A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of NV-5138 in Adults With Treatment Resistant Depression
Phase: PHASE2
Conditions: Treatment Resistant Depression
Sponsor: Navitor Pharmaceuticals, Inc.

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 1 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
TITLE PAGE 
Protocol Number: 
NAV-17A-007 
Title: 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of NV-5138 in Adults with 
Treatment Resistant Depression 
Sponsor: 
Navitor Pharmaceuticals, Inc. 
6 Liberty Square 
PMB #284 
Boston, MA 02109 USA 
Phone: 857 285 4328 
Fax: 857 998 6313 
Investigational 
New Drug (IND) 
number: 
155072 
Investigational 
Medicinal Product 
(IMP): 
NV-5138 
Indication: 
Treatment-resistant depression (TRD)  
Phase: 
2 
Protocol Version: 
5.0 
Amendment: 
4.0 
Date: 
07 Jun 2024 
Good Clinical 
Practice (GCP) 
Statement: 
This study is to be performed in full compliance with International 
Council for Harmonisation (ICH) Good Clinical Practices (GCP) and all 
applicable local regulations. All required study documentation will be 
archived as required by regulatory authorities. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 2 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
INVESTIGATOR’S SIGNATURE PAGE 
 
 
I, the undersigned, read this protocol and agree to conduct this trial in accordance with all 
stipulations of the protocol and in accordance with ICH GCP and all applicable local 
guidelines, including the Declaration of Helsinki and all its accepted amendments to date. 
 
 
 
 
 
Principal Investigator’s Signature 
 
 
Date 
 
 
 
 
 
 
Print Name 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 3 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
SUPERNUS PROTOCOL APPROVAL PAGE 
 
  
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 4 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
NAVITOR PROTOCOL APPROVAL PAGE 
 
Approver: 
  
 
 
 
 Thomas Hughes, PhD 
Chairman & Chief Executive Officer 
Navitor Pharmaceuticals 
 
Date 
 
 
 
 
 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 5 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
CLINICAL PROTOCOL SYNOPSIS 
Sponsor: Navitor Pharmaceuticals, Inc. 
Name of Product: NV-5138 
Name of Active Ingredient:  
(S)-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid 
Protocol Number: NAV-17A-007 
Phase of Development: 2 
Full Title of Study: A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of NV-5138 in Adults with Treatment Resistant 
Depression 
Number of Study Sites: Approximately 55 sites are planned in the United States (US). 
Number of Subjects: Approximately 800 outpatient adults with treatment-resistant depression 
(TRD) will be screened; approximately 268 subjects will be randomized to NV-5138 or 
placebo in a 1:1 ratio to achieve approximately 200 subjects completing the study. 
Indication: TRD 
Objectives:  
Primary Objective: 
• 
To evaluate the efficacy of NV-5138 compared to placebo when administered to adults 
with TRD on the Montgomery–Åsberg Depression Rating Scale (MADRS) total score 
Key Secondary Objective: 
• 
To evaluate the efficacy of NV-5138 compared to placebo in adults with TRD on the 
clinician’s impression of the severity of depressive symptoms 
Additional Secondary Objectives: 
• 
To evaluate the efficacy of NV-5138 compared to placebo in adults with TRD on the 
following: 
1) Clinical response in adults with TRD to Hamilton Depression Rating Scale-6 Item 
(HAM-D6)  
2) Onset of clinical response 
3) Depressive symptoms response 
4) Depressive symptoms remission 
5) Clinician’s impression of improvement of depressive symptoms  
6) Individual disability 
7) Anxiety symptoms 
8) Clinical response rate of severity 
9) Clinical response rate of improvement 
Safety Objective: 
• 
To assess the safety and tolerability of NV-5138 compared to placebo in adults with 
TRD 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 6 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
Exploratory Objectives: 
• 
To evaluate the efficacy of NV-5138 compared to placebo in adults with TRD on the 
following:  
1) Self-reported depressive symptoms 
2) Self-reported cognitive and physical function 
3) Self-reported sexual function 
• 
Pharmacogenomic (PGx) evaluations  
Endpoints: 
Primary Efficacy Endpoint: 
• 
Change from baseline (CFB) to the end of the treatment period on the MADRS total 
score 
Key Secondary Efficacy Endpoint: 
• 
CFB to the end of the treatment period on the Clinical Global Impression – Severity 
(CGI-S) score 
Additional Secondary Efficacy Endpoints: 
1) CFB to the end of each scheduled week on the HAM-D6 total score 
2) CFB to the end of each scheduled week on the MADRS total score 
3) Proportion of responders (defined as ≥50% reduction from baseline in the MADRS 
total score) at the end of each scheduled week 
4) Proportion of subjects in remission (MADRS total score ≤10) at the end of each 
scheduled week   
5) Clinical Global Impression – Improvement (CGI-I) score at the end of each 
scheduled week  
6) CFB to the end of each scheduled week on the Sheehan Disability Scale (SDS) 
total score 
7) CFB to the end of each scheduled week on the Generalized Anxiety Disorder 7-
item (GAD-7) scale total score 
8) Percentage of subjects with a CGI-S score of 1 or 2 at the end of each scheduled 
week 
9) Percentage of subjects with a CGI-I score of 1 or 2 at the end of each scheduled 
week 
Safety Endpoints: 
1) Safety endpoints are adverse events (AEs), clinical safety laboratory test results, 
vital signs measurements (including orthostatic blood pressure/pulse rate), weight, 
electrocardiograms (ECGs), and physical examination 
2) Suicidal ideation and behavior as measured by the Columbia-Suicide Severity 
Rating Scale (C-SSRS) score 
3) Dissociative symptomatology as measured by the Clinician Administered 
Dissociative States Scale (CADSS) total score 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 7 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
4) Psychopathology severity as measured by the Brief Psychiatric Rating Scale- 
positive symptom subscale (BPRS+) score 
Exploratory Endpoints: 
• 
CFB to the end of each scheduled week on the following:  
1) Patient Health Questionnaire 9-item (PHQ-9) scale total score 
2) Massachusetts General Hospital (MGH) Cognitive and Physical Functioning 
Questionnaire (CPFQ) total score 
3) Changes in Sexual Functioning Questionnaire (CSFQ) total score 
• 
PGx evaluation (optional) 
1) Correlation between baseline pharmacogenetic testing results and drug effects on 
efficacy, safety, and/or PK of NV-5138  
2) CFB in the concentration of brain-derived neurotrophic factor (BDNF) 
Study Design:   
The study will be conducted as a multicenter, randomized, double-blind, flexible-dose, 
placebo-controlled, parallel design of adjunctive NV-5138 in adults with TRD.  
The study consists of the following: (1) a Prospective Screening Period, (2) a Double-Blind 
Period, and (3) a Safety Follow-up Phone Call. 
Retrospective Prescreening:  
The retrospective period is the time before screening when the Investigator determines the 
duration (without restriction) of the current major depressive episode (MDE), and also 
establishes the medication history of the current MDE. Subjects will not be eligible if they 
previously responded for more than 4 weeks while on the current antidepressant treatment 
(ADT) and lost response (tachyphylaxis). Those subjects may qualify for the study if, after the 
current MDE started, they subsequently fail a trial with a new ADT or an increased dose of the 
previous ADT.  
At the screening visit (Visit 1), subjects must have a documented history of inadequate 
response to ≥1 but ≤4 prior ADTs which must include the present ADT for their current MDE. 
Subjects must also be taking the currently approved ADT for a minimum of 2 weeks at a stable 
therapeutic dose. 
Screening Period (Up to 6 Weeks, Day -42 to Day -1): 
The Screening Period is up to 6 weeks depending on how long subjects have been taking their 
current ADT and the number of failed ADTs. As shown below, subjects who have failed ≥2 
ADTs and have been taking the approved ADT at a stable dose for ≥4 weeks before screening 
are allowed the minimum 4-week Screening Period. A longer Screening Period is required for 
other subjects (for example, subjects who have been on their current ADT for 2 weeks will 
complete 6 weeks of screening, and subjects who have been on the current ADT for 3 weeks, 
will be in the Screening Period for 5 weeks).  
Subjects who have an inadequate response to only 1 ADT must be on the same ADT at the 
stable therapeutic dose for ≥2 weeks before the Screening Period and complete 6 weeks during 
the Screening Period. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 10 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
If the subject withdraws or is early terminated (ET), the subject will complete Visit 8/EOS/ET 
assessments. 
Safety Follow-Up (30 Days After Completion of the Study): 
After the last dose of SM in the Double-Blind Period and all study visits are completed 
including Visit 8, the study is considered completed. A safety follow-up phone call will occur 
approximately 30 days after the last dose of blinded SM only for subjects who completed the 
study or approximately 7 days for subjects who withdraw early from the study. 
Duration of Subject’s Participation:  
Up to 15 weeks total (including Screening and Safety Follow-up Periods).   
Investigational Medicinal Products, Reference Therapy, Doses and Mode of 
Administration 
Study Medication: NV-5138 400 mg 
Dose levels: 800 mg or 1600 mg once daily (QD) 
Reference Therapy: Matching placebo 
Mode of Administration: Orally as intact capsules each containing 400 mg of NV-5138 or 
matching placebo, in the morning, approximately 3 h after breakfast 
Statistical Methodology 
Sample Size: 
Two hundred subjects (100 per treatment group) in the Full Analysis Set (FAS) Population will 
yield 80% power in detecting superiority of NV-5138 to placebo at a significance level of 
0.05 (two-sided) using a two-sample t-test with equal allocation to the treatment groups. This 
assumes an effect size of 0.40 with a mean difference of 4.8 and a standard deviation (SD) of 
12.  Assuming a dropout rate of 25%, approximately 268 subjects will be randomized to 
achieve approximately 200 completing the study.  
Assuming a 67% rate of screen failure, approximately 800 potential subjects will be screened 
to obtain approximately 268 subjects randomized. 
Analysis Populations: 
The Randomized Population includes all subjects who are randomized. 
The Full Analysis Set (FAS) is a subset of subjects in the Randomized Population who take at 
least one dose of SM and have a baseline assessment of the MADRS total score. The efficacy 
analyses will be conducted using the FAS according to the randomized treatment assignment. 
The Per Protocol (PP) Population is a subset of subjects in the FAS who complete all 8 visits 
through EOS with no missing MADRS total score assessments and no important protocol 
deviations. Subjects in the PP Population will be analyzed according to the actual treatment 
received. 
The Safety Population includes all subjects randomized into the study who received at least 
one dose of SM. The safety analysis will be performed according to the actual treatment 
received. 
Statistical Methods: 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 11 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
Continuous variables will be summarized using descriptive statistics (number of subjects, 
mean, SD, median, interquartile range [Q1 and Q3], minimum, and maximum). Categorical 
(nominal) variables will be summarized using the number and percentage of subjects in each 
category. 
Efficacy Analyses: 
Primary Endpoint: CFB in the MADRS total score to the end of treatment period will be 
analyzed using a Mixed Model for Repeated Measures (MMRM). For subjects who are 
discontinued from the study due to AEs or lack of efficacy and for subjects who are dosed but 
have no post-baseline MADRS total score, missing data will be imputed based on the missing 
not at random (MNAR) assumption. For subjects who are discontinued from the study due to 
other reasons, no missing imputation will take place. The data collected at ET visit will be 
mapped to the next scheduled visit. The MMRM model will include baseline MADRS total 
score as a covariate, and treatment, visit, and treatment-by-visit interaction as fixed effects. The 
model parameters will be estimated using the restricted maximum likelihood method with an 
unstructured variance-covariance matrix and Kenward-Roger approximation to estimate the 
denominator degrees of freedom. If the MMRM model with the unstructured variance-
covariance matrix does not converge using the default Newton-Raphson fitting algorithm by 
PROC MIXED in SAS, the Fisher scoring algorithm, or the no-diagonal factor analytic 
structure will be used (Lu & Mehrotra, 2010).  
If the model still fails to converge, the following types of covariance structure with the 
sandwich estimators will be used to fit the model in a sequential order until the model 
converges:  
1) Heterogeneous Toeplitz  
2) Heterogeneous Autoregressive of order 1 
3) Toeplitz 
4) Autoregressive of order 1 
5) Compound symmetry  
The denominator degrees of freedom will be estimated using the BETWITHIN option in SAS 
when any of the covariance structures is used with the sandwich variance estimators. 
One hundred (100) imputed datasets based on the MNAR assumption will be created in case of 
subject discontinuation due to AE(s) or lack of efficacy and for those subjects who are dosed 
but have no post-baseline MADRS total score. The MMRM model for the primary efficacy 
analysis will be performed using each of these 100 imputed datasets. PROC MIANALYZE in 
SAS will be used to combine all the results from these 100 MMRM models and then make a 
final statistical inference. 
For the final statistical inference, the least squares (LS) mean of CFB to the end of treatment 
period for the MADRS total score for each treatment group will be presented along with the 
corresponding standard error (SE). The NV-5138 treatment will be compared with the placebo 
group by presenting the difference in the LS means between the NV-5138 and placebo groups 
(NV-5138 minus placebo) with its 95% confidence interval (CI) and the p-value. 
Sensitivity analysis: The sensitivity analysis will be performed using the placebo-based 
multiple imputation (MI) to fill in missing MADRS total scores. This approach assumes that, 
after discontinuation, subjects from the NV-5138 treatment group would adopt the outcome 
that is estimated from the placebo group. The CFB in MADRS total score to the end of 
treatment period based on each imputed dataset will be analyzed using the same MMRM 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 12 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
model described for the primary analysis. To combine all the results using each of the imputed 
datasets, PROC MIANALYZE in SAS will be used to make a final statistical inference.  
Key Secondary Endpoint: The key secondary endpoint, the CFB to the end of the treatment 
period in the CGI-S score, will be analyzed in the same manner as the primary efficacy 
endpoint. 
Additional Secondary Endpoints: The CFB to the end of each scheduled week for the MADRS, 
HAM-D6, SDS and GAD-7 scores and the absolute value of CGI-I at the end of each scheduled 
week will be analyzed using MMRM as appropriate based on the FAS. The NV-5138 treatment 
group will be compared with the placebo as described for the primary analysis. For 
dichotomous endpoints, such as responder analysis, the Pearson’s Chi-squared Test, or Fisher’s 
Exact Test, as applicable, will be used to compare the proportion of response between NV-
5138 and placebo groups. 
Exploratory Endpoints Analyses: The CFB to the end of each scheduled week for exploratory 
endpoints (PHQ-9, CPFQ, and CSFQ scores) will be analyzed using MMRM as appropriate 
based on the FAS. The NV-5138 treatment group will be compared with the placebo as 
described for the primary analysis. 
Safety Analyses: Safety analyses will be performed by treatment group based on the safety 
population. The incidence rate, severity, and relationship to SM for all AEs will be summarized 
by treatment group for each System Organ Class (SOC) and Preferred Term (PT). Descriptive 
statistics will be presented for demographics, data from the clinical laboratory test results, vital 
signs, weight, ECGs, physical examinations, CADSS, BPRS+ and C-SSRS scores. 
Pharmacogenomic Analyses: The blood samples will be stored for possible testing of genetic 
variation and BDNF concentration. Analyses may include the relationship between treatment 
effects and adverse events (eg, understand how the nonresponders react to treatment and/or 
subjects who show an unusual safety profile). The deoxyribonucleic acid (DNA) and 
ribonucleic acid (RNA) analyses will not be used for individual genetic characterization and 
the subject’s identity will be kept confidential. If analyzed, the results of the exploratory 
analyses will be presented in a stand-alone PGx report. 
Inclusion Criteria: 
1) Is male or female aged 18-70 years (inclusive) at screening;  
2) Is able to read, understand, write, and sign the Informed Consent Form (ICF); 
3) Is willing and able to follow the study protocol and procedures and attend study 
appointments within the specified time windows; 
4) Has a body mass index (BMI) between 19.0-40.0 kg/m2 (inclusive); 
5) Is able to swallow capsules whole without crushing, chewing, or opening; 
6) Has a diagnosis of major depressive disorder (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;  

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 13 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
7) Has a MADRS total score of ≥24 for the current MDE at the screening visits and baseline 
visit (Day 1); 
8) Has a CGI-S score of ≥4 (moderately ill or worse) at the screening visits and baseline visit; 
10) Has a history of inadequate response to ≥1 but ≤4 prior ADT therapies (including the 
current ADT for the current MDE) ≥2 weeks before screening and ≥8 weeks at baseline. 
An inadequate response is defined as <50% improvement in depressive symptoms on an 
ADT (taken at an adequate dose and duration) assessed by the Investigator with the 
administration of the MGH-ATRQ and confirmed by documented records. 
Note: Subjects who fail to respond to either a trial with a new ADT or an increased dose 
for the previous ADT (both of adequate dose and duration) can be enrolled (increased 
doses of the same ADT are counted as only 1 failed ADT). The ADT must have been started 
after the current MDE began; 
11) Has been on a stable therapeutic dose of one of the following study-approved ADTs for the 
current MDE for ≥2 weeks prior to screening: citalopram, escitalopram, paroxetine, 
fluoxetine, sertraline, duloxetine, venlafaxine (immediate release or extended release), 
desvenlafaxine, vilazodone, levomilnacipran, vortioxetine, bupropion or 
dextromethorphan/bupropion (see Appendix 11.17).  
Note: Subject must be on ADT monotherapy before randomization. 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 randomization into the study. 
If so, the second drug should be washed out at least 5 half-lives prior to baseline. If not, 
the subject should be excluded from the study; 
12) Has a detectable blood level of the approved ADT at both Visits 1 and 2 of the Screening 
Period. 
Note: A negative test may be repeated with permission of the Medical Monitor and 
Sponsor upon additional evidence of subject adherence to ADT or evidence of sample or 
laboratory error; 
13) Agrees to maintain a stable therapeutic dose of the approved ADT throughout the study; 
14) Has discontinued prohibited hypnotic medications 6 weeks prior to randomization. See 
Appendix 11.16.1 for allowed sleep medications; 
15) Nonpregnant females of childbearing potential (FOCP) who are exclusively in a same-sex 
relationship are included without the need for 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 ICF, throughout the study, and for 30 days following the last dose of the SM:  
a. Simultaneous use of male condom and intrauterine contraceptive device placed at least 
4 weeks prior to the first SM administration; 
b. Simultaneous use of male condom and diaphragm with spermicide; or 
c. Established hormonal contraceptive (started at least 4 weeks prior to the first dose of 
the SM). 
Female subjects are considered not to be of childbearing potential if they are either 
postmenopausal (amenorrhea for at least 2 years and serum follicle-stimulating hormone 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 14 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
[FSH] level of >40 IU/L) or permanently sterilized (eg, bilateral tubal ligation, bilateral 
oophorectomy, etc.) for 6 months minimum prior to screening. 
All FOCP must have a negative serum pregnancy test result before administration of SM. 
16) Male subjects: 
a. Who are exclusively in a same-sex relationship or have female partners considered not 
to be of childbearing potential are included without the need for acceptable birth 
control methods; 
b. Who have been surgically sterilized (6 months minimum) prior to screening visit are 
eligible to participate without any contraception; or 
c. 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 
Inclusion Criterion #15 which must be used from the time of signing the ICF until 
90 days after the last dose of SM. 
All male subjects must refrain from donating sperm from the date of first administration of 
SM until 90 days after the last dose of the SM. 
Exclusion Criteria: 
1) Has a MADRS total score improvement of ≥25% from the highest to the lowest score 
during the Screening Period and baseline visit; 
2) Has received new-onset psychotherapy or had a change in the intensity of psychotherapy 
within 4 weeks prior to screening. Psychotherapy initiated prior to screening must be 
maintained for the duration of the study; 
3) Has been treated with electroconvulsive therapy (ECT), transcranial magnetic stimulation 
(TMS), or vagal nerve stimulation (VNS) for the current MDE; 
4) Has received treatment with long-acting injectable antipsychotics (LAIs) within 3 months 
prior to screening; 
5) Has recurrent MDD, has been on an adequate dose and duration of ADT and had a >50% 
response for at least 4 weeks while using that ADT that was then followed by a loss of 
response (ie, tachyphylaxis) as assessed by the Investigator. The date of the loss of 
response is the start date of the current episode (from when the symptoms returned);   
6) Has demonstrated a nonresponse to esketamine or off-label use of ketamine or has taken 
esketamine or ketamine less than 6 months prior to screening visit (see Appendix 11.16.2); 
7) Is unable to discontinue treatment with trazodone at doses greater than 150 mg daily for a 
minimum of 5 half-lives before baseline. 
a. Trazodone 150 mg/day or less 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;  
8) Has unstable hypothyroidism. If the thyroid-stimulating hormone (TSH) 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. 
a. Treatment with thyroid hormones is allowed if prescribed at a stable dose for 
≥3 months and the subject’s thyroid levels are normal; 
9) Has clinically significant abnormal laboratory profiles (alanine aminotransferase [ALT] or 
aspartate aminotransferase [AST] values ≥3x the upper limit of normal [ULN] or total 
bilirubin ≥1.5 times the ULN), vital signs, or ECGs 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; 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 15 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
10) Has abnormal renal function as demonstrated by an estimated glomerular filtration rate 
(eGFR) of <60 mL/min according to the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation at the screening visit; 
11) Has a history of substance use disorder (SUD) within 6 months prior to screening or is 
currently using or has a positive result (UDS) at any screening or baseline visits for drugs 
of abuse (see Appendix 11.16.2). Positive results for specific medications must have a 
confirmed medical history; 
12) Has a history of alcohol use disorder within 6 months prior to screening. A subject who has 
a positive alcohol test result at any of the screening visits (V1 andV2), and if based on the 
Investigator opinion the subject does not have a history of alcohol use disorder, the subject 
may continue to the next visit. If the alcohol test result at baseline visit is positive, the 
subject should be excluded from the study. Subjects must refrain from using alcohol during 
the treatment phase of the study; 
13) Has a diagnosis of cannabis use disorder (CUD) within 6 months before screening and has 
a positive UDS for cannabis at screening. 
a. At the discretion of the Sponsor, recreational use of cannabis (not daily) is allowed and 
should be kept consistent during the study. Subjects must agree to refrain from using 
cannabis 48 h prior to the study visits; 
b. Medical cannabis prescribed for a medical condition (eg, muscle spasms, nausea, 
vomiting, pain) other than depression, seizures, and insomnia is allowed if taken at a 
stable regimen for at least 3 months prior to screening. Newly prescribed cannabis 
treatment and/or change to the existing regimen is prohibited (see Appendix 11.16.1). 
When applicable, subjects should show proof of their prescription for medical 
cannabis; 
14) 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 C-SSRS in the 2 years before screening; a history of suicide 
attempt in the last 6 months; or more than 2 lifetime suicide attempts; 
15) 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; 
16) Has a diagnosis within 12 months before screening or current diagnosis of post-traumatic 
stress disorder (PTSD), obsessive-compulsive disorder (OCD), 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 comorbid generalized anxiety disorder is allowed but subject to 
medication restrictions (anticonvulsants and beta-blockers are allowed, if on a stable 
regimen for 2 months prior to screening visit);  
b. Established attention-deficit/hyperactivity disorder (ADHD) diagnosis is allowed. 
Subjects must provide confirmation of ADHD diagnosis (ie, provide medical records 
for prescribed ADHD medications) and be on a stable dose of ADHD medication for at 
least 3 months prior to the screening visit; 
17) 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 (CNS) functioning; or 
c. Has current evidence of delirium or dementia; 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 16 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
18) 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 the following: 
a. Cardiovascular disorders: 
i. 
Clinically significant symptomatic orthostatic hypotension; 
ii. 
Uncontrolled hypertension despite diet, exercise, and antihypertensive 
medications (defined as a supine systolic blood pression [SBP] >140 mmHg or 
diastolic blood pressure [DBP] >90 mmHg) during screening and at baseline; 
iii. 
Acute coronary syndrome; 
iv. 
History of unexplained loss of consciousness, unexplained syncope, 
unexplained irregular heartbeats; 
v. 
QT interval corrected using Fridericia’s method (QTcF) ≥450 ms (for men) or 
≥470 ms (for women) at screening (see NoteNote:  
vi. 
Patient or family history of QT congenital syndrome; 
b. Oncological disorders: 
i. 
Malignant tumors within 5 years prior with the exception of benign skin 
tumors; and/or 
ii. 
Diagnosis or family history of tuberous sclerosis complex (TSC). 
c. Positive result for human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C (HCV) at screening unless: 
i. 
HIV positive: subjects must have a HIV Confirmation Test. If the confirmatory 
test is positive, the subject is eligible if on chronic suppressive antiviral 
medication for more than 6 months with an undetectable viral load; 
ii. 
HBsAg positive: subjects should be tested for anti-HBc, IgM anti-HBc, and 
anti-HBs to detect acute or chronic infection (ineligible). Subjects whose 
results indicate immunity (either by natural infection or vaccination) with no 
active infection are eligible; and/or 
iii. 
HCV positive: subjects must have undetectable HCV RNA to be eligible; 
d. Unintended recent clinically significant weight loss; 
e. Has chronic urinary tract infections (UTIs); 
f. Blood donation within 6 weeks of screening; and/or 
g. Is on any medication that could, in the Investigator’s opinion, interfere with the 
assessments of safety, tolerability, efficacy, or the conduct or interpretation of the 
study; 
19) Requires treatment with a medication or other substance that is prohibited by the protocol 
(see Section 5.8); 
20) Has history of severe drug allergy or hypersensitivity, or hypersensitivity to the SM or 
excipients; 
21) Female subjects who are pregnant, lactating, or planning to become pregnant while 
enrolled in the study; 
22) Has previously enrolled in a NV-5138 study; 
23) Is currently participating in another clinical trial or has participated in a clinical study 
within 30 days of screening visit. 
24) Is a member of study personnel or 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 pre-treatment period to determine eligibility. Repeat testing is not allowed 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 17 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
without justification from the site and agreement from the Medical Monitor and the Sponsor on 
a case-by-case basis. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 18 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
Table of Contents 
INVESTIGATOR’S SIGNATURE PAGE ..................................................................... 2 
SUPERNUS PROTOCOL APPROVAL PAGE ............................................................ 3 
NAVITOR PROTOCOL APPROVAL PAGE .............................................................. 4 
CLINICAL PROTOCOL SYNOPSIS ............................................................................ 5 
1 
LIST OF ABBREVIATIONS ............................................................................. 23 
2 
INTRODUCTION................................................................................................ 27 
2.1 
Background ..........................................................................................................27 
2.2 
NV-5138 ................................................................................................................27 
2.3 
Preclinical Studies ................................................................................................28 
2.3.1 
In Vitro Binding Studies ............................................................................. 28 
2.3.2 
In Vivo Pharmacology in Animals ............................................................. 28 
2.3.3 
In Vivo Pharmacology Studies in Animal Models of Depression .............. 29 
2.3.4 
In Vivo Binding Adverse Effects ................................................................ 30 
2.4 
Toxicological Studies ...........................................................................................30 
2.5 
Clinical Studies .....................................................................................................32 
2.5.1 
Phase 1 Studies ........................................................................................... 32 
2.5.1.1 
Study NAV-17A-001 ...................................................................................................... 32 
2.5.1.2 
Study NAV-17A-002 ...................................................................................................... 34 
2.5.1.3 
Study NAV-17A-003 ...................................................................................................... 34 
2.5.1.4 
Study NAV-17A-004 ...................................................................................................... 35 
2.5.1.5 
Study NAV-17A-005 ...................................................................................................... 36 
2.5.1.6 
Study NAV-17A-006 ...................................................................................................... 36 
2.6 
Study Rationale ....................................................................................................37 
3 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 39 
3.1 
Primary Objective ................................................................................................39 
3.2 
Key Secondary Objective ....................................................................................39 
3.3 
Additional Secondary Objectives .......................................................................39 
3.4 
Pharmacokinetics Objective ...............................................................................39 
3.5 
Safety Objective ...................................................................................................39 
3.6 
Exploratory Objectives ........................................................................................39 
3.7 
Primary Efficacy Endpoint .................................................................................39 
3.8 
Key Secondary Endpoint .....................................................................................40 
3.9 
Additional Secondary Endpoints ........................................................................40 
3.10 
Pharmacokinetics Endpoints ..............................................................................40 
3.11 
Safety Endpoints ..................................................................................................40 
3.12 
Exploratory Endpoints ........................................................................................40 
4 
INVESTIGATIONAL STUDY PLAN ............................................................... 42 
4.1 
Overall Study Design and Plan ...........................................................................42 
4.2 
Study Population ..................................................................................................48 
4.2.1 
Number of Subjects..................................................................................... 48 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 19 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
4.2.2 
Inclusion Criteria ........................................................................................ 48 
4.2.3 
Exclusion Criteria ....................................................................................... 50 
4.3 
Completion of Study ............................................................................................54 
4.4 
Discontinuation or Early Termination of Subjects ...........................................54 
5 
STUDY TREATMENT ....................................................................................... 56 
5.1 
Study Medication Identity, Packaging, and Labeling ......................................56 
5.2 
Study Medication Administration ......................................................................56 
5.3 
Missed Dose ..........................................................................................................57 
5.4 
Antidepressant Administration ..........................................................................57 
5.5 
Method of Assigning Subjects to Treatment Arm ............................................58 
5.6 
Blinding .................................................................................................................58 
5.6.1 
Maintaining Blind ....................................................................................... 58 
5.6.2 
Planned Unblinding .................................................................................... 59 
5.6.3 
Emergency Unblinding ............................................................................... 59 
5.7 
Study Medication Handling and Accountability ...............................................59 
5.8 
Concomitant and Prohibited Medications .........................................................60 
5.8.1 
Permitted Concomitant Medications ........................................................... 60 
5.8.2 
Prohibited Concomitant Medications ......................................................... 62 
6 
STUDY METHODS............................................................................................. 63 
6.1 
Study Visits and Procedures ...............................................................................63 
6.1.1 
Visit 1 – Screening (Days -42, -35, or -28, Depending on the Prescreening 
ADT History) ............................................................................................. 68 
6.1.2 
Visit 2 (Day -14 ± 1 Day) ........................................................................... 68 
6.1.3 
Visit 3 – Baseline (Randomization: Day 1 ± 2 Days) ................................. 69 
6.1.4 
Visits 4-8 – Treatment Period Including End of Study............................... 69 
6.1.5 
Follow-up Phone Call (Day 66 ± 7 Days) .................................................. 72 
6.1.6 
Unscheduled Visits ..................................................................................... 73 
6.1.7 
Post-Baseline Study Visits .......................................................................... 73 
6.1.8 
Pharmacokinetic Blood Sampling............................................................... 73 
6.1.9 
Pharmacogenomic Testing .......................................................................... 74 
7 
STUDY VARIABLES AND ASSESSMENTS .................................................. 75 
7.1 
Rater Qualification Process ................................................................................75 
7.2 
Efficacy Assessments ...........................................................................................75 
7.2.1 
Montgomery-Åsberg Depression Rating Scale .......................................... 75 
7.2.2 
Clinical Global Impression – Severity of Illness ........................................ 76 
7.2.3 
Generalized Anxiety Disorder 7-Item Scale ............................................... 76 
7.2.4 
Clinical Global Impression – Improvement ................................................ 77 
7.2.5 
Sheehan Disability Scale............................................................................. 77 
7.2.6 
Hamilton Depression Rating Scale – 6 Items ............................................. 78 
7.3 
Exploratory Assessments.....................................................................................78 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 20 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
7.3.1 
Cognitive and Physical Functioning Questionnaire .................................... 78 
7.3.2 
Patient Health Questionnaire 9-Item ........................................................... 78 
7.3.3 
Changes in Sexual Functioning Questionnaire ........................................... 79 
7.4 
Safety Variables and Assessments ......................................................................79 
7.4.1 
Adverse Events ........................................................................................... 79 
7.4.2 
Adverse Events of Special Interest ............................................................. 80 
7.4.3 
Overdose ..................................................................................................... 80 
7.4.4 
Causality ..................................................................................................... 80 
7.4.5 
Recording and Evaluation of Adverse Events ............................................ 80 
7.4.6 
Criteria for Assessing Severity ................................................................... 81 
7.4.7 
Criteria for Assessing Causality.................................................................. 81 
7.4.8 
Serious Adverse Events .............................................................................. 82 
7.4.9 
Investigator Responsibilities for Reporting SAEs ...................................... 82 
7.4.10 
Other Events Requiring Immediate Reporting ........................................... 83 
7.4.11 
Sponsor Responsibilities for Reporting SAEs ............................................ 83 
7.4.12 
Clinician-Administered Dissociative States Scale ...................................... 84 
7.4.13 
Brief Psychiatric Rating Scale .................................................................... 84 
7.5 
Treatment-Emergent Suicidal Ideation .............................................................85 
7.5.1 
Columbia-Suicide Severity Rating Scale .................................................... 85 
7.5.2 
Suicide Risk Management Plan .................................................................. 85 
7.5.2.1 
Assessment of Suicide Risk ............................................................................................ 85 
7.5.2.2 
Acute Suicidal Crisis ...................................................................................................... 85 
7.5.2.3 
Non-acute Suicidal Risk ................................................................................................. 86 
7.6 
Clinical Measurements ........................................................................................86 
7.6.1 
Screening and Clinical Safety Laboratory Assessments ............................. 86 
7.6.2 
Vital Signs and Weight ............................................................................... 87 
7.6.3 
Physical Examinations and Height ............................................................. 87 
7.6.4 
Electrocardiograms ..................................................................................... 87 
7.7 
PK Variables and Assessments ...........................................................................88 
7.8 
Screening Scales and Assessment Tools .............................................................88 
7.8.1 
Mini-International Neuropsychiatric Interview .......................................... 88 
7.8.3 
Medication Adherence Diary ...................................................................... 90 
7.9 
Placebo Response Reduction Training...............................................................91 
7.10 
Data Safety Monitoring Board ...........................................................................91 
8 
STATISTICAL METHODS ............................................................................... 92 
8.1 
General Considerations .......................................................................................92 
8.2 
Sample Size and Power Considerations .............................................................92 
8.3 
Estimand ...............................................................................................................92 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 21 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
8.3.1 
Primary Estimand........................................................................................ 92 
8.3.2 
Secondary Estimand.................................................................................... 93 
8.4 
Handling of Dropout or Missing Data ...............................................................93 
8.5 
Analysis Populations ............................................................................................94 
8.6 
Demographics and Baseline Analysis .................................................................94 
8.7 
Subject Disposition...............................................................................................94 
8.8 
Study Medication Exposure and Compliance ...................................................95 
8.9 
Concomitant Medications ...................................................................................95 
8.10 
Efficacy Analysis ..................................................................................................95 
8.10.1 
Primary Efficacy Analysis .......................................................................... 95 
8.10.2 
Sensitivity Analysis .................................................................................... 96 
8.11 
Secondary Efficacy Analyses ..............................................................................97 
8.11.1 
Key Secondary Efficacy Analyses .............................................................. 97 
8.11.2 
Additional Secondary Analyses .................................................................. 97 
8.12 
Exploratory Efficacy Analyses............................................................................97 
8.13 
Pharmacokinetic Analyses ..................................................................................97 
8.14 
Interim Analysis ...................................................................................................98 
8.15 
Pharmacogenomic Analyses ................................................................................98 
8.16 
Safety Analysis .....................................................................................................98 
9 
DOCUMENTATION ........................................................................................... 99 
9.1 
Adherence to the Protocol ...................................................................................99 
9.2 
Changes to the Protocol .......................................................................................99 
9.3 
Data Quality Assurance .......................................................................................99 
9.3.1 
Data Collection ......................................................................................... 100 
9.3.2 
Clinical Data Management ....................................................................... 100 
9.3.3 
Database Quality Assurance ..................................................................... 100 
9.3.4 
Bioanalytical Sample Handling ................................................................ 100 
9.4 
Retention of Records..........................................................................................101 
9.5 
Auditing Procedures ..........................................................................................101 
9.6 
Publication of Results ........................................................................................101 
9.7 
Financing and Insurance ...................................................................................101 
9.8 
Disclosure and Confidentiality .........................................................................102 
9.9 
Discontinuation of Study ...................................................................................102 
10 
ETHICS .............................................................................................................. 103 
10.1 
Institutional Review Boards ..............................................................................103 
10.2 
Ethical Conduct of the Study ............................................................................103 
10.3 
Investigators and Study Personnel ...................................................................103 
10.4 
Subject Information and Consent ....................................................................103 
11 
APPENDIX:........................................................................................................ 105 
11.1 
MADRS ...............................................................................................................105 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 22 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
11.1.1 
MADRS Past Week (Follow-up Evaluation) ............................................ 111 
11.2 
HAM-D6 ..............................................................................................................117 
11.3 
CGI-S ..................................................................................................................122 
11.4 
GAD-7 .................................................................................................................123 
11.5 
CGI-I ...................................................................................................................124 
11.6 
SDS ......................................................................................................................125 
11.7 
CPFQ ...................................................................................................................126 
11.8 
PHQ-9..................................................................................................................127 
11.9 
CSFQ ...................................................................................................................128 
11.10 CADSS ................................................................................................................130 
11.11 BPRS+ .................................................................................................................135 
11.12 C-SSRS ................................................................................................................137 
11.13 C-SSRS Since Last Visit ....................................................................................140 
11.14 Mini-International Neuropsychiatric Interview (MINI) ................................143 
11.15 Antidepressant Treatment Response Questionnaire (ATRQ) .......................181 
11.16 Prohibited and Permitted Concomitant Medications .....................................189 
11.16.1 : Permitted Concomitant Medications ...................................................... 189 
11.16.2 : Prohibited Concomitant Medications ..................................................... 192 
11.17 Approved Antidepressant Treatment ..............................................................194 
12 
REFERENCES ................................................................................................... 196 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 23 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
1 LIST OF ABBREVIATIONS 
ADHD 
attention deficit/hyperactivity disorder 
ADR 
adverse drug reaction 
ADT 
antidepressant therapy 
AE 
adverse event 
ALT 
alanine aminotransferase 
ASSR 
auditory steady-state response 
AST 
aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical (code) 
ATRQ 
Antidepressant Treatment Response Questionnaire 
AUC 
area under curve 
BDNF 
brain-derived neurotrophic factor 
BMI 
body mass index 
BPRS+ 
Brief Psychiatric Rating Scale-Positive Symptom Subscale  
CADSS 
Clinician Administered Dissociative States Scale 
CFB 
change from baseline 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity of Illness 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease-Epidemiology Collaboration 
CL/F 
apparent clearance 
ClinRO 
 
clinical reported outcome 
CLr 
renal clearance 
Cmax 
peak plasma concentration 
CNS 
central nervous system 
CPFQ 
Cognitive and Physical Functioning Questionnaire 
CRA 
clinical research associate 
CRO 
clinical research organization 
CSF 
cerebrospinal fluid 
CSFQ 
Changes In Sexual Functioning Questionnaire  
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTNI 
Clinical Trials Network Institute 
CUD 
cannabis use disorder 
CUS 
chronic unpredictable stress 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DNA 
deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – 5th Edition 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram/electrocardiography 
eCRF 
electronic case report form 
ECT 
electroconvulsive therapy 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 24 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
EDC 
electronic data capture 
EEG 
electroencephalography 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
ER 
extended-release 
ERP 
event-related potential 
ES 
effect size 
ET 
early termination 
FAS 
Full Analysis Set 
FCS 
fully conditional specification (method) 
FDA 
Food and Drug Administration 
FOCP 
females of childbearing potential 
FPC 
follow-up phone call 
FSH 
follicle-stimulating hormone 
FST 
Forced Swim Test 
FT4 
free thyroxine 
GAD-7 
Generalized Anxiety Disorder 7-Item Scale 
GCP 
Good Clinical Practice 
GLDH 
glutamate dehydrogenase 
GLP 
Good Laboratory Practice 
HAM-D6  
Hamilton Depression Rating Scale-6 Items 
HIV 
human immunodeficiency virus 
HTT 
human treat test 
IB 
Investigator’s Brochure 
ICE 
intercurrent events 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IR 
immediate release 
IRB 
institutional review board 
IRT 
interactive response technology 
LS 
least squares 
MADRS 
Montgomery–Åsberg Depression Rating Scale 
MAR 
missing at random 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH 
Massachusetts General Hospital 
MINI 
Mini International Neuropsychiatric Review 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
missing not at random 
mPFC 
medial prefrontal cortex 
mTORC1 
mammalian target of rapamycin complex 1 
NMDA 
N-methyl-D-aspartate 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 25 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
NMDAR 
N-methyl-D-aspartate receptor 
NOAEL 
no-observed-adverse-effect-level 
NSFT 
novelty-suppressed feeding test 
OCD 
obsessive-compulsive disorder 
p-EEG 
pharmaco-electroencephalography 
PFC 
prefrontal cortex 
PGx 
pharmacogenomics 
PHQ-9 
Patient Health Questionnaire 9-Item 
PK 
pharmacokinetics 
POC 
Point of Care 
PP 
Per Protocol 
PRR 
Placebo Response Reduction (Training) 
PT 
preferred term 
PTSD 
post-traumatic stress disorder 
Q1, Q3 
quartile 1, quartile 3 
QD 
once daily 
qEEG 
quantitative electroencephalography 
QTcF 
QT corrected using Fridericia’s method 
RNA 
ribonucleic acid 
RR 
respiratory rate 
SADR 
suspected adverse drug reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
 
 
SD 
standard deviation 
SDS 
Sheehan Disability Scale 
SIGMA 
Structured interview guide for the Montgomery–Åsberg Depression 
SM 
study medication 
SNRI 
serotonin and noradrenaline reuptake inhibitor 
SOC 
system organ class 
SOP 
standard operating procedure 
SSRI 
selective serotonin reuptake inhibitor 
SUD 
substance use disorder 
t½ 
terminal elimination half-life 
TDD 
total daily dose 
TEAE 
treatment-emergent adverse event 
Tmax 
time to peak plasma concentration 
TMS 
transcranial magnetic stimulation 
TR 
total radioactivity 
TRD 
treatment-resistant depression 
TSC 
tuberous sclerosis complex 
TSH 
thyroid-stimulating hormone 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 26 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
UDS 
urine drug screen 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
Vd/F 
apparent volume of distribution 
VNS 
vagal nerve stimulation 
WBC 
white blood cell 
WHO DD 
World Health Organization-Drug Dictionary 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 27 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
2 
INTRODUCTION 
2.1 
Background 
Major Depressive Disorder (MDD) is a leading disability that affects over 25.8 million 
people worldwide (Q. Liu et al., 2020). MDD is made up of major depressive episodes 
that are usually two weeks in duration and longer and may be recurring in nature. Based 
on the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5), out 
of the five diagnostic criteria needed to be diagnosed with MDD, at least one of the 
following must be present: depressed mood or loss of interest or pleasure. In addition to 
one of these symptoms, the individual must also experience one of the following: changes 
in appetite or weight, sleep disturbances, psychomotor changes (ie, agitation or 
retardation); decreased energy, sense of worthlessness or guilty, impaired ability to think, 
and thoughts of death, suicidal ideation or suicide attempts (DSM-5, 2013).  
First-line therapy for MDD is either psychotherapy, pharmacotherapy, or a combination 
of both. Antidepressants typically used as first-line medications are selective serotonin 
reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), 
bupropion, mirtazapine, and newer agents. Approximately 50-70% of patients with MDD 
do not achieve response or remission with at least one antidepressant treatment (ADT) of 
adequate dose and duration (Bartova et al., 2019; Knoth, Bolge, Kim, & Tran, 2010; 
Trivedi et al., 2006) resulting in treatment-resistant depression (TRD). The two currently 
Food and Drug Administration (FDA)-approved treatments for TRD are the 
Olanzapine/Fluoxetine hydrochloride combination and the nasal spray, Esketamine. 
There is a clear unmet need in the treatment of TRD for a novel pharmacotherapy that has 
less deleterious effects such as metabolic changes or potential addictive properties 
(Brunner, Tohen, Osuntokun, Landry, & Thase, 2014; FDA, 2019). There are novel 
antidepressants in clinical development and approved for the treatment of TRD that 
modulate the N-methyl-D-aspartate (NMDA) receptor (NMDAR), leading to rapid and 
sustained symptom relief in TRD patients (Abdallah, Averill, & Krystal, 2015; Moskal et 
al., 2017; Zarate & Machado-Vieira, 2017); however, acute modulation of the NMDAR 
with ketamine administration has been associated with frequent dissociative symptoms 
and other undesirable effects (Pennybaker, Luckenbaugh, Park, Marquardt, & Zarate, 
2017). Alternative therapeutic options not involving NMDAR modulation could be of 
great value in treating TRD patients. 
2.2 
NV-5138 
The investigational drug in this study is NV-5138, (S)-2-amino-5,5-difluoro-4,4-
dimenthylpentanoic acid, a novel, orally bioavailable, selective, activator of mammalian 
target of rapamycin complex 1 (mTORC1) cellular signaling. The activation of mTORC1 
involves the binding of NV-5138 to the primary cytoplasmic leucine sensor protein 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 28 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
isoforms sestrins 1 and 2, without binding to or modulating other synaptic receptors or 
other signaling proteins (eg, NMDAR).  
NV-5138 is intended to provide a rapid-onset antidepressant response whereas the 
standard first-line and second-line antidepressant therapies (SSRIs and SNRIs) typically 
require a longtime course to establish an antidepressant response (Ignacio et al., 2016). 
The central role of mTORC1 signaling in the rapid-acting antidepressant effect suggests 
that an activator of mTORC1 signaling may provide rapid antidepressant efficacy without 
the potential neurological side effects associated with some NMDAR-modulating 
compounds.  
2.3 
Preclinical Studies 
In animals, NV-5138 was rapidly and completely absorbed after oral administration. 
Following single oral administration in rats and monkeys, the increase in systemic 
exposure (area under the curve [AUC]) of NV-5138 was roughly proportional with dose. 
NV-5138 exhibited a moderate volume of distribution and low systemic clearance in all 
preclinical species.  
2.3.1 In Vitro Binding Studies 
The specificity of NV-5138 was evaluated in vitro by screening for binding and 
functional modulation across multiple categories of proteins, including multiple classes 
of enzymes and receptors. There was no significant binding to or modulation of several 
classes of enzymes, including an extensive number of kinases and over 100 different 
receptors, among them many of the most common receptors found in the central nervous 
system (CNS). This included all isoforms of the NMDAR where there was no binding or 
functional modulation when evaluated across ligand categories (Sengupta et al., 2019) .  
2.3.2 In Vivo Pharmacology in Animals 
Oral administration of NV-5138 in ad libitum fed rats resulted in significant activation of 
mTORC1 across various regions of rat brain including the prefrontal cortex (PFC), 
hippocampus, striatum and neocortex, with no significant activation observed in 
cerebellum (Sengupta et al., 2019). Similarly, oral administration of NV-5138 and 
leucine resulted in mTORC1 activation across multiple peripheral tissues, but not in 
whole brain. These data also show that the pattern of mTORC1 activation in the 
periphery appears to correlate with nutritional activation simulated by the use of leucine 
supplementation, indicating that there is no organ system other than the brain which 
appears more sensitive to NV-5138 versus the natural sestrin2/1 ligand leucine (Sengupta 
et al., 2019). The differential metabolism between NV-5138 and leucine in the brain leads 
to the greater relative activation of mTORC1 compared with that observed in the 
peripheral tissues examined, where there is greater direct competition between leucine 
and NV-5138 for sestrin-mediated activation and subsequent mTORC1 activation 
(Sengupta et al., 2019). 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 29 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
2.3.3 In Vivo Pharmacology Studies in Animal Models of Depression 
The pharmacological efficacy of NV-5138 at different doses was evaluated using models 
of stress-induced depressive behavior and anxiety, including the forced swim test (FST) 
and the novelty-suppressed feeding test (NSFT). These studies demonstrate that the 
pharmacological efficacy of NV-5138 in the FST and the NSFT was observed only after 
one dose of 160 mg/kg, up to 3 days following administration (Kato et al., 2019). Similar 
studies demonstrate that the pharmacological efficacy of NV-5138 in the FST and the 
NSFT was observed 24 h after daily dosing for 6 days at 80 mg/kg and out to 72 h 
following the end of the dosing period, suggesting that alternative dose administration 
strategies to achieve similar efficacy at lower doses clinically may be feasible. 
The chronic unpredictable stress (CUS) model is considered one of the more challenging 
models to evaluate antidepressant activity of new agents, since the model produces 
anhedonia, a core symptom of depression (Banasr et al., 2007; Li et al., 2011). Rats 
exposed to CUS had a significant decrease in sucrose preference compared to the 
non-CUS animals. The administration of a single dose of NV-5138 completely and 
significantly blocked the effects of CUS in the sucrose preference test. CUS also had a 
significant impact on the latency to feed in the NSFT which was significantly improved 
up to 3 days following the administration of NV-5138 (Kato et al., 2019). Since previous 
studies in rodents have established that ketamine and GLYX-13 require activation of the 
mTORC1 signaling pathway to elicit the observed rapid antidepressant efficacy (Hoeffer 
& Klann, 2010; Li et al., 2010; R. J. Liu et al., 2017), the effects of NV-5138 
(160 mg/kg) following a single oral administration on mTORC1 pathway activation, were 
compared to those of ketamine (10 mg/kg) following a single injection in male rats. 
Similar to ketamine, there was a robust and significant induction of S2448pmTOR by 
NV-5138 and a significant induction of GluR1 and synapsin1 by both NV-5138 and 
ketamine was observed (Kato et al., 2019). This is translated in increased dendritic spine 
formation in the layer V pyramidal neurons of the medial prefrontal cortex (mPFC). 
The human treat test (HTT) is another well-validated test procedure in the nonhuman 
primate which is sensitive to clinically active anxiolytics (Costall, Domeney, Gerrard, 
Kelly, & Naylor, 1988). NV-5138, similarly to ketamine, showed an 
anxiolytic/antidepressant-like profile 24 h after acute oral administration in the marmoset 
HTT as demonstrated by the ability to reduce the number of postures without causing a 
change in locomotor activity as assessed by the number of jumps performed by the 
animals. 
Pharmaco-electroencephalography (p-EEG) have been used extensively to characterize 
the impact of neuromodulating compounds, including rapid-acting antidepressants such 
as ketamine (Ahnaou, Huysmans, Biermans, Manyakov, & Drinkenburg, 2017; W. C. 
Duncan, Jr. & Zarate, 2013; W. C. Duncan et al., 2013). p-EEGs in animals and humans 
are being used to address extrapolation issues and to optimize the translational validity of 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 30 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
preclinical animal p-EEG paradigms such as quantitative electroencephalogram (qEEG). 
NV-5138 produces rapid and strong effects on the spectral EEG recorded from rat in both 
sleep and wake states. In two independent studies, induction of these effects required at 
least two doses (separated by 36 h) of NV-5138 with a third dose further accentuating the 
effects. 
2.3.4 In Vivo Binding Adverse Effects 
The in vitro plasma protein binding of NV-5138 was low (close to 0%) in all species 
tested, which indicates that NV-5138 is unlikely to produce adverse effects due to a 
pharmacokinetic drug interaction involving competition for plasma protein binding sites. 
After oral administration in rats, NV-5138 rapidly distributed to tissues, including the 
brain, where maximal concentrations in whole brain homogenates were achieved at 1 h 
postdose (Kato et al., 2019; Sengupta et al., 2019). 
 
 
 
 
 
 
 
 
 
 
2.4 
Toxicological Studies  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 31 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 32 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.5 
Clinical Studies 
2.5.1 Phase 1 Studies  
Four Phase 1 studies have been conducted; each is summarized below. For additional 
information, please refer to the Investigator’s Brochure (IB). 
2.5.1.1 Study NAV-17A-001 
This study was a Phase 1a/1b, randomized, two-part, double-blind, placebo-controlled, 
on-site study of single ascending dosage levels of NV-5138 or placebo in 48 healthy 
volunteers (Part A) and a single dose of NV-5138 2400 mg or placebo in 32 subjects with 
TRD (Part B).  
In Part A of the study, a single dose of NV-5138 was generally safe and well tolerated in 
healthy subjects at doses ranging from 150-2400 mg. Subjects treated with NV-5138 had 
a higher incidence of treatment-emergent adverse events (TEAEs) overall (36.1% 
compared with 16.7%) and of drug-related TEAEs (19.4% compared with 0) than 
subjects who received placebo; this was a disparity that was generally dose related. There 
were no serious adverse events (SAEs) or discontinuations due to TEAEs. Only two 
drug-related TEAEs occurred in more than 1 subject: dizziness (NV-5138, 3 subjects 
[8.3%]; placebo, 0) and nausea (NV-5138, 2 subjects [5.6%]; placebo, 0). All TEAEs in 
NV-5138-treated subjects were mild.
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 33 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
 
 
In Part B of the study, a single dose of NV-5138 2400 mg was generally safe and well 
tolerated in patients with TRD. NV-5138 was associated with a higher incidence of 
TEAEs (68.8% compared with 37.5%) and drug-related TEAEs (62.5% compared with 
25.0%) than placebo. There were no serious or severe TEAEs, or discontinuations due to 
TEAEs. Only 3 drug-related TEAEs occurred in more than 1 patient: somnolence (NV-
5138, 4 patients [25.0%]; placebo, 2 patients [12.5%]); dizziness (NV-5138, 2 patients 
[12.5%]; placebo, 0), and headache (NV-5138, 2 patients [12.5%]; placebo, 0). 
There were no dissociative effects in either Part A or Part B. There were no clinically 
meaningful trends or individual abnormalities in laboratory test results, vital signs, ECG 
data, Brief Psychiatric Rating Scale-Positive Symptoms Subscale (BPRS+), and Clinician 
Administered Dissociative States Scale (CADSS) scores, or neurological and physical 
examination findings in either part of the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 37 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
 
  
 
 
 
 
 
NV-5138 was well tolerated when administered to healthy male subjects as a single dose 
of 1600 mg [14C]-NV-5138 oral solution in the fasted state. There were no AEs, severe 
AEs, SAEs, or AEs leading to subject discontinuation or to death in this study. 
2.6 
Study Rationale 
A randomized, placebo-controlled trial is the gold standard for evaluating the efficacy of 
an investigational product. In preclinical antidepressant models, NV-5138 (Section 2.3) 
showed anxiolytic and antidepressant effects similar to ketamine. In addition in a pilot 
clinical study, NV-5138 has shown preliminary signals of efficacy in subjects with TRD. 
These efficacy signals, together with evidence of target engagement and a favorable 
safety and tolerability profile, support continued development of NV-5138 for TRD.   
Rationale for dose regimen 
 
 
 
 
 
 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 38 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
Rationale for Study Primary and Secondary Endpoints 
The appropriately selected scales as the primary and key secondary endpoints are the 
MADRS and Clinical Global Impression-Severity of Illness (CGI-S). 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 & Asberg, 
1979). Change in MADRS total score was selected as the primary outcome measure 
because MADRS is a clinician/Investigator-structured interview assessing the severity of 
MDD symptoms per the DSM-5 criteria.
 
 
  
The CGI-S was selected as a key secondary outcome measure because it is commonly 
used as a reliable measure of severity of a disease/disorder in clinical research as well as 
a measure of change in severity over time during an experimental treatment.  
The HAM-D6 focuses on six core depression symptoms and is sensitive to measuring 
rapid changes in depression symptoms. 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 39 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective 
• 
To evaluate the efficacy of NV-5138 compared to placebo when administered to 
adults with TRD on the MADRS total score 
3.2 
Key Secondary Objective 
• 
To evaluate the efficacy of NV-5138 compared to placebo in adult subjects with 
TRD on the clinician’s impression of the severity of depressive symptoms 
3.3 
Additional Secondary Objectives 
• 
To evaluate the efficacy of NV-5138 compared to placebo in adults with TRD on 
the following: 
1) Clinical response to HAM-D6 
2) Onset of clinical response 
3) Depressive symptoms response 
4) Depressive symptoms remission 
5) Clinician’s impression of improvement of depressive symptoms 
6) Individual disability 
7) Anxiety symptoms 
8) Clinical response rate of severity 
9) Clinical response rate of improvement 
3.5 
Safety Objective 
• 
To evaluate the safety and tolerability of NV-5138 compared to placebo in adults 
with TRD 
3.6 
Exploratory Objectives 
• 
To evaluate the efficacy of NV-5138 compared to placebo in adults with TRD on 
the following: 
1) Self-reported depressive symptoms 
2) Self-reported cognitive and physical function 
3) Self-reported sexual function 
• 
Pharmacogenomic evaluations 
3.7 
Primary Efficacy Endpoint 
• 
CFB to the end of the treatment period on the MADRS total score 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 40 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
3.8 
Key Secondary Endpoint 
• 
CFB to the end of the treatment period on the CGI-S score 
3.9 
Additional Secondary Endpoints 
1) CFB to the end of each scheduled week on the HAM-D6 total score 
2) CFB to the end of each scheduled week in the MADRS total score 
3) Proportion of responders (defined as ≥50% reduction from baseline in the 
MADRS total score) at the end of each scheduled week 
4) Proportion of subjects in remission (MADRS total score ≤10) at the end of 
each scheduled week 
5) Clinical Global Impression – Improvement (CGI-I) score at the end of each 
scheduled week  
6) CFB to the end of each scheduled week on the Sheehan Disability Scale 
(SDS) total score 
7) CFB to the end of each scheduled week on the Generalized Anxiety Disorder 
7 item (GAD-7) scale total score 
8) Percentage of subjects with a CGI-S score of 1 or 2 at the end of each 
scheduled week 
9) Percentage of subjects with a CGI-I score of 1 or 2 at the end of each 
scheduled week 
3.11 Safety Endpoints 
1) Safety endpoints are adverse events (AEs), clinical safety laboratory test 
results, vital signs (including orthostatic blood pressure/pulse rate), weight, 
ECGs, physical examination 
2) Suicidal ideation and behavior as measured by the Columbia-Suicide Severity 
Rating Scale (C-SSRS) score 
3) Dissociative symptomatology as measured by the CADSS total score 
4) Psychopathology severity as measured by the BPRS+ score 
3.12 Exploratory Endpoints 
• 
CFB to the end of each scheduled week on the following:   
1) Patient Health Questionnaire 9-item (PHQ-9) scale total score 
2) Massachusetts General Hospital (MGH) Cognitive and Physical Functioning 
Questionnaire (CPFQ) total score 
3) Changes in Sexual Functioning Questionnaire (CSFQ) total score 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 41 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
• 
Pharmacogenomic (PGx) evaluation (optional) 
1) Correlation between baseline pharmacogenetic testing results and drug effects 
on the efficacy, safety, and/or PK of NV-5138  
2) CFB in the concentration of brain-derived neurotrophic factor (BDNF)  

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 42 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
4 
INVESTIGATIONAL STUDY PLAN 
4.1 
Overall Study Design and Plan 
This is a multicenter, randomized, double-blind, flexible-dose, placebo-controlled, 
parallel design of adjunctive NV-5138 in adults with TRD. Approximately 800 outpatient 
subjects will be screened into the study and 268 subjects will be randomized to NV-5138 
or placebo in a 1:1 ratio to achieve about 200 subjects completing the study. Following 
up to 6 weeks of screening, there will be a 4-week treatment period with SM, a 1-week 
double-blinded placebo-washout period, and a safety follow-up phone call occurring 
approximately 30 days after the last dose of blinded SM. The total study duration from 
the screening visit to the end of the Treatment Period is up to 15 weeks (see Figure 2).  
Retrospective Prescreening: The retrospective period is the time before screening when 
the Investigator determines the duration (without restriction) of the current major 
depressive episode (MDE), and also establishes the medication history of the current 
MDE. Subjects will not be eligible if they previously responded for more than 4 weeks 
while on the current ADT and lost response (tachyphylaxis). Those subjects may qualify 
if, after the current MDE started, they subsequently fail a trial with a new ADT or an 
increased dose of the previous ADT. 
At the screening visit (Visit 1), subjects must have a documented history of inadequate 
response to ≥1 but ≤4 prior ADTs which must include the present ADT for their current 
MDE. Subjects must also be taking the currently approved ADT for a minimum of 2 
weeks at a stable therapeutic dose. 
Screening Period (Up to 6 Weeks; Day -42 to Day -1): The Screening Period is up to 
6 weeks depending on how long the subjects have been taking their current ADT and the 
number of failed ADTs. As shown in Figure 1, subjects who have failed ≥2 ADTs and 
have been taking the approved ADT at a stable dose for ≥4 weeks before screening are 
allowed the minimum 4-week Screening Period. A longer Screening Period is required 
for other subjects (for example, subjects who have been on their current ADT for 2 weeks 
will complete 6 weeks of screening, and subjects who have been on the current ADT for 
3 weeks will be in the Screening Period for 5 weeks).  
Subjects who have an inadequate response to only 1 ADT must be on the same ADT at 
the stable therapeutic dose for ≥2 weeks before the Screening Period and complete 
6 weeks during the Screening Period. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 43 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
Figure 1: Flexible Screening Period for Subjects Who Had Inadequate Response to 
≥2 ADTs  
 
Visit 1: 
At the initial screening visit (Visit 1, Day -42, Day -35 or Day -28, depending on the 
retrospective prescreening ADT history) after informed consent is obtained which 
includes an optional PGx consent, subjects will undergo initial screening evaluations 
including a blood sample to be analyzed to ensure detectable blood level of an 
antidepressant. Subjects will have their diagnosis of MDD confirmed by the Mini 
International Neuropsychiatric Interview (MINI). Their site-rated MADRS total score 
must be ≥24 and CGI S ≥4. Inadequate response (defined as <50% improvement in 
depressive symptoms on an ADT taken at ad adequate dose and duration) to the ADT for 
their current MDE will be assessed by the Investigator by the administration of the 
Antidepressant Treatment Response Questionnaire (ATRQ) which was developed by the 
MGH.  
 
 
 
 
 
During the Screening Period, subjects should maintain the current antidepressant stable 
therapeutic dose (see Appendix 11.17) for the study-approved ADTs. Dose adjustment of 
ADT will not be allowed during screening and throughout the duration of the study. 
ADTs approved for use in this study will not be supplied by the Sponsor. 
Antidepressant Adherence:  
Subjects will download the medication adherence app on their personal smartphone or 
receive a provisioned device. The application will enable confirmation of date and time 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 44 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
of the subject’s ingestion of the ADT. During the screening period, subject adherence to 
ADT must be confirmed with the medication adherence app and the ADT blood level.  
Visit 2: 
Visit 2 (Day -14) will occur for subjects who have been taking their approved 
antidepressant at a stable dose for a total of 6 weeks (ie, 2 weeks retrospectively prior to 
Visit 1 and 4 weeks during screening)
. At this 
visit, the Investigator will measure clinical response with the administration of the 
MADRS and CGI-S scales. To continue in the study, subjects must have a MADRS total 
score ≥24 and CGI-S ≥4 and meet all other eligibility criteria. Additional laboratory 
sampling of the subject’s antidepressant blood level will be conducted; subjects must 
have 2 positive test results for ADT during screening before proceeding to the baseline 
visit.  
It is recommended to perform Investigator-rated efficacy assessments (MADRS and CGI-
S) prior to performing any subject self-report efficacy assessments.  
If the MADRS total scores vary ≥25% between the highest and lowest scores during the 
Screening Period, subjects will be excluded from the study.  
Baseline and Randomization (Visit 3): To be eligible for randomization, subjects must 
have inadequate response to ≥1 but ≤4 ADTs for their MDE including the current ADT 
administered at a stable dose and duration for a total of ≥8 weeks (Figure 1). Subjects 
who have an inadequate response to only 1 ADT must be on the same ADT at the stable 
therapeutic dose for ≥2 weeks before the Screening period and complete 6 weeks during 
the Screening Period before randomization. Subjects who do not meet eligibility criteria 
at any time during the Screening Period will be excluded. Subjects’ eligibility will be 
reviewed by the Sponsor, and the site must receive an eligibility verification letter for 
each subject before proceeding to the baseline visit. 
Protocol waivers in the study will be granted on a case-by-case basis after approval from 
the Sponsor.  
Rescreening: 
Subjects that screen failed under previous protocol versions and subjects who screen 
failed due to tachyphylaxis or, due to the absence of a failed ADT for the current MDE 
are allowed on a case-by-case basis to re-screen after consultation with the MM and 
Sponsor’s approval. 
Double-Blind Period (Visits 3-8): The Double-Blind Period consists of a 4-week 
(28 days) flexible dosing treatment period with SM (Figure 2) and a 1-week placebo-
washout period. On Day 1, after eligibility has been confirmed and baseline assessments 
conducted, subjects will be randomized (1:1) to receive either adjunctive NV-5138 or 
matching placebo in conjunction with their current ADT. During the Double-Blind 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 45 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
Period, weekly study visits will be conducted. At each visit, ECG, vital signs, body 
weight and alcohol breath test will be performed; samples for urinalysis, hematology and 
chemistry laboratory tests; and UDS; and samples for ADT will be collected. Efficacy 
and safety scales will be assessed (see Table 2). 
Visits 4-7 (Study Medication Treatment):  
The starting dose of NV-5138 or matching placebo is 1600 mg QD. Dose adjustments are 
allowed at Visit 4 (Day 8) and Visit 5 (Day 15). Subjects who experience an intolerable 
adverse effect at 1600 mg may have their dose reduced to 800 mg. Subjects who have an 
inadequate response to 800 mg may have their dose increased again to 1600 mg per 
Investigator judgment to maximize their treatment response; however, no dose 
adjustments are allowed after Visit 5. The maximum NV-5138 dose in the study is 1600 
mg QD. The minimum NV-5138 dose is 800 mg QD; subjects who cannot tolerate NV-
5138 800 mg once daily or matching placebo should be discontinued from the study at 
the discretion of the Investigator. After completion of the 4-week treatment, all subjects 
will receive placebo in a double-blinded fashion and continue the treatment for one week. 
Throughout the duration of the Double-Blind Treatment Period, no adjustments in the 
ADT or dose are allowed (Section 6.1.4).  
Visit 8 (End of Study/Early Termination):  
EOS assessments will be collected. After completion of the EOS study procedures, SM 
will be discontinued, and subjects should continue with their ADT. If the subject 
withdraws or is early terminated, the subject will complete Visit 8 assessments.  
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 6.1.4). 
Safety Follow-up (30 Days After Completion of the Study: After the last dose of SM 
in the Double-Blind Period and all study visits are completed including Visit 8, the study 
is considered completed. A safety follow-up phone call will occur approximately 30 days 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 46 of 199 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or disclosure of such 
information that is not authorized in writing by the Sponsor is strictly prohibited. Such information may be used solely for the 
purpose of reviewing or performing this study. 
after the last dose of blinded SM only for subjects who completed the study. For subjects 
who withdraw from the study, a safety follow-up phone call will occur approximately 7 
days after withdrawal (Section 6.1.5).  
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 48 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
4.2 
Study Population 
4.2.1 Number of Subjects 
Approximately 800 subjects (400 per treatment arm) will be screened; 
approximately 268 subjects will be randomized to NV-5138 or placebo in a 1:1 
ratio to achieve approximately 200 subjects completing the study.  
4.2.2 Inclusion Criteria  
1. Is male or female aged 18-70 years (inclusive) at screening;  
2. Is able to read, understand, write, and sign the Informed Consent Form (ICF); 
3. Is willing and able to follow the study protocol and procedures and attend 
study appointments within the specified time windows; 
4. Has a body mass index (BMI) between 19.0 to 40.0 kg/m2 (inclusive); 
5. Is able to swallow capsules whole, without crushing, chewing, or opening. 
6. Has a diagnosis of major depressive disorder (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; 
7. Has a MADRS total score of ≥24 for the current MDE at the screening visits 
and baseline visit (Day 1); 
8. Has an CGI-S score of ≥4 (moderately ill or worse) at the screening visits and 
baseline visit; 
10. Has a history of inadequate response to ≥1 but ≤4 prior ADT therapies 
(including the current ADT for the current MDE) ≥2 weeks before screening 
and ≥8 weeks at baseline. An inadequate response is defined as <50% 
improvement in depressive symptoms on an ADT (taken at an adequate dose 
and duration) assessed by the Investigator with the administration of the MGH-
ATRQ and confirmed by documented records. 
Note: Subjects who fail to respond to either a trial with a new ADT or an 
increased dose for the previous ADT (both of adequate dose and duration) can 
be enrolled (increased doses of the same ADT are counted as only 1 failed 
ADT). The ADT must have been started after the current MDE began; 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 49 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
11. Has been on a stable therapeutic dose of one of the following study-approved 
ADTs for the current MDE for ≥2 weeks prior to screening: citalopram, 
escitalopram, paroxetine, fluoxetine, sertraline, duloxetine, venlafaxine 
(immediate release or extended release), desvenlafaxine, vilazodone, 
levomilnacipran, vortioxetine, bupropion or dextromethorphan/bupropion (see 
Appendix 11.17).  
Note: Subject must be on ADT monotherapy before randomization. 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 randomization into the study. If so, the second drug should be washed 
out at least 5 half-lives prior to baseline. If not, the subject should be excluded 
from the study; 
12. Has a detectable blood level of the approved ADT at both Visits 1 and 2 of the 
Screening Period. 
Note: A negative test may be repeated with permission of the MM and Sponsor 
upon additional evidence of subject adherence to ADT or evidence of sample 
or laboratory error; 
13. Agrees to maintain a stable therapeutic dose of the approved ADT throughout 
the study; 
14. Has discontinued prohibited hypnotic medications 6 weeks prior to 
randomization. See Appendix 11.16.1 for allowed sleep medications; 
15. Nonpregnant females of childbearing potential (FOCP) who are exclusively in 
a same-sex relationship are included without the need for 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 ICF, throughout the study, and for 30 days 
following the last dose of the SM: 
a. Simultaneous use of male condom and intrauterine contraceptive device 
placed at least 4 weeks prior to the first SM administration; 
b. Simultaneous use of male condom and diaphragm with spermicide; or 
c. Established hormonal contraceptive (started at least 4 weeks prior to the 
first dose of SM). 
Female subjects 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 
(eg, bilateral tubal ligation, bilateral oophorectomy, etc.) for 6 months 
minimum prior to screening. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 50 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
All FOCP must have a negative serum pregnancy test result before the 
administration of SM; 
16. Male subjects:  
a. Who are exclusively in a same-sex relationship or have female partners 
considered not to be of childbearing potential are included without the need 
for acceptable birth control methods; 
b. Who have been surgically sterilized (6 months minimum) prior to 
screening are eligible to participate without any contraception; or 
c. 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 Inclusion Criterion #15 which must be used from the time of 
signing the ICF until 90 days after the last dose of SM. 
All male subjects must refrain from donating sperm from the date of first 
administration of SM until 90 days after the last dose of the SM. 
4.2.3 Exclusion Criteria 
1. Has a MADRS total score improvement of ≥25% from the highest to the 
lowest score during the Screening Period and baseline visit;   
2. Has received new-onset psychotherapy or had a change in the intensity of 
psychotherapy within 4 weeks prior to screening. Psychotherapy initiated prior 
to screening must be maintained for the duration of the study; 
3. Has been treated with electroconvulsive therapy (ECT), transcranial magnetic 
stimulation (TMS), or vagal nerve stimulation (VNS) for the current MDE; 
4. Has received treatment with long-acting injectable antipsychotics (LAIs) 
within 3 months prior to screening; 
5. Has recurrent MDD, has been on an adequate dose and duration of ADT, and 
had a >50% response for at least 4 weeks while using that ADT that was then 
followed by a loss of response (ie, tachyphylaxis) as assessed by the 
Investigator. The date of the loss of response is the start date of the current 
episode (from when the symptoms returned);  
6. Has demonstrated a nonresponse to esketamine or off-label use of ketamine or 
has taken esketamine or ketamine less than 6 months prior to the screening 
visit (Appendix 11.16.2);  
7. Is unable to discontinue treatment with trazodone at doses greater than 150 mg 
daily for a minimum of 5 half-lives before baseline.  
a. Trazodone 150 mg/day or less 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; 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 51 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
8. Has unstable hypothyroidism. If the thyroid-stimulating hormone (TSH) 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.  
a. Treatment with thyroid hormones is allowed if prescribed at a stable dose 
for ≥3 months and the subject’s thyroid levels are normal; 
9. Has clinically significant abnormal laboratory profiles (ALT or AST values 
≥3x the upper limit of normal [ULN] or total bilirubin ≥1.5 times the ULN), 
vital signs, or ECGs, 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; 
10. Has abnormal renal function as demonstrated by an estimated glomerular 
filtration rate (eGFR) of <60 mL/min, according to the Chronic Disease 
Epidemiology Collaboration (CKD-EPI) equation at the screening visit;  
11. Has a history of substance use disorder (SUD) within 6 months prior to 
screening or is currently using or has a positive result (UDS) at any screening 
or baseline visits for drugs of abuse (Appendix 11.16.2). Positive results for 
specific medications must have a confirmed medical history; 
12. Has a history of alcohol use disorder within 6 months prior to screening. A 
subject who has a positive alcohol test result at any of the screening visits (V1 
andV2) and, if based on the Investigator opinion, the subject does not have a 
history of alcohol use disorder, the subject may continue to the next visit. If the 
alcohol test result at baseline visit is positive, subjects should be excluded from 
the study. Subjects must refrain from using alcohol during the treatment phase 
of the study; 
13. Has a diagnosis of cannabis use disorder (CUD) within 6 months before 
screening and has a positive UDS for cannabis at screening. 
a. 
At the discretion of the Sponsor, recreational use of cannabis (not daily) is 
allowed and should be kept consistent during the study. Subjects must 
agree to refrain from using cannabis 48 h prior to the study visits;  
b. 
Medical cannabis prescribed for a medical condition (eg, muscle spasms, 
nausea, vomiting, pain) other than depression, seizures, and insomnia is 
allowed if taken at a stable regimen for at least 3 months prior to 
screening. Newly prescribed cannabis treatment and/or change to the 
existing regimen is prohibited (Appendix 11.16.1). When applicable, 
subjects should show proof of their prescription for medical cannabis; 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 52 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
14. 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 C-SSRS in the 2 years 
before screening; a history of suicide attempt in the last 6 months; or more than 
2 lifetime suicide attempts; 
15. 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; 
16. Has a diagnosis within 12 months before screening or current diagnosis of 
post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), 
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 comorbid generalized anxiety disorder is allowed but 
subject to medication restrictions (anticonvulsants and beta-blockers are 
allowed, if on a stable regimen for 2 months prior to the screening visit);  
b. Established attention-deficit/hyperactivity disorder (ADHD) diagnosis is 
allowed. Subjects must provide confirmation of ADHD diagnosis 
(ie, provide medical records for prescribed ADHD medications) and be on 
a stable dose of ADHD medication for at least 3 months prior to the 
screening visit; 
17. Has a history of a psychiatric or neurologic conditions or symptoms that could 
impose undue risk or compromise the study, in the Investigator’s opinion, 
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 CNS functioning; or 
c. Has current evidence of delirium or dementia; 
18. Has a history of cardiovascular, respiratory, gastrointestinal, renal, hepatic, 
hematologic, or other medical disorder that could, in the Investigator’s opinion, 
impose undue risk or compromise the study including but not limited to the 
following: 
a. Cardiovascular disorders: 
i. Clinically significant symptomatic orthostatic hypotension; 
ii. Uncontrolled hypertension despite diet, exercise, and antihypertensive 
medications (defined as a supine systolic blood pression (SBP) 
>140 mmHg or diastolic blood pressure (DBP) >90 mmHg) during 
screening and at baseline; 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 53 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
iii. Acute coronary syndrome; 
iv. History of unexplained loss of consciousness, unexplained syncope, or 
unexplained irregular heartbeats; 
v. QT interval corrected using Fridericia’s method (QTcF) ≥ 450 ms (for 
men) or ≥ 470 ms (for women) at screening (see Note below); and/or 
vi. Patient or family history of QT congenital syndrome;  
b. Oncological disorders: 
i. Malignant tumors within 5 years prior with the exception of benign skin 
tumors; or 
ii. Diagnosis or family history of tuberous sclerosis complex (TSC); 
c. Positive result for human immunodeficiency virus (HIV), hepatitis B, or 
hepatitis C (HCV) at screening unless:  
i. HIV positive: subjects must have a HIV Confirmation Test. If the 
confirmatory test is positive, the subject is eligible if on chronic 
suppressive antiviral medication for more than 6 months with an 
undetectable viral load;  
ii. HBsAg positive: subjects should be tested for anti-HBc, IgM anti-HBc, 
and anti-HBs to detect acute or chronic infection (ineligible). Subjects 
whose results indicate immunity (either by natural infection or 
vaccination) with no active infection are eligible; and/or 
iii. HCV positive: subjects must have undetectable HCV ribonucleic acid 
(RNA) to be eligible; 
d. Unintended recent clinically significant weight loss; 
e. Has chronic urinary tract infections (UTIs); 
f. Blood donation within 6 weeks of screening; and/or 
g. Is on any medication that could, in the Investigator’s opinion, interfere with 
the assessments of safety, tolerability, efficacy, or the conduct or 
interpretation of the study; 
19. Requires treatment with a medication or other substance that is prohibited by 
the protocol (see Section 5.8); 
20. Has history of severe drug allergy or hypersensitivity, or hypersensitivity to the 
SM or excipients; 
21. Female subjects who are pregnant or lactating or planning to become pregnant 
while enrolled in the study; 
22. Has previously enrolled in a NV-5138 study;  
23. Is currently participating in another clinical trial or has participated in a clinical 
study within 30 days of screening visit; 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 54 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
24. Is a member of study personnel or 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 pretreatment period to determine 
eligibility. Repeat testing is not allowed without justification from the site and 
agreement from the MM 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 all visits 
up to and including Visit 8. 
All reasons for screening failure will be recorded.
 
 
 
 
 if a subject does not have 
a history of inadequate response to ≥1 but ≤4 prior ADTs and fails the MGH-
ATRQ administered by the Investigator, the reason will be recorded as Inclusion 
Criterion #10. If a subject experienced tachyphylaxis (ie, >50% response for at 
least 4 weeks while using that ADT followed by a loss of response) as assessed by 
the Investigator, the screening failure reason will be recorded as Exclusion 
Criterion #5.  
4.4 
Discontinuation or Early Termination of Subjects 
Subjects who are randomized and dosed with SM, but who withdraw or are 
withdrawn from participation in the study by the Investigator before the 
completion of the study (ie, after Visit 3 but prior to Visit 8), should complete an 
Early Termination (ET) visit. Procedures listed for Visit 8 (see Table 2) should be 
completed at ET visit with the following exception: 
If subject’s ET visit occurs: 
1) >4 days after the date of subject’s last dose, efficacy assessments should 
not be performed/collected at ET visit; or 
2) ≤4 days after the date of subject’s last dose, efficacy assessments should be 
performed/collected at ET visit.  
Subjects who are discontinued for a positive alcohol test or UDS should complete 
the ET visit. At that visit, efficacy assessments should not be performed/collected. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 55 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
The Investigator(s) or subjects themselves may stop SM treatment at any time for 
safety or personal reasons. A subject is free to withdraw from the study at any time 
for any reason without prejudice to their future medical care by the physician or at 
the institution. 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 MM and Investigator before the subject stops SM. Subjects 
removed from the study for any reason will not be replaced. 
Reasons for a subject’s early discontinuation may include: 
• Withdrawal of consent;  
• Noncompliance with study procedures (eg, positive alcohol test or UDS, 
missed more than two consecutive doses of SM, use of prohibited 
medications); 
• 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 (ie, for safety or tolerability reasons); or 
• Other (eg, study is terminated by the Sponsor, subject becomes pregnant, blind 
is broken, subject has relocated, or death, etc). 
If the subject withdraws consent or the Investigator discontinues the subject’s 
participation in the study, the primary reason for the subject’s withdrawal, or the 
Investigator’s discontinuation of the subject should be documented and captured 
on the eCRF. If a subject is withdrawn for more than one reason, each reason 
should be documented in the source document and the most medically significant 
reason should be entered on the eCRF. 
If the subject is lost to follow-up, every effort must be done 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. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 56 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
5 
STUDY TREATMENT 
5.1 
Study Medication Identity, Packaging, and Labeling 
SM is supplied by the Sponsor as capsules packaged in a double-blind 
configuration in bottles. Each bottle will include identical-looking capsules that 
contain 400 mg of NV-5138 or matching placebo. The capsule is size 00 elongated 
(00 EL) with white opaque cap and body. Each bottle contains 40 capsules to 
supply a subject with 7 days of dosing plus 3 extra days if needed. Each bottle will 
be labeled with the protocol number.    
5.2 
Study Medication Administration 
SM will be administered orally QD as intact capsules. Daily dosing should occur 
in the morning, approximately 3 h after breakfast. Splitting the daily dose 
(eg, taking part of the daily dose in the morning and the remainder of the daily 
dose in the evening) is not permitted. SM will be dispensed to the subject 
following randomization on Day 1 (Visit 3). Subject will take the first dose at the 
site at Visit 3 and resume the morning dosing the following day. If Visit 3 occurs 
after noon, subject will still take the first dose at the clinic and resume the morning 
dose the following day. The subject should not exceed 35 (+3) days of SM 
administration. 
During the first week of the Treatment Period, all subjects will take 1600 mg/day 
(equivalent to 4 capsules) QD. During Week 2 (starting at Visit 4) of the Treatment 
Period, per the Investigator’s discretion based on the subject’s clinical response 
and tolerability (adverse effects), the dose of NV-5138 can be tapered down to 
800 mg/day (equivalent to 2 capsules) to a target dose of 800 mg/day during the 
week (Table 1). During Week 3 (starting at Visit 5), per the Investigator’s 
discretion based on the subject’s clinical response and tolerability, the dose of 
NV-5138 can remain at 800 mg/day (2 capsules) or be titrated up to 1600 mg/day 
(4 capsules) to a target dose of 1600 mg/day (Table 1). After completion of the 
4-week treatment, all subjects will receive placebo in a double-blinded fashion and 
continue the treatment for one week. Dose adjustments are allowed at Visits 4 and 
5; in the event a subject experiences intolerable AE(s) to 1600 mg/day between 
Visit 4 and Visit 5, an unscheduled visit may be conducted for dose adjustment 
before the subject’s scheduled Visit 5; however, no further dose adjustments are 
allowed after Visit 5. The maximum NV-5138 dose in the study is 1600 mg QD. 
The minimum NV-5138 dose is 800 mg QD. Subjects who cannot tolerate 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 58 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
If subjects miss doses of ADT, the Investigator and/or study coordinator should 
follow up with the subjects on the importance of maintaining full compliance to 
protocol procedures throughout the study. 
Antidepressant treatments approved for use in this study will not be supplied by 
the Sponsor. 
5.5 
Method of Assigning Subjects to Treatment Arm 
Eligible subjects will be randomized in a 1:1 ratio at Visit 3 (baseline) to receive 
active NV-5138 or matching placebo.  
Allocation of study treatment will occur centrally via an interactive response 
technology (IRT) using a randomization schedule to determine the SM assignment 
for each subject being randomized. Subjects will be randomly assigned to one of 
the treatment groups based on the randomization schedule created by the 
designated Clinical Research Organization (CRO) biostatistician before the 
initiation of the study under the supervision of the Sponsor. The randomization 
files will be securely stored on the CRO’s server. The IRT vendor will receive the 
unblinded randomization schedule from the CRO unblinded biostatistician and 
assign a unique treatment code for the corresponding SM (containing either the 
active drug or placebo) for each subject (assigned treatment) according to the 
subject randomization schedule. The clinical site must confirm and record that the 
correct corresponding SM number was dispensed to the subject (actual study 
treatment).  
A bottle with SM will be dispensed to the subject at each study visit starting at 
Visit 3. 
5.6 
Blinding 
The subject and all personnel involved with the conduct and interpretation of the 
study including the Investigators, study site personnel, the Sponsor and CRO 
clinical staff including the MM will be blinded to SM. A limited number of 
Supernus personnel will perform the bioanalytical PK analysis during clinical 
study conduct. These personnel should not have access to the randomization 
schedule or be associated with the clinical conduct of the study and will not reveal 
to any clinical personnel involved in the study the treatment to which a subject is 
assigned. 
5.6.1 Maintaining Blind 
Randomization schedule data will be kept strictly confidential, filed securely by 
the IRT vendor, and accessible only to authorized persons until the time of the 
planned unblinding. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 59 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
5.6.2 Planned Unblinding 
The study blind will be broken only after the study has been completed and the 
study database has been locked. 
5.6.3 Emergency Unblinding 
The Study Investigator may contact the IRT vendor and unblind a subject in 
situations in which the subject experiences an unexpected SAE requiring special 
and/or acute emergency medical services (ie, hospitalization) for which the 
disclosure/knowledge of their assigned/actual treatment arm in the study is critical 
to the subject’s safety and medical care. Prior to breaking the treatment blind, it is 
recommended that the Investigator, who is directly responsible for the care of the 
subject (ie, the physician), discuss the need to unblind the subject with the 
Sponsor’s MM (or designee). If the Sponsor’s MM or designee cannot be reached, 
then the Investigator should unblind the subject and make every attempt to contact 
the Sponsor’s MM (or designee) as soon as possible. If a subject’s treatment 
assignment is unblinded, the Investigator should only share the subject’s study 
treatment information with the individual(s) responsible for the medical 
treatment/care of the subject. Under no circumstances should the Investigator 
disclose the subject’s unblinded treatment arm to any staff at the study site, CRO, 
Sponsor, etc. The Investigator must notify the Sponsor’s MM and properly 
document/record the event (unblinding) in the respective subject’s source 
documentation; this includes recording the Subject ID No., the date and time of the 
unblinding, the rationale/reasoning behind the necessity to unblind the subject’s 
study treatment, and the signature of the person who unblinded the subject. It is the 
Investigator’s responsibility to always keep the Sponsor’s MM (or designee) 
apprised of all unblinding activities and report all cases involving emergency 
unblinding to the Sponsor without disclosing the unblinded information. All 
unblinded subjects will be discontinued from participating in the study and will not 
be replaced in order to preserve the integrity of the study, and each subject should 
be followed up by the Investigator for safety purposes. 
5.7 
Study Medication Handling and Accountability 
All SM will be supplied by the Sponsor to the Investigator. SM supplies must be 
stored at 20-25o C in an appropriate secure area (eg, 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 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 60 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
supplies (receiving, shipment, dispensing, inventory, and record keeping) in a SM 
accountability log. A copy will be collected by the Sponsor at the end of the study. 
Under no circumstances will the Investigator allow the SM to be used other than as 
directed by this protocol. Clinical supplies will not be dispensed to any individual 
who is not enrolled into the study. 
An accurate and timely record of the receipt of all clinical supplies; dispensing of 
SM to the subject; collection of unused supplies; and subsequent return of unused 
SM to the Sponsor must be maintained with dates. This SM accountability log 
includes but may not be limited to: (a) documentation of receipt of clinical 
supplies, (b) SM inventory log, (c) SM accountability log, and (d) all shipping 
service receipts. Forms may be provided by the Sponsor. Any comparable forms 
that the study site wishes to use must be approved by the Sponsor. 
The supplies and inventory records must be made available upon request for 
inspection by the designated representative of the Sponsor or a representative of 
the 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 provision is made by the Sponsor for destruction of 
supplies and containers at the study site. Upon completion of SM accountability 
and reconciliation procedures by study site personnel and documentation 
procedures by Sponsor personnel, SM is to be returned to the Sponsor with a copy 
of the completed SM disposition form. 
5.8 Concomitant and Prohibited Medications  
Subjects may not be on any prohibited medication as indicated in the 
Inclusion/Exclusion Criteria. Please contact the MM for any questions related to 
the subject’s current concomitant medication(s). Additional concomitant 
medications may be allowed on a case-by-case basis at the discretion of the MM 
and the Sponsor.  
Permitted and prohibited medications are shown in Appendix 11.16. 
5.8.1 Permitted Concomitant Medications 
A comprehensive list of allowed medications is shown in Appendix 11.16.1. The 
list is not all inclusive. Contact the MM 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 11.16.1. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 61 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
• Treatment for hypercholesterolemia (eg, statins, gemfibrozil) and 
hyperlipidemia if on a stable dose for at least 3 months prior to screening; 
• Treatment for hypertension with 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 asthma control and 
no changes for at least 6 months prior to screening; 
• Treatment for diabetes if on a stable dose for at least 3 months before 
screening. Insulin will not be permitted; and/or 
• For ADHD treatment, psychostimulants, atomoxetine, guanfacine, and 
clonidine are allowed if on a stable dose for at least 3 months before screening. 
Confirmation of ADHD diagnosis will be required. 
The stable dose of all concomitant medications allowed in the study must be 
maintained throughout the duration of the study participation.  
As needed, the following treatments will also be allowed: 
• For sleeping, only the following medications are allowed if on a stable dose 
(dose increment is prohibited) for at least 4 weeks prior to screening (Appendix 
11.16.1):  
o Hypnotics (eg, 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 more than 12 h prior to any study visits; or   
o Trazodone (150 mg/day or less) as needed if the subject has been taking the 
same low dose of trazodone for insomnia for at least 3 months 
• Nutritional supplements (eg, multivitamins, fish oil, melatonin) 
• EMLA® or other numbing cream for venipuncture 
• Common over-the-counter therapies for minor transient ailments 
(eg, acetaminophen, ibuprofen for headache, fever, etc) 
• Recreational cannabis (not daily and not exceeding 3 times per week for either 
vape, edible, or smoke) is allowed at the discretion of the Sponsor if taken 
consistently during the study. Subjects must refrain from using cannabis 48 h 
prior to the study visits: at each visit, it is recommended that the Investigator 
assess the subjects for symptoms of cannabis intoxication (ie, motor 
impairment, euphoria, anxiety, impaired judgment, social withdrawal, redness 
of eyes, increased appetite, dry mouth, tachycardia). If subjects show 
symptoms of intoxication or do not refrain from using cannabis for 48 h prior 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 62 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
to the study visits, that study visit should not be conducted and an unscheduled 
visit should be scheduled.   
• Medical cannabis if prescribed for a medical condition (eg, muscle spasms, 
nausea, vomiting, pain) other than depression, seizures, and insomnia and 
taken at a stable regimen for at least 3 months prior to screening. When 
applicable, subjects should show proof of their prescription for medical 
cannabis.  
Note: Newly prescribed cannabis treatment and/or change to the existing 
regimen is prohibited.  
All concomitant medications will be recorded in the eCRF. 
5.8.2 Prohibited Concomitant Medications  
A comprehensive list of prohibited medications is shown in Appendix 11.16.2. The 
list is not all inclusive. Contact the MM for any questions related to the subject’s 
current concomitant medication(s). 
Prohibited medications should be discontinued for 5 half-lives before baseline. 
Where washout of prohibited medications is required prior to baseline, tapering 
rates are at the discretion of the Investigator and are 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 
discontinuation or any tapering is started. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 63 of 199 
 
 
This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing this stud 
6 
STUDY METHODS 
6.1 
Study Visits and Procedures 
All subjects who are randomized and take the initial dose of SM will be followed 
according to the protocol regardless of the number of doses of SM taken unless 
consent for follow-up is withdrawn. The Sponsor or Sponsor’s designee must be 
notified of all deviations from the protocol visit or procedures except as noted, and 
these procedures, if applicable, will be rescheduled or performed at the nearest 
possible time to the original schedule. Subjects will be instructed to call study 
personnel to report any AEs during the intervals in between study visits and to 
come to the study site if medical evaluation is needed and as the urgency of the 
situation indicates. For emergency and other unscheduled visits to a medical 
facility other than the study site, medical records will be obtained by the 
Investigator or qualified designee as source data for study follow-up. 
Investigator-rated efficacy assessments (MADRS, CGI-S, CGI-I, SDS, GAD-7 and 
HAM-D6) should be performed/conducted/collected in the order above prior to 
administering any self-report efficacy assessments to subjects.  
The Schedule of Events and Assessments for the study is shown in Table 2. 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 68 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
6.1.1 Visit 1 – Screening (Days -42, -35, or -28, Depending on the Prescreening 
ADT History) 
The following assessments will be conducted: 
• ICF signed including PGx consent 
• Administer MINI 
• Record social, medical, psychiatric, family psychiatric, and neurological histories 
• Record demographics and height 
• Review Inclusion/Exclusion Criteria 
• Record alcohol and cannabis consumption history 
• Perform physical examination  
• Record vital signs and weight (orthostatic blood pressure and pulse rate, respiratory 
rate [RR], oral temperature) 
• Perform ECG 
• Collect blood samples for: 
o FSH (postmenopausal females only) 
o Serum pregnancy test (FOCP only) 
o Hematology and serum chemistry (nonfasted sample allowed) 
o ADT 
• Collect urine samples for: 
o Urinalysis 
o “Standard” Urine drug and alcohol screen (Table 3) 
• Administer MADRS, CGI-S, C-SSRS, CADSS, and BPRS+ scales 
• Administer Investigator-rated ATRQ 
• Register subject in medication adherence diary 
• Record concomitant medications 
 
 
 
At this visit, in order to record accurate information of psychiatric, family psychiatric, 
and neurological histories, the site should request records from the pharmacy and medical 
records from the doctors who previously treated the subject. 
6.1.2 Visit 2 (Day -14 ± 1 Day)  
The following assessments will be conducted: 
• Review Inclusion/Exclusion Criteria 
• Record vital signs and weight (orthostatic blood pressure and pulse rate, RR, oral 
temperature)  

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 69 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
• Collect blood sample for ADT  
• Collect “Standard” urine sample for urine drug and alcohol screen 
• Record cannabis use 
• Complete subject placebo response reduction (PRR) training video  
• Review medications adherence  
• Administer MADRS, CGI-S, and C-SSRS 
• Review concomitant medications  
6.1.3 Visit 3 – Baseline (Randomization: Day 1 ± 2 Days) 
The following assessments will be conducted: 
• Review Inclusion/Exclusion Criteria 
• Record alcohol and cannabis use 
• Perform physical examination 
• Record vital signs and weight (orthostatic blood pressure and pulse rate, RR, oral 
temperature) 
• Perform ECG 
• Collect blood samples for: 
o Hematology and serum chemistry (nonfasted sample allowed) 
o PGx (optional) 
o ADT 
• Collect urine samples for:  
o Urine pregnancy test (FOCP only) 
o Urinalysis 
o “Point of Care” UDS 
• Breathalyzer for alcohol screen 
• Randomization 
• Review medications adherence  
• Administer MADRS, CGI-S, HAM-D6, SDS, GAD-7, CADSS, C-SSRS, BPRS+, 
CPFQ, PHQ-9, and CSFQ  
• Review AEs  
• Review concomitant medications  
• Dispense SM  
6.1.4 Visits 4-8 – Treatment Period Including End of Study 
Visit 4 – End of Week 1 (Day 8 ± 2 Days) 
The following assessments will be conducted: 
• Record alcohol and cannabis use 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 70 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
• Record vital signs and weight (orthostatic blood pressure and pulse rate, RR, oral 
temperature) 
• Perform ECG 
• Collect blood samples for: 
o Hematology and serum chemistry (nonfasted sample allowed) 
o ADT 
• Collect urine samples for: 
o Urine pregnancy test (FOCP only) 
o Urinalysis 
o “Point of Care” UDS   
• Breathalyzer for alcohol screen 
• Review medications adherence  
• Administer MADRS, CGI-S, CGI-I, HAM-D6, CADSS, C-SSRS, BPRS+, and CPFQ  
• Review AEs  
• Review concomitant medications  
• Dispense SM  
• SM return and assess drug accountability 
Visit 5 – End of Week 2 (Day 15 ± 2 Days) 
The following assessments will be conducted: 
• Record alcohol and cannabis use 
• Record vital signs and weight (orthostatic blood pressure and pulse rate, RR, oral 
temperature) 
• Perform ECG 
• Collect blood samples for: 
o Hematology and serum chemistry (nonfasted sample allowed) 
o ADT 
• Collect urine samples for: 
o Urine pregnancy test (FOCP only) 
o Urinalysis 
o “Point of Care” UDS 
• Breathalyzer for alcohol screen 
• Complete subject PRR training video  
• Review medications adherence  
• Administer MADRS, CGI-S, CGI-I, HAM-D6, CADSS, C-SSRS, BPRS+, and 
CPFQ  
• Review AEs  
• Review concomitant medications  
• Dispense SM  

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 71 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
• Collect SM and assess drug accountability  
Visit 6 – End of Week 3 (Day 22 ± 2 Days) 
The following assessments will be conducted: 
• Record alcohol and cannabis use 
• Record vital signs and weight (orthostatic blood pressure and pulse rate, RR, oral 
temperature) 
• Perform ECG 
• Collect blood samples for: 
o Hematology and serum chemistry (nonfasted sample allowed) 
o PGx (optional) 
o ADT 
• Collect urine samples for: 
o Urine pregnancy test (FOCP only) 
o Urinalysis 
o “Point of Care” UDS 
• Breathalyzer for alcohol screen 
• Review medications adherence  
• Administer MADRS, CGI-S, CGI-I, HAM-D6, SDS, GAD-7, CADSS, C-SSRS 
BPRS+, CPFQ, PHQ-9, and CSFQ  
• Review AEs  
• Review concomitant medications  
• Dispense SM  
• Collect SM and assess drug accountability  
Visit 7 – End of Week 4 (Day 29 ± 2 Days) 
The following assessments will be conducted: 
• Record alcohol and cannabis use 
• Record vital signs and weight (orthostatic blood pressure and pulse rate, RR, oral 
temperature) 
• Perform ECG 
• Collect blood samples for: 
o Hematology and serum chemistry (nonfasted sample allowed) 
o ADT 
• Collect urine samples for: 
o Urine pregnancy test (FOCP only) 
o Urinalysis 
o “Point of Care” UDS 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 72 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
• Breathalyzer for alcohol screen 
• Review medications adherence  
• Administer MADRS, CGI-S, CGI-I, HAM-D6, SDS, GAD-7, CADSS, C-SSRS, 
BPRS+, CPFQ, PHQ-9, and CSFQ  
• Review AEs  
• Review concomitant medications  
• Dispense SM  
• Collect SM and assess drug accountability  
Visit 8 – End of Week 5/EOS (Day 36 ± 2 Days) 
The following assessments will be conducted: 
• Record alcohol and cannabis use 
• Perform physical examination 
• Record vital signs and weight (orthostatic blood pressure and pulse rate, RR, oral 
temperature) 
• Perform ECG 
• Collect blood samples for: 
o Hematology and serum chemistry (nonfasted sample allowed) 
o ADT 
• Collect urine samples for: 
o Urine pregnancy test (FOCP only) 
o Urinalysis 
o “Point of Care” UDS  
• Breathalyzer for alcohol screen 
• Review medications adherence  
• Administer MADRS, CGI-S, CGI-I, HAM-D6, SDS, GAD-7, CADSS, C-SSRS, 
BPRS+, CPFQ, PHQ-9, and CSFQ  
• Review AEs  
• Review concomitant medications  
• SM return and assess drug accountability  
6.1.5 Follow-up Phone Call (Day 66 ± 7 Days) 
A safety follow-up phone call will occur approximately 30 days after the EOS Visit for 
subjects who completed the study. For subjects who withdraw from the study, a safety 
follow-up phone call will occur approximately 7 days after withdrawal. 
• Administer CADSS, C-SSRS, and BPRS+ scales 
• Review AEs 
• Review concomitant medications 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 73 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
6.1.6 Unscheduled Visits 
At the discretion of the Investigator throughout the study, unscheduled visits may be 
conducted to perform or repeat assessments, including record ECG, measure vital signs  
(orthostatic blood pressure/pulse rate) and weight, draw blood sample for hematology, 
ADT levels, and/or serum chemistry or serum pregnancy test (FOCP only), ethanol drug 
screen, obtain urine sample for urine pregnancy test and/or drug screen, administer C-
SSRS and perform physical examination.  
In the event a subject cannot tolerate 1600 mg/day between Visits 4 and 5, an 
unscheduled visit may be conducted for dose adjustment before the subject’s scheduled 
Visit 5. AEs and concomitant medications should also be recorded at all unscheduled 
visits. 
6.1.7 Post-Baseline Study Visits 
UDS should be completed and results known before any efficacy assessments are 
conducted at baseline and all post-baseline study visits (Visit 3-8/EOS). UDS will be 
performed as “Point of Care” (POC) with POC kits provided to sites. If a subject has a 
positive drug screen at baseline and any post-baseline visit (Visits 3-8), then the subject’s 
participation in the study should be terminated and no efficacy assessments (MADRS, 
CGI-S, CGI-I, HAM-D6, SDS, and GAD-7) should be performed at that visit (ET 
Visit). All safety assessments should still be performed at this visit. A follow-up phone 
call with the subject should also be performed 1 week following discontinuation of 
SM/study.  
At baseline and all post-baseline study visits, alcohol screening will be performed using 
breathalyzers provided by the Sponsor. Subjects should refrain from taking alcohol 
during the study after the first dose of SM. If a subject tested positive for ethanol at 
baseline and any post-baseline visit (Visits 3-8), then the subject’s participation in the 
study should be terminated and no efficacy assessments (MADRS, CGI-S, CGI-I, 
HAM-D6, SDS, and GAD-7) should be performed at that visit (ET Visit). All safety 
assessments should still be performed at the visit. A follow-up phone call with the subject 
should also be performed 1 week following discontinuation of SM/study.  

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 74 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
6.1.9 Pharmacogenomic Testing 
Subjects who have provided consent for PGx testing will have two blood samples taken 
at baseline (Visit 3) for DNA analysis of genetic variation and for BDNF blood levels 
measurement. One additional blood sample will be collected at Visit 6 for BDNF blood 
levels measurement. This additional research may start at any time during the sample 
storage period. If PGx testing is performed, results from individual tests will be used for 
research purposes only, and a report separate from the CSR will be generated. Samples 
will be identified only by the study subject number to maintain confidentiality. Samples 
will be stored for up to 10 years for potential future research purposes, such as possible 
testing of genes involved in the efficacy of the drug, and possible association with 
particular AEs of the drug (ie, to facilitate an understanding of nonresponders to 
treatment and/or individuals who show an unusual safety profile).  
Data from samples will not have diagnostic value. The DNA and RNA analyses will not 
be used for individual genetic characterization, or development of a commercial product, 
and the subject’s identity will be kept confidential. At the end of testing or after 10 years, 
any remaining samples will be destroyed.  
The subject may withdraw consent for PGx testing at any time. If consent is withdrawn, 
the subject’s sample will be destroyed.  
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 75 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
7 
STUDY VARIABLES AND ASSESSMENTS 
All clinical outcome assessments will be collected electronically using a tablet provided 
by the Sponsor, and then transferred to a portal.  
All scales assessments ratings recorded in the portal are subsequently manually entered 
into the eCRFs. 
Some of the scale assessments will be recorded for an internal independent review 
purpose conducted by a Sponsor’s designee to ensure data consistency and accuracy from 
each study visit.  
7.1 
Rater Qualification Process 
Identified raters from each site will be asked to provide information regarding their 
highest education degrees, field of studies, indication areas, and experience in each 
indication areas using an electronic platform. Once the rater’s profile is complete, the 
platform will automatically assign any Qualification Groups to raters that are eligible. 
Consequently, raters will be asked to provide scale experience information, and based on 
the information entered, the system will determine if raters are qualified to proceed to 
training. Raters can appeal their qualification status; final determination will be made by 
the Sponsor. All qualified study coordinators, Subinvestigators, and Investigators must 
complete the platform trainings. 
Sites will be considered activated once at least one rater per scale training is completed. 
7.2 
Efficacy Assessments 
We suggest, when possible, that the same qualified rater administer the primary and key 
secondary efficacy scales for the subject. 
For the administration of the MADRS and HAM-D6 scales, two separate raters for each 
scale are requested; each rater’s score should be blinded to the other rater’s score. 
It is recommended to administer the scales for the primary endpoint first (ie, MADRS 
and CGI-S) and then collect study visit assessments (chemistry, vital signs, etc), and 
lastly administer HAM-D6 and the self-rating scales. 
7.2.1 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 & Asberg, 1979). Each 
question is scored from 0-6, the sum of the 10 subtests score will yield a total score 
ranging from 0-60. A higher MADRS score indicates more severe depression. Successful 
therapy is indicated by a lower total score in subsequent testing (Appendix 11.1). 
There are 10 subtests based on each item: 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 76 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
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 ten 
MADRS items known as structured interview guide for the MADRS (SIGMA), a 
structured interview developed by Dr. Janet Williams and Dr. Kenneth Kobak, in order to 
increase inter-rater reliability, thus improving signal detection (Williams & Kobak, 
2008). 
The standard (including comparison to euthymic baseline for 3 items) and “Past Week” 
versions will be administered, with Standard at Visit 1 and “Past Week” version at 
Visits 2-8 (Appendix 11.1.1). Euthymic baseline is autopopulated based on the 
information captured at the 1st administration. 
The scale is a Clinician Reported Outcome (ClinRO) administered by the qualified raters 
at each visit during Screening Period and after Day 1 (Randomization/Baseline): 
Visits 1-8. 
7.2.2 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 Clinical Global Impression-Severity of Illness Scale (CGI-S; Appendix 11.3) 
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 TRD. The CGI-S is 
evaluated on a 7-point scale where 1 = Normal not at all, 2 = Borderline depressed, 
3 = Mildly depressed, 4 = Moderately depressed, 5 = Markedly depressed, 6 = Severely 
depressed, and 7 = Among the most extremely depressed patients. Successful therapy is 
indicated by a lower overall score in subsequent testing.  
The scale is a ClinRO administered by the qualified raters at each visit during Screening 
Period and after Day 1 (Randomization/Baseline): Visits 1-8.  
7.2.3 Generalized Anxiety Disorder 7-Item Scale  
GAD-7 is a self-reported 7-item questionnaire for Screening and measuring the severity 
of generalized anxiety disorder (Spitzer, Kroenke, Williams, & Lowe, 2006; Appendix 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 77 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.4). The GAD-7 measures the severity of various symptoms of generalized anxiety 
disorder over the past 2 weeks according to reported response categories with assigned 
points. The patient scores each GAD-7 item on a 4-point Likert scale where 0 = Not at 
all, 1 = Several days, 2 = Over half the days, and 3 = Nearly every day. The total score is 
obtained by summating all 7 items. GAD-7 total scores range from 0-21, where a total 
score of 1-4 = None/Minimal anxiety, 5-9 = Mild anxiety, 10-14 = Moderate anxiety, and 
≥15 = Severe anxiety. It takes less than 5 minutes to complete the GAD-7.   
The self-reported GAD-7 scale is administered at Visits 3, 6, 7, and 8.  
7.2.4 Clinical Global Impression – Improvement  
CGI-I (Appendix 11.5) is an assessment of how much the patient’s illness has improved 
or worsened relative to a baseline state at the beginning of treatment. The CGI-I is 
evaluated by the Investigator at each post-baseline study visit during treatment relative to 
the subject’s condition at baseline on a 7-point scale where 1 = Very much improved, 2 = 
Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 
6 = Much worse, and 7 = Very much worse. Successful therapy is indicated by a lower 
overall score in subsequent testing. The CGI-S assessment obtained at the baseline visit 
should serve as a basis for the Investigator’s CGI-I assessment of improvement in the 
subject’s conditions at each post-baseline study visit during the treatment period.  
The scale is a ClinRO administered by the qualified raters at Visits 4-8. 
7.2.5 Sheehan Disability Scale 
The SDS is a short self-report tool that assesses functional impairment in three inter-
related domains consisting of: 
1. Work/School  
2. Social Life 
3. Family Life/Home Responsibilities 
The subject will rate disruption in responsibilities of the three domains on a 10-point 
visual analog scale (Appendix 11.6). Scores from each item is summed to measure global 
functional impairment ranging from 0 (unimpaired) to 30 (highly impaired). On the first 
domain (work/school) before completing the assessment, the subject will be asked to 
state if have not worked/studied all during the past week due to reasons unrelated to 
depression. In such cases, subjects should not indicate disruption severity. If the subject’s 
symptoms interfere with the ability to find a job or contribute in any way to the current 
status of not working, the subject must give the score on the scale to indicate disruption 
severity. 
While there is no recommended cutoff score, subjects that have scores 5 and above in any 
of the 3 domains should be follow up as they are associated with significant functional 
impairment (Sheehan et al., 1998).  

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 78 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
The self-reported SDS scale is administered at Visits 3, 6, 7 and 8.   
7.2.6 Hamilton Depression Rating Scale – 6 Items 
The HAM-D6 rating scale is one of the most widely used clinician-administered 
depression scales (Hamilton, 1960). 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-items version of the scale, offers  sensitivity for 
measuring severity of detecting improvement of depression comparable to other more 
complex versions (Williams, 1988). 
Five of the six items (Depressed Mood, Work and Activities, Somatic Symptoms 
General, Feelings of Guilt, Anxiety Psychic, Retardation) are scored on a scale of 0-4, 
and one item (Somatic Symptoms General) is scored on a scale of 0-2, for a possible total 
score of 0-22 (Appendix 11.2).  
The scale is a ClinRO administered by the qualified raters at Visits 3-8. 
7.3 
Exploratory Assessments 
7.3.1 Cognitive and Physical Functioning Questionnaire 
The CPFQ is a brief self-rating scale to measure cognitive and executive dysfunction in 
mood and anxiety disorders (Fava, Iosifescu, Pedrelli, & Baer, 2009). It assesses the past 
month subjects’ satisfaction with their cognitive and physical functioning (ie, alertness, 
motivation, attention, memory, lethargy, lexical access, and mental acuity). The CPFQ 
consists of 7 questions, each rated on a scale from 1-6, with 1 = greater than normal, 2 = 
normal, 3 = minimally diminished, 4 = moderately diminished, 5 = markedly diminished 
and 6 = totally absent with a max score of 42. The sum of each of the questions results in 
the following scoring: ≤7 = greater than normal functioning; 8-14 = normal functioning; 
15-21 = minimally diminished functioning; 22-28 = moderately diminished functioning; 
29-35 = markedly diminished functioning; and 36-42 = totally absent functioning. 
(Appendix 11.7).  
The self-reported CPFQ scale is administered at Visits 3-8. 
7.3.2 Patient Health Questionnaire 9-Item 
The PHQ-9 is self-administered questionnaire (Spitzer, Kroenke, & Williams, 1999) 
consisting of the 9-item depression module derived from the full PHQ (Kroenke et al. 
2001). 
Major depression is diagnosed if 5 or more of the 9 depressive symptom criteria have 
been present at least “more than half the days” in the past 2 weeks, and 1 of the 
symptoms is depressed mood or anhedonia. Other depression is diagnosed if 2, 3, or 4 
depressive symptoms have been present at least “more than half the days” in the past 
2 weeks, and 1 of the symptoms is depressed mood or anhedonia. As a severity measure, 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 79 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
the PHQ-9 score can range from 0-27, since each of the 9 items can be scored from 0 (not 
at all) to 3 (nearly every day) (Appendix 11.8).  
The self-reported questionnaire is administered at Visits 3, 6, 7, and 8. 
7.3.3 Changes in Sexual Functioning Questionnaire 
The CSFQ, a structured interview/questionnaire designed to measure illness and 
medication-related changes in sexual functioning (Clayton, McGarvey, & Clavet, 1997) 
and the 14-point instrument is validated for measuring sexual function in females and 
males (Petersen, Kristensen, Giraldi, & Giraldi, 2020). The CSFQ-14 uses 5-point Likert 
scales to provide the subject an opportunity to self-evaluate the subject’s sexual behaviors 
or problems in a number of areas. For all items, higher scores reﬂect higher sexual 
functioning. For 12 of the 14 items, higher sexual functioning corresponds to greater 
frequency or enjoyment/pleasure (eg, 1 = never to 5 = every day). For two items (item 10, 
assessing loss of interest after arousal for women and priapism for men, and item 14, 
assessing painful orgasm), higher sexual functioning corresponds to lower frequency (eg, 
1= every day to 5 = never). Items 10 and 14 are included in the total score but not in any 
scale score (Keller, McGarvey, & Clayton, 2006). To calculate the total score, sum up the 
values for each of the 14 items. The total score in woman can range from 14-70 with a 
cutoff of ≤41 indicating sexual dysfunction. The total score in men can also range from 
14-70 but with a cutoff of ≤47 indicating sexual dysfunction (Appendix 11.9). 
The self-reported scale is administered at Visits 3, 6, 7 and 8. 
7.4 
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 signs and 
weight, 12-lead ECGs, C-SSRS, CADSS, BPRS+ and the performance of physical 
examinations as detailed in the Schedule of Events and Assessments (Table 2). 
Investigators are responsible for monitoring the safety of subjects who have entered this 
study and for alerting Supernus or its designee to any event that seems unusual, even if 
this event may be considered an unanticipated benefit to the subjects.  
7.4.1 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: 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 80 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
• 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; and/or 
• Recurrence of an intermittent medical condition (eg, headache) not present at 
baseline. 
Surgical procedures are not AEs; they are therapeutic measures for conditions that require 
surgery. The condition for which the surgery is required is an AE if it occurs or is 
detected during the study period.  
7.4.2 Adverse Events of Special Interest 
At the current time, no AEs of special interest (AESI) have been identified. This section 
will be updated when new information becomes available.  
7.4.3 Overdose 
No data are available. Should an overdose of NV-5138 be administered or ingested, the 
subject should be closely monitored for adverse signs and symptoms and appropriate 
medical supportive care administered.  
7.4.4 Causality 
Adverse events 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 drug and the AE, ie, there is a reasonable possibility that the drug caused the 
AE.  
ADRs are a subset of all SADRs for which there is reason to conclude that the drug 
caused the event. 
7.4.5 Recording and Evaluation of Adverse Events 
All subjects who are screened (Visit 1) will be questioned regarding any current and prior 
medical health status or diagnoses, and any medical records and pharmacy records will be 
documented as medical history. At each contact with the subject following the first dose 
of SM (post-Visit 3), 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 procedures 
results should be recorded in the source document, although they may be grouped under 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 81 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
one diagnosis. For example, fever, elevated white blood cell (WBC), cough, abnormal 
chest X-ray, etc., can all be reported as “pneumonia”. 
All AEs occurring after Visit 3 and throughout the study period must be recorded. A 
TEAE is defined as an AE with a start date on or after the first dose of SM is taken, or 
that worsened following first administration of SM. All AEs in this study will be 
recorded after administration of SM; therefore, all will be treatment emergent. The 
clinical course of each AE should be followed for at least 30 days following the date of 
last dose of SM (either due to EOS or ET), or until resolution, or until, in the medical 
judgment of the Investigator, the event has stabilized or is assessed as chronic. 
The Investigator is responsible for evaluating AEs and determining the following: 
• Serious vs. Non-serious: Is the event a Serious Adverse Event (SAE)? 
• Causality: Was AE related or not related to the SM? 
• Severity: How pronounced is the incapacity/discomfort caused by an AE? 
7.4.6 Criteria for Assessing Severity 
The Investigator will evaluate the comments of the subject and the response to treatment 
in order that the Investigator may judge the true nature and severity of the AE. Severity 
refers to the accumulated intensity of discomfort/impairment of health since the last 
recording of AEs and will be assessed according to the following criteria: 
• Mild: Awareness of sign, symptom, or event, but easily tolerated 
• Moderate: Discomfort enough to interfere with usual activity and may warrant 
intervention 
• Severe: Incapacitating with inability to do usual activities or significantly affects 
clinical status and warrants intervention 
The criteria for assessing severity are different from those used for seriousness. 
7.4.7 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. These are defined as follows: 
Not suspected: The temporal relationship of the AE to SM administration makes a causal 
relationship unlikely, or other drugs, therapeutic interventions, or underlying conditions 
provide a sufficient explanation for the observed event.  
• Not related:  Temporal relationship to SM administration is missing or implausible, 
or there is an evident other cause. 
• Unlikely related:  Temporal relationship to SM administration makes a causal 
relationship improbable; and other drugs, chemicals, or underlying disease provide 
plausible explanations. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 82 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
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, other drugs, or chemicals could also explain event. Information on 
drug withdrawal may be lacking or unclear. This will be reported as a SADR. 
• Definitely related: Temporal relationship to SM administration is plausible, and 
concurrent disease, other drugs, or chemicals cannot explain event. The response to 
withdrawal of the medication (rechallenge) should be clinically plausible. The event 
must be definitive pharmacologically or phenomenologically, using a satisfactory 
rechallenge procedure if necessary. This will be reported as an ADR. 
7.4.8 Serious Adverse Events 
Adverse events are classified as serious or non-serious. An AE or ADR is considered 
“serious” if, in the view of either the Investigator or Sponsor, it results in one of the 
following outcomes:  
• death 
• life-threatening AE (ie, the subject was at immediate risk of death from the AE as it 
occurred. This does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death.) 
• in-patient hospitalization or prolongation of existing hospitalization 
• persistent or significant disability or incapacity or substantial disruption of the ability 
to conduct normal life functions 
• a congenital anomaly or birth defect 
• an important medical event 
Important medical events are those that may not be immediately life threatening or result 
in death or hospitalization but are clearly of major clinical significance. They may 
jeopardize the subject and may require intervention to prevent one of the other serious 
outcomes noted above. For example, drug overdose or abuse, blood dyscrasias, a seizure 
that did not result in in-patient hospitalization or intensive treatment for allergic 
bronchospasm in an emergency department would typically be considered serious. 
7.4.9 Investigator Responsibilities for Reporting SAEs 
The Investigator must immediately report to the Sponsor all SAEs regardless of whether 
the Investigator believes they are drug related. 
All SAEs must be reported to the Drug Safety Contact within 24 h 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 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 83 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
(eg, hospital records, autopsy reports, and other relevant documents). The Investigator 
will keep a copy of this SAE Report form on file at the study site. 
The Investigator or study physician, after thorough consideration of all facts that are 
available, must include an assessment of the causality of an AE 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. 
7.4.10 Other Events Requiring Immediate Reporting 
The Investigator must report a pregnancy that occurs in a subject during a clinical study 
to the Drug Safety Contact within 24 h of first becoming aware of the event. Subjects 
who become pregnant during the study should be discontinued from SM immediately. 
Pregnancy should be reported on a Pregnancy Report Form. The Investigator should 
discuss the case with the Medical Monitor; the Investigator must follow any pregnant 
subject 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 Contact within 24 h of first becoming aware of the event. 
7.4.11 Sponsor Responsibilities for Reporting SAEs 
The Sponsor or designee will inform Investigators and regulatory authorities of 
reportable events in compliance with applicable regulatory requirements on an expedited 
basis (ie, within specific time frames). For this reason, it is imperative that study sites 
submit SAE information to the Sponsor or designee in the manner described above. 
Investigators must comply with the applicable regulatory requirements related to the 
reporting of SAEs to the Institutional Review Board (IRB). Investigators must also 
submit the safety information provided by the Sponsor to the IRB unless the country legal 
regulation requires that the Sponsor should be responsible for the safety reporting to the 
IRB. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 84 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
It is the responsibility of the Sponsor to notify all participating Investigators in a written 
IND safety report of any SADR that is both serious and unexpected. The Sponsor will 
also notify participating Investigators of any findings from other sources (other studies, 
animal, and in vitro testing, etc) that suggest a significant risk for human subjects. Such 
findings will typically lead to safety-related changes in the study protocol, Informed 
Consent, and/or Investigator’s Brochure (IB). 
7.4.12 Clinician-Administered Dissociative States Scale 
The CADSS is a 23-item clinician administered scale that measures present-state 
dissociative symptoms (Bremner et al., 1998). 
The subjective component 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 ranging from: 0 = not at all, 1 = mild, 2 = moderate, 
3 =severe, to 4 = extreme with a total score ranging from 0-92 (Appendix 11.10). 
The scale is a ClinRO administered by the qualified raters at screening Visit, baseline 
visit, Visits 4-8, and follow-up phone call (FPC). 
7.4.13 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, Berthoud, Ventura, & Merlo, 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 sixties, the BPRS 
was developed as a 16-item instrument (John E. Overall & Gorham, 1962), which was 
later extended to 18 items and was used for many years (J. E. 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, 
Liberman, & Nuechterlein, 1986). In its latest version (version 4.0), the manual of 
administration of the 24-item BPRS (Ventura J, 1993(b)) 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. For the study, the version used is adapted from the original BPRS 4-item positive 
symptoms (BPRS+). The scale is comprised of 4 items assessing a subject’s experience 
of psychosis, often referred as positive symptoms of Suspiciousness, Hallucinatory 
Behavior, Unusual Thought Content and Conceptual Disorganization. Of the 4 items 
assessed, the first three items are based on questions asked by the clinician to the subject, 
Conceptual Disorganization is a clinician rated item based on observation of subjects’ 
behavior and speech during the assessment (Appendix 11.11).  
The scale is a ClinRO administered by qualified raters at Screening Visit 1, Baseline 
Visit, Visits 4-8, and FPC.  

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 85 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
7.5 
Treatment-Emergent Suicidal Ideation 
Prospective assessment of suicidal ideation and suicidal behavior is a mandatory part of 
the safety evaluations for any drug developed for a psychiatric indication (FDA, 2012). In 
this study, the initial evaluation of subjects will be conducted prior to enrollment to 
assess lifetime suicidal ideation and to identify subjects who must not participate in the 
trial due to pre-existing suicidality risk. The assessment will then be repeated at each 
subsequent study visit to monitor the occurrence of new suicidal and self-injurious 
tendencies. 
7.5.1 Columbia-Suicide Severity Rating Scale 
Assessment of suicidal ideation and behavior will be conducted using the C-SSRS 
(Posner et al., 2011; [Baseline] Appendix 11.12; [Since Last Visit] Appendix 11.13). 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 qualified raters at each visit during the Screening 
Period and after Day 1 (Randomization/Baseline): at Visits 1-8, and FPC. 
7.5.2 Suicide Risk Management Plan 
The protocol procedures related to clinical care of patients with treatment-emergent 
suicidal ideation and behavior must be implemented to ensure proper management of the 
event and protection of subject’s safety. If a disclosure of suicidal ideation is revealed as 
part of the C-SSRS questionnaire or when a subject spontaneously expresses that the 
subject 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. 
7.5.2.1 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.  
7.5.2.2 Acute Suicidal Crisis 
A person evaluated as being at high risk should be transferred to an immediate care 
facility. The Investigator will guide intervention as clinically indicated and follow up 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 88 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
PR intervals will be determined for each of these ECGs from a single reading. Invalid 
measurements will be repeated. QTc will be reported as QTcF (QT corrected using 
Fridericia's method). 
7.8 
Screening Scales and Assessment Tools 
7.8.1 Mini-International Neuropsychiatric Interview 
The MINI is a short, structured diagnostic interview developed by psychiatrics and 
clinicians in the United States (US) and Europe for DSM disorders and has been updated 
to map to the DSM-5 (Hergueta & Weiller, 2013; Sheehan et al., 1998). With an 
administration time of approximately 15 minutes, the MINI is often used for psychiatric 
evaluation in clinical trials and is the most widely used psychiatric structured diagnostic 
interview instrument in the world (Appendix 11.14). 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 89 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 90 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
7.8.3 Medication Adherence Diary 
This study will use a medication diary to monitor adherence. The platform is provided on 
a smartphone application to confirm medication ingestion. Built-in reminders allow 
intervention in case of missed doses. Use of the platform is required for all subjects in the 
study to reinforce the proper dosing schedule and improve data integrity. Visit reminders 
are also included. 
Registration on the medication adherence platform 
• 
The platform can be downloaded as an app on the subject’s personal smartphone. 
If a subject does not own a smartphone or prefers not to use the subject’s personal 
smartphone, one of the backup provisioned devices should be provided.  
• 
The subject should be registered in the platform following completion of the 
screening visit to begin monitoring ADT. After completion of the registration 
process, a training mode will be automated and presented to the subject the first 
time the subject logs into the device.  
Ongoing use and monitoring of medication adherence  
• 
Subjects must use the application to record each daily intake of ADT and SM 
throughout the trial both remotely between visits and during the PK visit when 
SM is taken at the site.  
• 
Site study coordinator as well as CRO should regularly check the dashboard to 
ensure consistent medication adherence throughout the study. In cases of missed 
doses, the study coordinator will follow up with the subject as soon as possible to 
assess the reason for nonadherence and reinforce the importance of complying 
with the SM dosing schedule. If the subject reports that a dose was taken but not 
logged in the app, the site study coordinator can edit the data using the Manual 
Cloud Diary Entry role in electronic data capture (EDC).  
• 
Site study coordinator can perform interventions for nonadherent subjects directly 
through the site within EDC only under special circumstances. Sites are 
encouraged to document interventions performed within EDC to track their efforts 
in intervening. 
Data Privacy and Security on the smartphone platform  

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 91 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
The medication adherence platform is compliant with all applicable privacy and data 
security laws; data is captured, processed, and analyzed in a secure and compliant manner 
as outlined in the ICF. This includes the fact that the platform will collect a study ID and 
cell phone number if provided. All recordings and data are encrypted by the application 
and will be automatically forwarded to a secure server located in the US. Recordings are 
only accessible during the study by trained platform staff and all recordings and 
identifiable data will be deleted at the end of the study. 
7.9 
Placebo Response Reduction Training  
The PRR training for subjects involves an approximately 5-minute long eLearning 
module found on the eLearning training platform that aims to teach subjects about the 
appropriate expectations of personal benefit while participating in a clinical trial. The 
eLearning module is adapted to the protocol and includes case scenarios and interactive 
questions throughout the course. The content provides subjects with information that 
helps to neutralize the typical overestimation of personal benefit expectation that drives 
high placebo responses in clinical studies. Neutralizing staff and study subject’s 
expectations of benefit is a validated method used to decrease placebo response and 
improve the accuracy of assay sensitivity. A completion certificate is generated at the end 
of the course and will be filed in the subject chart.  
PRR training should be completed by the subject prior to completing study 
assessments at Visit 2; a refresher training is also requested at Visit 5.  
7.10 Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will monitor data on an ongoing basis to 
ensure the continuing safety of the subjects enrolled in the study. The committee will 
meet periodically to review safety data. After the reviews, the DSMB will make 
recommendations regarding the continuation of the study. The details are provided in a 
separate DSMB charter. The DSMB consists of two medical experts in the relevant 
therapeutic area; one is a qualified physician and one an independent biostatistician. The 
responsibilities, authorities, and procedures are documented in the DSMB charter. 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 92 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
8 
STATISTICAL METHODS 
8.1 General Considerations 
All tabulations of analysis results will include summaries for treatment arms of NV-5138 
and placebo.  
Where appropriate, variables will be summarized descriptively (frequency count and 
percentage for categorical variables; number of subjects [n], mean, SD, 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; these are sorted by unique subject 
identifier. All data available from the eCRFs will be listed. Unscheduled measurements 
will be excluded from the descriptive statistics and statistical analysis but will be 
included in listings. 
Complete details of the statistical analysis will be provided in a separate statistical 
analysis plan (SAP).  
8.2 
Sample Size and Power Considerations 
Two hundred subjects (100 per treatment group) in the FAS will yield 80% power in 
detecting superiority of NV-5138 to placebo at a significance level of 0.05 (two-sided) 
using a two-sample t-test with equal allocation to the treatment groups. This assumes an 
effect size of 0.40 with a mean difference of 4.8 and a SD of 12. Assuming a dropout rate 
of 25%, approximately 268 subjects will be randomized to achieve about 200 subjects 
completing the study. 
Assuming a 67% rate of screen failure, approximately 800 potential subjects will be 
screened to obtain about 268 subjects randomized. 
8.3 Estimand 
8.3.1 Primary Estimand 
The attributes below will be used to construct the primary estimand, thereby defining the 
treatment effect of NV-5138. 
1) Treatment:  To compare the treatment effect of NV-5138 versus placebo 
2) Population: The population targeted for the scientific question is defined by the 
Inclusion and Exclusion Criteria in adults with TRD 
3) Variable: CFB (Day 1) in MADRS total score to end of treatment period 
4) ICE: The treatment policy strategy will be followed for handling intercurrent 
events. For subjects who are discontinued due to AE(s) or lack of efficacy and for 
subjects who are dosed but have no post-baseline MADRS total score, missing 
data will be imputed using MI under the MNAR assumption; no imputation will 
be done for subjects discontinued due to other reasons 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 93 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
5) Population-level summary: difference in mean change in MADRS total score 
between the NV-5138 and placebo groups will be compared using the MMRM 
methodology 
8.3.2 Secondary Estimand 
The attributes below will be used to construct the secondary estimand, thereby defining 
the treatment effect of NV-5138.  
1) Treatment: To compare the treatment effect of NV-5138 versus placebo 
2) Population: The population targeted for the scientific question is defined by the 
Inclusion and Exclusion Criteria in adults with TRD  
3) Variable: CFB (Day 1) in the CGI-S score to the end of treatment period 
4) ICE: The treatment policy strategy will be followed for handling ICEs. For 
subjects discontinued due to AE(s) or lack of efficacy and for subjects who are 
dosed and have no post-baseline CGI-S scores, missing data will be imputed 
using MI under the MNAR assumption; no imputation will be done for subjects 
discontinued due to other reasons 
5) Population-level summary: The difference in mean change in CGI-S scores 
between the NV-5138 and placebo groups will be compared using the MMRM 
methodology 
8.4 
Handling of Dropout or Missing Data 
With respect to the primary analysis, the MMRM method, implemented via SAS® PROC 
MIXED (SAS/STAT Software), will be used for handling missing MADRS total scores 
under the missing at random (MAR) assumption; however, for subjects who are 
discontinued due to AE(s) or lack of efficacy and for subjects who are dosed but have no 
post-baseline MADRS total score, placebo-based MI will be used to fill in missing data 
before performing the MMRM analysis.  This approach assumes that missing data from 
the NV-5138 treatment group would adopt the outcomes estimated from the placebo 
group. The SAS procedure, PROC MI, will be used to apply the MNAR statement with 
the option of using the observations from the placebo group. MI will be carried out by the 
fully conditional specification (FCS) method. One hundred (100) imputed datasets will be 
created in case of subjects who are discontinued due to AE(s) or lack of efficacy and for 
subjects who are dosed but have no post-baseline MADRS total score.  The MMRM 
model for the primary efficacy analysis will be performed using each of these 100 
imputed datasets. PROC MIANALYZE in SAS will be used to combine all the results 
from these 100 MMRM models and then make a final statistical inference. 
A sensitivity analysis for the primary endpoint will be performed by assuming that 
missing MADRS total scores are MNAR using placebo-based MI to impute all missing 
data in the NV-5138 group. 
The same procedure will be applied to key secondary endpoint CGI-S. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 94 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
For analysis of additional secondary endpoints, missing values will be using MMRM 
which assumes missing values as MAR. 
For safety analyses, missing date for AEs and nonstudy medication use will be imputed 
as described in the SAP. Missing data for all other safety endpoints will not be imputed. 
8.5 
Analysis Populations 
The Randomized Population includes all subjects who are randomized. 
The Full Analysis Set (FAS) is a subset of subjects in the Randomized Population who 
take at least one dose of SM and have a baseline assessment of MADRS total score. The 
efficacy analyses will be conducted using the FAS according to the randomized treatment 
assignment. 
The Per Protocol (PP) Population is a subset of subjects in the FAS who complete all 
8 visits through EOS with no missing MADRS total scores assessments and no important 
protocol deviations. Subjects in the PP Population will be analyzed according to the 
actual treatment received. 
The Safety Population includes all subjects randomized into the study who receive at 
least one dose of SM. The safety analysis will be performed according to the actual 
treatment received. 
8.6 
Demographics and Baseline Analysis 
Demographic and baseline characteristics (eg, age, age group, sex, ethnicity, race, height, 
weight, and BMI) will be summarized using descriptive statistics for continuous variables 
and using counts and percentages for categorical variables. The descriptive summary will 
be presented by the treatment group for the FAS and Safety Populations. 
8.7 
Subject 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 and discontinued from the study 
and primary reason for early discontinuation will be summarized. The reason for early 
discontinuation may include any of the following: 
• 
Withdrawal of consent  
• 
Noncompliance with study procedures (eg, positive alcohol test or UDS, missed 
more than two consecutive doses of SM, use of prohibited medications) 
• 
Occurrence of unmanageable AEs 
• 
Lost to follow-up 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 95 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
• 
Lack of efficacy 
• 
The Investigator or the Sponsor believes it is in the best interest of the subject to 
discontinue the study (ie, for safety or tolerability reasons) 
• 
Other (eg, study is terminated by the Sponsor, subject becomes pregnant, blind is 
broken, subject has relocated or death, etc) 
8.8 
Study Medication Exposure and Compliance 
Duration of exposure is defined as the total number of days a subject is exposed to any 
SM. This will be calculated for each subject by taking the difference between the date of 
last dose minus the date of the first dose, plus 1 (date of last dose minus date of first 
dose +1). 
Duration of treatment exposure will be summarized by duration category (1-7 days, 
8-14 days, 15-21 days, 22-28 days, 29-35 days, and 35 days or more) and will also be 
summarized using descriptive statistics (n, mean, SD, median, interquartile range [Q1 and 
Q3], minimum, and maximum). 
Subject exposure will be summarized categorically by study week, dose (800 mg, 
1600 mg in separate rows [eg, 1600 mg for week 1, 800 or 1600 mg for rest weeks]), and 
treatment group. The number and percent of subjects in each dose group will be 
presented for each treatment. 
Percentage compliance will be calculated. For each treatment, SM compliance will be 
summarized by compliance category (<80%, 80-120%, and >120%) and number of 
subjects in each compliance category. SM compliance will also be summarized as a 
continuous variable using descriptive statistics (n, mean, SD, median, interquartile range 
[Q1 and Q3], minimum, and maximum) for each treatment. 
8.9 
Concomitant Medications 
Concomitant medications will be assigned an 11-digit code using the World Health 
Organization Drug Dictionary (WHO-DD) drug codes. Concomitant medications will be 
further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code 
indicating therapeutic classification. A tabular summary of concomitant medications by 
drug class will be presented for the Safety Population. 
8.10 Efficacy Analysis 
All efficacy endpoints will be analyzed based on the FAS. All efficacy data will be 
presented in data listings. 
8.10.1 Primary Efficacy Analysis 
The CFB in MADRS total score to the end of treatment period will be analyzed using a 
MMRM. For subjects who are discontinued from the study due to AE(s) or lack of 
efficacy and for subjects who are dosed but have no post-baseline MADRS total score, 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 96 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
missing data will be imputed based on the MNAR assumptions. For subjects who are 
discontinued from the study due to other reason, no missing imputation will take place. 
The data collected at the ET visit will be mapped to the next scheduled visit. The MMRM 
model will include baseline MADRS total score as a covariate, and treatment, visit, and 
treatment-by-visit interaction as fixed effects. The model parameters will be estimated 
using the restricted maximum likelihood method with an unstructured variance-
covariance matrix and Kenward-Roger approximation to estimate the denominator 
degrees of freedom. If the MMRM model with the unstructured variance-covariance 
matrix does not converge using the default Newton-Raphson fitting algorithm by PROC 
MIXED in SAS, the Fisher scoring algorithm or the no-diagonal factor analytic structure 
will be used (Lu & Mehrotra, 2010).  
If the model still fails to converge, the following types of covariance structure with the 
sandwich estimators will be used to fit the model in a sequential order until the model 
converges:  
1. Heterogeneous Toeplitz 
2. Heterogeneous Autoregressive of order 1 
3. Toeplitz 
4. Autoregressive of order 1 
5. Compound symmetry  
The denominator degrees of freedom will be estimated using the BETWITHIN option in 
SAS when any of the covariance structures is used with the sandwich variance estimator. 
One hundred (100) imputed datasets based on the MNAR assumption will be created in 
case of subject discontinuation due to AE(s) or lack of efficacy and for subjects who are 
dosed but have no post-baseline MADRS total score. The MMRM model for the primary 
efficacy analysis will be performed using each of these 100 imputed datasets. PROC 
MIANALYZE in SAS will be used to combine all the results from these 100 MMRM 
models and then make a final statistical inference. 
For the final statistical inference, the least squares (LS) mean of CFB to the end of 
treatment period for the MADRS total score for each treatment group will be presented 
along with the corresponding standard error (SE). The NV-5138 group will be compared 
with the placebo group by presenting the difference in the LS means between the NV-
5138 and placebo groups (NV-5138 minus placebo) with its 95% CI and the p-value. 
8.10.2 Sensitivity Analysis 
A sensitivity analysis will be performed using the placebo-based MI to fill in missing 
MADRS total scores. This approach assumes that after discontinuation, subjects from the 
NV-5138 treatment group would adopt the outcome that is estimated from the placebo 
group. Placebo-based MI will be used to fill in all missing values in the NV-5138 and 
placebo groups. The CFB in MADRS total score to the end of Treatment Period based on 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 97 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
each imputed dataset will be analyzed using the same MMRM model described for the 
primary analysis. To combine all the results using each of the imputed datasets, PROC 
MIANALYZE in SAS will be used to make a final statistical inference. 
8.11 Secondary Efficacy Analyses 
The secondary analyses will be based on the FAS. 
8.11.1 Key Secondary Efficacy Analyses 
The key secondary endpoint, the CFB to the end of the Treatment Period in the CGI-S 
score, will be analyzed using the same MMRM model as the primary efficacy analysis. 
Specifically, ICEs, missing data, and statistical methods for the key secondary efficacy 
endpoint analysis will be handled in the same manner as described in Sections 8.3.2, 8.4, 
and 8.10.2. Sensitivity analysis will be conducted in the same manner as described in 
Section 8.10.2. 
8.11.2 Additional Secondary Analyses 
For the MADRS, the CFB to end of each scheduled week will be analyzed using MMRM 
as appropriate based on the FAS. For the SDS, HAM-D6 and GAD-7 scores, the CFB to 
end of each scheduled week will be analyzed using MMRM as appropriate based on the 
FAS. For the CGI-I, the absolute value will be analyzed using MMRM. The NV-5138 
treatment group will be compared with the placebo as described for the primary analysis. 
The treatment groups for the proportion of responders (defined as ≥50% reduction from 
baseline in MADRS total score), the proportion of subjects in remission (MADRS total 
score ≤10), the percentage of subjects with a CGI-S score of 1 or 2, and the percentage of 
subjects with a CGI-I score of 1 or 2 at the end of each scheduled week will be compared 
using Pearson’s Chi-squared Test or Fisher’s Exact Test as applicable. 
8.12 Exploratory Efficacy Analyses 
The CFB to the end of each scheduled week in PHQ-9, CPFQ, and CSFQ scale scores 
will be analyzed using MMRM as appropriate based on the FAS. The NV-5138 treatment 
group will be compared with the placebo as described for the primary analysis. A 
subgroup analysis of the primary efficacy endpoint will be explored using the history of 
inadequate response to the prior ADT medications and speech latencies. If applicable, 
subgroup analyses of some efficacy endpoints will be explored (eg, by sex, prior ADT 
failure category, and speech latency category).  

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 98 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
8.14 Interim Analysis 
No interim analysis will be performed. 
8.15 Pharmacogenomic Analyses 
The blood samples will be stored for possible testing of genetic variation and BDNF 
concentration. Analyses may include the relationship to treatment effects and AEs (eg, 
understand how the non-responders react to treatment and/or subjects who show an 
unusual safety profile). The DNA and RNA analyses will not be used for individual 
genetic characterization and the subject identity will be kept confidential. If analyzed, the 
results of the exploratory analyses will be presented in a stand-alone PGx report. 
8.16 Safety Analysis 
Safety analyses will be performed by treatment arm based on the Safety Population.  
The incidence rate of AEs will be calculated by treatment arm for each system organ 
class (SOC) and preferred term (PT). The severity of the AEs and the relationship to SM 
will be summarized by the treatment arm for each SOC and PT. 
AEs, serious AEs (including deaths), and AEs leading to withdrawal will be summarized 
by SOC and PT, separately for each treatment arm. The verbatim descriptions with 
Medical Dictionary for Regulatory Activities (MedDRA) coded SOCs and PTs for all AEs 
will be contained in the subject data listings. 
Clinical laboratory values will be summarized by the treatment arm for each visit using 
descriptive statistics. For quantitative laboratory parameters, both actual values and CFB 
will be summarized. 
Vital signs and weight will be summarized by visit by treatment arm using descriptive 
statistics. Both actual values and CFB will be summarized. 
ECG results will be summarized by the treatment arm for each visit using descriptive 
statistics (for quantitative ECG parameters) and frequency tables (for qualitative ECG 
parameters, including the overall ECG finding). 
C-SSRS outcomes will be summarized using number and percent of subjects by 
categories for suicidal ideation only, suicidal behavior only, and suicidality (ideation and 
behavior combined). The summary will be presented by the treatment arm for each visit. 
Descriptive statistics will be presented for demographics, physical examinations, 
CADSS, and BPRS+ scores. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 99 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
9 
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 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 
change that must be approved by the Sponsor before implementation. Amendments 
specifically affecting the safety of subjects, the scope of the investigation, or the 
scientific quality of the study require additional approval by the applicable IRB, and in 
some cases, filings to the regulatory authority. These requirements should in no way 
prevent any immediate action from being taken by the Investigator, or by the Sponsor, in 
the interest of preserving the safety of all subjects included in the study. If an immediate 
change to the protocol is felt by the Investigator to be necessary for safety reasons, the 
Medical Monitor, and IRB must be notified promptly. 
Changes to the protocol which are administrative in nature do not require formal protocol 
amendments or IRB approval, but the IRB must be kept informed of such changes. In 
these cases, the Sponsor or CRO will send a letter to the IRB detailing such changes. 
9.3 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures (SOPs), working practice documents, and applicable 
regulations and guidelines. Site visit audits may be made periodically by the Sponsor’s 
Quality Assurance team or qualified designee, which is an independent function from the 
study conduct team. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 100 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
9.3.1 Data Collection 
The primary source document will be the subject’s medical and pharmacy records. If 
separate research records are maintained by the Investigator(s), 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. 
Data recorded on source documents will be transcribed into the eCRFs in accordance 
with the eCRF Completion Instructions that are provided to the study sites. The 
Investigator is responsible for ensuring that all sections of each eCRF are completed 
correctly, and that entries can be verified against source documents. The eCRFs will be 
monitored for completeness and accuracy against the source documents by the CRA(s) on 
a regular basis. Inconsistencies between the eCRFs and source documents will be 
resolved in accordance with the principles of GCP. 
9.3.2 Clinical Data Management 
External data outside of the clinical database (eg, 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. The procedure for handling missing data will be 
addressed in the SAP. Data queries requiring clarification will be documented and 
returned to the study site for resolution. Only authorized personnel will make corrections 
to the clinical database, and all corrections will be documented in an audit trail.  
9.3.4 Bioanalytical Sample Handling 
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.  

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 101 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
9.4 
Retention of Records 
The Investigator has the responsibility to retain all study “essential documents”, as 
described in ICH E6 for at least two years after approval of a marketing application or 
after formal discontinuation of the clinical program. Essential documents include but not 
limited to the protocol, eCRFs, source documents, laboratory test results, SM inventory 
records, IBs, regulatory agency registration documents (eg, FDA form 1572, ICFs, and 
IRB correspondence). The Investigator must obtain written permission from Supernus 
prior to the destruction of any study document.  
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 SOPs to evaluate compliance with the 
principles of ICH GCP and all applicable local regulations. A government regulatory 
authority may also wish to conduct an inspection (during the study or after its 
completion). If an inspection is requested by a regulatory authority, the Investigator must 
inform the Sponsor and the CRO immediately that this request has been made. 
These records must be made available at reasonable times for inspection and duplication, 
if required, by a properly authorized representative of the US FDA in accordance with the 
US 21 Code of Federal Regulation (CFR) 312.68 or other national or foreign regulatory 
authorities in accordance with regulatory requirements. 
9.6 
Publication of Results 
Any presentation or publication of data collected as a direct or indirect result of this trial 
will be considered as a joint publication by the Investigator(s) and the appropriate 
personnel at the Sponsor’s site. Authorship will be determined by mutual agreement. All 
manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the Sponsor prior to submission for 
publication or presentation. No publication or presentation with respect to the study shall 
be made until all Sponsor comments on the proposed publication or presentation have 
been addressed to the Sponsor’s satisfaction. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be outlined in the 
agreement between each Investigator and the Sponsor or designee. 
9.7 
Financing and Insurance 
Financing and Insurance information will be set forth in a separate document between the 
Investigator and Sponsor (provided by the Sponsor or designee). 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 102 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
9.8 
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, use of live-in facilities, laboratory tests, and other professional fees. 
The Investigator will refund the excess of payments made in advance. 
The Investigator reserves the right to discontinue the study should the Investigator’s 
judgment so dictate. The Investigator will notify the IRB in case of study discontinuation. 
Study records must be retained as noted above. 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 103 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
10 
ETHICS 
10.1 Institutional Review Boards 
The IRB that approved this study and the approval letters will be included in the CSRfor 
this protocol. 
The protocol, any protocol amendments, and the ICF will be reviewed and approved by 
the appropriate IRB before subjects are enrolled. The Investigators or Sponsor will 
submit, depending on local regulations, periodic reports and inform the IRB of any 
reportable AEs per ICH guidelines and local IRB standards of practice. 
10.2 Ethical Conduct of the Study 
This study will be conducted in accordance with SOPs from both the Sponsor and the 
CRO. These SOPs are designed to ensure adherence to GCP guidelines as required by: 
• Declaration of Helsinki, 1964 (“Recommendations Guiding Physicians in Biomedical 
Research Involving Human Patients”), and all its accepted amendments to date 
concerning medical research in humans 
• ICH Guideline for GCP (Committee for Proprietary Medicinal Products/ICH/135/95) 
of the European Agency for the Evaluation of Medicinal Products, Committee for 
Proprietary Medicinal Products, ICH of Pharmaceuticals for Human Use 
• US CFR dealing with clinical studies (21 CFR, including parts 50 and 56 concerning 
Patient Informed Consent/Assent and IRB regulations) 
• Local, national legal guidelines 
10.3 Investigators and Study Personnel 
This study will be conducted by qualified Investigators 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 each investigational site. The study will be monitored by qualified personnel from the 
Sponsor or their designees, such as the CROs for their respective sites. Laboratory tests 
will be conducted by a central laboratory as designated in the reference binder.  
 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. 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 104 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
The process for obtaining informed consent will be in accordance with all applicable 
regulatory requirements. The Investigator (or designee) and subject must sign and date 
the ICF before the subject can participate in the study. The subject will be given a copy of 
the signed and dated ICF, and the original will be retained in the investigational site study 
records. 
The decision regarding subject participation in the study is entirely voluntary. The 
Investigator (or designee) must emphasize to the subject that consent, regarding study 
participation may be withdrawn at any time without penalty or loss of benefits to which 
the subject is otherwise entitled. 
If the ICF is amended during the study, the Investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICF by the IRB and use 
the amended ICF (including ongoing subjects). 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 105 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11 APPENDIX:   
11.1 MADRS 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 106 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 107 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 108 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 109 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 110 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 111 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.1.1 MADRS Past Week (Follow-up Evaluation) 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 112 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 113 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 114 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 115 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 116 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 117 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.2 HAM-D6 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 118 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 119 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 120 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 121 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 122 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.3 CGI-S 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 123 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.4 GAD-7 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 124 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.5 CGI-I 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 125 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.6 SDS 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 126 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.7 CPFQ 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 127 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.8 PHQ-9 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 131 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 132 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 133 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 134 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 135 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.11 BPRS+ 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 136 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 137 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.12 C-SSRS 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 138 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 139 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 140 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.13 C-SSRS Since Last Visit 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 141 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 142 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 143 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.14 Mini-International Neuropsychiatric Interview (MINI) 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 144 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 145 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 146 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 147 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 148 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 149 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 150 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 151 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 152 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 153 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 154 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 155 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 156 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 157 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 158 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 159 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 160 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 161 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 162 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 163 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 164 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 165 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 166 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 167 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 168 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 169 of 199 
 
 
 
  
  
 
 
 
 
 
 
 
 
ng or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 170 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 171 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 172 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 173 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 174 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 175 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 176 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 177 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
C NFIDENTI L 
07 Jun 2024 
 
 
  
 
  
Page 178 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 179 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 180 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 181 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
11.15 Antidepressant Treatment Response Questionnaire (ATRQ) 
Non-Geriatric 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 182 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 183 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 184 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 185 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
Geriatric 
 
 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 186 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 187 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 
 
 
 
 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 188 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
 
 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 195 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
Dextromethorphan/Bupropion AUVELITY 
45/105 mg/day 
90/210 mg/day 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 196 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
12 
REFERENCES 
Abdallah, C. G., Averill, L. A., & Krystal, J. H. (2015). Ketamine as a promising 
prototype for a new generation of rapid-acting antidepressants. Ann N Y Acad Sci, 
1344, 66-77. doi:10.1111/nyas.12718 
Ahnaou, A., Huysmans, H., Biermans, R., Manyakov, N. V., & Drinkenburg, W. (2017). 
Ketamine: differential neurophysiological dynamics in functional networks in the 
rat brain. Transl Psychiatry, 7(9), e1237. doi:10.1038/tp.2017.198 
Banasr, M., Valentine, G. W., Li, X. Y., Gourley, S. L., Taylor, J. R., & Duman, R. S. 
(2007). Chronic unpredictable stress decreases cell proliferation in the cerebral 
cortex of the adult rat. Biol Psychiatry, 62(5), 496-504. 
doi:10.1016/j.biopsych.2007.02.006 
Bartova, L., Dold, M., Kautzky, A., Fabbri, C., Spies, M., Serretti, A. Kasper, S. (2019). 
Results of the European Group for the Study of Resistant Depression (GSRD) - 
basis for further research and clinical practice. World J Biol Psychiatry, 20(6), 
427-448. doi:10.1080/15622975.2019.1635270 
Bremner, J. D., Krystal, J. H., Putnam, F. W., Southwick, S. M., Marmar, C., Charney, D. 
S., & Mazure, C. M. (1998). Measurement of dissociative states with the 
Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress, 
11(1), 125-136. doi:10.1023/A:1024465317902 
Brunner, E., Tohen, M., Osuntokun, O., Landry, J., & Thase, M. E. (2014). Efficacy and 
safety of olanzapine/fluoxetine combination vs fluoxetine monotherapy following 
successful combination therapy of treatment-resistant major depressive disorder. 
Neuropsychopharmacology, 39(11), 2549-2559. doi:10.1038/npp.2014.101 
Clayton, A. H., McGarvey, E. L., & Clavet, G. J. (1997). The Changes in Sexual 
Functioning Questionnaire (CSFQ): development, reliability, and validity. 
Psychopharmacol Bull, 33(4), 731-745.  
Costall, B., Domeney, A. M., Gerrard, P. A., Kelly, M. E., & Naylor, R. J. (1988). 
Zacopride: anxiolytic profile in rodent and primate models of anxiety. J Pharm 
Pharmacol, 40(4), 302-305. doi:10.1111/j.2042-7158.1988.tb05254.x 
Desseilles, M., Dang-Vu, T. T., Sterpenich, V., & Schwartz, S. (2011). Cognitive and 
emotional processes during dreaming: a neuroimaging view. Conscious Cogn, 
20(4), 998-1008. doi:10.1016/j.concog.2010.10.005 
DSM-5. (2013). DSM-5: Diagnostic and statistical manual of mental disorders (5th ed.).  
Duncan, W. C., Jr., & Zarate, C. A., Jr. (2013). Ketamine, sleep, and depression: current 
status and new questions. Curr Psychiatry Rep, 15(9), 394. doi:10.1007/s11920-
013-0394-z 
Duncan, W. C., Sarasso, S., Ferrarelli, F., Selter, J., Riedner, B. A., Hejazi, N. S., Zarate, 
C. A. (2013). Concomitant BDNF and sleep slow wave changes indicate 
ketamine-induced plasticity in major depressive disorder. Int J 
Neuropsychopharmacol, 16(2), 301-311. doi:10.1017/S1461145712000545 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 197 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
Fava, M., Iosifescu, D. V., Pedrelli, P., & Baer, L. (2009). Reliability and validity of the 
Massachusetts general hospital cognitive and physical functioning questionnaire. 
Psychother Psychosom, 78(2), 91-97. doi:10.1159/000201934 
FDA. (2012). Guidance for Industry: Suicidal Ideation and Behavior: Prospective 
Assessment of Occurrence in Clinical Trials.  
FDA. (2019). FDA approves new nasal spray medication for treatment-resistant 
depression; available only at a certified doctor’s office or clinic.  
Guy, W. (1976). Clinical Global Impressions, ECDEU Assessment Manual for 
Psychopharmacology, revised (DHEW Publ. No. ADM 76-338). National 
Institute of Mental Health, Rockville, 218-222.  
Hamilton, M. (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry, 23, 
56-62. doi:10.1136/jnnp.23.1.56 
Hergueta, T., & Weiller, E. (2013). Evaluating depressive symptoms in hypomanic and 
manic episodes using a structured diagnostic tool: validation of a new Mini 
International Neuropsychiatric Interview (M.I.N.I.) module for the DSM-5 'With 
Mixed Features' specifier. Int J Bipolar Disord, 1, 21. doi:10.1186/2194-7511-1-
21 
Hoeffer, C. A., & Klann, E. (2010). mTOR signaling: at the crossroads of plasticity, 
memory and disease. Trends Neurosci, 33(2), 67-75. 
doi:10.1016/j.tins.2009.11.003 
Ignacio, Z. M., Reus, G. Z., Arent, C. O., Abelaira, H. M., Pitcher, M. R., & Quevedo, J. 
(2016). New perspectives on the involvement of mTOR in depression as well as 
in the action of antidepressant drugs. Br J Clin Pharmacol, 82(5), 1280-1290. 
doi:10.1111/bcp.12845 
Kato, T., Pothula, S., Liu, R. J., Duman, C. H., Terwilliger, R., Vlasuk, G. P., Duman, R. 
S. (2019). Sestrin modulator NV-5138 produces rapid antidepressant effects via 
direct mTORC1 activation. J Clin Invest, 129(6), 2542-2554. 
doi:10.1172/JCI126859 
Keller, A., McGarvey, E. L., & Clayton, A. H. (2006). Reliability and construct validity 
of the Changes in Sexual Functioning Questionnaire short-form (CSFQ-14). J Sex 
Marital Ther, 32(1), 43-52. doi:10.1080/00926230500232909 
Knoth, R. L., Bolge, S. C., Kim, E., & Tran, Q. V. (2010). Effect of inadequate response 
to treatment in patients with depression. Am J Manag Care, 16(8), e188-196.  
Kroenke, K., Spitzer, R. L., & Williams, J. B. (2001). The PHQ-9: validity of a brief 
depression severity measure. J Gen Intern Med, 16(9), 606-613. 
doi:10.1046/j.1525-1497.2001.016009606.x 
Li, N., Lee, B., Liu, R. J., Banasr, M., Dwyer, J. M., Iwata, M., Duman, R. S. (2010). 
mTOR-dependent synapse formation underlies the rapid antidepressant effects of 
NMDA antagonists. Science, 329(5994), 959-964. doi:10.1126/science.1190287 
Li, N., Liu, R. J., Dwyer, J. M., Banasr, M., Lee, B., Son, H., Duman, R. S. (2011). 
Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral 

 
CONFIDENTIAL 
07 Jun 2024 
NAV-17A-007, Amendment No. 4 
Version 5.0  
Page 199 of 199 
 
 This document is confidential. It contains proprietary information of Navitor Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing this study. 
adults. Am J Psychiatry, 168(12), 1266-1277. 
doi:10.1176/appi.ajp.2011.10111704 
Sengupta, S., Giaime, E., Narayan, S., Hahm, S., Howell, J., O'Neill, D., Saiah, E. (2019). 
Discovery of NV-5138, the first selective Brain mTORC1 activator. Sci Rep, 9(1), 
4107. doi:10.1038/s41598-019-40693-5 
Sheehan, D. V., Lecrubier, Y., Sheehan, K. H., Amorim, P., Janavs, J., Weiller, 
E., Dunbar, G. C. (1998). The Mini-International Neuropsychiatric Interview 
(M.I.N.I.): the development and validation of a structured diagnostic psychiatric 
interview for DSM-IV and ICD-10. J Clin Psychiatry, 59 Suppl 20, 22-33;quiz 
34-57.  
Spitzer, R. L., Kroenke, K., & Williams, J. B. (1999). Validation and utility of a 
self-report version of PRIME-MD: the PHQ primary care study. Primary Care 
Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA, 282(18), 
1737-1744. doi:10.1001/jama.282.18.1737 
Spitzer, R. L., Kroenke, K., Williams, J. B., & Lowe, B. (2006). A brief measure for 
assessing generalized anxiety disorder: the GAD-7. Arch Intern Med, 166(10), 
1092-1097. doi:10.1001/archinte.166.10.1092 
Trivedi, M. H., Rush, A. J., Wisniewski, S. R., Nierenberg, A. A., Warden, D., Ritz, L., 
Team, S. D. S. (2006). Evaluation of outcomes with citalopram for depression 
using measurement-based care in STAR*D: implications for clinical practice. Am 
J Psychiatry, 163(1), 28-40. doi:10.1176/appi.ajp.163.1.28 
Ventura J, L. D., Nuechterlein KH, Liberman RP, Green M, Shaner A. . (1993(b)). 
Appendix 1: Brief Psychiatric Rating Scale (BPRS) Expanded version (4.0) 
scales, anchor points and administration manual. . International Journal of 
Methods in Psychiatric Research, 3, 227-244.  
Williams, J. B. (1988). A structured interview guide for the Hamilton Depression Rating 
Scale. Arch Gen Psychiatry, 45(8), 742-747. 
doi:10.1001/archpsyc.1988.01800320058007 
Williams, J. B., & Kobak, K. A. (2008). Development and reliability of a structured 
interview guide for the Montgomery Asberg Depression Rating Scale (SIGMA). 
Br J Psychiatry, 192(1), 52-58. doi:10.1192/bjp.bp.106.032532 
Zanello, A., Berthoud, L., Ventura, J., & Merlo, M. C. (2013). The Brief Psychiatric 
Rating Scale (version 4.0) factorial structure and its sensitivity in the treatment of 
outpatients with unipolar depression. Psychiatry Res, 210(2), 626-633. 
doi:10.1016/j.psychres.2013.07.001 
Zarate, C. A., Jr., & Machado-Vieira, R. (2017). Ketamine: translating mechanistic 
discoveries into the next generation of glutamate modulators for mood disorders. 
Mol Psychiatry, 22(3), 324-327. doi:10.1038/mp.2016.249