1.2.3.  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, 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 
The pharmacological similarity of viloxazine to other agents with proven efficacy in 
ADHD provides the rationale for a clinical trial to test its long-term effectiveness and 
safety in this indication. The effectiveness and safety of SPN-812 has been 
demonstrated 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 that assessed the 
effects of 200 mg/day and two separate trials assessing the effects of 400 mg/day. The 
proposed doses of 200 to 600 mg/day SPN-812 in the current open label extension 
study (812P311) and the previous randomized, double-blind, placebo-controlled study 
(812P306) are expected to provide similar exposure in adults compared to that provided 
by 200 to 400 mg/day in children and adolescents. This dose range was used in 
previous Phase I (single and multiple dose) studies where a low number of AEs were 
observed, and those AEs that were observed were mild to moderate in severity. This 
Open-Label Extension (OLE) study will determine the additional long-term safety and 
efficacy of SPN-812 in adult patients with ADHD among eligible subjects that have 
completed 812P306. 
 
 


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2.  STUDY OBJECTIVES AND ENDPOINTS 
2.1.  Primary Safety Objective: 
To monitor and collect long-term safety data on the use of SPN-812 as monotherapy for 
the treatment of ADHD in the adult population. 
2.2.  Secondary Efficacy Objective 
To evaluate the efficacy of SPN-812 as monotherapy for the treatment of ADHD in the 
adult population. 
2.3.  Primary Safety Endpoints 
The primary safety endpoints are adverse events (AEs), clinical safety laboratory test 
results, vital signs, weight, electrocardiograms (ECGs), physical examination, and the 
Columbia Suicide Severity Rating Scale (C-SSRS). 
2.4.  Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
1) Change from baseline (CFB) in the AISRS total score by visit. 
2) CFB in the CGI-S score by visit. 
3) Percentage of subjects with a CGI-S score of 1 or 2 by visit. 
4) CGI-I score by visit. 
5) Percentage of subjects with a CGI-I score of 1 or 2 by visit. 
6) CFB in the GAD-7 total score by visit. 
7) CFB in the AISRS Inattention subscale score and Hyperactivity/Impulsivity subscale 
scores by visit. 
8) AISRS 50% Responder rate (defined as the percentage of subjects with a ≥ 50% 
reduction in the CFB AISRS total score) by visit. 
9) AISRS 30% Responder rate (defined as the percentage of subjects with a ≥ 30% 
reduction in the CFB AISRS total score) by visit. 
10) CFB in the BRIEF-A Global Executive Composite (GEC) T-score by visit. 
11) CFB in the BRIEF-A T-score by each Summary Index Scale and subscale by visit. 
12) CFB in the SDQ total score by visit. 
13) CFB in the SDQ subscale scores by visit. 
14) CFB in the AAQoL total score by visit. 
15) CFB in the AAQoL subscale scores by visit. 
 


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3.  INVESTIGATIONAL STUDY PLAN 
3.1.  Overall Study Design and Plan 
This is an open-label, long-term, multicenter, flexible-dose study of SPN-812 in adults 
diagnosed with ADHD. Up to 366 subjects will be enrolled. Subjects who have 
completed Study 812P306 (a randomized, double-blind, placebo-controlled study of 
SPN-812 for the treatment of ADHD) will be eligible for enrollment into the Study 
812P311. Interest and suitability will be ascertained at the last 1 to 2 visits of 812P306 to 
allow immediate enrollment into Study 812P311 for subjects who complete Study 
812P306. 
For subjects who complete Study 812P306 and rollover into Study 812P311 on the 
same day as or ≤7 days after 812P306 EOS visit, use INCLUSION/EXCLUSION 
CRITERIA ‘A’ (Section 3.3.2. ) and follow SCHEDULE ‘A’ (Table 1; Figure 1). All 
efficacy and safety assessments collected at the subject’s end of study (EOS) Visit 
(812P306) will serve as their efficacy and safety assessments for Visit 1 (812P311). 
For subjects who complete Study 812P306, but who rollover into Study 812P311 more 
than 7 days after their EOS Visit (812P306), use INCLUSION/EXCLUSION CRITERIA 
‘B’ (Section 3.3.3. ) and follow SCHEDULE ‘B’ (Table 2; Figure 2). All efficacy and 
safety assessments will be collected at a screening visit (Visit ‘S’) to determine eligibility, 
and subjects will return to the clinical site for Visit 1 within 28 days of screening to make 
final eligibility determination and complete baseline efficacy and safety assessments.  
De novo subjects (individuals who did not screen/enroll in Study 812P306) may screen 
and, if eligible, enroll in Study 812P311, but only after a “Note To File” has been 
submitted by the Sponsor to the IRB and approved. The clinical sites will be notified 
when the approval is granted. For these subjects, use INCLUSION/EXCLUSION 
CRITERIA ‘B’ (Section 3.3.3. ) and follow SCHEDULE ‘B’ (Table 2; Figure 2). Subjects 
who follow SCHEDULE ‘B’ and are taking any prohibited medications at screening (e.g., 
ADHD medications) should discontinue use (washout) at least 7-days prior to first dose 
of OLE SM. 
On a case-by-case basis, a subject who did not complete Study 812P306 (e.g., 
randomized, dosed SM and had at least one post-baseline AISRS assessment and then 
early terminated) may be allowed to screen and, if eligible, enroll in Study 812P311, but 
only after receiving approval from the Site Investigator, Medical Monitor, and the 
Sponsor. For these subjects, use INCLUSION/EXCLUSION CRITERIA ‘B’ (Section 
3.3.3. ) and follow SCHEDULE ‘B’ (Table 2; Figure 2). 
All subjects will initiate SPN-812 dosing at 200 mg/day once daily (QD) during the first 2 
weeks of the study. At Visit 2 and all subsequent study visits, per the Investigator’s 
discretion and based on Investigator’s assessment of the subject’s clinical response and 
tolerability, the dose of SPN-812 can be titrated up or tapered down in increments of 50 
mg/day, 100 mg/day, 150 mg/day, or 200 mg/day per week to a target dose within the 
ranges between 200 and 600 mg/day. Additionally, after the first 12 weeks of dosing 
(after Visit 4), at the discretion of the Investigator and based on the subject’s clinical 


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response, the optimized dose of SPN-812 may be supplemented with an adjunctive 
FDA-approved stimulant treatment (see Section 4.3. ). 
Following the day that the subject takes first dose of SPN-812 (Day 1), the subject will 
have a study visit every 2 weeks for the first 4 weeks of the study (Visit 2 and Visit 3). 
After Visit 3, study visits (Visits 4-22) will occur 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 
100, 108, 116, 124, 132, 140, 148 and 156 weeks after first dose of SPN-812 
(approximately every 8 weeks). A Point of Care (POC) urine drug screen (Test 1 and 2) 
will be completed at Visits 1, 6, 8, 10, 12, 14, 16, 18, and 20 (Table 3). In addition, the 
site should conduct a follow-up phone call (FPC) with each subject 4 weeks after Study 
Visits 3 thru Visit 21 to assess adverse events, changes in concomitant medications and 
obtain results of home pregnancy test (FOCP only). Subjects will also be contacted for 
final safety follow-up (FPC) approximately 1 week after the End of Study (EOS) visit. 
The timing of Study Visits 2-22 and FPCs should occur per the Schedule of Events and 
Assessments (SCHEDULE ‘A’ [Table 1] or SCHEDULE ‘B’ [Table 2]) by day of study 
relative to the date of subject’s first dose of SPN-812.  
Note: The same assessments/procedures are performed at Study Visits 2-22 between 
SCHEDULE ‘A’ and SCHEDULE ‘B’. 
For subjects who follow SCHEDULE ‘A’, the total study duration per subject from Visit 1 
to Visit 22/EOS will be ~156 weeks (3 years) or until SPN-812 becomes approved and 
commercially available for Adults.  
For subjects who follow SCHEDULE ‘B’, the total study duration per subject is up to 
160 weeks, including screening (up to 4 weeks) and from Visit 1 to Visit 22/EOS (up to 
~156 weeks [3 years]), or until SPN-812 becomes approved and commercially available 
for Adults. 
Details of each study visit are provided in Section 5.  
Unscheduled visits may be conducted at the discretion of the Investigator for safety 
reasons or to dispense additional SM throughout the study. AEs, concomitant 
medications and caffeine use will be assessed at all scheduled and unscheduled visits. 
 
 


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Figure 1 
SCHEDULE ‘A’ Study Schematic 
 
Note: Subjects who complete Study 812P306 and rollover into Study 812P311 on the same day 
as or ≤ 7 days after their 812P306 EOS visit will follow SCHEDULE ‘A. The assessments 
collected during 812P306 EOS Visit will serve as assessments for 812P311 Visit 1 (Day -1). All 
subsequent study visits (2-22) will occur relative to the day/date of subject’s first dose of SPN-812 
(Day 1). Subjects who follow SCHEDULE ‘A’ will take first dose of OLE SM the morning after 
Visit 1. All subjects will initiate SPN-812 dosing at 200 mg once daily (QD) during the first 2 
weeks of the study. At and after Visit 2, 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 50 mg/day, 100 mg/day, 150 mg/day, or 200 mg/day per week to a target dose 
within the range between 200 and 600 mg/day. Subjects who complete the OLE Safety study 
should receive a follow-up phone call for safety 1 week after EOS. 
 
 


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Figure 2 
SCHEDULE ‘B’ Study Schematic 
 
Note: Subjects who complete Study 812P306, but who rollover into Study 812P311 more than 
7 days after their EOS Visit (812P306), subjects who were early terminated during Study 
812P306, and de novo subjects will follow SCHEDULE ‘B’. Screening is up to 28 days after 
obtaining informed consent at Visit ‘S’. Subject taking any prohibited medications at screening 
(e.g., ADHD medications) should discontinue use (washout) at least 7-days prior to first dose of 
OLE SM. All subsequent study visits (2-22) will occur relative to the day/date of subject’s first 
dose of SPN-812 (Day 1). Subjects who follow SCHEDULE ‘B’ will take first dose of OLE SM the 
morning of Visit. All subjects will initiate SPN-812 dosing at 200 mg once daily (QD) during the 
first 2 weeks of the study. At and after Visit 2, 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 50 mg/day, 100 mg/day, 150 mg/day, or 200 mg/day per week to a target 
dose within the range between 200 and 600 mg/day. Subjects who complete the OLE Safety 
study should receive a follow-up phone call for safety 1 week after EOS. 
 
 


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3.2.  Rationale for Study Design 
An open-label uncontrolled study with safety as the primary endpoint is a standard 
design for evaluating the long-term safety of an investigational product in a clinical trial 
setting. The secondary efficacy endpoints for this study were selected to align with the 
efficacy endpoints used in the Phase 3 adult ADHD study 812P306 from which subjects 
would be enrolled.  
A dose level range of 200 to 600 mg/day SPN-812 was selected based on the efficacy 
results from the Phase 2 adult and child phase 2 and Phase 3 pediatric studies, with 
flexible dosing permitted to align with real-world prescribing and treatment practices for 
ADHD. 
3.3.  Study Population 
3.3.1.  Number of Subjects 
Up to 366 subjects will be enrolled. Subjects who completed Study 812P306 (a 
randomized, double-blind, placebo-controlled study of SPN-812 for the treatment of 
ADHD) will be eligible for enrollment into Study 812P311. 
On a case-by-case basis, a subject who did not complete Study 812P306 (e.g., 
randomized, dosed SM and had at least one post-baseline AISRS assessment and then 
early terminated) may be allowed to screen and, if eligible, enroll in Study 812P311, but 
only after receiving approval from the Site Investigator, Medical Monitor, and the 
Sponsor.  
De novo subjects (individuals who did not screen/enroll in Study 812P306) may screen 
and, if eligible, enroll in Study 812P311, but only after a “Note To File” has been 
submitted by the Sponsor to the IRB and approved. The clinical sites will be notified 
when the approval is granted. 
3.3.2.  INCLUSION/EXCLUSION CRITERIA ‘A’ 
Use only for subjects who completed Study 812P306 and rolled over into Study 
812P311 on same day as or ≤ 7 days after their 812P306 EOS visit.  
3.3.2.1.  Inclusion Criteria ‘A’ 
1. Is a male or female who completed Study 812P306 and opts/consents to participate 
in the study if approved by PI.  
2. Continues to be medically healthy and with clinically normal laboratory profiles, vital 
signs, and electrocardiograms (ECGs), in the opinion of the Investigator, assessed 
at Visit 1. 
3. Is able to read and understand the Informed Consent Form (ICF). 
4. Has signed the ICF. 


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5. Is willing and able to attend study appointments within specified time windows. 
6. Is a female of childbearing potential (FOCP) who is either sexually inactive 
(abstinent) or, if sexually active, agrees 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 their 
Visit 1). 
7. Is a male who: 
a. Agrees to use 2 methods of contraception in combination if his female partner 
is of childbearing potential; this combination of contraceptive methods must 
be used from Visit 1 to ≥ 1 month after the last dose of SM,  
OR 
b. Has been surgically sterilized prior to Visit 1. 
3.3.2.2.  Exclusion Criteria ‘A’ 
1. Is currently participating in another clinical trial other than Study 812P306. 
2. Has any current psychiatric disorder per Diagnostic and Statistical Manual of Mental 
Disorders - 5th Edition (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. 
3. Current diagnosis of significant systemic disease and/or of a major psychiatric or 
neurological disorder, including history or family history of seizures or seizure-like 
disorders. 
4. Current evidence of suicidality (suicidal thoughts or behaviors). 
5. 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. 
6. Has a positive result on urine drug screen at Visit 1. 
7. Use of prohibited concomitant medications including known CYP1A2 substrates 
(e.g., theophylline, melatonin) at the Visit 1 for the duration of the study. 
8. Has a clinical laboratory value, vital sign value or ECG result at Visit 1 that is 
considered to be clinically significant in the opinion of the Investigator. 


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9. Has one or more clinical laboratory test values outside the reference range at Visit 1 
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. 
10. Has any of the following cardiology findings at Visit 1 (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. 
11. Any reason that, in the opinion of the Investigator, would prevent the subject from 
participating in the study.  
Note: For subjects who follow SCHEDULE ‘A’, with the approval from the investigator 
and the sponsor, repeat testing for clinical laboratory tests, vital signs, and ECG 
parameters is permitted one time within 1 week following Visit 1 prior to first dose for 
each test to determine eligibility. 
3.3.3.  INCLUSION/EXCLUSION CRITERIA ‘B’ 
Use only for delayed rollover subjects (rolled over into Study 812P311 more than 7 days 
after their 812P306 EOS Visit), subjects who were early terminated during Study 
812P306, and de novo subjects. 
3.3.3.1.  Inclusion Criteria ‘B’: 
1. Is male or female, aged 18 to ≤ 65 years at screening.  
2. Is able to read and understand the Informed Consent Form (ICF). 
3. Written informed consent obtained from the subject (a signed ICF).  
4. Weight within the normal or overweight ranges according to accepted values of the 
Body Mass Index (BMI) Chart (18.0 to 35.0 kg/m2). 
5. Is able to swallow capsules whole, without crushing, chewing or cutting. 
6. Is willing and able to attend study appointments within the specified time windows. 
7. Has a primary diagnosis of ADHD according to the DSM-5 classification, with 
diagnosis made at least 6 months prior to screening and confirmed with Structured 
Clinical Interview for DSM-5 Clinical Trials version (SCID-5-CT; de novo subjects). 
8. Has an AISRS total score of ≥ 24 at the screening (Visit ‘S’). 
9. Has a CGI-S score of ≥ 4 (mildly ill or worse) at the screening (Visit ‘S’). 


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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 28 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 Visit 1 (baseline) to ≥ 1 month after the last dose of SM; or 
b. Have been surgically sterilized prior to the Screening Visit. 
3.3.3.2.  Exclusion Criteria ‘B’ 
1. Is currently participating in another clinical trial or has participated in a clinical trial 
within 60 days prior to screening, with the exception of Study 812P306. 
2. Is a member of the study personnel or of their immediate families, or is a 
subordinate (or immediate family member of a subordinate) to any of the study 
personnel. 
3. 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. 
4. Has a history of severe drug allergy or hypersensitivity, or known hypersensitivity, to 
the study medication. 
5. 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 Encephalopathy 
6. 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. 
7. Has any current psychiatric disorder (per DSM-5 criteria) other than ADHD with the 
following exceptions: ADHD is primary diagnoses with comorbidity/secondary 


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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. 
8. Has organic mental disorders, or mental disorders due to a general medical 
condition (per DSM-5 criteria). 
9. 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. 
10. 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 (Visit ‘S’) 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 Visit 1 within the allotted screening period (results must be 
received prior to Visit 1). 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 Visit 1. 
11. Is a (known or self-identified) current habitual/chronic cannabis user (medicinal or 
recreational); or 
 
Has a positive urine drug screen for cannabis at screening (Visit ‘S’) 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 (Visit ‘S’) 
and follow-up drug screen (Visit 1), 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 screening 
(Visit ‘S’) 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 Visit 1 prior to 
randomization. Subjects must agree to refrain from cannabis use throughout study. 
12. Has treatment-resistant ADHD based on a history of receipt of >2 approved ADHD 
medications that failed to adequately improve the subject’s symptoms, with the 


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exception of subjects who completed Study 812P306. A subject who is naïve to 
ADHD treatment is not excluded from study participation. 
13. 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. 
14. 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. 
15. 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 
16. Exhibits clinically significant abnormal vital signs at screening (see Note below).  
17. 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. 
18. 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. 


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19. 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. 
20. 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. 
21. Lost or donated more than 450 mL of blood during the 30 days prior to screening. 
22. 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 Visit 1 (baseline) (whichever is longer) during the screening period or 
anticipated for the duration of the study. 
23. History of unexplained loss of consciousness, unexplained syncope, unexplained 
irregular heartbeats or palpitations or near drowning with hospital admission. 
24. 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. 
25. In the Investigator's opinion, is unlikely to comply with the protocol or is unsuitable 
for any other reason.  
Note:  For subjects who follow SCHEDULE ‘B’, with the approval from the investigator, 
medical monitor and the sponsor, 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 28-day screening 
period (prior to first study dose) 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 22 (EOS).   
If SPN-812 is not approved for Adults at the time of Visit 22, subjects may choose to 
continue in the study; repeating Visit 21 procedures every 8 weeks (including FPC in 4 
weeks after each subsequent study visit) until SPN-812 becomes approved and 
commercially available for Adults. 
Subjects who are enrolled 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., prior to 
Visit 22), should complete an early termination (ET) Visit. Procedures listed for the EOS 
visit should be completed at the ET Visit.  
All reasons for screen failure will be recorded. 
The Investigator(s) or subjects themselves may stop SM treatment at any time for safety 
or personal reasons. A subject is free to withdraw from the study at any time for any 
reason without prejudice to their future medical care by the physician or at the institution. 


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viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 
The Sponsor may also withdraw subject participation in the study without consent for 
any reason, but is in the best 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: 
 
Subject lost to follow-up 
 
Subject’s withdrawal of consent 
 
Investigator ended subject’s participation in study 
 
Other 
The primary reason for the subject’s early discontinuation must be recorded in the 
subject’s medical record and on the electronic case report form (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. 


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4.  Study Treatment 
4.1.  Study Medication Identity, Packaging and Labeling 
Study medication is supplied as capsules that contain 100 mg, 150 mg and 200 mg of 
SPN-812, packaged in bottles. Each bottle will be labeled with the protocol number and 
subject ID, at a minimum. 
4.2.  Study Medication Administration 
Study medication will be administered orally once daily (QD) as intact capsules, with or 
without food. The daily dose should be taken 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. Confirm that subject is taking daily dose in the morning; if 
subject reports that he/she is taking daily dose later in the day (e.g., evening) without 
prior Site Investigator or Sponsor approval, the medical monitor must be informed 
immediately. The medical monitor must then inform the Sponsor. 
Subjects who follow:  
 
SCHEDULE ‘A’ will take first dose of OLE SM the morning after Visit 1 at home.  
 
SCHEDULE ‘B’ will take first dose of OLE SM the day of Visit 1 at clinic.  
All subjects will initiate SPN-812 dosing at 200 mg/day during first 2 weeks of the study. 
At and after Visit 2, 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 50 mg/day, 100 mg/day, 150 mg/day, or 200 mg/day per week to a target 
dose within the range between 200 and 600 mg/day.  
Doses: 
 
200 mg/day = (200 mg capsule × 1) [once daily] 
 
250 mg/day = (100 mg capsule × 1) + (150 mg capsule × 1) [once daily] 
 
300 mg/day = (200 mg capsule × 1) + (100 mg capsule × 1) [once daily] 
 
350 mg/day = (200 mg capsule × 1) + (150 mg capsule × 1) [once daily]) 
 
400 mg/day = (200 mg capsule × 2) [once daily] 
 
450 mg/day = (150 mg capsule × 3) [once daily] 
 
500 mg/day = (200 mg capsule × 2) + (100 mg capsule × 1) [once daily] 
 
550 mg/day = (200 mg capsule × 2) + (150 mg capsule × 1) [once daily] 
 
600 mg/day = (200 mg capsule × 3) [once daily] 
4.3.  Adjunctive Stimulant Therapy 
If after 12 weeks of dosing SPN-812 (Visit 4) the Site Investigator determines that 
administration of the optimized dose of SPN-812 is not eliciting an adequate clinical 
response, the Site Investigator may consider supplementing SPN-812 therapy with an 
adjunctive FDA -approved stimulant for use in ADHD [e.g., Vyvanse® (lisdexamfetamine 
dimesylate), Concerta® (methylphenidate)]. Adjunctive stimulant therapy should be 
initiated at the lowest recommended daily dose, and the dosing and safety management 
guidelines provided in the prescribing information for the stimulant must be followed. 


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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. 
Dose adjustment for the stimulant as well as evaluation of clinical response will be at the 
Investigator’s discretion. Regardless of the dose of stimulant administered, the subject 
must continue to receive SPN-812 at the optimized dose determined per the study 
protocol. Subjects with known previous allergic reactions to either methylphenidate or 
amphetamine or other ingredients found in those dosage forms are not eligible for 
concomitant stimulant therapy. Adjunctive stimulant therapy should be carefully 
documented. 
4.4.  Method of Assigning Subjects to Treatment Arm 
This is an open-label study. All eligible subjects will receive active treatment (SPN-812).  
4.5.  Blinding 
This is an open-label study. 
4.6.  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 
Depot 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 
empty containers, are to be returned to the Depot 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 Depot with a copy of the completed SM disposition form to the Sponsor. 


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15Dec2020 
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viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
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4.7.  Concomitant Medications  
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 who follow SCHEDULE ‘B’ and are taking any prohibited medications at 
screening (e.g., ADHD medications) should discontinue use (washout) at least 7 days 
prior to first dose of OLE SM. 
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). 
 
Following the first 12 Weeks of dosing OLE SM, subjects may supplement SPN-
812 with an adjunctive FDA approved stimulant for use in ADHD [e.g., Vyvanse® 
(lisdexamfetamine dimesylate), Concerta® (methylphenidate)] (See Section 4.3. 
). 
All concomitant medications will be recorded in the eCRF, including Adjunctive Stimulant 
Therapy (carefully document reason for use). 
Caffeine use is permitted during the study and will be recorded in the eCRF. 


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viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
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5.  STUDY METHODS 
5.1.  Study Visits and Procedures 
All subjects who are enrolled and take the initial dose of SPN-812 will be followed 
according to the protocol regardless of the number of doses of SPN-812 taken, unless 
consent for follow-up is withdrawn. The Sponsor or 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.  
For subjects who complete Study 812P306 and rollover into Study 812P311 on the 
same day as or ≤7 days after their 812P306 EOS visit, use INCLUSION/EXCLUSION 
CRITERIA ‘A’ (Section 3.3.2. ) and follow SCHEDULE ‘A’ (Table 1; Figure 1). All 
efficacy and safety assessments collected at the subject’s end of study (EOS) Visit 
(812P306) will serve as their efficacy and safety assessments for Visit 1 (812P311). 
For subjects who complete Study 812P306, but who rollover into Study 812P311 more 
than 7 days after their EOS Visit (812P306), use INCLUSION/EXCLUSION CRITERIA 
‘B’ (Section 3.3.3. ) and follow SCHEDULE ‘B’ (Table 2; Figure 2). All efficacy and 
safety assessments will be collected at a screening visit (Visit ‘S’) to determine eligibility, 
and subject will return to the clinical site for Visit 1 within 28 days of screening to make 
final eligibility determination and complete baseline efficacy and safety assessments. 
On a case-by-case basis, a subject who did not complete Study 812P306 (e.g., 
randomized, dosed SM and had at least one post-baseline AISRS assessment and then 
early terminated) may be allowed to screen and, if eligible, enroll in Study 812P311, but 
only after receiving approval from the Site Investigator, Medical Monitor, and the 
Sponsor. For these subjects, use INCLUSION/EXCLUSION CRITERIA ‘B’ (Section 
3.3.3. ) and follow SCHEDULE ‘B’ (Table 2; Figure 2). 
De novo subjects (individuals who did not screen/enroll in Study 812P306) may screen 
and, if eligible, enroll in Study 812P311, but only after a “Note To File” has been 
submitted by the Sponsor to the IRB and approved. The clinical sites will be notified 
when the approval is granted. For these subjects, use INCLUSION/EXCLUSION 
CRITERIA ‘B’ (Section 3.3.3. ) and follow SCHEDULE ‘B’ (Table 2; Figure 2). 
The timing of each study visit (Visit 2-Visit 22) and each FPC should occur per the 
Schedule of Events and Assessments relative to the date of subject’s first dose of SPN-
812 (Day 1) [e.g., Visit 4 occurs on Day 85 (± 7 days) or 85 days (± 7 days) after the 
date of subject’s first dose of SPN-812]. 


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15Dec2020 
812P311 
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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. 
Table 1 
SCHEDULE ‘A’:  Schedule of Events and Assessments 
Study Period 
Initial 
Visit 
Treatment 
EOS/ ET 
Safety 
follow-up 
phone call 
Visit Number 
1 
- 
2 
3 
FPCa  
4, 5, 6, 7,  
8, 9, 10, 11, 
12, 13, 14, 15, 
16, 17, 18, 19,  
20, 21 
22 
FPC 
Day of Study 
(days since first dose of SM) 
-1 
1 
15 
29 
57, 113, 169, 225, 
281, 337, 393, 449, 
505, 561, 617, 673, 
729, 785, 841, 897, 
953, 1009, 1065  
85, 141, 197, 253, 
309, 365, 421, 477, 
533, 589, 645, 701, 
757, 813, 869, 925, 
981, 1037 
1093 
1100 
Week of Study  
(week since first dose of SM) 
-- 
-- 
2 
4 
8, 16, 24, 32,  
40, 48, 56, 64,  
72, 80, 88, 96,  
104, 112,120, 128, 
136, 144, 152 
12, 20, 28, 36,  
44, 52, 60, 68,  
76, 84, 92, 100, 
108, 116, 124, 132, 
140, 148 
156 
157 
Study Visit Window     
(days relative to nominal visit) 
-- 
-- 
± 3 
±3 
±3 
±7 
±7 
±2 
Signed informed consent  
 
 
 
 
 
 
 
Relevant histories     
(social, medical, psychiatric, 
neurological, family 
psychiatric) 
 
 
 
 
 
 
 
 
Demographics  
 
 
 
 
 
 
 
 
Smoking, alcohol 
consumption 
 
 
 
 
 
 
 
 
Physical examination  
 
 
 
 
 
 
 
 
Blood sample for FSH 
(post-menopausal 
females only) 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
 
 
 
 
 
 
 
 
POC Urine drug screen 
f 
 
 
 
 
 f 
 
 
Urine pregnancy test 
(FOCP only) 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
Blood sample for 
chemistry  
 
 
 
 
 
 
 
 
Blood sample for 
hematology 
 
 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
 
 
Orthostatic blood 
pressure c 
 
 
 
 
 
 
 
 
Vital signs b, weight 
 
 
 
 
 
 
 
 
Dispensed home 
pregnancy test kit 
(FOCP only) 
 
 
 
 
 
 
 
 
C-SSRS (SLV) 
 
 
 
 
 
 
 
 
AISRS d 
 
 
 
 
 
 
 e 
 
CGI-S d 
 
 
 
 
 
 
 e 
 


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15Dec2020 
812P311 
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Study Period 
Initial 
Visit 
Treatment 
EOS/ ET 
Safety 
follow-up 
phone call 
Visit Number 
1 
- 
2 
3 
FPCa  
4, 5, 6, 7,  
8, 9, 10, 11, 
12, 13, 14, 15, 
16, 17, 18, 19,  
20, 21 
22 
FPC 
Day of Study 
(days since first dose of SM) 
-1 
1 
15 
29 
57, 113, 169, 225, 
281, 337, 393, 449, 
505, 561, 617, 673, 
729, 785, 841, 897, 
953, 1009, 1065  
85, 141, 197, 253, 
309, 365, 421, 477, 
533, 589, 645, 701, 
757, 813, 869, 925, 
981, 1037 
1093 
1100 
Week of Study  
(week since first dose of SM) 
-- 
-- 
2 
4 
8, 16, 24, 32,  
40, 48, 56, 64,  
72, 80, 88, 96,  
104, 112,120, 128, 
136, 144, 152 
12, 20, 28, 36,  
44, 52, 60, 68,  
76, 84, 92, 100, 
108, 116, 124, 132, 
140, 148 
156 
157 
Study Visit Window     
(days relative to nominal visit) 
-- 
-- 
± 3 
±3 
±3 
±7 
±7 
±2 
CGI-I d 
 
 
 
 
 
 
 e 
 
GAD-7 
 
 
 
 
 
 
 e 
 
BRIEF-A 
 
 
 
 
 
 
 e 
 
SDQ 
 
 
 
 
 
 
 e 
 
AAQoL 
 
 
 
 
 
 
 e 
 
Review concomitant 
medications and caffeine 
use 
 
 
 
 
 
 
 
 
Review adverse events 
 
 
 
 
 
 
 
 
Confirm home 
pregnancy test results 
(FOCP only) g 
 
 
 
 
 
 
 
 
SM dispensed 
 
 
 
 
 
 
 
 
SM return and 
accountability  
 
 
 
 
 
 
 
 
Subject take 1st dose 
 
 
 
 
 
 
 
 
AAQoL = Adult ADHD Quality of Life scale; ADHD = Attention-Deficit/Hyperactivity Disorder; AISRS = Adult 
ADHD Investigator Symptom Rating Scale; 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 (SLV) = Columbia Suicide Severity Rating Scale Since Last Visit Version; 
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; POC = Point of Care UDS; SDQ = Symptoms of Depression Questionnaire; SM = study 
medication. 
a. 
After Visit 3, a follow-up phone call should be conducted 4 weeks after each study visit. 
b. 
This includes orthostatic blood pressure/heart rate, as well as respiratory rate and oral temperature. 
c. 
Orthostatic blood pressure/heart rate should be measured after the subject has been seated for at least 
5 minutes and again within 3 minutes of subject standing 
d. 
Investigator-rated efficacy assessments should be performed/conducted/collected prior to administering 
any self-reported efficacy assessments to the subject. 
e. 
If the subject’s ET Visit is conducted >7 days after the date of the subject's last dose of SM, do not 
perform efficacy assessments at the ET Visit. 
f. 
Point of Care urine drug screen (Test 1 and 2) at Visits 1, 6, 8, 10, 12, 14, 16, 18, and 20 (see Table 3). 
g. 
FOCPs should perform the home pregnancy test within 3 days prior to the monthly FPC. 


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Table 2 
SCHEDULE ‘B’:  Schedule of Events and Assessments 
Study Period 
Screen 
Treatment 
EOS/ET 
Safety 
follow-up 
phone call 
Visit Number 
S 
1 
2 
3 
FPCa  
4, 5, 6, 7,  
8, 9, 10, 11, 
12, 13, 14, 15, 
16, 17, 18, 19, 
20, 21 
22 
FPC 
Day of Study 
(days since first dose of SM) 
-28 to 
-1  
1 
15 
29 
57, 113, 169, 225, 
281, 337, 393, 449, 
505, 561, 617, 673, 
729, 785, 841, 897, 
953, 1009, 1065 
85, 141, 197, 253, 
309, 365, 421, 477, 
533, 589, 645, 701, 
757, 813, 869, 925, 
981, 1037 
1093 
1100 
Week of Study  
(week since first dose of SM) 
-- 
-- 
2 
4 
8, 16, 24, 32,  
40, 48, 56, 64,  
72, 80, 88, 96,  
104, 112, 120, 128, 
136, 144, 152 
12, 20, 28, 36,  
44, 52, 60, 68,  
76, 84, 92, 100, 
108, 116, 124, 132, 
140, 148 
156 
157 
Study Visit Window     
(days relative to nominal visit) 
-- 
-- 
±3 
±3 
±3 
±7 
±7 
±2 
Signed informed 
consent 
 
 
 
 
 
 
 
 
Relevant histories 
(social, medical, 
psychiatric, neurological, 
family psychiatric) 
 
 
 
 
 
 
 
 
Demographics  
 
 
 
 
 
 
 
 
Smoking, alcohol 
consumption 
 
 
 
 
 
 
 
 
Physical examination  
 
 
 
 
 
 
 
 
Blood sample for FSH 
(post-menopausal 
females only) 
 
 
 
 
 
 
 
 
SCID-5-CT i 
 h 
 
 
 
 
 
 
 
Serology 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
 
 
 
 
 
 
 
 
Serum ethanol 
 
 
 
 
 
 
 
 
Standard urine drug 
screen 
 
 
 
 
 
 
 
 
POC urine drug screen 
 g 
 f 
 
 
 
 f 
 
 
Serum pregnancy test 
(FOCP only) 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(FOCP only) 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
Blood sample for 
chemistry  
 
 
 
 
 
 
 
 
Blood sample for 
hematology 
 
 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
 
 


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812P311 
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Study Period 
Screen 
Treatment 
EOS/ET 
Safety 
follow-up 
phone call 
Visit Number 
S 
1 
2 
3 
FPCa  
4, 5, 6, 7,  
8, 9, 10, 11, 
12, 13, 14, 15, 
16, 17, 18, 19, 
20, 21 
22 
FPC 
Day of Study 
(days since first dose of SM) 
-28 to 
-1  
1 
15 
29 
57, 113, 169, 225, 
281, 337, 393, 449, 
505, 561, 617, 673, 
729, 785, 841, 897, 
953, 1009, 1065 
85, 141, 197, 253, 
309, 365, 421, 477, 
533, 589, 645, 701, 
757, 813, 869, 925, 
981, 1037 
1093 
1100 
Week of Study  
(week since first dose of SM) 
-- 
-- 
2 
4 
8, 16, 24, 32,  
40, 48, 56, 64,  
72, 80, 88, 96,  
104, 112, 120, 128, 
136, 144, 152 
12, 20, 28, 36,  
44, 52, 60, 68,  
76, 84, 92, 100, 
108, 116, 124, 132, 
140, 148 
156 
157 
Study Visit Window     
(days relative to nominal visit) 
-- 
-- 
±3 
±3 
±3 
±7 
±7 
±2 
Orthostatic blood 
pressure c 
 
 
 
 
 
 
 
 
Vital signs b and weight 
 
 
 
 
 
 
 
 
C-SSRS (B/S)  
 
 
 
 
 
 
 
 
C-SSRS (SLV) 
 
 
 
 
 
 
 
 
AISRS d 
 
 
 
 
 
 
e 
 
CGI-S d 
 
 
 
 
 
 
e 
 
CGI-I d 
 
 
 
 
 
 
e 
 
GAD-7 
 
 
 
 
 
 
e 
 
BRIEF-A 
 
 
 
 
 
 
e 
 
SDQ 
 
 
 
 
 
 
e 
 
AAQoL 
 
 
 
 
 
 
e 
 
Review concomitant 
medications and 
caffeine use 
 
 
 
 
 
 
 
 
Review adverse events 
 
 j 
 
 
 
 
 
 
Dispensed home 
pregnancy test kit 
(FOCP only) 
 
 
 
 
 
 
 
 
Confirm home 
pregnancy test results 
(FOCP only)h 
 
 
 
 
 
 
 
 
SM dispensed 
 
 
 
 
 
 
 
 
SM return and 
accountability  
 
 
 
 
 
 
 
 
Subject take 1st dose 
 
 
 
 
 
 
 
 
AAQoL = Adult ADHD Quality of Life scale; ADHD = Attention-Deficit/Hyperactivity Disorder; AISRS = Adult 
ADHD Investigator Symptom Rating Scale; 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 (B/S) = Columbia Suicide Severity Rating Scale Baseline/Screening 
Version; C-SSRS (SLV) = Columbia Suicide Severity Rating Scale Since Last Visit Version; ECG = 
electrocardiogram; EOS = end of study; ET = early termination; FOCP = females of childbearing potential; 


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15Dec2020 
812P311 
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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. 
FPC = Follow-up Phone Call; FSH = follicle stimulating hormone; GAD-7 = Generalized Anxiety Disorder 7-
item scale; POC = Point of Care UDS; 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. 
After Visit 3, a follow-up phone call should be conducted 4 weeks after each study visit. 
b. 
This includes orthostatic blood pressure/heart rate, as well as respiratory rate and oral temperature. 
c. 
Orthostatic blood pressure and heart rate should be measured after the subject has been seated for at 
least 5 minutes and again within 3 minutes of subject standing 
d. 
Investigator-rated efficacy assessments should be performed/conducted/collected prior to administering 
any self-reported efficacy assessments to the subject. 
e. 
If the subject’s ET Visit is conducted >7 days after the date of the subject's last dose of SM, do not 
perform efficacy assessments at the ET Visit. 
f. 
Point of Care urine drug screen (Test 1 and 2; see Table 3) at Visit 1 and only at Visits 6, 8, 10, 12, 14, 
16, 18, and 20. 
g. 
Point of Care urine drug screen Test 2 only (see Table 3) at Visit ‘S’. 
h. 
FOCPs should perform the home pregnancy test within 3 days prior to the monthly FPC. 
i. 
The SCID-5-CT is performed at Visit ‘S’ for de novo subjects only. 
j. 
Event(s) occurring after first dose of OLE SM should be captured as an adverse event; event(s) 
occurring prior to first dose of OLE SM should be captured as medical history. 
 
 


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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. 
5.1.1.  Study Initiation 
5.1.1.1.  SCHEDULE ‘A’ [‘Same day/Short Delayed (≤7 day)’ Rollover Subjects]:  
5.1.1.1.1.  Visit 1 – Initial Study Visit  
The following assessments will be conducted: 
 
Review Inclusion/exclusion criteria  
 
ICF signed 
 
Social, medical, psychiatric, family psychiatric, and neurological histories 
 
Demographics 
 
Smoking and alcohol consumption use/history 
 
Physical examination 
 
Blood sample for: 
o FSH (post-menopausal females only) 
o Chemistry and hematology 
 
Urine sample for: 
o Urinalysis 
o Urine pregnancy test (FOCP only) 
o Point of Care Urine Drug Screen Test 1/Test 2 (see Table 3) 
 
Vital signs (includes orthostatic blood pressure/heart rate) and weight 
 
Perform ECG 
 
C-SSRS (‘Since Last Visit’ version) 
 
AISRS, CGI-I, CGI-S, GAD-7, BRIEF-A, SDQ and AAQoL 
 
Review concomitant medications and Caffeine use  
 
Review adverse events (events occurring before first dose of SPN-812 should be 
recorded as medical history; events occurring after first dose of SPN-812 should 
be recorded as an AE) 
 
Dispense Study Medication; subject should take first dose of SPN-812 at home in 
the morning the next day after Visit 1. 
 
 


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5.1.1.2.  SCHEDULE ‘B’ [‘Long Delayed’ (>7days) Rollover & De Novo Subjects] 
5.1.1.2.1.  Visit ‘S’ – Screening Visit [SCHEDULE ‘B’] 
The following assessments will be conducted: 
 
ICF signed 
 
SCID-5-CT 
 
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 Drug Screen: Standard UDS & Point of Care UDS Test 2 only (Table 3) 
 
Vital signs (includes orthostatic blood pressure/heart rate) and weight 
 
Perform ECG 
 
C-SSRS (‘Baseline/Screening’ version) 
 
AISRS and CGI-S 
 
Review Inclusion/Exclusion criteria 
 
Concomitant medications and caffeine use 
Note: Remind subject to discontinue any prohibited medications ≥7 days prior to Visit 1 
5.1.1.2.2.  Visit 1 – Baseline [SCHEDULE ‘B’] 
The following assessments will be conducted: 
 
Blood sample for hematology/serum chemistry (non-fasted allowed) 
 
Urine sample for: 
o Urinalysis 
o Urine pregnancy test (FOCP only) 
o Point of Care Urine Drug Screen, Test 1 and Test 2 (Table 3) 
 
Vital signs (includes orthostatic blood pressure/heart rate) and weight 
 
Perform ECG 
 
C-SSRS (‘Since Last Visit’ version) 
 
AISRS, CGI-S, GAD-7, BRIEF-A, SDQ and AAQoL 
 
Review adverse events (events occurring before first dose of SPN-812 should be 
recorded as medical history; events occurring after first dose of SPN-812 should 
be recorded as an AE) 
 
Review Concomitant medications and caffeine use 
 
Review Inclusion/Exclusion criteria 
 
Dispense Study Medication; subject should take first dose of SPN-812 at clinic 
day of Visit 1 


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viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
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5.1.2.  Visit 2 – Treatment Period 
The following assessments will be conducted: 
 
Vital signs (includes orthostatic blood pressure/heart rate) and weight 
 
Urine sample for urine pregnancy test (FOCP only) 
 
C-SSRS (‘Since Last Visit’ version) 
 
AISRS, CGI-S, CGI-I, and GAD-7  
 
Review concomitant medications and Caffeine use 
 
Review adverse events  
 
SM dispensed  
 
SM return and accountability 
5.1.3.  Visit 3 – Treatment Period 
The following assessments will be conducted: 
 
Blood sample for chemistry and hematology 
o Chemistry 
o Hematology  
 
Urine sample for:  
o Urinalysis 
o Urine pregnancy test (FOCP only) 
 
Vital signs (includes orthostatic blood pressure/heart rate) and weight 
 
Perform ECG 
 
C-SSRS (‘Since Last Visit’ version) 
 
AISRS, CGI-S, CGI-I, GAD-7, BRIEF-A, SDQ and AAQoL  
 
Review concomitant medications and Caffeine use 
 
Review adverse events  
 
Dispense Home Pregnancy Test kit with instructions (FOCPs only) ** 
 
SM dispensed  
 
SM return and accountability 


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15Dec2020 
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viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
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5.1.4.  Visit 4 to Visit 21 – Treatment Period 
The following assessments will be conducted: 
 
Blood sample for  
o Chemistry 
o Hematology  
 
Urine sample for:  
o Urinalysis 
o Urine pregnancy test (FOCP only) 
o Point of Care Urine Drug Screen, Test 1 and Test 2 (Table 3) 
 Only at Visits 6, 8, 10, 12, 14, 16, 18, and 20  
 
Vital signs (includes orthostatic blood pressure/heart rate) and weight 
 
Perform ECG 
 
C-SSRS (‘Since Last Visit’ version) 
 
AISRS, CGI-S, CGI-I, GAD-7, BRIEF-A, SDQ, and AAQoL  
 
Review concomitant medications and Caffeine use 
 
Review adverse events 
 
Dispense Home Pregnancy Test kit with instructions (FOCPs only) ** 
 
SM dispensed  
 
SM return and accountability 
5.1.5.  Visit 22 – End of Study / Early Termination 
The following assessments will be conducted at EOS/ET* visit: 
 
Blood sample for:  
o Chemistry 
o Hematology  
 
Physical examination  
 
Urine sample for:  
o Urinalysis 
o Urine pregnancy test (FOCP only) 
 
Vital signs (includes orthostatic blood pressure/heart rate) and weight 
 
Perform ECG 
 
C-SSRS (‘Since Last Visit’ version) 
 
AISRS, CGI-S, CGI-I, GAD-7, BRIEF-A, SDQ, and AAQoL * 
 
Review concomitant medications and Caffeine use  
 
Review adverse events  
 
SM return and accountability 
*  For subjects who discontinue/terminate early (ET Visit), the EOS assessments will be 
performed at that visit. If the subject’s ET Visit is conducted >7 days after the date of 
the subject's last dose of SM, efficacy assessments should not be performed at the 
ET Visit.  
** FOCPs should perform the home pregnancy test within 3 days prior to the monthly 
FPC. 


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5.1.6.  Safety Follow-up Phone Call (FPC) 
After Visit 3 until EOS, the site should conduct a follow-up phone call with each subject 
4 weeks after each study visit to assess adverse events, changes in concomitant 
medications, caffeine use, and confirm results of Home Pregnancy Test (FOCPs only). 
Subjects who are FOCPs should perform the home pregnancy test within 3 days prior to 
the monthly FPC. 
In addition, the site should also conduct a follow-up phone call with each subject 
approximately 1 week after the EOS/ET Visit: 
 
AEs 
 
Concomitant medications and Caffeine use 
5.1.7.  Unscheduled Visits 
At the discretion of the investigator throughout the study, unscheduled visits may be 
conducted to perform or repeat assessments, including ECG, measure vital signs and 
weight, draw blood sample for hematology and/or serum chemistry or serum pregnancy 
test (FOCP), obtain urine sample for urine pregnancy test and/or urine drug screen 
(POC [if applicable]; see Table 3), administer C-SSRS (‘Since Last Visit’ version), 
perform physical examination. AEs, concomitant medications and ‘caffeine use’ should 
also be assessed at all unscheduled visits. SM may also be dispensed and/or returned 
at unscheduled visits, if needed. 
 
 


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6.  STUDY VARIABLES AND ASSESSMENTS 
6.1.  Efficacy Assessments 
6.1.1.  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). 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.  
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
 
) 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-item scale (GAD-7) is a self-reported 7-item 
questionnaire for measuring the severity of generalized anxiety disorder (
 
 Spitzer et al., 2006). 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.  
Data Redacted
Data Redacted
Data Redacted


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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; 
 
) 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 Investigator/rater should 
consider their total clinical experience with the subject who has ADHD and rate 
improvement in the subject’s condition compared to his/her’s baseline assessment at the 
beginning of the subject’s randomized, double-blind, placebo-controlled study.  
The CGI-S score obtained at the baseline serves as a good basis for making this 
assessment. The CGI-I is evaluated on a 7-point scale with 1 = Very much improved, 2 = 
Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much 
worse, and 7 = Very much worse. Successful therapy is indicated by a lower overall 
score in subsequent testing.  
Please note the following before assessing CGI-I: 
 
For subjects who follow SCHEDULE ‘A’, Baseline = Visit 2 (812P306) 
 
For subjects who follow SCHEDULE ‘B’, Baseline = Visit 1 (812P311) 
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). 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  
Data Redacted
Data Redacted


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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 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). 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. 
Data Redacted


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6.1.7.  Adult ADHD Quality of Life Scale (AAQoL)  
The AAQoL is a self-report rating scale designed to assess health-related quality of life 
(HRQL) that has been validated in adult patients with ADHD (
 Brod et 
al., 2006; Brod et al., 2015). Development of the scale followed the industry guidance 
‘‘Patient-Reported Outcome Measures: Use in Medical Product Development to Support 
Labeling Claims’’ set by the Food and Drug Administration 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM193282.pdf). The AAQoL is a 29-item questionnaire that measures how 
ADHD has impacted the subject’s quality of life over the past 2 weeks. The AAQoL 
includes 4 domains:  
1) Life Productivity: 11 items, including “getting things done on time,” “completing 
projects or tasks,” “remembering important things,” and “balancing multiple 
projects”; 
2) Psychological Health: 6 items, including “feeling anxious,” “overwhelmed,” and 
“fatigued”; 
3) Relationships: 5 items, including “tension,” “annoyance,” and “frustration in 
relationships”; and 
4) Life Outlook: 7 items, including “perceptions that energy is well spent,” “people 
enjoy spending time with you,” “you can successfully manage your life,” and “you 
are as productive as you would like to be”.  
The subject rates/scores each item on a 5-point Likert scale, where 1 = Not at all/Never, 
2 = A little, 3 = Somewhat, 4 = A lot, and 5 = Extremely/Very often. To derive overall and 
subscale scores, item scores are transformed to a 0 to 100-point scale, and higher 
scores indicate better HRQL. It takes approximately 5 to 10 minutes to complete the 
AAQoL. 
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. 
Site Investigators are responsible for monitoring the safety of subjects who have entered 
this study and for alerting Supernus or its designee to any event that seems unusual, 
even if this event may be considered an unanticipated benefit to the subjects. 
6.3.  Adverse Events 
As defined by the ICH Guideline for Good Clinical Practice (GCP), an adverse event 
(AE) is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with treatment. 
Data Redacted


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Examples of AE include but are not limited to: 
• 
Any new disease, inter-current injuries, or exacerbation of an existing disease. 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG) that results in 
symptoms, a change in treatment, or discontinuation from SM. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 
Surgical procedures are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. 
6.3.1.  Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) are defined as seizure or AEs that might 
represent a seizure. This includes, but is not limited to syncope/syncopal episode, 
pseudoseizure, myoclonus, and severe muscle spasms. 
6.3.2.  Causality 
Adverse events may be categorized as either Adverse Drug Reactions or Suspected 
Adverse Drug Reactions based on their relationship to SM and the degree of certainty 
about causality. 
Suspected adverse drug reactions (SADRs) are a subset of adverse events for which 
there is evidence to suggest a causal relationship between the drug and the AE, i.e., 
there is a reasonable possibility that the drug caused the adverse event.  
Adverse drug reactions (ADRs) are a subset of all SADRs for which there is reason to 
conclude that the drug caused the event. 
6.3.3.  Recording and Evaluation of Adverse Events 
All subjects who enter the study (Visit 1 under SCHEDULE ‘A’; or Visit ‘S’ under 
SCHEDULE ‘B’) 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 OLE SM, the Site 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 first dose 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 OLE 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 


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(either due to EOS or ET) or until resolution, or until, in the medical judgment of the 
Investigator, the event has stabilized or is assessed as chronic. 
The Investigator is responsible for evaluating AEs and determining the following: 
• 
Serious vs. Non-serious: Is the event a Serious Adverse Event (SAE)? 
• 
Causality: Was AE related or possibly related to the SM? 
• 
Severity: How pronounced is the incapacity/discomfort caused by an AE? 
6.3.4.  Criteria for Assessing Severity 
The Site 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. 
6.3.5.  Criteria for Assessing Causality 
The site 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 


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response to withdrawal of the medication (dechallenge) should be clinically 
plausible. The event must be definitive pharmacologically or 
phenomenologically, using a satisfactory rechallenge procedure if necessary. 
This will be reported as an Adverse Drug Reaction (ADR). 
6.3.6.  Serious Adverse Events 
Adverse events are classified as serious or non-serious. An AE or ADR is considered 
“serious” if, in the view of either the Investigator or Sponsor, it results in one of the 
following outcomes:  
 
death 
 
life-threatening AE (i.e., the subject was at immediate risk of death from the AE 
as it occurred. This does not include an event that, had it occurred in a more 
severe form or was allowed to continue, might have caused death.) 
 
in-patient hospitalization or prolongation of existing hospitalization 
 
persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions 
 
a congenital anomaly or birth defect 
 
an important medical event 
Important medical events are those that may not be immediately life threatening or result 
in death or hospitalization, but are clearly of major clinical significance. They may 
jeopardize the subject, and may require intervention to prevent one of the other serious 
outcomes noted above. For example, drug overdose or abuse, blood dyscrasias, a 
seizure that did not result in in-patient hospitalization or intensive treatment for allergic 
bronchospasm in an emergency department would typically be considered serious. 
6.3.7.  Investigator Responsibilities for Reporting SAEs 
The site 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 Site Investigator and/or study/safety physician, after thorough consideration of all 
facts that are available, must include an assessment of causality of an AE to SM in the 
report to the Sponsor. 
Follow-up information, or new information available after the initial report, should be 
actively sought and reported to the Sponsor, as it becomes available, using the SAE 
Report Form. 


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The Drug Safety Contact for SAE reporting is: 
6.3.8.  Other Events Requiring Immediate Reporting 
The Site 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 Site 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. 
6.3.9.  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. 
6.4.  Treatment-Emergent Suicidal Ideation 
Prospective assessment of suicidal ideation and suicidal behavior is a mandatory part of 
the safety evaluations for any drug developed for a psychiatric indication (FDA, 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. 
Data Redacted


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6.4.1.  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). The C-SSRS is an FDA-
recommended prospective assessment instrument that directly classifies suicidal 
ideation and behavior events into 11 preferred categories, including 5 levels of suicidal 
ideation, 5 levels of suicidal behavior, and the category of self-injurious behaviors with 
no suicidal intent. The C-SSRS “Baseline/Screening” version should only be 
administered at Visit ‘S’ to subjects who follow SCHEDULE ‘B’ 
. 
The C-SSRS “Since Last Visit” version should be administered at every study visit, 
including Visit 1 
 for all subjects. 
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. 
6.4.2.  Suicide Risk Management Plan 
The protocol procedures related to clinical care of patients with treatment-emergent 
suicidal ideation and behavior must be implemented to ensure proper management of 
the event and protection of subject’s safety. If a disclosure of suicidal ideation is 
revealed as part of the C-SSRS questionnaire or when a subject spontaneously 
expresses that he/she may be a threat to him/herself, the study team should be 
prepared to quickly evaluate the event and to determine the appropriate course of 
action. 
6.4.2.1.  Assessment of Suicide Risk 
Any indication of suicidal ideation should be evaluated as soon as possible by 
appropriately trained staff. The Investigator is responsible for making the final judgment 
regarding potential suicide risk and need subsequent action.  
6.4.2.2.  Acute Suicidal Crisis 
A person evaluated as being at high risk should be transferred to an immediate care 
facility. The Investigator will guide intervention as clinically indicated and follow up with 
the subject within 1 week and/or refer him/her to a qualified mental health professional. 
6.4.2.3.  Non-acute Suicidal Risk 
The Investigator will conduct safety planning with the subject and will follow up within 
1 week. 
Reference materials for subjects and caregivers should include lists of mental health 
organizations and professionals, outpatient behavioral services, local crisis and peer 
support groups and Suicide/Crisis Hotlines. 
Data Redacted
Data Redacted


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6.5.  Clinical Measurements 
6.5.1.  Clinical Safety Laboratory Assessments 
With the exception of urine pregnancy tests and urine drug screen tests, clinical 
laboratory tests are performed by a central laboratory as specified in the reference 
binder. 
Details for collecting, handling, and shipping samples (including shipment addresses) 
are detailed in a separate clinical laboratory manual. The Schedule of Events and 
Assessments (Table 1 [SCHEDULE ‘A’] or Table 2 [SCHEDULE ‘B’]) shows the time 
points at which blood and urine samples are collected. Table 3 presents the clinical 
laboratory tests to be performed. 
Table 3 
Clinical Laboratory Tests 
Category 
Parameters 
Serology 
Human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B, 
hepatitis C; Visit ‘S’, SCHEDULE ‘B’ only 
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;  Visit ‘S’, SCHEDULE ‘B’ only 
‘Standard’  
Urine Drug Screen (UDS) 
amphetamines, barbiturates, benzodiazepines, buprenorphine, 
cocaine, ecstasy, methadone, methamphetamine, opiates, 
oxycodone, phencyclidine, propoxyphene, tricyclic 
antidepressant, THC (cannabinoids); 
Visit ‘S’, SCHEDULE ‘B’ only 
Point of Care Urine Drug 
Screen 
Test 1: amphetamines, barbiturates, benzodiazepines, 
buprenorphine, cocaine, ecstasy, methadone, methamphetamine, 
opiates, oxycodone, phencyclidine, propoxyphene, tricyclic 
antidepressant, THC (cannabinoids). 
 
Test 2: methylphenidate 
On site Urine Pregnancy 
Test (at all study visits) 
FOCP only 
Home Urine Pregnancy 
Test (in between study 
visits following study visit 3) 
FOCP only 
(dispense home pregnancy kit at Study Visits 3 thru 21) 
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. 


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6.5.2.  Vital Signs and Weight 
Vital signs measurements (e.g., orthostatic blood pressure/heart rate, oral temperature, 
and respiratory rate) and body weight is obtained at the time points shown in Schedule 
of Events and Assessments (Table 1 [SCHEDULE ‘A’] or Table 2 [SCHEDULE ‘B’]). 
Orthostatic blood pressure/heart rate are measured after the subject has been sitting for 
at least 5 minutes and again within 3 minutes of subject standing. Vital signs may be 
taken at any other time, as deemed necessary by the Investigator. 
6.5.3.  Physical Examinations and Height 
Physical examinations are obtained at the time points shown in the Schedule of Events 
and Assessments (Table 1 [SCHEDULE ‘A’] or Table 2 [SCHEDULE ‘B’]). The physical 
examination conducted at the initial study visit will include assessments of all body 
systems except genitourinary. Any findings during initial study visit in this study (prior to 
first dose of OLE SM) will be recorded as medical history and any clinically significant 
abnormal findings during treatment period (after the first dose of OLE SM until the end of 
the study) will be recorded as an AE. For the physical examination at EOS, only changes 
from the initial study visit of this study (812P311) will be noted.  
6.5.4.  Electrocardiograms (ECGs) 
A 12-lead ECG will be obtained at the time points shown in the Schedule of Events and 
Assessments (Table 1 [SCHEDULE ‘A’] or Table 2 [SCHEDULE ‘B’]). 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  
). 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. Only administered SCID-5-CT to de novo subjects (Visit ‘S’ [SCHEDULE ‘B’]). 
Da


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7.  STATISTICAL METHODS 
7.1.  General Considerations 
In general, continuous variables will be summarized with standard descriptive statistics 
including number of subjects (n), mean, standard deviation (SD), median, minimum, and 
maximum. Categorical variables will be summarized with frequencies and percentages. 
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. 
Additional 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 
If applicable, missing efficacy data will be imputed using multiple imputation.  
Missing dates for occurrence of adverse events and non-study medication use will be 
imputed using the following rules:  
1. Start dates with both missing day and month will be set to the 1st of January of that 
year, except as noted in rule 4 below. End dates with both missing day and month will 
be set to the 31st of December of that year.  
2. Start dates with missing day only will be imputed with the first day of the month, except 
as noted in rule 4 below. End dates with missing day only will be imputed with the last 
day of the month.  
3. Start dates with missing month only will be imputed by setting the month to January of 
the year. End dates with missing month only will be imputed to December of the year.  
4. If a start date has missing day only with month and year the same as the month and 
year of the first dose date, then the start date will be set to the first dose date. If a start 
date has missing day and month with the year the same as the year of the first dose 
date, then the start date will be set to the first dose date. 
7.3.  Analysis Populations 
The Safety Population is all subjects who are enrolled and receive at least one dose of 
SM. All statistical analyses will be based on the Safety Population. 
7.4.  Demographics and Baseline Analysis 
Demographic/baseline variables including age, age group, sex, ethnicity, race, height 
and weight at Visit 1, 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 optimized dose group and overall for the 
Safety Population.  


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7.5.  Subject Disposition 
A disposition of subjects will include the number and percentage of subjects in the 
Safety Population. 
The number and percentage of subjects who completed and discontinued from the study 
and primary reason for early discontinuation will be summarized. The reason for early 
discontinuation may include any of the following: 
 
Withdrawal of consent  
 
Noncompliance 
 
Occurrence of unmanageable AEs 
 
Lost to follow-up 
 
Related to COVID-19 
 
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 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 (WHO DD) drug codes. Concomitant medications will be 
further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating 
therapeutic classification. A tabular summary of concomitant medications by drug class 
will be presented for the Safety Population. 


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7.8.  Efficacy Analysis 
The efficacy analysis will be based on the safety population. Each efficacy endpoint will 
be listed and summarized descriptively by group of the optimized dose, if applicable. In 
addition, if applicable, subjects who received adjunctive stimulant therapy will be 
identified by flagging for categorical summary. Total and subscale scores/points for 
AISRS, CGI-S, CGI-I, GAD-7, BRIEF-A, SDQ, and AAQoL will be summarized by 
optimized dose (if applicable) and visit and will be examined. Baseline will be defined for 
all subjects as the last non-missing value prior to SPN-812 dosing in Study 812P311. 
7.9.  Safety Analysis 
Safety analyses will be performed by optimized dose group and overall based on the 
Safety Population.  
The incidence rate of AEs will be calculated for each system organ class (SOC) and 
preferred term (PT). The severity of the AEs and the relationship to SM will be 
summarized 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. 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 optimized dose group and 
overall using descriptive statistics. For quantitative laboratory parameters, both actual 
values and change from baseline values will be summarized. 
Vital signs will be summarized by visit by optimized dose group and overall using 
descriptive statistics. Both actual values and change from baseline will be summarized. 
ECG results will be summarized by visit by optimized dose group and overall 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 optimized dose group and 
overall. 
7.10.  Sample Size and Power Considerations 
There is no consideration for power or sample size determination in this open label 
study. The present study is an extension of the blinded 812P306 study in patients with 
ADHD. 
 
 


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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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This document is confidential. It contains proprietary information of Supernus® Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 
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. 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.  
8.4.  Retention of Records 
The Investigator has the responsibility to retain all study “essential documents”, as 
described in ICH E6 for at least two years after approval of a marketing application or 
after formal discontinuation of the clinical program. Essential documents include but not 
limited to the protocol, eCRFs, source documents, laboratory test results, SM inventory 
records, Investigator's Brochure, regulatory agency registration documents (e.g., FDA 
form 1572, ICFs, and IRB correspondence). The Investigator must obtain written 
permission from Supernus prior to the destruction of any study document.  
8.5.  Auditing Procedures 
In addition to the routine monitoring procedures, the Sponsor’s Corporate Quality 
Assurance department or qualified designee may conduct audits of clinical research 
activities in accordance with the Sponsor’s written SOPs to evaluate compliance with the 
principles of ICH GCP and all applicable local regulations. A government regulatory 
authority may also wish to conduct an inspection (during the study or after its 
completion). If an inspection is requested by a regulatory authority, the Investigator must 
inform the Sponsor and the CRO immediately that this request has been made. 


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This document is confidential. It contains proprietary information of Supernus® Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 
These records must be made available at reasonable times for inspection and 
duplication, if required, by a properly authorized representative of the US FDA in 
accordance with the US 21 Code of Federal Regulation (CFR) 312.68 or other national 
or foreign regulatory authorities in accordance with regulatory requirements. 
8.6.  Publication of Results 
Any presentation or publication of data collected as a direct or indirect result of this trial 
will be considered as a joint publication by the Investigator(s) and the appropriate 
personnel at the Sponsor’s site. Authorship will be determined by mutual agreement. All 
manuscripts, abstracts or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the Sponsor, prior to submission for 
publication or presentation. No publication or presentation with respect to the study shall 
be made until all Sponsor comments on the proposed publication or presentation have 
been addressed to the Sponsor’s satisfaction. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be outlined in the 
agreement between each Investigator and the Sponsor or designee. 
8.7.  Financing and Insurance 
Financing and Insurance information will be set forth in a separate document between 
the Investigator and Sponsor (provided by the Sponsor or designee). 
8.8.  Disclosure and Confidentiality 
The contents of this protocol, any amendments, and results obtained during the course 
of this study will be kept confidential by the Investigator, the Investigator’s staff, and the 
IRB and will not be disclosed in whole or in part to others or used for any purpose other 
than reviewing or performing the study without the written consent of the Sponsor. No 
data collected as part of this study will appear in any written work, including publications, 
without the written consent of Sponsor. 
All persons assisting in the performance of this study must be bound by the obligations 
of confidentiality and non-use set forth in the Confidentiality Agreement between the 
Investigator and Sponsor. 
8.9.  Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative 
reasons at any time. The Investigator will be reimbursed for reasonable expenses 
covering subjects, use of live-in facilities, laboratory tests, and other professional fees. 
The Investigator will refund the excess of payments made in advance. 
The Investigator reserves the right to discontinue the study should his/her judgment so 
dictate. The Investigator will notify the IRB in case of study discontinuation. Study 
records must be retained as noted above. 
 
 


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This document is confidential. It contains proprietary information of Supernus® Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 
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.  
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. 
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 


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This document is confidential. It contains proprietary information of Supernus® Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 
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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This document is confidential. It contains proprietary information of Supernus® Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 
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. 
Briars L and Todd T. A review of pharmacological management of attention-
deficit/hyperactivity disorder. J Pediatr Pharmacol Ther. 2016;21(3):192-206. 
Brod M, Johnston J, Able S, Swindle R. Validation of the adult attention-
deficit/hyperactivity disorder quality-of-life Scale (AAQoL): a disease-specific quality-of-
life measure. Qual Life Res. 2006;15(1):117-129. 
Brod M, Adler LA, Lipsius S, Tanaka Y, Heinloth AN, Upadhyaya H. Validation of the 
adult attention-deficit/hyperactivity disorder quality-of-life scale in European patients: 
comparison with patients from the USA. Atten Defic Hyperact Disord. 2015;7(2):141-150. 
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. 
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. 
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.  
Guy W. Clinical global impressions. ECDEU Assessment manual for 
Psychopharmacology, Rockville, MD: US National Institutes of Health, 
Psychopharmacology Research Branch, 1976. 
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. 


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This document is confidential. It contains proprietary information of Supernus® Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. 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, et al. 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-
629. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SAP_003.pdf: 
Supernus Pharmaceuticals, Inc. 
CONFIDENTIAL 
12Dec2022 
812P311 
 
Version 3.0 
 
This document is confidential. It contains proprietary information of Supernus® Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 
COVER PAGE – STATISTICAL ANALYSIS PLAN (SAP) 
 
Protocol Number: 
812P311 
Title: 
An Open-Label Extension Study to Evaluate the Long-Term 
Safety and Efficacy of SPN-812 in Adults with Attention-
Deficit/Hyperactivity Disorder 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
9715 Key West Avenue 
Rockville, MD 20850 
United States 
Phone: (301) 838-2500 
Fax: (240) 403-0065 
SAP Version: 
3.0 
Date: 
12Dec2022 
NCT: 
NCT04143217 


Supernus Pharmaceuticals, Inc. 
812P311 Statistical Analysis Plan 
CONFIDENTIAL 
Page i of 24 
 
 
STATISTICAL ANALYSIS PLAN  
Study 812P311 
An Open-Label Extension Study to Evaluate the Long-Term Safety and 
Efficacy of SPN-812 in Adults with Attention-Deficit/Hyperactivity 
Disorder 
 
Name of Test Drug: 
SPN-812 ER 
Sponsor: 
Supernus Pharmaceuticals, Inc.  
9715 Key West Ave 
Rockville, MD 20850  
United States  
Prepared by: 
 Supernus Pharmaceuticals, Inc.  
Document Date: 
12 December 2022 
Document Version: 
V3.0 
 
 
 
CONFIDENTIALITY STATEMENT 
This document is confidential. It contains proprietary information of Supernus Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing the study. 
 




Supernus Pharmaceuticals, Inc. 
812P311 Statistical Analysis Plan 
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DOCUMENT HISTORY 
See Appendix A: Document History 
 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE ................................................................................................... 2 
DOCUMENT HISTORY............................................................................................. 3 
TABLE OF CONTENTS ............................................................................................. 4 
ABBREVIATIONS ..................................................................................................... 6 
1 
INTRODUCTION .................................................................................... 8 
2 
DATA CONVENTIONS FOR ANALYSIS ............................................ 8 
2.1 
Disposition of Subjects and Withdrawals ................................................. 8 
2.2 
Protocol Deviations .................................................................................. 9 
2.3 
Demographic Characteristics .................................................................... 9 
2.4 
Study Drug Exposure ................................................................................ 9 
2.5 
Efficacy Data ............................................................................................ 9 
2.6 
Safety Data .............................................................................................. 11 
 
Adverse Events ....................................................................................... 11 
 
Prior and Concomitant Medications ....................................................... 11 
 
Laboratory Evaluations ........................................................................... 12 
 
Vital Signs .............................................................................................. 12 
 
Electrocardiogram ................................................................................... 12 
3 
STATISTICAL METHODS ................................................................... 13 
3.1 
General Methods ..................................................................................... 13 
3.2 
Baseline Values ...................................................................................... 13 
3.3 
Handling of Missing Data ....................................................................... 13 
3.4 
Computing Environment ........................................................................ 13 
4 
ANALYSES ........................................................................................... 14 
4.1 
Subject Disposition ................................................................................. 14 
4.2 
Demographic Characteristics .................................................................. 14 
4.3 
Study Drug Exposure .............................................................................. 14 
4.4 
Efficacy Analyses ................................................................................... 14 
4.5 
Safety Analyses ...................................................................................... 15 
 
Treatment-emergent Adverse Events ..................................................... 16 


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Special Safety Categories: Death, Serious Adverse Events and Adverse 
Events Leading to Study Drug Discontinuation ..................................... 16 
4.5.2.1 
Deaths ..................................................................................................... 16 
4.5.2.2 
Serious Adverse Events .......................................................................... 16 
4.5.2.3 
Adverse Events Leading to Study Drug Discontinuation ....................... 16 
 
Laboratory Data ...................................................................................... 17 
4.5.3.1 
Potentially Clinically Significant Laboratory Values ............................. 17 
4.5.3.2 
Abnormal Liver Enzymes and Liver Function Values ........................... 18 
 
Vital Signs .............................................................................................. 18 
 
ECG Data ................................................................................................ 18 
 
C-SSRS Data .......................................................................................... 19 
 
Caffeine Intake ........................................................................................ 19 
 
Prior and Concomitant Medications ....................................................... 19 
5 
TABLES AND LISTINGS ..................................................................... 20 
5.1 
List of Tables .......................................................................................... 20 
5.2 
List of Listings ........................................................................................ 21 
5.3 
List of Figures ......................................................................................... 22 
6 
REFERENCES ....................................................................................... 23 
 
 
 






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1 INTRODUCTION  
Study 812P311 is an open-label extension (OLE), long-term, multicenter, flexible-dose study 
of SPN-812 in adults diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD). Up 
to 366 subjects will be enrolled. Subjects who have completed Study 812P306 (a 
randomized, double-blind, placebo-controlled study of SPN-812 for the treatment of ADHD) 
will be eligible for enrollment into Study 812P311. Interest and suitability will be ascertained 
at the last 1 to 2 visits of 812P306 to allow immediate enrollment into Study 812P311 for 
subjects who complete Study 812P306 
2   DATA CONVENTIONS FOR ANALYSIS 
The Safety Population is defined as all subjects who are enrolled and receive at least one 
dose of SPN-812 during the OLE study. 
Safety will be assessed from data based on the analysis of adverse events (AE), potentially 
clinically significant (PCS) laboratory evaluations, abnormal liver enzymes and liver 
function tests, abnormal vital signs, electrocardiogram (ECG) results, Columbia Suicide 
Severity Rating Scale (C-SSRS) and caffeine intake. Subject disposition (including reasons 
for premature terminations), subject demographics, physical assessment, and exposure to 
study drug will also be presented.  
 
2.1 
Disposition of Subjects and Withdrawals 
Subject disposition summary will be presented for the Safety Population. Disposition will 
include tabulations of the number and percentage of subjects in each of the following 
categories: 
• Subjects dosed 
• Subjects completed study 
• Subjects early discontinued 
The primary reason for early discontinuation will be summarized. The reason for early 
discontinuation may include any of the following: 
• Adverse event 
• Death 
• Lost to follow-up 
• Non-compliance with study drug 
• Withdrawal of consent by subject 
• Lack of efficacy 
• Investigator’s decision 
• Misuse or abuse of study drug 


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• Study terminated by sponsor 
• Other 
2.2 
Protocol Deviations 
A protocol deviation is defined as any change, divergence, or departure from the study design 
or procedures defined in the protocol. Protocol deviations will be listed and summarized.  
 
2.3 
Demographic Characteristics 
Demographic characteristics include:  
• Age (18-44, 45-65) 
• Sex (male, female) 
• Race  
• Ethnicity (Hispanic, Non-Hispanic) 
• Height 
• Weight 
• Body mass index (BMI)  
The number and percent of subjects reporting various medical histories, grouped by Medical 
Dictionary of Regulatory Activities (MedDRA) system organ class (SOC) and preferred term 
(PT) will be analyzed. Medical history will be coded using MedDRA Version 22.1 This 
analysis will be conducted for the Safety Population. 
Alcohol, tobacco, and substance use collected at screening will be listed. Subject training 
module data will also be listed. 
 
2.4 
Study Drug Exposure 
Study drug exposure is collected as both actual and planned dose and duration of exposure to 
SPN-812.  
 
2.5 
Efficacy Data 
1) 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 subjects7. It is a semi-structured clinical interview with suggested 
prompts for each item to improve inter-rater reliability. The scale consists of 18 items 
that directly correspond to the 18 symptoms of ADHD and are further subdivided into 2 
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, 


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and 3 = Severe, with a maximum total score of 54 points and maximum subscale scores 
of 27 points each. 
 
2) The Clinical Global Impressions 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 the 
administration of SPN-812. The Clinical Global Impression – Severity of Illness (CGI-S) 
is a single item clinician rating of clinician’s assessment of the severity of the ADHD 
symptoms in relation to the clinician’s total experience with subjects with ADHD. The 
Clinical Global Impression – Improvement Scale (CGI-I) is an assessment of how much 
the subject’s illness has improved or worsened relative to a baseline state prior to 
treatment. Both CGI-S and CGI-I are rated on a 7-point scale of 1 to 7 with 7 being 
“extremely ill” or “very much worse”, respectively. Successful therapy is indicated by a 
lower overall score in subsequent testing.  
 
3) The CGI-S is evaluated on a 7-point scale with 1 = Normal/not at all ill, 2 = Borderline 
Ill, 3 = Mildly Ill, 4 = Moderately Ill, 5 = Markedly Ill, 6 = Severely Ill, and 7 = 
Extremely Ill. 
 
4) CGI-I, relative to the condition at baseline, will be evaluated by the investigator at each 
post-baseline visit on a 7-point scale with 1 = Very much improved, 2 = Much improved, 
3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = 
Very much worse. 
 
5) Generalized Anxiety Disorder 7 scale (GAD-7) is a self-reported 7-item questionnaire for 
screening and measuring the severity of generalized anxiety disorder9. 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 subject 
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. 
 
6) 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 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 (MI) 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 MI 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 using Appendix A of the 
BRIEF-A Professional Manual10, and the change from baseline in T-scores will be 
calculated. 


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7) The Symptoms of Depression Questionnaire (SDQ) is a 44-item, self-reported depression 
scale, designed to measure the severity of symptoms of depression that inquires about an 
extensive number of depressive symptoms. The subject self-rates/scores each item on a 6-
point scale (1 to 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 to 6). SDQ subscales are as 
follows: 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; and SDQ-5 subscale includes items on changes in 
appetite and weight. 
8) Adult ADHD Quality of Life (AAQoL) is a 29-item questionnaire that measures how 
ADHD has impacted the subject’s quality of life over the past 2 weeks. The AAQoL 
includes 4 subscales: life productivity, psychological health, relationships, and life 
outlook. The subject rates/scores each item on a 5-point Likert scale, where 1 = Not at 
all/Never, 2 = A little/Rarely, 3 = Somewhat/Sometimes, 4 = A lot/Often, and 
5 = Extremely/Very often. For subscale calculations, items are transformed such that a 
score of 1 = 0, 2 = 25, 3 = 50, 4 = 75, and 5 = 100 and then the sum of these transformed 
subscale items is averaged by the number of items.  
Life productivity scores come from items 1, 2, 3, 4, 5, 11, 22, 23, 24, 25 and 26 and the 
values are reversed, i.e., a score of 1 becomes a score of 5, a score of 2 becomes a score 
of 4, a score of 3 remains a 3, and so on. This is then transformed and averaged as stated 
above. 
Psychological health scores come from items 6, 7, 8, 13, 20 and 21 and the values are 
reversed, i.e., a score of 1 becomes a score of 5, a score of 2 becomes a score of 4, a score 
of 3 remains a 3, and so on. This is then transformed and averaged as stated above. 
Relationships scores come from items 9, 10, 12, 18 and 19. This is then transformed and 
averaged as stated above. 
Life outlook scores come from items 14, 15, 16, 17, 27, 28 and 29. This is then 
transformed and averaged as stated above. 
2.6 
Safety Data 
 
Adverse Events 
All AEs will be coded using MedDRA Version 22.1 for consistency with the Study 812P306 
AE analyses. Study-level Lower Level Terms (LLT) will be assigned to the corresponding 
PT and SOC in MedDRA Version 22.1.  
 
 
Prior and Concomitant Medications 
A concomitant treatment refers to all treatment, including concomitant therapies as well as 
herbal treatments, vitamins, behavioral treatment, and non-pharmacological treatment, such 
as psychotherapy, taken between the dates of the first dose of study drug and the end of the 
subject’s participation in the study (Visit 22/EOS), inclusive. 


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Treatments that started prior to the first dose of study drug are considered prior treatments 
whether or not they were stopped prior to the first dose of study drug. Any treatment starting 
on or after the first dose of study drug will be considered as concomitant. If a treatment starts 
prior to the first dose of study drug and continues after the first dose of study drug, the 
medication will be considered both prior and concomitant. 
Prior and concomitant medications will be coded using World Health Organization Drug 
Dictionary (WHO-DD Enhanced version September 2019), Anatomical Therapeutic 
Chemical (ATC) level 4 for ATC class and level 5 (clinical substance) for preferred name 
(PN). 
 
 
Laboratory Evaluations 
Laboratory tests will include hematology, serum chemistry, and urinalysis. Values will be 
presented using the international system of units (SI).  
Hematology: 
Hematology parameters will include complete blood count (CBC), white blood cell count 
with differential, platelet count, red blood cell (RBC) count, hemoglobin, and hematocrit.  
Serum Chemistry: 
Serum chemistry parameters will include albumin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), bicarbonate, bilirubin (direct), bilirubin 
(total), blood urea/blood urea nitrogen (BUN), calcium, chloride, creatinine, phosphate, 
potassium, sodium, total protein, and glucose. 
Urinalysis: 
Urinalysis parameters will include bilirubin, glucose, ketones, nitrites, occult blood, pH, 
protein, specific gravity, urobilinogen, and WBCs.  
Other: 
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. 
 
 
Vital Signs 
Vital signs data will include weight (kg), BMI (kg/m2), systolic blood pressure (mmHg), 
diastolic blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per 
minute) and temperature (°C). Blood pressure and heart rate measurements taken in the 
standing and the seated position will be analyzed. 
 
 
Electrocardiogram 
The ECG parameters to be summarized include heart rate, PR interval (msec), QRS interval 
(msec), QT interval (msec), and QT interval corrected for heart rate using Fridericia's (QTcF) 
correction formula. 
 


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3 STATISTICAL METHODS 
3.1 
General Methods 
Premier Research, the designated CRO, will perform all statistical analysis using SAS 
version 9.4 or higher. Premier Research will be responsible for creating table, listing, and 
figure reports by SAS programming and delivering the reports, as well as the programs, to 
Supernus at study completion.  
All analyses will be based on subjects who received any amount of study drug in Study 
812P311. This will be referred to as the Safety Population. Since subjects received variable 
dosing in this study, all subject data will be summarized together under All SPN-812. 
For categorical variables, summary statistics will include the number and percentage of 
subjects within each category (with a category for missing data). Percentages will be based 
on the total number of subjects with non-missing data. For continuous variables, summary 
statistics will include the number of non-missing observations, mean, standard deviation 
(SD), median, and interquartile range (Q1, Q3), minimum, maximum. 
 
3.2 
Baseline Values 
For all safety assessments, baseline will be defined as the last non-missing value prior to 
SPN-812 dosing in the 812P311 study. 
 
For all efficacy assessments, subjects enrolled into 812P311 ≤ 7 days after their last 812P306 
visit, the “baseline” efficacy assessment is defined as the assessment that subject completed 
at Visit 2 in 812P306 prior to the first dose of SPN-812 in 812P306.  Additionally, for 
subjects enrolled into 812P311 > 7 days after their last 812P306 visit, the baseline efficacy 
assessment is defined as the assessment that was completed at Visit 1 in 812P311 prior to the 
first dose SPN-812 in 812P311.   
  
All post-baseline assessments are defined as any assessments that were completed after the 
first dose of SPN-812 in the 812P311 study. 
3.3 
Handling of Missing Data 
There will be no imputation made for missing data points and hence, only observed data will 
be used for analyses.  
 
3.4 
Computing Environment 
All descriptive statistical analyses will be performed using SAS (Version 9.4), unless 
otherwise noted. 
 


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4 ANALYSES 
4.1 
Subject Disposition 
The number and percentage of subjects that were dosed, completed the study, or discontinued 
early will be displayed. Reasons for early discontinuation will be tabulated. 
 
4.2 
Demographic Characteristics 
Descriptive statistics for demographic characteristics will be calculated for all continuous 
variables and frequencies and percentages will be presented for categorical variables.  
 
4.3 
Study Drug Exposure 
Duration of exposure in days will be calculated from the first and last dates of the study drug 
administration. The duration of exposure will be calculated as date of last dose minus date of 
first dose + 1. Duration of exposure (days) will be summarized by categories, descriptive 
statistics, and by age group (18 to 44, 45 to 65, and overall). The categories for duration of 
exposure are: 0 to <13, 13 to <26, 26 to <39, 39 to < 52, 52 to < 65, 65 to < 78, 78 to < 91, 
91 to <104, 104 to < 117, 117 to < 130, 130 to < 144, and 144 or more weeks. The actual 
average daily dose (0 to ≤200, 200 to ≤300, 300 to ≤400, 400 to ≤500, and > 500 mg/day) 
will be summarized by duration of exposure categories and by age group. Descriptive 
statistics for planned dose (n, mean, SD, median, min, max, and Q1, Q3) will be summarized 
by visit and by age group. The actual average daily dose is calculated as dispensed SPN-812 
in mg minus returned SPN-812 in mg divided by days taken SPN-812 across all available 
visits.  
4.4 
Efficacy Analyses 
For the analyses of change from baseline of 812P311 efficacy variables (e.g., descriptive 
statistics), a subject must have both a valid baseline assessment and at least 1 valid post-
baseline assessment to be included in the analyses. 
Analysis of efficacy will include: 


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1) The Change from baseline (CFB) in the AISRS total score will be summarized using 
descriptive statistics by visit. 
2) The CFB in the CGI-S score will be summarized using descriptive statistics by visit.  
3) The CGI-S will be dichotomized at each visit: CGI-S will be classified as ‘responder’ if 
the score is 1 or 2 and ‘non-responder’ if the score is 3 to 7. The number and percentage 
of CGI-S responders will be presented by visit. 
4) The CGI-I will be summarized using descriptive statistics by visit.  
5) The CGI-I will be dichotomized at each visit: CGI-I will be classified as ‘responder’ if 
the score is 1 or 2 and ‘non-responder’ if the score is 3 to 7. The number and percentage 
of CGI-I responders will be presented by visit.  
6) The CFB in the GAD-7 total score will be summarized using descriptive statistics by 
visit. 
7) The CFB in the AISRS Inattention subscale score and Hyperactivity/Impulsivity subscale 
scores will be summarized using descriptive statistics by visit 
8) The AISRS 50% responder rate: A 50% responder rate is defined as the percentage of 
subjects with ≥ 50% reduction in AISRS total score from baseline at each visit, where % 
reduction =100*(AISRS total score - Baseline AISRS total score)/ Baseline AISRS total 
score.  
9) The AISRS 30% responder rate: A 30% responder rate is defined as the percentage of 
subjects with ≥ 30% reduction in AISRS total score from baseline at each visit, where % 
reduction =100*(AISRS total score - Baseline AISRS total score)/ Baseline AISRS total 
score.  
10) The CFB in the Behavior Rating Inventory of Executive Function – Adult Version 
(BRIEF-A) Global Executive Composite (GEC) T-score will be summarized using 
descriptive statistics by visit. 
11) The CFB in the BRIEF-A T-score by BRI, MI and their subscales will be summarized 
using descriptive statistics by visit. 
12) The CFB in the Symptoms of Depression Questionnaire (SDQ) total score will be 
summarized using descriptive statistics by visit. 
13) The CFB in the SDQ subscale scores will be summarized using descriptive statistics by 
visit. 
14) The CFB in the Adult ADHD Quality of Life (AAQoL) total score will be summarized 
using descriptive statistics by visit. 
15) The CFB in the AAQoL subscale scores will be summarized using descriptive statistics 
by visit. 
Where appropriate, the above endpoints will be summarized descriptively (frequency count 
and percent) for categorical variables, and number of subjects (n), mean, SD, median, 
interquartile range (Q1 and Q3), minimum, and maximum for continuous variables.  
4.5 Safety Analyses 
Safety measures include monitoring, evaluation, and recording of all concomitant 
medications, and the evaluations of AEs, clinical laboratory test results, vital signs, 12-lead 
ECGs, C-SSRS, and the performance of physical examinations. 


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Treatment-emergent Adverse Events 
AEs will be coded using MedDRA Version 22.1. All AEs will be considered as treatment-
emergent adverse events (TEAEs) and included in the AE summaries. 
Adverse events will be categorized by MedDRA SOC and/or PT. A subject experiencing the 
same AE multiple times will only be counted once for that preferred term. Similarly, if a 
subject experiences multiple AEs within the same SOC, that subject will be counted only 
once for that SOC.   
For displays, SOCs will be presented in alphabetical order and PTs will be sorted by 
decreasing incidence under each SOC.   
An overview of TEAEs will be provided, this will include summaries of incidence rates 
(frequencies and percentages) of subjects who had at least one TEAE, serious TEAE, TEAE 
leading to death, TEAE by maximum severity, TEAE by relationship, TEAE leading to study 
drug discontinuation, related serious TEAE and Adverse Event of Special Interest (AESI). 
TEAEs occurring in at least 5% of subjects will be presented by SOC and PT. TEAEs 
occurring in at least 5% of subjects by PT will also be presented. In addition, the incidence of 
TEAEs will also be summarized by MedDRA SOC, PT and maximum severity, in which 
subjects are counted once for each unique preferred term and each SOC under the known 
maximum severity at which it was experienced. If severity is unknown for all occurrences of 
a particular PT, it will be counted under ‘severe’. The incidence of TEAEs by MedDRA 
SOC, PT and relationship to study drug will be produced in the same fashion. 
AESIs include seizures or AEs that might represent a seizure (e.g., syncope/syncopal 
episode, pseudo seizure, myoclonus, severe muscle spasms). To identify the AESI, the 
following search terms will be used to search among the PTs as well as the verbatim terms: 
seizure, syncope, syncopal episode, pseudo seizure, myoclonus, and muscle spasms (that is 
categorized as severe only). The incidence of AESIs will be summarized by MedDRA SOC 
and PT. For subjects who experienced the same AESI multiple times, the event will be 
counted once.  
 
 
Special Safety Categories: Death, Serious Adverse Events and Adverse Events 
Leading to Study Drug Discontinuation 
4.5.2.1 Deaths 
A listing of deaths will be presented. 
4.5.2.2 Serious Adverse Events 
The incidences of SAEs will be presented by SOC and PT, and a listing of all SAEs will be 
presented.  
4.5.2.3 Adverse Events Leading to Study Drug Discontinuation 
The incidences of TEAEs leading to study drug discontinuation will be presented by SOC 
and PT, and a listing of AEs that led to discontinuation of study drug will be presented.  






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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.  
All ECG results will be displayed in the data listings. 
 C-SSRS Data 
C-SSRS outcomes will be summarized and listed. The number and percentages of subjects 
with a response of “Yes” at any visit by categories for suicidal ideation only, suicidal behavior 
only, suicidality (ideation and behavior combined) items, and non-suicidal self-injurious 
behavior will be presented.  
 
Caffeine Intake 
Weekly caffeine intake will be summarized by consumption category. Weekly caffeine 
consumption categories include no caffeine intake, 0 to <250 mg, 250 to ≤500 mg, 500 to 
≤750 mg, 750 to ≤1000 mg, 1000 to ≤1250 mg, 1250 to ≤1500 mg, 1500 to ≤1750 mg, 1750 to 
≤2000 mg, and ≥2000 mg.  
 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized separately by ATC Class Level 4 and 
PN.  
 










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10. Roth RM, Isquith PK, Gioia GA. Behavior Rating Inventory of Executive Function® – Adult 
Version. Psychological Assessment Resources, 2005.