A Randomized, Double-Blind Controlled Comparison of NRX-101 to Lurasidone for Adults With Bipolar Depression and Subacute Suicidal Ideation or Behavior
Phase: PHASE2
Conditions: Bipolar Depression, Suicidal Ideation and Behavior
Sponsor: NeuroRx, Inc.

 
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COVER PAGE 
 
Clinical Study Protocol 
NRX101-003 
 
 
 
Study Title: A Randomized, Double-Blind Controlled 
Comparison of NRX-101 to Lurasidone for Adults  
with Bipolar Depression and Subacute Suicidal  
Ideation or Behavior 
 
 
 
Principal Investigator 
Andrew Nierenberg, MD 
 
Study Sponsor 
NRx Pharma, Inc., Inc. 
1201 N Market Street; Suite 111 
Wilmington, DE  19801 
 
IND Number  
 
Phase 
 
Document Status  
129194 
 
2b 
 
Final 
 
Version, Date 
4.0 09NOV2023 
 
This document is the confidential property of NRx Pharmaceuticals, Inc. and may not  
be disclosed or used without the prior written consent of NRx Pharmaceuticals, Inc.  
 

 
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1. 
CONTACT INFORMATION 
Role in Study 
Name 
Telephone 
NeuroRx, Inc. Chief Scientist 
Jonathan C. Javitt, MD, MPH 
202-340-1352 
NeuroRx, Inc. Medical Monitor 
Martin Brecher, MD 
215-208-8580 
Principal Investigator 
Andrew Nierenberg, MD 
617-724-0837 
 
 
 

 
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2. 
Study Synopsis 
Name of 
Investigational 
Product: 
NRX-101 
Name of Active 
Ingredient: 
NRX-101: Oral capsule containing a fixed-dose combination of D-cycloserine 
(DCS) + lurasidone HCl (NRX-101)  
Reference 
Product(s):  Lurasidone HCl (“lurasidone”) + placebo 
Title of Study: A Randomized, Double-Blind, Controlled Comparison of NRX-101 to 
lurasidone for Treatment of Bipolar Depression in Adults with Subacute Suicidal 
Ideation or Behavior  
Short Title: Comparison of NRX-101 to Standard of Care for Bipolar Depression with 
Subacute Suicidal Ideation or Behavior 
Phase of 
Development: Phase 2b 
Study Sites: 10-20 sites located in the United States 
Total Patient 
Number: 74 participants  
Study Duration: Up to 10-weeks per patient: Screening 1 up to 10 days, Treatment from Day 1 to 
Day 42, and Follow-up on Day 70 
Background and 
Rationale: 
There is no currently-approved pharmacotherapy for patients with Severe 
Bipolar Depression and Suicidal Ideation or behavior. The purpose of this phase 
2b trial is to determine whether patients with Severe Bipolar Depression and 
subacute Suicidal Ideation or Behavior (i.e. those not requiring inpatient care) 
can be treated effectively with NRX-101. 
Objectives: Primary Objective: 
• 
To test the hypothesis that treatment with NRX-101 is superior to 
lurasidone (a standard of care medicine) in improving symptoms of 
depression as measured by the Montgomery Åsberg Depression Rating 
Scale (MADRS-10) total score in adults with severe bipolar depression 
and subacute suicidal ideation or behavior (SSIB). 
Key Secondary Objectives: 
• 
To test the hypothesis that NRX-101 is superior to lurasidone in 
reducing suicidal ideation or behavior as measured by the Clinical 
Global Impression of Severity of Suicidality Scale (CGI-SS). 
• 
To test the hypothesis that NRX-101 is superior to lurasidone in time to 
treatment failure as defined as: study discontinuation due to adverse 
events; psychiatric hospitalization; or requiring a change in 
antidepressant treatment. 

 
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Additional Secondary Objectives:  
• 
To test the hypothesis that treatment with NRX-101 is superior to 
standard of care (lurasidone) in reducing suicidal ideation (MADRS item 
10). 
• 
To test the hypothesis that treatment with NRX-101 is superior to 
lurasidone in reducing the frequency of suicidal thoughts, suicidality and 
risk (SIBAT Module 7). 
• 
To test the hypothesis that treatment with NRX-101 is superior to 
treatment with lurasidone in the subgroup of participants recently (i.e. 
within two weeks of enrollment) treated with approved medications for 
bipolar depression (olanzapine/fluoxetine, quetiapine, cariprazine, 
lumateprone, or lurasidone). 
Safety Objectives: 
• 
To test the hypothesis that treatment with NRX-101 is superior to 
lurasidone (a standard of care drug) in reducing suicidality in depressed 
bipolar patients with SSIB, as measured by the Columbia Suicide 
Severity Rating Scale (C-SSRS). 
• 
To test the hypothesis that participants treated with NRX-101 are less 
likely to suffer from akathisia than those treated with lurasidone as 
measured by the Barnes Akathisia Rating Scale (BARS). 
• 
To test the hypothesis that fewer participants treated with NRX-101 will 
be discontinued for lack of efficacy or exacerbation of suicidality than 
participants treated with lurasidone. 
Efficacy 
Endpoint(s): 
Primary Endpoint:  
• 
Change from baseline over 42 days in MADRS total score. 
Key Secondary Endpoints:  
• 
Change from baseline over 42 days in CGI-SS. 
• 
Time to treatment failure in each arm. 
Additional Secondary Endpoints:  
• 
Mean change from baseline in Suicidal Thoughts on the MADRS 
(MADRS item 10). 
• 
Change from baseline to Day 14 in MADRS total score. 
• 
Change from baseline in each item of the Suicide Ideation and Behavior 
Assessment Tool (SIBAT) Module 7 (clinical global impressions of 
frequency of suicidal thinking, severity of suicidality, and imminent and 
long-term risks). 
• 
Change from baseline to endpoint (Day 42/exit) in MADRS total score 
in the subgroup of participants who were recently (within 2-weeks) on 
approved medications for bipolar depression. 
• 
Percent in remission from suicidality at Day 42/exit (exploratory 
endpoint). 
Study Design: A multicenter, randomized, stratified, double-blind, parallel-group, two-arm 
outpatient study of 74 participants comparing NRX-101 to lurasidone in a 1:1 
ratio for the treatment of bipolar depression in participants with Subacute 
Suicidal Ideation or behavior and not requiring hospitalization, as reflected by a 

 
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rating of 3 or 4 on the C-SSRS at screening. A priori sample size suggests > 90% 
power based on effect size of >1 seen in phase 2 STABIL-B trial. There is 80% 
power to detect a 0.66 effect size; a 0.462 effect size would reach two-sided 
p=0.05. 
Two interim analyses are planned.  The first interim analysis (IA) assessing 
safety will be conducted six weeks after the first 30-35 participants have been 
followed for 6 weeks and the second IA assessing futility (primary efficacy 
endpoint) will be performed after the first 45-50 participants have been followed 
for 6 weeks.  
Each interim analysis has a different objective with neither interim analysis 
spending any Type 1 error.  The study will be stopped at the first interim 
analysis if Serious Adverse Events are deemed statistically significantly more 
common in the NRX-101 group compared to the lurasidone group in a manner 
deemed by the DMC to pose a potential danger to human subjects.  The study 
will be stopped at the second IA for futility if the conditional power (CP) is less 
than 10%.  In the event that the study is not stopped for either safety or futility, 
then enrollment will continue until a total of 74 subjects are randomized.  This 
preserves two-sided p=0.05 for the final analysis. 
 
Inclusion Criteria: A patient is eligible for inclusion in this study only if all of the following criteria 
apply: 
1. 18 to 65 years of age, inclusive, at Screening. 
2. Able to understand and provide written and dated informed consent prior 
to Screening.  
3. Deemed likely to comply with the study protocol, including 
communication of adverse events (AEs) and other clinically important 
information, including adherence to the text messaging component of 
the trial. 
4. Will follow medical directions for psychiatric care, as appropriate, per 
the standard of care.  
5. Resides in a stable living situation. A stable living situation will be 
defined as a minimum of 3 months at the same address with a 
reasonable expectation that the situation will continue such that the 
patient’s ability to participate in the study will not be affected. Please 
note that housing in a shelter of any kind will not be deemed stable 
housing. 
6. Previously diagnosed and treated for Bipolar Disorder (BD) I or II 
according to the criteria defined in the DSM-V. 
7. Has an identified reliable informant/care partner that is willing to 
provide information and/or supportive care as necessary. 
8. The diagnosis of BD will have been made by a psychiatrist or other 
qualified licensed psychiatric provider able to render a diagnosis and be 
supported by the MINI 7.0.2. 
9. Treatment with a medication indicated for use in bipolar disorder in the 
past five years (See Appendix 4 for list). 

 
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10. Confirmed active suicidal ideation, (without the intention to act) as 
evidenced by an answer of ‘Yes’ on item 3 and/or item 4 and not 
requiring hospitalization at Screening and an answer of “No” on item 5 
of the C-SSRS within 4-weeks of Screening. 
11. A total score greater than or equal to 30 on the 10 items of the MADRS. 
12. No co-morbidities as ascertained by medical history, physical 
examination (including measurement of vital signs), clinical laboratory 
evaluations, and electrocardiogram (ECG) which might interfere with 
compliance or the ability to assess efficacy or safety. 
13. If female, a status of non-childbearing potential or use of an acceptable 
form of birth control per the following criteria, and agrees to continue 
use of the same method of birth control for the duration of study 
participation: 
a. Non–childbearing potential: physiologically incapable of 
becoming pregnant (i.e., permanently sterilized [status post-
hysterectomy, bilateral tubal ligation], or post-menopausal with 
last menses at least one year prior to Screening); or 
b. Childbearing potential, and meets the following criteria: 
i. Use of any form of hormonal birth control for at least 
2 months prior to Screening, on hormone replacement 
therapy that started prior to 12 months of amenorrhea, 
using an intrauterine device (IUD) for at least 1 month 
prior to Screening, in a monogamous relationship with a 
partner who has had a vasectomy, or sexually abstinent.  
ii. Negative urinary pregnancy test at Screening, confirmed 
by a second negative urinary pregnancy test at Day 1, 
prior to receiving study treatment. 
14. Body mass index (BMI) between 18-40 kg/m2; BMI up to 45 kg/m2 is 
allowed with Medical Monitor review and approval. 
15. If receiving concurrent psychotherapy, the type and frequency of the 
therapy (e.g., weekly or monthly) has been stable for at least 3 months 
prior to Screening and is expected to remain stable for the duration of 
study participation. 
16. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, 
benzodiazepines, maximum 2 mg daily, or trazodone) will be allowed if 
the therapy has been stable for at least 4-weeks prior to screening and if 
it is expected to remain stable during the course of the patient’s 
participation in the study.  
17. Concurrent treatment with benzodiazepines is allowed up to a maximum 
dose 2mg/daily used for anxiety if therapy has been stable relative to 
dose and schedule for at least four-weeks prior to screening and if it is 
expected to remain stable during the course of the patient’s participation 
in the study.  
18. If women are receiving hormone replacement therapy or estrogen 
replacement, the therapy has been stable for at least 3 months prior to 
screening and is expected to remain stable for the duration of the study 
participation. 

 
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Exclusion criteria: A patient is ineligible for inclusion in this study if any of the following criteria 
apply: 
1. Female of childbearing potential who is not willing to use one of the 
specified forms of birth control during the study. 
2. Female who is pregnant or breastfeeding. 
3. Female with a positive pregnancy test at Screening or prior to 
randomization. 
4. Current DSM-5 diagnosis of moderate or severe substance use disorder 
(except marijuana or tobacco use disorder) within the 12 months prior to 
Screening. (Note: Substance use disorder cannot be the precipitant for 
study entry). 
5. A lifetime history of  
a.  phencyclidine (PCP)/ketamine drug abuse, or 
b.  failed use of ketamine for depression or suicidality. 
6. History of schizophrenia or schizoaffective disorder, or any history of 
psychotic symptoms when not in an acute bipolar mood episode. 
7. History of anorexia nervosa, bulimia nervosa, eating disorder not 
otherwise specified (NOS), or other specified feeding and eating 
disorders (OSFED) within 3 years of Screening.  
8. Has dementia, delirium, amnestic, or any other cognitive disorder. 
9. Current major psychiatric disorder, diagnosed at Screening with the 
MINI 7.0.2 which is the primary focus of treatment, with bipolar 
disorder as the secondary focus of treatment, within the past 6 months.  
10. Estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 
using the Cockcroft-Gault formula. 
11. A clinically significant abnormality on the Screening physical 
examination that may affect safety or study participation, or that may 
confound interpretation of study results according to the study clinician. 
12. Current episode of: 
a. Myocardial infarction within 1 year of Screening. 
b. Diagnosis of angina pectoris. 
c. Prolonged QTc interval, as measured by Fridericia’s correction 
formula (QTcF) ≥450 msec at Screening for males or ≥ 470 
msec for females on 2 of 3 measurements at least 15 minutes 
apart prior to randomization on Day 1. 
13. Diagnosis of chronic lung disease, excluding asthma. 
14. Lifetime history of any of the following: surgical procedures involving 
the brain or meninges, encephalitis, meningitis, degenerative central 
nervous system (CNS) disorder (e.g., Alzheimer’s Disease, Parkinson’s 
Disease), epilepsy, mental retardation, or any other 
disease/procedure/accident/intervention that, according to the clinician, 
is deemed associated with significant injury to, or malfunction of, the 
CNS. 
15. History of significant head trauma within the past two years. 

 
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16.  Diabetes mellitus fulfilling any of the following criteria: 
a. Unstable diabetes mellitus defined as glycosylated hemoglobin 
(HbA1c) >8.0 percent at Screening. 
b. Admitted to the hospital for treatment of diabetes mellitus or 
diabetes mellitus–related illness in the past 12 weeks. 
c. Not under physician care for diabetes mellitus. 
d. Not on the same dose of oral hypoglycemic drug(s) and/or diet 
for the 4 weeks prior to Screening.  
e. Not on the same dose of oral thiazolidinediones (glitazones) for 
the 8 weeks prior to Screening.  
17. Any current or past history of any physical condition which, in the 
opinion of the investigator, may put the patient at risk or interfere with 
study results interpretation. 
18. Diagnosis of HIV/AIDS. 
19. Diagnosis of Hepatitis C. 
20. On exclusionary concomitant psychotropic and non-psychotropic 
medications (see Appendix 1).  
21. Prescribed more than one agent in each of the following categories at 
randomization: 
a. Approved SSRIs. 
b. Approved serotonin and norepinephrine reuptake inhibitors 
(SNRIs). 
c. Approved tetracyclic antidepressants (TeCAs). 
Note: Any/all 5hT2A medications will be discontinued at study entry.  
Participants currently on Lurasidone will be randomized to either 
standard of care or NRX-101 at the indicated starting dose. 
22. Currently prescribed oxcarbazepine or carbamazepine. 
23. Exclusionary laboratory values or any other clinically significant 
abnormal laboratory result at Screening. Within normal limits (WNL) 
will be determined based on lab values of the local lab used. 
24. Known allergies to lurasidone or Latuda®, cycloserine or Seromycin®, or 
the following excipients: mannitol, croscarmellose sodium, magnesium 
stearate, silicon dioxide, and/or hydroxypropylmethylcellulose (HPMC). 
25. Participation in any clinical trial with an investigational drug or device 
within the past month or planned concurrent study participation. 
26. Study site personnel and/or persons employed by NRx Pharma, Inc., the 
Contract Research Organization (CRO), the investigator, or study site 
(i.e., permanent, temporary contract worker, or designee responsible for 
the conduct of the study), or an immediate family member (i.e., spouse, 
parent, child, or sibling [biological or legally adopted]) of such persons. 
27. Positive urine toxicity screening for use of any cocaine, opiates, non-
prescribed amphetamines, or non-prescribed barbiturates. (Note: 
cannabinoids or marijuana use is not exclusionary, unless patient meets 
the DSM-5 criteria for cannabis withdrawal). 

 
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28. Signs and symptoms of active or residual COVID-19, or unresolved 
symptoms of COVID-19 that impact health, e.g. requirements for 
oxygen supplementation, etc. Discharged from an inpatient 
hospitalization for more than 48 hours for COVID-19 within the past 28 
days. 
Analysis Sets: For efficacy analyses, the intent-to-treat (ITT) population is defined as all 
participants who are randomized and receive at least one dose of investigational 
product and have evaluable data from at least one subsequent visit. For safety 
analyses; the Safety population will include data from all participants who are 
randomized and receive at least one dose of investigational product. 
Pharmacokinetic 
Assessments: None 
Safety 
Assessments: 
The safety of NRX-101 will be assessed via: 
• 
Adverse Events 
• 
Vital signs (blood pressure, heart rate), weight  
• 
12-lead ECGs 
• 
Clinical laboratory evaluations 
• 
Physical examination findings 
Other Assessments: 
• 
Mean change from baseline to endpoint (Day 42/exit) in C-SSRS score 
• 
Mean change from baseline to Day 14 in C-SSRS score 
• 
Mean change in BARS through Day 42 to assess akathisia 
• 
Rates of discontinuation between arms 
Dosage, Route of 
Administration, 
and Schedule: 
On Day 1, eligible participants will be randomized to blinded NRX-101 or 
lurasidone and placebo capsules administered twice daily (BID).  
Investigational product will be titrated over 2 days. In the case of randomization 
to NRX-101, the blinded investigational product will consist of daily doses of 
700 mg DCS and 33 mg lurasidone and increasing the dose to 950 mg DCS and 
66 mg lurasidone on second day. The total daily NRX-101 maintenance dose for 
Day 3 through Day 42 is 950 mg DCS and 66 mg lurasidone. In the event a 
patient experiences agitation or psychosis, a blinded up-titration is permitted. 
Similarly, a blinded step-down titration is allowed for somnolence. In order to 
maintain the blind, lurasidone/placebo capsules will be administered to ensure 
participants take the same number of capsules with each dose administration. 
NRX-101 is supplied in capsules that contain 237.5 mg or 175 mg of DCS and a 
second capsule that contains 8.25 mg, 16.5 mg, or 33 mg of lurasidone. In order 
to maintain the blind, lurasidone/placebo capsules will be administered to ensure 
participants take the same number of capsules with each dose administration. 
In the case of randomization to lurasidone, the blinded investigational product 
will start with doses of 33 mg lurasidone and increasing the dose to 66 mg. The 
total daily lurasidone maintenance dose for Day 3 through Day 42 is 66 mg.  
Endpoint 
Adjudication 
All rating sessions for MADRS-10 and C-SSRS will be recorded as audio files 
and reviewed by central master-raters with >25 years’ experience. Any MADRS-
10 total score the differs by more than three points from the master-rater score 

 
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will be deemed non-congruent. All non-congruent subject-visits from any site 
with >10% non-congruent scores will be sent to an independent adjudicator 
previously determined to have >90% concordance with study master raters on 
standardized training data. In the event of adjudication as above, the independent 
outside rater score shall be considered as the subject-visit primary study 
endpoint. 
Statistical 
Methods: 
All randomized participants will be evaluated for depression (MADRS) 
suicidality (C-SSRS), and other efficacy endpoints while on the study.  Analyses 
will be conducted under ICH E9 (R1) guidelines. 
Change from baseline in MADRS total scores through study exit to compare 
treatments will be analyzed using Mixed Model Repeated Measures analysis 
(SAS PROC MIXED) with Last Observation Carried Forward (LOCF) 
containing BPI rating scale (none, any) and evidence of a suicidal event in their 
lifetime (none, any) as stratification factors. Additional analyses will 
alternatively rely on multiple imputation to assess the impact of dropouts. The 
NRX-101 and lurasidone treatment groups will be compared using stratified and 
unstratified log rank tests, as well as a proportional hazard model for time to 
relapse.  
Sample Size 
Calculation: 
Participants will be randomized in a 1:1 ratio (NRX-101:lurasidone). With 37 
participants per group, there is an 80 percent power to detect a mean 8.85-unit 
advantage for NRX-101 vs lurasidone for the CFB to Day 42, assuming a SD of 
13.4 for NRX-101 versus lurasidone at 6 weeks for a two-sided hypothesis test 
with two-sided 5 percent Type I error. This equates to a 0.66 effect size. 
Interim Analysis  Two interim analyses are planned.  The first interim analysis (IA) assessing 
safety will be conducted six weeks after the first 30-35 participants have been 
followed for 6 weeks and the second IA assessing futility (primary efficacy 
endpoint) will be performed after the first 45-50 participants have reached 42 
days post-randomization.  
Each interim analysis has a different objective with neither interim analysis 
spending any Type 1 error.  The study will be stopped at the first interim 
analysis if Serious Adverse Events are deemed statistically significantly more 
common in the NRX-101 group compared to the lurasidone group in a manner 
deemed by the DMC to pose a potential danger to human subjects.  The study 
will be stopped at the second IA for futility if the conditional power (CP) is less 
than 10%.  In the event that the study is not stopped for either safety or futility, 
then enrollment will continue until a total of 74 subjects are randomized.  This 
preserves two-sided p=0.05 for the final analysis. 
 
 
 

 
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3. 
PROTOCOL SIGNATURE PAGE 
I have read this protocol and agree to adhere to the requirements. I will provide copies of this 
protocol and all pertinent information to the study personnel under my supervision. I will discuss 
this material with them and ensure they are fully informed regarding the conduct of the study 
according to 21 Code of Federal Regulations (CFR) parts 50, 54, 56 and 812, 45 CFR 46, to Good 
Clinical Practice (GCP), as described in International Conference on Harmonisation (ICH) 
guidelines E6 and E, and to Institutional Review Boards. 
 
 
 
_____________________________________ 
 
_________________________ 
Clinical Site Investigator Signature  
 
 
Date 
 
 
_____________________________________ 
Clinical Site Investigator Printed Name 
 
 
_____________________________________ 
 
_________________________ 
Sponsor Signature 
 
Jonathan C. Javitt, MD, MPH 
Chief Scientist  
 
_____________________________________ 
 
_________________________ 
Sponsor Signature 
 
Andrew Nirenberg, MD 
Principal Investigator 
 
 

 
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4. 
TABLE OF CONTENTS 
COVER PAGE.................................................................................................................................1 
1. 
CONTACT INFORMATION ..................................................................................................2 
2. 
STUDY SYNOPSIS ................................................................................................................3 
3. 
PROTOCOL SIGNATURE PAGE .......................................................................................11 
4. 
TABLE OF CONTENTS .......................................................................................................12 
4.1 
List of Tables ....................................................................................................................15 
4.2 
List of Figures ...................................................................................................................15 
5. 
ABBREVIATIONS ...............................................................................................................16 
6. 
INTRODUCTION .................................................................................................................18 
6.1 
Suicidal Ideation and Behavior in Bipolar Disorder ........................................................18 
6.2 
Current Treatment Options ...............................................................................................18 
6.3 
Preclinical Models of Anxiety and Akathisia ...................................................................19 
6.4 
Clinical Experience with DCS ..........................................................................................19 
6.5 
Investigational Therapy ....................................................................................................21 
6.6 
Dose Selection ..................................................................................................................21 
7. 
OBJECTIVES ........................................................................................................................22 
7.1 
Primary Objective .............................................................................................................22 
7.2 
Key Secondary Objectives ................................................................................................22 
7.3 
Additional Secondary Objectives .....................................................................................22 
7.4 
Safety Objectives ..............................................................................................................23 
7.5 
Overview ..........................................................................................................................23 
8. 
SELECTION OF PARTICIPANTS ......................................................................................24 
8.1 
Inclusion Criteria ..............................................................................................................24 
8.2 
Exclusion Criteria .............................................................................................................25 
9. 
STUDY VISITS .....................................................................................................................28 
9.1 
Study Visits.......................................................................................................................28 
9.1.1 Screening Period ....................................................................................................... 30 
9.1.2 Treatment and Follow-up Periods ............................................................................. 30 
9.1.3 Early Termination Visit ............................................................................................ 31 
10. TREATMENT OF PARTICIPANTS ....................................................................................31 
10.1 Investigational Drug Dose and Administration ................................................................31 
10.2 Investigational Product .....................................................................................................31 

 
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10.3 Investigational Product Titration ......................................................................................32 
11. INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT ........................33 
11.1 Packaging and Labeling ....................................................................................................33 
11.1.1 Storage ...................................................................................................................... 35 
11.1.2 Accountability ........................................................................................................... 35 
11.1.3 Handling and Disposal .............................................................................................. 35 
11.2 Study Drug Monitoring ....................................................................................................35 
12. EFFICACY ASSESSMENTS ...............................................................................................35 
12.1 Montgomery Asberg Depression Rating Scale (MADRS)...............................................35 
12.2 Clinical Global Impression-Severity for Suicide ..............................................................36 
12.3 Brief Psychiatric Rating Scale (BPRS psychosis subscale) .............................................36 
12.4 Concise Health Risk Tracking – Self Report (CHRT-SR) and Clinician Rating 
(CHRT-C).........................................................................................................................36 
13. OTHER DIAGNOSTIC INSTRUMENTS ............................................................................36 
13.1 Mini International Neuropsychiatric Interview (MINI) 7.0.2 ..........................................36 
13.2 Bipolarity Index (BPI) ......................................................................................................36 
14. ASSESSMENT OF EFFICACY ...........................................................................................37 
14.1 Primary Efficacy Endpoint ...............................................................................................37 
14.2 Key Secondary Efficacy Endpoints ..................................................................................37 
14.3 Additional secondary efficacy endpoints: ........................................................................37 
15. ASSESSMENT OF SAFETY ................................................................................................37 
15.1 Safety Scales .....................................................................................................................37 
15.1.1 Columbia Suicide Severity Rating Scale (C-SSRS) ................................................. 37 
15.1.2 Patient Rated Inventory of Side Effects (PRISE) ..................................................... 38 
15.1.3 Barnes Akathisia Scale (BARS) ............................................................................... 38 
15.2 Adverse Events and Serious Adverse Events ...................................................................38 
15.2.1 Definition of Adverse Events .................................................................................... 38 
15.2.2 Adverse Event Intensity and Relationship ................................................................ 39 
15.2.3 Recording of Adverse Events ................................................................................... 40 
15.2.4 Definition of Serious Adverse Events ....................................................................... 40 
15.2.5 Reporting Serious Adverse Events ........................................................................... 41 
15.2.6 Anticipated Serious Adverse Events ......................................................................... 41 
15.3 Concomitant Medications, Therapies, and Alcohol Restrictions .....................................42 

 
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15.3.1 Concomitant Medications ......................................................................................... 42 
15.3.2 Concomitant Therapy ................................................................................................ 43 
15.3.3 Alcohol Restrictions .................................................................................................. 43 
15.3.4 Positive Drug Screen ................................................................................................. 43 
15.4 Laboratory/Diagnostic Procedures ...................................................................................44 
15.5 Physical Examinations, Vital Signs, Height, and Weight ................................................44 
15.6 Electrocardiograms ...........................................................................................................44 
15.7 Study Monitoring by the Drug Safety Monitoring Board (DSMB) .................................44 
16. STATISTICS .........................................................................................................................45 
16.1 Randomization ..................................................................................................................45 
16.2 Study Populations .............................................................................................................45 
16.3 Hypothesis Tests ...............................................................................................................45 
16.3.1 Treatment Comparisons ............................................................................................ 45 
16.3.2 Primary Hypothesis ................................................................................................... 45 
16.3.3 Key Secondary Hypotheses ...................................................................................... 46 
16.4 Efficacy Endpoints ...........................................................................................................47 
16.4.1 Primary Efficacy Endpoints ...................................................................................... 47 
16.4.2 Secondary Efficacy Endpoints .................................................................................. 47 
16.4.3 Other Exploratory Efficacy Endpoints ...................................................................... 47 
16.4.4 Other Efficacy Endpoints of Interest ........................................................................ 48 
16.4.5 Diagnostic Metric ...................................................................................................... 48 
16.5 Safety Assessments...........................................................................................................48 
16.5.1 Overall Adverse Events ............................................................................................ 48 
16.5.2 Other Safety Measures .............................................................................................. 49 
16.6 Sample Size Calculations .................................................................................................49 
16.6.1 Background ............................................................................................................... 49 
16.6.2 Power and Significance ............................................................................................. 49 
16.6.3 Interim Analyses ....................................................................................................... 50 
16.7 Adjudication of Primary Endpoint ...................................................................................50 
16.8 Statistical Analysis Approach ...........................................................................................51 
16.8.1 Software .................................................................................................................... 51 
16.8.2 Display Formats ........................................................................................................ 51 
16.8.3 Conventions .............................................................................................................. 51 

 
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16.8.4 Estimand Structure .................................................................................................... 51 
16.8.5 General Methodology ............................................................................................... 53 
16.8.6 Other Time to Event Efficacy Endpoints .................................................................. 53 
16.8.7 Secondary Efficacy Endpoints .................................................................................. 54 
16.8.8 Other Endpoints of Interest ....................................................................................... 54 
16.8.9 Safety Endpoints ....................................................................................................... 55 
17. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................................................55 
17.1 Study Monitoring ..............................................................................................................55 
17.2 Audits and Inspections......................................................................................................57 
17.3 Institutional Review Board (IRB).....................................................................................57 
18. QUALITY CONTROL AND QUALITY ASSURANCE .....................................................57 
18.1 Source Data and Records ..................................................................................................57 
18.2 Reporting Study Data .......................................................................................................58 
18.2.1 Clinical Trial Registry ............................................................................................... 58 
18.3 Confidentiality of Patient Data .........................................................................................58 
19. ETHICAL CONSIDERATIONS ...........................................................................................59 
19.1 Ethical Conduct of the Study ............................................................................................59 
19.2 Patient Information and Consent ......................................................................................59 
20. REFERENCES ......................................................................................................................60 
21. APPENDICES .......................................................................................................................63 
 
4.1 
List of Tables 
Table 1  
Schedule of Assessments .......................................................................................... 29 
Table 2  
NRX-101 Dose Titration ........................................................................................... 32 
Table 3  
Lurasidone Dose Titration ........................................................................................ 32 
Table 4 
NRX-101 Blinded Kits ............................................................................................. 33 
Table 5 
Lurasidone Blinded Kits ........................................................................................... 34 
Table 6 
MADRS-10 Change From Baseline Outcomes: T-tests .......... Error! Bookmark not 
defined. 
 
4.2 
List of Figures 
Figure 1 
DCS vs. Placebo for Treatment of Depression ......................................................... 20 

 
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Figure 2 
Randomization to NRX-101 vs. lurasidone following stabilization with ketamine . 21 
Figure 3 
Study Schema ............................................................................................................ 23 
5. 
ABBREVIATIONS 
Table of Abbreviations 
Full Terms 
ACPC 
Aminocyclopropanecarboxylic Acid 
AE 
Adverse Event 
SSIB 
Subacute Suicidal Ideation or Behavior 
BARS 
Barnes Akathisia Rating Scale 
BDRM 
Biostatistics Data Review Meeting 
BID 
Twice Daily 
BMI 
Body Mass Index 
BPI 
Bipolarity Index 
BPRS(+) 
Brief Psychiatric Rating Scale(+) 
CFB 
Change from Baseline 
CFR 
Code of Federal Regulations 
CGI-SS 
Clinical Global Impressions of Severity for Suicidality 
CHF 
Congestive Heart Failure 
CHRT-C 
Concise Health Risk Tracking-Clinician 
CHRT-SR 
Concise Health Risk Tracking-Self Report 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum Concentration 
CNS 
Central Nervous System 
CP 
Conditional Power 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DCS 
D-cycloserine 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
ECT 
Electroconvulsive Therapy 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Glycosylated Hemoglobin 
HDPE 
High Density Polyethylene 

 
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Table of Abbreviations 
Full Terms 
HIPAA 
Health Insurance Portability and Accountability Act 
HPMC 
Hydroxymethylcellulose 
ICH 
International Conference on Harmonisation 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IWRS 
Interactive Web Response System 
Lurasidone 
Lurasidone HCl 
LOCF 
Last Observation Carried Forward 
MADRS 
Montgomery Asberg Depression Rating Scale  
MDD 
Major Depressive Disorder 
MMRM 
Mixed Model Repeated Measures 
NMDAR 
N-methyl-D-aspartate Receptor 
NOS 
Not Otherwise Specified 
OSFED 
Other Specified Eating Disorder 
PCP 
Phencyclidine 
PRISE 
Patient Rated Inventory of Side Effects 
QTcF 
Fridericia’s Correction Formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIBAT 
Suicide Ideation and Behavior Assessment Tool 
SNRI 
Serotonin and Norepinepherine Reuptake Inhibitors 
SOP 
Standard Operating Procedure 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TB 
Tuberculosis 
TeCA 
Tetracyclic Antidepressant 
TTF 
Time to Treatment Failure 
 
 
 
 

 
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6. 
INTRODUCTION 
6.1 
Suicidal Ideation and Behavior in Bipolar Disorder 
Bipolar Disorder (formerly known as manic depressive disorder) is a well-established psychiatric 
diagnosis, with a prevalence of about 2.6% in the United States (approximately 8.5 million people) 
(Kessler et al., 2005). The risk of subacute suicidal ideation or behavior (SSIB) is uniquely high 
in patients during bipolar depressive episodes, compared to those with major depressive disorder 
(MDD), thought disorders, and personality disorders. Lifetime suicide behavior occurs in 25% to 
56% of people with bipolar disorder (Nierenberg et al., 2001). About 40% of the nearly 50,000 
annual deaths from suicide in the United States are associated with bipolar disorder (Mahli et al., 
2015). The overall rate of death by suicide among patients with bipolar disorder is 164 per 100,000 
person years, compared to about 14 per 100,000 person years for the general population. Those 
who have attempted suicide are 2.3 times more likely to die by suicide compared to those without 
a suicide attempt (Coryell et al., 2016). Thus, bipolar depression with suicidal ideation has 
uniquely lethal clinical characteristics (Pompili, et al., 2013). 
6.2 
Current Treatment Options 
Despite its lethal characteristics, there is no approved pharmacologic treatment for patients with  
bipolar depression and suicidal ideation. Electroconvulsive therapy (ECT), often combined with 
inpatient psychiatric care, remains the only Food and Drug Administration (FDA)-approved 
treatment for patients with acute suicidal ideation in bipolar depression, despite ECT’s well-
documented side effects that include memory loss and confusion, along with its high cost. 
However, the toxicity of ECT is such that it is less likely to be used in patients with subacute levels 
of suicidal ideation and no oral medication has been shown to reduce suicidal ideation in patients 
with depression in general or bipolar depression in specific. Physicians are increasingly cautious 
about the use of selective serotonin release inhibitors (SSRIs), particularly in patients with  suicidal 
ideation because of evidence that SSRIs and other antidepressants may actually increase the risk 
of suicidal ideation, particularly in younger patients (Stone et al., 2009). This evidence has resulted 
in an FDA warning on the label of current antidepressants. Moreover, it seems clear that 
antidepressants do not decrease SSIB in proportion to their mitigating effect on symptoms of 
depression.  
In recent years, several combined D2/5-HT2A antagonists have shown efficacy in treating bipolar 
depression (olanzapine/fluoxetine combination, quetiapine, and lurasidone) with treatment 
guidelines endorsing common use as first-line standard of care treatment in acute bipolar 
depression. While these medications are effective at reducing overall symptoms of depression, 
they do not specifically reduce suicidal ideation, as shown in recent clinical trials of lurasidone 
(Loebel et al., 2014a; Loebel et al., 2014b). Moreover, in these two studies, individuals with active 
suicidal ideation (Montgomery Asberg Depression Rating Scale [MADRS] item 10 ≥ 4) were 
specifically excluded because of concerns regarding the possibility of exacerbating suicidality with 

 
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these medications. Similarly, acutely suicidal patients are routinely excluded from clinical trials of 
other experimental anti-depressive agents. Thus, bipolar depression with suicidal ideation 
represents a major unmet medical need that must frequently be treated with voluntary or 
involuntary hospitalization under highly supervised conditions and ECT. 
6.3 
Preclinical Models of Anxiety and Akathisia  
Although the mechanisms mediating antidepressant-related increases in suicide remain unclear, 
leading theories suggest that increases in anxiety/akathisia may play a critical role (Harada et al., 
2014; Popovic et al., 2015). Serotonin-related anxiety/akathisia may be modeled in rodents using 
several well-established assay systems, such as the elevated plus maze, and are known to be 
sensitive to serotonergic agents (Sachdev and Brune, 2000). In this assay, reduced percent time 
spent in the open arms of the maze is believed to be associated with increased akathisia and anxiety. 
In contrast, increased total distance traveled in the maze is thought to be a signal related to 
psychosis. As shown by Javitt (2014), D-cycloserine (DCS) significantly reduces the anxiogenic 
effects of lurasidone and quetiapine, as measured by time spent in open arms, suggesting that this 
treatment might reduce medication-induced suicidality, as well as suicidality associated with 
bipolar depression itself.  
Preclinical data, using the Rodent Akathisia model, suggests a potential synergistic interaction 
between DCS and lurasidone. On one hand, as described above, DCS appears to block the 
anxiogenic effects of lurasidone. On the other hand, lurasidone may reverse low-level 
psychotomimetic effects of DCS. Lurasidone mediates its antipsychotic effects at both D2 and 5-
HT2A receptors. As opposed to pure serotonergic agents used in the treatment of major depressive 
disorders (e.g., SSRIs), the additional D2 blockade of lurasidone makes it a clinically effective 
antipsychotic; thus, it could also be effective in treating the psychotic symptoms that may be 
induced by an N-methyl-D-aspartate receptor (NMDAR) antagonist. 
Clearly, the phenomena observed in rodents should not be viewed as isomorphic with drug-
induced akathisia and/or restlessness/anxiety syndrome in humans. However, these findings 
provide a rationale for combining glycine site-binding NMDAR antagonists with 5-HT2A 
antagonists in phase 2 and 3 studies of otherwise-safe drugs for the treatment of bipolar depression. 
This is particularly true in situations where akathisia is believed to predispose vulnerable patients 
to suicide. 
6.4 
 Clinical Experience with DCS 
Antidepressant effects of high-dose DCS were first noted in the late 1950s, when it was introduced 
as a treatment for tuberculosis (TB). Several clinicians noted dramatic improvement in patients’ 
depressive symptoms, leading to suggestions of DCS’ potential psychotropic effects. These effects 
were subsequently confirmed in small-scale clinical studies (Crane, 1959 and 1961). The 
mechanism of action was unknown at the time, and the finding was not pursued. The interaction 
of DCS with the NMDAR was first demonstrated in 1989 (Hood et al., 1989), leading to some 

 
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interest in NMDAR blockers as potential antidepressant treatments (Trullas and Skolnick, 1990; 
Skolnick 
et 
al., 
1996). 
For 
example, 
both 
DCS 
and 
the 
related 
compound 
aminocyclopropanecarboxylic acid (ACPC) were shown to be active in mice, using the forced 
swim test for depression (Lopes et al., 1997). To the best of our knowledge, no clinical 
antidepressant research programs targeting the NMDA receptor were initiated at that time. 
Interest in the potential clinical use of DCS as an antidepressant agent was renewed following 
Berman’s fortuitous observation of ketamine’s rapid antidepressant effect (Berman et al., 2000). 
An initial study performed with DCS at a dose of 250 mg/day did not show therapeutic effects, but 
it did demonstrate a relative lack of psychotomimetic side effect when DCS was combined with 
concurrent antidepressant treatment (Heresco-Levy et al., 2006). Based upon these safety data, a 
study using a higher dose of 1000 mg/day was initiated, with results reported in 2013 (Heresco-
Levy et al., 2013). At the higher dose of 1000 mg/day, significant beneficial effects were observed 
in 13 subjects vs. placebo control with SSRI-nonresponsive depressive symptoms. The 
improvements were manifested within 2 weeks and persisted throughout the 6-week treatment 
period. These data suggest a >0.9 effect size. In that study, a slow DCS titration was used, with 
250 mg/day for 3 days, followed by 500 mg/day for 18 days (i.e., until the end of week 3); followed 
by 750 mg/day for 1 week (i.e., until the end of week 4), followed by 1000 mg/day (i.e., until the 
end of study). A statistically significant improvement was observed in the DCS group compared 
to placebo by the end of week 4, i.e., within 1 week of initiation of a DCS dose >500 mg/day (see 
Figure 1). 
Figure 1 
DCS vs. Placebo for Treatment of Depression 
 
Source: Heresco-Levy et al., 2013 
 
The data above provided initial evidence that DCS may be useful as an NMDAR-targeted 
antidepressant, but the time of onset for DCS alone was suboptimal for treating acutely depressed 
individuals (Figure 1).  

 
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The data below provides evidence of efficacy from a study of NRX-101 versus Lurasidone in 
patients with severe bipolar depression (MADRS ≥ 30) and Acute Suicidal Ideation or behavior 
(C-SSRS 4, or 5), after an initial stabilization with a single infusion of ketamine. 
Figure 2 
Randomization to NRX-101 vs. lurasidone following stabilization with 
ketamine 
 
Source: Javitt et. al. 2018 
6.5 
Investigational Therapy 
In accordance with FDA experience with lurasidone being used to successfully treat depression in 
bipolar disorder, participants will be randomized on Day 1 in a 1:1 ratio (NRX-101:lurasidone + 
placebo) and will receive maintenance treatment with matched twice-daily oral capsules. 
Participants will continue oral therapy through Day 42, according to treatment assignment.  
It is anticipated that participants will also be receiving concurrent bipolar disorder–directed 
treatment with various predefined combinations of medications. This treatment regimen will be 
maintained upon entry into the study. However, any use of lurasidone, quetiapine, aripiprazole, 
risperidone, brexpiprazole, olanzapine, cariprazine, or lumateperone, will be discontinued at study 
entry. The treating psychiatrist should ensure that any medications to be discontinued can be done 
so safely. At entry, at the discretion of the investigators or the delegated treating physician subjects 
may continue their mood stabilizers which should not change over the course of the trial. In 
addition, participants receiving olanzapine/fluoxetine combination will continue to receive the 
fluoxetine component. 
6.6 
 Dose Selection 
Lurasidone is an FDA-approved medication for depressive episodes associated with Bipolar I 
Disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate 
at doses of 20 mg to 120 mg daily. The target dose of 66 mg/day is based on the mean daily dose 

 
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of lurasidone observed during the fixed titration phase of the lurasidone registration trial for its 
indication in bipolar depression (Loebel et al., 2014b) and further validated in the STABIL-B trial 
(Javitt, et. al. 2018). Up-titrations are permitted if needed to doses of 99 or 132 mg/day, and down-
titrations are permitted to 33 or 49.5 mg/day, which span the range of doses used in clinical studies 
of lurasidone (Loebel et al., 2014a; Loebel et al., 2014b). 
DCS is well tolerated as a second-line treatment for TB at therapeutic split daily oral doses in the 
range of 500 to 1000 mg/day. Based on prior clinical results and animal studies, it is anticipated 
that therapeutic effects of DCS will be associated with plasma doses in excess of 25 μg/mL, which 
in turn are generally associated with daily oral doses in excess of 10 mg/kg (i.e., 700 mg/day for a 
70 kg) individual. A starting daily dose at 700 mg DCS and 33 mg lurasidone will be used, and 
then titrated over 2 days to the target dose of 950 mg DCS and 66 mg lurasidone. Down-titrations 
of DCS to 825 or 700 mg/day are available in the case of side effects to permit reduced dosing 
within the anticipated therapeutic range (700 – 950 mg/day). The maximum dose of 950 mg/day 
is within FDA-approved dosing limits for DCS. 
7. 
OBJECTIVES 
7.1 
 Primary Objective 
The primary objective of the study is: 
• To test the hypothesis that treatment with NRX-101 is superior to lurasidone (a standard 
of care medicine) in improving symptoms of depression as measured by the Montgomery 
Åsberg Depression Rating Scale (MADRS-10) total score in participants with severe 
bipolar depression and subacute suicidal ideation or behavior (SSIB). 
7.2 
Key Secondary Objectives 
• To test the hypothesis that NRX-101 is superior to lurasidone in reducing suicidal 
ideation or behavior as measured by the Clinical Global Impression of Severity of 
Suicidality Scale (CGI-SS) 
• To test the hypothesis that NRX-101 is superior to lurasidone in time to treatment failure 
as defined as: study discontinuation due to adverse events; psychiatric hospitalization; or 
requiring a change in antidepressant treatment 
7.3 
Additional Secondary Objectives 
• To test the hypothesis that treatment with NRX-101 is superior to standard of care 
(lurasidone) in reducing suicidal ideation (MADRS item 10) 
• To test the hypothesis that treatment with NRX-101 is superior to lurasidone in reducing 
the frequency of suicidal thoughts, suicidality and risk (SIBAT Module 7) 
• To test the hypothesis that treatment with NRX-101 is superior to treatment with 
lurasidone in the subgroup of participants recently (i.e. within two weeks of enrollment) 

 
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treated with approved medications for bipolar depression (olanzapine/fluoxetine, 
quetiapine, cariprazine, lumateprone, or lurasidone). 
7.4 
Safety Objectives 
• To test the hypothesis that treatment with NRX-101 is superior to lurasidone (a standard 
of care drug) in reducing suicidality in depressed bipolar participants with SSIB, as 
measured by the Columbia Suicide Severity Rating Scale (C-SSRS) 
• To test the hypothesis that participants treated with NRX-101 are less likely to suffer 
from akathisia than those treated with lurasidone as measured by the Barnes Akathisia 
Rating Scale (BARS) 
• To test the hypothesis that fewer participants treated with NRX-101 will be discontinued 
for lack of efficacy or exacerbation of suicidality than participants treated with 
lurasidone. 
7.5 
Overview 
This is a group sequential, multicenter, randomized, double-blind, parallel-group, two-arm study 
comparing NRX-101 (n=37) to lurasidone (n=37) in a 1:1 ratio for the treatment of bipolar 
depression in participants with subacute levels of suicidal ideation, as reflected by the patient 
answering “yes” to item 3 and 4 on the C-SSRS within 4-weeks of screening, and do not require 
hospitalization. 
Participants will be screened to ensure study eligibility prior to randomization on Day 1. 
Randomized participants will take either oral NRX-101 or lurasidone and placebo, in accordance 
with their treatment assignment, for 42 days. Participants will return to the investigational site on 
Day 70 for a follow-up visit (see Study Schema, Figure 3). During these visits, multiple 
psychometric scales will be completed, and participants will be assessed for safety, including the 
risk of increase in depression or suicidal ideation to the point where inpatient care or an alternative 
treatment is indicated.  
Figure 3 
Study Schema 
 
 
 

 
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8. 
SELECTION OF PARTICIPANTS 
Participants must meet all of the inclusion and none of the exclusion criteria to be qualified to 
participate in this study. 
8.1 
Inclusion Criteria 
1. 18 to 65 years of age, inclusive, at Screening. 
2. Able to understand and provide written and dated informed consent prior to screening. 
3. Deemed likely to comply with the study protocol, including communication of adverse 
events (AEs) and other clinically important information, including adherence to the text 
messaging component of the trial. 
4. Will follow medical directions for psychiatric care, as appropriate, per the standard of 
care. 
5. Resides in a stable living situation. A stable living situation will be defined as a minimum 
of 3 months at the same address with a reasonable expectation that the situation will 
continue such that the patient’s ability to participate in the study will not be affected. 
Please note that housing in a shelter of any kind will not be deemed stable housing. 
6. Previously diagnosed and treated for Bipolar Disorder (BD) I or II according to the 
criteria defined in the DSM-V. 
7. Has an identified reliable informant/care partner, that is willing to provide information 
and/or supportive care as necessary. 
8. The diagnosis of BD will have been made by a psychiatrist or other qualified licensed 
psychiatric provider able to render a diagnosis and be supported by the MINI 7.0.2. 
9. Treatment with a medication indicated for use in bipolar disorder in the past five years 
(See Appendix 4 for list). 
10. Confirmed active suicidal ideation (without the intention to act) as evidenced by an 
answer of ‘Yes’ on item 3 and/or 4 and not requiring hospitalization at Screening and an 
answer of ‘No’ on item 5 of the C-SSRS within 4-weeks of Screening. 
11. A total score greater than or equal to 30 on the 10 items of the MADRS. 
12. No co-morbidities, as ascertained by medical history, physical examination (including 
measurement of vital signs), clinical laboratory evaluations, and electrocardiogram 
(ECG) which might interfere with compliance or the ability to assess efficacy or safety. 
13. If female, a status of non-childbearing potential or use of an acceptable form of birth 
control per the following criteria, and agrees to continue use of the same method of birth 
control for the duration of study participation: 

 
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a. Non-childbearing potential: physiologically incapable of becoming pregnant (i.e. 
permanently sterilized [status post-hysterectomy, bilateral tubal ligation] or post-
menopausal with last menses at least one year prior to screening); or  
b. Childbearing potential, and meets the following criteria: 
i. Use of any form of hormonal birth control for at least 2 months prior to 
Screening, on hormone replacement therapy that started prior to 12 
months of amenorrhea, using an intrauterine device (IUD) for at least 1 
month prior to Screening, in a monogamous relationship with a partner 
who has had a vasectomy, or sexually abstinent. 
ii. Negative urine pregnancy test at Screening, confirmed by a second 
negative urinary pregnancy test at Day 1, prior to receiving any study 
treatment. 
14. Body mass index (BMI) between 18-40 kg/m2; BMI up to 45 kg/m2 is allowed with Medical 
Monitor review and approval. 
15. If receiving concurrent psychotherapy, the type and frequency of the therapy (e.g., 
weekly or monthly) has been stable for at least 3 months prior to Screening and is 
expected to remain stable for the duration of study participation. 
16. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines, 
maximum 2mg/daily, or trazodone) will be allowed if the therapy has been stable for at 
least 4-weeks prior to screening and if it is expected to remain stable during the course of 
the patient’s participation in the study.  
17. Concurrent treatment with benzodiazepines is allowed up to a maximum dose 2mg/daily 
used for anxiety if therapy has been stable relative to dose and schedule for at least 4-
weeks prior to screening and if it is expected to remain stable during the course of the 
patient’s participation in the study.  
18. If women are receiving hormone replacement therapy or estrogen replacement, the 
therapy has been stable for at least 3 months prior to Screening and is expected to remain 
stable for the duration of study participation. 
8.2 
Exclusion Criteria 
1. Female of childbearing potential who is not willing to use one of the specified forms of 
birth control during the study. 
2. Female who is pregnant or breastfeeding. 
3. Female with a positive pregnancy test at Screening or prior to randomization. 

 
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4. Current DSM-5 diagnosis of moderate or severe substance use disorder (except marijuana or 
tobacco use disorder) within the 12 months prior to Screening. (Note: Substance use disorder 
cannot be the precipitant for study entry). 
5. A lifetime history of 
a. phencyclidine (PCP)/ketamine drug abuse, or  
b. failed use of ketamine for depression or suicidality. 
6. History of schizophrenia or schizoaffective disorder, or any history of psychotic 
symptoms when not in an acute bipolar mood episode. 
7. History of anorexia nervosa, bulimia nervosa, eating disorder not otherwise specified 
(NOS), or other specified feeding and eating disorders (OSFED) within 3 years of 
Screening.  
8. Has dementia, delirium, amnestic, or any other cognitive disorder. 
9. Current major psychiatric disorder, diagnosed at Screening with the MINI 7.0.2 which is 
the primary focus of treatment, with bipolar disorder as the secondary focus of treatment, 
within the past 6 months.  
10. Estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 using the 
Cockcroft-Gault formula. 
11. A clinically significant abnormality on the Screening physical examination that may 
affect safety or study participation, or that may confound interpretation of study results 
according to the study clinician. 
12. Current episode of: 
a. Myocardial infarction within 1 year of Screening. 
b. Diagnosis of angina pectoris. 
c. Prolonged QTc interval, as measured by Fridericia’s correction formula (QTcF) 
≥450 msec at Screening for males or ≥ 470 msec for females on 2 of 3 
measurements at least 15 minutes apart prior to randomization on Day 1. 
13. Diagnosis of chronic lung disease, excluding asthma. 
14. Lifetime history of any of the following:  surgical procedures involving the brain or 
meninges, encephalitis, meningitis, degenerative central nervous system (CNS) disorder 
(e.g., Alzheimer’s Disease, Parkinson’s Disease), epilepsy, mental retardation, or any 
other disease/procedure/accident/intervention that, according to the clinician, is deemed 
associated with significant injury to, or malfunction of, the CNS. 
15. History of significant head trauma within the past two years. 
16.  Diabetes mellitus fulfilling any of the following criteria: 

 
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a. Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.0 % 
at Screening. 
b. Admitted to the hospital for treatment of diabetes mellitus or diabetes mellitus–
related illness in the past 12 weeks. 
c. Not under physician care for diabetes mellitus. 
d. Not on the same dose of oral hypoglycemic drug(s) and/or diet for the 4 weeks 
prior to Screening.  
e. Not on the same dose of oral thiazolidinediones (glitazones) for the 8 weeks prior 
to Screening.  
17. Any current or past history of any physical condition which, in the opinion of the 
investigator, may put the patient at risk or interfere with study results interpretation. 
18. Diagnosis of HIV/AIDS. 
19. Diagnosis of Hepatitis C. 
20. On exclusionary concomitant psychotropic and non-psychotropic medications (see 
Appendix 1).  
21. Prescribed more than one agent in each of the following categories at randomization: 
a. Approved SSRIs. 
b. Approved serotonin and norepinephrine reuptake inhibitors (SNRIs). 
c. Approved tetracyclic antidepressants (TeCAs). 
Note: Any/all 5hT2A medications will be discontinued at study entry. Participants currently on 
Lurasidone will be randomized to either standard of care or NRXx-101 at the indicated starting 
dose. 
22. Currently prescribed oxcarbazepine or carbamazepine. 
23. Exclusionary laboratory values or any other clinically significant abnormal laboratory 
result (as determined by the investigator and Medical Monitor) at Screening. 
24. Known allergies to lurasidone or Latuda®, cycloserine or Seromycin®, or the following 
excipients: mannitol, croscarmellose sodium, magnesium stearate, silicon dioxide, and/or 
hydroxypropylmethylcellulose (HPMC). 
25. Participation in any clinical trial with an investigational drug or device within the past 
month or planned concurrent study participation.  
26.  Study site personnel and/or persons employed by NRx Pharma, Inc., the Contract 
Research Organization (CRO), the investigator, or study site (i.e., permanent, temporary 
contract worker, or designee responsible for the conduct of the study), or an immediate 

 
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family member (i.e., spouse, parent, child, or sibling [biological or legally adopted]) of 
such persons. 
27. Positive urine toxicity screening for use of any cocaine, opiates and non-prescribed 
amphetamine and non-prescribed barbiturates (Note: Cannabinoids or Marijuana use is 
not exclusionary unless the patient meets the criteria for cannabis withdrawal). 
28. Signs and symptoms of active or residual COVID-19, or unresolved symptoms of 
COVID-19 that impact health, e.g. requirements for oxygen supplementation, etc. 
Discharge from an inpatient hospitalization for more than 48 hours for COVID-19 within 
the past 28 days. 
9. 
STUDY VISITS 
9.1 
Study Visits 
Study subjects are required to undergo the below frequency of assessments, 2 of which can be 
done by video / conference if required due to COVID-19 circumstances. Investigators may 
always conduct unscheduled visits to monitor subject safety. The schedule of assessments is 
synchronous with the main protocol and congruent with monitoring participants of lesser acuity.  
A schedule of study visits and assessments is provided in Table 1. 
 
 

 
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Table 1  
Schedule of Assessments 
 
Screening 
Treatment 
Follow up1 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Study Day 
Day   
-10 to -1 
Day 12 
Baseline 
Day 7 
Day 143 
Day 283 
ET/Day 423 
Day 70 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility Review  
X 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Psychiatric History 
X 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
MINI Severity/Disability 
 
X 
 
 
 
X 
 
Subject Eligibility 
X 
X 
 
 
 
 
 
Physical Exam4 
X 
 
 
 
 
X 
 
Vital Signs, Weight5 
X 
X 
 
X 
X 
X 
 
ECG6 
X 
X 
 
 
 
X 
 
Pregnancy Test (Urine 
dipstick)  
X 
X 
 
 
 
 
 
Drugs of Abuse Screen 
(Urine dipstick) 7 
X 
X 
X 
X 
X 
X 
 
Fasting Chemistry, 
Hematology 
X 
 
 
 
 
X 
 
C-SSRS8 
X 
X 
X 
X 
X 
X 
 
MADRS 
X 
X 
X 
X 
X 
X 
 
CGI-SS 
X 
X 
X 
X 
X 
X 
 
CHRT-C, -SR 
X 
 
X 
X 
X 
X 
 
BPRS psychosis subscale 
X 
X 
X 
X 
X 
X 
 
BARS 12 
X 
X 
X 
X 
X 
X 
 
PRISE 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Adherence device 
training9 
 
X 
 
 
 
 
 
Dispense investigational 
product and review 
adherence10 
 
X 
X 
X 
X 
 
 
Site monitoring of 
adherance11 
 
 
X 
X 
X 
X 
 
1 Follow up visit will be a phone call; the study visit may occur within ± 7 days of the scheduled day (anchored to the Day 1 
visit). 
2 Day 1 procedures need to meet eligibility criteria and will be performed prior to first dose. 
3 Study visits occurring after Day 7 may occur within ± 3 days of the scheduled day (anchored to the Day 1 visit). Study visits 3, 
4, 5, 7 may be done virtually, preference is through videoconference.  
4 Full physical exam (including a neurological exam and height) at Screening and Visit 6 will be performed, and a brief exam 
(Blood Pressure, Respiration Rate, Heart Rate, and Temperature) will be performed at subsequent time points. 
5 After 5 min at rest, supine or sitting systolic and diastolic blood pressure and heart rate are recorded at each indicated visit. 
Weight is measured only at Screening and Visits 2,4,5, and 6.  
6 12-lead ECG.  
7 Subjects who have 2 consecutive positive urine screens should be withdrawn from study, in case of a subject not being able to 
visit a site due to COVID-19 restrictions or impediments arrangements should be made for an outpatient test, or the 
investigators should note this and make an assessment during the tele visit, annotation should be included in the EDC why the 
drug screen text could not be done. In the case where the subject has 2 consecutive negative urine screens, the subject can skip 

 
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the next urine screen. Investigators can bring the subject in for a urine screen at any time if suspected drug use. Note: Since 
Cannabis use is not exclusionary, a positive UDS will not require that patient be withdrawn from the study. 
8 “Baseline” version should be administered at screening and “Since Last Visit” version should be administered at all other time 
points. 
9 Adherence device training should be performed pre-dose on Day 1 or with the first dose. Additional training will be provided 
as necessary. The subject’s cellphone number will be input in a secure field of the EDC by the study site personnel, this field 
will only be accessible to designated study site personnel. The system will send a text message at designated hours to the 
subject as a reminder to take study the medication. The subject must respond affirmatively to enable compliance tracking. 
Absence of a response or a negative response will trigger a notification to the site.  
10 Medication adherence will be reviewed and returned pills recorded. 
11 Sites will monitor / review compliance for a target goal of 85 percent compliance of all doses taken. If more than 2 consecutive 
doses are missed they should contact the subject and counsel the subject on the need for compliance before the next scheduled 
dose.  
12 Rating akathisia using BARS needs to be a video call if completed remotely and will be documented. 
 
9.1.1 Screening Period 
Once a patient agrees to participate in the study, indicated by signing the informed consent form, 
the patient is admitted to the study. A full medical and psychiatric history will be taken, and a 
physical and laboratory examination will be performed, as outlined in the Schedule of Assessments 
(Table 1). The Screening period may extend to 10 days following the signing of the informed 
consent form in order to allow sufficient time for Screening procedures to be completed and results 
reported.  
9.1.1.1 
Rating Scale 
The site will upload digital audio files and score summaries of the MINI and MADRS, and the 
score summary for the C-SSRS. The MINI diagnostic interview, MADRS, and C-SSRS scores 
will be reviewed by an Expert Psychometrician for all study participants. 
9.1.1.2 
eGFR Calculation 
Using the results of the chemistry panel, glomerular filtration rate will be estimated by using the 
creatinine clearance value calculated using the Cockgroft-Gault formula, as follows: 
•  CrCl (male) = ([140-age] × weight in kg)/(serum creatinine × 72)  
•  CrCl (female) = CrCl (male) × 0.85  
Because participants with renal insufficiency may accumulate cycloserine, participants with 
moderate renal insufficiency (eGFR < 60 ml/min/1.73 m2) or worse will be excluded from study 
participation. 
9.1.1.3 
Screen Failures 
In the event a patient is a screen failure, the patient may be rescreened at the discretion of the 
investigator and Medical Monitor. 
9.1.2 Treatment and Follow-up Periods 
Participants that continue to meet MADRS and C-SSRS eligibility will be randomized to receive 
the first dose of blinded treatment on Day 1. This visit will be followed by Treatment Period visits 
at Days 7, 14, 28, and 42. Following completion of the Treatment Period, participants will be 

 
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contacted via telephone for follow-up on Day 70. In order to allow scheduling flexibility, and 
(considering pandemic related limitations), visit windows will be allowed as noted in Table 1. 
Participants will be withdrawn from the study if their urine toxicology screenings at two 
consecutive study treatment visits are positive for cocaine, opiates, non-prescribed amphetamines, 
or non-prescribed barbiturates. 
9.1.3 Early Termination Visit 
Every effort will be made to keep the participants in the study for the full study period. However, 
if a patient decides to discontinue the investigational product, the patient will be asked about the 
reason(s) for discontinuation and the presence of any AEs. If possible, the patient will be asked to 
complete the Day 42/Early Termination (ET) visit prior to discontinuation, and day 70 to assess 
safety. Following completion of the Early Termination Visit, the patient will either be treated by 
the investigator with standard of care or, should the patient choose, return to treatment by a 
prior/referring physician. In this case, the investigator will facilitate and coordinate follow-up to 
ensure continuity of care.  
Participants who discontinue from the study will not be replaced. 
10. 
TREATMENT OF PARTICIPANTS  
10.1 Investigational Drug Dose and Administration 
Participants will be instructed to take all oral investigational product with food. Participants will 
be trained to ingest food prior to or immediately after ingestion of investigational product, and 
they will be reminded of this requirement at each study visit as part of adherence monitoring.  
Participants should be instructed to avoid eating grapefruit or drinking grapefruit juice while on 
study as it may affect the amount of medication in the blood. This fruit and its juice can raise blood 
levels of some antipsychotic drugs such as lurasidone. 
10.2 Investigational Product 
NRX-101 is a capsule intended for oral administration. Each NRX-101 capsule contains DCS and 
lurasidone HCl. Inactive ingredients include mannitol, croscarmellose sodium, silica dioxide, and 
magnesium stearate. 
The physical description and composition of each capsule is described in the Investigator 
Brochure. NRX-101, lurasidone, and placebo capsules are matched in terms of size, shape, and 
color with no discernible difference in appearance or physical description. The lurasidone capsules 
contain lurasidone at the same dosage as the matched NRX-101 capsules. 

 
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10.3 Investigational Product Titration 
Investigators will have the ability to increase the lurasidone dose at any point after the initial 
titration period for control of agitation or psychotic symptoms, or to decrease both the DCS and 
lurasidone dose in response to somnolence. No other dose modifications will be allowed. 
Titrations of investigational product will be affected while maintaining a blinded study design (see 
Table 2 for NRX-101 and Table 3 for lurasidone). Up-titration will increase the lurasidone dose, 
and will not alter the DCS dose. Down-titration decreases the total daily dose of both lurasidone 
and DCS in the NRX-101 group and only the lurasidone dose in the lurasidone group. 
Table 2  
NRX-101 Dose Titration 
Day 
Morning Dose (mg) 
     DCS        Lurasidone 
Evening Dose (mg) 
    DCS       Lurasidone 
Total Daily Dose (mg) 
    DCS       Lurasidone 
1 
350 
16.5 
350  
16.5 
700 
33 
2 
475 
33 
475  
33 
950 
66 
3 
475 
33 
475 
33 
950 
66 
4 
475 
33 
475 
33 
950 
66 
5 
475 
33 
475 
33 
950 
66 
Maintenance Dose 
475 
33 
475 
33 
950 
66 
Up-titration (if needed) 
step 1 
475 
33 
475 
66 
950 
99 
step 2 
475 
66 
475 
66 
950 
132 
Down-titration (if needed) 
step 1 
350 
16.5 
475 
33 
825 
49.5 
step 2 
350 
16.5 
350 
16.5 
700 
33 
 
Table 3  
Lurasidone Dose Titration 
Day 
Morning Dose (mg) 
     DCS        Lurasidone 
Evening Dose (mg) 
    DCS       Lurasidone 
Total Daily Dose (mg) 
    DCS       Lurasidone 
1 
0 (placebo) 
16.5 
0 (placebo) 
16.5 
0 (placebo) 
33 
2 
0 (placebo) 
33 
0 (placebo) 
33 
0 (placebo) 
66 
3 
0 (placebo) 
33 
0 (placebo) 
33 
0 (placebo) 
66 
4 
0 (placebo) 
33 
0 (placebo) 
33 
0 (placebo) 
66 
5 
0 (placebo) 
33 
0 (placebo) 
33 
0 (placebo) 
66 
Maintenance Dose 
0 (placebo) 
33 
0 (placebo) 
33 
0 (placebo) 
66 
Up-titration (if needed) 
step 1 
0 (placebo) 
33 
0 (placebo) 
66 
0 (placebo) 
99 
step 2 
0 (placebo) 
66 
0 (placebo) 
66 
0 (placebo) 
132 
Down-titration (if needed) 
step 1 
0 (placebo) 
16.5 
0 (placebo) 
33 
0 (placebo) 
49.5 
step 2 
0 (placebo) 
16.5 
0 (placebo) 
16.5 
0 (placebo) 
33 
 

 
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11. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
11.1 Packaging and Labeling 
Investigational product will be supplied in high-density polyethylene (HDPE) bottles with a foil 
induction seal and screw-top closures. Each bottle will contain two capsules, the required dose for 
either morning or evening administration, as well as a desiccant to aid stability. The bottles will 
be packaged into a cardboard kit containing two bottles for each day.  
Six kit types will be available for each patient. Kit 1 will contain a 7-day titration pack consisting 
of 14 bottles, each containing two capsules, for use during the first 7 days of the study (+2 days). 
Kits 2 to 5 will contain three-day step-up or step-down packs with six bottles, each containing two 
capsules and will only be dispensed if the patient requires a dose titration. Kit 6 will contain a 
7-day maintenance dose pack with 14 bottles, each containing two capsules. A description of the 
six kit types are provided in Table 4 for NRX-101 and in Table 5 for lurasidone. 
Table 4 
NRX-101 Blinded Kits 
Kit Type 
Day 
Morning Dose 
(mg) 
Evening Dose 
(mg) 
Total Daily Dose 
(mg) 
 
 
DCS 
Lurasidone 
DCS 
Lurasidone 
DCS 
Lurasidone 
1 (7 Days) 1 
350 
16.5 
350 
16.5 
700 
33 
2 
475 
33 
475 
33 
950 
66 
3 
475 
33 
475 
33 
950 
66 
4 
475 
33 
475 
33 
950 
66 
5 
475 
33 
475 
33 
950 
66 
6 
475 
33 
475 
33 
950 
66 
7 
475 
33 
475 
33 
950 
66 
 
Up-
titration 
2 (3 Days) step 1 
475 
33 
475 
66 
950 
99 
3 (3 Days) step 2 
475 
66 
475 
66 
950 
132 
 
Down-titration 
4 (3 Days) step 1 
350 
16.5 
475 
33 
825 
49.5 
5 (3 Days) step 2 
350 
16.5 
350 
16.5 
700 
33 
6 (7 Days) Maintenance 
475 
33 
475 
33 
950 
66 
 

 
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Table 5 
Lurasidone Blinded Kits 
Kit Type 
Day 
Morning Dose 
(mg) 
Evening Dose 
(mg) 
Total Daily Dose 
(mg) 
 
 
DCS 
Lurasidone 
DCS 
Lurasidone 
DCS 
Lurasidone 
1 (7 Days) 1 
0 (placebo) 
16.5 
0 (placebo) 
16.5 
0 (placebo) 
33 
2 
0 (placebo) 
33 
0 (placebo) 
33 
0 (placebo) 
66 
3 
0 (placebo)     33 
0 (placebo) 
33 
0 (placebo) 
66 
4 
0 (placebo) 
33 
0 (placebo) 
33 
0 (placebo) 
66 
5 
0 (placebo) 
33 
0 (placebo) 
33 
0 (placebo) 
66 
6 
0 (placebo) 
33 
0 (placebo) 
33 
0 (placebo) 
66 
7 
0 (placebo) 
33 
0 (placebo) 
33 
0 (placebo) 
66 
 
Up-
2 (3 Days) step 1 
0 (placebo) 
33 
0 (placebo) 
66 
0 (placebo) 
99 
3 (3 Days) step 2 
0 (placebo) 
66 
0 (placebo) 
66 
0 (placebo) 
132 
 
Down-titration 
4 (3 Days) step 1 
0 (placebo) 
16.5 
0 (placebo) 
33 
0 (placebo) 
49.5 
5 (3 Days) step 2 
0 (placebo) 
16.5 
0 (placebo) 
16.5 
0 (placebo) 
33 
6 (7 Days) Maintenance 
0 (placebo) 
33 
0 (placebo) 
33 
0 (placebo) 
66 
 
Each investigational product label will include the following information: 
• Name of sponsor and address 
• Protocol number  
• Number of capsules 
• Storage conditions 
• Investigational drug statement (for clinical trial use only) 
• Drug packager lot number 
• Kit/Medication number 
• Contents 
• Administration statement 
• Bar code 
• Child warning 
• Grapefruit warning 
• Spaces to record: 
o Subject number 
o Date dispensed 

 
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11.1.1 Storage 
Investigational product will be stored at room temperature of 20°C to 25°C (68°F to 77°F); 
excursions will be permitted to 15°C to 30°C (59°to 86°F).  
11.1.2 Accountability 
The clinical site is required to maintain current drug dispensation and accountability logs 
throughout the study. All unused supplies will be checked against the drug dispensation and 
accountability logs during the study and/or at the end of the study.  
11.1.3 Handling and Disposal 
There are no special handling requirements for the investigational product. Unused investigational 
product will be returned to the drug depot for disposal.  
Please refer to the Pharmacy Manual for further information. 
11.2 Study Drug Monitoring 
An Electronic Patient Reported Outcome (ePRO) System will be used in this study. The ePRO 
will send daily reminders at designated hours to participants enrolled in the study to take their 
study drug via text messages to each patient’s own cell phone. The patient must respond 
affirmatively to enable compliance tracking. 
The ePRO system will also host an audit trail for recording patient responses and an email alert 
message system to the site staff if no response or negative response is received from the patient. 
The ePRO system will be available to authorized site users through the Prevail Single 
Interface TM (SI). 
Patient will grant the study site permission to contact him/her on the mobile device if a personal 
telephone number(s) cannot be reached. Additionally, sites will review drug utilization through 
receipt of used drug kits and assessments with participants. 
12. 
EFFICACY ASSESSMENTS 
Study procedures are described below. Assessment time points are included in the Schedule of 
Assessments (Table 1). 
12.1 Montgomery Asberg Depression Rating Scale (MADRS) 
The Montgomery Åsberg Depression Rating Scale is a 10-item clinician-rated scale, with each 
item rated on a 0–6 severity scale (Montgomery, Åsberg 1979). The timeframe for the baseline 
MADRS-10 recorded at Screening and Day 1 is the past seven days; for the MADRS-10 recorded 
at all time points thereafter, the timeline measured will be since the last assessment.  

 
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12.2 Clinical Global Impression-Severity for Suicide 
The three Clinical Global Impression scales represent the final three global ratings from the 
Suicidality Ideation Inventory and Behavior Assessment Tool (SIBAT Module 7), which is 
designed for the clinician to assess the relative risk and overall risk of suicide across different time 
scales (Alphs et al., 2016). The questions assess the clinician’s global impression of immediate 
risk of suicide (that day), imminent risk of suicide (over the next 7 days), and long-term risk (i.e., 
likely to end their life by suicide sometime in the future). Each risk (immediate, imminent, long-
term) is rated along a graded impressions scale starting at 0 (‘normal’, ‘not suicidal’ or ‘no risk’) 
and ranges to 6 (‘among the most extremely suicidal’ or ‘extreme risk for imminent’/’long-term 
suicide’).  
12.3 Brief Psychiatric Rating Scale (BPRS psychosis subscale) 
Overall the Brief Psychiatric Rating Scale (BPRS) is an 18-item clinician-rated scale that assesses 
a range of psychotic and affective symptoms, rated from both observation of the patient and the 
patient’s own report (Overall and Gorham, 1962). Only the 4-item positive symptom subscale 
referred to in this document as the “BPRS psychosis subscale” (i.e., suspiciousness, hallucinations, 
unusual thought content, and conceptual disorganization) will be used.  
12.4 Concise Health Risk Tracking – Self Report (CHRT-SR) and Clinician Rating 
(CHRT-C) 
The Concise Health Risk Tracking – Self Report (CHRT-SR) and – Clinician (CHRT-C) are 
assessments of suicidality and related thoughts and behaviors (Trivedi et al., 2011). The CHRT-
SR is a 16-item self-report suicidal ideation scale, and the CHRT-C is a 9-item clinician-rated 
behavioral module. Items are rated on a fully anchored five-point Likert scale with responses 
ranging from 1 (strongly disagree) to 5 (strongly agree). The time frame is the past seven days.  
13. 
OTHER DIAGNOSTIC INSTRUMENTS 
13.1 Mini International Neuropsychiatric Interview (MINI) 7.0.2 
The MINI (Sheehan et al., 1998) is a short, structured diagnostic interview developed initially in 
1990 by psychiatrists and clinicians in the United States and Europe for DSM-III-R and ICD-10 
psychiatric disorders. The tool has been updated to map to DSM-5 diagnostic criteria in the MINI 
7.0.2. 
13.2 Bipolarity Index (BPI) 
For this study, the BPI is integrated with the patient eligibility evaluation. The BPI (Aiken et al., 
2015) is a clinician-rated scale that rates cardinal features of bipolar disorder across five domains: 
episode characteristics (signs and symptoms); age of onset (first episode); course of illness; 
response to treatment; and family history. Possible scores range from 0–100 and a score of 50 has 

 
NRX-101_003 
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a high sensitivity and specificity for the identification of bipolar disorder. The index scores will 
not be used for study entry, but will help inform diagnostic impression. 
14. 
ASSESSMENT OF EFFICACY 
14.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is: 
• Mean change from baseline in total MADRS score 
14.2 Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoint are: 
• Change from baseline over 42 days in CGI-SS 
• Time to treatment failure in each arm 
14.3 Additional secondary efficacy endpoints: 
• Mean change from baseline in Suicidal Thoughts on the MADRS (MADRS item 10)  
• Change from baseline to Day 14 in MADRS total score 
• Change from baseline in each item of the Suicide Ideation and Behavior Assessment Tool 
(SIBAT) Module 7 (clinical global impressions of frequency of suicidal thinking, severity 
of suicidality, and imminent and long-term risks)  
• Change from baseline to endpoint (Day 42/exit) in MADRS total score in the subgroup of 
participants who were recently (within 2-weeks) on approved medications for bipolar 
depression 
• 
Percent in remission at Day 42/exit. 
15. 
ASSESSMENT OF SAFETY 
Study procedures are described below. Assessment time points are included in the Schedule of 
Assessments (Table 1). 
15.1 Safety Scales 
15.1.1 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters 
Study to assess severity and track suicidal events through any treatment (Posner et al., 2007). The 
timeframe for assessment is for both lifetime and the past 4-weeks for the Screening scale and 
since the last visit for all other ratings. 

 
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15.1.2 Patient Rated Inventory of Side Effects (PRISE) 
The Patient Rated Inventory of Side Effects (PRISE) is a self-rated questionnaire (Rush and 
Asberg, 1999; Wisniewski et al., 2006) will be used to assess the specific symptoms considered 
by participants to be more or less tolerable drug side effects. The timeframe for assessment is at 
Screening for the Screening scale and in the past week for all other ratings. 
15.1.3 Barnes Akathisia Scale (BARS) 
The Barnes Akathisia (BARS) (Barnes, 1989) is a clinician-rated scale to assess drug-induced 
akathisia as absent, mild, moderate, or severe. It comprises items for rating the observable, restless 
movements which characterize the condition, the subjective awareness of restlessness, and any 
distress associated with the akathisia. In addition, there is an item for rating global severity. The 
timeframe for the scale is “at this time.” 
15.2 Adverse Events and Serious Adverse Events 
15.2.1 Definition of Adverse Events 
An AE is any untoward medical occurrence in a clinical study patient administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship to the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that medicinal 
(investigational or non-investigational) product. 
This definition includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
The following variables will be collected for each AE: 
• AE (verbatim) 
• The date and time when the AE started and stopped 
• Maximum intensity or changes in intensity 
• Whether the AE is serious or not (see Section 15.2.3) 
• Expectedness 
• Investigator assessment of relationship to investigational product 
• Action taken with regard to the investigational product (uptitration, downtitration, 
temporarily discontinued, permanently discontinued or no action taken) 

 
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• AE caused patient’s withdrawal from the study (yes or no) 
• Outcome 
Adverse events will be collected from the time of signature on the informed consent form 
throughout the Follow-up visit or early termination. Whenever possible, diagnoses will be given 
when signs and symptoms are due to a common etiology (e.g., cough, runny nose, sneezing, sore 
throat, and head congestion will be reported as “upper respiratory infection”). 
Worsening symptoms of the primary study condition (i.e., bipolar depression) will be recorded as 
a primary endpoint rating.  
Any AE(s) that are unresolved at the follow-up visit (Day 70) will continue to be followed by the 
investigator for as long as medically indicated, but without further recording in the eCRF. The 
Contract Research Organization (CRO) and its representative retain the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if deemed 
medically necessary. 
15.2.2 Adverse Event Intensity and Relationship 
Intensities for each AE will be assessed by the investigator as: 
• Mild: Awareness of sign or symptom, but easily tolerated; 
• Moderate: Discomfort sufficient to cause interference with normal activities; or 
• Severe: Incapacitating, with inability to perform normal activities. 
Relationship to investigational product will be assessed by the investigator according to the 
following categories: 
• Not Related: Clearly and incontrovertibly due only to extraneous causes and does not meet 
criteria listed under possible or probable. 
• Unlikely Related: Does not follow a reasonable temporal sequence from administration. 
May have been produced by the patient’s clinical state or by environmental factors or other 
therapies administered. 
• Possibly Related: Follows a reasonable temporal sequence from administration but may 
have been also produced by the patient’s clinical state, environmental factors, or other 
therapies administered. 
• Related: Clear-cut temporal association with administration with improvement on 
cessation of investigational product or reduction in dose. Reappears upon re-challenge. 
Follows a known pattern of response to the investigational product. 

 
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15.2.3 Recording of Adverse Events 
AE(s) spontaneously reported by the patient in response to an open-ended question from study 
personnel, such as, “Have you had any health problems since the previous visit?” or that are 
revealed by observation will be recorded at each visit. When reporting AE(s), the recording of 
diagnosis is preferred (when possible), rather than reporting the list of signs and symptoms. 
However, if a diagnosis is known and there are other signs or symptoms that are not generally part 
of the diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
Participants should be encouraged to contact the investigator or a member of the clinical site staff 
at any time between visits concerning AE(s)or worsening of symptoms.  
15.2.4 Definition of Serious Adverse Events 
The following criteria define an SAE: 
• Death 
• Life-threatening event 
• Inpatient hospitalization >24 hours or prolongation >24 hours of inpatient hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• Medically important event, as defined in this protocol* 
*Medical and scientific judgment will be exercised in deciding whether expedited reporting is also 
appropriate in other situations, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These will usually 
be considered serious. 
In addition, the following variables will be collected, where applicable, for SAEs: 
• Date AE met criteria for SAE 
• Date investigator became aware of SAE 
• Description of SAE 
• Explanation of seriousness of the AE 
• Date of hospitalization 
• Date of discharge 
• Probable cause of death 
• Date of death 
• Autopsy performed 

 
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• Causality assessment in relation to investigational product 
• Causality assessment in relation to other medication 
It is important to distinguish between serious and severe AE(s). Severity is a measure of intensity, 
whereas seriousness is defined by these criteria. An AE of severe intensity need not necessarily be 
considered serious. If inpatient hospitalization results from worsening psychiatric symptoms or 
suicidal ideation, the hospitalization will be reported as an SAE. 
SAEs will be reported from the time of informed consent through the Follow-up visit or early 
termination. Unsolicited SAEs will be collected up to 30 days after the last study treatment. 
15.2.5 Reporting Serious Adverse Events 
When an SAE is discovered, it will be reported immediately (within 24 business hours of the site’s 
knowledge of the event) to the Sponsor/CRO Medical Monitor. Reportable events which do not 
meet the criteria for an SAE will include (but will not be limited to): (a) pregnancy, and (b) 
clinically significant (in the judgment of the investigator) severe psychiatric complications.  
The eCRF will provide a mechanism for sites to report SAEs, and for investigators and the Medical 
Monitor to sign off on the SAE reports.  
Reportable SAEs will be sent to the FDA by the sponsor and sites will be notified. Sites are 
responsible for submission of SAE reports to their IRB(s), in accordance with IRB policies.  
15.2.6 Anticipated Serious Adverse Events 
Tan et al (2021) publication Identifying Anticipated Events of Future Clinical Trials 
by Leveraging Data from the Placebo Arms of Completed Trials looked at 18 Randomized, 
double-blind, controlled trials of Bipolar Depression that met similar inclusion and exclusion 
criteria to identify the most common Serious Adverse Events. 
Based on this publication, the anticipated Serious Adverse Events are: 
• Hospitalization, psychiatric symptoms 
• Suicidal behavior, overdose 
• Cholecystitis 
• Fall 
• Road traffic accident, injury 
15.2.6.1 Overdose 
Overdose of the investigational product will be considered an SAE, even when there are no 
symptoms or additional AEs, and will be reported according to the guidelines in Section 15.2.5. 
An overdose associated with symptoms must be reported as an AE. 

 
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15.2.6.2 Suicidal Ideation and Clinical Management 
The documentation and proper management of suicidal ideation by sites will be documented with 
the use of the C-SSRS, completed by site clinicians during all visits. Safety will be evaluated 
throughout the course of the study. 
Any patient who, based on the investigator’s judgment, poses an imminent risk of suicide should 
be discontinued from the study. Suicide risk is assessed by the clinician at every visit.  
Suicide, self-harm, and attempted suicide, irrespective of the method, will be reported as AEs (all 
suicides are SAEs; attempted suicides are considered to be SAEs). The event will be identified as 
suicide or attempted suicide, and the method of the suicide or attempt will be provided. If an 
attempted suicide meets the criteria for an SAE, the event must be reported according to the 
guidelines in Sections 15.2.4. If a suicide attempt does not meet the criteria for an SAE, it will be 
considered a reportable AE, and a Suicidal Ideation or behavior Reportable Event Form will be 
completed by the investigator and submitted in accordance with the SAE reporting procedure in 
Section 15.2.5. 
15.2.6.3 Pregnancy 
If a patient (or patient’s partner) becomes pregnant during the study, it must be reported within 24 
business hours of the time the investigator becomes aware of the event and in accordance with the 
procedures described on the Pregnancy Report Form. Although pregnancy itself is not regarded as 
an SAE/AE, unless there is a suspicion that a study drug may have interfered with the effectiveness 
of a contraceptive medication, the pregnancy details will be captured in the AE/SAE module of 
the eCRF. Any pregnancy that occurs from Visit 1 to 30 days following the last dose given will be 
followed for gestational outcome, and the outcome will be reported to the sponsor. The female 
patient will be discontinued from investigational product, but will continue to attend study visits 
for the duration of her participation in the study.  
15.3 Concomitant Medications, Therapies, and Alcohol Restrictions 
15.3.1 Concomitant Medications 
Lurasidone is contraindicated with the use of strong CYP3A4 inhibitors (e.g., ketoconazole) and 
strong CYP3A4 inducers (e.g., rifampin) (see Appendix 1). The lurasidone dose should not exceed 
40 mg/day if co-administered with moderate CYP3A4 inhibitors. There are no known reported 
interactions between DCS and lurasidone. 
It is anticipated that participants entering the study will be receiving concurrent disorder-directed 
treatment with various combinations of medications, including: 
• Approved antidepressants (e.g., SSRIs, SNRIs, TeCAs, fluoxetine), but not 5-HT-2A 
antagonists (lurasidone, aripiprazole, olanzapine/fluoxetine, quetiapine, cariprazine, or 
lumateperone) 

 
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• Mood stabilizers (e.g., lithium, valproic acid, and lamotrigine) 
Participants will be permitted into the study if they are treated with no more than one drug from 
each category of the indicated classes. Approved antidepressants and mood stabilizers will be 
maintained at stable dosages throughout the study. This is both to ensure continued treatment and 
to prevent withdrawal symptoms that may occur if such drugs are rapidly discontinued. 
Participants taking aripiprazole, risperidone, brexpiprazole, lumateperone, olanzapine, 
cariprazine, or quetiapine will discontinue these medications prior to Randomization in order to 
avoid overlap with lurasidone.  
Allowed concomitant medications include any prescription or over-the-counter medication not 
specifically excluded by the protocol (see Appendix 1), as well as stable, ongoing antidepressant 
or mood stabilizer therapy and stable allowed hypnotic therapy. Participants requiring excluded 
medications will be discontinued from the study and an Early Termination Visit will be performed 
in accordance with Section 9.1.3.  
Prohibited concomitant medications that the patient and the investigator agree to discontinue for 
the purpose of study entry will be washed out for a period defined by the Investigator in 
consultation with the Medical Monitor. In the event concomitant medication washout is 
appropriate for a patient per investigator judgment, the patient must sign the informed consent 
form prior to beginning the washout period. Clinically appropriate tapering regimens should be 
used, if applicable. The Screening period may be extended, upon consultation with the Medical 
Monitor, to allow for a sufficient washout period.  
All concomitant medications taken during the study and 4-weeks prior to study entry will be 
recorded in the electronic case report form (eCRF) for each patient, along with dosage information 
and start and stop dates.  
15.3.2 Concomitant Therapy 
Participants receiving concurrent psychotherapy that has been stable in type and frequency (e.g., 
weekly, monthly) for at least 3 months prior to Screening are eligible for study entry if the 
psychotherapy is expected to remain stable for the duration of the patient’s participation in the 
study. Any changes in psychotherapy type and/or frequency during the study should be discussed 
with the Medical Monitor as soon as the investigator is aware of the proposed change. 
15.3.3 Alcohol Restrictions 
Participants should not use alcohol during the study. Ethyl alcohol may increase the possibility 
and risks of seizures in participants with a history of alcoholism receiving cycloserine. 
15.3.4 Positive Drug Screen  
Participants who have a positive urine drug screen two times in a row for use of any cocaine, 
opiates and non-prescribed amphetamine and non-prescribed barbiturates will be withdrawn 
from the study. 

 
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15.4 Laboratory/Diagnostic Procedures 
Clinical laboratory safety testing will be performed locally at the study site using a Clinical 
Laboratory Improvement Amendments (CLIA)-certified laboratory. The frequency and type of 
procedures are detailed in the Schedule of Assessments (Table 1). Local laboratory normal ranges 
must be reported according to gender.  
Participants will have their blood drawn for clinical chemistry (ALT, AST, GGT, ALK 
phosphatase, Creatinine, T4, T3,TSH, Albumin, BUN, Calcium, Sodium, Potassium, Chloride, 
Glucose, Total Bilirubin, Direct Billirubin, Total Protein, Total Cholesterol, HDL/LDL, 
Triglycerides, Uric Acid, HbA1c) and hematology testing (Red blood cell count, White blood cell 
count, Platelet count, Hemoglobin, Hematocrit, Neutrophils Absolute or percent, Lymphocytes 
Absolute or percent, Monocytes Absolute or percent, Eosinophils Absolute or percent, Basophils 
Absolute or percent). Urine sample testing for pregnancy and drug screen will be by dipstick. In 
the event of clinically significant abnormal laboratory test result(s), follow-up laboratory testing 
may be conducted, at the discretion of the investigator. If applicable, clinically significant changes 
from baseline in laboratory results will be noted as AE(s), in accordance with Section 15.2.1. 
15.5 Physical Examinations, Vital Signs, Height, and Weight 
Physical examinations, vital signs, height, and weight will be obtained at the noted visits. Vital 
signs (blood pressure and heart rate) may be repeated 15 min apart, as needed, in order to obtain a 
resting reading. If applicable, clinically significant changes from baseline in physical examination 
parameters, vital signs, and weight will be noted as AE(s), in accordance with Section 15.2.1. 
15.6 Electrocardiograms 
Twelve-lead ECGs will be obtained after the patient has been resting in a semi-recumbent position 
for at least 5 minutes. All digital ECGs will include the date and time obtained, heart rate, QRS 
duration, PR interval, RR interval, QT interval, and QTcF interval using Fridericia formula 
(Puddu et al., 1988). If indicated, additional ECG assessments may be performed, at the discretion 
of the investigator. If applicable, clinically significant changes from baseline in ECG assessments 
will be noted as AE(s), in accordance with Section 15.2.1. 
15.7 Study Monitoring by the Drug Safety Monitoring Board (DSMB) 
The study will be monitored for safety, futility, and efficacy by a DSMB. Interim analysis for 
safety will be conducted six weeks after the first 30-35 participants complete Day 42 based on 
reported Adverse Events and Serious Adverse Events. The study may be stopped for safety 
concerns. A second DSMB assessment for safety and futility will be conducted when 45-50 
participants have reached day 42.  

 
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16. 
STATISTICS 
The study analyses will be conducted in a GCP environment (ICH E6 and E9 [R1]). All analyses 
will be pre-specified in a Statistical Analysis (SAP) and finalized prior to database lock. If the 
methods in the SAP do not agree with this protocol, the methods described in the SAP will govern 
the analysis.  
16.1 Randomization 
Randomization will be stratified by evidence of a suicidal event in the prior 12 months (none, any).  
16.2 Study Populations 
The study includes prospectively defined study populations. The Intent to Treat (ITT) population 
will include all participants who received at least one dose of the oral treatment and had any post–
randomization efficacy assessments. The modified ITT (mITT) population will include the ITT 
population with at least one post-baseline efficacy observation; the mITT population will also 
exclude subjects with a major protocol deviation, e.g. ineligibility, unreliable MADRS-10 scoring, 
proscribed treatment.  The Per Protocol (PP) population will include the subset of ITT participants 
who were eligible, who have any post–randomization efficacy assessments within one day of 
scheduled visits through Day 7 and within three days of scheduled visits through Day 42, and who 
had no major protocol violations. The Safety population will include all participants as treated with 
study treatment and with any post–randomization safety data. 
The mITT population will be used for the primary analyses for efficacy. If <5 percent are to be 
excluded from the ITT population, then the analysis will not be performed for the PP population.  
Protocol violations will be reviewed in real time and prospective rules will be set for exclusions 
from the PP population. A Biostatistics Data Review Meeting (BDRM) will be held to identify all 
major protocol deviations prior to database lock inclusive of any case exclusions from the mITT 
and PP population as well as to censor any efficacy data following proscribed treatments. 
16.3 Hypothesis Tests 
16.3.1 Treatment Comparisons 
In order to preserve the Type 1 error associated with multiple endpoints (per FDA guidance), all 
efficacy endpoints will be evaluated in this pre-defined order: (1) MADRS through Week 6. Each 
will be hypothesis testing driven. 
16.3.2 Primary Hypothesis 
MADRS 
The primary study hypothesis is that treatment with NRX-101 is superior to lurasidone in 
improving symptoms of depression as measured by the MADRS over 6 weeks of treatment. The 
primary study hypothesis is that treatment with NRX-101 is superior to lurasidone in improving 

 
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symptoms of depression as measured by the MADRS over 6 weeks of treatment. The null 
hypothesis for the primary endpoint is the mean change from baseline of MADRS-10 for NRX-
101 is the same as lurasidone. Baseline is defined as MADRS-10 score at study entry.  
The null hypothesis is no difference in the mean change in the MADRS-10 score from baseline to 
Day 42/exit between both treatment groups, while the alternative hypothesis is that there is a larger 
mean improvement in the NRX-101 group than the lurasidone group. The study is to have 80% 
power to detect a 0.66 effect size post-baseline for a two-sided test with 5% Type 1 error using 
mixed model repeated measures (MMRM).  
16.3.3 Key Secondary Hypotheses 
The key secondary hypothesis are that: 
• treatment with NRX-101 is superior to lurasidone in improving symptoms of suicidality as 
measured by the CGI-SS over 6 weeks of treatment. The null hypothesis for the primary 
endpoint is the mean change from baseline of CGI-SS for NRX-101 is greater than or equal 
to the mean change from baseline of CGI-SS for lurasidone while the alternative hypothesis 
is that the mean change from baseline of CGI-SS is less than the mean change from baseline 
of CGI-SS for lurasidone (improvement). Baseline is defined as CGI-SS score at this study 
entry. 
• that NRX-101 is superior to lurasidone in time to treatment failure as defined as: study 
discontinuation due to Adverse Events; psychiatric hospitalization; or requiring a change 
in antidepressant treatment. Time to treatment failure may be ascertained as the treating 
physician’s determination of a study discontinuation due to lack of efficacy; withdrawal 
due to a treatment related adverse event a psychiatric hospitalization; or the patient 
requiring any change in their baseline antidepressant, mood stabilizer, or antipsychotic 
medication. Titration or change in timing of administration of study medication will not be 
considered a failure of therapy. Lack of efficacy is defined as the need to implement a new 
treatment plan or an increase in suicidal ideation (a score of 4 or 5 on the C-SSRS, emergent 
suicidality requiring hospitalization), or increase in depressive symptoms (a score increase 
of ≥5 for two consecutive visits on the MADRS total score). The need to implement a new 
treatment plan includes the addition of new antidepressant medication or somatic treatment 
(e.g. ECT or rTMS treatment) or an escalation of care such as hospitalization (i.e. moving 
the patient from outpatient care to initiating inpatient, partial or day hospitalization). Time 
to failure will be assessed using a Kaplan-Meier lifetable. The formal hypothesis test will 
be to detect a 0.421 hazard ratio (HR) with 80% power for a two-sided test using a 
proportional hazard model; a 0.545 hazard ratio reaches two-sided p=0.05. 

 
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16.4 Efficacy Endpoints 
16.4.1 Primary Efficacy Endpoints 
The primary efficacy endpoint is the change from baseline in the total MADRS score as measured 
by psychometric raters assessed over 42 days post randomization by mixed-model repeated 
measures analysis. 
16.4.2 Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are: 
• Change from baseline in CGI-SS score as measured by treating prescriber assessed over 
42 days post randomization by mixed-model repeated measures analysis. 
• Time to Treatment Failure (TTF) A Kaplan-Meier lifetable will be constructed for the time 
to failure of therapy. Failure of therapy will be defined as the treating physician’s 
determination of a study discontinuation due to lack of efficacy; withdrawal due to a 
treatment related adverse event a psychiatric hospitalization; or the patient requiring any 
change in their baseline antidepressant, mood stabilizer, or antipsychotic medication. 
Titration or change in timing of administration of study medication will not be considered 
a failure of therapy. 
The additional efficacy endpoints are: 
• Change from baseline to endpoint in Suicidal Thoughts on the MADRS (MADRS item 10)  
• Mean change from baseline to Day 14 in total MADRS score 
• Change from baseline to endpoint in each item of the Suicide Ideation and Behavior 
Assessment Tool (SIBAT) Module 7 (clinical global impressions of frequency of suicidal 
thinking, severity of suicidality, and imminent and long-term risks)  
16.4.3 Other Exploratory Efficacy Endpoints 
The following other efficacy endpoints will be explored: 
• Remission from suicidality: A Kaplan-Meier lifetable will be constructed for the 
remission duration from response onset where remission is defined as reaching CSSR-S ≤ 2 
and remaining through the study. Remission rate is defined as percent remaining in 
remission. 
Collectively, symptom improvement will be evaluated by assessing changes in the secondary 
outcome measures within and between treatment groups for each of the following at the times 
specified on the Schedule of Study Activities: 
• Montgomery Asberg Depression Rating Scale (MADRS) (Montgomery, Åsberg 1979) 
• Clinical Global Impression of Severity of Suicidality Scale (CGI-SS) 

 
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• Concise Health Risk Tracking – Self Report (CHRT-SR) and Clinician Rating (CHRT-C) 
scales (Trivedi et al., 2011) 
• Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962). 
16.4.4 Other Efficacy Endpoints of Interest 
The following additional endpoints will be recorded and analyzed by treatment group: 
• Dose per treatment group 
• Suicide rates (attempted and completed) 
• Time to all-cause study discontinuation (and reason for discontinuation) due to any reason 
such as withdrawal due to an adverse event, or patient or investigator decision to withdraw 
• Rate of participants who achieve a resolution of suicide risk by Clinical Global Judgement 
of Suicide Risk [CGI-SR] 0 or 1) or by MADRS (suicidal ideation item #10 of 0 or 1) 
• Proportion of participants who are treated with new SSRIs or have increased SSRI dosages 
• Proportion of participants who discontinue SSRIs or have reduced SSRI dosages 
• Efficacy for each MADRS factor; mania, depression, irritability, anxiety, and psychosis 
16.4.5 Diagnostic Metric 
The following metrics will be evaluated at baseline: 
• MINI 7.0.2 
16.5 Safety Assessments 
• Change from baseline to endpoint (Day 42) in C-SSRS score 
• Change from baseline to endpoint (Day 14) in C-SSRS score 
• Mean change in BARS through Day 42 to assess akathisia 
• Percent in remission at Day 42/exit, defined as having achieved a MADRS score of ≤ 10 
during the last two visits (14 days) 
• Rates of discontinuation between the arms 
16.5.1 Overall Adverse Events 
Separate and combined safety analyses will be performed for the Safety population. All safety 
results will be presented separately for each treatment group. Safety endpoints will include adverse 
events (AEs), vital signs, ECGs, and laboratory parameters. 
The principle of treatment emergence will be employed for the analysis of AE data. Treatment 
emergence is defined as any event that occurred following the initiation of therapy and was not 

 
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present at baseline, or one which represents an exacerbation of a condition present prior to study 
entry (pre-existing). 
Unresolved AE outcomes at the end of the study will be followed for an additional seven days or 
until resolution, whichever occurs earlier. 
Adverse events will be classified by the Medical Dictionary for Regulatory Activities (MedDRA). 
For each study treatment, safety data will be collected and analyzed until treatment-emergent AEs 
are resolved. The type, incidence, timing (onset, duration), relationship, and severity of treatment-
emergent AEs will be reported. Reasons for withdrawal due to AEs will also be reported. 
Two-sided Fisher Exact tests will be performed to compare the two treatment groups with respect 
to incidence at the system order class level and for any preferred terms with >10 percent overall 
incidence. 
16.5.2 Other Safety Measures 
The timing and incidence of adverse findings will be compiled following planned surveillance of 
all study participants by a designated safety monitor. 
Vital signs and ECGs will also be evaluated within and between study treatment groups. The 
overall ECG interpretation will be reported as normal or abnormal; if abnormal, then the percent 
clinically significant will be reported. 
While symptom improvement will be evaluated by assessing changes in the secondary outcome 
measures (CHRT, MADRS, and CGI-SS), safety measures in the C-SSRS, PRISE, BPRS, and 
BARS (including the global severity rating) will be evaluated within and between study treatment 
groups. The timeframe is for both lifetime and the past six months for the baseline Screening scale 
and since the last visit for the Since Last Visit scale. 
16.6 Sample Size Calculations  
16.6.1 Background 
For DCS treatment group in major depressive disorder Heresco-Levy identified a 0.91 effect size 
for Hamilton-D Total and a 0.95 effect size for BDI-II (Heresco-Levy, 2013) and an effect size of 
>1 was seen in the phase 2 STABIL-B study with a similar effect size observed by Chen and 
Heresco-Levy.  
A more modest 0.66 effect size is targeted in the sample size calculations assuming a 1:1 allocation 
for a two-sided hypothesis test with 5 percent Type I error. 
16.6.2 Power and Significance 
These sample size calculations are based on the alternative hypothesis corresponding to a 0.66 
effect size which corresponds to a mean 8.85-unit MADRS-10 advantage change from baseline 
for NRX-101 vs control.  A total of 74 subjects are to be randomized 1:1 to support the final 
analysis.  As summarized below in Table 6, there is 80% power to detect a 0.66 effect size; a 

 
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0.462 effect size would reach two-sided p=0.05.  A 0.462 (moderate) effect size reflects a 50 
percent drop (based on lurasidone published data) in mean change from baseline for lurasidone 
with an assumed standard deviation of 13.4; this approximately corresponds to a -16 mean CFB 
for NRX-101 and a -10 mean CFB for lurasidone. 
Table 6 
MADRS-10 Change From Baseline Outcomes: T-tests 
Power 
Significance 
 Test significance level, α 
0.05 
0.05 
 1 or 2 sided test 
2 
2 
 Effect size, d = |m1 - m2| / s 
0.66 
0.462 
 Power (%) 
80 
NA 
 N per group 
37 
37 
The secondary efficacy hypotheses will also be evaluated using a hierarchical testing strategy 
where testing continues as long as two-sided p<0.05 is reached. The first such hypothesis to be 
tested will be for primary endpoint MADRS change from baseline to endpoint, then change from 
baseline in CGI-SS, followed by time to treatment failure in the NRX-101 and lurasidone groups. 
16.6.3 Interim Analyses 
Two interim analyses are planned.  The first interim analysis (IA) assessing safety will be 
conducted six weeks after the first 30-35 participants have been followed for 6 weeks and the 
second IA assessing futility (primary efficacy endpoint) will be performed after the first 45-50 
participants have been followed for 6 weeks.  
Each interim analysis has a different objective with neither interim analysis spending any Type 1 
error.  The study will be stopped at the first interim analysis if Serious Adverse Events are deemed 
statistically significantly more common in the NRX-101 group compared to the lurasidone group 
in a manner deemed by the DMC to pose a potential danger to human subjects.  The study will be 
stopped at the second IA for futility if the conditional power (CP) is less than 10%.  In the event 
that the study is not stopped for either safety or futility, then enrollment will continue until a total 
of 74 subjects are randomized.  This preserves two-sided p=0.05 for the final analysis. 
The unblinded Sponsor biostatistician will perform the interim analyses for the Data Safety 
Monitoring Board (DSMB). The blinded Sponsor biostatistician will then adjudicate cases with 
respect to intercurrent events which impact analysis inclusion.   
16.7 Adjudication of Primary Endpoint 
All rating sessions for MADRS-10 and C-SSRS will be recorded as audio files and reviewed by 
central master-raters with > 25 years of experience. Any MADRS-10 total score the differs by 
more than three points from the master-rater score will be deemed non-congruent. All non-
congruent subject-visits from any site with >10% non-congruent scores will be sent to an 
independent adjudicator, previously determined to have >90% concordance with study master 

 
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raters on standardized training data. In the event of adjudication as above, the independent 
outside rater score shall be considered as the subject-visit primary study endpoint. 
16.8 Statistical Analysis Approach 
16.8.1 Software 
All calculations will be performed using SAS statistical software, version 9.3 or later, and 
StatXact, version 10 or later.  
16.8.2 Display Formats 
All efficacy and safety data will be displayed in tables and listings separately for each treatment 
group.  
16.8.3 Conventions 
Study visit dates will be analyzed using the nominal visit instead of the actual visit date. 
Means, mean changes, standard deviations, and ranges will be presented separately for each 
treatment group. These endpoints will be evaluated using a paired t-test and between study 
treatment groups using an unpaired t-test at each time; these p-values will be presented as 
descriptive statistics. 
For continuous variables, the mean, standard deviation, minimum, median and maximum will be 
presented, together with the total number of observations and the number of missing and non-
missing values.  
For ordinal and categorical variables, absolute and relative frequencies will be reported. Relative 
frequencies will be based on all observations and reported as percentages. Unless otherwise 
specified, percentages will be based on the number of participants with data and will not be 
calculated for missing categories. 
Adverse events, medical histories, and concomitant medications will be reported on a patient and 
an event basis. Percentages will be calculated using the number of participants in the Safety 
population analysis set as the denominator. 
All hypotheses will be tested at 5 percent (final analysis) level of significance using a two-sided 
test unless otherwise specified. 
16.8.4 Estimand Structure 
Analyses will be conducted in accordance with ICH E9 (R1) analysis principles as summarized 
below. 
Primary scientific question of 
interest 
The primary study hypothesis is that treatment with NRX-
101 is superior to lurasidone in improving symptoms of 
depression as measured by the MADRS over 6 weeks of 
treatment. The null hypothesis for the primary endpoint is 

 
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the mean change from baseline of MADRS-10 for NRX-
101 is the same as lurasidone while the alternative 
hypothesis is that the mean change from baseline of 
MADRS-10 is larger than the mean change from baseline 
of MADRS-10 for lurasidone. Baseline is defined as 
MADRS-10 score at study entry.  
 
Target population 
The mITT population will be the primary analysis 
population. The mITT population is defined through 
appropriate inclusion/exclusion criteria as specified in the 
protocol and blinded BDRM decisions. 
 
Treatment of interest 
NRX-101 
Outcome Variable 
MADRS-10 (and C-SSRS) will be recorded as audio files 
and reviewed by central master-raters with any non-
congruent subject-visits from any site with >10% non-
congruent scores sent to a qualified independent adjudicator 
to be considered as the subject-visit primary study endpoint. 
 
Summary Measure 
The contrast-estimated MADRS-10 Week 6 MMRM will 
use all post-baseline data with LOCF in the mITT 
population excluding all outcomes after BDRM-approved 
exclusions.  The model will include treatment and the 
following four baseline stratification factors in addition to 
baseline MADRS-10: (1) sex, (2) mood stabilizer use, (3) 
anti-psychotic use, and (4) evidence of suicide event in their 
lifetime. The model will include treatment group, study 
visit, the interaction between study visit and treatment 
group, baseline MADRS-10, and the four baseline 
covariates as fixed effects. An unstructured error structure 
will be assumed.  
 
Intercurrent Events 
A BDRM will adjudicate all intercurrent events which may 
redact outcomes after disqualifying events; these 
intercurrent events may represent major protocol 
deviations.  Any ITT subject with no post-baseline 
MADRS-10 observations will use the baseline MADRS-10 
observation to replace all post-baseline MADRS-10 
observations.  
 
 
  

 
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16.8.5 General Methodology 
The Mixed-Effect Model Repeated Measure (MMRM) will be the primary analysis for the primary 
efficacy endpoint (MADRS change from baseline); an unpaired t-test will be a secondary analysis. 
The proportional hazard model (PHREG) will be the primary analysis for time to event endpoints 
(time to relapse, time to discontinuation); the unstratified log rank test will be a secondary analysis. 
The MMRM and PHREG models will all include treatment and the following four baseline 
stratification factors: 
• sex 
• mood stabilizer use 
• anti-psychotic use 
• evidence of suicide event in their lifetime. 
All primary analyses will be in the ITT population as primary and repeated in the Per Protocol 
population if >5 percent are excluded. 
All of the instruments used to measure SSIB or depression constitute serial continuous and ordinal 
outcomes that will be analyzed using MMRM with LOCF to account for missing data and early 
discontinuations. The models will include treatment group, study visit, the interaction between 
study visit and treatment group, the baseline level of the variable being analyzed, and the above 
four pre-defined baseline stratification factors as fixed effects. The primary endpoint change from 
baseline MADRS-10 will be analyzed using the MMRM model which will include baseline 
MADRS; treatment group; study visit; study visit*treatment; sex, mood stabilizer use, anti-
psychotic use, and evidence of suicide event in their lifetime as defined above. An unstructured 
error structure will be assumed. 
SAS PROC MIXED will be used for continuous endpoints and PROC GENMOD will be used for 
binary endpoints. 
In addition, multiple imputation will be performed to address any missing data. The method of 
Little and Rubin will be used. The presentation of the results for the primary efficacy endpoints 
using the ITT population will be based on the observed data with multiple imputation for missing 
endpoint data using SAS PROC MI. Missing data will be imputed using MCMC imputation under 
the assumption of a missing at random using the ITT population. The SAS® procedure PROC MI 
will be used for the MCMC imputation of 25 complete data sets. 
16.8.6 Other Time to Event Efficacy Endpoints 
Other time-to-event outcomes (all-cause discontinuation, and remission duration) further 
characterize this multi-component disorder. Time to event is a more sensitive measure than an 
assessment at a fixed time. Time to such events will be displayed using a Kaplan-Meier lifetable, 
with the treatment groups compared using two-sided unstratified log rank tests (secondary) and a 
proportional hazard model (primary) to include the above cited baseline covariates.  

 
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Treatment Failure will be centrally judged blind in real time by the study physician using baseline 
measures of depression and suicidality as a guide. Treatment failure is defined above. 
16.8.7 Secondary Efficacy Endpoints 
All of the instruments used to measure SSIB or depression constitute serial continuous and ordinal 
outcomes that will be analyzed using MMRM with LOCF, which accounts for missing data and 
early discontinuations. Results will be presented separately for each treatment group. 
The models will include treatment group, study visit, the interaction between study visit and 
treatment group, the randomization baseline of the variable being analyzed, and the three baseline 
stratification factors as fixed effects. The reason for missing data will be evaluated as a condition 
of MMRM analysis.  
16.8.8 Other Endpoints of Interest  
The following additional endpoints will be recorded and analyzed by treatment group for both 
study phases: 
• Dose per treatment group 
• Suicide rates 
• Proportion of participants who are treated with new SSRIs or have increased SSRI dosages 
• Proportion of participants who discontinue SSRIs or have reduced SSRI dosages 
• Efficacy for each BPI factor. 
Dose per treatment group will be displayed graphically over time per study treatment group. The 
percent decreasing and increasing over time relative to starting dose will be displayed per study 
treatment group.  
Time to all-cause study discontinuation and time to discharge will be displayed using a Kaplan-
Meier lifetable. 
The following three measures will be separately evaluated using a two-sided Fisher Exact test to 
compare treatments: 
• the need to implement a new treatment plan. 
• an increase in suicidal ideation (a score of >4 on the C-SSRS, emergent suicidality 
requiring hospitalization). 
• an increase in depressive symptoms (a score increase of ≥5 for two consecutive visits on 
the MADRS total score).  
The incidence of hospitalization and ER visits will be evaluated using a Wilcoxon Rank Sum test 
to compare each study treatment group. 

 
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The proportions of participants discontinuing SSRIs or reducing SSRI dosages will be displayed 
graphically over time per study treatment group. The percent discontinuing SSRIs and reducing 
SSRI dosages relative to starting dose will be displayed per study treatment group.  
16.8.9 Safety Endpoints 
Adverse events will be classified by MedDRA. For each study treatment, safety data will be 
collected and analyzed while on treatment or until treatment-emergent adverse events are resolved. 
The type, incidence, timing (onset, duration), relationship, and severity of AEs will be reported for 
treatment-emergent and SAEs. Reasons for withdrawal due to AEs will also be reported. 
Narratives will be written for every AE classified as serious or associated with attempted suicide 
or death.  
Safety and tolerability will be assessed using two-sided Fisher Exact tests to compare overall 
adverse event incidence for NRX-101 vs. lurasidone. Mean changes from randomization baseline 
will be displayed for each serum chemistry and hematology parameter as well as the shift; unpaired 
t-tests will be used to compare treatments. In addition, paired t-tests will be performed for the 
changes from randomization baseline for each study treatment group. 
Vital signs and ECGs (means and mean changes from baseline will also be evaluated within 
treatment groups using paired t-tests and between study treatment groups using unpaired t-tests. 
Percent with abnormal vital signs, heart rate, QRS duration, PR interval, RR interval, QT, and 
QTcF will be reported. McNemar paired comparison tests will be performed within study 
treatment groups for the abnormal discordant percent while two-sided Fisher Exact tests will be 
performed to compare incidences between treatment groups. 
Blood draws for chemistries and hematologies will be evaluated within and between study 
treatment groups. Abnormality rates will be presented relative to established site-specific normal 
ranges and whether or not the abnormality is clinically significant. McNemar paired comparison 
tests will be performed within study treatment groups for the abnormal percents while two-sided 
Fisher Exact tests will be performed to compare incidences between treatment groups. 
17. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
17.1 Study Monitoring 
Potential study sites will be evaluated by the sponsor in conjunction with the CRO to determine 
suitability for the proposed study. Information reviewed will include, but will not be limited to, 
facility details and site capabilities, past performance in similar studies, investigator and staff 
experience, ongoing studies at the site, projected enrollment, and FDA or other agency audit 
findings. Study sites may be asked to complete a study-specific Site Selection Questionnaire and 
other documents for consideration for participation, and clinical study monitors may make a Site 
Qualification Visit prior to completing the evaluation process. Upon completion of this evaluation, 
the sponsor will invite the chosen sites for participation. 

 
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Prior to patient enrollment, a study initiation visit will be completed at each investigational site to 
ensure the following: IRB approval has been obtained and documented prior to patient screening, 
the investigators and study personnel are appropriately trained and clearly understand the study, 
and the investigators and study personnel accept the obligations incurred in undertaking this 
clinical investigation. Due to the current COVID-19 Pandemic these visits may be a virtual 
videoconference visit. 
Raters proposed by each site will be evaluated on the basis of experience and education for each 
instrument used in the study. Raters with the appropriate levels of experience and education will 
be trained by an independent third party in the use of each instrument and approved to administer 
that instrument in the study. Sites will not be approved to begin enrollment activities until they 
have at least one rater approved for each clinician-administered instrument (See Appendix 3: Rater 
Training Manual). 
Qualified clinical monitors will conduct investigational site monitoring visits on a routine basis to 
ensure that all investigators conduct the study in compliance with the protocol and applicable 
regulations. These monitoring visits may be virtual visits video/teleconference visits. The site will 
receive notification prior to each monitoring visit during the course of the study. It is expected that 
the investigator and/or sub-investigator and other appropriately trained study staff are available on 
the day of the visit in case any questions may arise. Due to the Pandemic situation, sites may also 
provide a secure access to portions of electronic medical records, and or upload de-identified 
information onto a secure platform. 
Periodic monitoring visits will be made in accordance with the approved monitoring plan at all 
active study sites throughout the clinical study to ensure that the investigator obligations are being 
fulfilled and all applicable regulations and guidelines are being followed. These visits will assess 
continued acceptability of the facilities, ensure the protocol and investigational plan are being 
followed, the IRB has been notified of approved protocol changes as required, complete records 
are being maintained, appropriate and timely reports have been made to the sponsor, CRO, and the 
IRB, and the site’s Principal Investigator is executing all agreed activities. 
The sponsor retains the right to remove either the Principal Investigator or the investigational site 
from the study for issues of non-compliance with the protocol or regulatory requirements. 
On one or more occasion, the study site may be inspected or audited by the sponsor representative 
or a third party. The investigator will be informed in advance of the visit(s). 
Upon completion of the clinical study (when all participants at the site have completed follow up 
visits, all data has been entered in EDC and cleaned, all queries resolved, and final electronic 
signatures have been obtained), a study closeout visit will be performed. Any unused study 
materials and equipment will be collected and returned to the depot. The monitor will help to 
ensure that the investigator’s regulatory files are up to date and complete and that any outstanding 
issues from previous visits have been resolved. Other issues that will be reviewed at this visit 

 
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include: discussing retention of study files, possibility of site audits, publication policy, and 
ensuring that the investigator will notify the IRB regarding study closeout. 
17.2 Audits and Inspections 
The Sponsor and its representatives will have direct access to source data and documents for study 
monitoring. Additionally, the IRB and FDA may review source data following appropriate 
guidelines for this process. 
17.3 Institutional Review Board (IRB) 
The study protocol and any amendments will be reviewed by an IRB. The IRB will review the 
informed consent form, their updates (if any), and any written materials given to the participants.  
IRB approval will be obtained and documented prior to patient enrollment and screening. Before 
study initiation, the investigator must have written and dated approval from the IRB for the 
protocol, consent form, patient recruitment materials/process (e.g., advertisements), and any other 
written information to be provided to participants. 
The investigator will provide the IRB with reports, updates, and other information (e.g., Safety 
Updates, Amendments, and Administrative Letters) according to regulatory requirements and 
Institution procedures. 
A detailed list of required regulatory documents to be submitted to the CRO and/or sponsor, will 
be sent upon final approval of the protocol. 
18. 
QUALITY CONTROL AND QUALITY ASSURANCE 
18.1 Source Data and Records  
Source data are all the information in original records and certified copies of original records of 
clinical findings, observations, laboratory reports, and data sheets provided by the sponsor or other 
activities in the study, that are necessary for the reconstruction and evaluation of the study. The 
investigator will permit study-related monitoring, audit(s), IRB review(s), and regulatory 
inspection(s), with direct access to all the required source records. 
All study records will be retained for at least two years following the date on which the drug is 
approved by the regulatory authority for marketing for the purposes that were the subject of the 
investigation. In other situations (e.g., where the investigation is not in support of or as part of an 
application for a research or marketing permit), the requirement will be two years following the 
date on which the entire clinical program is completed, terminated, or discontinued, or when the 
investigational application under which the investigation is being conducted is terminated or 
withdrawn by the regulatory authorities. 

 
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In the event the site’s Principal Investigator retires, relocates or for any other reason withdraws 
from the responsibility for maintaining records for the period of time required, custody of the 
records may be transferred to any other person who will accept responsibility for the records. 
Notice of such a transfer must be given in writing to the Sponsor. The Investigator must contact 
the Sponsor prior to disposal of any records related to this study.  
18.2 Reporting Study Data 
The eCRF is an integral part of the study and subsequent reports. The eCRF will be used to capture 
all study data recorded in the patient’s medical record that is applicable to this study. The eCRF 
must be kept current to reflect patient status during the course of the study.  
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in the eCRF, an Internet-based electronic data collection system. All 
details regarding eCRF completion and correction will be explained to the investigator. The eCRF 
includes edit check and query systems that seamlessly integrate with the data entry system. All 
modifications to the data in the eCRF are tracked by an electronic audit trail (date and identity of 
the person making the change are instantaneously recorded). The eCRF is 21CFR Part 11 
compliant. 
If the investigator authorizes other persons to make entries in the eCRF, the names, positions, and 
signatures of these persons must be supplied to the sponsor. 
The Investigator, or designated representative, should complete the eCRF as soon as possible after 
information is collected, preferably on the same day that a study patient is seen for an examination, 
treatment, or any other study procedure. By design, an explanation must be provided for all missing 
data, altered data, and/or out of range data. 
The completed eCRF must be reviewed and signed by the site’s Principal Investigator or by a 
designated sub-investigator. 
Final monitored eCRFs will be provided by the sponsor to the sites at the end of the study in the 
format of a PDF file for archival purposes. 
18.2.1 Clinical Trial Registry 
The study will be posted to Clinicaltrials.gov, and results will be reported in accordance with 
Clinicaltrials.gov guidelines. 
18.3 Confidentiality of Patient Data 
The risk of loss of privacy is judged to be minimal. Sites will enter patient data directly into the 
eCRF, which will be managed by the CRO or contracted data management company. Participants 
will be assigned study ID numbers. 
Potential risks to data confidentiality will be mitigated by requirements for the de-identification of 
all study data and by security protocols for all data capture systems. All users will be tracked and 

 
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provided access in a secure fashion following established Standard Operating Procedures (SOPs) 
for this process. 
As with all research data, information gathered by the study will be used only for aggregate 
analysis; it will not be released with any information that identifies research participants. Uses and 
risks related to data collection will be outlined in the informed consent and reviewed with the 
participants. 
19. 
ETHICAL CONSIDERATIONS 
19.1 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki, in compliance with the approved protocol, GCP, and applicable regulatory 
requirements. 
Participants must be capable of understanding the nature of this study, its potential risks, 
discomforts, and benefits. Study physicians will obtain consent after they have fully explained the 
study purpose and its procedures, and after potential participants have demonstrated an 
understanding of the protocol, willingness to participate, and competency to consent.  
19.2 Patient Information and Consent 
Participants must be capable of understanding the nature of this study and its potential risks, 
discomforts, and benefits. Study physicians will obtain consent after they fully explain the study 
purpose and its procedures, and the potential patient demonstrates an understanding of the 
protocol, willingness to participate, and competency to consent.  
The investigator must ensure that participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical trials in which they volunteer to 
participate. Preparation of the site-specific informed consent form is the responsibility of the site 
Principal investigator and must include all elements required by CFR 21 Part 50.25 and the IRB. 
Each patient will receive the informed consent form for the study. The document will be read by 
the patient and also reviewed by the patient with a clinician on the research staff prior to 
participating in the study. Any questions, concerns, or ambiguities will be clarified by the site 
investigator or another study clinician prior to the patient signing the informed consent form. 
Participants will only begin study participation after signing the informed consent form. 
 
 
 

 
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20. 
REFERENCES 
Aiken, C.B., Weisler, R.H., & Sachs, G.S. (2015). The Bipolarity index: a clinician-rated measure 
of diagnostic confidence. Journal of Affective Disorders, 177, 59–64. 
Alphs L, Canuso C, Williamson D. P.1.k.032 The Suicide Ideation and Behavior Assessment Tool: 
development of a novel measure of suicidal ideation and behavior and perceived risk of 
suicide. Eur Neuropsychopharmacol. 2015;25:S371. 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 May;154:672-6 
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant 
effects of ketamine in depressed patients. Biol Psychiat. 2000;47(4):351-4. 
Coryell W, Kriener A, Butcher B, Nurnberger J, McMahon F, Berrettini W, Fiedorowicz J. Risk 
factors for suicide in bipolar I disorder in two prospectively studied cohorts. J Affective Disorders. 
2016; 190:1-5. 
Crane GE. Cycloserine as an anti-depressant agent. Am J Psychiat. 1959;115:1025–9. 
Crane GE. The psychotropic effects of cycloserine: a new use for an antibiotic. Compr Psychiat. 
1961;2:51–9. 
Cyrus R. Mehta, Stuart J., Pocock. Adaptive Increase in Sample Size when Interim Results are 
Promising: A Practical Guide with Examples. Statist. Med. 2000; 00:1–6. 
Harada T, Inada K, Yamada K, Sakamoto K, Ishigooka J. A prospective naturalistic study of 
antidepressant-induced jitteriness/anxiety syndrome. Neuropsychiatric disease and treatment. 
2014;10:2115-21. 
Heresco-Levy U, Javitt DC, Gelfin Y, Gorelik E, Bar M, Blanaru M, et al. Controlled trial of D-
cycloserine adjuvant therapy for treatment-resistant major depressive disorder. J Affect 
Disorders. 2006;93(1-3):239-43. 
Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, et al. A randomized add-on 
trial of high-dose D-cycloserine for treatment-resistant depression. Int J Neuropsychop. 
2013;16(3):501-6. 
Hood WF, Compton RP, Monahan JB. D-cycloserine: a ligand for the N-methyl-D-aspartate 
coupled glycine receptor has partial agonist characteristics. Neurosci Lett. 1989;98(1):91-5. 
Javitt DC, Composition and method for treatment of psychosis and depression in humans. US 
patent application 2014/0018348, filed Jan 2014. www.uspto.gov. 
Javitt D, Nirenberg A, Mathew S, et. al. Sequential Treatment With IV Ketamine Followed by 
Combined Oral D-Cycloserine + Lurasidone (NRX-101) forSevere Bipolar Depression and 
Suicidality: Preclinical and Clinical Findings. Neuropsychopharmacol 2018:W134. 
https://doi.org/10.1038/s41386-018-0268-5 

 
NRX-101_003 
Page 61 of 75 
09 NOVEMBER 2023 
 
Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of twelve-
month DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Archives 
of Genera. Psychiatry, 2005 Jun;62(6):617–27. 
Krystal JH, Bennett A, Abi-Saab D, et al. Dissociation of ketamine effects on rule acquisition and 
rule implementation: possible relevance to NMDA receptor contributions to executive 
cognitive functions. Biol Psychiatry. 2000;47(2):137–43. 
Little R, Rubin D. Statistical Analysis with Missing Data. John Wiley and Sons, New York 2002. 
Loebel A, Cucchiaro J, Silva R, Kroger H, Hsu J, Sarma K, et al. Lurasidone monotherapy in the 
treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J 
Psychiat. 2014a;171(2):160–8. 
Loebel A, Cucchiaro J, Silva R, Kroger H, Sarma K, Xu J, et al. Lurasidone as adjunctive therapy 
with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, 
placebo-controlled study. Am J Psychiat. 2014b;171(2):169–77. 
Lopes T, Neubauer P, Boje KM. Chronic administration of NMDA glycine partial agonists induces 
tolerance in the Porsolt swim test. Be. 1997;58(4):1059–64. 
Mahli, GS,  Thoughts on suicidal thinking in bipolar disorder. Bipolar Disord. 2015 Feb; 17(1):19–
21. doi: 10.1111/bdi.12276. Epub 2014 Nov 3. 
Mehta CR, Pocock SJ. Adaptive Increase in Sample Size when Interim Results are Promising: A 
Practical Guide with Examples. Statist. Med. 2011; 30, 28, 3267-3284. 
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Brit J 
Psychiatry 1979;134(4):382-89. 
Nierenberg, A. A., Gray, S. M., & Grandin, L. D. (2001). Mood disorders and suicide. J Clin 
Psychiatry, 62 Suppl 25, 27-30. 
Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychol Rep. 1962;10(3):799-812. 
Pompili M, Gonda X Serafini G. Epidemiology of Suicide in Bipolar Depression. Bipolar 
Disorders. 2013;15(5):457-90. 
Popovic D, Vieta E, Azorin JM, Angst J, Bowden CL, Mosolov S, et al. Suicide attempts in major 
depressive episode: evidence from the BRIDGE-II-Mix study. Bipolar Disorders. 2015. 
Posner K, Oquendo MA, Gould M, Stanley B, and Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry 2007. 164:1035-43. 
Puddu PE., Jouve R., Marlotti S., et al. Evaluation of 10 QT prediction formulas in 881 middle-
aged men from the Seven Countries study: emphasis on the cubic root Fridericia's equation. J 
Electrocardiol 1988. 2:219–29. 

 
NRX-101_003 
Page 62 of 75 
09 NOVEMBER 2023 
 
Rush, A.J., Asberg, M., 1999. Patient Rated Inventory of Side Effects (PRISE). Unpublished rating 
scale. University of Texas, University of Texas Southwestern Medical Center, Dallas.  
Sachdev PS, Brune M. Animal models of acute drug-induced akathisia - a review. Neurosci Behav 
R. 2000;24(3):269–77. 
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. 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. 
1998;59:22–33. 
Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R. Adaptation of N-methyl-D-aspartate 
(NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy 
of depression. Pharmacopsychiatry. 1996;29(1):23-6. 
Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A, et al. Risk of suicidality 
in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food 
and Drug Administration. BMJ. 2009;339: b2880. 
Tan XL, Kern DM, Cepeda MS. Identifying Anticipated Events of Future Clinical Trials by 
Leveraging Data from the Placebo Arms of Completed Trials. Ther Innov Regul Sci. 2021 
Mar;55(2):454-461. doi: 10.1007/s43441-020-00237-w. Epub 2020 Nov 9. PMID: 33165761; 
PMCID: PMC7864837. 
Targum SD, Pendergrass JC. Site-independent confirmation of subject selection for CNS trials: 
`dual’ review using audio-digital recordings. Ann Gen Psychiatry. 2014;13(1):21. 
Trivedi MH, Wisniewski SR, Morris DW, Fava M, Gollan JK, Warden D, Nierenberg AA, Gaynes 
BN, Husain MM, Luther JF, Zisook S, Rush AJ Concise Health Risk Tracking scale: a brief 
self-report and clinician rating of suicidal risk J Clin Psychiatry 2011 Jun 72 6 757-64. 
Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit 
antidepressant actions. Eur J Pharmacol. 1990;185(1):1-10. 
Wisniewski SR, Rush AJ, Balasubramani GK, Trivedi MH, Nierenberg AA, for the STARD 
Investigators. Self-rated global measure of the frequency, intensity, and burden of side effects. 
J Psychiatr Pract 2006;12:71–9. 
 
 

 
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21. 
APPENDICES 
Appendix 1: Concomitant Medications 
Appendix 2: Assessment Tools (provided as separate document) 
Appendix 3:  Rater Training Manual 
Appendix 4:  Medications Indicated for Use in Bipolar Disorder 
 
 

 
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Appendix 1 
Concomitant Medications 
Medications Allowed (Y) and Not Allowed (N) as Concomitant Medications 
Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Analgesics 
Y 
Y 
Nonnarcotic analgesics are allowed. Medically 
appropriate episodic use of narcotic analgesics is 
allowed for acute medical indications but is 
limited to no more than three days for each 
episode. Chronic NSAID use is exclusionary; 
tramadol is also not allowed. 
Anesthetics, general 
Y 
(except for 
ketamine, 
which is 
excluded) 
— 
If procedures requiring general anesthesia are to 
occur/have occurred, please contact Medical 
Monitor to report the medical condition(s). 
Anesthetics, local 
Y 
N 
— 
Anorexics 
N 
N 
— 
Antacids 
Y 
Y 
— 
Antiacne 
Y 
Y 
Topical agents only, including topical 
antibiotics. Isotretinoin (Accutane) is not 
allowed. 
Antianginal agents 
N 
N 
— 
Antiarrhythmics 
N 
N 
Amiodarone is excluded. 
Antiasthma agents 
Y 
Y 
— 
Antibiotics 
Y 
Y 
Chronic use of topical antibiotics for acne is 
allowed, with the exception of the MAOI 
linezolid (Zyvox) and isoniazid, which are not 
allowed. Nafcillin, Erythromycin, 
clarithromycin, rifampin are excluded. 
Anticoagulants 
N 
N 
Warfarin (Coumadin) is not allowed. 
Antiplatelet agents are allowed (see 
“Antiplatelets”). 
Anticholinergics 
Y 
Y 
Except for scopolamine. 
Anticonvulsants 
N 
Y 
Gabapentin, lamotrigine and pregabalin are 
allowed. Other anticonvulsants are not allowed, 
including carbamazepine and oxcarbamazepine, 
phenytoin, phenobarbital, rufinamide (CYP3A4 
inducers). 
Stable in dosing at least four weeks prior to 
randomization is required. 

 
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Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Antidepressants 
N 
Y 
Stable (for at least 4 weeks prior to screening), 
ongoing antidepressant therapy is required 
during the course of the study. No dose changes 
are allowed during the study. Monoamine 
oxidase inhibitors (which may have unknown 
drug-drug interactions) are excluded. 
Concomitant use of trazodone (up to 200mg 
daily) is allowed. Nefazodone and St John’s 
Wort are excluded (CYP3A4 inhibitor, inducer, 
respectively).  
Antidiarrheal preparations 
Y 
N 
Only loperamide HCl (Imodium), bismuth 
subsalicylate (Pepto-Bismol), and kaolin 
preparations are allowed. 
Antifungals, systemic 
N 
Y 
Ketoconazole, itraconazol, rifampin and 
rifabutin are excluded. 
Antifungals, topical 
Y 
Y 
Ketoconazole and itraconzole are excluded. 
Antihistamines 
Y 
Y 
The use of combinations containing 
pseudoephedrine or phenylephrine is not 
allowed. Combination products containing the 
word nighttime or are specifically marketed for 
before sleep routinely include an antihistamine 
and are not allowed. Combination products 
ending in “-D” routinely contain a stimulant 
such as phenylephrine, and the appropriate 
limits above apply to them. (See “Cough and 
Cold Preparations” for combination products.) 
Antihypertensives 
N 
Y 
Diltiazem, verapamil are excluded. 
Anti-impotence 
medications 
Y 
Y 
— 
Anti-inflammatory drugs 
Y 
Ya 
Indomethacin (Indocin) and systemic 
corticosteroids are not allowed. Chronic NSAID 
use is exclusionary. 
Antimigraine 
N 
N 
Triptans are not allowed. 
Antinauseants/ 
Antiemetics 
Y 
N 
Phosphoric acid preparations (Emetrol, 
Emecheck), bismuth subsalicylate (Pepto-
Bismol), cola syrup, 5-HT3 receptor antagonists 
(e.g., ondansetron), and prokinetic agents 
(metoclopramide) are allowed. Scopolamine is 
not allowed (see section on anticholinergic). 
Antineoplastics/ 
Immunosuppressant agents 
N 
Yc 
Interferons, methotrexate, and other 
immunosuppressant agents are not allowed. Call 
Medical Monitor for approval for certain cases 
in cancer remission maintaining therapy. 

 
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Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Antiobesity/Appetite 
suppressants 
N 
N 
OTC Alli (Xenical), sibutramine (Meridia), and 
phentermine (Adipex-P and others) are not 
allowed. 
Antiplatelet agents 
N 
Yb 
Aspirin (maximum 325 mg/day) and clopidogrel 
(Plavix) are allowed. Note that use of an SSRI 
or of a triple uptake inhibitor may increase 
bleeding times and possibly prothrombin times. 
Antipsoriatic treatments 
Y 
Y 
Only topical agents are allowed. Acitretin 
(Soriatane) is not allowed. 
Antipsychotics 
N 
Y 
Stable in dosing at least four weeks prior to 
randomization is allowed. Lurasidone will be 
discontinued at study entry. Quetiapine, 
aripiprazole, risperidone, brexpiprazole, 
olanzapine, cariprazine, or lumateperone should 
be discontinued prior to randomization. 
Antismoking medications 
N 
Yc 
Varenicline (Chantix) is not allowed. Chronic 
nicotine replacement may be allowed in certain 
cases after review with Medical Monitor. 
Antiviral agents 
Y 
Y 
Only oral or topical agents are allowed. Only 
acyclovir, famciclovir, valacyclovir, penciclovir, 
docosanal, trifluridine, and vidarabine are 
allowed. Amantadine, rimantadine, and protease 
inhbitors (atazanavir, darunavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, 
tipranavir) are not allowed. Tamiflu (oseltamivir 
phosphate), and Relenza (zanamivir) inhalants 
are permitted for influenza prophylaxis but use 
is limited to a 7- to 14-day course in accordance 
with prescribing information. Interferons are not 
allowed.  
Anxiolytics 
N 
Y 
Chronic, stable treatment with benzodiazepines 
is allowed. Stable in dosing at least four weeks 
prior to randomization is required. 
Barbiturates 
N 
N 
Barbiturates are not allowed. 
Benign prostatic 
hyperplasia treatments 
N 
Yb 
Male patients who have symptoms of obstructed 
voiding should not be included in the study. 
Surgically or medically treated patients must be 
asymptomatic and receiving a stable dosage of 
allowed medications (α-1 blockers, finasteride, 
or dutasteride) for one month before screening. 
Buspirone 
N 
Y 
Stable in dosing at least four weeks prior to 
randomization is allowed. 

 
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Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Cough/cold preparations 
Y 
N 
Use of cough and cold preparations containing 
pseudoephedrine or dextromethorphan is not 
allowed, as are those containing phenylephrine 
Combination products ending in “-D” routinely 
contain a stimulant such as phenylephrine, and 
the appropriate limits apply to them. (See 
“Antihistamines”.) 
Diuretics 
Y 
Yb 
Episodic use of diuretics is restricted to 
treatment of premenstrual symptoms. For 
chronic use, medication and dosage should be 
stable for 1 month before screening. 
Dopaminergics 
N 
Y 
Dopamine agonists for restless leg syndrome are 
allowed. 
Ethyl alcohol 
N 
N 
Participants should not use alcohol during the 
course of the trial because ethyl alcohol may 
increase the possibility and risks of seizures in 
participants receiving cycloserine. 
Gastrointestinal: 
• 
H2-blockers/ 
• 
proton pump 
inhibitors/ 
• 
prokinetic agents 
Y 
Y 
Cimetidine (Tagamet) is not allowed. 
Metoclopramide is not allowed. 
Hormonal 
(noncontraceptive) 
therapies 
N 
Y 
See below. 
Hormone suppressants 
N 
Yb 
Only finasteride (Proscar) and dutasteride 
(Avodart) are allowed. 
Hormones: reproductive 
N 
Y 
Systemic hormonal contraceptives (oral 
contraceptives of estrogen and progestin 
combinations, depot injections such as Depo-
Provera, the contraceptive implant Implanon, 
and/or transdermally delivered contraceptives 
such as Ortho Evra) are allowed. 
Hormones: thyroid 
N 
Y 
Thyroid hormone replacement is allowed 
(dosage of thyroid medication should be stable 
for three months before screening). Therapeutic 
use for psychiatric disorders (e.g., T3 
augmentation) is not allowed. 
Hypoglycemic agents 
N 
Y 
Oral hypoglycemic agents are allowed. Insulin 
is allowed. 
Hypolipidemics 
N 
Yb 
Ezetimibe (Zetia) is allowed. 

 
NRX-101_003 
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Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Hypolipidemics: 
bile acid sequestrants 
N 
N 
— 
Hypolipidemics: fibrates 
N 
Yb 
Gemfibrozil and fenofibrate are allowed 
Hypolipidemics: niacin 
N 
N 
Niacin and niacinamide are not allowed. 
Hypolipidemics: statins 
N 
Yb 
Lovastatin, simvastatin, pravastatin, 
atorvastatin, fluvastatin, and rosuvastatin are 
allowed. 
Laxatives 
Y 
Ya 
Only fiber-based products and docusate sodium 
(Colace) are allowed. 
Lithium 
N 
Y 
Stable in dosing at least four weeks prior to 
randomization is allowed. 
Medications that are 
primarily metabolized by 
CYP2C8 (e.g., 
cerivastatin, paclitaxel, 
repaglinide, sorafenib, and 
torsemide) 
N 
N 
— 
Muscle relaxants 
N 
N 
— 
NMDA receptor 
antagonist 
N 
N 
Memantine is excluded. 
Opioid agonists/analgesics 
(e.g., codeine, 
hydrocodone, methadone, 
morphine, maperidine, 
propoxyphene) and 
antagonists (e.g., 
naltrexone, naloxone, 
nalmefene) 
N* 
N* 
See section on analgesics for exceptions. 
Sedatives/hypnotics 
N 
Y 
Ongoing, stable hypnotic therapy (e.g., 
zolpidem, zaleplon, benzodiazepine hypnotics, 
and low-dose trazodone 50-200mg) will be 
allowed during the course of the study. 
Eszopiclone is not allowed.  
Steroids/systemic 
Y 
N 
Systemic steroid treatment will be allowed only 
for medical emergencies, such as severe allergic 
reactions. 
Steroids/topical and 
inhalant 
Y 
Y 
— 
Steroids/intra-articular 
Y 
NA 
— 

 
NRX-101_003 
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Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Stimulants 
N 
N 
Oral or transdermal methylphenidate, 
amphetamine products or prodrugs, 
pseudoephedrine, modafinil (Provigil), and other 
medications of same category are not allowed. 
Vaccines 
Y 
NA 
— 
a 
If being taken prior to enrolling in the study. 
b 
If being taken for at least three months prior to enrolling in the study and the dose has been stable for 
at least 1 month. 
c 
If approved by Medical Monitor5-HT3 = 5-hydroxytryptomine receptor type 3; 5-
HTP = 5-hydroxytryptophan; ACE = angiotensin-converting enzyme; CR = controlled release; 
DHEA = dehydroepiandrosterone; N = no; NA = not applicable; OTC = over the counter; 
PRN = as needed (prorenataT3prorenataT3=triiodothyronine; Y = yes. 
 
 
 

 
NRX-101_003 
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Appendix 2 
Assessment Tools 
(Provided as separate document) 
• MINI (version 7.0.2) 
• C-SSRS (and the retrospective C-CASA component) 
• CHRT (CHRT-SR and CHRT-C) 
• MADRS 
• PRISE 
• CGI-Severity Suicidality (SIBAT Module 7) 
• BPRS-psychosis subscale 
• BARS 
 
 

 
NRX-101_003 
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Appendix 3 
Rater Manual: Rater Training & Certification Documentation 
STANDARD OPERATING POLICY AND PROCEDURE FOR NRX RATER TRAINING & 
CERTIFICATION DOCUMENTATION 
  
 
1.  POLICY 
To establish NRX Policy for psychometric Rater Training that adheres to site level Institutional 
and Federal Regulatory Guidelines. This Policy is central to the protection of human subjects 
participating in research-related activities and extends to all NRX Staff, <<CRO or Designees, 
including Prevail Infoworks, Obvio Health, etc>> engaged in Clinical Trial activity. All Training, 
Certification, and documentation activity will be designed, implemented, and overseen by NRX 
Rater Program Manager, working in concert with Clinical Operations and Regulatory Affairs, 
which will review and approve all related processes, guidelines, and documentation in compliance 
with NRX and Federal Regulatory Guidelines. 
 
2.  SCOPE 
The scope of this Policy applies to all studies conducted by NRX, and is summarized in the NRX 
Rater Training Guidelines [V4] and NRX 101-003 Psychometric Rater Training 
22Aug22_V5 documents. These policies and procedures apply to NRX, its employees, <<CRO or 
Designees, including Prevail Infoworks, Obvio Health, etc >> as well as subcontractors and others 
who train, manage, oversee and conduct research regulated by the FDA. Rater Experience 
Surveys will document that Staff performing study procedures are appropriately trained. Further, 
protocol-specific Psychometric Rater Training will also be completed prior to the initiation of the 
study-specific assessments. All Documentation and Training will be updated during the study if there 
are any changes to the personnel completing psychometric assessments. All Rater Training 
documentation will be maintained by the NRX Rater Program Manager, and copies will be shared 
with the <<CRO or Designees, including Prevail Infoworks>>  Trial Master File for Study 
Documentation purposes. The scope of procedures applies to all clinical trial related psychometric 
assessments, including planning, performing data collection and reporting the results. Rater 
Training will be overseen by NRX Rater Program Manager, working in concert with <<CRO or 
Designees, including Prevail Infoworks>> and the Site Principal Investigator, who will supervise 
site level Psychometricians and Study Coordinators. 
 
3.  RESPONSIBILITY 
NRX and the Site Principal Investigator share responsibility for ensuring that all Psychometricians 
are qualified by training and experience to conduct their designated research-related duties. The 
NRX Rater Program Manager is responsible for providing initial and continuing training to all 
personnel, documenting and filing training certifications accordingly, and assessing training 
effectiveness through appropriate testing strategies. The NRX Rater Program Manager will ensure 
that protocol-specific psychometric assessments will be completed by an individual who has 
SOP General_001-V1 
Issue Date: 27-Feb-2023 
Effective Date: 01-MAY-2019 
Author: Marc Korczykowski 
RATER TRAINING & 
CERTIFICATION 
DOCUMENTATION 
 
Supersedes Document:  
17Sept 2019 

 
NRX-101_003 
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09 NOVEMBER 2023 
 
achieved the necessary education, experience, qualifications, and protocol-specific training to 
complete study-specific psychometric assessments. The Rater Program Manager will also 
implement training effectiveness measures for primary and secondary clinical endpoints. All Rater 
Training records will be signed by the both the Rater Program Manager and Study Staff member 
receiving the training. Training will reflect both General and Study-Specific conduct of 
psychometric assessments for human subjects research. The Rater Qualification Approval Form 
will be completed and signed by the Rater Program Manager when all training is complete. 
Training, including HIPAA & GCP certifications, will be maintained in the General and Study-
Specific Regulatory Binders (e.g. eMSB or EDC), and will be reviewed on a yearly basis as 
required by FDA regulations. Periodic psychometric assessment reviews will occur at a priori 
defined time points to address any significant risks to quality, safety, or efficacy of the Clinical 
Trial, in addition to any significant risks to human subjects.  
 
4.  APPLICABLE REGULATIONS AND GUIDELINES 
21 CFR 812.40 
General Responsibilities of NRX 
21 CFR 812.43 
Selecting Investigators and Monitors 
ICH E6, 2.8 
The Principles of ICH GCP 
ICH E6, 5.5 
Trial Management, Data Handling and Record Keeping 
ICH E6, 5.18.2 
Selection and Qualification of Monitors 
 
5.  REFERENCES TO OTHER APPLICABLE SOPS & SOURCE DOCUMENTATION 
This SOP affects all other SOPs. 
 
6.  ATTACHMENTS 
GA 103-A: NRX Rater Training Guidelines [V4] 
GA 103-B: Rater Experience Survey 
GA 103-C: NRX 101-003 Psychometric Rater Training 22Aug22_V5 
GA 104-D: Rater Qualification Approval Form  
 
7.  PROCESS OVERVIEW 
General Training and Documentation Plan is defined in: GA 103-C: NRX 101-003 
Psychometric Rater Training 22Aug22_V5 
1. General Training 
2. Protocol-Specific Training 
3. Training Documentation filed in accordance with Institutional and FDA Regulations  
4. Periodic Review & Retraining (*if necessary) 
 

 
NRX-101_003 
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09 NOVEMBER 2023 
 
8.  SPECIFIC PROCEDURES 
A. Training Plan 
1.  Initial Training 
# 
Who 
Task 
Attachment 
Related 
SOP 
1.  
<<NRX Rater 
Program 
Manager>> 
Provide an appropriate period of time for 
Psychometricians to demonstrate 
understanding of General & Study-specific 
requirements, typically 14 days from SIV.  
 
 
2.  
<<NRX Rater 
Program 
Manager>> 
Supervise all Rater training and ensure 
validity and reliability of psychometric 
assessments following GA-103C 
  GA 103-C: 
Psychometric 
Rater 
Training 
 
 
Notes: 
 
2.  Continuing Education 
# 
Who 
Task 
Attachment Related 
SOP 
1.  
<<NRX Rater 
Program 
Manager>> 
Schedule additional Rater Training if 
psychometric validity and reliability does 
not occur, following GA-103C 
 GA 103-C: 
Psychometric 
Rater 
Training 
 
 
Notes: 
 
3.  Periodic Rater Review & Retraining 
# 
Who 
Task 
Attachment Related 
SOP 
1.  
<<NRX Rater 
Program 
Manager>> 
Annually, review all Psychometricans to 
assess competence in performing clinical 
research related duties 
 
 
2.  
<<NRX Rater 
Program 
Manager>> 
If performance deficiencies are noted, 
retrain if necessary 
 
 
 
Notes: 
 

 
NRX-101_003 
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09 NOVEMBER 2023 
 
4.  Documentation of Rater Training 
# 
Who 
Task 
Attachment 
Related 
SOP 
1.  
<<NRX Rater 
Program 
Manager>> 
Provide Rater Training to ensure training 
and experience to conduct protocol-
specific assessments.  
 
 
2.  
<<NRX Rater 
Program 
Manager>> 
Maintain updated Rater training records. 
Provide copies of certificates of 
completion of external training programs 
to the training files and monitor employee 
training and compliance with annual 
performance evaluations. If deficiencies 
are identified, retrain as necessary.  
GA 103-B: 
Rater 
Experience 
Survey & GA 
104-D: Rater 
Qualification 
Approval 
Form  
 
 
Notes: 
 
Revision History: 
Revision 
Date 
Description of changes 
Requested By 
1.0 
17-Sept-2017 
Initial Release 
Margaret Mitchell 
2.0 
27-Feb-2023 
Reference to new Training 
Documents 
Marc Korczykowski 
 
Rater Training SOP Review and Authorization: 
___________________________ 
Marc Korczykowski, MB, MA 
Director Clinical Operations, Psychometrics 
 
 

 
NRX-101_003 
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Appendix 4 
Medications Indicated for Use in Bipolar Disorder 
Brand Name 
Generic Name 
 Abilify 
 Aripiprazole  
 Zyprexa 
 Olanzapine 
 Seroquel 
 Quetiapine  
 Risperdal 
 Risperidone 
 Rexulti 
 Brexpiprazole 
 Vraylar 
 Cariprazine 
 Caplyta 
 Lumaterperone 
 Lurasidone 
 Latuda  
 Ziprasidone 
 Geodon 
 Saphris 
 Asenapine 
 Eskalith, Lithobid 
 Lithium 
 Lamotrigine 
 Lamictal 
 Eprontia, Qudexy XR 
Sprinkle, Topamax, Topamax 
Sprinkle, Trokendi XR, Topiragen, 
Topiramate ER (Eqv-Qudexy XR) 
 Topiramate 
 Depakote 
 Divalproex sodium 
 Tegretol 
 Carbamazepine 
 Trileptal 
 Oxcarbazepine