Conditions: Healthy Lactating Women
Keywords: Healthy Lactating Women Healthy Pregnancy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: yes

Brief summary:
This is an open label, single treatment, multiple doses lactation study of SPN-812 in healthy lactating women. The study is designed to assess the excretion of viloxazine and its major metabolite 5-HVLX-gluc into breast milk following repeated administration of SPN-812 600 mg, QD.

This study is comprised of Screening, Inpatient Admission, Treatment Period and End of Study (EOS). The total duration of the study is up to 32 days including Screening up to 28 days and 4 days of Treatment Period. Subjects will remain in the inpatient unit for 5 days, including the day of admission to the inpatient unit (Day -1), 3 days of dosing SM (Days 1-3), and the day of discharge (Day 4).

Detailed description:
This is an open label, single treatment, multiple doses, lactation study of SPN-812 at steady state in healthy lactating women. The study is designed to assess the excretion of viloxazine and its major metabolite 5-HVLX-gluc into breast milk following repeated administration of SPN-812 600 mg daily for 3 days. The study is designed to assess the excretion of viloxazine and its major metabolite 5-HVLX-gluc into breast milk following repeated administration of SPN-812 600 mg, QD.

This study is comprised of Screening, Inpatient Admission, Treatment Period, End of Study (EOS) with FU phone call. The total duration of the study is up to 32 days including Screening up to 28 days and 4 days of Treatment Period. Subjects will remain in the inpatient unit for 5 days, including the day of admission to the inpatient unit (Day -1), 3 days of dosing SM (Days 1-3), and the day of discharge (Day 4).

Subjects will complete the screening visit, after informed consent is obtained, within 28 days prior to dose initiation. Inclusion/exclusion criteria will be reviewed to determine the subject's eligibility at Screening. A lactation consultant will be available to provide lactation support to subjects once they are enrolled.

Since the mother's infant cannot receive breast milk for 7 consecutive days (Day-1 to Day 6), the mother will be reminded at Screening to make plans to have their infant fed 7 consecutive days with either (a) formula or (b) stored breast milk (e.g., breast milk pumped and stored in the freezer during the screening period between the screening visit and the day of admission to inpatient unit).

Subjects will be admitted to the inpatient unit on Day -1 to confirm eligibility. Subjects will receive 600 mg SPN-812 in the morning of Days 1, 2 and 3 after completion of safety assessments. SM should be administered at the same time in the morning (±30 min) of dosing days. Breast milk and blood sample for PK analysis will then be collected on Day 3 per schedule. Non-PK breast milk expressed on Days -1, 1, and 2 will be collected over the time intervals and these samples will not be analyzed for drug concentrations. The volume and the start and end times of the collection of each non-PK and PK breast milk sample will be recorded. The end of study (EOS) procedures will be conducted prior to discharge on Day 4 following the last breast milk and blood sample collection. If subject discontinues early, all EOS procedures will be conducted.

Arms:
arm 1: Up to 15 healthy, lactating women will be enrolled in the study.

Interventions: intervention 1: SPN-812 (600mg, QD)
Intervention descriptions: intervention 1: Viloxazine ER

Protocol document:
Prot_000.pdf: 


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


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


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CLINICAL PROTOCOL SYNOPSIS 
Name of Product:   
SPN-812 (viloxazine extended-release capsule) 
Name of Active Ingredient: 
Viloxazine Hydrochloride 
Full Title of Study: Evaluation of the Excretion of Viloxazine and Its Metabolite 5-Hydroxy-
viloxazine Glucuronide into Breast Milk Following Multiple Doses of SPN-812 (600mg, QD) in 
Healthy Lactating Women 
Phase of Development:  4 
Investigator(s) / Center(s): Up to 2 study sites in the US 
Objective:  
Primary Objective: 
 To evaluate the pharmacokinetics (PK) of viloxazine and its major metabolite 5-hydroxy-
viloxazine glucuronide (5-HVLX-gluc) in breast milk in healthy lactating women following 
multiple oral doses of SPN-812. 
Secondary Objectives: 
 To evaluate the PK of viloxazine and 5-HVLX-gluc in plasma in healthy lactating women 
following multiple oral doses of SPN-812. 
 To evaluate the overall exposure between breast milk and plasma in healthy lactating 
women following multiple oral doses of SPN-812. 
 To estimate daily infant dose of SPN-812 via breast milk. 
Safety Objective: 
 To evaluate the safety and tolerability of multiple doses of SPN-812 in healthy lactating 
women. 
Endpoints 
Primary Endpoints: 
Breast milk PK parameters when SPN-812 reaches plasma steady-state: 
 AUCtau,milk, Cmax,milk, Tmax,milk, Ctrough,milk, Cave,milk for viloxazine and 5-HVLX-gluc  
 Total amount of drug in breast milk (Ammilk, mg/day) over a period of 24 hours for viloxazine 
and 5-HVLX-gluc  
Secondary Endpoints: 
 Plasma AUCtau,ss, Cmax,ss, Tmax,ss, CL/Fss, Cave,ss and Ctrough,ss for viloxazine and 5-HVLX-
gluc at plasma steady-state, if applicable 
 Breast milk-plasma ratio (ML/PL) based on AUC over 24 hours for viloxazine and 5-HVLX-
gluc at plasma steady-state 
 Estimated daily infant dosage (EDID, mg/kg/day) and relative infant dose (RID, %) at 
plasma steady-state (Table 2) 


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Safety Endpoints: 
 Adverse Events (AEs) 
 Clinical laboratory test results (clinical chemistry, hematology and urinalysis) 
 12-lead Electrocardiogram (ECG) 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Vital signs 
 Physical examination 
 Concomitant medications 
Study Design:   
This is an open label, single treatment, lactation study of repeated doses of 600mg SPN-812, 
QD, in healthy lactating women.    
Number of Subjects:   
Up to 15 healthy, lactating women will be enrolled in the study. 
Inclusion/Exclusion Criteria: 
Inclusion Criteria: 
1. Healthy lactating females, 18 to 45 years of age, who are actively breastfeeding 
(including baby to breast, bottle feeding mother's expressed breast milk) and are at least 
12 weeks postpartum of a healthy term newborn infant (no medical complications) and 
not more than 2 years postpartum. Lactation must be well established and the mother is 
exclusively breast feeding her baby (not providing supplemental formula) prior to the day 
of admission to inpatient unit. 
2. Has a body mass index between 18 to 35 kg/m2, included. 
3. Is considered medically healthy by the Investigator via assessment of physical 
examination (neurological examinations included), medical history, clinical laboratory 
tests, vital signs, Columbia-Suicide Severity Rating Scale (C-SSRS) and 
electrocardiogram (ECG).  
4. Is willing to temporarily discontinue breastfeeding their infant and discard all their breast 
milk for 7 consecutive days, including day of admission to inpatient unit (Day -1), 3 
consecutive days of dosing SM while in the inpatient unit (Days 1 to 3), and 3 
consecutive days after last dose of SM (including day of discharge from the inpatient unit 
and 2 days at home; Days 4 to 6); and willing to store sufficient amount of breastmilk 
(e.g., breast milk pumped and stored in freezer before the day of admission), and/or 
infant formula to feed infant during these 7 consecutive days. 
5. Is either sexually inactive (abstinent) or, if sexually active, must agree to use/practice 
one of the following acceptable birth control methods beginning during the screening 
period prior to the first dose of SM, throughout the inpatient study, and for 3 days 
following the last dose of SM (Day 3):  
 intra-uterine contraceptive device;  
 barrier method: condom with spermicidal foam/gel/film/cream/suppository or 
occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository; 


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 is surgically sterile or male partner is surgically sterile;  
 established use of a patch, vaginal ring, oral, injected or implanted hormonal 
methods of contraception that can be used in lactating women;  
 Essure® procedure performed at least 6 months prior to Screening and had 
hysterosalpingogram after the Essure procedure to document tubal occlusion prior to 
screening.   
6. Must not be in the process of weaning before admission and have maintained an 
adequate breast milk supply with regularly pumping or routine breastfeeding (e.g., 
pumping or feeding 3-4 times a day) at admission. 
7. Is currently a non-smoker who has not used tobacco or nicotine-containing products 
(chewed or smoked) or replacement products, including electronic cigarettes, within 3 
months prior to screening and a negative cotinine test result at Screening. 
8. Agrees to use only the emollient or nipple cream recommended by the investigator for 
use during the sampling period, if needed. 
9. Able to voluntarily provide written informed consent to participate in the study. 
10. Able to understand and willing to comply with all study requirements. 
11. Able and willing to swallow capsules whole, without crushing, chewing or cutting.  
Exclusion Criteria: 
1. Participation in any other investigational study drug trial in which receipt of an 
investigational study drug within 30 days or 5 half-lives before Screening, whichever is 
longer. 
2. Is unwilling or unable to comply with the Lifestyle guidelines presented in the protocol 
during the study period. 
3. Has history or presence of clinically significant systemic disease (including psychological 
and psychiatric disorders). 
4. Is currently using, or tests positive at Screening for cotinine, alcohol or drugs (opiates, 
methadone, cocaine, amphetamines [including ecstasy], barbiturates, PCP, 
benzodiazepines, and THC/cannabis). 
5. Is pregnant (has positive serum pregnancy test at Screening) or becomes pregnant 
during study (has positive urine pregnancy test).   
6. Has history of breast implants, breast augmentation, or breast reduction surgery.  
7. Has history of mastitis within 30 days, breast cancer and/or has had a mastectomy or 
lumpectomy with the exception of a benign fibroma or lipoma removal at the 
investigator’s discretion; and/or a clinically significant abnormality observed in either 
breast during a clinical breast exam at Screening or Admission (Day -1). 
8. Has a history of alcohol use disorder within 1 year of Screening; or assessed by the PI 
as having regularly consumed alcohol exceeding 14 units per week (1 unit equals 340 
mL of beer, 115 mL of wine, or 43 mL of spirits) within 1 year of Screening. 


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9. Is using recreational or illicit drug(s) (e.g., cannabis /tetrahydrocannabinol (THC), 
opiates, methadone, cocaine, amphetamines [including ecstasy], barbiturates, and 
benzodiazepines) within 1 year of Screening. 
10. Has clinically significant vital signs abnormalities (systolic blood pressure less than 90 or 
greater than 140 mmHg, diastolic blood pressure less than 60 or greater than 90 mmHg, 
or pulse rate (PR) less than 50 or greater than 100 bpm at Screening.  
11. Has a clinical laboratory test values outside the reference range at Screening that, in the 
opinion of the investigator, are clinically significant, or any of the following: 
 Serum creatinine >1.5 times the upper limit of normal (ULN) 
 Serum total bilirubin >1.5 times ULN 
 Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 
times ULN 
12. Has a clinically significant ECG abnormalities at Screening, including:  
 PR interval >220 ms 
 QRS interval >130 ms 
 QTcF interval >470 ms  
13. Has any disease or medication that could, in the investigator's opinion, interfere with the 
assessments of safety, tolerability, or interfere with the conduct or interpretation of the 
study. 
14. Has evidence of infection with hepatitis B and C, and human immunodeficiency virus 
HIV-1 and HIV-2, as determined by results of testing at Screening. 
15. Has a condition or planned procedure that may interfere with the absorption, 
metabolism, or elimination of the study drug (e.g., cholecystectomy).  
16. Is using prescription medication within 14 days prior to administration of SM or 5 half-
lives, whichever is longer, with the exception of hormonal contraceptives. 
17. Is using over-the-counter products (including vitamins, herbal products and natural food 
supplements) within 14 days prior to administration of SM or 5 half-lives, whichever is 
longer. Exceptions include postnatal vitamins, topical products without systemic 
absorption and acetaminophen (< 2 g/day). 
18. Has an allergy to viloxazine. 
19. Has an Edinburgh Postnatal Depression Scale score >13. 
20. 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 12 months prior to screening). 
21. In the investigator's opinion, is unlikely to comply with the protocol or is unsuitable for 
any other reason.   
Treatment, Dose, and Mode of Administration: 
Study medication, SPN-812 (QELBREE®, viloxazine extended-release capsule) 600 mg (3 x 
200 mg capsule), will be administered orally once daily with or without food. 
Duration of Treatment and Study Duration:  
Up to 32 days including up to 28 days for Screening Period and 4 days for Treatment Period. 


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Treatment Schedule: 
Screening Period 
Subjects will be screened within 28 days prior to dosing. After informed consent is obtained, 
information (including demographics, medical history and maternal-related information) from 
subjects will be collected, and subjects will undergo screening evaluations. Inclusion/exclusion 
criteria will be reviewed to determine the subject’s eligibility at Screening.  
Inpatient Admission 
Eligible subjects will be admitted to inpatient unit on Day -1. Inclusion/exclusion criteria will be 
reviewed to confirm eligibility. Breast milk (non-PK samples) will be collected per subject’s 
pumping routine prior to first dose on Day 1. Subjects will remain in the inpatient unit for 5 
consecutive days; including the day of admission to inpatient unit (Day -1), 3 days of dosing 
SM (Day 1-3), and the day of discharge from inpatient unit (Day 4).  
Treatment Period 
Subjects will receive 600 mg SPN-812 in the morning on Days 1, 2, and 3 after the completion 
of safety assessments. On Day 2 and Day 3, SM will be administered at the same time in the 
morning (±30 min) relative to the time that SM administration occurred on Day 1. On Days 1-4, 
breast milk will be pumped/collected from each breast per the PK breast milk sampling schedule 
or subject’s pumping routine. For each breast milk collection period, the start and end times of 
the collection will be recorded, and the total volume (mL) of breast milk collected will be 
measured and recorded. 
Serial breast milk and blood samples will be collected on Day 3 to 4 for PK analysis. Breast 
milk samples collected out of the PK sampling period (non-PK breast milk sample) will not be 
analyzed for drug concentrations. The end of study (EOS) procedures will be conducted prior 
to discharge on Day 4 following the last breast milk and blood sample collection. If subject 
discontinues early, all EOS procedures will be conducted.   
Pharmacokinetic Sampling: 
Breast Milk:  
A total of 9 expressed breast milk samples will be collected on Day 3 at the following time 
intervals:   
Day 1: -4 to <0 hours pre-dose; 
Day 3: -4 to <0 hours pre-dose, and ‘0 to 4’, ‘4 to 6’, ‘6 to 8’, ‘8 to 10’, ‘10 to 12’, ‘12 to 16’ and 
‘16 to 24’ hours post-dose.  
Breast milk from each breast will be emptied as thoroughly as possible at each session using 
an electric breast pump at the planned time intervals. To ensure that the pump completely 
removes milk from the breasts, double pump for no less than 10 minutes until milk flow ceases. 
The length of each expressing session should be no longer than 30 minutes. 
Non-PK breast milk samples (not to be analyzed for drug concentrations but volume will be 
recorded) will be collected at the following time intervals:  
 
Day -1: store milk as pumped per subject’s pumping routine 
 
Day 1: 0 to 24 hours post-dose per subject’s pumping routine 
 
Day 2: 0 to 20 hours post-dose per subject’s pumping routine 


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Blood:  
A total of 13 blood draws (4 mL each) for PK will be collected on Day 1 pre-dose, Day 3 pre-
dose, and Day 3 at 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 16.0 and 24.0 hours post-dose. 
The following windows are permitted relative to the protocol-specified PK sample collection 
times:  
Pre-dose:  -15 minutes 
< 1 hour post-dose:   ± 3 minute 
1 to 8 hours post-dose:   ± 5 minutes 
> 8 to 24 hours post-dose:  ± 10 minutes 
Bioanalytical Methods   
Concentrations of viloxazine and 5-HVLX-gluc in plasma and breast milk will be determined 
using validated achiral chromatographic tandem mass spectrometry methods. 
Safety Monitoring: 
See Table 1 for safety monitoring procedures. Adverse event (AE) and concomitant medication 
monitoring will be performed throughout the study. 
Statistical Methods 
Analysis Populations 
 
The Safety Population will include all subjects who receive at least one dose of SM. 
 
The PK Population will include all subjects in the safety population who have a 
sufficient PK profile to derive at least 1 PK parameter without major events that could 
impact the PK data (e.g., emesis).  
Pharmacokinetic Analyses 
The PK Population will be used to generate breast milk and plasma PK parameters of viloxazine 
and 5-HVLX-gluc for all subjects.  
Descriptive statistics (number of subjects, mean, standard deviation [SD], and coefficient of 
variation [CV], minimum, median, and maximum) will be used to summarize breast milk and 
plasma concentration data at each planned sampling time point for each analyte in breast milk 
and plasma. The midpoint time for breast milk expressions will be used as the milk sampling 
time. Breast milk and plasma PK parameters calculated from the concentrations and actual 
times will be summarized by analyte using descriptive statistics (including geometric mean and 
geometric CV). Individual and mean breast milk and plasma concentration-time profiles for 
viloxazine and 5-HVLX-gluc will be presented graphically on linear and semi-logarithmic scales. 
All PK parameters will be derived using a non-compartmental analysis method. 
Sample Size Determination 
The sample size selected is not based on statistical power considerations. Up to 15 healthy 
lactating women volunteers will be enrolled in the study, with the expectation that 12 subjects 
will complete the study. A sample size of 12 subjects is considered sufficient to achieve the 
primary objective of this study. 
Safety Analysis:  
AEs coded by system organ class and preferred term will be listed and summarized. Vital signs, 
ECG, C-SSRS, physical examination and clinical laboratory values will be summarized and 
listed with abnormal values flagged.  


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TABLE OF CONTENTS 
 
TITLE PAGE ....................................................................................................................................1 
SUPERNUS PHARMACEUTICALS, INC. PROTOCOL APPROVAL PAGE ...............................3 
Endpoints ....................................................................................................................................4 
LIST OF ABBREVIATIONS .......................................................................................................... 15 
1 
INTRODUCTION .................................................................................................................... 16 
1.1 
Background ................................................................................................................... 16 
1.2 
Clinical Information ....................................................................................................... 16 
1.2.1 
Phase 1 Studies ............................................................................................................... 16 
1.2.2 
Phase 2 Studies ............................................................................................................... 18 
1.2.3 
Phase 3 Studies ............................................................................................................... 18 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................ 19 
2.1 
Study Objectives ........................................................................................................... 19 
2.1.1 
Primary Objective ............................................................................................................. 19 
2.1.2 
Secondary Objectives ...................................................................................................... 19 
2.1.3 
Safety Objective: .............................................................................................................. 19 
2.2 
Study Endpoints ............................................................................................................ 19 
2.2.1 
Primary Endpoints ............................................................................................................ 19 
2.2.2 
Secondary Endpoints ....................................................................................................... 19 
2.2.3 
Safety Endpoints: ............................................................................................................. 19 
3 
STUDY DESIGN ..................................................................................................................... 20 
3.1 
Overall Study Design and Plan .................................................................................... 20 
3.2 
Rationale of Study Design ........................................................................................... 21 
4 
STUDY POPULATION ........................................................................................................... 22 
4.1 
Number of Subjects ...................................................................................................... 22 
4.2 
Inclusion Criteria ........................................................................................................... 22 
4.3 
Exclusion Criteria .......................................................................................................... 23 
4.4 
Subject Withdrawal ....................................................................................................... 24 
5 
STUDY TREATMENT ............................................................................................................ 26 
5.1 
Study Medication Identity, Packaging, and Labeling ............................................... 26 
5.2 
Treatment Assignment and Administration ............................................................... 26 
5.3 
Blinding .......................................................................................................................... 26 


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5.4 
Study Medication Handling and Accountability ........................................................ 26 
5.5 
Prior and Concomitant Medications ........................................................................... 26 
6 
STUDY SCHEDULE AND PROCEDURES ........................................................................... 28 
6.1 
Study Schedule ............................................................................................................. 28 
6.1.1 
Screening Period (Study Days -28 to -1) ...................................................................... 28 
6.1.2 
Inpatient Admission (Study Day -1) ............................................................................... 28 
6.1.3 
Treatment Period (Study Days 1, 2, and 3) .................................................................. 28 
6.1.4 
Inpatient Discharge (Study Day 4); End of Study (EOS)/Early Termination (ET) .. 28 
6.1.5 
Follow-up Phone Call (FPC) ........................................................................................... 28 
6.1.6 
Repeat Safety Assessments (Unscheduled Visits) ..................................................... 28 
6.2 
Study Procedures ......................................................................................................... 30 
6.2.1 
Screening Period (Study Day -28 to Study Day -1) .................................................... 30 
6.2.2 
Inpatient Admission (Study Day-1) ................................................................................ 30 
6.2.3 
Treatment Period (Study Days 1 to 3; Inpatient) ......................................................... 31 
 
Study Days 1 and 2 ......................................................................................................... 31 
 
Study Day 3 ..................................................................................................................... 31 
6.2.4 
Inpatient Discharge (Study Day 4); EOS/ET ................................................................ 31 
6.2.5 
Follow-up Phone Call (Study Day 11 [±2 days]) .......................................................... 31 
6.3 
Study Restrictions ........................................................................................................ 32 
6.3.1 
Meals and Water Consumption ...................................................................................... 32 
6.3.2 
Physical Activity Restrictions .......................................................................................... 32 
6.3.3 
Prohibitions ........................................................................................................................ 32 
7 
STUDY ASSESSMENTS ....................................................................................................... 33 
7.1 
Baseline Characteristics .............................................................................................. 33 
7.2 
Pharmacokinetic Assessments ................................................................................... 33 
7.2.1 
Pharmacokinetic Sample Collection .............................................................................. 33 
 
Breast Milk ....................................................................................................................... 33 
 
Blood ............................................................................................................................... 33 
7.2.2 
Drug Concentration Measurements .............................................................................. 34 
7.2.3 
Pharmacokinetic Parameters ......................................................................................... 34 
7.3 
Pharmacodynamic Assessments ................................................................................ 36 
7.4 
Safety Assessment ....................................................................................................... 36 
7.4.1 
Clinical Laboratory Measurements ................................................................................ 36 


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7.4.2 
Vital Signs .......................................................................................................................... 37 
7.4.3 
Physical Examinations ..................................................................................................... 37 
7.4.4 
Clinical Breast Examination ............................................................................................ 37 
7.4.5 
Electrocardiograms (ECGs) ............................................................................................ 37 
7.4.6 
Prospective Assessment of Suicidality via C-SSRS ................................................... 38 
 
C-SSRS findings ............................................................................................................. 38 
7.4.7 
Adverse Event ................................................................................................................... 39 
 
Causality .......................................................................................................................... 39 
 
Recording and Evaluation of Adverse Events ................................................................. 39 
 
Criteria for Assessing Severity ........................................................................................ 40 
 
Criteria for Assessing Causality ...................................................................................... 40 
 
Serious Adverse Events (SAE) ....................................................................................... 41 
7.5 
Screening Scales and Assessment Tools.................................................................. 41 
7.5.1 
Edinburgh Postnatal Depression Scale (EPDS) .......................................................... 41 
8 
STATISTICAL METHODS ..................................................................................................... 43 
8.1 
Statistical and Analytical Plans ................................................................................... 43 
8.1.1 
Analysis Populations ........................................................................................................ 43 
8.1.2 
Demographics/Baseline Analysis .................................................................................. 43 
 
Protocol Deviations ......................................................................................................... 43 
 
Study Medication ............................................................................................................. 43 
 
Prior and Concomitant Medications ................................................................................ 43 
8.1.3 
Pharmacokinetics Analysis ............................................................................................. 44 
 
Pharmacokinetic Concentrations .................................................................................... 44 
 
Pharmacokinetic Parameters .......................................................................................... 44 
8.1.4 
Efficacy Analysis ............................................................................................................... 44 
8.1.5 
Safety Analysis ................................................................................................................. 44 
 
Adverse Events ............................................................................................................... 45 
 
Laboratory Values ........................................................................................................... 45 
 
Vital Signs, Physical Examination, and Clinical Breast Examination .............................. 45 
 
ECG Results .................................................................................................................... 45 
 
Prospective Suicidality Monitoring (C-SSRS) ................................................................. 45 
8.2 
Sample Size and Power Considerations .................................................................... 46 
8.3 
Interim Analyses ........................................................................................................... 46 
9 
REPORTING OF ADVERSE EVENTS .................................................................................. 47 


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9.1 
Investigator Responsibilities for Reporting SAEs .................................................... 47 
9.2 
Other Events Requiring Immediate Reporting .......................................................... 47 
9.3 
Sponsor Responsibilities for Expedited Reporting of SAEs ................................... 47 
10 DOCUMENTATION ................................................................................................................ 49 
10.1 
Adherence to the Protocol ........................................................................................... 49 
10.2 
Changes to the Protocol .............................................................................................. 49 
10.3 
Protocol Deviations ...................................................................................................... 49 
10.4 
Data Quality Assurance ................................................................................................ 50 
10.4.1 
Data Collection ................................................................................................................. 50 
10.4.2 
Clinical Data Management .............................................................................................. 50 
10.4.3 
Database Quality Assurance .......................................................................................... 50 
10.4.4 
Bioanalytical Sample Handling ....................................................................................... 50 
10.5 
Retention of Records .................................................................................................... 51 
10.6 
Auditing Procedures ..................................................................................................... 51 
10.7 
Publication of Results .................................................................................................. 51 
10.8 
Financing and Insurance .............................................................................................. 51 
10.9 
Disclosure and Confidentiality .................................................................................... 52 
10.10 Discontinuation of Study ............................................................................................. 52 
11 Final Report ........................................................................................................................... 53 
12 ETHICS ................................................................................................................................... 54 
12.1 
Institutional Review Boards / Independent Ethics Committees .............................. 54 
12.2 
Ethical Conduct of the Study ....................................................................................... 54 
12.3 
Investigators and Study Personnel............................................................................. 54 
12.4 
Subject Information and Consent ............................................................................... 55 
13 REFERENCES ....................................................................................................................... 56 
14 APPENDIX ............................................................................................................................. 57 
14.1 
Screening/Safety Assessment Scales ........................................................................ 57 
14.1.1 
EDINBURGH POSTNATAL DEPRESSION SCALE (EPDS) .................................... 58 
14.1.2 
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) ................................ 59 
 C-SSRS “Baseline/Screening” Version ........................................................................... 59 
 C-SSRS “Since Last Visit” version .................................................................................. 62 


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LIST OF TABLES AND FIGURES 
Table 1: 
Schedule of Events and Assessments .............................................................................. 29 
Table 2.  
Pharmacokinetic Parameter for Plasma/Breast Milk ...................................................... 35 
Table 3: 
Clinical Laboratory Tests ..................................................................................................... 36 
  
Figure 1:  Study Schematic ..................................................................................................................... 21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
5-HVLX-gluc 
5-hydroxy-viloxaine glucuronide, the major metabolite of viloxazine 
ADHD 
Attention-Deficit Hyperactivity Disorder 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BLQ 
Below the Lower Limit of Quantification 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
EPDS 
Edinburgh Postnatal Depression Scale 
EOS 
End of Study 
ER 
Extended-Release 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IR 
Immediate Release 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetics 
PR 
Interval between the P and R waves on the electrocardiogram tracing
QD 
Once Daily 
QT 
Interval between the Q and T waves on the electrocardiogram tracing
QTc 
Corrected value of the interval between the Q and T waves on the 
QTcF 
QT interval corrected using Fridericia's method 
RR 
Interval between successive R waves on the electrocardiogram  
SADR 
Suspected Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SD 
Standard deviation  
SOP 
Standard Operating Procedure 
SM 
Study Medication 
RR 
Respiratory Rate 
TEAE 
Treatment Emergent Adverse Event 
NOTE: Pharmacokinetic parameters are defined in Section 7.2.3 


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1 
INTRODUCTION 
To distinguish between data in the public domain and that generated by Supernus, historical data 
will be associated with the term “viloxazine” and data generated by Supernus will be associated 
with the term “SPN-809V [IR], SPN-812, SPN-812 IR, or SPN-812 ER.  
1.1 
Background 
SPN-812 (viloxazine extended-release capsules; QELBREE®) is a structurally distinct, bicyclic, 
norepinephrine reuptake inhibitor. The active substance in SPN-812 is viloxazine, whose 
mechanism of action is multimodal with antagonistic activity observed at 5-HT2B and agonistic 
activity at 5-HT2C receptors, as well as weaker antagonistic effects at ADRα1B, ADRβ2 and 5-
HT7 receptors. Additionally, SPN-812 acts as a modulator with inhibitory effects at the 
norepinephrine reuptake transporter. Viloxazine was previously marketed in several European 
countries as an antidepressant as an immediate-release (IR) product. An extended-release (ER) 
formulation of viloxazine, SPN-812, has been developed by Supernus to prolong the release and 
absorption of viloxazine post-administration, thereby allowing longer dosing intervals for a drug 
with a relatively short half-life. As of April 2022, SPN-812 (QELBREE PI) is FDA-approved for the 
treatment of ADHD in persons 6 years of age and older based on clinical trials described below.   
1.2 
 Clinical Information 
Thirteen Phase 1 studies in adults, one Phase 2 and one Phase 3 studies in adults with ADHD, 
one Phase 2 in children with ADHD and four Phase 3 studies in children and adolescents with 
ADHD have been conducted with SPN-812. Data collection in two open-label extension studies 
evaluating long-term safety and efficacy of SPN-812 in ADHD patients, one inchildren and 
adolescents (6 to 17 years of age) with ADHD and one in adults (18-65 years of age) with ADHD, 
has concluded; final results are pending.  
1.2.1 Phase 1 Studies 
Phase 1 studies include comparison of various ER formulations to an equivalent daily dose of IR 
viloxazine (812P101), comparison of single- and two-bead SPN-812 ER formulations to an IR 
formulation at single and multiple doses (812P102 and 812P103, respectively), an evaluation of 
maximum tolerable doses in a single- and multiple-ascending dose study (812P120), as well as 
an evaluation of food and sprinkling effects (812P105) and alcohol (812P115). In addition, a 
[14C]-labelled oral solution was used to examine absorption, metabolism, and excretion 
(812P111). Drug-drug interaction of SPN-812 on cytochrome P450 (CYP) 1A2, 2D6, and 3A4 
isoenzymes was evaluated in study 812P113.1. Drug-drug interaction studies with stimulants 
were performed with d-amphetamine and methylphenidate in the 812P113.2 and 812P113.3 
studies, respectively. A study evaluating the DDI potential of paroxetine (strong inhibitor of 
CYP2D6) as a perpetrator of SPN-812 metabolism (812P113.4) was conducted. The effect of a 
multiple supratherapeutic dose of SPN-812 on QT interval has also been evaluated (812P117). 
Further, the effect of renal and hepatic impairment on the pharmacokinetics (PK) of SPN-812 has 
also been evaluated in 812P112.1 and 812P112.2, respectively. 
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 


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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 PK parameters was observed following multiple 
administration of SPN-812 compared to single dose administration, during the same time interval.  
Food and sprinkling did not affect the relative bioavailability of viloxazine following administration 
of SPN-812 capsules (812P105). SPN-812 interacted as a strong inhibitor of CYP1A2, a weak 
inhibitor of CYP2D6, a weak inhibitor of CYP3A4; and displayed no significant differences in 
metabolism within CYP2D6 poor metabolizers and CYP2D6 extensive metabolizers (812P113.1). 
There was no DDI between SPN-812 and d-amphetamine (812P113.2) nor between SPN-812 
and methylphenidate (812P113.3). There was no clinically relevant impact of paroxetine on SPN-
812 (812P113.4). 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). Hepatic impairment (HI) resulted in 
approximately 21% increase and up to 6% decrease in AUC of viloxazine for mild and moderate 
HI subject receiving SPN-812 400mg compared to matched healthy subjects; severe HI subjects 
receiving 200mg of SPN-812 had a 25% increase in AUC of viloxazine compared to matched 
healthy subjects (812P112.2). Multiple doses of 1800 mg (supra-therapeutic) 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 (812P120), SPN-
812 was well tolerated up to 2100 mg/day as a single dose and up to 1800 mg/day as multiple 
doses given once daily for 5 consecutive days. Intolerable adverse events (AEs) were not 
observed at doses of up to 1800 mg/day. SPN-812 at a single supratherapeutic dose had no 
effect on cardiac repolarization or other electrocardiographic parameters, other than slight 
increase in heart rate consistent with the known anticholinergic effect of viloxazine (812P120).  
In the human absorption, metabolism, and excretion study (812P111), 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 5-hydroxyviloxazine-glucuronide (5-HVLX-gluc).   
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. 


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1.2.2 Phase 2 Studies 
Study 812P201, conducted in adults with ADHD using an earlier, IR formulation of viloxazine, was 
a randomized, blinded, proof-of-concept study. Subjects received either placebo or IR formulation 
of viloxazine three times a day in a dose range of 150 to 300 mg/day (26 subjects per treatment). 
The most common AEs the treatment group were nausea, decreased appetite, headache, and 
insomnia. No serious adverse events (SAEs) or deaths occurred during the study. 
In the Phase 2 dose finding study, 812P202, children 6-12 years old with ADHD were randomized 
in a 1:2:2:2:2 ratio to received placebo or 100, 200, 300, or 400 mg SPN-812 ER once daily for 
5-8 weeks (titration and 5 weeks of maintenance). SPN-812 ER at 200-400 mg was shown to be 
efficacious on the primary objective, reduction of ADHD-RS-IV Total Score. All doses of SPN-812 
were well tolerated with no serious or severe AEs. 
1.2.3 Phase 3 Studies 
Four pediatric pivotal Phase 3, randomized, double-blind, placebo-controlled, multicenter, 3-arm, 
parallel-group clinical trials evaluating the efficacy and safety of SPN-812 for the treatment of 
ADHD in children and adolescents have been conducted, including two clinical trials in children 6 
to 11 years of age with ADHD (Studies 812P301 and 812P303; evaluated 100 mg, 200 mg, and 
400 mg) and two clinical trials in adolescents 12 to 17 years of age with ADHD (Studies 812P302 
and 812P304; evaluated 200 mg, 400 mg, and 600 mg). In April 2021, the Food and Drug 
Administration (FDA) approved SPN-812 (Qelbree®; viloxazine extended-release capsules) 100-
400mg for the treatment of ADHD in pediatric patients 6 to 17 years of age. The most common 
adverse events (100-400mg) for were somnolence, decreased appetite, fatigue, nausea, 
vomiting, insomnia, and irritability.  
A single pivotal Phase 3, randomized, double-blind, placebo-controlled, multicenter, 2-arm, 
parallel-group clinical trial evaluating the efficacy and safety of SPN-812 (200-600mg) for the 
treatment of ADHD in adults 18 to 65 years of age with ADHD (Study 812P306) was also 
conducted. Subjects were randomized in a 1:1 ratio to placebo or SPN-812 (200 to 600mg/day) 
for a total of 6 weeks of treatment. In total, 374 subjects were randomized and 372 subjects were 
treated: 183 subjects with placebo and 189 subjects with SPN-812. SPN-812 was well tolerated 
in all dose levels, with no deaths, and 2 SAEs were reported in 2 subjects receiving placebo 
(cardiac failure congestive and pancreatitis), and no SAE occurred in any subject receiving SPN-
812. No safety concerns were identified in this study. The most frequently reported treatment-
emergent adverse events (≥5%) were insomnia, nausea, dry mouth, constipation, headache, 
fatigue and decreased appetite. 
As of July 2022, data collection in two open-label extension studies evaluating the long-term 
safety and efficacy of SPN-812 has concluded, including one in children and adolescents (6 to 17 
years of age) with ADHD (Study 812P310) and one in adults (18 to 65 years of age) with ADHD 
(Study 812P311); final results for both are pending. 
Information and data from clinical studies are available in greater detail in the current SPN-812 
Investigator Brochure. 
 
 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 Primary Objective 
 
To evaluate the pharmacokinetics (PK) of viloxazine and its major metabolite 5-hydroxy-
viloxazine glucuronide (5-HVLX-gluc) in breast milk in healthy lactating women following 
multiple oral doses of SPN-812. 
2.1.2 Secondary Objectives 
 
To evaluate the PK of viloxazine and 5-HVLX-gluc in plasma in healthy lactating women 
following multiple oral doses of SPN-812. 
 
To evaluate the overall exposure between breast milk and plasma in healthy lactating 
women following multiple oral doses of SPN-812. 
 
To estimate daily infant dose of SPN-812 via breast milk. 
2.1.3 Safety Objective: 
 
To evaluate the safety and tolerability of multiple doses of SPN-812 in healthy lactating 
women. 
2.2 
Study Endpoints 
2.2.1 Primary Endpoints 
Breast milk PK parameters when SPN-812 reaches plasma steady-state: 
 
AUCtau,milk, Cmax,milk, Tmax,milk, Ctrough,milk, Cave,milk for viloxazine and 5-HVLX-gluc  
 
Total amount of drug in breast milk (Ammilk, mg/day) over a period of 24 hours for viloxazine 
and 5-HVLX-gluc  
2.2.2 Secondary Endpoints 
 
Plasma AUCtau,ss, Cmax,ss, Tmax,ss, CL/Fss, Cave,ss and Ctrough,ss for viloxazine and 5-HVLX-
gluc at plasma steady-state, if applicable 
 
Breast milk-plasma ratio (ML/PL) based on AUC over 24 hours for viloxazine and 5-HVLX-
gluc at plasma steady-state 
 
Estimated daily infant dosage (EDID, mg/kg/day) and relative infant dose (RID, %) at 
plasma steady-state (Table 2) 
2.2.3 Safety Endpoints: 
 
Adverse Events (AEs) 
 
Clinical laboratory test results (clinical chemistry, hematology and urinalysis) 
 
12-lead Electrocardiogram (ECG) 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Vital signs 
 
Physical examination 
 
Concomitant medications 


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3 
STUDY DESIGN 
3.1 
Overall Study Design and Plan 
This is an open label, single treatment, lactation study of SPN-812 in healthy lactating women. 
The study is designed to assess the excretion of viloxazine and its major metabolite 5-HVLX-gluc 
into breast milk following repeated administration of SPN-812 600 mg, QD.  
This study is comprised of Screening, Inpatient Admission, Treatment Period and End of Study 
(EOS). The total duration of the study is up to 1 month including Screening up to 28 days and 4 
days of Treatment Period. Subjects will remain in the inpatient unit for 5 days, including the day 
of admission to the inpatient unit (Day -1), 3 days of dosing SM (Days 1-3), and the day of 
discharge (Day 4). 
Subjects will be screened within 28 days prior to dosing. After informed consent is obtained, 
information from subjects will be collected (including maternal-related information) and subjects 
will undergo screening evaluations (see Table 1). Inclusion/exclusion criteria will be reviewed to 
determine the subject’s eligibility at Screening. A lactation consultant will be available to provide 
lactation support to subjects once they are enrolled.  
Subjects will be admitted to inpatient unit on Day -1 to confirm eligibility. Subjects will receive 600 
mg SPN-812 on the morning of Days 1, 2 and 3 after completion of safety assessments. SM 
should be administered at the same time in the morning (±30 min) of dosing days. Breast milk 
and blood sample for PK analysis will then be collected on Day 3 per schedule in Section 7.2.1.1 
and Section 7.2.1.2, respectively. Non-PK breast milk expressed on Days -1, 1, and 2 will be 
collected over the time intervals in Section 7.2.1.1, and these samples will not be analyzed for 
drug concentrations. The volume and the start and end times of the collection of each non-PK 
and PK breast milk sample will be recorded. The end of study (EOS) procedures will be conducted 
prior to discharge on Day 4 following the last breast milk and blood sample collection. If subject 
discontinues early, all EOS procedures will be conducted. Study schematic is shown in Figure 1, 
and Schedule of Events and Procedures is presented in Table 1. 


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Figure 1:  Study Schematic 
 
 
3.2 
Rationale of Study Design 
SPN-812, an extended-release oral capsule formulation of viloxazine, has been approved for the 
treatment of ADHD in pediatric patients 6 to 17 years of age. A Phase 3 clinical trial for the 
treatment of ADHD in adults has been completed and is under FDA review. Per FDA request, a 
post-marketing lactation study needs to be conducted “in lactating women who have received 
therapeutic doses of viloxazine extended-release capsules to assess concentrations of viloxazine 
in breast milk”. This study will be conducted in healthy lactating women, and drug concentration 
in breast milk and estimated infant dose via breastfeeding will be assessed following the FDA 
guidance (FDA guidance for clinical lactation studies, May 2019); the mother-infant pair will not 
be enrolled in this study, since there is no information available about the extent of drug transfer 
into breast milk, including evidence that the drug accumulates in breast milk and if the drug is 
likely to be absorbed by the breastfed infant. In this study, a multiple-dose design will be used 
since SPN-812 is administered chronically to treat patients with ADHD. The plasma steady-state 
will be reached after two days of once-daily administration without obvious accumulation 
(QELBREE PI). In this study, the dose of SPN-812 will not be titrated up in incremental doses 
since a previous multiple ascending dose study of up to 2100 mg/day SPN-812 (812P120) has 
been conducted and no safety concerns were reported. The dose to be administered in the study, 
600 mg SPN-812 once daily, is the highest dose administered in pivotal Phase 3 studies 
conducted/completed in adolescents (812P304) and adults (812P306) with ADHD.  
 
 


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4 
STUDY POPULATION 
4.1 
 Number of Subjects 
Up to 15 healthy, lactating women will be enrolled in the study. 
4.2 
Inclusion Criteria   
1. Healthy lactating females, 18 to 45 years of age, who are actively breastfeeding (including 
baby to breast, bottle feeding mother's expressed breast milk) and are at least 12 weeks 
postpartum of a healthy term newborn infant (no medical complications) and not more than 
2 years postpartum. Lactation must be well established and the mother is exclusively breast 
feeding her baby (not providing supplemental formula) prior to the day of admission to 
inpatient unit. 
2. Has a body mass index between 18 to 35 kg/m2, included. 
3. Is considered medically healthy by the Investigator via assessment of physical examination 
(neurological examinations included), medical history, clinical laboratory tests, vital signs, 
Columbia-Suicide Severity Rating Scale (C-SSRS) and electrocardiogram (ECG).  
4. Is willing to temporarily discontinue breastfeeding their infant and discard all their breast 
milk for 7 consecutive days, including (day of admission to inpatient unit (Day -1), 3 
consecutive days of dosing SM while in the inpatient unit (Days 1 to 3), and 3 consecutive 
days after last dose of SM (including the day of discharge from the inpatient unit and 2 days 
at home; Days 4 to 6); and willing to store sufficient amount of breastmilk (e.g., breast milk 
pumped and stored in freezer before the day of admission), and/or infant formula to feed 
infant during these 7 consecutive days. 
5. Is either sexually inactive (abstinent) or, if sexually active, must agree to use/practice one 
of the following acceptable birth control methods beginning during the screening period 
prior to the first dose of SM, throughout the inpatient stay, and for 3 days following the last 
dose of SM (Day 3):  
 
intra-uterine contraceptive device;  
 
barrier method: condom with spermicidal foam/gel/film/cream/suppository or 
occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository; 
 
is surgically sterile or male partner is surgically sterile; 
 
established use of a patch, vaginal ring, oral, injected or implanted hormonal 
methods of contraception that can be used in lactating women;  
 
Essure® procedure performed at least 6 months prior to Screening and had 
hysterosalpingogram after the Essure procedure to document tubal occlusion prior 
to screening. 
6. Must not be in the process of weaning before admission to inpatient unit and have 
maintained an adequate breast milk supply with regularly pumping or routine breastfeeding 
(e.g., pumping or feeding 3-4 times a day) at admission. 


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7. Is currently a non-smoker who has not used tobacco or nicotine-containing products 
(chewed or smoked) or replacement products, including electronic cigarettes, within 3 
months prior to screening and a negative cotinine test result at Screening. 
8. Agrees to use only the emollient or nipple cream recommended by the investigator for use 
during the sampling period, if needed. 
9. Able to voluntarily provide written informed consent to participate in the study. 
10. Able to understand and willing to comply with all study requirements. 
11. Able and willing to swallow capsules whole, without crushing, chewing or cutting. 
4.3 
Exclusion Criteria 
1. Participation in any other investigational study drug trial in which receipt of an 
investigational study drug within 30 days or 5 half-lives before Screening, whichever is 
longer. 
2. Is unwilling or unable to comply with the Lifestyle guidelines presented in the protocol during 
the study period. 
3. Has history or presence of clinically significant systemic disease (including psychological 
and psychiatric disorders). 
4. Is currently using, or tests positive at Screening for cotinine, alcohol or drugs (opiates, 
methadone, 
cocaine, 
amphetamines 
[including 
ecstasy], 
barbiturates, 
PCP, 
benzodiazepines, and THC/cannabis). 
5. Is pregnant (has positive serum pregnancy test at Screening) or becomes pregnant during 
study (has positive urine pregnancy test).   
6. Has history of breast implants, breast augmentation, or breast reduction surgery.  
7. Has history of mastitis within 30 days, breast cancer and/or has had a mastectomy or 
lumpectomy with the exception of a benign fibroma or lipoma removal at the investigator’s 
discretion; and/or a clinically significant abnormality observed in either breast during a 
clinical breast exam at Screening or Admission (Day -1). 
8. Has a history of alcohol use disorder within 1 year of Screening; or assessed by the PI as 
having regularly consumed alcohol exceeding 14 units per week (1 unit equals 340 mL of 
beer, 115 mL of wine, or 43 mL of spirits) within 1 year of Screening. 
9. Is using recreational or illicit drug(s) (e.g., cannabis /tetrahydrocannabinol (THC), opiates, 
methadone, cocaine, amphetamines [including ecstasy], barbiturates, benzodiazepines) 
within 1 year of Screening. 
10. Has clinically significant vital sign abnormalities (systolic blood pressure less than 90 or 
greater than 140 mmHg, diastolic blood pressure less than 60 or greater than 90 mmHg, or 
pulse rate (PR) less than 50 or greater than 100 bpm at Screening.  


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11. Has a clinical laboratory test values outside the reference range at Screening that, in the 
opinion of the investigator, are clinically significant, or any of the following: 
 Serum creatinine >1.5 times the upper limit of normal (ULN) 
 Serum total bilirubin >1.5 times ULN 
 Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times 
ULN 
12. Has a clinically significant ECG abnormalities at Screening, including:  
 PR interval >220 ms 
 QRS interval >130 ms 
 QTcF interval >470 ms  
13. Has any disease or medication that could, in the investigator's opinion, interfere with the 
assessments of safety, tolerability, or interfere with the conduct or interpretation of the 
study. 
14. Has evidence of infection with hepatitis B and C, and human immunodeficiency virus HIV-
1 and HIV-2, as determined by results of testing at Screening. 
15. Has a condition or planned procedure that may interfere with the absorption, metabolism, 
or elimination of the study drug (e.g., cholecystectomy).  
16. Is using prescription medication within 14 days prior to administration of SM or 5 half-lives, 
whichever is longer, with the exception of hormonal contraceptives. 
17. Is using -over-the-counter products (including vitamins, herbal products and natural food 
supplements) within 14 days prior to administration of SM or 5 half-lives, whichever is 
longer. Exceptions include postnatal vitamins, topical products without systemic absorption 
and acetaminophen (< 2 g/day). 
18. Has an allergy to viloxazine. 
19. Has an Edinburgh Postnatal Depression Scale score >13. 
20. 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 12 months prior to screening). 
21. In the investigator's opinion, is unlikely to comply with the protocol or is unsuitable for any 
other reason. 
4.4 Subject Withdrawal 
A subject is free to withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the physician or at the institution. Subjects who withdraw from the 
study will undergo the EOS procedures prior to exit from the unit. The primary reason for 
withdrawal will be recorded. If a subject is withdrawn for more than one reason, each reason will 
be documented. Subjects who discontinue due to an AE will be followed until resolution of the AE 


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or until, in the medical judgment of the Principal/Site Investigator, the event has stabilized or 
resolved. A subject removed from the study for any reason will not be replaced. 
Subject withdrawal will be done in accordance with the clinical site’s SOP. Over the course of the 
study, the Sponsor and the Principal/Site Investigator or designee may withdraw any subject from 
the study for reasons including but not limited to the following: 
 
Safety reason 
 
Non-compliance with protocol requirements 
 
Significant protocol deviation 
Withdrawal of subjects experiencing emesis should be considered on a case-by-case basis. PK 
samples collected from the subject withdrawn will be analyzed.  
 


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5 
STUDY TREATMENT 
5.1 
Study Medication Identity, Packaging, and Labeling 
Study medication, SPN-812 (QELBREE®, viloxazine extended-release capsule), will be provided 
at a strength of 200 mg. The 200 mg capsule is formulated to deliver viloxazine hydrochloride in 
the quantity of 200 mg viloxazine freebase.  
5.2 
Treatment Assignment and Administration 
Each subject will receive 600 mg (3 x 200 mg) SPN-812 capsules. SM will be orally administered 
to subjects in the morning with water and with or without food. Subject will receive SPN-812 
capsules at approximately the same time each day (Day 1, 2, and 3). 
5.3 
Blinding 
Not applicable as this is an open-label study. 
5.4 
Study Medication Handling and Accountability 
All SM will be supplied to the Investigator by the Sponsor. SM supplies must be kept in an 
appropriate secure area (e.g., locked cabinet) and stored according to the conditions specified on 
the SM labels. Following Sponsor instructions and in compliance with 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 will be collected by the Sponsor at the end of the 
study.  
Under no circumstances will the Investigator allow the SM to be used in a manner other than as 
directed by this protocol. Clinical supplies will not be dispensed to any individual who is not 
enrolled in the study. An accurate and timely record of the receipt of all clinical supplies; 
dispensing of SM to the subject; collection of unused supplies; and subsequent return of unused 
SM to the Sponsor must be maintained with dates. This SM accountability log includes, but may 
not be limited to: (a) documentation of receipt of clinical supplies, (b) SM inventory log, (c) SM 
accountability log, and (d) all shipping service receipts.  Forms may be provided by the Sponsor.   
Any comparable forms that the study site wishes to use must be approved by the Sponsor. 
The supplies and inventory records must be made available, upon request, for inspection by the 
designated representative of the Sponsor, or a representative of the FDA. The assigned CRA will 
review these documents along with all other study conduct documents at specified intervals once 
SM has been received by the study site.  All used, partly used, and unused clinical supplies, 
including empty containers, are to be returned to the Sponsor at the conclusion of the study, 
unless provision is made by the Sponsor for destruction of supplies and containers at the study 
site.   
5.5 
Prior and Concomitant Medications  
Prior medications are defined as those taken up to 30 days prior to dosing and concomitant 
medications are those starting or ongoing while the subject is on study drug. All prior and 


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concomitant medications will be recorded in the document source. No concomitant medications 
except for the following will be allowed during the study: 
 
Hormonal birth control or hormone replacement 
 
Medical management of an AE (e.g., acetaminophen, ≤2 g/day)  
 
Postnatal vitamins 
 
Topical products without significant systemic absorption 
The use of any concomitant medication, including acetaminophen, will be evaluated on a case-
by-case basis by the Investigator and Medical Monitor. 
 
 


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for the purpose of reviewing or performing this study. 
6 
STUDY SCHEDULE AND PROCEDURES 
6.1 
Study Schedule 
The study consists of Screening, Inpatient Admission, Treatment and End of Study (EOS). All 
subjects who consent to be in this study are required to follow the study protocol events and 
procedures as described in Table 1. Blood/breast milk sample collections and safety variables 
are described in detail in Section 7.2.1 and Section 7.4, respectively. 
6.1.1 Screening Period (Study Days -28 to -1) 
Subjects will complete the screening visit, after informed consent is obtained, within 28 days prior 
to dose initiation. Since the mother’s infant cannot receive breast milk for 7 consecutive days (Day 
-1 to Day 6), the mother will be reminded at Screening to make plans to have their infant fed 7 
consecutive days with either (a) formula or (b) stored breast milk (e.g., breast milk pumped and 
stored in freezer during screening period between screening visit and day of admission to 
inpatient unit). 
6.1.2 Inpatient Admission (Study Day -1) 
Subjects will be admitted to the inpatient unit on Day -1 to confirm eligibility. A subject must meet 
all of the Inclusion Criteria and none of the Exclusion Criteria to remain eligible for enrollment in 
the study. Non-PK breast milk samples will be collected according to the schedule described in 
Section 7.2.1.1. Subject will remain in the inpatient unit for 5 consecutive days, including day of 
admission to inpatient unit (Day -1), 3 days of dosing SM (Days 1 to 3) and day of discharge from 
inpatient unit (Day 4).  
6.1.3 Treatment Period (Study Days 1, 2, and 3) 
All eligible subjects will receive 600 mg SPN-812 on Days 1, 2, and 3. Subjects will remain in the 
inpatient unit during this time. The Treatment Period includes collections of blood and breast milk 
samples, according to the schedule described in Section 7.2.1.1 and Section 7.2.1.2. 
6.1.4 Inpatient Discharge (Study Day 4); End of Study (EOS)/Early Termination (ET) 
EOS procedures will be completed and subject will be discharged from the inpatient unit on Day 
4, 24 hours after the final dose has been administered and the breast milk and plasma PK 
sampling is completed (Section 6.2.4), or if the subject is discontinued during the inpatient before 
Day 4. 
6.1.5 Follow-up Phone Call (FPC) 
Subjects will be contacted via telephone 7 (± 2) days after discharge or final dose of SM for safety 
follow-up. 
6.1.6 Repeat Safety Assessments (Unscheduled Visits) 
At discretion of investigator, repeat assessments, including ECG, measure vital signs/weight, 
draw blood sample for hematology and/or serum chemistry and/or urine for urinalysis/drug screen, 
administer C-SSRS (Since Last Visit version), physical examination can be performed before, 
during and after inpatient study. AEs and concomitant medications should also be assessed at all 
unscheduled visits. The investigator should notify the medical monitor that they are planning to 
perform or have performed one of the above assessments again and provide the reason/rationale 
for repeating one of these assessments. 




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6.2 
Study Procedures 
6.2.1 Screening Period (Study Day -28 to Study Day -1) 
A voluntary, written study-specific informed consent will be obtained from the participant before 
enrollment and before any study-related procedures are performed. The following procedures will 
be performed during Screening on subjects choosing to participate in this study and may be 
performed on more than one day. Abnormal results on screening laboratory tests and vital signs 
may be repeated at the discretion of the Investigator.  
 
Obtain written Informed Consent 
 
Confirm Inclusion/Exclusion criteria 
 
Obtain the participant’s demography (including date of birth, sex, race, and ethnicity) 
 
Obtain medical history 
 
Obtain psychiatric history (including the Edinburgh Postnatal Depression Scale) 
 
Obtain maternal-related information/history (gestational age at delivery, stage of lactation, 
and length of time postpartum) 
 
Record concomitant medications  
 
Measure and record vital signs and weight 
 
Measure and record height (calculate baseline BMI) 
 
Perform physical examination  
 
Perform clinical breast examination (see Section 7.4.4) 
 
Administer C-SSRS (Baseline/Screening version) 
 
Perform 12-lead ECG 
 
Collect blood sample for: 
o Serum chemistry and hematology 
o Serum pregnancy test  
o Serology  
 
Collect urine sample for: 
o Urinalysis 
o Urine drug screen (including urine or breath alcohol and cotinine) 
6.2.2 Inpatient Admission (Study Day-1) 
Subjects will be admitted to the clinical study inpatient facility and will remain in the unit until 
completion of the study. The procedures that will be performed on this day are listed below: 
 
Admitted to the inpatient unit on Day – 1; begin inpatient stay  
 
Confirm eligibility status (inclusion/exclusion criteria) 
 
Administer C-SSRS (Since Last Visit version) 
 
Review/update Medical history  
 
Review concomitant medications 
 
Perform clinical breast examination 
 
Measure and record vital signs and weight 
 
Collect blood sample for: 
o Serum chemistry and hematology 
o Serum pregnancy test 
 
Collect urine sample for:  
o Urinalysis 
o Urine drug screen (including urine or breath alcohol and cotinine) 
 
Collect non-PK breast milk samples per schedule in Section 7.2.1.1  


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6.2.3 Treatment Period (Study Days 1 to 3; Inpatient) 
Treatment period is comprised of repeated doses of SPN-812 and collections of PK blood and 
breast milk samples on Day 3. The procedures to be performed are:  
 Study Days 1 and 2 
 
Measure and record vital signs and weight before morning dose  
 
Administer of 600 mg SPN-812 
 
Review concomitant medications 
 
Assess and record adverse events 
 
Collect non-PK breast milk samples per schedule in Section 7.2.1.1 
 
Collect pre-dose PK breast milk sample on Day 1  
 
Collect pre-dose PK blood sample on Day 1  
 Study Day 3  
 
Measure and record vital signs and weight before morning dose 
 
Administer 600 mg SPN-812 
 
Collect breast milk PK samples per Section 7.2.1.1 
 
Collect PK blood samples per Section 7.2.1.2 
 
Review concomitant medications 
 
Assess and record adverse events 
6.2.4 Inpatient Discharge (Study Day 4); EOS/ET  
The following procedures will be performed at study completion (EOS) or early termination (ET): 
 
Collect ‘16-24’ h post-dose breast milk sample (breast milk sample not required at ET) 
 
Collect 24-h post-dose PK blood sample (PK blood draw not required at ET) 
 
Measure and record vital signs  
 
Perform 12-lead ECG  
 
Perform physical examination and note any changes from baseline 
 
Perform clinical breast examination and note any changes from baseline  
 
Administer C-SSRS (Since Last Visit version) 
 
Collect blood sample for chemistry and hematology  
 
Collect urine sample for urinalysis and pregnancy test 
 
Assess and record adverse events 
 
Review concomitant medications 
 
Remind mother: no breast feeding, discard all breast milk for the next 2 consecutive days. 
 
Discharge from inpatient unit 
6.2.5 Follow-up Phone Call (Study Day 11 [±2 days])  
The following procedures will be performed: 
 
Assess and record adverse events 
 
Review concomitant medications 


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6.3 
Study Restrictions 
6.3.1 Meals and Water Consumption 
Subjects may consume only the food given to them while in the unit. Coffee or caffeine containing 
drinks will not be supplied.   
6.3.2 Physical Activity Restrictions 
For safety reasons, subjects will be required to remain seated or in a semi-supine position and 
avoid lying down or sleeping for the first two hours after drug administration. However, failure of 
subjects to comply with these requirements does not constitute a deviation from the protocol if it 
is medically necessary, procedurally required, or to go to the bathroom. Vigorous activity will be 
prohibited at all times during the confinement. 
Outings will be permitted at the discretion of the Principal/Site Investigator and under supervision 
by clinical site staff to ensure compliance with protocol and will be limited to the grounds 
surrounding the clinical site as per appropriate SOP. 
6.3.3 Prohibitions 
No subject may take prescription medication (other than topical products without systemic 
absorption and hormonal contraception) within 14 days of the first dose or at any time while on 
study. Herbal products, natural food supplements, and vitamins (except postnatal vitamins) will 
not be permitted within 14 days prior to the first dose until the end of the study. 
Smoking, alcohol, and illicit drugs are prohibited at any time while on study.  
Consumption of foods, beverages or products containing the following substances will be 
prohibited while on study as indicated:  
 
Alcohol-based products from 48 hours prior to the first dosing until after the last study day.  
 
Food containing poppy seeds within 24 hours prior to admission until after the last study 
day. 
 
Food or beverages containing xanthine derivatives or xanthine-related compounds (e.g. 
caffeine) or energy drinks from 72 hours prior to the first dosing until after the last study 
day. 
 
Natural health products (including herbal remedies such as homeopathic and traditional 
medicines, probiotics, food supplements such as vitamins, minerals, amino acids, 
essential fatty acids, and protein supplements used in sports) from 14 days prior to the 
first dosing until the last study day. 
 
 


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7 
STUDY ASSESSMENTS 
7.1 
Baseline Characteristics 
The following demographic parameters will be captured: date of birth, gender, race, and ethnicity. 
The following will be assessed as related to the eligibility criteria as listed in Section 4.2 and 
Section 4.3 and will include the following: 
 
Medical History 
 
Medication History (including all medications taken within 30 days before Screening) 
 
History of drug, tobacco, and alcohol use 
7.2 
Pharmacokinetic Assessments 
7.2.1 Pharmacokinetic Sample Collection 
 Breast Milk  
A total of 9 expressed PK breast milk samples will be collected for PK analysis at the following 
time intervals:  
 
Day 1: -4 to <0 hours pre-dose; 
 
Day 3: -4 to <0 hours pre-dose, and ‘0 to 4’, ‘4 to 6’, ‘6 to 8’, ‘8 to 10’, ‘10 to 12’, ‘12 to 16’ 
 
and ‘16 to 24’ hours post-dose.  
Breast milk from each breast will be emptied as thoroughly as possible at each session using an 
electric breast pump at the planned time intervals. To ensure that the pump completely removes 
milk from the breasts, double pump for no less than 10 minutes until milk flow ceases. The length 
of each expressing session should be no longer than 30 minutes.  
Non-PK breast milk samples (not to be analyzed for drug concentrations but volume will be 
recorded) will be collected at the following time intervals:  
 
Day -1: store milk as pumped per subject’s pumping routine; 
 
Day 1: 0 to 24 hours post-dose per subject’s pumping routine; 
 
Day 2: 0 to 20 hours post-dose per subject’s pumping routine. 
The type of breast pump preferred will be determined on an individual basis. Those subjects with 
their own pumps and sterilizers will be permitted to continue using these. Subjects without their 
own pumps will be provided with a breast pump by the clinic. For each breast milk collection 
period, the start and end times of the collection will be recorded, and the total volume (mL) of 
breast milk collected will be measured and recorded. 
 Blood  
A total of 13 blood draws (4 mL each) for PK will be collected on Day 1 pre-dose, Day 3 pre-dose 
and Days 3 at 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 16.0 and 24.0 hours post-dose. The 
following windows are permitted relative to the specified PK sample collection times:  
Pre-dose: - 15 minutes 
< 1 hour post-dose: ± 3 minutes 
1 to 8 hours post-dose: ± 5 minutes 
> 8 to 24 hours post-dose: ± 10 minutes 


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The actual time and date of each blood sample collection will be recorded. PK blood samples will 
be collected in blood collection tubes containing K2EDTA. As an alternative procedure to multiple 
blood draws, a catheter may be inserted into the arm to collect blood samples, if judged 
necessary. 
The maximum total volume of blood drawn during the study will be up to 110 mL. This total blood 
volume includes samples for PK, screening, Day -1, and End of Study safety labs. In addition to 
repeat tests, additional laboratory tests may be performed to ensure the safety of the subject. 
7.2.2 Drug Concentration Measurements 
Concentrations of viloxazine and 5-HVLX-gluc in plasma and breast milk will be determined using 
validated achiral chromatographic tandem mass spectrometry methods.   
7.2.3 Pharmacokinetic Parameters 
Table 2 shows the PK parameters that will be calculated based on plasma and milk concentration-
time data using standard non-compartmental methods: 






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All laboratory tests will be reviewed in a timely manner by qualified clinic personnel to ensure 
safety. Abnormal laboratory findings may be confirmed, if necessary, by one repeated testing at 
the discretion of the Investigator.  A laboratory abnormality may qualify as an AE (see Section 
7.4.7) if deemed so in the Investigator’s judgment. 
7.4.2 Vital Signs  
Vital signs’ measurements, including orthostatic blood pressure, pulse rate, oral temperature and 
respiratory rate, will be obtained at times (+/- 15 minutes) designated in the Schedule of Events 
and Assessments (Table 1). Orthostatic blood pressure and pulse rate will be measured after the 
subject has been seated for a minimum of 5 minutes and within 3 minutes of standing. Vital signs 
(resting or non-resting) may also be taken at any other time, as deemed necessary by the 
Principal/Site Investigator. 
7.4.3 Physical Examinations  
The physical examination conducted at Screening and EOS/ET will include assessments of head, 
eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen, lymph 
nodes, and musculoskeletal. Measurement of height and weight will be performed at Screening.  
Any clinically significant findings during screening will be recorded as medical history and any 
clinically significant abnormal findings during treatment will be recorded as an AE. At the EOS 
physical examination, only changes from Baseline will be noted. 
7.4.4 Clinical Breast Examination  
The clinical breast examination conducted at Screening, Baseline (day of admission to inpatient 
unit prior to first dose), and at EOS/ET, is a physical examination of each breast, including visual 
inspection of the skin and nipples, and an assessment of the underarms and collarbone area. Any 
clinically significant findings during screening and/or baseline will be recorded as medical history 
and any clinically significant abnormal findings during or after treatment (after first dose of SM) 
will be recorded as an AE. Only changes from Baseline will be noted for the clinical breast 
examination at the EOS. 
7.4.5 Electrocardiograms (ECGs) 
A single 12-lead ECG will be obtained as per the Schedule of Events and Assessments (Table 
1). Additional ECGs may be performed at other times if deemed necessary by the Principal/Site 
Investigator. 
The ECG will be recorded while the subject is resting in a supine position for at least 5 minutes. 
The ECG will electronically measure the PR, QRS, QT, RR, and QTc intervals, and heart rate. 
All ECG tracings will be reviewed within 24 hours by the Principal/Site 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).  


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7.4.6 Prospective Assessment of Suicidality via C-SSRS 
Suicidality assessment will be performed using the Columbia Suicide Severity Rating Scale (C-
SSRS), which will be administered by a trained professional during Screening, Day -1, and at End 
of Study. 
The C-SSRS is a questionnaire that prospectively assesses suicidal ideation and behavior using 
a semi-structured interview to probe subject’s responses (Posner et al., 2011).  The C-SSRS 
versions applicable to the current study are the “Baseline/Screening” version (Appendix 14.1.2.1) 
and the “Since Last Visit” version (Appendix 14.1.2.2).  
 
The Baseline/Screening version of the scale assesses suicidal ideation and behavior for 
lifetime and last 6 months. This version is suitable as part of a subject’s first interview and 
will be used at Screening to identify volunteers who must not participate in the trial due to 
their suicidal tendencies.   
 
The Since Last Visit version of the scale assesses any suicidal thoughts or behaviors the 
subjects may have had since the last administration of the C-SSRS.   
 
Training will be provided on the administration and interpretation of the C-SSRS. 
 C-SSRS findings 
Positive suicidality reports are generated for ANY of the following findings: 
 
Suicidal ideation with intention to act 
 
Suicidal ideation with specific plan and intent 
 
Made suicide attempt 
 
Interrupted suicide attempt 
 
Aborted suicide attempt 
 
Preparatory behaviors for making a suicide attempt 
Should the interview reveal that a subject has a positive suicidal ideation, the site staff should 
take appropriate steps to refer the subject to a psychiatrist for a follow-up evaluation.  The subject 
should not be released from the evaluation site until it is confirmed that the questionnaire answers 
are reviewed by the Principal/Site Investigator or designee and the subject is not considered to 
be at risk. Ultimately, the determination of suicidality and risk is up to the Principal/Site 
Investigator’s judgment.  
Any confirmed positive findings occurring after initiation of the SM dosing may qualify as 
treatment-emergent suicidality and should be recorded as an AE on the AE CRF. Positive suicidal 
findings recorded as an AE should be evaluated by the Principal/Site Investigator, in consultation 
with the Sponsor Medical Monitor or designee, as a potential important medical event (Section 
7.4.7.3). If the suicidal indication has been determined to be an SAE, the subject must be 
immediately withdrawn from the study and the SAE must be reported to the Sponsor using the 
SAE Form (See Section 9.1). 


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7.4.7 Adverse Event 
Subjects will be monitored throughout the study by Principal/Site Investigator for AEs. Adequate 
medical surveillance will be assured during the confinement period and a physician will be 
available on call at all times.  If necessary, a physician, either at the study site or in a nearby 
hospital, will administer treatment for any AEs. Subjects experiencing AEs will be re-evaluated for 
eligibility criteria to assess their continuation in the study. 
As defined by the ICH Guideline for GCP, an adverse event (AE) is any untoward medical 
occurrence in a patient or clinical investigation subject administered a pharmaceutical product 
and which does not necessarily have to have a causal relationship with treatment. 
An AE can be: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
 
Any new disease, intercurrent injuries, or exacerbation of an existing disease. 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG) that results in 
symptoms, a change in treatment or discontinuation from SM. 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline. 
Surgical procedures are not AEs; they are therapeutic measures for conditions that require 
surgery.  The condition for which the surgery is required is an AE, if it occurs or is detected during 
the study period. 
 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 SM and the AE, i.e., there is a 
reasonable possibility that the SM caused the adverse event. 
Adverse Drug Reactions (ADRs) are a subset of all SADRs for which there is reason to conclude 
that the SM caused the event. 
 Recording and Evaluation of Adverse Events 
All subjects who are enrolled and who receive SM will be monitored and questioned regarding 
the occurrence of AEs. Adverse events occurring prior to SM administration on Study Day 1 will 
become part of the subject’s medical history. Throughout the study, the Investigator must seek 
information on AEs by specific questioning and, as appropriate, by examination.  
Information on all AEs should be recorded immediately in the source document and also in the 
appropriate section of the case report form (CRF). 
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 


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example, fever, elevated WBC, cough, abnormal chest X-ray, etc., can all be reported as 
“pneumonia”. 
All AEs occurring after enrollment and receipt of SM 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 SM, or that worsened following first administration of SM, therefore, all 
AEs will be treatment-emergent.  The clinical course of each AE should be followed until resolution 
or until, in the medical judgment of the Investigator, the event has stabilized. Subjects that have 
experienced AE(s) may be re-evaluated for eligibility criteria to assess their continuation in the 
study as determined by the Investigator and the Sponsor. 
The Investigator is responsible for evaluating AEs and determining the following: 
 
Severity: How pronounced is the incapacity/discomfort caused by an AE? 
 
Causality: Was AE related or possibly related to the SM? 
 
Serious vs. Non-serious: Is the event a Serious Adverse Event (SAE)? 
 Criteria for Assessing Severity 
The Investigator will evaluate the comments of the subject and the response to treatment in order 
that he or she may judge the true nature and severity of the AE.  Severity refers to the accumulated 
intensity of discomfort/impairment of health since the last recording of AEs and will be assessed 
according to the following criteria: 
 
Mild:  Awareness of sign, symptom or event, but easily tolerated 
 
Moderate: Discomfort enough to interfere with usual activity and may warrant intervention 
 
Severe: Incapacitating with inability to do usual activities or significantly affects clinical 
status and warrants intervention 
 Criteria for Assessing Causality 
The Investigator is responsible for determining the relationship between the administration of SM 
and the occurrence of an AE as not suspected or as a suspected reaction to SM.  These are 
defined as follows: 
Not suspected: The temporal relationship of the AE to SM administration makes a causal 
relationship unlikely, or other drugs, therapeutic interventions, or underlying conditions provide 
a sufficient explanation for the observed event.  
 
Not related:  Temporal relationship to SM administration is missing or implausible, or 
there is an evident other cause. 
 
Unlikely related:  Temporal relationship to SM administration makes a causal relationship 
improbable; and other drugs, chemicals, or underlying disease provide plausible 
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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 medication 
withdrawal may be lacking or unclear.  This will be reported as a Suspected Adverse 
Drug Reaction (SADR). 
 
Definitely related: Temporal relationship to SM administration is plausible, and 
concurrent disease or other drugs or chemicals cannot explain event.  The response to 
withdrawal of the medication (de-challenge) should be clinically plausible.  The event must 
be definitive pharmacologically or phenomenologically, using a satisfactory re-challenge 
procedure if necessary.  This will be reported as an Adverse Drug Reaction (ADR). 
 Serious Adverse Events (SAE) 
AEs are classified as serious or non-serious.  An AE or adverse drug reaction (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 dependence 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.  
7.5 
Screening Scales and Assessment Tools 
7.5.1 Edinburgh Postnatal Depression Scale (EPDS)  
The Edinburgh Postnatal Depression Scale (EPDS) is a commonly used screening tool developed 
to assist in identifying possible symptoms of depression in women during pregnancy and during 
the postnatal period (Cox et al., 1987; Wisner et al., 2002; see Appendix 14.1.1).  The EPDS is a 
10-item self-report questionnaire; items of the scale correspond to various clinical depression 
symptoms, such as guilt feeling, sleep disturbance, low energy, anhedonia, and suicidal ideation.  
The individual rates themselves on each item on a 4-point Likert (various response option 


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equivalent to “not at all” to “all the time”) based on how they have felt in the last 7 days. For items 
1, 2, and 4, the four response options are assigned a numeric value of 0-3 top to bottom. For 
items 3 and 5-10, the four response options are assigned a numeric value of 3-0 top to bottom. A 
total score is calculated by summating the ratings of all 10 items. The total score ranges between 
0 and 30, and a total score of >13 represents presence of depression. It takes approximately 3-5 
minutes to complete the EPDS. 
 
 


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8 
STATISTICAL METHODS 
All statistical analysis will be performed by CRO after the completion of the trial. A statistical 
analysis plan (SAP) will be written by CRO, reviewed, and approved by the Sponsor prior to 
database lock.  
Summaries for continuous variables will include the number of subjects, mean, standard 
deviation, median, minimum, and maximum. Summaries for discrete variables will include the 
tabulation of frequencies and percentages, except zero (n=0) where percentages will not be 
displayed. All statistical analysis will be conducted by using SAS Version 9.4 or higher. 
8.1 
Statistical and Analytical Plans 
8.1.1 Analysis Populations 
The Safety Population will include all subjects who receive at least one dose of study medication. 
The PK Population will include all subjects in the safety population who have a sufficient PK 
profile to derive at least 1 PK parameter without major events that could impact the PK data (e.g., 
emesis).  
For subjects experiencing emesis: 
PK parameters will be determined and listed for subjects experiencing emesis following the 
administration of SPN-812, however, parameters for these subjects may be excluded from the 
affected statistical analysis (i.e., descriptive statistics) per PK scientist’s discretion.  
Subjects experiencing emesis before study Day 3 may be invited to continue participation in the 
study if deemed appropriate by the Principal/Site Investigator. The accurate time of emesis should 
be recorded. 
8.1.2 Demographics/Baseline Analysis 
For continuous demographic variables, (age, height, weight, and BMI) results for each treatment 
administered will be summarized using descriptive statistics.  For categorical variables (ethnicity, 
race, and gender), the number and percentage of subjects will be used. All demographic 
characteristics will be listed by subject. 
 Protocol Deviations 
Protocol deviations (both site and individual) will be categorized and listed by subject. 
 Study Medication 
The dose administration details (including treatment received, date and time of dose, and dose 
level administered) will be listed by subject.  
 Prior and Concomitant Medications 
Prior and/or concomitant medications will be monitored and coded using the World Health 
Organization Drug Dictionary and listed by subject. Concomitant medications will be further coded 
to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating therapeutic 
classification and a listing will be provided. 


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Summary tables will be presented for the reported use of all concomitant medications subsequent 
to receiving the first administration of the study treatment. 
8.1.3 Pharmacokinetics Analysis 
The PK Population as defined in Section 8.1.1 will be used to generate breast milk and plasma 
PK parameters of viloxazine and 5-HVLX-gluc for all subjects. Descriptive statistics (number of 
subjects, mean, standard deviation [SD], and coefficient of variation [CV], minimum, median, and 
maximum) will be used to summarize breast milk and plasma concentration data at each planned 
sampling time point for each analyte in breast milk and plasma. The midpoint of the breast milk 
collection interval will be used as the milk sampling time. Breast milk and plasma PK parameters 
calculated from the concentrations and actual times will be summarized by analyte using 
descriptive statistics (including geometric mean and geometric CV). Individual and mean breast 
milk and plasma concentration-time profiles for viloxazine and 5-HVLX-gluc will be presented 
graphically on linear and semi-logarithmic scales. All PK parameters will be derived using a non-
compartmental analysis method.  
 Pharmacokinetic Concentrations 
Descriptive statistics will be used to summarize evaluable breast milk and plasma concentration 
data at each planned sampling time point for each treatment. A listing of the actual sampling times 
and corresponding concentrations will be provided for all PK samples. Generally, concentrations 
below the lower limit of quantification (BLQ) will be treated as zero in the summary statistics for 
concentration data. However, if a BLQs value in the profile of Day 3 is between two quantifiable 
concentrations, then the BLQ value may be treated as missing at PK scientist’s discretion.   
Viloxazine and 5-HVLX-gluc mean breast milk and plasma concentration versus time profiles will 
be presented by using the scheduled sampling time on both linear and semi-logarithmic scales. 
Individual breast milk and plasma concentrations by actual sampling time will be provided on both 
linear and semi-logarithmic scales.  
 Pharmacokinetic Parameters 
Viloxazine and 5-HVLX-gluc PK parameters (see Section 7.2.3) will be calculated from breast 
milk and plasma concentration-time data by standard non-compartmental methods using 
Phoenix™ WinNonlin® (Version 8.0 or higher, Certara) and will be summarized using descriptive 
statistics. All individual subject parameter data will be listed. A list of PK parameters for plasma 
and breast milk are presented in Table 2. 
8.1.4 Efficacy Analysis 
There will be no efficacy analysis in this study. 
8.1.5 Safety Analysis 
Evaluation of safety will be performed on the safety population.  Safety analysis will include AEs, 
clinical laboratory tests’ results, vital signs, physical examination, C-SSRS, and ECGs. Safety and 
tolerability data will be reported using descriptive statistics. A complete description of the 


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statistical analyses to be performed with the safety and tolerability data will be presented in the 
SAP. 
 Adverse Events 
AEs will be classified into standardized medical terminology from the verbatim description 
(Investigator term) using the Medical Dictionary for Regulatory Activities (MedDRA) and will be 
presented by preferred term nested within System Organ Class.  All AE data listings will include 
the verbatim term and MedDRA Preferred Term. 
AEs are recorded only after SM has been administered; therefore, all AEs are treatment-
emergent. 
AEs will be summarized in tables. Listings of all AEs including deaths, SAEs, and AEs resulting 
in treatment discontinuation. 
 AEs will be summarized in tables. Listings of all AEs including deaths, SAEs, and  AEs leading 
to treatment discontinuation will be provided. 
 Laboratory Values 
Listings of all clinical laboratory results will be provided with the abnormal values flagged and the 
clinical significance assessment added, when appropriate.  Listings will include normal ranges.  
Descriptive statistics for each clinical laboratory test will be presented. Change from baseline to 
EOS will also be presented.  Laboratory test results will be assigned a low, normal, or high (LNH) 
classification according to whether the values were below (L), within (N), or above (H) the 
laboratory parameters’ reference ranges provided by the central laboratory.  For each laboratory 
parameter, shift from baseline to end of study visit will be presented in 3 by 3 tables based on 
LNH classification for each laboratory test, as applicable. 
 Vital Signs, Physical Examination, and Clinical Breast Examination 
Vital signs values and physical examination and clinical breast exam assessments will be 
evaluated on an individual basis, by subject, only for purposes of entry into the study and safety 
evaluation. Individual subject vital signs will be listed. For vital signs, both actual values and 
change from Screening values will be summarized.  
 ECG Results 
Subject tabular summaries of the quantitative ECG parameters and the overall ECG findings 
(normal, abnormal not clinically significant, or abnormal clinically significant) will be presented. 
QTc will be reported as QTcF (QTcF=QT corrected using Fridericia's method). For the quantitative 
ECG parameters, both actual values and change from Screening values will be summarized.  
Individual subject ECGs will be listed. 
 Prospective Suicidality Monitoring (C-SSRS) 
Suicidality monitoring data will be evaluated individually by subject and the C-SSRS findings will 
be presented in data listings. 


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8.2 
Sample Size and Power Considerations 
The sample size is not based on statistical power considerations.  Based on clinical judgement, 
up to 15 healthy lactating volunteers will be enrolled in the study, with the expectation that at least 
12 subjects will complete the study.  
8.3 
Interim Analyses 
No interim analysis is planned. 
 
 


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9 
REPORTING OF ADVERSE EVENTS 
9.1 
Investigator Responsibilities for Reporting SAEs 
The Investigator must report all SAEs to Sponsor within 24 hours of first becoming aware of the 
SAE, regardless of whether the Investigator believes they are drug related. The Principal/Site 
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 Principal/Site Investigator will keep a copy of this SAE Report 
Form on file at the study site. 
The Principal/Site Investigator, after thorough consideration of all facts that are available, must 
include an assessment of causality of the SAE to study medication.  
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. 
Principal/Site Investigator must comply with the applicable regulatory requirements related to the 
reporting of SAEs to the IRB including submission of relevant safety information provided by the 
Sponsor.  
The Drug Safety Contact for SAE reporting is:  
PPD Medical Monitor 
Telephone (24 Hour): 1-888-483-7729  
Email: rtpsafety@ppd.com 
9.2 
Other Events Requiring Immediate Reporting 
The Principal/Site Investigator must report a pregnancy that occurs in a subject during a clinical 
study to the Sponsor Medical Monitor within 24 hours of first becoming aware of the event.  
Pregnancy should be reported on a Pregnancy Report Form. The Investigator must follow-up with 
any pregnant subject for 3 months after the child is born.  Any AEs concerning the pregnancy of 
the subject or the child after birth must be documented and reported to the Sponsor. 
In the case a subject has or manifested any clinical signs characteristic of a reportable disease 
or condition (e.g., tuberculosis, SARS), it is the responsibility of the Medical Director of CRO to 
notify the applicable Public Health authorities within 48 hours after becoming aware of the 
information. 
9.3 
Sponsor Responsibilities for Expedited Reporting of SAEs 
The Sponsor will inform Principal/Site Investigator and regulatory authorities of adverse drug 
reaction (ADRs) that are both serious and unexpected, in compliance with applicable regulatory 
requirements, on an expedited basis (i.e., within specific timeframes). For this reason, it is 
imperative that study site submit SAE information to the Sponsor in the manner described above. 
Principal/Site Investigator must also submit the safety information provided by the Sponsor to the 
IRB/IEC unless the country legal regulation requires that the Sponsor should be responsible for 
the safety reporting to the IRB/IEC. 


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It is the responsibility of the Sponsor to notify FDA/regulatory authorities and the Principal/Site 
Investigator, in a written IND safety report, of any SADR that is both serious and unexpected, as 
per their applicable SAE reporting guidelines. The Sponsor will also notify Principal/Site 
Investigator 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. 
 
 


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10 DOCUMENTATION 
10.1 Adherence to the Protocol 
The Principal/Site 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 Principal/Site Investigator and the Sponsor’s representative must sign the protocol and its 
amendments (if any) before initiating the study. 
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 Principal/Site 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 Principal/Site Investigator will 
immediately send the notice of study suspension or termination by the IRB to the Sponsor. 
10.2 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. 
10.3 Protocol Deviations 
There are to be no Investigator-initiated deviations from the protocol. The date of and reason for 
deviations must be documented in all cases. Important deviations that significantly impact the 
completeness, accuracy, and/or reliability of the study data or that may significantly affect a 
subject's rights, safety, or well-being must be reported by the Investigator to the IRB immediately. 
Reporting of all other protocol deviations must adhere to the requirements of the governing IRB.  
Changes to the procedures which may impact the quality of the PK data will be considered 
important deviations.  These changes will include any circumstances that will alter the evaluation 
of the PK.  Examples include, but may not be limited to:  
 
Sample handling or processing errors that invalidate bioanalytical results  
 
Inaccurate dosing on the day of PK sampling  


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In the case of an important deviation, collected blood samples will be analyzed. However, PK 
concentrations and PK parameters affected by the deviations (per PK scientist’s discretion) will 
be excluded from the study results.  
Other changes to the procedures which do not impact the quality of the PK data will not be 
considered important deviations.  If such changes occur, data will be included but the analysis 
will be adjusted accordingly. A common example of an unimportant deviation is a missed blood 
sample or deviations from blood collection times. Although these changes are not significant, they 
are deviations from the protocol and should be documented in the clinical study report.  
10.4 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. 
10.4.1 Data Collection 
All clinical data will be recorded on site by the clinical staff on source documents and/or recorded 
electronically using validated software.  The Principal/Site Investigator and/or the site staff will 
assume the responsibility of ensuring the completeness and accuracy of the clinical data. 
10.4.2 Clinical Data Management 
The clinical database will be populated directly from electronic data as specified in the CRO’s 
data management plan.  However, recording of data may be done on raw data sheets (e.g., ECG 
data) and will be manually transcribed into the validated software. As a result, the CRFs will be 
populated directly from the validated software database and will be used solely for submission 
purposes.  Quality control and data validation procedures will be applied to ensure the validity 
and accuracy of the clinical database.   
10.4.3 Database Quality Assurance 
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  Data queries requiring 
clarification will be documented and returned to the investigational site for resolution. Only 
authorized personnel will make corrections to the clinical database, and all corrections will be 
documented in an audit trail.  All data will be verified for quality control and will also be subject to 
audits from CRO’s Quality Assurance Unit. 
10.4.4 Bioanalytical Sample Handling 
All collected PK breast milk and blood samples will be analyzed. Bioanalytical sample analyses 
for viloxazine and 5-HVLX-gluc will be performed at Supernus bioanalytical facility and/or a 
Supernus designated bioanalytical facility. Samples and Sample Inventory Forms/Manifests will 
be shipped to Supernus bioanalytical facility or the Supernus designated bioanalytical facility, 
according to instructions provided in a separate document. Primary and secondary (backup) 
samples will be transported in at least two separate shipments. The samples should be packed 


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on sufficient dry ice to ensure they will remain and arrive frozen.  The bioanalytical reports will be 
included as appendices to the clinical study report.   
10.5 Retention of Records 
The Principal/Site Investigator has the responsibility to retain all study “essential documents”, as 
described in ICH E6.  Essential documents include but are not limited to the protocol, copies of 
paper CRFs, source documents, laboratory test results, SM inventory records, Investigator's 
Brochure, and regulatory agency registration documents (e.g., FDA form 1572, ICFs, and IRB/IEC 
correspondence). The Investigator should take measures to prevent accidental or premature 
destruction of these documents.  Study essential documents should be retained until at least two 
years after the last approval of a marketing application or after formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement with 
the Sponsor. The Principal/Site Investigator must obtain written permission from the Sponsor prior 
to the destruction of any study document. 
It is requested that at the completion of the required retention period, or should the CRO relocate, 
the Sponsor should be contacted and give the option of permanently retaining the study records. 
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 
CFR 312.68 or other national or foreign regulatory authorities in accordance with regulatory 
requirements. 
10.6 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).  Any inspections requested by a regulatory 
authority must be communicated immediately by CRO to the Sponsor. 
10.7 Publication of Results 
Any presentation or publication of data collected as a direct or indirect result of this trial will be 
considered as a joint publication by the Investigator(s) and the appropriate personnel at the 
Sponsor.  Authorship will be determined by mutual agreement.  All manuscripts, abstracts or other 
modes of presentation arising from the results of the study must be reviewed and approved in 
writing by the Sponsor, prior to submission for publication or presentation. No publication or 
presentation with respect to the study shall be made until any Sponsor comments on the proposed 
publication or presentation have been addressed to the Sponsor’s satisfaction. 
10.8 Financing and Insurance 
Financing and Insurance information will be set forth in a separate document between CRO and 
the Sponsor. 


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10.9 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 Principal/Site Investigator, the Clinical Trial Site’s staff(s), 
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. 
10.10  Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative reasons at 
any time.  The Principal/Site 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 Principal/Site Investigator reserves the right to discontinue the study should his/her judgment 
so dictate.  The Principal/Site Investigator will notify the IRB in case of study discontinuation.  
Study records must be retained as noted above. 
 
 


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11 Final Report 
A final report including clinical and statistical sections will be the responsibility of CRO and will be 
signed and approved by the Sponsor. 
In the event that the study is prematurely terminated, CRO will produce an abbreviated safety 
report. In such an event, raw data will not be submitted with the abbreviated report but will be 
archived at CRO, unless requested by the Sponsor. 
 
 


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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. 
12 ETHICS 
12.1 Institutional Review Boards / Independent Ethics Committees 
The Institutional Review Board (IRB) and/or Independent Ethics Committee (IEC) that approved 
this study and the approval letters will be included in the clinical study report for this protocol. 
The protocol, any protocol amendments, and the informed consent form(s) (ICF) will be reviewed 
and approved by the appropriate IRB before subjects are enrolled. A properly executed written 
ICF shall be read, signed, and dated by each subject prior to entering the trial or prior to 
performing any study procedure. The original signed and dated ICF will be kept at CRO and a 
copy will be given to the subject. If a revised ICF is introduced during the study, each subject’s 
further consent must be obtained. The new version of the ICF must be approved by the IEC, prior 
to subsequently obtaining each subject’s consent. 
 The Principal/Site Investigators or Sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB of any reportable adverse events (AEs) per International Conference 
on Harmonization (ICH) guidelines and local IRB standards of practice. 
12.2 Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures (SOPs) from both 
the Sponsor and 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) Code of Federal Regulations (CFR) dealing with clinical studies 
(21 CFR, including parts 50 and 56 concerning Patient Informed Consent and IRB 
regulations). 
 
Local, national legal guidelines. 
12.3 Investigators and Study Personnel 
This study will be conducted by Principal/Site Investigators under the sponsorship of Supernus 
Pharmaceuticals, Inc. (Sponsor) at CRO. 
Contact person(s) at the Sponsor’s Medical Monitor and contact information for Serious Adverse 
Event (SAE) reporting can be found in Section 9.3 of the protocol. Additional details on AE and 
SAE reporting can be found in Section 9 of the protocol. Contact information for other Sponsor 
personnel are listed in the Regulatory Binder, maintained by CRO.  
The study will be monitored by qualified personnel from Supernus. Data management and 
statistical analyses will be the responsibility of the CRO data management and biostatistics 
groups.  


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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. 
12.4 Subject Information and Consent 
The Principal/Site 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 Principal/Site Investigator (or designee) and subject must sign and date the 
Informed Consent Form(s) (ICF) before the subject can participate in the study.  The subject will 
be given a copy of the signed and dated ICF and the original will be retained in the investigational 
site study records.  
The decision regarding subject participation in the study is voluntary.  The Principal/Site 
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 ICFs are amended during the study, the Principal/Site Investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICFs by the IRB and use the 
amended informed consent form(s) for all subjects (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. 
13 REFERENCES 
Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-
item Edinburgh Postnatal Depression Scale. Br J Psychiatry. 1987 Jun;150:782-786. 
FDA Guidance for Industry: Clinical Lactation Studies: Considerations for Study Design, May 
2019. 
QELBREE® Prescribing Information, April 2022;  
https://www.accessdata.fda.gov/drugsatfda docs/label/2022/211964s003lbl.pdf     
Posner K, Brown GK, Stanley B, 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; 168:1266-1277. 
 
 


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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. 
14 APPENDIX 
14.1 Screening/Safety Assessment Scales 
 
 


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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. 
14.1.1 EDINBURGH POSTNATAL DEPRESSION SCALE (EPDS) 
 


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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. 
14.1.2 COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) 
 C-SSRS “Baseline/Screening” Version
 


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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. 
 


Supernus Pharmaceuticals, Inc. 
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02 September 2022 
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Version 2.0 
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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. 
 


Supernus Pharmaceuticals, Inc. 
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02 September 2022 
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Version 2.0 
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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. 
 C-SSRS “Since Last Visit” version 
 


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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. 
 
 


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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. 
 

SAP_001.pdf: 
 
Confidential 
 
 
 
 
 
 
 
 
 
Supernus Pharmaceuticals, Inc. 
 
812P418 
 
Evaluation of the Excretion of Viloxazine and Its Metabolite 5-
Hydroxyviloxazine Glucuronide into Breast Milk Following Multiple Doses of 
SPN-812 (600mg, QD) in Healthy Lactating Women 
 
11 August 2023 
 
Final Statistical Analysis Plan 
 
Version 1.0 
 
 


 
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Page 2 of 20 
 
TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS 
 
3 
1. 
INTRODUCTION 
 
5 
2. 
OBJECTIVES AND ENDPOINTS 
 
5 
2.1 
PRIMARY OBJECTIVE AND ENDPOINTS 
5 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS 
6 
2.3 
SAFETY OBJECTIVE AND ENDPOINTS 
6 
3. 
STUDY DESIGN 
 
7 
4. 
GENERAL STATISTICAL CONSIDERATIONS 
8 
4.1. 
SAMPLE SIZE 
9 
4.2. 
RANDOMIZATION, STRATIFICATION, AND BLINDING 
9 
4.3. 
ANALYSIS POPULATION 
9 
5. 
SUBJECT DISPOSITION 
 
9 
5.1 
DISPOSITION 
9 
5.2 
PROTOCOL DEVIATIONS 
10 
5.3 
INCLUSION AND EXCLUSION CRITERIA 
10 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
10 
6.1 
DEMOGRAPHICS 
10 
6.2 
MEDICAL, PSYCHIATRIC, AND MATERNAL HISTORY 
10 
7. 
TREATMENTS AND MEDICATIONS 
11 
7.1 
PRIOR AND CONCOMITANT MEDICATIONS 
11 
7.2 
STUDY MEDICATION 
11 
8. 
PHARMACOKINETICS 
 
11 
8.1 
DATA ANALYSES 
11 
8.2 
BREAST MILK COLLECTIONS 
12 
8.3 
PLASMA COLLECTIONS 
12 
8.4 
PHARMACOKINETIC PARAMETERS 
13 
9. 
SAFETY ANALYSIS 
 
14 
9.1 
ADVERSE EVENTS 
14 
9.2 
CLINICAL LABORATORY EVALUATIONS 
16 
9.3 
VITAL SIGN MEASUREMENTS 
16 
9.4 
PHYSICAL EXAMINATIONS 
17 
9.5 
CLINICAL BREAST EXAMINATIONS 
17 
9.6 
ELECTROCARDIOGRAMS 
17 
9.7 
PROSPECTIVE ASSESSMENT OF SUICIDALITY 
18 
10. 
INTERIM ANALYSIS 
 
18 
11. 
CHANGES IN THE PLANNED ANALYSIS 
18 
12. 
REFERENCES 
 
18 
13. 
SCHEDULE OF ASSESSMENTS 
 
19 
 
 
 


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List of Abbreviations 
5-HVLX-gluc 
5-hydroxyviloxazine glucuronide 
ADR 
adverse drug reaction 
AE 
adverse event 
Ammilk 
total amount of drug excreted in breast milk 
ATC-4 
Anatomical Therapeutic Chemical Level 4 
AUC 
area under the concentration-time curve 
AUCtau,milk 
area under the concentration-time curve over a 24-hour dosing interval in 
breast milk 
AUCtau,ss 
area under the concentration-time curve over a 24-hour dosing interval in 
plasma at steady-state 
BLQ 
below the limit of quantification 
BMI 
body mass index 
Cave,milk 
average concentration in breast milk 
Cave,ss 
average concentration in plasma at steady-state 
CL/Fss 
apparent total body clearance in plasma at steady-state 
Cmax,milk 
maximum observed concentration in breast milk 
Cmax,ss 
maximum observed concentration in plasma at steady-state 
Ctrough,milk 
drug trough concentration immediately before the next dose in breast milk 
Ctrough,ss 
drug trough concentration immediately before the next dose in plasma at 
steady-state 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
coefficient of variation 
DID 
daily infant dosage 
EDID 
estimated daily infant dosage 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
HR 
heart rate 
MedDRA 
Medical Dictionary for Regulatory Activities 
ML/PL 
breast milk-plasma ratio 
NCA 
non-compartmental analysis 
PK 
pharmacokinetic 
PN 
preferred name 
PT 
preferred term 
Q1 
first quartile 


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Q3 
third quartile 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RID 
relative infant dose 
SADR 
suspected adverse drug reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SM 
study medication 
SOC 
system organ class 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
Tmax,milk 
time of maximum observed concentration in breast milk 
Tmax,ss 
time of maximum observed concentration in plasma at steady-state 
WHODrug 
World Health Organization Drug Dictionary  
 
 


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1. Introduction 
SPN-812 (viloxazine extended-release capsules; QELBREE®) is a structurally distinct, bicyclic, 
norepinephrine reuptake inhibitor. The active substance in SPN-812 is viloxazine, whose 
mechanism of action is multimodal with antagonistic activity observed at 5-HT2B and agonistic 
activity at 5-HT2C receptors, as well as weaker antagonistic effects at ADRα1B, ADRβ2 and 
5-HT7 receptors. Additionally, SPN-812 acts as a modulator with inhibitory effects at the 
norepinephrine reuptake transporter. Viloxazine was previously marketed in several European 
countries as an antidepressant as an immediate-release product. An extended-release formulation 
of viloxazine, SPN-812, has been developed by Supernus to prolong the release and absorption 
of viloxazine post-administration, thereby allowing longer dosing intervals for a drug with a 
relatively short half-life. As of April 2022, SPN-812 (QELBREE® PI) is Food and Drug 
Administration-approved for the treatment of Attention-Deficit Hyperactivity Disorder in 
persons 6 years of age and older. 
This is an open label, single treatment, lactation study of SPN-812 in healthy lactating women. 
The study is designed to assess the excretion of viloxazine and its major metabolite 
5-hydroxyviloxazine glucuronide (5-HVLX-gluc) into breast milk following repeated 
administration of SPN-812 600 mg, once daily (QD). 
The purpose of this statistical analysis plan (SAP) is to define the planned statistical analysis of 
the study data consistent with the study objectives. This SAP is written based on protocol 
812P418, version 2.0, dated 02 September 2022. 
2. Objectives and Endpoints 
2.1 
Primary Objective and Endpoints 
The primary objective is to: 
• Evaluate the pharmacokinetics (PK) of viloxazine and its major metabolite 
5-hydroxyviloxazine glucuronide (5-HVLX-gluc) in breast milk in healthy lactating 
women following multiple oral doses of SPN-812. 
The primary endpoints of this study are as below: 
• Breast milk PK parameters for viloxazine and 5-HVLX-gluc when SPN-812 reaches 
plasma steady-state: 
o Area under the concentration-time curve (AUC) over a 24 hour dosing interval in 
breast milk (AUCtau,milk) 
o Maximum observed concentration in breast milk (Cmax,milk) 
o Time of maximum observed concentration in breast milk (Tmax,milk) 
o Drug trough concentration immediately before the next dose in breast milk 
(Ctrough,milk)  


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o Average drug concentration in breast milk (Cave,milk ) 
o Total amount of drug excreted in breast milk (Ammilk, mg/day) over a period of 24 
hours 
2.2 
Secondary Objectives and Endpoints 
The secondary objectives are to: 
• Evaluate the PK of viloxazine and 5-HVLX-gluc in plasma in healthy lactating women 
following multiple oral doses of SPN-812. 
• Evaluate the overall exposure between breast milk and plasma in healthy lactating 
women following multiple oral doses of SPN-812. 
• Estimate daily infant dose of SPN-812 via breast milk. 
The secondary endpoints of this study are as below: 
• Plasma PK parameters for viloxazine and 5--HVLX--gluc at plasma steady-state, if 
applicable: 
o AUC over a 24 hour dosing interval in plasma at steady-state (AUCtau,ss)  
o Maximum observed concentration in plasma at steady-state (Cmax,ss) 
o Time of maximum observed concentration in plasma at steady-state (Tmax,ss) 
o Apparent total body clearance in plasma at steady-state (CL/Fss) 
o Average concentration in plasma at steady-state (Cave,ss) 
o Drug trough concentration immediately before the next dose in plasma at 
steady-state (Ctrough,ss) 
• Breast milk-plasma ratio (ML/PL) based on AUC over 24 hours for viloxazine and 
5-HVLX-gluc at plasma steady-state 
• Estimated daily infant dosage (EDID, mg/kg/day) and relative infant dose (RID, %) at 
plasma steady-state 
2.3 Safety Objective and Endpoints 
The safety objective is to: 
• Evaluate the safety and tolerability of multiple doses of SPN-812 in healthy lactating 
women. 
The safety endpoints of this study are as below: 
• Adverse events (AEs) 
• Clinical laboratory test results (clinical chemistry, hematology, and urinalysis) 
• 12-lead electrocardiogram (ECG) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Vital signs 
• Physical examination 
• Concomitant medications 


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3. Study Design 
This is an open label, single treatment, lactation study of SPN-812 in healthy lactating women. 
The study is designed to assess the excretion of viloxazine and its major metabolite 
5-HVLX-gluc into breast milk following repeated administration of SPN-812 600 mg, once daily 
(QD). 
This study is comprised of Screening, Inpatient Admission, Treatment Period, and End of Study 
(EOS). The total duration of the study is up to around 1 month including Screening up to 28 days 
and 4 days of Treatment Period. Subjects will remain in the inpatient unit for 5 days, including 
the day of admission to the inpatient unit (Day -1), 3 days of dosing study medication (SM) 
(Days 1-3), and the day of discharge (Day 4). 
Subjects will be screened within 28 days prior to dosing. After informed consent is obtained, 
information from subjects will be collected (including maternal-related information) and subjects 
will undergo screening evaluations (see Table 13-1). Inclusion/exclusion criteria will be 
reviewed to determine the subjects’ eligibility at Screening. A lactation consultant will be 
available to provide lactation support to subjects once they are enrolled. 
Subjects will be admitted to inpatient unit on Day -1 to confirm eligibility. Subjects will receive 
600 mg SPN-812 on the morning of Days 1, 2, and 3 after completion of safety assessments. 
Study medication should be administered at the same time in the morning (±30 min) of dosing 
days. Breast milk and blood sample for PK analysis will then be collected on Day 3 to 4  per 
schedule in Section 8.2 and Section 8.3, respectively. Non-PK breast milk expressed on Days -1, 
1, and 2 will be collected over the time intervals in Section 8.2, and these samples will not be 
analyzed for drug concentrations. The volume and the start and end times of the collection of 
each non-PK and PK breast milk sample will be recorded. The EOS procedures will be 
conducted prior to discharge on Day 4 following the last breast milk and blood sample 
collection. If subject discontinues early, all EOS procedures will be conducted. Study schematic 
is shown in Figure 3-1 and Schedule of Events and Procedures is presented in Table 13-1. 


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Figure 3-1: Study Schematic 
 
4. General Statistical Considerations 
All statistical analyses will be conducted using statistical analysis system SAS® Version 9.4 or 
higher (SAS Institute, Cary, NC).  
Descriptive statistics for continuous variables will include number of subjects, mean, standard 
deviation (SD), median, first quartile (Q1), third quartile (Q3), minimum, and maximum, unless 
otherwise noted. For categorical variables, frequencies and percentages will be presented.  
All tables, listings, and figures will be presented with treatment. The treatment below will be 
used for presentations: 
• SPN-812 600 mg QD 
All data listings will be sorted by subject number. 
No algorithm for imputation of missing data will be employed. 
Study days are calculated with respect to the first dose date as below: 
• If the assessment/observation date is on or after the first dose date, then Study Day = 
Assessment/Observation Date – First Dose Date + 1 
• Otherwise, Study Day = Assessment/Observation Date – First Dose Date 
Baseline will be defined as the last non-missing assessment (including repeated and unscheduled 
assessments) before the first dose of SM administration, unless otherwise specified. 
For summary of safety assessments, if there are repeated measurements at a time point, the first 
non-missing assessment at that time point will be used in the summary tables.  


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Unscheduled results will not be included in the summary tables, except for determining Baseline, 
but will be presented in data listings. 
The methodology and data handling specifications for PK data are detailed in Section 8. 
4.1. 
Sample Size 
The sample size is not based on statistical power considerations. Based on clinical judgement, up 
to 15 healthy lactating volunteers will be enrolled in the study, with the expectation that at least 
12 subjects will complete the study. 
4.2. 
Randomization, Stratification, and Blinding 
This is an open label, single treatment study, no randomization, stratification, and blinding will 
be used. 
4.3. 
Analysis Population 
The Enrolled Population will include all subjects who sign the informed consent form. 
The Safety Population will include all subjects who receive at least one dose of SM. 
The PK Population will include all subjects in the Safety Population who have a sufficient PK 
profile to derive at least 1 PK parameter without major events that could impact the PK data 
(e.g., emesis). 
For subjects experiencing emesis following the administration of SPN-812, PK parameters will 
be determined and listed, however, parameters for these subjects may be excluded from the 
affected statistical analysis (i.e., descriptive statistics) per the study pharmacokineticist’s 
discretion.  
Subjects experiencing emesis before study Day 3 may be invited to continue participation in the 
study if deemed appropriate by the Principal/Site Investigator. The accurate time of emesis 
should be recorded. 
5. Subject Disposition 
5.1 
Disposition 
The following will be summarized for the Enrolled Population for all subjects: 
• The number of subjects who completed screening 
• The number of subjects who did not complete screening  
o Reasons for discontinuation from screening 
• The number of subjects who completed study 


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• The number of subjects who did not complete study  
o Reasons for discontinuation from the study 
• The number of subjects in each analysis population 
Subject disposition data will be presented in data listings. 
5.2 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. An important deviation (sometimes referred to as a major or significant 
deviation) is a subset of protocol deviations that significantly affects the subject’s rights, safety, 
or well-being and/or the completeness, accuracy, and reliability of the study data, and may affect 
the conclusion of the safety and PK analyses. Important protocol deviations will be summarized 
for the Safety Population. All protocol deviations will be presented in a data listing. 
5.3 
Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria deviations will be presented in a data listing. 
6. Demographics and Baseline Characteristics 
6.1 
Demographics 
Demographic information collected at Screening will be presented in a data listing. 
Descriptive statistics will be calculated for the following continuous demographic characteristics:  
• Age (years) 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) (kg/m2) 
Frequency counts and percentages will be tabulated for the categorical variables: 
• Sex 
• Race 
• Ethnicity 
The summaries will be presented for the Safety Population. 
6.2 
Medical, Psychiatric, and Maternal History 
The medical and psychiatric history data will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA, version 26.0) and presented in a data listing. 


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Edinburgh Postnatal Depression Scale and maternal (infant gestational age at delivery, stage of 
lactation, length of time postpartum, and feeding method [pumping or breastfeeding]) history 
will be presented in separate data listings. 
7. Treatments and Medications 
7.1 
Prior and Concomitant Medications 
Medications that stop prior to the first dose of SM will be classified as prior medication. 
Medications that start on or after the first dose of SM will be classified as concomitant. If a 
medication starts before the first dose of SM and stops on or after the first dose of SM, then the 
medication will be classified as both prior and concomitant. 
Prior and concomitant medications will be summarized by Anatomical Therapeutic Chemical 
Level 4 (ATC-4) and preferred name (PN) for the Safety Population. All prior and concomitant 
medications will be coded according to the World Health Organization Drug Dictionary 
(WHODrug, version March 2023) and presented in a data listing. 
7.2 
Study Medication 
The SM administration and drug accountability data (including treatment received, date and time 
of dose, and dose level administered) as collected on electronic case report form (eCRF) will be 
presented in a data listing. 
8. Pharmacokinetics 
All PK listings and individual concentration-time profiles will be presented using the Safety 
Population. The PK tables and mean figures will be presented using the PK Population. 
8.1 
Data Analyses  
Data rounding specifications for PK data are documented in the PK tables, listings, and figures 
shells. 
For presentation of the individual data and summary statistics, viloxazine and 5-HVLX-gluc 
breast milk and plasma concentrations below the limit of quantitation (BLQ) will be set to zero. 
For the PK analysis (non-compartmental analysis [NCA]), concentrations BLQ up to the time of 
the first quantifiable concentration will be treated as zero. Embedded (values between 2 
quantifiable concentrations) and terminal BLQ concentrations will be treated as “missing”. 
Descriptive statistics (number of observations [n], number of BLQ values [nBLQ], mean, SD, 
coefficient of variation [CV], minimum, median, and maximum) will be used to summarize 
breast milk and plasma concentration data at each planned sampling time point for each analyte. 
The midpoint of the breast milk collection interval will be used as the breast milk sampling time. 


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A listing of the actual sampling times and corresponding concentrations will be provided for all 
PK samples. Individual breast milk volumes collected at each time interval as indicated in 
section 8.2 for both PK and non-PK samples will also be presented in breast milk data listing. 
Viloxazine and 5-HVLX-gluc mean breast milk and plasma concentration versus time profiles 
will be presented by using the scheduled sampling time on both linear and semi-logarithmic 
scales. Individual breast milk and plasma concentrations by actual sampling time will be 
provided on both linear and semi-logarithmic scales. 
8.2 
Breast Milk Collections 
A total of 9 expressed PK breast milk samples will be collected for PK analysis at the following 
time intervals: 
• Day 1: -4 to <0 hours pre-dose; 
• Day 3: -4 to <0 hours pre-dose, and ‘0 to 4’, ‘4 to 6’, ‘6 to 8’, ‘8 to 10’, ’10 to 12’, ’12 to 
16’, and ’16 to 24’ hours post-dose. 
Non-PK breast milk expressed on Days -1, 1, and 2 will be collected over the time intervals as 
below, and these samples will not be analyzed for drug concentrations: 
• Day -1: store milk as pumped per subject’s pumping routine; 
• Day 1: 0 to 24 hours post-dose per subject’s pumping routine; 
• Day 2: 0 to 20 hours post-dose per subject’s pumping routine. 
For each breast milk collection period, the start and end times of the collection will be recorded, 
and the total volume (mL) of breast milk collected will be measured and recorded.  
8.3 
Plasma Collections 
A total of 13 blood draws for PK will be collected on Day 1 pre-dose, Day 3 pre-dose, and Day 3 
at 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 16.0, and 24.0 hours post-dose. The following 
windows are permitted relative to the specified PK sample collection times: 
• Pre-dose: - 15 minutes; 
• < 1 hour post-dose: ± 3 minutes; 
• 1 to 8 hours post-dose: ± 5 minutes; 
• 8 to 24 hours post-dose: ± 10 minutes. 
The actual time and date of each blood sample collection will be recorded. Pharmacokinetic 
collections that have an actual sampling time that deviates from the predefined collection time 
windows will be flagged in the data listings. 


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8.4 
Pharmacokinetic Parameters 
Viloxazine and 5-HVLX-gluc breast milk and plasma concentration-time data will be analyzed 
by NCA using Phoenix® WinNonlin® Version 8.3.4 or higher (Certara USA, Inc., Princeton, NJ). 
The following PK parameters will be calculated for viloxazine and 5-HVLX-gluc, where data 
permits: 
Breast milk: 
PK Parameter 
Definition 
Cmax,milk 
Maximum observed concentration in breast milk. 
Cave,milk 
Average drug concentration in breast milk calculated as the ratio of 
AUCtau,milk/24. 
Ctrough,milk 
Drug trough concentration immediately before the next dose in breast 
milk. 
Tmax,milk 
Time of maximum observed concentration in breast milk. 
AUCtau,milk 
Area under the concentration-time curve over a 24 hour dosing 
interval in breast milk, calculated using the linear up/log down rule. 
Ammilk 
Total amount of drug excreted in breast milk, calculated as the sum of 
the product of breast milk volumes and concentrations from each time 
period. 
ML/PL 
Breast milk-plasma ratio, calculated as AUCtau,milk/AUCtau,ss. 
DID 
Daily infant dosage (mg/day); total drug present in breast milk and 
consumed by the infant per day, which is equal to Ammilk. 
EDID 
Estimated daily infant dosage (mg/kg/day) calculated as ML/PL × the 
average maternal concentration in plasma (Cave,ss) × 150 mL/kg/day 
(EDID 150) and 200 mL/kg/day (EDID 200), respectively 
RID 
Relative infant dose (%); the percent of the weight-adjusted maternal 
dosage consumed in breast milk over 24 hours, calculated as EDID 
(mg/kg/day)/maternal dosage (mg/kg/day) × 100%. 
Plasma: 
PK Parameter 
Definition 
Cmax,ss 
Maximum observed concentration in plasma at steady-state. 
Cave,ss 
Average concentration in plasma at steady-state calculated as the ratio 
of AUCtau,ss/24. 
Ctrough,ss 
Drug trough concentration immediately before the next dose in 
plasma at steady-state. 


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PK Parameter 
Definition 
Tmax,ss 
Time of maximum observed concentration in plasma at steady-state. 
AUCtau,ss 
Area under the concentration-time curve over a 24 hour dosing 
interval in plasma at steady-state, calculated using the linear up/log 
down rule. 
CL/Fss* 
Apparent total body clearance in plasma at steady-state, calculated as: 
Dose/AUCtau,ss. 
*not calculated for 5-HVLX-gluc 
Actual sampling times and actual midpoint times will be used for the estimation of all PK 
parameters in breast milk and plasma, respectively.  
Analysis: Viloxazine and 5-HVLX-gluc breast milk and plasma PK parameters will be presented 
in data listings and summarized by analyte using descriptive statistics (n, mean, SD, CV, 
minimum, median, maximum, geometric mean, and geometric CV). Tmax will be summarized 
using n, median, minimum, and maximum only. 
9. Safety Analysis 
All safety summaries and analyses will be based upon the Safety Population. 
9.1 
Adverse Events 
An AE is defined as 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. 
A treatment-emergent AE (TEAE) is defined as an AE with a start date on or after the first dose 
of SM, or that worsened following first administration of SM. Adverse events are recorded only 
after SM has been administered; therefore, all AEs are treatment-emergent. 
Suspected Adverse Drug Reactions (SADRs) are a subset of AEs for which there is evidence to 
suggest a causal relationship between the SM and the AE, i.e., there is a reasonable possibility 
that the SM caused the AE. Adverse Drug Reactions (ADRs) are a subset of all SADRs for which 
there is reason to conclude that the SM caused the event. 
A serious AE (SAE) is defined as an AE or ADR if, in the view of either the investigator or 
Sponsor, it results in one of the following outcomes: 
• Death 


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• 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 
The AE’s relationship to SM will be evaluated by the investigator. The following relationships 
will be collected on eCRF: definitely related, possibly related, unlikely related, or not related.  
The AEs that are evaluated as definitely related or possibly related will be considered 
treatment-related AEs for summary purpose. 
The severity of AEs will be classified by the investigator as mild, moderate, or severe. 
An overall AE summary will be generated presenting the frequency and percentage of subjects 
and the number of AEs for the following: 
• Any TEAE 
• Any treatment-related TEAE  
• Any moderate TEAE 
• Any treatment-related moderate TEAE 
• Any severe TEAE 
• Any treatment-related severe TEAE 
• Any SAE 
• Any treatment-related SAE 
• Any TEAE leading to study discontinuation 
• Any TEAE leading to treatment discontinuation 
• Any TEAE leading to treatment adjustment (including dose increased, dose reduced, or 
drug interrupted) 
• Any death 
All AEs will be coded using MedDRA version 26.0. The TEAEs will also be summarized by 
system organ class (SOC), PT, and by severity and relationship to SM.  
The TEAE summary tables will be sorted by SOC and PT. System organ class will be displayed 
in descending order of overall frequency then alphabetically. Preferred term will be displayed in 
descending order of overall frequency and then alphabetically within SOC. A subject with 2 or 
more events within the same level of summarization will be counted only once in that level using 




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will also be calculated using the measurements at standing position minus the measurements at 
sitting position at the same timepoint if data permit. 
9.4 
Physical Examinations 
The physical examination will include assessments of head, eyes, ears, nose, throat, skin, thyroid, 
neurological, lungs, cardiovascular, abdomen, lymph nodes, and musculoskeletal, and will be 
performed at the timepoints indicated in the schedule of assessments (Section 13). Any clinically 
significant findings during Screening will be recorded as medical history and any clinically 
significant abnormal findings during treatment will be recorded as an AE. At the EOS physical 
examination, only changes from Baseline will be noted. 
All physical examination results will be presented in a data listing. 
9.5 
Clinical Breast Examinations 
The clinical breast examination is a physical examination of each breast, including visual 
inspection of the skin and nipples, and an assessment of the underarms and collarbone area, and 
will be performed at the timepoints indicated in the schedule of assessments (Section 13). Any 
clinically significant findings during Screening and/or Baseline will be recorded as medical 
history and any clinically significant abnormal findings during or after treatment (after first dose 
of SM) will be recorded as an AE. Only changes from Baseline will be noted for the clinical 
breast examination at the EOS. 
All clinical breast examination results will be presented in the physical examination data listing. 
9.6 
Electrocardiograms 
The ECG will be recorded while the subject is resting in a supine position for at least 5 minutes. 
Heart rate (HR), PR interval, QRS duration, RR interval, QT interval, QT interval corrected for 
heart rate using Fridericia’s formula (QTcF), and interpretation of ECG will be captured on the 
eCRF. 
Single 12-lead ECG will be performed at the timepoints indicated in the schedule of assessments 
(Section 13). Additional ECGs may be performed at other times if deemed necessary by the 
Principal/Site Investigator. 
The actual values and changes from baseline values for numeric ECG data at each time point will 
be summarized for the Safety Population. 
Shift from baseline in interpretation of ECG results will be summarized for the Safety Population 
using the frequency count and percentage of subjects in each category (normal, abnormal and not