An Open-Label, Single-Group Study to Evaluate the Efficacy and Safety of SPN-820 in Adults With Major Depressive Disorder
Phase: PHASE2
Conditions: Major Depressive Disorder
Sponsor: Navitor Pharmaceuticals, Inc.

 
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TITLE PAGE 
 
Protocol Number: 
NAV-17A-008 
Title: 
An Open-Label, Single-Group Study to Evaluate the Efficacy and Safety 
of SPN-820 in Adults With Major Depressive Disorder 
Sponsor: 
Navitor Pharmaceuticals, Inc. 
6 Liberty Square 
PMB #284 
Boston, Massachusetts 02109 USA 
 
Office: 857-285-4328 
Fax: 857-998-6313 
IND Number: 
155072 
Investigational 
Medicinal Product: 
NV-5138 
SPN-820 (Supernus Pharmaceuticals, Inc. product alternative identification 
number) 
Indication: 
Major Depressive Disorder 
Phase: 
2 
Protocol Version: 
3.0 
Amendment: 
Not applicable 
Date: 
14 February 2024 
Good Clinical 
Practice Statement: 
This study is to be performed in full compliance with the International 
Council for Harmonisation Good Clinical Practices and all applicable 
local regulations. All required study documentation will be archived as 
required by regulatory authorities. 

 
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CLINICAL PROTOCOL SYNOPSIS 
Sponsor: Navitor Pharmaceuticals, Inc. 
Investigational Medicinal Product: NV-5138 
SPN-820 (Supernus Pharmaceuticals, Inc. 
alternative product identification number) 
Name of Active Ingredient: 
(S)-2-amino-5,5-difluoro-4,4-dimethylpentanoic 
acid 
Protocol Number: NAV-17A-008 
Phase of Development: 2 
Study Title: An Open-Label, Single-Group Study to Evaluate the Efficacy and Safety of SPN-820 in 
Adults With Major Depressive Disorder 
Number of Study Sites: Up to 6 investigational sites are planned in the United States (US)  
Number of Subjects: Approximately 50 subjects will be enrolled to achieve approximately 40 
subjects completed. 
Indication: Major Depressive Disorder (MDD) 
Objectives: 
Primary Objective: 
• 
To evaluate the efficacy of SPN-820 administered once every 3 days for a 7-day treatment 
period in adults with MDD. 
Secondary Objectives: 
• 
To evaluate the safety and tolerability of SPN-820 administered once every 3 days for a 7-day 
treatment period in adults with MDD. 
Exploratory Objective: 
• 
To characterize the effect of SPN-820 on brain-derived neurotrophic factor (BDNF) 
concentrations. 
Endpoints: 
Primary Endpoint: 
• 
Change from baseline to each time point in the Hamilton Depression Rating Scale-6 Items 
(HAM-D6) total score. 
Secondary Efficacy Endpoints: 
• 
Change from baseline to each time point in the Montgomery–Åsberg Depression Rating Scale 
(MADRS) total score. 
• 
Change from baseline to each time point in the Clinical Global Impression – Severity of Illness 
(CGI-S) total score. 
• 
Proportion of subjects achieving a ≥50% reduction from baseline in the MADRS total score. 
• 
Proportion of subjects in remission (MADRS total score ≤10) at each time point. 

 
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• 
Percentage of subjects with a CGI-S score of 1 or 2 at each time point. 
Safety Endpoints: 
• 
Treatment-emergent adverse events (TEAEs). 
• 
Clinical safety laboratory test results. 
• 
Vital sign measurements including orthostatic blood pressure and pulse rate. 
• 
Body weight. 
• 
Electrocardiography (ECG) findings. 
• 
Physical examination findings. 
• 
Suicidal ideation and behavior as measured by the Columbia Suicide Severity Rating Scale 
(C-SSRS) score. 
• 
Dissociative symptomatology as measured by Clinician-Administered Dissociative State Scale 
(CADSS) score. 
• 
Psychopathology severity as measured by Brief Psychiatric Rating Scale Positive Subscale 
(BPRS+) score. 
Exploratory Endpoint: 
• 
Change from baseline to each time point for BDNF concentrations. 
Study Design: 
This is an open-label study of SPN-820 administered orally every 3 days for a 7-day treatment period 
in adult subjects with MDD. The study consists of a 28-day screening period, a 10-day evaluation 
period (clinic and home), and a safety follow-up phone call approximately 5 (+2) days after the last 
administration of study medication (SM). 
To be eligible, subjects must be taking 1 approved antidepressant medication (i.e., an approved therapy 
for depression; Appendix 11.2) at a stable dosage for a minimum of 6 weeks before the screening visit. 
If a subject is taking a second antidepressant or an augmentation therapy, the investigator will decide 
the appropriate medication that should be discontinued. The second medication should be discontinued 
for at least 5 half-lives before baseline. In addition, subjects must maintain a MADRS total score ≥22, 
a CGI-S score ≥4, and a detectable level of antidepressant therapy (ADT) during the screening period 
to be eligible. If the MADRS total scores vary ≥25% between the highest and lowest score from 
screening to baseline (Day 1), subjects will be excluded. All subjects who meet the eligibility criteria 
will take 2400 mg (six 400 mg capsules) of SPN-820 orally and continue their ADT at a stable and 
therapeutic dose while in the study. 
The evaluation period includes 4 clinic visits (on days 1, 4, 7 and 10). Subjects will receive SM at the 
clinic on days 1, 4 and 7. Subjects will not receive SM on days 2, 3, 5, 6, 8, 9 and 10. Subjects will 
continue their ADT throughout the study. All safety, efficacy, 
, and pharmacodynamic (PD) 
assessments and procedures will be performed as outlined in Table 1 and Table 2. 

 
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At the end of study (EOS; Day 10) or early termination (ET), if applicable, subjects will return to the 
clinic for the EOS visit. Approximately 5 days (+2 days) after the last administration of SM (Day 7) 
and once all study visits are completed; subjects will receive a safety follow-up phone call. Subjects 
who discontinue the study due to adverse events (AEs) will be followed for at least 30 days following 
the date of last administration of SM or until resolution, or until, in the medical judgment of the 
investigator, the event has stabilized or is assessed as chronic. 
Duration of Subjects’ Participation: 
The total study duration for each subject’s participation is up to 40 days (screening period [up to 
28 days], evaluation period [10 days], and safety follow-up phone call [5 days from Day 7]). 
Investigational Medicinal Products, Reference Therapy, Doses and Mode of Administration: 
Study Medication: SPN-820 400 mg capsules 
Dosage: 2400 mg (six 400-mg capsules) administered once a day every 3 days 
Mode of Administration: Oral, as intact capsules, in the morning approximately 3 hours after breakfast 
Sampling for 
 Pharmacodynamic Assessments: 
 
 
. 
Seven total blood samples will be collected for measurement of BDNF concentrations: 3 pre-dose 
collections on days 1, 4, and 7; 3 post-dose collections 4 hours after SM administration on days 1, 4, 
and 7; and 1 collection on Day 10.  
Statistical Methodology: 
Sample Size: Approximately 50 subjects will be enrolled to achieve approximately 40 subjects 
completed. This sample size is based on clinical judgment without a power calculation. 
Analysis Populations: 
The full analysis set (FAS) includes all subjects who receive at least one dose of SM and have a 
baseline and at least one post-baseline measurement of HAM-D6. 
The safety population includes all subjects who receive at least one dose of SM. 
 
. 
The PD population includes subjects who receive at least one dose of SM and have a baseline and at 
least one post-baseline BDNF concentration. 
Statistical Methods: Continuous variables will be summarized using descriptive statistics (i.e., number 
of subjects, mean, standard deviation, median, interquartile range [Q1and Q3], minimum and 
maximum values). Categorical variables will be summarized with counts and percentages. 
The efficacy, safety, 
 and PD endpoints will be analyzed descriptively using the FAS, safety, 
 
and PD populations, respectively. Unless otherwise specified, no missing data will be imputed. Details 
of data analyses will be described in the statistical analysis plan. 

 
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Inclusion Criteria: 
1. Is a male or female subject, aged 18 to 65 years (inclusive) at screening. 
2. Capable of giving signed informed consent, able to understand and comply with protocol 
requirements, instructions, and protocol-related restrictions, and likely to complete the study as 
planned. 
3. Has a body mass index 19.0 to 40.0 kg/m2 (inclusive). 
4. Is able to swallow each capsule whole, without crushing, chewing, or opening. 
5. Has a current diagnosis of MDD according to the Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition (DSM-5) for either recurrent or single episode MDD without psychotic 
features that is confirmed by the Mini International Neuropsychiatric Interview (MINI) at 
screening. 
6. Has a MADRS total score of ≥22 for the current major depressive episode (MDE) at screening 
and baseline (Day 1) before SM administration. 
7. Has a CGI-S score of ≥4 (moderately ill or worse) at screening and baseline (Day 1) before 
SM administration. 
8. Has been on a stable, therapeutic dose of one of the following study-approved ADTs for the 
current MDE for ≥6 weeks prior to screening: citalopram, escitalopram, paroxetine, fluoxetine, 
sertraline, duloxetine, venlafaxine (immediate release or extended release), desvenlafaxine, 
vilazodone, levomilnacipran, vortioxetine, bupropion, or dextromethorphan/bupropion. Subject 
must be on antidepressant monotherapy before baseline. 
Note: If a subject is taking a second ADT or augmentation therapy at screening, the 
investigator should decide if it is medically appropriate to discontinue the second drug before 
baseline. If so, the second drug should be discontinued for at least 5 half-lives prior to baseline. 
If not, the subject should be excluded from the study. 
9. Agrees to maintain a stable therapeutic dose of the approved ADT throughout the study. 
10. Non-pregnant female subjects of childbearing potential (FOCP) who are exclusively in a same-
sex relationship are included without the need of acceptable birth control methods. 
FOCP who are sexually active with a male partner (who is biologically capable of having 
children), must agree to use one of the following acceptable birth control methods after signing 
the informed consent form (ICF), throughout the study, and for 30 days following the last dose 
of SM: 
a. Simultaneous use of male condom and intra-uterine contraceptive device placed at least 
4 weeks prior to the first administration of SM. 
b. Simultaneous use of a male condom and diaphragm with spermicide. 
c. Established hormonal contraceptive (started at least 4 weeks prior to the first dose of SM). 
Female subjects are considered to be not of childbearing potential if they are either 
postmenopausal (amenorrhea for at least 2 years and serum follicle-stimulating hormone level 
of >40 IU/L) or permanently sterilized (e.g., bilateral tubal ligation, bilateral oophorectomy, or 
bilateral salpingectomy etc.) for a minimum of 6 months prior to screening. 
All FOCP must have a negative serum pregnancy test result before administration of SM. 
11. Male subjects 
a. Who have been surgically sterilized (6 months minimum) prior to Screening visit are 
eligible to participate without any contraception. 
b. Who are biologically capable of having children and have female partners of childbearing 
potential must use one or more methods of contraception as stated in IC #10 which must be 
used from the time of signing the ICF until 90 days after the last dose of SM. 

 
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c. Who are exclusively in a same-sex relationship or have female partners considered not to 
be of childbearing potential are required to use a condom from the first administration of 
SM through 7 days after the last administration of SM. 
All male subjects must refrain from donating sperm from the first administration of SM until 
90 days after the last administration of SM. 
Exclusion Criteria: 
1) Has a MADRS total score improvement of ≥25% from the highest to the lowest score from 
screening to baseline. 
2) Has been treated with electroconvulsive therapy, transcranial magnetic stimulation, or vagal nerve 
stimulation for the current MDE within 6 months prior to screening. 
3) Has received treatment with long-acting injectable antipsychotics within 3 months prior to 
screening. 
4) Has demonstrated a non-response to esketamine or off-label use of ketamine; or has taken 
esketamine or ketamine <6 months prior to screening. 
5) If treated with trazodone, is unable to discontinue treatment with doses >150 mg daily for a 
minimum of 5 half-lives before baseline. 
Note: trazodone ≤150 mg/day for sleep is permitted as needed if the subject has been taking the 
same low dose of trazodone for insomnia for at least 3 months. 
6) Has unstable hypothyroidism. If the thyroid-stimulating hormone value is out of range 
(>4.0 mIU/L), regardless of thyroid history, a free thyroxine (FT4) will be measured. If the FT4 
value is abnormal (levels <0.8 mIU/L) and considered to be clinically significant (after discussion 
with the Medical Monitor), the subject will not be eligible. 
Note: treatment with thyroid hormones is allowed if taken at a stable dose for ≥ 3 months and the 
subject’s thyroid levels are normal. 
7) Has clinically significant abnormal laboratory profiles (alanine aminotransferase or aspartate 
aminotransferase values ≥3 × the upper limit of normal [ULN] or total bilirubin ≥1.5 × ULN), vital 
sign measurements, or ECGs prior to baseline, per investigator judgment (see Note below). If there 
are any abnormalities that are not specified in the inclusion and exclusion criteria, the investigator 
must determine their clinical significance and record it in the subject’s source documents. 
8) Has abnormal renal function as demonstrated by an estimated glomerular filtration rate 
≤60 mL/min according to the Chronic Kidney Disease Epidemiology Collaboration equation 
(CKD-EPI) equation at screening and baseline. 
9) Has a history of substance use disorder within 6 months prior to screening or is currently using or 
has a positive result (urine drug screen) at screening or baseline for drugs of abuse (except for 
cannabis, see exclusion 11). 
10) Has a history of alcohol use disorder within 6 months prior to screening. A subject who has a 
positive alcohol test result at screening and, if based on the investigator’s opinion the subject does 
not have a history of alcohol use disorder, the subject may continue to the baseline visit. Subjects 
who have a positive alcohol test result at baseline will be excluded. Subjects should refrain from 
using alcohol during the study. Subjects who have a positive alcohol test result on days 1, 4, or 7 
will be withdrawn from the study. 
11) Has a diagnosis of cannabis use disorder within 6 months before screening and has a positive urine 
drug screen for cannabis at screening. 
a. At the discretion of the Sponsor, recreational use (not daily) is allowed and should be kept 
consistent during the study. Subjects must agree to refrain from using cannabis 48 hours prior 
to the clinic visits. 
b. Medical cannabis prescribed for a medical condition (e.g., muscle spasms, nausea, vomiting, 
pain) other than depression and seizures is allowed if taken at a stable regimen for at least 3 

 
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months prior to screening (Appendix 11.1.1). Newly prescribed cannabis treatment and/or a 
change to the existing regimen are/is prohibited. When applicable, subjects should show proof 
of their prescription for medical cannabis. 
12) Has had any suicidal behavior or suicidal ideation of type 4 (active suicidal ideation with some 
intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and intent) 
based on the C-SSRS in the 1 year before screening; a history of suicide attempt in the last 2 years; 
or more than 2 lifetime suicide attempts. 
13) Has a lifetime history of psychotic disorder, including but not limited to schizophrenia, MDD with 
psychotic features, or bipolar I/II disorder with and without psychotic features. 
14) Has a diagnosis within the last 12 months before screening or current diagnosis of post-traumatic 
stress disorder, obsessive-compulsive disorder, panic disorder, acute stress disorder, or has a 
history of intellectual disability, autism, or cluster A or B personality disorder (per DSM-5 
criteria). 
a. Current diagnosis of co-morbid generalized anxiety disorder is allowed but is subject to 
medication restrictions (anticonvulsants and beta-blockers are allowed if the subject is on a 
stable regimen for 2 months prior to screening). 
b. Established attention-deficit/hyperactivity disorder (ADHD) diagnosis is allowed. Subjects 
must provide confirmation of ADHD diagnosis (i.e., provide medical records for prescribed 
ADHD medications) and be on a stable dose of ADHD medication for at least 3 months prior 
to screening. 
15) Has a history of a psychiatric or neurologic condition or symptoms that could impose undue risk or 
compromise the study including but not limited to: 
a. History of seizure disorder or history of epilepsy (except history of absence or uncomplicated 
childhood febrile seizures). 
b. History of clinically significant or moderate head trauma that, in the investigator's opinion, is 
likely to affect central nervous system functioning. 
c. Has current evidence of delirium or dementia. 
16) Has a history of cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other 
medical disorder that could impose undue risk or compromise the study, in the investigator’s 
opinion, including but not limited to: 
a. Cardiovascular: 
i. 
Clinically significant symptomatic orthostatic hypotension. 
ii. 
Uncontrolled hypertension despite diet, exercise, and antihypertensive medications. 
iii. 
Acute coronary syndrome. 
iv. 
History of unexplained loss of consciousness, unexplained syncope, unexplained 
irregular heartbeats. 
v. 
QT interval corrected using Fridericia’s method ≥450 msec (for men) or ≥470 msec 
(for women) at screening (see Note below). 
vi. 
Subject or family history of congenital long QT syndrome. 
b. Oncological: 
i. 
Malignant tumors within 5 years prior, with the exception of benign skin tumors. 
ii. 
Diagnosis or family history of tuberous sclerosis complex. 
c. Positive result for human immunodeficiency virus 1/2 antigen/antibody (HIV 1/2 Ag/Ab), 
hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCV Ab) at screening, unless: 
i. 
HIV 1/2 Ag/Ab positive: subjects must have an HIV confirmation test. If the 
confirmatory test is positive, subjects are eligible if they are on chronic suppressive 
antiviral medication for >6 months with an undetectable viral load at screening. 

 
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ii. 
HBsAg positive: subjects should be tested for immunoglobulin M antibody to hepatitis 
B core antigen and hepatitis B surface antibody to detect acute or chronic infection 
(ineligible). Subjects whose results indicate immunity (either by natural infection or 
vaccination) with no active infection are eligible. 
iii. 
HCV Ab positive: subjects must have undetectable HCV ribonucleic acid to be 
eligible. 
d. Unintended recent clinically significant weight loss in the investigator’s opinion. 
e. Has chronic urinary tract infections. 
f. Blood donation or loss of blood of ≥500 mL within 56 days prior to screening. 
g. Is on any medication that could, in the investigator’s opinion, interfere with the assessments of 
safety, tolerability, or efficacy, or interfere with the conduct or interpretation of the study. 
17) Requires treatment with a medication or other substance that is prohibited by the protocol (see 
Section 5.7.2). 
18) Has history of severe drug allergy or hypersensitivity, or hypersensitivity to the SM or excipients. 
19) Female subjects who are pregnant or lactating or planning to become pregnant while enrolled in 
the study. 
20) In the investigator's opinion, is unlikely to comply with the protocol or is unsuitable for any other 
reason. 
21) Has previously enrolled in a NV-5138 study. 
22) Is currently participating in another clinical trial or has received an investigational product in 
another clinical trial within 30 days of screening. 
23) Is a member of study personnel or of their immediate families or is a subordinate (or immediate 
family member of a subordinate) to any of the study personnel. 
 
Note: Repeat testing for clinical laboratory parameters, vital signs, and ECG is permitted one time for 
each test, at the discretion of the investigator, as long as the repeat test result is available within the 
28-day screening period to determine eligibility. Repeat testing is not allowed without justification 
from the study site and agreement from the Medical Monitor and the Sponsor on a case-by-case basis. 

 
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Table of Contents 
TITLE PAGE ............................................................................................................................... 1 
INVESTIGATOR’S SIGNATURE PAGE ................................................................................ 2 
SUPERNUS PROTOCOL APPROVAL PAGE ....................................................................... 3 
NAVITOR PROTOCOL APPROVAL PAGE ......................................................................... 4 
CLINICAL PROTOCOL SYNOPSIS ....................................................................................... 5 
1 
LIST OF ABBREVIATIONS ....................................................................................... 15 
2 
INTRODUCTION ......................................................................................................... 17 
2.1 
Background ............................................................................................................ 17 
2.2 
SPN-820 ................................................................................................................ 17 
2.3 
Nonclinical Studies ................................................................................................ 17 
2.4 
Clinical Studies ...................................................................................................... 18 
2.5 
Study Rationale...................................................................................................... 20 
2.6 
Summary of Benefits and Risks ............................................................................ 21 
3 
STUDY OBJECTIVES AND ENDPOINTS ............................................................... 22 
3.1 
Objectives .............................................................................................................. 22 
3.2 
Endpoints ............................................................................................................... 22 
4 
INVESTIGATIONAL STUDY PLAN ......................................................................... 24 
4.1 
Overall Study Design and Plan .............................................................................. 24 
4.2 
Study Population .................................................................................................... 25 
4.3 
Completion of Study .............................................................................................. 31 
4.4 
Discontinuation or Early Termination of Subjects ................................................ 31 
5 
STUDY TREATMENT ................................................................................................. 33 
5.1 
Study Medication Identity, Packaging, and Labeling ............................................ 33 
5.2 
Study Medication Administration .......................................................................... 33 
5.3 
Missed Study Medication Administrations or At-Home Phone Calls .......................... 33 
5.4 
Subjects’ Antidepressant Therapy .......................................................................... 33 
5.5 
Method of Assigning Subjects to Treatment ......................................................... 34 
5.6 
Study Medication Handling and Accountability .................................................... 34 
5.7 
Concomitant and Prohibited Medications .............................................................. 35 
6 
STUDY METHODS ...................................................................................................... 37 
6.1 
Clinic Study Visits and Procedures ....................................................................... 44 
6.2 
Home Evaluations ................................................................................................. 47 
6.3 
Safety Follow-Up Phone Call (Day 12) ................................................................ 48 
6.4 
Unscheduled Visits ................................................................................................ 48 
6.5 
Urine Drug and Alcohol Screen ............................................................................ 48 
6.6 
Pharmacokinetic Blood Sampling ......................................................................... 48 
6.7 
Pharmacodynamic Blood Sampling ...................................................................... 49 
7 
STUDY VARIABLES AND ASSESSMENTS ............................................................. 50 

 
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7.1 
Rater Qualification Process ................................................................................... 50 
7.2 
Safety Variables and Assessments ......................................................................... 52 
7.3 
Treatment-Emergent Suicidal Ideation .................................................................. 56 
7.4 
Clinical Measurements .......................................................................................... 58 
7.5 
 
7.6 
Pharmacodynamic Variables and Assessments..................................................... 59 
7.7 
Screening Scales and Assessment Tools................................................................ 60 
8 
STATISTICAL METHODS ......................................................................................... 61 
8.1 
General Considerations .......................................................................................... 61 
8.2 
Sample Size and Power Considerations ................................................................. 61 
8.3 
Handling of Dropout or Missing Data ................................................................... 61 
8.4 
Analysis Populations ............................................................................................. 61 
8.5 
Demographics and Baseline Analysis ................................................................... 61 
8.6 
Population Disposition .......................................................................................... 61 
8.7 
Study Medication Exposure .................................................................................. 62 
8.8 
Medical History ..................................................................................................... 62 
8.9 
Prior and Concomitant Medications ...................................................................... 62 
8.10 
Efficacy Analyses .................................................................................................. 62 
8.11 
 
8.12 
Pharmacodynamic Analysis .................................................................................. 63 
8.13 
Safety Analysis ...................................................................................................... 63 
8.14 
Interim Analysis .................................................................................................... 63 
9 
DOCUMENTATION .................................................................................................... 64 
9.1 
Adherence to the Protocol ..................................................................................... 64 
9.2 
Changes to the Protocol ......................................................................................... 64 
9.3 
Data Quality Assurance ......................................................................................... 64 
9.4 
Retention of Records ............................................................................................. 65 
9.5 
Auditing Procedures .............................................................................................. 66 
9.6 
Publication of Results ............................................................................................ 66 
9.7 
Financing and Insurance ........................................................................................ 66 
9.8 
Disclosure and Confidentiality .............................................................................. 66 
9.9 
Discontinuation of Study ....................................................................................... 66 
10 
ETHICS .......................................................................................................................... 68 
10.1 
Institutional Review Boards .................................................................................. 68 
10.2 
Ethical Conduct of the Study ................................................................................. 68 
10.3 
Investigator and Study Personnel .......................................................................... 68 
10.4 
Subject Information and Consent .......................................................................... 68 
11 
APPENDIX .................................................................................................................... 70 
11.1 
Prohibited and Permitted Concomitant Medications ............................................... 70 
11.2 
Approved Antidepressant Treatment ..................................................................... 74 

 
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12 
SUMMARY OF AMENDMENT CHANGES ............................................................ 76 
13 
REFERENCES .............................................................................................................. 77 
 
 
 
List of Tables 
 
Table 1:  
Schedule of Events and Assessments .................................................................... 38 
Table 2: 
Detailed Schedule of Timed Assessments (Window) ........................................... 42 
Table 3:  
Clinical Laboratory Tests ...................................................................................... 58 
 

 
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1 LIST OF ABBREVIATIONS 
Abbreviation 
Definition of Term 
ACE 
angiotensin-converting enzyme 
ADHD 
attention-deficit/hyperactivity disorder 
ADR 
adverse drug reaction 
ADT 
antidepressant therapy 
AE 
adverse event 
AUC 
area under the concentration-time curve 
BDNF 
brain-derived neurotrophic factor 
BPRS+ 
Brief Psychiatric Rating Scale Positive Subscale 
CADSS 
Clinician-Administered Dissociative State Scale 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression – Severity of Illness 
ClinRO 
clinician-reported outcome 
Cmax 
maximum observed concentration 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
Ctrough 
trough concentration 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – 5th Edition 
ECG 
electrocardiography 
eCRF 
electronic case report form 
EOS 
end of study 
ES 
effect size 
ET 
early termination 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FOCP 
female subjects of childbearing potential 
FPC 
follow-up phone call 
FSH 
follicle-stimulating hormone 
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
HAM-D6 
Hamilton Depression Rating Scale – 6 Items 
HBsAg 
hepatitis B surface antigen 
HCV Ab 
hepatitis C antibody 
HIV 1/2 Ag/Ab 
human immunodeficiency virus 1/2 antigen/antibody 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
MADRS 
Montgomery–Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MINI 
Mini International Neuropsychiatric Review 
mTORC1 
mechanistic target of rapamycin complex 1 
NMDAR 
N-methyl-D-aspartate receptor 
PD 
pharmacodynamics 

 
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Abbreviation 
Definition of Term 
PK 
pharmacokinetics 
POC 
point-of-care 
PT 
Preferred Term 
QTcF 
QT corrected using Fridericia’s method 
SADR 
suspected adverse drug reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SM 
study medication 
SOC 
System Organ Class 
TDD 
total daily dose 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum observed concentration 
TRD 
treatment-resistant depression 
ULN 
upper limit of normal 
US 
United States 
 

 
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2 
INTRODUCTION 
2.1 
Background 
SPN-820 (Supernus Pharmaceuticals, Inc. product alternative identification number) is being 
developed to provide rapid-onset antidepressant response via oral administration for the 
treatment of adult patients with treatment-resistant depression (TRD). Major depressive disorder 
(MDD) is a common psychiatric disorder, with a lifetime prevalence of approximately 13 to 17% 
in the United States (US) (Hasin 2005; Kessler 2005; Otte 2016). Although options for 
pharmacologic treatment have expanded significantly in the past 25 years, patients with MDD 
typically require 6 to 12 weeks to respond to pharmacotherapy. Up to two-thirds of patients with 
MDD will not respond to the first antidepressant prescribed, and up to one-third will not respond 
to multiple interventions; the latter is commonly defined as TRD (Berlim 2008; Cain 2007; 
Karasu 2000). 
There are several novel antidepressants either in clinical development or approved for the 
treatment of TRD that modulate the N-methyl-D-aspartate and its receptor, N-methyl-D-
aspartate receptor (NMDAR), leading to rapid and sustained symptom relief in patients with 
TRD (Abdallah 2015; Zarate 2017). However, acute modulation of the NMDAR has been 
associated with dissociative and other undesirable neurological effects. Thus, alternative 
therapeutic options for TRD not involving NMDAR modulation could be of great value in 
treating patients with TRD (Pennybaker 2017). There is substantial evidence from animal models 
that rapid-acting antidepressants such as ketamine require post-synaptic activation of mechanistic 
target of rapamycin complex 1 (mTORC1) signaling following NMDAR modulation for their 
antidepressant effects (Harmer 2017). The central role of mTORC1 signaling in the rapid-acting 
antidepressant effects of several agents suggests that a direct activator of mTORC1 signaling 
may provide rapid antidepressant efficacy without the potential neurological side effects 
associated with some NMDAR-modulating compounds. 
2.2 
SPN-820 
SPN-820 (also called NV-5138 [in a joint development agreement with Navitor Pharmaceuticals, 
Inc.]) is a first-in-class, orally bioavailable, selective activator of the mTORC1 signaling 
pathway. The proposed mechanism of SPN-820, via the direct activation of mTORC1 signaling, 
involves the compound binding to sestrin protein isoforms 1 and 2 leading to the direct activation 
of mTORC1 signaling without binding to, or modulating, other synaptic receptors or other 
signaling proteins (e.g., NMDAR). 
2.3 
Nonclinical Studies 
In multiple preclinical rodent models of stress-induced depressive behavior, including the female 
urine sniffing test, the novelty-suppressed feeding test, chronic unpredictable stress test, the 
forced swimming test, and the non-human primate human threat test, oral administration of SPN-
820 was shown to be comparable to injectable ketamine in terms of efficacy and duration of 
antidepressant effect (Section 4.1.3 of the Investigator’s Brochure [IB]; Supernus 
Pharmaceuticals 2022). Like ketamine (Li 2011), the antidepressant effects of SPN-820 were 
shown to be dependent on the activation of mTORC1 signaling and brain-derived neurotrophic 
factor (BDNF) and were associated with an increase in synaptic protein expression (e.g., 

 
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glutamate ionic receptor AMPA type subunit 1, synapsin1) and the induction of dendritic spine 
formation in layer V pyramidal neurons in the medial prefrontal cortex. In addition to 
demonstrating efficacy in several models of stress-induced depressive behavior, SPN-820 was 
also shown to significantly increase relative power in the delta band frequency of the 
electroencephalography profile following a second and third sequential dose in conscious rats, 
suggesting a potential translational approach to measuring the effects of the compound clinically. 
Detailed information from the SPN-820 clinical development program (e.g., nonclinical 
pharmacology, pharmacokinetics [PK] and drug metabolism in animals, and toxicology) are 
provided in the IB (Supernus Pharmaceuticals 2022). 
2.4 
Clinical Studies 
The PK, pharmacodynamics (PD), preliminary efficacy, and safety of SPN-820 have been 
evaluated in 6 completed Phase 1 clinical studies. 
Completed Studies 
A total of 145 adult subjects have been exposed to SPN-820 in the Phase 1 studies, including 129 
healthy subjects and 16 subjects with TRD. Single doses up to 2400 mg and multiple doses up to 
3000 mg for 7 days have been administered in the Phase 1 clinical studies. 
• Study NAV-17A-001 was a Phase 1a/1b, randomized, two-part, double-blind, 
placebo-controlled, on-site study of single ascending dosage levels of SPN-820 or 
placebo in 48 healthy subjects (Part A) and a single dose of SPN-820 2400 mg or placebo 
in 32 subjects with TRD (Part B). 
• Study NAV-17A-002 was a Phase 1, randomized, double-blind, placebo-controlled, 
on-site, single-dose study to evaluate the safety, PK, metabolomic and proteomic profiles 
of SPN-820 in plasma and cerebrospinal fluid (CSF) in healthy male subjects between the 
ages of 18 and 55 years. 
• Study NAV-17A-003 was a randomized, double-blind, placebo-controlled, on-site study 
of the effects on quantitative electroencephalography and event-related potential of 2 
sequential doses of SPN-820 or placebo administered 48 hours apart, to healthy adult 
male subjects. 
• Study NAV-17A-004 was a Phase 1, randomized, double-blind, placebo-controlled, 
single-center study of the safety, tolerability, and PK of multiple ascending doses of 
SPN-820 in healthy subjects. 
• Study NAV-17A-005 was a Phase 1, 4-period, 4-treatment, 4-sequence crossover study in 
which subjects received a single dose of SPN-820 400 mg oral solution, 400 mg capsule, 
1600 mg oral solution, and 1600 mg capsule under fasted conditions. 
• Study NAV-17A-006 was a Phase 1, open-label, singe-dose, mass balance study to assess 
the disposition of [14C]-SPN-820 in healthy male subjects. 

 
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Completed Study Results 
Safety 
The majority of treatment-emergent adverse events (TEAEs) reported by healthy subjects were 
reported as mild, none were severe, and all resolved. The most frequently reported TEAEs by 
healthy subjects included dizziness (postural dizziness and orthostatic hypotension) nausea, 
headache, and somnolence. Two subjects who received single doses of SPN-820 400 mg 
discontinued due to adverse events (AEs): muscle strain, nausea, and vomiting (n=1); vomiting 
(n=1). 
The most frequently reported TEAEs by subjects with TRD (n=32) included somnolence, 
dizziness, and headache. The majority of TEAEs did not require treatment and resolved without 
sequelae. 
Preliminary Assessments of Efficacy 
 
 
 
 
 
 
 
 

 
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Ongoing Study 
• Study NAV-17A-007 is an ongoing Phase 2, randomized, double-blind, 
placebo-controlled, multicenter study to evaluate the efficacy of flexible doses of 
SPN-820 800 to 1600 mg or placebo in subjects with TRD. 
2.5 
Study Rationale 
SPN-820, the investigational medicinal product for this study, is being developed to provide a 
rapid-onset antidepressant response via oral administration and is currently being investigated in 
a Phase 2 study (Study NAV-17A-007) for the treatment of depression in adult subjects with 
TRD. This study (Study NAV-17A-008) is designed to characterize the antidepressant response 
and early onset of response of SPN-820 when administered every 3 days for a 7-day treatment 
period in adult subjects with MDD. The exposure-response relationship at the efficacious dose of 
SPN-820 and the engagement of mTORC1 activation will also be explored. 
Rationale for Dose Regimen 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale for Primary and Secondary Endpoints 
The appropriately selected scales as the primary and secondary efficacy endpoints are the 
HAM-D6, MADRS, and CGI-S. 

 
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The Hamilton Depression Rating Scale is one of the most widely used clinician-administered 
depression scales (Hamilton 1960; Williams 1988). Because the HAM-D6 is sensitive to 
short-term changes in depression symptoms, change in HAM-D6 total score was selected as the 
primary outcome measure for this study. 
The MADRS is a validated tool that measures the severity of depressive episodes in patients and 
is designed to be sensitive to changes brought on by treatment (Montgomery 1979). Change in 
MADRS total score was selected as a secondary outcome measure because MADRS is a 
clinician/investigator structured interview assessing the severity of MDD symptoms per the 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria. MDD 
severity is also addressed by the inclusion criteria related to severity score of several MADRS 
items. 
The CGI-S is a 7-point scale of the clinician’s assessment of the severity of symptoms in relation 
to the clinician’s total experience with the patient population. The CGI-S was selected as a 
secondary outcome measure because it is commonly used as a reliable measure of severity of a 
disease/disorder in clinical research, as well as a measure of change in severity over time during 
an experimental treatment. 
2.6 
Summary of Benefits and Risks 
Detailed information about the known and expected benefits and risks and reasonably expected 
AEs of SPN-820 is provided in the current SPN-820 IB (Supernus Pharmaceuticals 2022). 
Single dose SPN-820 2400 mg produced rapid and sustained efficacy signals on the core 
symptoms of depression as measured by the HAM-D6, including statistically significant 
improvement at 4- and 12-hours post-dose compared to placebo. 
Subjects in the study will contribute to the process of developing a novel, oral, adjunctive 
antidepressant.

 
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3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 Objectives 
3.1.1 Primary Objective 
• To evaluate the efficacy of SPN-820 administered once every 3 days for a 
7-day treatment period in adults with MDD. 
3.1.2 Secondary Objectives 
• To evaluate the safety and tolerability of SPN-820 administered once every 3 
days for a 7-day treatment period in adults with MDD. 
 
 
 
3.1.3 Exploratory Objective 
• To characterize the effect of SPN-820 on BDNF concentrations. 
3.2 Endpoints 
3.2.1 Primary Endpoint 
• Change from baseline to each time point in the HAM-D6 total score. 
3.2.2 Secondary Efficacy Endpoints 
• Change from baseline to each time point in the MADRS total score. 
• Change from baseline to each time point in the CGI-S total score. 
• Proportion of subjects achieving a ≥50% reduction from baseline in the 
MADRS total score. 
• Proportion of subject in remission (MADRS total score ≤10) at each time 
point. 
• Percentage of subjects with a CGI-S score of 1 or 2 at each time point. 
 
 
 
 
. 
3.2.4 Safety Endpoints 
• TEAEs. 
• Clinical safety laboratory test results. 
• Vital sign measurements including orthostatic blood pressure and pulse rate. 

 
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• Body weight. 
• Electrocardiography (ECG) findings. 
• Physical examination findings. 
• Suicidal ideation and behavior as measured by the Columbia Suicide Severity 
Rating Scale (C-SSRS) score. 
• Dissociative symptomatology as measured by the Clinician-Administered 
Dissociative State Scale (CADSS) score. 
• Psychopathology severity as measured by the Brief Psychiatric Rating Scale 
Positive Subscale (BPRS+) score. 
3.2.5 Exploratory Endpoint 
• Change from baseline to each time point for BDNF concentrations. 

 
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4 
INVESTIGATIONAL STUDY PLAN 
4.1 
Overall Study Design and Plan 
This is an open-label study of SPN-820 administered orally once every 3 days for a 7-day 
treatment period in adult subjects with MDD. Approximately 50 subjects will be enrolled 
into the study. The study consists of a 28-day screening period, a 10-day evaluation period 
(clinic and home), and a safety follow-up phone call approximately 5 (+2) days after the 
last administration of study medication (SM). The total study duration from the screening 
visit to completion of the safety follow-up phone call is up to 40 days. 
The Schedule of Events and Assessments is provided in Table 1, and a detailed Schedule of 
Timed Assessments with windows is provided in Table 2. 
Screening Period (up to 28 days, Day -28 to Day -1): The screening period is up to 
28 days, and after informed consent is obtained, subjects will undergo initial screening 
evaluations as outlined in Table 1. Subjects will have their diagnosis of MDD confirmed 
by the Mini International Neuropsychiatric Interview (MINI). To be eligible, subjects must 
be taking 1 study-approved antidepressant medication (i.e., an approved therapy for 
depression; Appendix 11.2) at a stable dosage for a minimum of 6 weeks before the 
screening visit. If a subject is taking a second antidepressant or an augmentation therapy, 
the investigator will decide the appropriate medication that should be discontinued. The 
second medication should be discontinued for at least 5 half-lives before baseline. 
Subjects should maintain their current, stable antidepressant therapeutic dose for their 
study-approved antidepressant therapy (ADT) through the screening period. Dose 
adjustment of ADT will not be allowed at any time during the study. ADTs approved for 
use in this study will not be supplied by the Sponsor. 
In addition, subjects must maintain a MADRS total score ≥22, a CGI-S score ≥4, and a 
detectable level of ADT during the screening period to be eligible. If the MADRS total 
scores vary ≥25% between the highest and the lowest score from screening to baseline 
(Day 1), subjects will be excluded. 
Subjects who do not meet eligibility criteria at any time during the screening period will be 
excluded. Re-screening is not permitted. Protocol waivers in the study will be granted on a 
case-by-case basis after approval from the Sponsor. 
Evaluation Period (Day 1 [baseline] to Day 10): All eligible subjects will receive 
SPN-820 orally at 2400 mg (six 400 mg capsules) once every 3 days for a 7-day treatment 
period (on days 1, 4, and 7). The 10-day evaluation period consists of 4 clinic visits (on 
days 1, 4, 7, and 10) and 6 at-home phone call assessments (on days 2, 3, 5, 6, 8, and 9). 
All safety, efficacy, 
 and PD assessments will be performed as outlined in Table 1 
(Schedule of Events and Assessments) and Table 2 (Detailed Schedule of Timed 
Assessments). 

 
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Subjects should maintain their current, stable antidepressant therapeutic dose for the study-
approved ADT through the evaluation period. Subjects will take their ADT at home and 
record the administration in a paper ADT adherence diary. Dose adjustments of ADTs will 
not be allowed at any time during the study. ADTs approved for use in this study will not 
be supplied by the Sponsor. 
Clinic Visits 
On days 1 (baseline), 4, and 7, during their in-clinic visits, subjects will receive a single, 
oral dose of SPN-820 2400 mg (six 400 mg capsules). After Day 7, SM will be 
discontinued, and subjects should continue with their ADT. 
At-Home Phone Call Assessments 
On days 2, 3, 5, 6, 8, and 9, subjects will continue taking their ADT at home. Subjects will 
receive a telephone call for remote efficacy (i.e., HAM-D6 and MADRS) and safety 
(i.e., review of AEs, review of concomitant medications, C-SSRS [Since Last Visit 
Version], CADSS, and BPRS+) assessments. 
End of Study/Early Termination 
Subjects will have completed the study after completing the safety follow-up phone call at 
Day 12 (±2). After completion of the end of study (EOS) study procedures, subjects should 
continue with their ADT. If the subject withdraws or is terminated early, he/she will 
complete, at the earliest convenience, early termination (ET) assessments as outlined in 
Table 1 (Day 10). 
Unscheduled visits may be conducted at the discretion of the investigator throughout the 
study. AEs and concomitant medications will be assessed at all scheduled and unscheduled 
visits. (Section 6.4). 
Safety Follow-Up Phone Call (Day 12 [+2]): Subjects will receive a safety follow-up 
phone call approximately 5 (+2) days after the last administration of SM on Day 7 
(Section 6.3). 
4.2 
Study Population 
4.2.1 Number of Subjects 
Approximately 50 subjects will be enrolled to complete approximately 40 subjects. 
4.2.2 Inclusion Criteria 
1. Is male or female, aged 18 to 65 years (inclusive) at screening. 
2. Capable of giving signed informed consent, able to understand and comply with 
protocol requirements, instructions, and protocol-related restrictions, and likely to 
complete the study as planned. 
3. Has a body mass index 19.0 to 40.0 kg/m2 (inclusive). 

 
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4. Is able to swallow capsules whole, without crushing, chewing, or opening. 
5. Has a current diagnosis of MDD according to the DSM-5 for either recurrent or 
single episode MDD without psychotic features that is confirmed by the MINI at 
screening. 
6. Has a MADRS score of ≥22 for the current major depressive episode (MDE) at 
screening and baseline (Day 1) before SM administration. 
7. Has a CGI-S score of ≥4 (moderately ill or worse) at screening and baseline 
(Day 1) before SM administration. 
8. Has been on a stable therapeutic dose of one of the following study-approved 
ADTs for the current MDE for ≥6 weeks prior to screening: citalopram, 
escitalopram, paroxetine, fluoxetine, sertraline, duloxetine, venlafaxine (immediate 
release or extended release), desvenlafaxine, vilazodone, levomilnacipran, 
vortioxetine, bupropion, or dextromethorphan/bupropion. Subject must be on 
antidepressant monotherapy before baseline. 
Note: If a subject is taking a second ADT or augmentation therapy at screening, 
the investigator should decide if it is medically appropriate to discontinue the 
second drug before baseline. If so, the second drug should be discontinued for at 
least 5 half-lives prior to baseline. If not, the subject should be excluded from the 
study. 
9. Agrees to maintain a stable therapeutic dose of the approved ADT throughout 
the study. 
10. Non-pregnant female subjects of childbearing potential (FOCP) who are 
exclusively in a same-sex relationship are included without the need of 
acceptable birth control methods. 
FOCP who are sexually active with a male partner (who is biologically 
capable of having children), must agree to use one of the following acceptable 
birth control methods after signing the informed consent form (ICF), 
throughout the study, and for 30 days following the last dose of SM: 
a. Simultaneous use of male condom and intra-uterine contraceptive device 
placed at least 4 weeks prior to the first administration of SM. 
b. Simultaneous use of a male condom and diaphragm with spermicide. 
c. Established hormonal contraceptive (started at least 4 weeks prior to the first 
dose of SM). 
Females are considered not to be of childbearing potential if they are either 
postmenopausal (amenorrhea for at least 2 years and serum follicle-
stimulating hormone [FSH] level of >40 IU/L) or permanently sterilized 

 
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(e.g., bilateral tubal ligation, bilateral oophorectomy, or bilateral 
salpingectomy, etc.) for a minimum of 6 months prior to screening. 
All FOCP must have a negative serum pregnancy test result before administration 
of SM. 
11. Male subjects: 
a. Who have been surgically sterilized (6 months minimum) prior to Screening 
visit are eligible to participate without any contraception. 
b. Who are biologically capable of having children and have female partners of 
childbearing potential must use one or more methods of contraception as stated 
in IC #10 which must be used from the time of signing the ICF until 90 days 
after the last dose of SM. 
c. Who are exclusively in a same-sex relationship or have female partners 
considered not to be of childbearing potential are required to use a condom 
from the first administration of SM through 7 days after the last administration 
of SM. 
All male subjects must refrain from donating sperm from the first administration 
of SM until 90 days after the last administration of SM. 
4.2.3 Exclusion Criteria 
1. Has a MADRS total score improvement of ≥25% from the highest to the lowest 
score from screening to baseline. 
2. Has been treated with electroconvulsive therapy, transcranial magnetic stimulation, 
or vagal nerve stimulation for the current MDE within 6 months prior to screening. 
3. Has received treatment with long-acting injectable antipsychotics within 3 months 
prior to screening. 
4. Has demonstrated a non-response to esketamine or off-label use of ketamine; or 
has taken esketamine or ketamine <6 months prior to screening. 
5. If treated with trazodone, is unable to discontinue treatment with doses >150 mg 
daily for a minimum of 5 half-lives before baseline. 
Note: trazodone ≤150 mg/day for sleep is permitted as needed if the subject has 
been taking the same low dose of trazodone for insomnia for at least 3 months. 
6. Has unstable hypothyroidism. If the thyroid-stimulating hormone value is out of 
range (>4.0 mIU/L), regardless of thyroid history, a free thyroxine (FT4) will be 
measured. If the FT4 value is abnormal (levels <0.8 mIU/L) and considered to be 
clinically significant (after discussion with the Medical Monitor), the subject will 
not be eligible. 
Note: treatment with thyroid hormones is allowed if taken at a stable dose for 

 
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≥3 months and the subject’s thyroid levels are normal. 
7. Has clinically significant abnormal laboratory profiles (alanine aminotransferase or 
aspartate aminotransferase values ≥3 × upper limit of normal [ULN] or total 
bilirubin ≥1.5 × ULN), vital sign measurements, or ECGs at screening, per 
investigator judgment (see Note below). If there are any abnormalities that are not 
specified in the inclusion and exclusion criteria, the investigator must determine 
their clinical significance and record it in the subject’s source documents. 
8. Has abnormal renal function as demonstrated by an estimated glomerular filtration 
rate ≤60 mL/min according to the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation at screening and baseline. 
9. Has a history of substance use disorder within 6 months prior to screening or is 
currently using or has a positive result (urine drug screen) at screening or baseline 
for drugs of abuse (except for cannabis, see exclusion 11). 
10. Has a history of alcohol use disorder within 6 months prior to screening. A subject 
who has a positive alcohol test result at screening and, if based on the 
investigator’s opinion, the subject does not have a history of alcohol use disorder, 
the subject may continue to the baseline visit. Subjects who have a positive alcohol 
test result at baseline will be excluded. Subjects should refrain from using alcohol 
during the study. Subjects who have a positive alcohol test result on days 1, 4, or 7 
will be withdrawn from the study. 
11. Has a diagnosis of cannabis use disorder within 6 months before screening and has 
a positive urine drug screen for cannabis at screening. 
a. At the discretion of the Sponsor, recreational use (not daily) is allowed and 
should be kept consistent during the study. Subjects must agree to refrain from 
using cannabis 48 hours prior to the clinic visits. 
b. Medical cannabis prescribed for a medical condition (e.g., muscle spasms, 
nausea, vomiting, pain) other than depression and seizures is allowed if taken 
at a stable regimen for at least 3 months prior to screening (Appendix 11.1.1). 
Newly prescribed cannabis treatment and/or change to the existing regimen 
are/is prohibited. When applicable, subjects should show proof of their 
prescription for medical cannabis. 
12. Has had any suicidal behavior or suicidal ideation of type 4 (active suicidal 
ideation with some intent to act, without specific plan) or type 5 (active suicidal 
ideation with specific plan and intent) based on the C-SSRS in the 1 year before 
screening; a history of suicide attempt in the last 2 years; or more than 2 lifetime 
suicide attempts. 

 
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13. Has a lifetime history of psychotic disorder, including but not limited to 
schizophrenia, MDD with psychotic features, or bipolar I/II disorder with and 
without psychotic features. 
14. Has a diagnosis within the last 12 months before screening or current diagnosis of 
post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, acute 
stress disorder or has history of intellectual disability, autism, or cluster A or B 
personality disorder (per DSM-5 criteria). 
a. Current diagnosis of co-morbid generalized anxiety disorder is allowed but is 
subject to medication restrictions (anticonvulsants and beta-blockers are 
allowed if the subject is on a stable regimen for 2 months prior to screening). 
b. Established attention-deficit/hyperactivity disorder (ADHD) diagnosis is allowed. 
Subjects must provide confirmation of ADHD diagnosis (i.e., provide medical 
records for prescribed ADHD medications) and be on a stable dose of ADHD 
medication for at least 3 months prior to screening. 
15. Has a history of a psychiatric or neurologic conditions or symptoms that could 
impose undue risk or compromise the study including but not limited to: 
a. History of seizure disorder or history of epilepsy (except history of absence or 
uncomplicated childhood febrile seizures). 
b. History of clinically significant or moderate head trauma that, in the 
investigator's opinion, is likely to affect central nervous system functioning. 
c. Has current evidence of delirium or dementia. 
16. Has a history of cardiovascular, respiratory, gastrointestinal, renal, hepatic, 
hematologic, or other medical disorder that could impose undue risk or 
compromise the study, in the investigator’s opinion, including but not limited to: 
a. Cardiovascular: 
i. Clinically significant symptomatic orthostatic hypotension. 
ii. Uncontrolled hypertension despite diet, exercise, and antihypertensive 
medications. 
iii. Acute coronary syndrome. 
iv. History of unexplained loss of consciousness, unexplained syncope, 
unexplained irregular heartbeats. 
v. QT interval corrected using Fridericia’s method ≥450 msec (for men) or 
≥470 msec (for women) at screening (see Note below). 
vi. Subject or family history of congenital long QT syndrome. 

 
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b. Oncological: 
i. Malignant tumors within 5 years prior, with the exception of benign 
skin tumors. 
ii. Diagnosis or family history of tuberous sclerosis complex. 
c. Positive result for human immunodeficiency virus 1/2 antigen/antibody (HIV 1/2 
Ag/Ab), hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV Ab) at 
screening, unless: 
i. HIV 1/2 Ag/Ab positive: subjects must have an HIV confirmation test. 
If the confirmatory test is positive, subjects are eligible if they are on 
chronic suppressive antiviral medication for >6 months with an 
undetectable viral load at screening. 
ii. HBsAg positive: subjects should be tested for immunoglobulin M 
antibody to hepatitis B core antigen and hepatitis B surface antibody to 
detect acute or chronic infection (ineligible). Subjects whose results 
indicate immunity (either by natural infection or vaccination) with no 
active infection are eligible. 
iii. HCV Ab positive: subjects must have undetectable HCV ribonucleic 
acid to be eligible. 
d. Unintended recent clinically significant weight loss in the investigator’s opinion. 
e. Has chronic urinary tract infections. 
f. Blood donation or loss of ≥500 mL within 56 days prior to screening. 
g. Is on any medication that could, in the investigator’s opinion, interfere with the 
assessments of safety, tolerability, or efficacy, or interfere with the conduct or 
interpretation of the study. 
17. Requires treatment with a medication or other substance that is prohibited by the 
protocol (see Section 5.7.2). 
18. Has history of severe drug allergy or hypersensitivity, or hypersensitivity to the SM 
or excipients. 
19. Female subjects who are pregnant or lactating or planning to become pregnant 
while enrolled in the study. 
20. In the investigator's opinion, is unlikely to comply with the protocol or is unsuitable 
for any other reason. 
21. Has previously enrolled in a NV-5138 study. 
22. Is currently participating in another clinical trial or has received an investigational 
product in another clinical trial within 30 days of screening. 

 
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23. Is a member of study personnel or of their immediate families or is a subordinate 
(or immediate family member of a subordinate) to any of the study personnel. 
Note: Repeat testing for clinical laboratory parameters, vital signs, and ECG is permitted 
one time for each test, at the discretion of the investigator, as long as the repeat test result is 
available within the 28-day screening period to determine eligibility. Repeat testing is not 
allowed without justification from the study site and agreement from the Medical Monitor 
and the Sponsor on a case-by-case basis. 
4.3 
Completion of Study 
Subjects will be considered to have completed the study if they complete the safety follow-
up phone call at Day 12 (±2). 
All reasons for screening failure will be recorded in the electronic case report form (eCRF). 
4.4 
Discontinuation or Early Termination of Subjects 
Subjects who receive SM but withdraw or are withdrawn from participation in the study by 
the investigator before completion of the study (i.e., after SM administration on Day 1 but 
prior Day 10), should complete at the earliest time an ET visit. Procedures and assessments 
listed for Day 10 (see Table 1) should be completed at the ET visit. 
If subject’s ET visit occurs ≥72 h after the date of subject’s last dose, efficacy assessments 
should not be performed/collected at the ET visit. 
The investigator or subjects themselves may stop SM administration at any time for safety 
or personal reasons. A subject is free to withdraw from the study at any time for any reason 
without prejudice to their future medical care by the investigator or at the institution. The 
Sponsor may also withdraw the subject at any time in the interest of the subject’s safety. 
The withdrawal of a subject from the study should be discussed with the Medical Monitor 
and the investigator before the subject discontinues SM. Subjects removed from the study 
for any reason will not be replaced. 
Reasons for a subject’s early discontinuation may include: 
• Withdrawal of consent 
• Noncompliance of study procedures 
• Occurrence of unmanageable AEs 
• Lost to follow-up 
• Lack of efficacy 
• The investigator or the Sponsor believes it is in the best interest of the 
subject to discontinue the study (i.e., for safety or tolerability reasons) 
• Other 
If the subject withdraws consent or the investigator discontinues the subjects from the 
study, the primary reason for the subject’s withdrawal, or the investigator’s discontinuation 

 
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of the subject should be documented and captured in the eCRF. If a subject is withdrawn 
for more than one reason, each reason should be documented in the source document and 
the primary reason should be entered in the eCRF. 
If the subject is lost to follow-up, every effort must be made by the study site to contact the 
subject and to determine the reason for discontinuation/withdrawal. This should include at 
minimum 3 phone calls, certified letters, email, etc. The measures taken to follow-up must 
be documented. 
Subjects who withdraw will not be replaced. 

 
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5 
STUDY TREATMENT 
5.1 
Study Medication Identity, Packaging, and Labeling 
SM is supplied by the Sponsor as capsules packaged in bottles. Each capsule will contain 
400 mg of SPN-820 (Supernus Pharmaceuticals, Inc. product alternative identification 
number). The capsule is Size 00 elongated (00 EL), white opaque cap and body. Each 
bottle will contain 40 capsules of 400 mg SPN-820. Each bottle will be labeled with the 
protocol number. 
5.2 
Study Medication Administration 
SM will be administered orally in the clinic once every 3 days for a 7-day treatment period. 
SM should be administered in the morning, approximately 3 hours after breakfast. 
Subjects will receive a single dose of SPN-820 2400 mg as six 400 mg capsules on days 1, 
4, and 7. The capsules will be consumed intact, and splitting the daily dose (e.g., taking 
part of the daily dose in the morning and the remainder of the daily dose in the evening) is 
not permitted. 
Subjects who cannot tolerate SPN-820 2400 mg should be discontinued from the study at 
the discretion of the investigator. 
Subject will not receive SM on days 2, 3, 5, 6, 8, 9, or 10. 
5.3 
Missed Study Medication Administrations or At-Home Phone Calls 
Subjects may be discontinued from the study at the discretion of the investigator and in 
consultation with the Medical Monitor and the Sponsor if: 
1) the subject misses 1 of the 3 SM administrations, or 
2) the subject misses >1 of the at-home phone calls. 
All discontinuation procedures will be followed as listed on Day 10 of Table 1. 
5.4 
Subjects’ Antidepressant Therapy 
All subjects must be on stable (for ≥6 weeks before screening) therapeutic doses of one of 
the study-approved ADTs for treatment of their current MDE. The following are the 
antidepressants approved for the study: citalopram, escitalopram, paroxetine, fluoxetine, 
sertraline, duloxetine, venlafaxine (immediate release or extended release), desvenlafaxine, 
vilazodone, levomilnacipran, vortioxetine, bupropion, or dextromethorphan/bupriopion 
(see Appendix 11.2 for study-approved ADTs). If a subject is taking a second ADT or 
augmentation therapy at screening, the investigator should decide if it is medically 
appropriate to discontinue the second drug before baseline. If so, the second drug should be 
discontinued at least 5 half-lives prior to baseline. 
Subjects will continue to take their ADT for their current MDE throughout the study and 
after completion of the study. Subjects will bring their daily supply of ADT at each clinic 

 
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visit and continue to take their ADT at home (on days 2,3,5, 6, 8 and 9). Dose adjustments 
or changes of subjects’ ADTs will not be allowed at any time during the study. ADTs 
approved for use in this study will not be supplied by the Sponsor. 
Subjects will receive a paper ADT adherence diary at screening and document the day of 
each dose of their ADT throughout the study. Subjects must bring their diaries to each 
clinic visit for review of subject’s compliance. This should be reinforced at each clinic 
visit. 
5.5 
Method of Assigning Subjects to Treatment 
All eligible subjects will receive SPN-820 2400 mg (six 400 mg capsules) on each dosing 
day. 
5.5.1 Blinding 
Not applicable. 
5.6 
Study Medication Handling and Accountability 
All SM will be supplied by the Sponsor to the investigator. SM supplies must be stored at 
20 to 25°C in an appropriate, secure area (e.g., locked cabinet) and stored according to the 
conditions specified on the SM label. 
Following Sponsor instructions and in compliance with International Council for 
Harmonisation (ICH) E6 as well as local, state, and federal regulations, the investigator and 
study staff will be responsible for the accountability of all clinical supplies (receiving, 
shipment, dispensing, inventory, and record keeping) in a SM accountability log, a copy of 
which will be collected by the Sponsor at the end of the study. 
Under no circumstances will the investigator allow the SM to be used other than as directed 
by this protocol. SM 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; collection of unused 
clinical supplies must be maintained with dates. This SM accountability log includes but 
may not be limited to: 1) documentation of receipt of SM, 2) SM inventory log, and 3) all 
shipping service receipts. Forms may be provided by the Sponsor. Any comparable forms 
that the study site wishes to use must be approved by the Sponsor. 
The supplies and inventory records must be made available, upon request, for inspection by 
the designated representative of the Sponsor, or a representative of the Food and Drug 
Administration (FDA). The assigned Clinical Research Associate (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 a provision is made by the Sponsor for destruction of supplies and containers at the 
study site. Upon completion of SM accountability and reconciliation procedures by study 

 
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site personnel and documentation procedures by Sponsor personnel, SM is to be returned to 
the Sponsor with a copy of the completed SM disposition form. 
5.7 Concomitant and Prohibited Medications 
Subjects may not be on any prohibited medications as indicated in the Inclusion/Exclusion 
Criteria. Please contact the Medical Monitor for any questions related to the subject’s 
current concomitant medication(s). Additional concomitant medications may be permitted 
on a case-by-case basis at the discretion of the Medical Monitor and the Sponsor. 
Lists of permitted and prohibited medications are provided in Appendix 11.1. 
5.7.1 Permitted Concomitant Medications 
A comprehensive list of permitted medications is shown in Appendix 11.1.1. The list is not 
all inclusive. Contact the Medical Monitor for any questions related to the subject’s current 
concomitant medication(s). Most of the concomitant medications are allowed if on a stable 
dose for at least 3 months prior to screening or otherwise specified in Appendix 11.1.1. 
• Treatment for hypercholesterolemia (e.g., statins, gemfibrozil) and 
hyperlipidemia if on a stable dose for ≥3 months prior to screening. 
• Treatment for hypertension with angiotensin-converting enzyme (ACE) 
inhibitors, angiotensin receptor blockers, calcium channel blockers, and 
beta-blockers, alone or in combination with diuretics if on a stable dose for 
≥2 weeks before screening. 
• Inhalers for the treatment of asthma, if the subject has stable, controlled 
asthma and no changes for ≥6 months prior to screening. 
• Treatment for diabetes if on a stable dose for ≥3 months before 
screening. Insulin will not be permitted. 
• For ADHD treatment, psychostimulants, atomoxetine, guanfacine, and 
clonidine are allowed, if on a stable dose for ≥3 months before 
screening. Confirmation of ADHD diagnosis will be required. 
The stable dose of all concomitant medications permitted in the study must be maintained 
throughout the duration of the study participation. 
As needed, the following treatments will also be permitted: 
• For sleeping, the following medications are permitted if on a stable dose (dose 
incrementation is prohibited) for ≥4 weeks prior to screening (Appendix 
11.1.1): 
o Hypnotics (e.g., zaleplon and zolpidem). 
o Benzodiazepines: lorazepam (2 mg total daily dose [TDD]), 
clonazepam (0.5 mg TDD), and flurazepam (30 mg TDD). 
Benzodiazepines should be taken >12 hours prior to any study visits. 

 
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o Trazodone (≤150 mg/day) as needed if the subject has been taking the 
same low dose of trazodone for insomnia for ≥3 months. 
• Nutritional supplements (e.g., multivitamins, fish oil, melatonin). 
• EMLA® or other numbing cream for venipuncture. 
• Common over-the-counter therapies for minor, transient ailments 
(e.g., acetaminophen or ibuprofen for headaches, fever, etc.). 
All concomitant medications will be recorded in the eCRF. 
Subjects must be on a stable dose of 1 study-approved antidepressant medication; a list of 
these ADTs is provided in Appendix 11.2. 
5.7.2 Prohibited Concomitant Medications 
A comprehensive list of prohibited medications is provided in Appendix 11.1.2. The list is 
not all inclusive. Contact the Medical Monitor for any questions related to a subject’s 
current concomitant medication(s). 
Prohibited medications should be discontinued for 5 half-lives before baseline. Where a 
washout of a prohibited medication(s) is required prior to baseline, the tapering rate is at the 
discretion of the investigator and is to be determined on an individual basis, with 
consideration to subject state, dose, and known PK of the medication being discontinued. 
The subject must be consented before any medication tapering is started or any medication 
is discontinued. 

 
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6 
STUDY METHODS 
The Schedule of Events and Assessments is provided in Table 1, and a detailed schedule of 
timed assessments (Window) is provided in Table 2. 
All subjects who are enrolled and receive the initial administration of SM on Day 1 will be 
followed according to the protocol regardless of the number of doses of SM taken, unless 
consent for follow-up is withdrawn. The Sponsor or Sponsor’s designee must be notified of 
all deviations from the protocol clinic visits or procedures, except as noted, and these 
procedures, if applicable, will be rescheduled or performed at the nearest possible time to 
the original schedule. AEs should be reported during clinic visits and during at-home 
contacts. Subjects will also be instructed to call study personnel to report any AEs during 
the intervals outside the established study contacts and to come to the clinic/or seek 
medical care if medical evaluation is needed and as the urgency of the situation indicates. 
For emergencies and other unscheduled visits to a medical facility other than the clinic, 
medical records will be obtained by the investigator or qualified designee as source data for 
study follow-up. 
 

 
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diaries to each clinic visit for review of subject compliance. 
m. ADT will not be provided by the Sponsor. Subject’s ADT will have started and have been stable for at least 6 weeks prior to screening and will continue through the safety 
follow-up phone call. 
 

 
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Table 2: 
Detailed Schedule of Timed Assessments (Window) 
Study Day 
Clinic Visit 
Number 
Location 
Timea 
HAM-D6b 
MADRSb 
CGI-S 
BDNFc 
1 
2 
Clinic 
  Pre-dose 
X (-60 min) 
X (-60 min) 
X (-60 min) 
X (-60 min) 
  1 hour 
 
 
 
 
  2 hours 
X (±30 min) 
 
 
 
  4 hours 
X (±30 min) 
X (±30 min) 
 
X (±30 min) 
  8 hours 
X (±30 min) 
 
 
 
2 
– 
Home 
  24 hours 
X (±2 h)e 
 
 
 
3 
– 
Home 
  48 hours 
X (±2 h)f 
 
 
 
4 
3 
Clinic 
  Pre-dose 
Xe (-60 min) 
X (-60 min) 
X (-60 min) 
X (-60 min) 
  1 hour 
 
 
 
 
  2 hours 
X (±30 min) 
 
 
 
  4 hours 
X (±30 min) 
X (±30 min) 
 
X (±30 min) 
  8 hours 
X (±30 min) 
 
 
 
5 
– 
Home 
  24 hours 
X (±2 h)e 
 
 
 
6 
– 
Home 
  48 hours 
X (±2h)f 
 
 
 
7 
4 
Clinic 
  Pre-dose 
Xf (-60 min) 
X (-60 min) 
X (-60 min) 
X (-60 min) 
  1 hour 
 
 
 
 
  2 hours 
X (±30 min) 
 
 
 
  4 hours 
X (±30 min) 
X (±30 min) 
 
X (±30 min)  
  8 hours 
X (±30 min) 
 
 
 
8 
– 
Home 
  24 hours 
X (±2 h)e 
 
 
 
9 
– 
Home 
  48 hours 
X (±2 h)f 
 
 
 
10 
5 
Clinic 
  72 hours  
X (±2 h)g 
X (±2 h) 
X (±2 h) 
X (±60 min) 
BDNF = brain-derived neurotrophic factor; CGI-S = Clinical Global Impression – Severity of Illness; h = hours; HAM-D6 = Hamilton Depression Rating Scale-6 Items; 
MADRS = Montgomery–Åsberg Depression Rating Scale; min = minutes; 
 
a. Time either before (pre-dose) or after SM administration. 
b. Administration of the HAM-D6 and MADRS will be performed preferably by 2 different raters. 
c. Seven total blood samples will be collected for measurement of BDNF concentrations: 3 pre-dose collections on days 1, 4 and 7; 3 post-dose collections 4 hours after SM 

 
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administration on days 1, 4 and 7; and 1 collection on Day 10. 
 
e. The HAM-D6 will be administered remotely on days 2, 5, and 8, approximately 24 hours (±2 hours) after SM was administered in the clinic on days 1, 4, and 7, respectively. 
f. The HAM-D6 will be administered remotely on days 3, 6, and 9, approximately 48 hours (±2 hours) after SM was administered in the clinic on days 1, 4, and 7, respectively. 
g. The HAM-D6, MADRS, and CGI-S will be administered on Day 10, approximately 72 hours (±2 hours) after SM was administered in the clinic on Day 7. The HAM-D6, MADRS, 
and CGI-S will be administered prior to any safety assessments. 
 
 

 
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6.1 Clinic Study Visits and Procedures 
6.1.1 Visit 1 – Screening (Day -28 to Day -1) 
The following assessments will be conducted: 
• Obtain written informed consent 
• Confirm MDD diagnosis and conduct the MINI 
• Review Inclusion/Exclusion Criteria 
• Confirm stable, therapeutic dose of one study-approved ADT 
• Record relevant history (social [including alcohol and cannabis consumption], medical, 
psychiatric, family psychiatric, and neurological) 
• Record demographics, height, and body weight 
• Record prior and concomitant medications 
• Perform a complete physical examination, including the calculation of body mass 
index 
• Record vital signs (orthostatic blood pressure and pulse rate, respiratory rate, and 
oral temperature) 
• Perform 12-lead ECG 
• Collect blood sample for: 
o FSH (postmenopausal females only) 
o Serum pregnancy test (FOCP only) 
o Hematology and serum chemistry (non-fasted sample allowed) 
o Serology (i.e., HIV 1/2 Ag/Ab, HBsAg, and HCV Ab) 
• Collect urine sample for: 
o Urinalysis 
o Drug and alcohol screen (Table 3) 
• Administer efficacy assessments (HAM-D6, MADRS, and CGI-S) 
• Administer safety assessments (C-SSRS [Screening/Baseline Version], CADSS, and 
BPRS+ scales) 
• Provide the subject a paper ADT adherence diary 
6.1.2 Visit 2 – Baseline (Day 1) 
The assessments listed below will be conducted. See Table 2 for details for efficacy assessments 
and blood collections for 
 BDNF. 
• Review eligibility criteria 
• Record body weight 
• Record vital signs (orthostatic blood pressure and pulse rate, respiratory 
rate, and oral temperature) 
• Perform complete physical examination 

 
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• Perform 12-lead ECG 
• Collect blood samples for: 
o Hematology and serum chemistry (non-fasted sample allowed) 
o BDNF pre-dose 
• Collect urine sample for: 
o Urine pregnancy test (FOCP only) 
o Urinalysis 
o Drug and alcohol screen 
• Administer efficacy assessments (pre-dose HAM-D6, MADRS, and CGI-S) 
• Administer safety assessments (C-SSRS [Since Last Visit Version], CADSS, and 
BPRS+ scales) 
• Review concomitant medications 
• Administer SM 
• Review AEs 
• Administer efficacy assessments following SM administration (HAM-D6 and 
MADRS) 
 
 
 
• Collect blood sample for BDNF concentration following SM administration (after 
efficacy assessments) 
• Review ADT adherence diary 
6.1.3 Visit 3 (Day 4) 
The assessments listed below will be conducted. See Table 2 for details for efficacy assessments 
and blood collections for 
 BDNF. 
• Record body weight 
• Record vital signs (orthostatic blood pressure and pulse rate, respiratory 
rate, and oral temperature) 
• Perform 12-lead ECG 
• Collect blood samples for: 
o BDNF pre-dose 
 
 
• Collect urine sample for: 
o Urine pregnancy test (FOCP only) 
o Drug and alcohol screen 
• Administer efficacy assessments (pre-dose HAM-D6, MADRS, and CGI-S) 

 
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• Administer safety assessments (C-SSRS [Since Last Visit Version]) 
• Review AEs 
• Review concomitant medications 
• Administer SM 
• Administer efficacy assessments following SM administration (HAM-D6 and 
MADRS) 
 
 
 
• Collect blood sample for BDNF concentration following SM administration (after 
efficacy assessments) 
• Review ADT adherence diary 
6.1.4 Visit 4 (Day 7) 
The assessments listed below will be conducted. See Table 2 for details for efficacy assessments 
and blood collections for 
 BDNF. 
• Record body weight 
• Record vital signs (orthostatic blood pressure and pulse rate, respiratory 
rate, and oral temperature) 
• Perform 12-lead ECG 
• Collect blood samples for: 
o Hematology and serum chemistry (non-fasted sample allowed) 
o BDNF pre-dose 
 
 
• Collect urine sample for: 
o Urine pregnancy test (FOCP only) 
o Urinalysis 
o Drug and alcohol screen 
• Administer efficacy assessments (pre-dose HAM-D6, MADRS, and CGI-S) 
• Administer safety assessments (C-SSRS [Since Last Visit Version], CADSS, and 
BPRS+ scales) 
• Review AEs 
• Review concomitant medications 
• Administer SM 
• Administer efficacy assessments following SM administration (HAM-D6 and 
MADRS) 
 
 
 
• Collect blood sample for BDNF concentration following SM administration (after 

 
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efficacy assessments) 
• Review ADT adherence diary 
6.1.5 Visit 5 – End of Study (Day 10) 
The assessments listed below will be conducted. See Table 2 for details of efficacy assessments. 
• Administer HAM-D6, MADRS, and CGI-S (approximately 72 hours after 
the SM administration on Day 7) 
• Perform a brief physical examination 
• Record body weight 
• Record vital signs (orthostatic blood pressure and pulse rate, respiratory 
rate, and oral temperature) 
• Perform 12-lead ECG 
• Collect blood samples for: 
o Hematology and serum chemistry (non-fasted sample allowed) 
o BDNF 
• Collect urine sample for: 
o Urine pregnancy test (FOCP only) 
o Urinalysis 
o Drug and alcohol screen 
• Administer safety assessments (C-SSRS [Since Last Visit Version], CADSS, and 
BPRS+ scales) 
• Review AEs 
• Review concomitant medications 
• Review and collect ADT adherence diary 
6.2 Home Evaluations 
On days 2, 3, 5, 6, 8, and 9, subjects will receive a telephone call for safety and efficacy 
assessments. Subjects will continue to take their ADT. 
6.2.1 Days 2, 3, 5, 6, 8 and 9 
The following assessments will be conducted remotely by telephone: 
• Review AEs 
• Review concomitant medications 
• Confirm compliance and remind subject to complete the ADT adherence diary 
• Administer HAM-D6 remotely approximately 24 and 48 hours (±2 hours) after each 
administration of SM on days 1, 4, and 7 as detailed in Table 2 

 
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6.3 Safety Follow-Up Phone Call (Day 12) 
Subjects who complete EOS/Study Day 10 will receive a safety follow-up phone call 
approximately 5 days (+2 days) after the administration of SM on Day 7. 
The following assessments will be conducted: 
• Administer safety assessments (C-SSRS [Since Last Visit Version], CADSS, and 
BPRS+ scales) 
• Review AEs 
• Review concomitant medications 
6.4 Unscheduled Visits 
At the discretion of the investigator throughout the study, unscheduled visits may be conducted 
to perform or repeat assessments, including to record an ECG, measure vital signs (orthostatic 
blood pressure/pulse rate) or body weight, draw a blood sample for hematology and/or serum 
chemistry or serum pregnancy test (FOCP) or alcohol drug screen, obtain urine sample for urine 
pregnancy test and/or drug screen, administer the C-SSRS, and/or perform a physical 
examination. AEs and concomitant medications should be reviewed and recorded at all 
unscheduled visits. 
6.5 Urine Drug and Alcohol Screen 
The urine drug screen should be completed, and results known before any efficacy assessments 
are conducted at baseline and all post-baseline clinic visits. Subjects should refrain from taking 
alcohol during the study after the first administration of SM. The urine drug screen will be 
performed as point-of-care (POC) testing with POC kits provided to study site(s). 
If a subject has a positive drug screen or tests positive for ethanol at baseline or any post-
baseline clinic visits (days 1, 4, and 7), then the subject should be withdrawn from the study and 
no efficacy assessments (HAM-D6, MADRS, and CGI-S) should be performed at that visit. All 
safety assessments should still be performed. The subject should receive a follow-up phone call 
approximately 1 week following discontinuation from the study. 

 
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6.7 Pharmacodynamic Blood Sampling 
Separate, additional blood draws will be collected to measure BDNF concentrations. Six blood 
samples (2.0 mL each) will be collected at clinic visits on days 1, 4, and 7, as follows: 
• Pre-dose (within 60 minutes of SM administration) 
• 4 hours (±30 minutes) following SM administration 
One blood sample (2.0 mL) will be collected at the clinic visit on Day 10 approximately 
72 hours after SM administration on Day 7. 
• 72 hours (±60 minutes) following SM administration 
 

 
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7 
STUDY VARIABLES AND ASSESSMENTS 
All clinical outcome assessments will be collected using paper scales/questionnaires. 
7.1 
Rater Qualification Process 
Identified raters from each study site will be asked to provide information regarding their 
highest degree of education, field of study, study indication and scale administration 
experience, and previous certifications using a rater qualification form provided by the Sponsor. 
Based on the information entered on the qualification form and accompanying certificates, the 
Sponsor or Sponsor’s designee will determine if raters are qualified to administer scales or 
require Sponsor provided training. Raters can appeal their qualification status; final 
determination will be made by the Sponsor. All qualified study coordinators, investigators, and 
designees must complete the Sponsor rater trainings. 
A site will be considered activated once at least one rater per scale training is completed. 
Investigators from recent previous Supernus Pharmaceutical Inc. studies will be considered as 
qualified raters. 
An attempt will be made to have the same qualified rater administer the same scales (efficacy) 
throughout the study for each subject. 
7.1.1 Hamilton Depression Rating Scale – 6 Items 
The Hamilton Depression Rating Scale is one of the most widely used clinician-administered 
depression scales (Hamilton 1960; Williams 1988). The original version contains 17 items 
related to symptoms of depression over the past week developed for hospital inpatients. The 
HAM-D6 derived from the original 17-item version of the scale offers sensitivity for measuring 
severity of detecting improvement of depression comparable to other more complex versions 
(O'Sullivan 1997). 
Five of the 6 items (Depressed Mood, Low Self-Esteem and Guilt, Social Life 
Activities/Interests, General Psychomotor Retardation, and Psychic Anxiety) are scored on a 
scale of 0 to 4, and 1 item (Tiredness and Pains) is scored on a scale of 0 to 2, for a possible 
total score of 0 to 22. 
The scale is a clinician-reported outcome (ClinRO) administered by a qualified rater at all clinic 
visits, and it will be administered remotely on days 2, 3 5, 6, 8, and 9 to subjects while at home. 
7.1.2 Montgomery-Åsberg Depression Rating Scale 
The MADRS is a 10-item investigator-rated diagnostic questionnaire used to measure the 
severity of depressive episodes in patients with mood disorders and is designed to be sensitive 
to changes brought on by treatment (Montgomery 1979). Each question is scored from 0 to 6, 
the sum of the 10 subtests score will yield a total score ranging from 0 to 60. A higher MADRS 
score indicates more severe depression. 
Successful therapy is indicated by a lower total score in subsequent testing 
(Montgomery-Åsberg Depression Rating Scale Past Week [Follow-Up Evaluation]). 

 
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There are 10 subtests based on each item: 
1. Reported sadness 
2. Apparent sadness 
3. Inner tension 
4. Reduced sleep 
5. Reduced appetite 
6. Concentration difficulties 
7. Lassitude 
8. Inability to feel 
9. Pessimistic thoughts 
10. Suicidal thoughts 
The rater will use a structured interview that standardizes the administration of the 10 MADRS 
items known as structured interview guide for the MADRS, a structured interview was 
developed by Dr. Janet Williams and Dr. Kenneth Kobak in order to increase inter-rater 
reliability, thus improving signal detection (Williams 2008). 
The Standard (including comparison to euthymic baseline for 3 items) and Past Week versions 
will be administered, with the Standard Version administered at screening and the Past Week 
Version administered on days 1, 4, 7, and 10. Euthymic baseline is auto populated based on the 
information captured at the first administration. 
The scale is a ClinRO administered by a qualified rater at all clinic visits. 
7.1.3 Clinical Global Impression – Severity of Illness 
The CGI scale was developed to provide a brief, stand-alone assessment of the clinician’s view 
of a subject’s global functioning prior to and after administration of SM (Guy 1976). The 
CGI-S is a single-item, clinician rating of the clinician’s assessment of the severity of 
symptoms in relation to the clinician’s total experience with patients with MDD. The CGI-S is 
evaluated on a 7-point scale, where: 
• 1=Normal, not at all ill, asymptomatic 
• 2=Borderline ill 
• 3=Mildly ill 
• 4=Moderately ill 
• 5=Markedly ill 
• 6=Severely ill 
• 7=Extremely ill 
Successful therapy is indicated by a lower overall score in subsequent testing. 
The scale is a ClinRO administered by a qualified rater at all clinic visits. 

 
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7.2 
Safety Variables and Assessments 
Safety assessments include monitoring, evaluation, and recording of all concomitant 
medications and AEs, and the evaluation of clinical laboratory test results, vital sign 
measurements, body weight, 12-lead ECGs, C-SSRS, CADSS, BPRS+, and the performance of 
physical examinations as detailed in the Schedule of Events and Assessments (Table 1). 
The investigator is responsible for monitoring the safety of subjects who have entered this study 
and for alerting the Sponsor or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the subjects. 
7.2.1 Adverse Events 
As defined by the ICH Guideline for Good Clinical Practice (GCP), an AE is any untoward 
medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have to have a causal relationship with treatment. 
An AE can be, for example: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• Any new disease, intercurrent injuries, or exacerbation of an existing disease. 
• 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. 
7.2.2 Adverse Events of Special Interest 
At the current time, no adverse events of special interest have been identified. This section will 
be updated when new information becomes available. 
7.2.3 Overdose 
No data are available. Should an overdose of SPN-820 be administered or ingested, the subject 
should be closely monitored for adverse signs and symptoms and appropriate supportive 
medical care administered. 
7.2.4 Causality 
AEs may be categorized as either adverse drug reactions (ADRs) or suspected adverse drug 
reactions (SADRs) based on their relationship to SM and the degree of certainty about 
causality. 
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). 

 
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ADRs are a subset of all SADRs for which there is reason to conclude that the SM caused the 
event. 
7.2.5 Recording and Evaluation of Adverse Events 
All subjects who are screened will be questioned regarding any current and prior medical health 
status or diagnoses and any medical records will be documented as medical history. At each 
contact with the subject following the first administration SM on Day 1, 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 AE module of the eCRF. All clearly related signs, symptoms, and abnormal 
diagnostic procedure results should be recorded in the source document, though they may be 
grouped under one diagnosis. For example, fever, elevated white blood cell count, cough, 
abnormal chest X-ray, etc., can all be reported as “pneumonia.” 
All AEs occurring after administration of SM throughout the study must be recorded. A TEAE 
is defined as an AE with a start date on or after the first dose of SM administration, or that 
worsened following first administration of SM. All AEs in this study will be recorded after 
administration of SM, therefore all will be considered TEAEs. The clinical course of each AE 
should be followed for at least 30 days following the date of last administration of SM (either 
due to EOS or ET) or until resolution, or until, in the medical judgment of the investigator, the 
event has stabilized or is assessed as chronic. 
The investigator is responsible for evaluating AEs and determining the following: 
• Serious versus non-serious: Is the event a serious adverse event (SAE)? 
• Causality: Was the AE related or not related to the SM? 
• Severity: How pronounced is the incapacity/discomfort caused by an AE? 
7.2.6 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 an AE and 
will be assessed according to the following criteria: 
• Mild: Awareness of sign, symptom, or event, but easily tolerated. 
• Moderate: Discomfort is enough to interfere with usual activity and may warrant 
intervention. 
• Severe: Incapacitating with inability to do usual activities or significantly affects 
clinical status and warrants intervention. 
The criteria for assessing severity are different from those used for seriousness. 
7.2.7 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, as defined 
below: 

 
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Not suspected: The temporal relationship of the AE to SM administration makes a causal 
relationship unlikely, or other drugs, therapeutic interventions, or underlying conditions provide 
a sufficient explanation for the observed event.  
• Not related: Temporal relationship to SM administration is missing or implausible, 
or there is an evident other cause. 
• Unlikely related:  Temporal relationship to SM administration makes a causal 
relationship improbable; and other drugs, chemicals, or underlying disease provide 
plausible explanations. 
Suspected: The temporal relationship of the AE to SM administration makes a causal 
relationship possible, and other drugs, therapeutic interventions, or underlying conditions do not 
provide a sufficient explanation for the observed event. 
• Possibly related: Temporal relationship to SM administration is plausible, but 
concurrent disease or other drugs or chemicals could also explain event. Information on 
drug withdrawal may be lacking or unclear. This event will be reported as a SADR. 
• Definitely related: Temporal relationship to SM administration is plausible, and 
concurrent disease or other drugs or chemicals cannot explain event. The response to 
withdrawal of the medication (dechallenge) should be clinically plausible. The event 
must be definitive pharmacologically or phenomenologically, using a satisfactory 
rechallenge procedure if necessary. This event will be reported as an ADR. 
7.2.8 Serious Adverse Events 
AEs are classified as serious or non-serious. An AE or ADR is considered “serious” if, in the 
view of either the investigator or Sponsor, it results in one of the following outcomes: 
• Death 
• Life-threatening AE (i.e., the subject was at immediate risk of death from the AE as 
it occurred. This does not include an event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death) 
• In-patient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability or incapacity or substantial disruption of the ability 
to conduct normal life functions 
• A congenital anomaly or birth defect 
• An important medical event 
Important medical events are those events that may not be immediately life-threatening or result 
in death or hospitalization but are clearly of major clinical significance. They may jeopardize 
the subject and may require intervention to prevent one of the other serious outcomes noted 
above. For example, drug overdose or abuse, blood dyscrasias, a seizure that did not result in in-
patient hospitalization or intensive treatment for allergic bronchospasm in an emergency 
department would typically be considered serious.  

 
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7.2.9 Investigator Responsibilities for Reporting Serious Adverse Events 
The investigator must immediately report to the Sponsor all SAEs, regardless of whether the 
investigator believes they are related to SM. 
All SAEs must be reported to the Drug Safety Team within 24 hours of first becoming aware of 
the SAE. The investigator must complete an SAE form and include a detailed description of the 
SAE, as well as other available information pertinent to the case (e.g., hospital records, autopsy 
reports, and other relevant documents). The investigator will keep a copy of this SAE report 
form on file at the study site. 
The investigator, after thorough consideration of all facts that are available, must include an 
assessment of causality of the SAE to SM in the report to the Sponsor or designee. 
SAEs should be followed until resolution or until no further/additional information can be 
obtained regarding the event. Follow-up information, or new information available after the 
initial report, should be actively sought and reported to the Sponsor or designee, as it becomes 
available, using the SAE report form. 
The drug safety contact for SAE reporting is: 
If the email was not successfully transmitted and a second attempt is unsuccessful, contact the 
study site CRA. 
7.2.10 Other Events Requiring Immediate Reporting 
The investigator must report a pregnancy that occurs in a subject during the study to the Drug 
Safety Team within 24 hours of first becoming aware of the event. 
Subjects who become pregnant during the study should be discontinued from SM immediately. 
A pregnancy should be reported on a pregnancy report form. The investigator should discuss the 
case with the Medical Monitor, and the investigator must follow any pregnant subject until 3 
months after the child is born. Any AEs concerning the pregnancy of the subject during 
pregnancy or the child after birth must be documented and reported to the Sponsor or designee. 
Acute suicidal crisis or clinically significant suicidal behavior or ideation should be reported to 
the Drug Safety Team within 24 hours of first becoming aware of the event. 
7.2.11 Sponsor Responsibilities for Reporting Serious Adverse Events 
The Sponsor or designee will inform the investigator and regulatory authorities of reportable 
events, in compliance with applicable regulatory requirements, on an expedited basis (i.e., 
within specific timeframes). For this reason, it is imperative that the study site submit SAE 
information to the Sponsor or designee in the manner described above. 
The investigator must comply with the applicable regulatory requirements related to the 
reporting of SAEs to the Institutional Review Board (IRB). The investigator must also submit 
the safety information provided by the Sponsor to the IRB unless the country legal regulation 
requires that the Sponsor should be responsible for the safety reporting to the IRB. 

 
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It is the responsibility of the Sponsor to notify the investigator, in a written Investigational New 
Drug Safety Report, of any SADR that is both serious and unexpected. The Sponsor will also 
notify the 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, ICF, and/or IB. 
7.2.12 Clinician-Administered Dissociative States Scale 
The CADSS is a 23-item, clinician-administered scale that measures present-state dissociative 
symptoms (Bremner, 1998). 
The subjective component of this scale consists of items administered by the clinician who 
begins each question with anchors and then reads the item to the subject. The subject then rates 
items on a 4-point Likert scale: 0=not at all, 1=mild, 2=moderate, 3=severe, and 4=extreme, 
with a total score ranging from 0 to 92. 
The scale is a ClinRO administered by a qualified rater at screening, days 1, 7, and 10 of the 
evaluation period, and during the safety follow-up phone call. 
7.2.13 Brief Psychiatric Rating Scale 
The BPRS is one of the most widely used instruments enabling the clinician to quickly gather 
information about the possible presence and severity of various psychiatric symptoms (Zanello 
2013). Varying in the number and type of symptoms assessed, clarity of anchor point definitions 
and administration and rating instructions, the BPRS exists in various forms. Originally in the 
early 1960s, the BPRS was developed as a 16-item instrument (Overall 1962), that was later 
extended to 18 items and was used for many years (Overall 1967). In order to increase its 
sensitivity to psychotic and affective disorders as well as to be used with patients living in the 
community, the BPRS was expanded to 24 items (Version 2, Lukoff 1986). In its latest version 
(Version 4.0), the manual of administration of the 24-item BPRS+ (Ventura 1993) not only 
offers a more detailed semi-structured interview containing more probe questions for each 
symptom but also provides supplementary rules for the rating (e.g., delusions) with better-
defined anchor points. 
The version used for this study is adapted from the original BPRS+. The scale is comprised of 4 
items assessing a subject’s experience of psychosis, often referred to as positive symptoms of 
Suspiciousness, Hallucinatory Behavior, Unusual Thought Content, and Conceptual 
Disorganization. Of the 4 items assessed, the first 3 items are based on questions asked by the 
clinician to the subject. Conceptual Disorganization is a clinician-rated item based on 
observation of a subject’s behavior and speech during the assessment. 
The scale is a ClinRO administered by a qualified rater at screening, days 1, 7, and 10 of the 
evaluation period, and during the safety follow-up phone call. 
7.3 
Treatment-Emergent Suicidal Ideation 
Prospective assessment of suicidal ideation and suicidal behavior is a mandatory part of the 
safety evaluations for any drug developed for a psychiatric indication (US Food and Drug 
Administration 2012). In this study, the initial evaluation of subjects will be conducted prior to 
enrollment to assess lifetime suicidal ideation and to identify subjects who must not participate 
in the study due to a pre-existing suicidality risk. The assessment will then be repeated at each 

 
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subsequent clinic visit as well as during the safety follow-up phone call to monitor the 
occurrence of new suicidal and self-injurious tendencies. 
7.3.1 Columbia Suicide Severity Rating Scale 
Assessment of suicidal ideation and behavior will be conducted using the C-SSRS 
(Baseline/Screening Version and Since Last Visit Version) (Posner 2011). The C-SSRS is an 
FDA-recommended, prospective assessment instrument that directly classifies suicidal ideation 
and behavior events into 11 preferred categories, including 5 levels of suicidal ideation, 5 levels 
of suicidal behavior, and the category of self-injurious behaviors with no suicidal intent. 
The instrument has been validated and used successfully in adult patients with various 
psychiatric disorders that do not involve cognitive impairment. The C-SSRS outcomes that can 
be used for clinical management and safety monitoring are suicidal lethality rating, suicidal 
ideation score, and suicidal ideation intensity rating. 
The scale is a ClinRO administered by a qualified rater at screening, days 1, 4, 7, and 10 of the 
evaluation period, and during the safety follow-up phone call. 
7.3.2 Suicide Risk Management Plan 
The protocol procedures related to clinical care of patients with treatment-emergent suicidal 
ideation and behavior must be implemented to ensure proper management of the event and 
protection of subjects’ safety. If a disclosure of suicidal ideation is revealed as part of the 
C-SSRS questionnaire or when a subject spontaneously expresses that he/she may be a threat to 
him/herself, the study team should be prepared to quickly evaluate the event and to determine 
the appropriate course of action. 
7.3.2.1 Assessment of Suicide Risk 
Any indication of suicidal ideation should be evaluated as soon as possible by appropriately 
trained staff. The investigator is responsible for making the final judgment regarding potential 
suicide risk and the need for subsequent action. 
Acute Suicidal Crisis 
A person evaluated as being at high risk for suicide should be transferred to an immediate care 
facility. The investigator will guide intervention as clinically indicated and follow-up with the 
subject within 1 week and/or refer him/her to a qualified mental health professional. 
Non-Acute Suicidal Risk 
The investigator will conduct safety planning with a subject evaluated as being a non-acute risk 
for suicide and will follow up within 1 week. 
Reference materials for subjects and caregivers should include lists of mental health 
organizations and professionals, outpatient behavioral services, local crisis and peer support 
groups, and suicide/crisis hotlines. 

 
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7.4 
Clinical Measurements 
7.4.1 Screening and Clinical Safety Laboratory Assessments 
All clinical laboratory tests will be performed by a local laboratory as specified in the reference 
binder. 
Details for collecting, handling, and shipping samples (including shipment addresses) will be 
detailed in a separate clinical laboratory manual. The Schedule of Events and Assessments 
(Table 1) shows the time points at which blood and urine samples will be collected. Table 3 lists 
the clinical laboratory tests to be performed. 
Table 3:  
Clinical Laboratory Tests 
Category 
Parameter 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, white blood 
cell count with differential 
Chemistry 
Electrolytes: chloride, phosphate, potassium, sodium 
Liver function tests: alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, total bilirubin, direct bilirubin 
Renal function parameters: blood urea nitrogen, serum creatininea 
Other: glucose, calcium, albumin, total protein, bicarbonate, thyroid-
stimulating hormone, free triiodothyronine (T3), free thyroxine (T4), 
follicle-stimulating hormone (postmenopausal females only) 
Serologyb 
HBsAg, HCV Ab, HIV 1/2 Ag/Ab 
Urinalysis 
Microscopic examinationc, pH, specific gravity, protein, glucose, ketone, 
occult blood, white blood cell count, nitrites, bilirubin, urobilinogen 
Standard Urine Drug 
Screend 
Amphetaminese, barbiturates, benzodiazepinese, buprenorphine, cocaine, 
ecstasy, ethanol, methadone, methamphetaminee, methylphenidatee, 
opiates, oxycodone, phencyclidine, propoxyphene, tricyclic 
antidepressants, tetrahydrocannabinol (cannabinoids) 
POCf Urine Drug 
Screen 
Amphetaminese, barbiturates, benzodiazepinese, buprenorphine, cocaine, 
ecstasy, methadone, methamphetaminee, opiates, oxycodone, 
phencyclidine, propoxyphene, tricyclic antidepressants, 
tetrahydrocannabinol (cannabinoids) 
Breathalyzerf 
Ethanol 
Pregnancy test 
(FOCP only)g 
Human chorionic gonadotropin 
ADHD = attention-deficit/hyperactivity disorder; FOCP = females of childbearing potential; HBsAg = hepatitis B surface 
antigen; HCV Ab = hepatitis C antibody; HIV = human immunodeficiency virus 1/2 antigen/antibody; POC = point-of-care 
a. Glomerular filtration rate will be calculated using the Chronic Kidney Disease Epidemiology Collaboration equation at 
screening only. 
b. Confirmatory serology testing for positive HIV, hepatitis B and HCV at screening will be performed. 
c. A microscopic examination will be performed on abnormal findings unless otherwise specified. 
d. Standard urine drug screen will be performed at screening. A positive test must be confirmed against medical history and 
concomitant medications. 

 
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e. Amphetamine, methamphetamine, and methylphenidate (methylphenidate will not be tested during the treatment period) positive 
tests are allowed only for subjects diagnosed with ADHD confirmed by a prescription record. Benzodiazepine positive test is 
allowed if used for insomnia. 
f. POC urine drug screen together with the breathalyzer will be performed at baseline (Day 1) and all post-baseline visits (days 4, 7, 
and 10). 
g. A serum pregnancy test will be performed at screening; a urine pregnancy test will be performed on days 1, 4, 7, and 10. 
7.4.2 Vital Signs and Weight 
Vital signs measurements (includes orthostatic blood pressure/pulse rate, respiratory rate, and 
oral temperature) and body weight will be obtained at the time points shown in the Schedule of 
Events and Assessments (Table 1). Orthostatic blood pressure and pulse rate should be 
measured after the subject has been sitting for 5 minutes and again within 3 minutes of subject 
standing. Vital sign measurements may be taken at any other time, as deemed necessary by the 
investigator. 
7.4.3 Physical Examinations and Height 
Physical examinations and measurement of height will be obtained at the time points shown in 
the Schedule of Events and Assessments (Table 1). The complete physical examination 
conducted at screening and baseline visits will include assessments of all body systems except 
genitourinary. Any abnormal findings during screening will be recorded as medical history and 
any clinically significant abnormal findings following the first administration of SM on Day 1 
will be recorded as TEAEs. Only changes from baseline observations will be noted during the 
brief physical examination at the EOS. 
 
7.4.4 Electrocardiography 
A 12-lead ECG will be obtained at the time points shown in the Schedule of Events and 
Assessments (Table 1). Additional ECGs may be performed at other times if deemed necessary 
by the investigator. 
The ECG will be recorded while the subject is resting in a supine position for at least 5 minutes. 
The ECG will electronically measure the PR, QRS, QT, QTc intervals, and heart rate. All ECG 
tracings will be reviewed within 24 hours by the investigator or qualified sub-investigator. PR 
intervals will be determined for each of these ECGs from a single reading. Invalid 
measurements will be repeated. QTc will be reported as QT interval corrected using Fridericia’s 
method (QTcF). 
 
 
 
 
 
7.6 Pharmacodynamic Variables and Assessments 
Concentrations of BDNF will be measured from blood samples collected as outlined in Table 2. 

 
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7.7 Screening Scales and Assessment Tools 
7.7.1 Mini International Neuropsychiatric Interview 
The diagnosis of MDD will be made by the investigator and supported by the MINI. The MINI 
is a short, structured diagnostic interview developed by psychiatrics and clinicians in the US and 
Europe for Diagnostic and Statistical Manual of Mental Disorders and has been updated to map 
to the DSM-5 (Hergueta 2013; Sheehan 1998). With an administration time of approximately 
15 minutes, the MINI is often used for psychiatric evaluation in clinical studies and is the most 
widely used psychiatric structured diagnostic interview instrument in the world. 
7.7.2 Montgomery-Åsberg Depression Rating Scale 
The MADRS is described in Section 7.1.2. Subjects must have a MADRS total score of ≥22 for 
their current MDE at screening and baseline (Day 1) before SM administration. The MADRS 
total score cannot vary ≥25% between the highest and the lowest score from screening to 
baseline (Day 1). 
7.7.3 Clinical Global Impression – Severity of Illness 
The CGI-S is described in Section 7.1.3. Subjects must have a CGI-S score of ≥4 (moderately 
ill or worse) at screening and baseline (Day 1) before SM administration. 
 

 
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8 
STATISTICAL METHODS 
8.1 General Considerations 
Where appropriate, variables will be summarized descriptively (frequency count and percentage 
for categorical variables; number of subjects, mean, standard deviation, median, interquartile 
range [Q1 and Q3], minimum, and maximum for continuous variables). 
The data summaries will be accompanied by individual subject data listings, as specified in 
Sections 16.2 and 16.4 of ICH Guidance E3, sorted by unique subject identifier. All data 
available from the eCRFs will be listed. 
Complete details of the statistical analysis will be provided in a separate statistical analysis plan 
(SAP). 
8.2 
Sample Size and Power Considerations 
Approximately 50 subjects will be enrolled to achieve approximately 40 subjects completed. 
This sample size is based on clinical judgment without a power calculation. 
8.3 
Handling of Dropout or Missing Data 
For safety analyses, a missing date for an AE and non-study medication use will be imputed as 
described in the SAP. Missing data for all other safety endpoints will not be imputed. 
8.4 
Analysis Populations 
The full analysis set (FAS) includes all subjects who receive at least one dose of SM and have a 
baseline and at least one post-baseline measurement of HAM-D6. 
The safety population includes all subjects who receive at least one dose of SM. 
 
. 
The PD population includes all subjects who receive at least one dose of SM and have a 
baseline and at least one post-baseline BDNF concentration. 
8.5 Demographics and Baseline Analysis 
Demographic variables including age, sex, ethnicity, race, height, body weight, body mass 
index, and other baseline efficacy measurements will be summarized descriptively using the 
safety population and the FAS. 
8.6 
Population Disposition 
A disposition of subjects will include the number and percentage of subjects in each of the 
analysis populations. 
The number and percentage of subjects who completed, discontinued from the study, and the 
primary reason for early discontinuation will be summarized. The reason for early 
discontinuation may include any of the following: 
• Withdrawal of consent 
• Noncompliance with study procedures 

 
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• Occurrence of unmanageable AEs 
• Lost to follow-up 
• Lack of efficacy 
• The investigator or the Sponsor believes it is in the best interest of the subject to 
discontinue the study (i.e., for safety or tolerability reasons) 
• Other 
8.7 
Study Medication Exposure 
Duration of exposure is defined as the total number of days a subject is exposed to any SM. 
This will be calculated for each subject by taking the difference between the date of last 
administration of SM minus the date of the first administration of SM + 1 (date of last dose – 
date of first dose + 1). Duration of treatment exposure will be summarized using descriptive 
statistics. The amount of the dosage will be summarized descriptively by visit and overall. 
 
8.8 
Medical History 
Medical histories will be tabulated and listed by subject. 
8.9 
Prior and Concomitant Medications 
Prior and concomitant medications will be assigned an 11-digit code using the World Health 
Organization Drug Dictionary drug codes. Concomitant medications will be further coded to the 
appropriate Anatomical-Therapeutic-Chemical code indicating therapeutic classification. A 
tabular summary of concomitant medications by drug class will be presented for the safety 
population. 
8.10 Efficacy Analyses 
All efficacy data will be summarized descriptively and listed. 
8.10.1 Primary 
The change from baseline to each time point in the HAM-D6 total score will be analyzed using 
descriptive statistics. The primary efficacy analysis will be performed with the FAS. 
8.10.2 Secondary 
The change from baseline at each time point in the MADRS and CGI-S total scores will be 
analyzed using descriptive statistics. Analyses for responders (proportion of subjects achieving 
a ≥50% reduction from baseline in the MADR total score), remission (proportion of subjects 
achieving MADRS ≤10 total score), and percentage of subjects with a CGI-S score of 1 or 2 
will be summarized. The secondary efficacy analyses will be performed using the FAS 
population. 
 
 
 
 
 

 
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8.12 Pharmacodynamic Analysis 
The PD analysis is an exploratory analysis and will be performed using the PD population. 
The change from baseline to each time point for BDNF concentration will be analyzed 
descriptively. 
8.13 Safety Analysis 
Safety analysis is a secondary analysis and will be performed using the safety population. 
Summaries will be presented for TEAEs and data from the clinical laboratory tests, vital sign 
measurements, body weight, ECGs, C-SSRS, CADSS, and BPRS+. Physical examination 
results will be listed by subject. 
TEAEs: The incidence rate for all TEAEs will be summarized for each System Organ Class 
(SOC) and Preferred Term (PT). The severity of the TEAEs, the relationship to SM, SAEs, AEs 
leading to SM withdrawn, and deaths will be summarized for each SOC and PT. Common 
TEAEs (≥5%) will be summarized by PT. The verbatim descriptions with Medical Dictionary 
for Regulatory Activities coded SOCs and PTs for all AEs will be contained in the subject data 
listings. 
Clinical Laboratory Values, Vital Sign Measurements, and Body Weight: Both actual values 
and change from baseline and shift from baseline will be summarized for clinical laboratory 
values, vital sign measurements, and body weight. 
ECG results will be summarized using descriptive statistics (for quantitative ECG parameters) 
and frequency tables (for qualitative ECG parameters, including the overall ECG finding). 
C-SSRS outcomes will be summarized using number and percentage of subjects by categories 
for suicidal ideation only, suicidal behavior only, and suicidality (ideation and behavior 
combined). 
CADSS outcomes will be summarized using descriptive statistics. 
BPRS+ outcomes will be summarized using descriptive statistics. 
8.14 Interim Analysis 
No interim analysis will be performed. 

 
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9 
DOCUMENTATION 
9.1 
Adherence to the Protocol 
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described within and to the principles of ICH GCP as well as all governing local regulations 
and principles for medical research. 
The protocol, ICF, and appropriate related documents must be reviewed and approved by an 
IRB constituted and functioning in accordance with ICH E6 and any local regulations. 
Documentation of IRB compliance with the ICH and any local regulations regarding 
constitution and review conduct will be provided to the Sponsor. 
A signed letter of study approval from the IRB must be sent to the investigator with a copy to 
the Sponsor prior to study start and the release of SM to the study site by the Sponsor or its 
designee. If the IRB decides to suspend or terminate the study, the investigator will immediately 
send the notice of study suspension or termination by the IRB to the Sponsor. 
9.2 
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 letter 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 Contract Research Organization (CRO) will send a letter to the IRB 
detailing such changes. 
9.3 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Study site visit audits may be made periodically by the Sponsor’s Quality Assurance team or 
qualified designee, which is an independent function from the study conduct team. 
9.3.1 Data Collection 
The primary source document will be the subject’s medical records. If separate research records 
are maintained by the investigator, both the medical record and the research record will be 
considered the source documents for the purposes of monitoring and auditing the study. 
Electronic data collection techniques will be used to collect data directly from the study sites 
using eCRFs. The electronic data will be stored centrally in a fully validated clinical database. 

 
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Data recorded on source documents will be transcribed into the eCRFs in accordance with the 
eCRF completion instructions that are provided to the study site(s). The investigator is 
responsible for ensuring that all sections of each eCRF are completed correctly, and that entries 
can be verified against source documents. The eCRFs will be monitored for completeness and 
accuracy against the source documents by the CRA(s) on a regular basis. Inconsistencies 
between the eCRFs and source documents will be resolved in accordance with the principles of 
GCP. 
9.3.2 Clinical Data Management 
External data outside of the clinical database (e.g., laboratory data) will be reconciled with the 
database as specified in the data management plan. Quality control and data validation 
procedures will be applied to ensure the validity and accuracy of the clinical database. 
9.3.3 Database Quality Assurance 
In accordance with the vendor’s procedures, the clinical database will be reviewed and checked 
for omissions, apparent errors, and values requiring further clarification using computerized and 
manual procedures. Procedure details for handling missing data will be addressed in the SAP. 
Data queries requiring clarification will be documented and returned to the study site(s) for 
resolution. Only authorized personnel will make corrections to the clinical database, and all 
corrections will be documented in an audit trail. 
9.3.4 Bioanalytical Sample Handling 
Bioanalytical samples will be shipped according to instructions provided by the Sponsor or 
according to a Sponsor-reviewed sample processing/handling manual. Primary and backup 
samples will be transported in separate shipments to the Sponsor-designated bioanalytical 
facility. The samples should be packed on sufficient dry ice to keep them frozen during 
shipment. 
 
 
 
 
Blood samples for determination of BDNF concentrations will be shipped to a Sponsor-
designated analytical laboratory. BDNF concentrations will be determined using a validated 
enzyme-linked immunosorbent assay method as specified in the laboratory manual. 
 
9.4 
Retention of Records 
The investigator has the responsibility to retain all essential documents from this study, as 
described in ICH E6 for at least 2 years after approval of a marketing application or after formal 
discontinuation of the clinical program. Essential documents include but are not limited to the 
protocol, eCRFs, source documents, laboratory test results, SM inventory records, IB, and 
regulatory agency registration documents (e.g., FDA form 1572, ICFs, and IRB 
correspondence). The investigator must obtain written permission from the Sponsor prior to the 
destruction of any study document. 

 
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9.5 
Auditing Procedures 
In addition to the routine monitoring procedures, the Sponsor’s Corporate Quality Assurance 
department or qualified designee may conduct audits of clinical research activities in 
accordance with the Sponsor’s written standard operating procedures to evaluate compliance 
with the principles of ICH GCP and all applicable local regulations. A government regulatory 
authority may also wish to conduct an inspection (during the study or after its completion). If an 
inspection is requested by a regulatory authority, the investigator must inform the Sponsor and 
the CRO immediately that this request has been made. 
These records must be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the US FDA in accordance with the US 21 
Code of Federal Regulation (CFR) 312.68 or other national or foreign regulatory authorities in 
accordance with applicable regulatory requirements. 
9.6 
Publication of Results 
Any presentation or publication of data collected as a direct or indirect result of this study will 
be considered as a joint publication by the investigator and the appropriate personnel at the 
Sponsor’s site. Authorship will be determined by mutual agreement. All manuscripts, abstracts, 
or other modes of presentation arising from the results of the study must be reviewed and 
approved in writing by the Sponsor, prior to submission for publication or presentation. No 
publication or presentation with respect to this study shall be made until all Sponsor comments 
on the proposed publication or presentation have been addressed to the Sponsor’s satisfaction. 
Detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to this study shall be outlined in the agreement 
between the investigator and the Sponsor or designee. 
9.7 
Financing and Insurance 
Financing and insurance information will be set forth in a separate document between the 
investigator and the Sponsor (provided by the Sponsor or designee). 
 
9.8 
Disclosure and Confidentiality 
The contents of this protocol, any amendments, and results obtained during the course of this 
study will be kept confidential by the investigator, the investigator’s staff, and the IRB and will 
not be disclosed in whole or in part to others or used for any purpose other than reviewing or 
performing the study without the written consent of the Sponsor. No data collected as part of 
this study will appear in any written work, including publications, without the written consent 
of Sponsor. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in the confidentiality agreement between the investigator 
and Sponsor. 
9.9 
Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative reasons at 
any time. The investigator will be reimbursed for reasonable expenses covering subjects, 

 
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laboratory tests, and other professional fees. The investigator will refund the excess of 
payments made in advance. 
The investigator reserves the right to discontinue the study should his/her judgment so dictate. 
The investigator will notify the IRB in case of study discontinuation. Study records must be 
retained as noted above. 

 
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10 
ETHICS 
10.1 Institutional Review Boards 
The IRB that approves this study and the approval letters will be included in the appendices of 
the clinical study report for this protocol. 
The protocol, any protocol amendments, and the ICF will be reviewed and approved by the 
appropriate IRB before subjects are enrolled. The investigator or Sponsor will submit, 
depending on local regulations, periodic reports and inform the IRB of any reportable AEs per 
ICH guidelines and local IRB standards of practice. 
10.2 Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures from both the 
Sponsor and the CRO. These standard operating procedures 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. 
• US CFR dealing with clinical studies (21 CFR, including Parts 50 and 56 concerning 
patient informed consent and IRB regulations). 
• Local, national legal guidelines. 
10.3 Investigator and Study Personnel 
This study will be conducted by a qualified investigator(s) under the sponsorship of Navitor 
Pharmaceuticals, Inc. and its partner Supernus Pharmaceuticals, Inc. 
Contact persons at the Sponsor and the CROs are listed in the reference binder provided to the 
study site(s). The study will be monitored by qualified personnel from the Sponsor or their 
designees, such as the CROs, for their respective sites. Laboratory tests will be conducted by a 
local laboratory as designated in the reference binder. 
The study will be monitored by qualified personnel from the CRO and Sponsor. Data 
management and statistical analyses will be the responsibility of the CRO data management and 
biostatistics groups. 
10.4 Subject Information and Consent 
The investigator (or designee) will inform the subject of all aspects pertaining to the subject’s 
participation in the study and will provide oral and written information describing the nature 
and duration of the study, the procedures involved, the expected duration, the potential risks and 
benefits involved, and any potential discomfort. The process for obtaining informed consent 
will be in accordance with all applicable regulatory requirements. The investigator (or 
designee) and subject must sign and date the ICF before the subject can participate in the study. 

 
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The subject will be given a copy of the signed and dated ICF, and the original will be retained 
in the investigational site study records. 
The decision regarding subject participation in the study is entirely voluntary. The investigator 
(or designee) must emphasize to the subject that consent, regarding study participation, may be 
withdrawn at any time without penalty or loss of benefits to which the subject is otherwise 
entitled. 
If the ICF is amended during the study, the investigator must follow all applicable regulatory 
requirements pertaining to approval of the amended ICF by the IRB and use the amended ICF 
(including ongoing subjects). 
 

 
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12 
SUMMARY OF AMENDMENT CHANGES 
Document History 
Document 
Date 
Version 3.0 
14FEB2024 
Version 2.0 
01DEC2023 
Version 1.0 
09OCT2023 
Amendment 3.0 (14 February 2024) 
Supersedes previous version; date 
Version 2.0; 01DEC2023 
Current version; date 
Version 3.0; 14FEB2024 
Substantial changes to the protocol and their location within the protocol are summarized 
below. In addition, corrections of typographical errors that have been made throughout the 
protocol are not explained here. 
Primary Reason for the Substantial Modification of the Protocol: 
Revised select Inclusion Criteria to align with current clinical and regulatory definitions or 
guidance. 
Summary of Changes 
Section # 
Section Title 
Description of Changes in Protocol Version Amendment 
Version 3.0; 14 February 2024 
Brief Rationale for 
Change 
Inclusion 
Criterion 8, 
Synopsis and 
Section 4.2.2; 
Global  
Revised inclusion criterion #8 to include subjects that have received 
a stable dose of study-approved antidepressant for at least 6 weeks 
instead of 4. 
To align with current 
clinical and regulatory 
definitions for 
adequate duration of 
treatment. 
Exclusion 
Criterion 12, 
Synopsis and 
Section 4.2.2 
Revised exclusion criterion #12 to update accepted timeframes for 
type 5 suicidal ideations based on C-SSRS and history of suicide 
attempt. 
To better align with 
understanding of 
targeted study 
population 
Inclusion 
Criterion 10 
and 11, 
Synopsis and 
Section 4.2.2 
Revised inclusion criterion #10 to remove sexual abstinence as an 
acceptable form of contraception in both sexes. 
To align with current 
regulatory guidance 
for contraception in 
clinical studies. 
Sections 4.1, 
4.3, 6.3 
Revised definition of study completers to include follow-up phone 
call on Day 12 (±2). 
Administrative 
clarification. 
Section 7.4.1; 
Table 3: 
Clinical 
Laboratory 
Tests 
Revised “Other” clinical laboratory tests to specify that “free” 
triiodothyronine (T3) and “free” thyroxine (T4) testing will be 
conducted. 
Administrative 
clarification: T3 and 
T4 testing will not 
include bound T3 and 
T4 testing. 
Section 11.1 
Revised permitted and prohibited concomitant medication lists; 
removal of antiseizure medications as permitted medication. 
Exclusion criterion 
#15 excludes subjects 
with history of seizure 
disorder. 
 

 
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13 
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