Conditions: Bipolar Depression Suicidal Ideas Suicidal Ideation Suicide, Attempted
Keywords: d-cycloserine lurasidone ketamine randomized controlled trial
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 22
Healthy volunteers: no

Brief summary:
NeuroRx is developing NRX-101, a fixed-dose combination oral capsule composed of d-cycloserine (DCS) and lurasidone for the maintenance of remission from Severe Bipolar Depression with Acute Suicidal Ideation (C-SSRS level 4 or 5) or Behavior (ASIB) in following initial stabilization. Patients with Severe Bipolar Depression and ASIB will be recruited in both inpatient and outpatient settings and, following informed consent, will be given an intravenous infusion of ketamine 0.5mg/kg over 40 minutes. Those who exhibit a satisfactory clinical response to ketamine will be randomly allocated to NRX-101 or to lurasidone alone (the comparator group). This study is conducted as a feasibility study for a pivotal phase 2b/3 clinical trial and the primary outcomes for this phase 2 study were blood levels of NRX-101, in order to confirm pharmaco-kinetics with remission from depression, as measured by BISS-derived MADRS and relapse as secondary outcomes.

Detailed description:
NeuroRx is developing NRX-101, a fixed-dose combination oral capsule composed of D-cycloserine (DCS) and lurasidone for the maintenance of remission from Severe Bipolar Depression with Acute Suicidal Ideation or Behavior (ASIB) in adults with Bipolar Depression following initial stabilization with ketamine. In recent years, intravenous and intranasal ketamine have demonstrated rapid and potent effects in achieving remission from both depression and suicidal ideation in both bipolar depression and major depressive disorder. However ketamine is will understood to induce hallucination and other dissociative side effects, to be addictive and have high abuse potential, and to have potential neurotoxic effects. Moreover, ketamine can only be administered in a monitored hospital or clinic setting. NRX-101 was developed with the objective of seeking a safe, non-hallucinogenic, non-addictive, oral medication that might maintain the effects of ketamine in patients with severe depression and acute suicidal ideation and which might be considered as initial therapy for patients with depression and non-acute suicidal ideation. The D-cycloserine component of NRX-101 is believed to act by inhibiting the brain's NMDA receptor and raising levels of glutamate/glutamine (Glx) in the anterior cingulate cortex. Increased Glx, as measured by magnetic resonance spectroscopy, has been associated with clinical improvement following electroconvulsive therapy (ECT) and following administration of IV ketamine.

The proposed oral combination product is intended to be administered as part of a sequential therapy consisting of the following 2 components:

1. an initial, one-time intravenous (iv) infusion of ketamine (0.5 mg/kg administered over 40 min), followed one day later by
2. twice daily oral capsules of NRX 101 (DCS + lurasidone), dosing of which is initiated 1 day after ketamine administration, titrated over 5 days to a maintenance dose and continued for up to 6 weeks. Each NRX-101 oral capsule contains DCS (237.5 or 175.0 mg) and lurasidone (8.25, 16.5, or 33.0 mg). It is anticipated that subjects entering the study will be receiving concurrent disorder-directed treatment with other approved medications. This treatment regime will be maintained upon entry into the study. However, any use of lurasidone, quetiapine, or olanzapine will be stopped at study entry, so as to avoid either duplication with study drug (groups 1 and 2) or undermining of the control group.

The clinical efficacy goal is to provide extended relief from symptoms associated with Severed Bipolar Depression and ASIB in adults with Bipolar Disorder, after initial stabilization with iv ketamine in a clinic, emergency department, or inpatient setting.

The proposed NRX-101 product takes advantage of a unique synergistic confluence of combining two active pharmaceutical ingredients (DCS and lurasidone) that respectively inhibit the NMDA and the D2/5-HT2A receptors in the brain. NMDA receptor antagonists, most notably ketamine, have been shown in many studies to rapidly reduce depressive and suicidal ideation. However, numerous studies have demonstrated the potential of NMDA antagonists to cause hallucination and other dissociative side effects. Similarly, D2/5HT2A receptor antagonists, such as lurasidone have demonstrated antidepressant effects in bipolar depression, but have demonstrated a propensity to cause akathisia in some patients. The goals of combining these drugs into a single course of treatment is to maximize the beneficial effects of the specific subcomponents while overcoming potential treatment-limiting side effects associated with those subcomponents.

Beneficial effects of the proposed dosage regimen include 1) well-documented pharmacodynamic effects of ketamine in treating both persistent depressive symptoms and suicidal ideation in bipolar disorder (McCloud, 2015; Naughton, 2014; Newport, 2015; Price, 2014), 2) well-documented pharmacodynamic effects of oral DCS against persistent symptoms of depression (Heresco-Levy, 2013) and 3) the FDA-approved efficacy of lurasidone in treatment-resistant depression (Sunovion Pharmaceuticals, 2013). Due to the synergistic effects, the proposed NRX-101 combination capsule is also expected to avoid or minimize the significant undesired adverse effects associated with the usage of these drugs as single agents (eg, negative consequences of repeated use of ketamine (JHP Pharmaceuticals, 2012), potential psychotomimetic effects of long-term treatment with DCS alone (Kantrowitz, 2010) and potential akathisia and susceptibility for increased suicidality associated with lurasidone alone (Sunovion Pharmaceuticals, 2013).

The risk of ASIB is higher in bipolar depression than other psychiatric disorder and the majority of currently available antidepressants are contraindicated for patients with bipolar depression. NeuroRx believes that the proposed NRX-101 treatment regimen (ketamine administration followed by NRX-101) will demonstrate superiority over ketamine followed by lurasidone in maintaining remission from depression and in delaying the time to documented relapse from depression and suicidality in bipolar disorder, providing a new treatment option for patients with Severe Bipolar Depression and ASIB.

There is currently no FDA-approved product for the treatment of ASIB. NeuroRx proposes that NRX-101 will fulfill an urgent medical need for safe and effective treatment for ASIB.

Patients with Severe Bipolar Depression and ASIB will be recruited in inpatient settings and, following informed consent, will be given an intravenous infusion of either ketamine 0.5mg/kg over 40 minutes or normal saline (placebo). Those who exhibit a satisfactory clinical response to ketamine will be randomly allocated to NRX-101 or to lurasidone along (the comparator group). The primary outcome variable for this phase 2 study will be blood level (pharmacokinetic) exposure of NRX-101 and its D-cycloserine component with remission from depression, as measured on the MADRS scale and relapse as secondary endpoints. Relapse is defined as return of either depression or suicidality OR the need to alter therapy, which might include re-hospitalization, additional antidepressant medication, or electroconvulsive therapy (ECT).

Arms:
arm 1: NRX-101 is a fixed dose combination of d-cycloserine and lurasidone arm 2: Lurasidone will be administered in the same dosages as the lurasidone component of NRX-101

Interventions: intervention 1: NRX-101 Oral Capsule intervention 2: Lurasidone Oral Capsule intervention 3: Ketamine Intravenous Infusion intervention 4: Saline Solution Intravenous Infusion
Intervention descriptions: intervention 1: Prospective Randomized Factorial Design Study as per arm/group descriptions intervention 2: Prospective Randomized Factorial Design Study as per arm/group descriptions intervention 3: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio intervention 4: Randomized administration of Ketamine or Placebo in a 3 to 1 ratio

Protocol document:
Prot_SAP_000.pdf: 
Protocol NRX-101-001 
 
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Clinical Study Protocol 
 
 
NRX-101 for the Treatment of Acute Suicidal Ideation and  
Behavior in Bipolar Depression 
IND 129194 
 
 
 
 
Principal Investigator 
Andrew Nierenberg, MD 
Study Sponsor 
NeuroRx, Inc. 
913 North Market St., Suite 200 
Wilmington, DE  19801 
 
 
 
Phase 
 
Document Status  
2b/3 
 
Final 
 
Version, Date 
Version 1.0 17 November 2016 
 
 
This document is the confidential property of NeuroRx and may not be disclosed or used without the 
prior written consent of NeuroRx 


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Contact Information 
Role in Study 
Name 
Address and Telephone 
Principal Investigator 
Andrew Nierenberg 
617-724-0837 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
SYNOPSIS  
Name 
of 
Investigational 
Product:  
NRX-101 (administered to subjects who respond to an intravenous 
infusion of ketamine - 0.5 mg/kg administered over 40 min; on Day 
0) 
Name of Active Ingredient:  Fixed dose combination of d-cycloserine + lurasidone 
Reference Product(s):  
Lurasidone/placebo 
Title of Study: 
NRX-101 for the Treatment of Acute Suicidal Ideation and 
Behavior (ASIB) in Bipolar Depression 
Phase of Development: 
Phase 2b/3 
Study Site(s): 
Approximately 12 study sites which may be either inpatient 
psychiatric hospitals or community mental health centers/bipolar 
clinics with immediate access to inpatient care facilities.  All sites 
will have a minimum of 12 months prior experience in the use of 
ketamine for stabilization of patients with ASIB in Bipolar 
Depression as part of their practice of medicine. 
Study Duration: 
Screening: up to 48 hours; IV ketamine Day 0; 6-week treatment; 4 
week follow up 
Background and Rationale: 
 
 
DCS and Lurasidone, taken together, have been shown to maintain 
a 50% reduction in depression and a 75% reduction in suicidality 
following a single infusion of ketamine in patients with suicidal 
ideation and bipolar depression. Ketamine is increasingly used in 
medical practice to achieve rapid stabilization of patients with 
ASIB.  However, the duration of ketamine effect is limited and its 
repeated use for maintenance of stabilization is not proven. 
Objectives: 
The objectives of the study are as follows: 
Primary Objective: 
• 
The primary objective of the study is to test the hypothesis 
that following stabilization of depression and ASIB in 
response to initial ketamine infusion, NRX-101 is superior 
to lurasidone alone and also superior to placebo as oral-
therapy for delaying time to relapse (resulting in a new 
treatment plan or the subject relapsing to baseline levels of 
depression or suicidality) in subjects with documented 
bipolar depression presenting with symptoms of 
depression and suicidal ideation. 
Secondary Objectives: 
• 
To demonstrate superiority over placebo and over 
lurasidone alone in maintaining remission from depression 
in bipolar disorder. 
• 
To demonstrate efficacy can be sustained with NRX-101 
dosing regimens 
• 
To demonstrate NRX-101 safety   


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Endpoint(s) 
Primary Endpoint: 
• 
The primary outcome measure will be time to relapse, 
defined as the need to implement a new treatment plan or a 
return to baseline levels on the Columbia-Suicide Severity 
Rating Scale (C-SSRS), or the Montgomery Asberg 
Depression Rating Scale (MADRS) subset on the Bipolar 
Inventory of Symptom Severity (BISS). 
Study Design 
IV Ketamine infusion followed by a double blind, placebo –
controlled, parallel arm trial 
Inclusion Criteria: 
A subject will be eligible for inclusion in this study only if all of the 
following criteria apply: 
 
1. Male or female, 18 to 65 years of age, inclusive, at 
screening. 
2. Able to read, understand, and provide written, dated 
informed consent prior to screening. Participants will be 
deemed likely to comply with study protocol and 
communicate with study personnel about AEs and other 
clinically important information. 
3. Diagnosed with Bipolar Disorder (BD) according to the 
criteria defined in the DSM-5. The diagnosis of BD will be 
made by a site psychiatrist and supported by the MINI 
7.0.2. The diagnosis will be confirmed by remote, 
independent raters, via teleconference between the screen 
visit and the baseline visit. 
4. Suicidal ideation or behavior of sufficient severity to meet 
the requirements for a score of 4, or 5 on the C-SSRS 
(suicide attempt, interrupted attempt, aborted attempt, 
preparatory actions toward imminent suicidal behaviors, 
active method, intent +/- plan). 
5. A score equal to or greater than 20 on the MADRS items 
of the BISS. 
6. In good general health, in the opinion of the investigator, 
as ascertained by medical history, physical examination 
(PE) (including measurement of seated vital signs), clinical 
laboratory evaluations, and electrocardiogram (ECG). 
7. If female, a status of non-childbearing potential or use of 
an acceptable form of birth control per the following 
specific criteria: 
a. Non-childbearing potential (e.g., physiologically 
incapable of becoming pregnant, i.e., permanently 
sterilized [status post hysterectomy, bilateral tubal 


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ligation], or is post-menopausal with her last menses at 
least one year prior to screening); or 
b. Childbearing potential, and meets the following 
criteria: 
i. 
Childbearing potential, including women 
using any form of hormonal birth control, on 
hormone replacement therapy started prior to 
12 months of amenorrhea, using an 
intrauterine device (IUD), having a 
monogamous relationship with a partner who 
has had a vasectomy, or is sexually abstinent. 
ii. 
Negative urinary pregnancy test at screening, 
confirmed by a negative urinary pregnancy 
test at randomization prior to receiving study 
treatment. 
iii. 
Willing and able to continuously use one of 
the following methods of birth control during 
the course of the study, defined as those which 
result in a low failure rate (i.e., less than 1% 
per year) when used consistently and 
correctly: implants, injectable or patch 
hormonal contraception, oral contraceptives, 
IUD, double-barrier contraception, sexual 
abstinence. The form of birth control will be 
documented at screening and baseline. 
8. Body mass index between 18-35 kg/m2. 
9. Concurrent psychotherapy will be allowed if the type (e.g., 
supportive, cognitive behavioral, insight-oriented) and 
frequency (e.g., weekly or monthly) of the therapy has 
been stable for at least three months prior to screening and 
if the type and frequency of the therapy is expected to 
remain stable during the course of the subject’s 
participation in the study. 
10. Concurrent hypnotic therapy (e.g., with zolpidem, 
zaleplon, melatonin, benzodiazepines 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 subject’s participation in the 
study. Subjects can also continue treatment with 
benzodiazepines used for sleep or  anxiety if 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 
subject’s participation in the study. 


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Exclusion criteria: 
A subject will not be eligible 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 that is pregnant or breastfeeding. 
3. Female with a positive pregnancy test at screening or 
baseline. 
4. Current diagnosis of a substance use disorder (abuse or 
dependence, as defined by DSM-5, with the exception of 
nicotine dependence), at screening or within 6 months 
prior to screening. 
5. Current Axis I disorder, diagnosed at screening with the 
use of the MINI 7.0.2, that is the primary focus of 
treatment and BD the secondary focus of treatment for the 
past 6 months or more.  
6. History of schizophrenia or schizoaffective disorders, or 
any history of psychotic symptoms. 
7. History of anorexia nervosa, bulimia nervosa, or eating 
disorder not otherwise specified, within 5 years of 
screening. 
8. Any Axis I or Axis II Disorder, which at screening is 
clinically predominant to their BD or has been 
predominant to their BD at any time within 6 months prior 
to screening. 
9. Has dementia, delirium, amnestic, or any other cognitive 
disorder. 
10. Has a clinically significant abnormality on the screening 
physical examination that might affect safety, study 
participation, or confound interpretation of study results 
according to the study clinician. 
11. Participation in any clinical trial with an investigational 
drug or device within the past month or concurrent to 
study participation. 
12. Current episode of: 
a. Hypertension, Stage 1 as defined by a systolic blood 
pressure ≥140 mmHg or diastolic blood pressure ≥90 
mmHg at screening on two of three measurements at 
least 15 minutes apart. 


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b. Hypertension, Stage 1 as defined by a systolic blood 
pressure ≥155 mmHg or diastolic blood pressure ≥99 
mmHg at the Baseline Visit (Visit 1) within 1.5 hours 
prior to ketamine infusion on two of three 
measurements at least 15 minutes apart. 
c. Recent myocardial infarction (within one year) or a 
history of myocardial infarction. 
d. Syncopal event within the past year. 
e. Congestive heart failure (CHF) New York Heart 
Association Criteria >Stage 2 
f. Angina pectoris. 
g. Heart rate <50 or >105 beats per minute at screening 
or randomization (Baseline Visit). 
h. QTcF (Fridericia-corrected) ≥450 msec at screening or 
randomization (Baseline Visit). 
13. Current history of hypertension, or on antihypertensives 
for the purpose of lowering blood pressure, with either an 
increase in antihypertensive dose or increase in the number 
of antihypertensive drugs used to treat hypertension over 
the last 2 months. 
14. Chronic lung disease excluding asthma. 
15. Lifetime history of surgical procedures involving the brain 
or meninges, encephalitis, meningitis, degenerative central 
nervous system (CNS) disorder (e.g., Alzheimer’s or 
Parkinson’s Disease), epilepsy, mental retardation, or any 
other disease/procedure/accident/intervention which, 
according to the screening clinician, is deemed associated 
with significant injury to or malfunction of the CNS, or 
history of significant head trauma within the past 2 years. 
16. Presents with any of the following lab abnormalities: 
a. Subjects with diabetes mellitus fulfilling any of the 
following criteria: 
i. 
Unstable diabetes mellitus defined as 
glycosylated hemoglobin (HbA1c) >8.5% at 
screening. 
ii. 
Admitted to hospital for treatment of diabetes 
mellitus or diabetes mellitus-related illness in 
the past 12 weeks. 
iii. 
Not under physician care for diabetes mellitus. 


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iv. 
Has not been on the same dose of oral 
hypoglycemic drug(s) and/or diet for the 4 
weeks prior to screening. For 
thiazolidinediones (glitazones) this period 
should not be less than 8 weeks. 
b. Any other clinically significant abnormal laboratory 
result (determined as such by the investigator and 
medical monitor) at the time of the screening. 
17. Any current or past history of any physical condition 
which in the investigator’s opinion might put the subject at 
risk or interfere with study results interpretation. 
18. Positive screening urine test for drugs of abuse at 
screening: cocaine, amphetamines, barbiturates, opiates. 
19. Subjects with exclusionary laboratory values, or requiring 
treatment with exclusionary concomitant medications as 
defined in the study manual 
20. Subjects on exclusionary concomitant psychotropic 
medications. 
21. Subjects with a lifetime history of illicit PCP/ketamine 
drug use or previous failed use of ketamine for depression. 
22. Liver Function Tests higher than 2.5 times upper limit of 
normal as defined in the study manual. 
23. Known allergies to Lurasidone or Latuda, Cycloserine or 
Seromycin, Mannitol, Croscarmellose Sodium, 
Magnesium Stearate, Silicon Dioxide, and/or HPMC 
(hydroxypropylmethylcellulose) 
 
Analysis Sets: 
 
Pharmacokinetic 
Assessments: 
A single sample of blood will be collected at the following time 
points:  
 
Blood draws for NRX-101 analyses 2 hours after the initial dose, 
prior to administration of NRX-101 on day 14 and pre-dose plus 2-
hours post-dose on day 42 
 
Safety Assessments: 
• 
The safety and tolerability of NRX-101 will be assessed via: 
o Adverse events (AEs)  
o Vital signs (blood pressure, heart rate), weight  
o 12-Lead electrocardiograms (ECGs) 
o Clinical laboratory evaluations 


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o Physical examination (PE) findings 
o Suicidality assessment (C-SSRS) 
o Suicidal Ideation and Behavior Questionnaire (SIBQ)  
o Clinician-Administered Dissociative States Scale 
(CADSS) 
o Brief Psychiatric Rating Scale (BPRS)  
o Concise Health Risk Tracking – Self Report (CHRT-SR) 
and Clinician Rating (CHRT-C) scales  
Barnes Akathesia Scale (BARS) 
Dosage, Route of 
Administration and 
Schedule: 
All eligible subjects will receive an intravenous infusion of 
ketamine (0.5 mg/kg administered over 40 min; on Day 0) 
Ketamine responders will be randomised to the 6-week treatment 
period and will receive oral medication. Subjects will be instructed 
to take two capsules, one each morning and evening.  
Statistical Methods: 
Fisher exact test and t-test for determination of primary study 
endpoint. See protocol for detailed explanation 
Sample Size Calculation: 
Randomization of 124 subjects will yield a type I error of less than 
0.05 at a study power of 90%.  See protocol 


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2. 
TABLE OF CONTENTS 
Contact Information ........................................................................................................................................ 2 
1. 
Synopsis ................................................................................................................................................... 3 
2. 
Table of contents ................................................................................................................................... 10 
3. 
List of Abbreviations ............................................................................................................................. 15 
4. 
Introduction ........................................................................................................................................... 16 
4.1 
Acute Suicidal Ideation and Behavior in Bipolar Disorder ............................................................. 16 
4.2 
Current Treatment Options .............................................................................................................. 16 
4.3 
Rationale for Clinical Development Plan ........................................................................................ 17 
4.4 
Preclinical Experience ...................................................................................................................... 17 
4.5 
Clinical Experience .......................................................................................................................... 21 
4.6 
Investigational Therapy .................................................................................................................... 23 
4.7 
Dosing Rationale .............................................................................................................................. 24 
5. 
Objectives .............................................................................................................................................. 25 
5.1 
Primary Objective ............................................................................................................................ 25 
5.2 
Secondary Objective ........................................................................................................................ 25 
6. 
Study Design ......................................................................................................................................... 27 
6.1 
Overview .......................................................................................................................................... 27 
6.2 
Methods ............................................................................................................................................ 27 
6.3 
Study Schema ................................................................................................................................... 28 
6.4 
Study Population .............................................................................................................................. 28 
7. 
Selection and Withdrawal of Subjects ................................................................................................... 30 
7.1 
Inclusion Criteria .............................................................................................................................. 30 
7.2 
Exclusion Criteria ............................................................................................................................ 31 
7.3 
Selection and Withdrawal of Subjects ............................................................................................. 33 
7.4 
Replacement of Subjects .................................................................................................................. 33 
8. 
Study Assessments – Plan and Methods ............................................................................................... 34 
8.1 
Site of Care and Study Conduct ....................................................................................................... 34 
8.1.1 Study Visits and Assessments ................................................................................................... 35 
8.1.2 Screening Period ........................................................................................................................ 39 
8.1.3 Remote Interview ...................................................................................................................... 39 
8.1.4 Stage 1:  Ketamine Infusion ...................................................................................................... 39 
8.1.5 Post Discharge Phone Visit ....................................................................................................... 40 
8.1.6 Randomization ........................................................................................................................... 40 


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8.1.7 Early Termination Visit ............................................................................................................. 40 
8.1.8 Post Ketamine Infusion Follow-Up ........................................................................................... 40 
8.1.9 Concomitant Medications .......................................................................................................... 41 
8.1.10 
Subject Recruitment ............................................................................................................... 41 
8.1.11 
Inclusion of Children ............................................................................................................. 41 
8.2 
Procedures ........................................................................................................................................ 41 
8.2.1 Laboratory/Diagnostic Procedures ............................................................................................ 41 
8.2.2 Drug Levels ............................................................................................................................... 42 
8.2.3 Randomization phase ................................................................................................................ 42 
8.2.4 Blinding Procedures .................................................................................................................. 42 
8.2.5 Outcome and Safety Measures .................................................................................................. 42 
8.2.6 Study Instruments ...................................................................................................................... 46 
8.2.7 Reliability Training ................................................................................................................... 49 
8.2.8 Subject Adherence to Protocol .................................................................................................. 49 
9. 
Treatment of Subjects ............................................................................................................................ 51 
9.1 
Investigational Drug Dose and Administration ............................................................................... 51 
9.2 
Treatment Compliance ..................................................................................................................... 51 
9.3 
Randomization/Method of Assigning Subjects to Treatment .......................................................... 52 
9.4 
Blinding ............................................................................................................................................ 52 
9.5 
Dose Adjustment and Stopping Rules ............................................................................................. 53 
10. 
Study Drug Materials and Management .............................................................................................. 55 
10.1 
Study Drugs .................................................................................................................................. 55 
10.1.1 
Storage ................................................................................................................................... 61 
10.1.2 
Accountability ........................................................................................................................ 61 
10.1.3 
Handling and Disposal ........................................................................................................... 61 
11. 
Assessment of Efficacy ....................................................................................................................... 62 
12. 
Assessment of Safety ........................................................................................................................... 63 
12.1 
Suicidal Ideation and Clinical Management ................................................................................. 63 
12.2 
Definition of Adverse Events ....................................................................................................... 64 
12.3 
Definition of Serious Adverse Events .......................................................................................... 65 
12.4 
Relationship to Study Drugs ......................................................................................................... 66 
12.5 
Recording of Adverse Events ....................................................................................................... 67 
12.6 
Reporting of Adverse Events ........................................................................................................ 68 
12.6.1 
Reporting of Serious Adverse Events .................................................................................... 68 
13. 
Statistics ............................................................................................................................................... 71 


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13.1 
Study Design ................................................................................................................................. 71 
13.2 
Randomization .............................................................................................................................. 71 
13.3 
Study Populations ......................................................................................................................... 71 
13.4 
Hypothesis Tests ........................................................................................................................... 72 
13.4.1 
Primary Hypotheses ............................................................................................................... 72 
13.4.2 
Secondary Hypotheses ........................................................................................................... 72 
13.5 
Efficacy Endpoints ........................................................................................................................ 72 
13.5.1 
Primary Efficacy Endpoint ..................................................................................................... 72 
13.5.2 
Secondary Efficacy Endpoints ............................................................................................... 72 
13.5.3 
Diagnostic Metrics ................................................................................................................. 73 
13.6 
Additional Endpoints .................................................................................................................... 73 
13.7 
Safety Endpoints ........................................................................................................................... 73 
13.7.1 
Overall Adverse Events ......................................................................................................... 73 
13.7.2 
Other Safety Measures ........................................................................................................... 74 
13.8 
Sample Size Calculations ............................................................................................................. 75 
13.8.1 
Allocation ............................................................................................................................... 75 
13.8.2 
Stage 1 .................................................................................................................................... 75 
13.8.3 
Stage 2 .................................................................................................................................... 75 
13.9 
Overall Type 1 Error Control ....................................................................................................... 78 
13.10 
Analysis Approach .................................................................................................................... 79 
13.10.1 
Software .............................................................................................................................. 79 
13.10.2 
Display Formats .................................................................................................................. 79 
13.10.3 
Conventions ........................................................................................................................ 79 
13.10.4 
General Methodology ......................................................................................................... 80 
13.10.5 
Primary Efficacy Endpoint ................................................................................................. 80 
13.10.6 
Secondary Efficacy Endpoints ............................................................................................ 81 
13.10.7 
Other Endpoints .................................................................................................................. 81 
13.10.8 
Safety Endpoints ................................................................................................................. 81 
14. 
Direct Access to Source Data/Documents ........................................................................................... 83 
14.1 
Study Monitoring .......................................................................................................................... 83 
14.2 
Audits and Inspections .................................................................................................................. 84 
14.3 
Institutional Review Board (IRB) ................................................................................................. 85 
15. 
Quality Control and Quality Assurance .............................................................................................. 86 
15.1 
Source Data and Records .............................................................................................................. 86 
15.2 
Reporting of Results ..................................................................................................................... 86 


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15.3 
Confidentiality of Subject Data .................................................................................................... 87 
16. 
Ethical Considerations ......................................................................................................................... 88 
16.1 
Ethics Review ............................................................................................................................... 88 
16.2 
Ethical Conduct of the Study ........................................................................................................ 88 
16.3 
Subject Information and Consent ................................................................................................. 89 
17. 
Data Handling and Recordkeeping ...................................................................................................... 90 
17.1 
Data Capture ................................................................................................................................. 90 
17.2 
Retention of Records .................................................................................................................... 90 
17.3 
Use of Information and Publication Policy .................................................................................. 90 
18. 
Protocol Signature Page ...................................................................................................................... 91 
19. 
References ........................................................................................................................................... 92 
20. 
Appendices .......................................................................................................................................... 95 
Appendix 1: 
Concomitant Medications ................................................................................................... 96 
Appendix 2: 
Assessment Tools ............................................................................................................. 103 
 
 
 
 


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Table of Tables 
Table 1 
Effect of NMDA and 5-HT2a Antagonists in Rodent Akathisia Model ...................... 20 
Table 2 
Exclusionary Safety Values of Potential Clinical Concern .......................................... 33 
Table 3 
Schedule of Study Activities ........................................................................................ 36 
Table 4 
Laboratory Assessments ............................................................................................... 42 
Table 5 
Protocol Violation Definitions ...................................................................................... 50 
Table 6 
Dose Titration ............................................................................................................... 51 
Table 7 
NRX-101 Kits ............................................................................................................... 56 
Table 8 
Active Capsule Composition and Physical Description ............................................... 57 
Table 9 
Lurasidone .................................................................................................................... 58 
Table 10 
Placebo ...................................................................................................................... 58 
Table 11 
Investigational Product Identification ....................................................................... 60 
Table 12 
Time to Relapse: Interim Analysis Futility Looks .... Error! Bookmark not defined. 
Table 13 
Time to Relapse: K/N and K/L Groups Followed for 6 WeeksError! Bookmark not defined. 
Table 14 
Two Group T-test: Equal Effect Sizes ...................... Error! Bookmark not defined. 
Table 15 
Two Group Log Rank Test: Time to All-cause DiscontinuationError! Bookmark not 
defined. 
Table 16 
One Group t-test: No Mean Change .......................... Error! Bookmark not defined. 
Table 17 
 Fisher Exact Test: Normalized C-SSRS Score Percent ScenariosError! Bookmark not 
defined. 
 
Table of Figures 
Figure 1 
DCS vs. Placebo for Treatment of Depression .......................................................... 22 
Figure 2 
Depression Score after Ketamine followed by DCS + 5-HTZA ............................... 23 
Figure 3 
Suicidal Ideation after Ketamine followed by DCS + 5-HTZA ................................ 23 
Figure 4 
NRX-101 for the Treatment of Acute Suicidal Ideation and Behavior in Bipolar Depression 
 
21 
 


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3. 
LIST OF ABBREVIATIONS 
Abbreviations 
Full Terms 
ACPC 
Aminocyclopropanecarboxylic acid 
APA 
American Psychiatric Association 
ASIB 
Acute Suicidal Ideation and Behavior 
BARS 
Barnes Akathesia Scale 
BISS 
Bipolar Inventory of Symptoms Scale 
BPD 
Bipolar Depression 
BPRS 
Brief Psychiatric Rating Scale 
CADSS 
Clinician Administered Dissociative State Scale 
CHRT 
Concise Health Risk Tracking 
CYP3A4 
Cytochrome P450 3A4 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DCS 
D-cycloserine 
ECG 
Electrocardiogram 
FDC 
Fixed Dose Combination  
HAM-D 
Hamilton Depression Scale 
IV 
Intravenous 
MADRS 
Montgomery Asberg Depression Rating Scale 
MGH CTNI 
Massachusetts General Hospital Clinical Network and Institute 
MDD 
Major Depressive Disorder 
MMRM 
Mixed Effect Model Repeated Measure 
NMDA 
N-methyl-D-aspartate 
NMDAR 
N-methyl-D-aspartate Receptor 
PI 
Package Insert 
POC 
Proof of Concept 
PRISE 
Patient Rated Inventory of Side Effects 
RAAD 
Rapid Acting Anti-depressants 
RCT 
Randomized Clinical Trial 
rh 
Relative humidity 
SIBQ 
Suicidal Ideation and Behavior Questionnaire 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TB 
Tuberculosis 
 


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4. 
INTRODUCTION 
4.1  Acute Suicidal Ideation and Behavior in Bipolar Disorder 
Bipolar disorder (i.e., formerly known as manic depressive disorder) is a well-established psychiatric 
diagnosis, with a prevalence in about 2.6% in the United States (approximately 8.5 million people) (Kessler 
et al., 2005). The risk of acute suicidal ideation and behavior (ASIB) 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 BD (Nierenberg 
et al., 2001). About 3% to 14% of the total 30,000 annual deaths from suicide in the United States are 
associated with bipolar depression (Mahli et al., 2015). The overall rate of death by suicide among bipolar 
patients is 164 per 100,000 person years, compared to about 14 per 100,000 person years for the general 
population. Those who have a suicide attempt are 2.3 times more likely to die by suicide compared to those 
without a suicide attempt (Coryell et al., 2016). Thus, ASIB in bipolar depression has uniquely lethal 
clinical characteristics (Pompili, Gonda, &Serafini, 2013). 
4.2  Current Treatment Options 
Despite its lethal characteristics, there is no approved pharmacologic treatment for patients with ASIB in 
bipolar depression. As a result, electroconvulsive therapy, often combined with inpatient psychiatric care 
remains the treatment of last resort for patients with ASIB in bipolar depression, despite its well-
documented side effects that include memory loss and confusion, along with its high cost.  No 
antidepressants have Federal Drug Administration (FDA) approval for use in patients with bipolar 
depression and acute suicidality. Physicians are increasingly cautious about the use of selective serotonin 
release inhibitors (SSRI’s), particularly in patients with ASIB because of evidence that SSRI’s 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 suicidal ideation and behavior in proportion 
to their effect on symptoms of depression. 
In recent years, 5-HT2a antagonists have been shown to have efficacy in treating bipolar depression 
(olanzapine fluoxetine combination, quetiapine, and lurasidone). 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 (MADRS item 10 ≥ 4) were specifically excluded because 
of concerns regarding exacerbating suicidality. Similarly, acutely suicidal patients are routinely excluded 
from clinical trials of other experimental anti-depressive agents. Thus, ASIB in bipolar depression 
represents a major unmet medical need that must frequently be treated with voluntary or involuntary 
hospitalization under highly supervised conditions and electroconvulsive therapy (ECT). 
Whereas all approved drugs for depression act primarily through monoaminergic mechanisms, the 
serendipitous discovery that ketamine has a rapid and profound effect on depression and suicidality 


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(Berman, et. al., 2000) led to the realization that the glutamate system and the Nmethyl-D-aspartate 
receptor (NMDAR) may play an important role in depression and suicidality. 
4.3  Rationale for Clinical Development Plan 
To meet the unmet need for the treatment of ASIB in adults with BD, NeuroRx, Inc. is developing NRX-
101, a fixed-dose combination oral capsule composed of d-cycloserine (DCS) and lurasidone, intended as a 
component of a sequential therapy, which takes advantage of a unique synergistic confluence of three 
FDA-approved drugs with long histories of safety.  
The combination of the drugs for the proposed sequential therapy (DCS, lurasidone, ketamine) has been 
tested in an acute toxicity study under a protocol reviewed in advance by FDA and found to have no 
evidence of neurotoxicity, even at otherwise toxic doses (i.e. 2000 mg/kg) of lurasidone. Each of the 
proposed drugs has a long history of safe use in humans and their AE profiles are well characterized. The 
safety of the three drugs, given in combination has been tested in a human phase 2 study that was deemed 
IND-exempt by FDA. 
DCS is a broad spectrum antibiotic approved for the treatment of tuberculosis (TB). DCS has been used in 
millions of individuals without report of significant safety concerns.  
Lurasidone is an atypical antipsychotic with approval for the treatment of depressive episodes associated 
with bipolar depression. Of the other drugs in its class, lurasidone requires the lowest treatment dose and 
demonstrates the fewest side effects. 
Ketamine is a nonbarbiturate, rapid-acting general anesthetic for intravenous (IV) or intramuscular 
injection, approved for surgical anesthesia. Ketamine has a wide margin of safety. Its use for more than 
12,000 types of operative and diagnostic procedures was studied in over 10,000 subjects participating in 
105 separate clinical studies. 
Ketamine has been shown in multiple randomized clinical trials to induce nearly immediate remission from 
acute suicidality and depression, however the clinical effect has been demonstrated to diminish at 3 days 
post-dose. Whereas Ketamine is a direct NMDA channel blocker which binds to the PCP binding site, DCS 
in high doses has an NMDA antagonist effect by binding to the glycine site.  This effect is apparently 
unrelated to its properties as an anti-infective By combining the potential of DCS to extend the anti-
depressant effects of ketamine with the antipsychotic properties of lurasidone (Stone et al., 2009), NRX-10 
has potential to stabilize individuals with bipolar depression during acute crisis and address a serious 
medical need. 
For details regarding the physical, chemical, and pharmaceutical properties of the three drug product 
components of the proposed sequential therapy, please see the Investigator’s Brochure (IB), which also 
provides a review of relevant non-clinical and clinical experience for each. Safety information is also 
provided in the product safety labeling for each of the drugs in the Investigator’s Brochure. 
4.4  Preclinical Experience 


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Although the mechanisms mediating anti-depressant-related increases in suicide are not totally established, 
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, Brune, 2000) In this assay, increased 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) and in  


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Table 1 (below), DCS significantly reduces the anxiogenic effects of lurasidone and quetiapine as 
measured by % time spent in open arm, suggesting that this treatment might reduce medication-induced 
suicidality as well as suicidality associated with BD itself. These findings are consistent with the 
documented anti-suicidal effectiveness of acute ketamine treatment (DiazGranados et al., 2010; Ballard et. 
al., 2014), including theories that ketamine’s reductions in suicidality are associated with reductions not 
only in depression but also in anxiety.  


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Table 1 
Effect of NMDA and 5-HT2a Antagonists in Rodent Akathisia Model 
 
Source: Javitt, 2014 
 
Our preclinical research, using the Rat Akathisia model, suggests an additional synergistic interaction 
between DCS and lurasidone. On one hand, as described above, DCS appears to block the anxiogenic 
effects of lurasidone. Conversely, lurasidone may in turn have the ability to reverse low-level 
psychotomimetic effects of DCS and ketamine. This signal may be appreciated from the decrease in 
distance traveled when lurasidone is added to 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 and, thus, also potentially effective in treatment of psychotic symptoms that may be induced 
by NMDA antagonists. 
Clearly the phenomena observed in rodents should not be viewed as isomorphic with drug- induced 
akathisia and/or jitteriness/anxiety syndrome in humans. However, we believe that 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 to suicide in vulnerable patients. 


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4.5  Clinical Experience 
Antidepressant effects of high dose DCS were first noted in the late 1950’s when it was first introduced as 
a treatment for tuberculosis (TB). Several clinicians noted dramatic improvement in patients’ depressive 
symptoms, leading to suggestions of 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 NMDA receptor was first 
demonstrated in 1989, (Hood et al., 1989), leading to some interest in NMDAR blockers as potential 
antidepressant treatments. (Trullas, Skolnick 1990; Skolnick et al., 1996). For example, both DCS and the 
related compound 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 in 2000. An initial study performed with 
DCS at a dose of 250 mg/d did not show therapeutic effect, but did demonstrate relative lack of 
psychotomimetic side effect when DCS was combined with concurrent antidepressant treatment (Heresco-
Levy, Javitt et al., 2006). Based upon these safety data, a study using a higher dose of 1000 mg/d) was 
initiated with results reported in 2013 (Heresco-Levy et al., 2013) (see Figure 1). At the higher, 1000 mg 
dose, significant beneficial effects were observed in 13 subjects vs placebo control with SSRI-
nonresponsive depressive symptoms. The improvements were manifest within 2 weeks and persisted 
throughout the 6-week treatment period. 


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Figure 1 
DCS vs. Placebo for Treatment of Depression 
 
Source: Kantrowitz, 2015 
The 2013 Heresco-Levy study provided initial evidence that DCS might be useful as an NMDAR- targeted 
antidepressant, but the time of onset for DCS alone was suboptimal for treating acutely depressed 
individuals. Therefore, an open-label study was performed in which subjects with bipolar depression 
received an infusion of ketamine on Day 1, followed by oral administration of DCS, titrated to a dose of 
1000mg/day combined with lurasidone 66mg/day as individual commercially-supplied medications. Seven 
of 8 subjects completed the study and no adverse effects were noted. Over a period of 8 weeks, a > 75% 
reduction in suicidal ideation and a 50% reduction in depression was noted, using the Hamilton Depression 
Scale (HAM-D). (Figure 2; Kantrowitz, 2015). Note that suicidal ideation was eliminated entirely at 4 
hours post-infusion of ketamine (Figure 3; Kantrowitz, 2014). 


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Figure 2 
Depression Score after Ketamine followed by DCS + 5-HTZA 
 
Source: Kantrowitz, 2015 
 
Figure 3 
Suicidal Ideation after Ketamine followed by DCS + 5-HTZA 
 
Source: Kantrowitz, 2014 
 
4.6  Investigational Therapy 
The investigational therapy to be evaluated in this study consists of sequential treatment consisting of the 
following components:  
1. an initial, one-time intravenous infusion of ketamine (0.5 mg/kg administered over 40 min) on Day 
0, followed by 
2. twice daily oral capsules of NRX 101 (d-cycloserine [DCS] + lurasidone), which is initiated on Day 
1 (in subjects who respond to ketamine) and continued for up to 6 weeks. It is anticipated that 
subjects entering the study will be receiving concurrent disorder-directed treatment with various 
predefined combinations of medications.  This treatment regime will be maintained upon entry 
into the study.  However, any use of lurasidone, quetiapine, or olanzapine will be stopped at study 
entry.This regimen may be supplemented with mood stabilizers at the discretion of the treating 
physician. 


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Our clinical objective is to offer patients the clinical benefit of rapid reduction in symptoms of depression 
and suicidal ideation that has been observed with intravenous ketamine, while maintaining that benefit with 
a daily oral agent that does not have ketamine’s potential for abuse and psychosis.  
4.7  Dosing Rationale 
The doses chosen for the three components of the sequential therapy are based on current dosing 
recommendations for each. In Stage1, the one-time IV infusion of ketamine on Day 0 at 0.5 mg/kg over 
40 minutes is below the lowest recommended IV concentration (1 mg/kg) to induce anesthesia, and is 
consistent with studies of ketamine for use in depression.  
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. The recommended oral dose of lurasidone for the treatment of acute depressive BD is 
20 to 120 mg/day for up to 6 weeks. Therefore, dosing of the fixed-dose combination NRX 101 during 
Stage 2 will be twice daily over 6 weeks. The starting doses at 350 mg DCS and 16.5 mg lurasidone, and 
the titration over 5 days to a maximum of 950 mg DCS and 66 mg lurasidone are planned accordingly. Up-
titration is built in to the dosing strategy in the case of subject agitation and a stepdown is allowed for 
somnolence. 
For complete details regarding dosing recommendations, please see the product safety labeling for each of 
the drugs, which are included in the Investigator Brochure (IB). 


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5. 
OBJECTIVES 
5.1  Primary Objective 
The primary objective of the study is to test the hypothesis that following response to initial ketamine 
infusion, experimental drug NRX-101 (DCS + lurasidone) is superior to lurasidone alone and placebo as 
oral-therapy for delaying time to relapse (resulting in a new treatment plan or the subject relapsing to 
baseline levels of depression or suicidality) in subjects with documented bipolar depression presenting with 
symptoms of depression and suicidal ideation. 
The primary study hypothesis (alternative hypothesis) is that ketamine and experimental drug NRX-101 
(K/N) delays the time to documented relapse as compared to both lurasidone (L) and placebo (P) as measured 
by the hazard ratio (h) versus the null hypothesis of no delay in time to relapse for either comparator treatment 
(ketamine/lurasidone [K/L] and ketamine/placebo [K/P]) as follows: 
H0: hNRX-101 < hL and hP 
Ha: hNRX-101 > hL and hP. 
The primary outcome measure will be time to relapse, defined as the need to implement a new treatment 
plan or a return to baseline levels on the Columbia-Suicide Severity Rating Scale (C-SSRS), or the 
Montgomery Asberg Depression Rating Scale (MADRS) subset on the Bipolar Inventory of Symptom 
Severity (BISS). 
All relapses will be documented by the site physician and reviewed on a monthly basis by a Relapse 
Adjudication Committee. The Relapse Adjudication Committee (RAC) will determine whether the relapse 
met the primary endpoint criteria.  
5.2  Secondary Objective 
The secondary objectives of the study are the following: 
• To demonstrate bipolar depression efficacy 
• To demonstrate efficacy can be sustained with NRX-101 dosing regimens 
• To demonstrate NRX-101 safety   
The secondary study hypotheses (alternative hypotheses favoring K/N vs. K/L and K/P) are the following: 
1. K/N will favorably separate from both K/L and K/P by 72 hours, with sustained difference between 
groups thereafter. 
2. All cause discontinuation (including discontinuation for continued suicidal ideation) will be lower 
for K/N than both K/L and K/P. 
3. K/N will favorably separate from K/L and K/P starting at day 7, with sustained difference 
thereafter.  
4. Improvements within the K/N group observed at Week 2 will remain stable to end of study.  


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5. C-SSRS scores will remain <4 for 4 weeks following treatment discontinuation (i.e., “crisis” will 
resolve within the 6 week time period with more favorable outcomes in the K/N group as compared 
to K/L and K/P. 
Additionally, symptom improvement will be evaluated by assessing changes in the secondary outcome 
measures: C-SSRS, CHRT, and the BISS (including its subscales). These measures will be assessed at the 
times specified on the Study Activity Schedule, Table 3. 


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6. 
STUDY DESIGN 
6.1  Overview 
The multi-center study will consist of a 6-week, parallel group, double-blind, randomized, adaptive, 
superiority trial designed to test the hypothesis that following response to ketamine infusion, experimental 
drug NRX-101 (DCS + lurasidone) is superior to both lurasidone alone and placebo as oral-therapy for 
delaying time to relapse (resulting in a new treatment plan or the subject relapsing to baseline levels of 
depression or suicidality) in subjects with documented bipolar depression presenting with symptoms of 
depression and suicidal ideation.  
6.2  Methods 
In Stage 1 eligible subjects will initially receive an infusion of open-label ketamine 0.5mg/Kg. Those who 
do not respond to ketamine infusion as measured by a ≥25% improvement in the MADRS subset on the 
BISS and a reduction in C-SSRS suicidal ideation to ≤ 3 at 24 hours post infusion will be withdrawn from 
the study and treated according to standard of care for subjects with suicidal ideation or behaviors. 
Subjects who respond successfully to ketamine infusion, as defined above (≥25% improvement in the 
MADRS subset of the BISS and C-SSRS ≤3) at 24 hours post infusion will proceed to Stage 2 and be 
randomized to either experimental drug NRX-101 (DCS + lurasidone), lurasidone alone, or placebo. 
Efficacy data will be collected for the subjects responding to ketamine through 6 weeks or until earlier 
rescue. 
Subjects may be terminated from the study and rescued with alternative therapy at any time if, in the 
opinion of the investigator, subjects have a significant safety risk for clinical deterioration or suicide. 
 
 


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6.3  Study Schema 
Figure 4.  NRX-101 for the Treatment of Suicidality in Bipolar Disorder 
 
 
 
6.4  Study Population 
The study analyses will be conducted in a GCP environment (ICH E6). All analyses will be pre-specified in 
a Statistical Analysis Plan (SAP) prior to beginning subject enrollment. The study will have prospectively 
defined study populations including separate evaluability rules for the ketamine treatment (Stage 1) and 
randomized treatment (Stage 2). 
For Stage 1, the Intent-to-Treat (ITT) population will include all subjects who received the ketamine 
infusion and have the 24-hour post-infusion efficacy assessments. The Per-Protocol Population will include 
the subset of ITT subjects who were eligible, who had the 24-hour post-infusion efficacy assessments 
within 18 to 30 hours post the start of the initial infusion, and who had no major protocol violations. The 
Safety Population will include all subjects treated with ketamine who have any post-baseline safety data. 
For Stage 2, the ITT population will include all subjects who received the randomized study treatment and 
have any post-baseline efficacy assessments. The Per-Protocol population will include the subset of ITT 
subjects who were eligible, who have any post-baseline efficacy assessments within 1 day of scheduled 
visits through Day 7 and within 2 days of scheduled visits through Day 42, and who had no major protocol 
violations. The Safety Population will include all subjects as treated with study treatment who have any 
post-baseline safety data through Day 70. 
Subjects 
who 
report 
bipolar 
disorder 
with 
suicidal ideation 
C
O
N
S
E
N
T 
I 
N
F
U
S 
I 
O
N 
NON-RESPONSE 
C
O
M
P
L
E
T
E 
Exit to additional
Standard of Care
treatment 
A 
S 
S 
E 
S 
S 
 
R 
E 
S 
P
O
N
S 
E 
Screening Phase 
        48 hours 
Stage 1 
Ketamine Infusion 
24 hours 
RESPONSE 
R
A
N
D
O
M
I 
Z 
E 
Placebo + Lurasidone 
Placebo 
NRX-101 
Stage 2  
Randomized 
Treatment 
24 hr-Day 42 
Follow 
Up Visit 
 Day 70 


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The ITT population will be used for the primary analyses. If <5% are to be excluded from the ITT 
population, then the analysis will not be performed for the PP population.   
Every effort will be made to encourage subjects to comply with the procedures and the assessments 
involved in study. Non-compliance will be tracked. Protocol violations will be reviewed in real time; rules 
will be set for exclusions from the PP population.  
A sufficient number (estimated to be 192 subjects) will be entered into Stage 1 in order to have 124 
randomized subjects to complete Stage 2. IRB-approved written informed consent will be obtained from all 
subjects before any protocol-specified procedures are carried out. The subjects will be drawn from a 
sample of subjects with BD with suicidal ideation, diagnosed with the use of the MINI 7.0.2 for DSM 5. 
For entry into the study, all inclusion criteria must be met, and none of the exclusion criteria can be met. 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects must meet all of the inclusion and none of the exclusion criteria to be qualified to participate in 
this study. 
7.1  Inclusion Criteria 
1. Male or female, 18 to 65 years of age, inclusive, at screening. 
2. Able to read, understand, and provide written, dated, informed consent prior to screening. 
Participants will be deemed likely to comply with study protocol and communicate with study 
personnel about AEs and other clinically important information. 
3. Diagnosed with BD according to the criteria defined in the DSM-5. The diagnosis of BD will be 
made by a site psychiatrist and supported by the MINI 7.0.2. The diagnosis will be confirmed by 
remote, independent raters via teleconference between the screen visit and the baseline visit. 
4. Suicidal ideation or behavior of sufficient severity to meet the requirements for a score of 4 or 5 on 
the C-SSRS. 
5. A score equal to or greater than 20 on the MADRS items of the BISS. 
6. In good general health, as ascertained by medical history, physical examination (PE) (including 
measurement of seated vital signs), clinical laboratory evaluations, and electrocardiogram (ECG). 
7. If female, a status of non-childbearing potential or use of an acceptable form of birth control per the 
following specific criteria: 
c. Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, i.e., 
permanently sterilized [status post hysterectomy, bilateral tubal ligation], or is post-menopausal 
with her last menses at least one year prior to screening); or 
d. Childbearing potential, and meets the following criteria: 
iv. 
Childbearing potential, including women using any form of hormonal birth control, on 
hormone replacement therapy started prior to 12 months of amenorrhea, using an 
intrauterine device (IUD), having a monogamous relationship with a partner who has 
had a vasectomy, or is sexually abstinent. 
v. 
Negative urinary pregnancy test at screening, confirmed by a negative urinary pregnancy 
test at randomization prior to receiving study treatment. 
vi. 
Willing and able to continuously use one of the following methods of birth control 
during the course of the study, defined as those which result in a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly: implants, injectable or 
patch hormonal contraception, oral contraceptives, IUD, double-barrier contraception, 
sexual abstinence. The form of birth control will be documented at screening and 
baseline. 
8. Body mass index between 18-35 kg/m2. 


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9. Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive behavioral, 
insight-oriented) and frequency (e.g., weekly or monthly) of the therapy has been stable for at least 
three months prior to screening and if the type and frequency of the therapy is expected to remain 
stable during the course of the subject’s participation in the study. 
10. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines 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 subject’s participation in the study. 
Subjects can also continue treatment with benzodiazepines used for anxiety if 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 subject’s participation in the study. 
7.2  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 that is pregnant or breastfeeding. 
3. Female with a positive pregnancy test at screening or baseline. 
4. Current diagnosis of a substance use disorder (abuse or dependence, as defined by DSM-5, with the 
exception of nicotine dependence), at screening or within 6 months prior to screening. 
5. Current Axis I disorder, diagnosed at screening with the use of the MINI 7.0.2, that is the primary 
focus of treatment and BD the secondary focus of treatment for the past 6 months or more.  
6. History of schizophrenia or schizoaffective disorders, or any history of psychotic symptoms when 
not in acute bipolar mood episode. 
7. History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified, within 5 
years of screening. 
8. Any Axis I or Axis II Disorder, which at screening is clinically predominant to their BD or has been 
predominant to their BD at any time within 6 months prior to screening. 
9. Has dementia, delirium, amnestic, or any other cognitive disorder. 
10. Has a clinically significant abnormality on the screening physical examination that might affect 
safety, study participation, or confound interpretation of study results according to the study 
clinician. 
11. Participation in any clinical trial with an investigational drug or device within the past month or 
concurrent to study participation. 
12. Current episode of: 
i. Hypertension, Stage 1 as defined by a systolic blood pressure ≥140 mmHg or diastolic blood 
pressure ≥90 mmHg at screening on two of three measurements at least 15 minutes apart. 


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j. Hypertension, Stage 1 as defined by a systolic blood pressure ≥155 mmHg or diastolic blood 
pressure ≥99 mmHg at the Baseline Visit (Visit 1) within 1.5 hours prior to ketamine infusion 
on two of three measurements at least 15 minutes apart. 
k. Recent myocardial infarction (within one year) or a history of myocardial infarction. 
l. Syncopal event within the past year. 
m. Congestive heart failure (CHF) New York Heart Association Criteria >Stage 2 
n. Angina pectoris. 
o. Heart rate <50 or >105 beats per minute at screening or randomization (Baseline Visit). 
p. QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline Visit). 
13. Current history of hypertension, or on antihypertensives for the purpose of lowering blood pressure, 
with either an increase in antihypertensive dose or increase in the number of antihypertensive drugs 
used to treat hypertension over the last 2 months. 
14. Chronic lung disease excluding asthma. 
15. Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, 
degenerative central nervous system (CNS) disorder (e.g., Alzheimer’s or Parkinson’s Disease), 
epilepsy, mental retardation, or any other disease/procedure/accident/intervention which, according 
to the screening clinician, is deemed associated with significant injury to or malfunction of the 
CNS, or history of significant head trauma within the past 2 years. 
16. Presents with any of the following lab abnormalities: 
c. Subjects with diabetes mellitus fulfilling any of the following criteria: 
v. 
Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5% at 
screening. 
vi. 
Admitted to hospital for treatment of diabetes mellitus or diabetes mellitus-related 
illness in the past 12 weeks. 
vii. 
Not under physician care for diabetes mellitus. 
viii. 
Has not been on the same dose of oral hypoglycemic drug(s) and/or diet for the 4 weeks 
prior to screening. For thiazolidinediones (glitazones) this period should not be less than 
8 weeks. 
d. Any other clinically significant abnormal laboratory result (determined as such by the 
investigator and medical monitor) at the time of the screening. 
17. Any current or past history of any physical condition which in the investigator’s opinion might put 
the subject at risk or interfere with study results interpretation. 
18. Positive screening urine test for drugs of abuse at screening: cocaine, amphetamines, barbiturates, 
opiates. 


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19. Subjects with exclusionary laboratory values (see Table 2), or requiring treatment with exclusionary 
concomitant medications (see Appendix 1). 
20. Subjects on exclusionary concomitant psychotropic medications. 
21. Subjects with a lifetime history of PCP/ketamine drug use. 
22. Liver Function Tests higher than 2.5 times upper limit of normal. 
23. Known allergies to Lurasidone or Latuda, Cycloserine or Seromycin, Mannitol, Croscarmellose 
Sodium, Magnesium Stearate, Silicon Dioxide, and/or HPMC (hydroxypropylmethylcellulose). 
 
Table 2 
Exclusionary Safety Values of Potential Clinical Concern 
Hematology 
 
Leukocytes 
<2 or >17.5 x 103/mm3 
Platelets 
<75 or >700 x 103/mm3 
Chemistry 
 
Total bilirubin 
>2.5 times the upper limit of the reference range 
AST 
>2.5 times upper limit of the reference range 
ALT 
>3 times upper limit of the reference range 
GGT 
>3 times upper limit of the reference range 
Alk Phosphatase 
>3 times upper limit of the reference range 
Creatinine 
>1.3 times upper limit of the reference range 
BUN/Urea 
>1.3 times upper limit of the reference range 
Glucose 
<70 mg/dl or >2 times the limits of the reference range  
HbA1c 
>7.0% 
Uric acid 
>1.5 times upper limit of the reference range 
7.3  Selection and Withdrawal of Subjects 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects 
and to ensure that the results of the study are meaningful in relation to the research hypotheses. It is 
imperative that subjects fully meet all eligibility criteria. 
7.4  Replacement of Subjects 
Subjects who withdraw will not be replaced. 


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8. 
STUDY ASSESSMENTS – PLAN AND METHODS 
8.1  Site of Care and Study Conduct 
Subjects may be recruited upon presentation in an outpatient psychiatric practice, emergency department, 
community mental health setting, or psychiatric hospital.  The site of care will be either (1) a community 
mental health/bipolar clinic setting with overnight observation capability and with immediate access to a 
psychiatric inpatient facility or (2) an inpatient setting.  Only sites that have been using ketamine for 
stabilization of patients with bipolar depression as part of their practice of medicine for at least 12 months 
will be included as study sites in the trial.  Eligible study sites will already have written policies and 
procedures around the use of ketamine, will be properly licensed by the Drug Enforcement Administration 
for the storage and use of ketamine, and will have written criteria for ensuring the safety of patients under 
their care who receive ketamine. 
It should be emphasized that dedicated (typically for-profit) psychiatric research facilities whose physicians 
do not otherwise provide ongoing care to patients with suicidal bipolar depression are not eligible to 
participate as study sites because of concerns that such facilities may not have adequate clinical experience 
or resources to ensure patient safety over the course of the study. 
The study protocol does not dictate the site of care (inpatient vs. outpatient).  That is determined by the 
treating physician in consultation with the patient and family, based upon assessment of the patient’s 
acuity, the patient’s home environment, and other factors that psychiatrists expert in the management of 
this patient population use in determining the appropriate site of care.  It is anticipated that subjects 
enrolled at C-SSRS level 4 are likely to be managed in the outpatient setting, whereas those enrolled at C-
SSRS level 5 will be maintained under continuous professional observation until they have stabilized at a 
C-SSRS level 3 or lower.  Just as site of care is determined by the treating physician, the decision to 
discharge those subjects who begin in the inpatient setting is entirely up to the study physician, based upon 
the same protocols and criteria already in place to determine discharge for patients with suicidal bipolar 
depression.  The study sponsor and the study protocol will not influence this decision in any way.  The 
sponsor does require, however, that subjects with C-SSRS level 5 ideation or behavior be under continual 
professional observation from the time of enrollment and ketamine infusion to the point at which the 
patient is deemed to have stabilized and is randomly assigned to one of the study arms. 
All eligible subjects will receive ketamine infusion according to the procedures in this protocol. All 
infusions will be conducted in a clinic-like or hospital setting with a licensed anesthetist, standard 
monitoring equipment, and full emergency backup available. Subjects who experience sufficient 
improvement and are stable after the ketamine infusion may be hospitalized or discharged at the discretion 
of the treating physician.  Discharge will only be allowed if there is an established support structure and 
agreement to follow the safety plan whereby sites will contact subjects twice daily for the next week either 
in person or through a video connection provided by sponsor and then at least weekly through the end of 
the study to collect study data to support efficacy and safety. The election to follow subjects who respond 
to initial ketamine on an inpatient or outpatient basis will be made by the treating study physician with the 
consent of the subject.  
Subjects who meet study criteria for relapse at any point during the study will be withdrawn from the study 
and offered clinically-appropriate treatment as determined by the treating study physician, which may 


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include inpatient hospitalization, repeated administration of ketamine, electroconvulsive therapy (ECT), or 
other treatments determined by professional judgment. Subjects who demonstrate therapeutic benefit from 
experimental drug NRX-101 (DCS+ lurasidone) at study completion may be offered prescribed DCS by 
their treating psychiatrist. 
The Schedule of Study Activities (Table 3) summarizes the frequency and timing of efficacy, PK, and 
safety measurements applicable to this study. With the exception of post-dose assessments, visit-specific 
subject-reported outcomes assessments should be conducted or completed before any tests, procedures, or 
other consultations for that clinic visit to prevent influencing subject perceptions. A recommended order of 
study procedures will be provided to sites as a separate document. 
Actual dates and times of assessments will be recorded in the source documentation and electronic Case 
Report Form (eCRF). 
 
8.1.1 
Study Visits and Assessments 
A schedule of study visits and assessments is provided in Table 3 Schedule of Study ActivitiesTable 3


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Table 3 
Schedule of Study Activities 


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Stage 1 
 
Stage 2 
Follow 
Up /ET 
Study Day 
Screenin
g Period 
 
Day 0 
Day 1 
Day 6 
Day 7 Day 10 Day 14 Day 21 Day 28 Day 35 Day 42 
 
 
Day 70 
48 hrs 
Ket. 
Dosing 
4 hr 
 
10 hr +2 
hours 
24 hr 
post 
dose 
+/- 1 
day 
 
Assessment/Activity 
Visit 
Name/No. Screen 
Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
10 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 7.0.2 DSM 5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Vital Signs 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Concomitant Medications 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Phone Visit* 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CHRT—C, SR 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
Remote Independent 
Rater Interview 
 
X** 
 
 
 
 
 
 
 
 
 
 
 
 
 
CADSS 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
BISS 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
SIBQ 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Blood Draw for drug 
analyses 
 
X 
 
 
 
X*** 
 
 
 
X*** 
 
 
 
X*** 
 
BARS 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
BPRS 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
PRISE 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry, CBC 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Urine Tox Screen 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Pregnancy Test (Urine) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Ketamine Infusion 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Drug Dispensation & Pill 
Count 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 


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*This phone visit should be performed by the site Principal Investigator, or Sub-Investigator. **The independent interview is performed remotely by telephone by independent  raters. 
***Blood draws for drug analyses 2 hours after the initial dose, prior to administration of NRX-101 on days 14 and 42, and 2 hours after administration of NRX-101 on day 42.  


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8.1.2 
Screening Period 
Once subjects agree to participate in the study by signing the informed consent document, a full 
medical and psychiatric history will be taken and a physical and laboratory examination will be 
performed, as outlined in the Schedule of Study Activities (Table 3). The screening period may 
extend for up to 48 hours following the signing of the informed consent in order to allow time for 
the independent third party raters’ interview to be conducted and the ketamine infusion to be 
scheduled. Upon determination by the site investigator(s) that the subject meets the inclusion and 
exclusion criteria for the study, a remote interview will be scheduled with an independent rater. 
8.1.3 
Remote Interview 
To ensure that appropriate subjects are entered into the trial, remote diagnostic assessments (for 
Bipolar Disorder, C-SSRS and BISS) will be performed by remote, independent third party 
raters’. The interview will be performed remotely by the independent, third party rater, via 
telephone during the 24 hour screening period. Depending on level of suicidal ideation and 
behavior, the subject may be contacted while at home or while being managed in an ED, 
hospital, or other acute care facility. Sites will be notified of the results within 2 business hours 
of the interview completion. 
8.1.4 
Stage 1:  Ketamine Infusion 
For entry into Stage 1 of the study (ketamine infusion), all eligibility criteria MUST continue to 
be met (i.e., all inclusion criteria and no exclusion criteria). 
All subjects will receive ketamine by continuous infusion for 40 minutes by use of an electronic 
pump. The start and stop times of the ketamine infusions will be documented in the eCRF. 
Detailed instructions for dose preparation will be provided to site research pharmacists in an 
additional guidance document. Storage conditions should be followed according to the package 
insert. Dosing procedures will be provided to the clinical unit in a separate infusion document. 
Assessments: During the infusion, the Clinician Administered Dissociative Symptom Scale 
(CADSS) and the Brief Psychiatric Rating Scale (BPRS) are administered at 0 (-5 minutes), 40 
minutes (completion of infusion) and 4 hours.  Both are administered by a clinician. 
Physiological Monitoring: Each participant will be allowed to rest in a semi-recumbent position. 
Each subject will receive an intravenous (IV) line. The monitoring will include a non-invasive 
blood pressure cuff, a 3- or 5-lead ECG, a pulse oximeter and oxygen by face mask or nasal 
cannula at 4 to 6 liters per minute, as needed. Vital signs will be monitored continuously and 
recorded every 20 minutes. Each subject will receive an infusion for 40 minutes.  
The IV line will be left in place for at least 1 hour following the infusion to allow for additional 
medications to control emergent side effects. Medical staff monitoring the infusion will be 
prepared to treat increases in blood pressure greater than 180/100 mmHg or heart rate greater 
than 110 bpm, or follow their institutional guidelines if more conservative. If these elevations 
resolve spontaneously within a short time period, they will generally not be treated. The study 


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infusion will be discontinued in the event that three consecutive measurements remain above 
protocol-defined limits for 20 minutes or more, or according to institutional guidelines if more 
conservative, despite antihypertensive administration. The psychiatry research staff member will 
administer rating scales at -5, 40 minutes and 4 hours. All side effects and vital parameters will 
be recorded during the infusion and for the 4 hours following at 1 hour intervals. Clinically 
relevant vital sign changes will be recorded as AEs. The subject may be released after the 4 hour 
measurements are complete as long as they have achieved pre-treatment vital signs 
measurements or are deemed to be clinically stable” or something along those lines..  Subjects 
will be required to have an adult escort them home post-administration of ketamine, or may be 
transported home by a medical transport company provided that presence of a responsible adult 
at the home location has been verified.  Participants who cannot ensure a reliable adult transport 
or home observer will not be allowed to enroll in the study.  Subjects will be instructed not to 
drive or operate heavy machinery for at least 24 hours post-administration. 
 
8.1.5 
Post Discharge Phone Visit 
At 10 hours post the start of the ketamine infusion (plus/minus 2 hours) the patient will be 
assessed by a study investigator (in-person or called at home if subject were to be discharged).  
During this phone visit, the procedures listed in Table 3 (C-SSRS (since last visit), and an 
assessment of AEs) will be completed. 
8.1.6 
Randomization 
Subjects will be assessed in person 24 hours post-infusion for response to ketamine. Those who 
do not respond will be provided standard of care for ongoing suicidal ideation. Following the 
documented observance of a therapeutic response to intravenous ketamine as defined by a 25% 
or greater reduction in the on the MADRS subset of the BISS score and a score of <3 on the C-
SSRS at 24 hours post infusion, subjects will be randomized 2:1:1 to either a fixed dose 
combination of experimental drug NRX-101 (DCS + lurasidone), or to an identical capsule 
containing placebo + lurasidone, or to an identical capsule containing placebo.  Randomization 
blocks will be allocated at the site level to ensure that treatment and control groups are balanced 
per site. An Interactive Web Response System will be used. 
8.1.7 
Early Termination Visit 
If a subject withdraws consent, or is otherwise terminated from the study, every effort should be 
made by the site to perform the procedures listed for Day 70. 
8.1.8 
Post Ketamine Infusion Follow-Up 
Subjects who are non-responders at 24 hours following the start of the ketamine infusion will be 
withdrawn from the study and treated according to the site’s standard treatment procedure. Non-
response is defined as less than a 25% reduction on the MADRS subset of the BISS score and a 
score of ≥4 on the C-SSRS. 


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8.1.9 
Concomitant Medications 
All concomitant medications taken during the study will be recorded in the Concomitant 
Medication Log for each subject, along with dosage information and start and stop dates.  
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 antipsychotic therapy and stable allowed hypnotic therapy. Subjects requiring excluded drugs 
will be discontinued from the study.  
Prohibited concomitant medications which the patient and the study investigator agree may be 
discontinued, will be washed out for a period of 5 half lives or one week, whichever is longer.   
Clinically appropriate tapering regimens may be used if necessary.  The screen period may be 
extended, upon consultation with the medical monitor, to allow for a sufficient washout period.  
A list of prohibited concomitant medications is included in Appendix 1. 
 
8.1.10 
Subject Recruitment 
Subjects will be recruited through study clinicians from patients who present at the site with 
bipolar depression and suicidal ideation. Those deemed eligible will be scheduled for a screening 
visit with one of the study physicians at the site.  Appropriate recruitment strategies such as 
advertising, primary care physician referrals and internet based outreach may be used as well.  
Any patient facing materials will be submitted for IRB approval. 
8.1.11 
Inclusion of Children 
Adolescents between the ages of 18 and 21 will be elegible for enrollment. We are not including 
children younger than age 18. We have decided to exclude children under the age of 18 because 
there are specific safety considerations, as well as treatment considerations in pediatric bipolar 
depression that exceed the scope of this study. However, if treatments from this proposal are 
found efficacious and well tolerated, a next step may be the consideration of use in children of 
younger ages. 
8.2  Procedures 
8.2.1 
Laboratory/Diagnostic Procedures 
Clinical laboratory safety testing will be conducted locally by the study site using CLIA-
approved laboratories that have been audited by study personnel for compliance. Once the 
subject has signed the informed consent document, the urine pregnancy test will be performed at 
the Screen Visit, and Visits 5 and 9. ECGs will be measured at the Screen Visit, the Baseline 
Visit (at the 24-hour time point), and at Visits 5 and 9. Chemistry and complete blood count 
(CBC) will also be obtained at the Screen Visit, and at Visits 5 and 9. Weight, BMI, oral 
temperature, seated pulse and seated blood pressure (vital signs) will be recorded at each visit. At 


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Screen, and Visit 5 and 10, subjects will have a physical examination. The laboratory tests 
required are listed in Table 4, below.  
Table 4 
Laboratory Assessments 
Laboratory Test 
Frequency 
CBC 
Screen, Visits 5 and 9 
Chemistry (Total bilirubin, AST, ALT, GGT, ALK 
Phosphatase, Creatine, BUN/Urea, Glucose, Uric 
Acid) 
Screen, Visits 5 and 9 
HbA1c (only for diabetics) 
Screen 
Pregnancy Test 
Screen, Visits 5 and 9 
Urine Toxicity Screen 
Screen, Visits 5 and 9 
 
8.2.2 
Drug Levels 
Blood samples for monitoring therapeutic drug levels will be collected on all subjects to verify 
exposure and consistency with the randomization schedule. The timing of the blood draws are 
defined in Table 3 and include both pre-dosage (time 0) and post initial dosing of investigational 
product within the first 2 hours. Analyses of the samples will be conducted by the central 
laboratory. 
8.2.3 
Randomization phase  
Following the documented observance of a therapeutic response to IV ketamine as defined by a 
25% or greater reduction in the baseline MADRS and a C-SSRS < 3 at 24 hours post infusion, 
subjects will be randomized 2:1:1 to either a fixed dose combination of experimental drug NRX-
101 (DCS + lurasidone) or to an identical capsule containing placebo + lurasidone or to an 
identical capsule containing placebo. Institution balancing will be used to ensure that treatment 
and control groups are balanced with stratification according to C-SSRS 24 hours post-infusion 
(1, 2). Subjects who respond to ketamine will be followed for 6 weeks or until they require 
additional treatment.  
8.2.4 
Blinding Procedures 
Investigational product will be provided in a blinded fashion to sites for dispensation to subjects.  
8.2.5 
Outcome and Safety Measures 
8.2.5.1 
Outcome Measures 
8.2.5.1.1 Primary Efficacy Endpoint 
The primary outcome measure will be time to relapse, defined as (1) a return to a score of >4 on 
the C-SSRS, (2) a score of >20 on the MADRS subset of the BISS following a response to 


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ketamine at 24 hours, or (3) the treating physician’s determination that a change in treatment 
plan, such as re-hospitalization, ECT, or addition of new antidepressant drugs is required. 
All site-defined relapses will be adjudicated by a Relapse Adjudication Committee (RAC) which 
will review documentation provided by the site for each incidence and determine whether the 
relapse meets the protocol definition of relapse. The RAC will meet monthly. The RAC is 
authorized to determine that relapse occurred even if the site does not make this determination. 
8.2.5.1.2. Secondary Efficacy Endpoints 
Additionally, symptom improvement will be evaluated by assessing changes in the secondary 
outcome measures: C-SSRS, Concise Health Risk Tracking –Clinician, -Self-Rated (CHRT-C 
and –SR), and BISS. These measures will be assessed at the times specified on the Schedule of 
Study Activities, Table 3.  
The C-SSRS (and the retrospective Columbia-Classification Algorithm of Suicide Assessment 
(C-CASA component), Suicide Ideation and Behavior Questionnaire (SIBQ), BPRS, CHRT-C 
and –SR, will be evaluated within and between study treatment groups. Mean changes from 
baseline for the differences from baseline and after randomization baseline will be evaluated 
using a paired t-test within each study group and an unpaired t-test for K/N vs. K/L and K/P. 
8.2.5.1.3. Diagnostic Metric 
The following diagnostic metric will be evaluated at baseline: 
• MINI 7.0.2 
8.2.5.1.4. Additional Endpoints 
The following additional endpoints will be recorded and analyzed for both study stages: 
• Study dose per treatment group 
• All-cause discontinuation (and reason for discontinuation) 
• Suicide rates 
• Incidence of hospitalization and ER visits for disease-related outcomes 
• Proportion of subjects who are treated with new SSRIs or have increased SSRI dosages 
• Proportion of subjects who discontinue SSRIs or have reduced SSRI dosages. 
8.2.5.2 
Safety Endpoints 
8.2.5.2.1. Overall Adverse Events 
Separate safety analyses will be performed for the two stages for the Safety population. Safety 
endpoints will include adverse events (AE), vital signs, and relevant clinical chemistries and 
hematology parameters. 


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The principle of treatment emergence will be employed for the analysis of AE data. Treatment 
emergence is defined to be any event that occurred during the observation period and was not 
present at baseline, or one which represents an exacerbation of a condition present at baseline.  
Events emerging during ketamine treatment will be counted during the randomized phase of the 
study if not resolved by the start of randomized treatment initiation. Unresolved AE outcomes at 
the end of randomized treatment will be followed for an additional seven days or until resolution, 
whichever occurs earlier. 
Adverse events will be classified by MedDRA. For each study treatment, safety data will be 
collected and analyzed per stage or until treatment-emergent AEs are resolved. The type, 
incidence, timing (onset, duration), relationship, and severity of AEs will be reported for 
treatment-emergent and suspected adverse reactions. Reasons for withdrawal due to AEs will 
also be reported. Narratives will be written for every AE classified as serious or associated with 
death. Safety results will be displayed separately for each stage and combined. 
Safety and tolerability will be assessed using two-sided Fisher Exact tests to compare K/N vs. 
K/L and K/P. Mean changes from baseline will be displayed for each serum chemistry and 
hematology parameter as well as the shift; unpaired t-tests will be used to compare K/N vs. K/L 
and K/P; in addition, paired t-tests will be performed for the changes from baseline for each 
study treatment group.   
8.2.5.2.2. Safety Measures 
The Patient Rated Inventory of Side Effects (PRISE), CADSS, and Barnes Akathesia Scale 
(BARS) (including the global severity rating) will be evaluated within and between study 
treatment groups. Mean changes from baseline for the differences from baseline and after 
randomization baseline will be evaluated using a paired t-test within each study group and an 
unpaired t-test for K/N vs. K/L and K/P. 
 
8.2.5.2.3. Other Safety Measures 
It is expected that some subjects in both groups (more among those randomized to 
placebo+lurasidone and placebo) will have recurrence of their depression and, possibly 
suicidality. Therefore, the investigators plan to effect careful surveillance of all study subjects as 
follows: 
Subjects who receive ketamine will be maintained under continuous professional observation 
until stabilization is documented or ketamine is deemed not to have achieved stabilization and 
the treating physician has elected another therapeutic option (which in most cases will be 
hospitalization with ECT).  In general, study subjects will be maintained under direct observation 
in a mental health center or inpatient setting during the 24 hour stabilization period.  At the 
election of the treating physician in consultation with the patient and family, patients may return 
home during the 24 hour stabilization period, provided the treating physician has made 


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arrangements with the patient and family to maintain close professional contact during this 
period and a responsible adult will be escorting the patient at all times.  Participants who cannot 
ensure a reliable adult transport will not be allowed to enroll in the study.  Subjects will be 
instructed not to drive or operate heavy machinery for at least 24 hours post-administration. 
Daily contact with a physician, psychologist, or psychiatric nurse who will assess symptoms and 
any subject or family/significant other concerns. The contact will be either through a telephone 
or actual visit.  All on-site study visits will include a meeting with a study psychiatrist. 
The study will employ the use of HIPAA-compliant, electronic video monitoring of medication 
compliance, with the capability to send an immediate alert for outreach with any missed doses of 
medication.  A non-adherence period of 12 hours (i.e. 2 missed doses will trigger outreach by 
study personnel). 
In case of loss of phone contact or repeated non-adherence to medication, study staff will contact 
an identified family member/significant other.  If study staff determines that hospitalization is 
urgent, either the family member will take the subject to the emergency room or the staff will 
contact 911 for an ambulance.  
The investigators recognize that although DCS has been used as an anti-infective in millions of 
individuals without report of significant safety concerns, DCS has thus far been used in 21 
subjects at the 1000mg dose in formal studies of psychiatric illness. Therefore, the study medical 
monitors will surveil for safety issues via frequent safety listings reviews.  
The timing and incidence of adverse findings will be compiled following planned surveillance of 
all study subjects by study medical monitors. The number of such episodes will be evaluated 
using a Poisson regression model to compare study treatment groups controlling for C-SSRS 24 
hours post infusion (1, 2), age (<25, 25-39, >40), and gender. 
Vital signs will be obtained at every office visit. ECGs will be measured at the Screen Visits, and 
at Visits 1, 5, and 10. Digital ECGs will be obtained after the subject has been resting in a semi-
recumbent position for at least 10 minutes. All digital ECGs will be documented by recording 
date, time, heart rate, QRS duration, PR interval, RR interval, QT, and QTcF intervals. Mean 
differences will be calculated using the Fridericia formula (Puddu et al., 1988). Vital signs and 
ECGs will also be evaluated within and between study treatment groups. If indicated, additional 
ECG assessments can be made at the discretion of the investigator. The investigator will judge 
the overall interpretation as normal or abnormal. If abnormal, it will be decided as to whether or 
not the abnormality is clinically significant or not clinically significant and the reason for the 
abnormality will be recorded on the eCRF. Abnormal values shall not be recorded as AEs unless 
deemed clinically significant. 
At the Screen visit, and at Visits 1, 5, and 9, subjects will have their blood drawn for chemistry 
and CBC blood tests. At Screen, and at Visits 5 and 10, subjects will have a physical 
examination.  If these tests or exams are abnormal per established site-specific normal ranges, it 
will be decided by the site investigator whether or not the abnormality is clinically significant or 


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not clinically significant and recorded on the eCRF. Abnormal and clinically significant lab 
values will be reported as AEs if they fulfill any of the SAE criteria or are the reason for 
discontinuation of treatment with the study drug. Abnormal lab values (clinically significant and 
clinically non-significant), will be reviewed monthly by the medical monitor for trends. Should 
any abnormal lab values exceed rates described in the IB, the FDA and SPONSOR will be 
notified within regulatory timelines. McNemar paired comparison tests will be performed within 
study treatment groups for the abnormal percents while two-sided Fisher Exact tests will be 
performed between treatment groups. 
8.2.6 
Study Instruments 
Study instruments will be administered in accordance to the schedule in Table 3. 
8.2.6.1 
Efficacy Measures 
Bipolar Inventory of Symptom Scale (BISS) (Bowden et al., 2007): The BISS is a 44-item 
clinician-rated scale (22 items for the depression subscale and 22 items for the mania scale), in 
which each items is rated on a 0-4 severity scale which is which operationally defines each item, 
confining the assessment to only one behavioral construct. Items are grouped into 10 established 
symptom clusters, based on prior studies of phenomenology and reports of symptom clusters and 
principal components in ratings of BD. The timeframe for the BISS is the past 7 days.  The BISS 
scale has been found to have high internal consistency (Chronbach's alpha=0.93 for the Total 
Scale, 0.92 for the depression subscale, and 0.90 for the mania subscale) and inter-rater 
reliability (ICC=0.96 for total scale, 0.98 for depression subscale, and 0.95 for mania subscale) 
(Gonzalez, et al, 2008).  Regarding discriminant validity, the BISS total score was able to 
significantly distinguish between patients in a depressed, manic or mixed episode from 
subsyndromal patients, recovered patients, and healthy controls (Gonzalez et al, 2008).  
Convergent validity was demonstrated by strong Pearson correlations (i.e., r=.64 to .94) between 
the BISS total score and the BISS depression subscale and the MADRS, and between the BISS 
total score and the mania subscale and the YMRS across all patient and control groups described 
above;  divergent validity was demonstrated by smaller and (i.e., r=-.14-0.30) correlations 
between the BISS depression subscale and the YMRS scale, and between the BISS mania scale 
and the MADRS (r=-.06-.31). 
 
The Columbia Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2007): 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. It is a clinical interview providing a 
summary of both ideation and behavior that can be administered during any evaluation or risk 
assessment to identify the level and type of suicidality present. The C-SSRS can also be used 
during treatment to monitor for clinical worsening. The C-SSRS will be performed to assess 
suicidal ideation and behavior. C-CASA is the retrospective counterpart of the more detailed 


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classification instrument C-SSRS. The C-SSRS tool was first developed for a prospective 
national study of treatment for adolescent suicide attempts. C-SSRS was developed by reliance 
on evidence stemming from two decades of research. It contains a 1-to-5 rating scale for suicidal 
ideation of increasing severity (from a “wish list to die” to an “active thought of killing oneself 
with plan and intent”), in contrast to C-CASA, which only has one ideation item. (IOM, 2010) 
The time frame 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. 
Brief Psychiatric Rating Scale (BPRS) (Overall & Gorham, 1962): The BPRS is an 18-item 
clinician rated scale that is used to assess a range of psychotic and affective symptoms, rated 
from both observation of the subject and the subject’s own report. It has been widely used to 
measure change in pharmacologic and nonpharmacologic treatment trials and provides a rapid 
and efficient evaluation of treatment response in clinic drug studies and in clinical settings. Only 
the 4-item positive symptom subscale BPRS+ (i.e., suspiciousness, hallucinations, unusual 
thought content, and conceptual disorganization) will be used in this study. It is highly sensitive 
to change, and excellent inter-rater reliability can be achieved (i.e., ICC>.80) with training and a 
standard interview procedure.  Concurrent validity has been established by r=.92 between the 
positive symptom subscale and the corresponding subscale of the Positive and Negative 
Syndrome Scale, and sensitivity to change has been demonstrated by significant associations in 
change between the BPRS total score and the CGI and the HDRS. 
Concise Health Risk Tracking – Self Report (CHRT-SR) and Clinician Rating (CHRT-C) 
scales (Trivedi et al, 2011): This is both a subject self-report assessment of suicidality and 
related thoughts and behaviors, with a corresponding clinician rated scale. The scales are 
designed to quickly and easily track suicidality in a manner consistent with the Columbia 
Classification Algorithm of Suicide Assessment (C-CASA) (Posner et al, 2007). 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 5-point Likert scale with responses 
ranging from 1 (strongly disagree) to 5 (strongly agree). The time frame is the past seven (7) 
days. The CHRT-SR has good internal consistency (Cronbach's alpha 0.88-0.90), convergent 
validity with MADRS suicide item (r=.60) and QIDS suicide item (r=0.59), and divergent 
validity with the YMRS (r=.02).  Predictive validity was established by prospective prediction of 
suicidality-related serious adverse events among 482 patients with bipolar disorder in a 
multicenter trial (Reilly-Harrington et al, 2016). 
Suicidal Ideation and Behavior Questionnaire (SIBQ): The purpose of this instrument is to 
ensure clinicians properly assess and document suicidal ideation and behavior as well as any 
study decisions (study exclusion of subject, filing of a serious adverse event) pertaining to 
suicidality. It will be completed by site investigators during all visits.  
 
 


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8.2.6.2 
Safety Measures 
 
In addition to the measures described under efficacy, including CSSR-S, BISS (MADRS) 
CHRT-SR and CHRT-C and SIBQ, the following safety measures will be employed:  
Patient Rated Inventory of Side Effects (PRISE): The self-reported PRISE questionnaire will 
be used for the specific symptoms considered by the patients as more or less tolerable drug side 
effects. The nine domains (gastrointestinal, heart, skin, nervous system, genital ⁄ urinary, sleep, 
sexual functioning, and other symptoms) will be individually and cumulatively evaluated using a 
paired t-test with each study group and an unpaired t-test for K/N vs. K/L and K/P to assess the 
mean side effect or adverse event.  Reasons for premature discontinuation and dose reduction, 
including intolerable side effects, will be recorded.  Drug interactions between DCS and 
lurasidone will be examined. 
Clinician-Administered Dissociative States Scale (CADSS): The CADSS is a 23-item scale 
(Bremner et al 1998). It is a reliable, valid instrument. The severity of each dissociative symptom 
ranges from 0 (not present) to 4 (extreme). The CADSS total score will be calculated as the sum 
of the individual item scores. For the CADSS, change from the first time point to each 
subsequent time point will be calculated as the 40-minute, 80-minute, and 120-minute 
assessment minus the 0 (-5 minutes) score. The scale is administered at 0 (-5 minutes), 40, 80, 
and 120 minutes from the start of the infusion. The timeframe is “at this moment”.  The CADSS 
has been validated in healthy subjects and patients with psychiatric illness. 
Barnes Akathesia Scale (BARS): The Barnes Akathesia Scale (Barnes TR, 1989) is a clinician-
rated scale to assess drug-induced akathisia and classify it 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. It is the scale used most commonly in trials 
comparing incidence and severity of akathisia between antipsychotic medications and placebo.  
The time frame is “at this time”. With trained raters, the BARS has demonstrated strong inter-
rater reliability (Kappa= 0.74-0.95) (Barnes , 2003).  The BARS has been used to support the 
concurrent validity of actigraphic monitoring in akathisia (Barnes, 2003).   
 
8.2.6.3 
Other Diagnostic Instruments 
MINI 7.0.2: The M.I.N.I. International Neuropsychiatric Interview (M.I.N.I.) 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. 


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8.2.7 
Reliability Training 
All clinicians chosen to be involved in the assessment of study subjects are experienced using 
standardized clinician-rated measures. They will have all received extensive training in the use of 
these instruments in coordination with MGH CTNI. Raters will be certified in the use of the C-
SSRS and the BISS prior to participation in the study. 
8.2.8 
Subject Adherence to Protocol 
Every effort will be made to encourage subjects to comply with the procedures and the 
assessments involved in study. Subjects will be compensated for their time at each visit, at a rate 
determined appropriate by the sponsor and the IRB (estimated compensation: $20/hour). We 
believe that this level of subject compensation, while non-coercive, facilitates adherence to 
assessments and procedures that require frequent, inconvenient visits.  


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Table 5 
Protocol Violation Definitions 
 
Major Protocol Violation 
Minor Protocol Violation 
The list of examples is intended as a guide and is not all-inclusive. 
Definition 
A violation that may: 
• 
Impact subject safety, 
• 
Affect the integrity of study data, and/ 
or 
• 
Affect the subject’s willingness to 
participate in the study, and/or 
• 
Introduce bias. 
A violation that does not: 
• 
Impact subject safety, 
• 
Compromise the integrity of study 
data, and/ or 
• 
Affect the subject’s willingness to 
participate in the study, and/or 
• 
Introduce bias. 
Examples  
(not all-
inclusive) 
• 
Failure to obtain informed consent 
• 
Informed consent obtained by an 
unauthorized individual 
• 
Enrollment of a subject who did not 
meet eligibility criteria for whom a 
protocol exception was not obtained 
• 
Performing a study procedure that is 
not approved by the IRB and/or is not 
in the protocol 
• 
Failure to perform a required lab test 
that, in the opinion of the Site 
Investigator, may affect subject safety 
or data integrity 
• 
Failure to perform or follow a study 
procedure that, in the opinion of the 
Site Investigator, may affect subject 
safety or data integrity 
• 
Failure to follow safety (AE) 
management plan 
• 
Failure to report a SAE to the IRB 
and/or Coordination Center 
• 
Implementation of unapproved 
recruitment procedures 
• 
Only a photocopy of the signed/ 
dated consent form is available (the 
original is missing) 
• 
Pages are missing from the signed/ 
dated informed consent form 
• 
Use of invalid consent form (i.e., 
without IRB approval or 
outdated/expired form) 
• 
Failure to perform or follow an 
approved study procedure that, in 
the opinion of the Site Investigator, 
does not affect subject safety or 
data integrity 
• 
Study procedure conducted out of 
sequence 
• 
Failure to perform a required lab 
test 
• 
Missing lab results 
• 
Study Visit out of approved 
window 
• 
Over-enrollment 
• 
Enrollment of subjects after IRB 
approval of the study has expired 
• 
Failure to submit a continuing 
review application to the IRB 
before study expiration  
Reporting 
Requirements 
• 
Record the date discovered, date 
occurred, description of event in the 
Protocol Deviation Log. 
• 
Notify the Coordinating Center within 
24 business hours. 
• 
Record the date discovered, date 
occurred, description of event in the 
Protocol Deviation Log. 
• 
Notify the Coordinating Center  
A Relapse Adjudication Committee (RAC) will be assembled and managed by MGH CTNI. All 
site-reported relapse events will be reviewed by the RAC, and a determination made as to 
whether the event met study criteria for relapse.  The results of each adjudication will be entered 
into the study database.  The RAC will meet monthly to adjudicate the events. 


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9. 
TREATMENT OF SUBJECTS 
9.1  Investigational Drug Dose and Administration 
In our planned study, physicians will have the ability to increase the lurasidone at any point after 
the initial titration period for control of agitation, or decrease both the DCS and lurasidone dose 
according to the titration table below, in response to somnolence or extrapyramidal side effects. 
This titration will be effected while maintaining a blinded study design. The titration strategy is 
outlined in Table 6. 
Table 6 
Dose Titration 
AM dose 
PM dose 
Total Daily dose 
Day 
DCS 
Lurasidone 
DCS 
Lurasidone 
DCS 
Lurasidone 
1 
350 
16.5 
0 
16.5 
350 
33 
2 
475 
16.5 
0 
16.5 
475 
33 
3 
350 
16.5 
350 
33 
700 
49.5 
4 
350 
16.5 
475 
33 
825 
49.5 
5 
475 
33 
475 
33 
950 
66 
Uptitration 
for Agitation 
step 1 
475 
33 
475 
66 
950 
99 
step 2 
475 
66 
475 
66 
950 
132 
Stepdown 
for 
Somnolence 
step 1 
350 
16.5 
475 
33 
825 
49.5 
step 2 
350 
16.5 
350 
16.5 
700 
33 
Preferred dose 
475 
33 
475 
33 
950 
66 
9.2  Treatment Compliance 
Subjects who miss one visit will be allowed to make up that visit at the end of the dosing week. 
Subjects who miss more than one visit will be discontinued from the study.  
Subjects will be allowed to titrate up or down, as outlined above, in the event of intolerable side 
effects. No other dose modifications will be allowed. 


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A statement has been added to the Product Monograph specifying the contraindication of 
lurasidone with strong CYP3A4 inhibitors (e.g., ketoconazole) and strong CYP3A4 inducers 
(e.g., rifampin). Lurasidone dose should not exceed 40 mg/day if co-administered with moderate 
CYP3A4 inhibitors. DCS has never been reported to have any interaction with lurasidone. 
It is anticipated that subjects entering the study will be receiving concurrent disorder-directed 
treatment with various combinations of medications including: 
1. Approved antidepressants (e.g., SSRIs, SNRIs, TeCAs, fluoxetine), but no 5-HT-2a 
antagonists (lurasidone, olanzapine, quetiapine). 
2. Mood stabilizers (e.g., lithium, carbamazepine, valproic acid) 
Subjects will be permitted into the study if they are treated with no more than 1 from each 
category of the indicated classes. Approved antidepressants and mood stabilizers will be 
maintained at pre-existing 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. Subjects taking either olanzapine or quetiapine will have these medications 
discontinued in order to avoid overlap with lurasidone. Subjects taking more than 66 mg of 
lurasidone per day at baseline will be maintained on this higher dose as a protocol exception. 
Subject compliance with dosing will be monitored using HIPAA-compliant, visual imaging 
technology allowing for confirmation of oral dosing of investigational product and date/time of 
the dosing. 
9.3  Randomization/Method of Assigning Subjects to Treatment 
 
Following the documented observance of a therapeutic response to intravenous ketamine as 
defined by a 25% or greater reduction in the MADRS score and a score of ≤3 on the C-SSRS, at 
24 hours post infusion, patients will be randomized 2:1:1 to either a fixed dose combination of 
DCS + lurasidone (NRX-101), to an identical capsule containing placebo+lurasidone, or to an 
identical capsule containing placebo.  Site blocking will be used to ensure that treatment and 
control groups are balanced per site. 
9.4  Blinding 
The investigator, subject, and study staff will be blinded. Packaging and labeling of the study 
drugs will be performed in a way to ensure blinding throughout the study. 
No member of the study team at study sites nor the CRO (the group responsible for study data 
management and site monitoring) will have access to the randomization scheme during the 
conduct of the study with the exception of the group responsible for maintaining the IWRS. That 
group will be able to identify patient-specific treatment according to the uniquely assigned kit 
number. 
 


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The unblinding of specific kits will be performed by the sponsor’s Chief Medical Officer. 
 
No treatment groups or kits will be otherwise unblinded after database lock. 
 
Breaking the blind in a clinical trial on an emergency basis by the site should only occur when 
knowledge of the treatment to which a subject was allocated would have implications for the 
medical management of the subject in case of a Serious Adverse Event (SAE). However, subjects 
that relapse or experience a SAE will require real-time interaction with the medical monitor to 
confirm the event and to decide if the event must be reported to regulatory agencies or IRBs. 
The Data Safety and Monitoring Board (DSMB) (refer to Section 14.2) can request a code break, 
either for an individual subject or on a group basis as described in the DSMB charter. The 
DSMB may request to break the blind if: 
• There is an imbalance in safety parameters between groups 
and/or 
• In case of single or multiple significant AEs/SAEs that might be drug-related. 
In such a case, the chair of the DSMB would request unblinding, either of an individual subject or 
on a group basis, and the CRO would then request unblinding from the third party keeper of the 
randomization codes. 
 
9.5  Dose Adjustment and Stopping Rules 
Subjects will be allowed to titrate up or down, as outlined above, in the event of intolerable side 
effects. No other dose modifications will be allowed. 
Every effort will be made to keep the subject in the study for the full study period consisting of 
7 days of acute treatment plus 6 weekly follow-up assessments (Days 10, 14, 21, 28, 35, and 42). 
Acceptable reasons for early discontinuation include the following: 1) non-response to ketamine 
treatment, 2) request of subject, 3) decision of physician, 4) SAE, 5) and protocol violation. 
A subject who decides to discontinue the investigational product will always be asked about the 
reason(s) and the presence of any AEs. If possible, they will be seen and assessed by an 
investigator. Adverse events will be followed up (see Section 12.6) until resolution. 
If a subject discontinues from the study before randomization to Stage 2, then no further follow-
up will be expected. However, if the subject discontinues after randomization, to Stage 2 but 
before receiving any study treatment, the subject will be asked to return for a final study visit, 
during which the procedures outlined in the Early Termination Visit procedures will be 
completed, including AEs and concomitant medication assessments. 


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If a subject discontinues from the study before completion of Stage 2 and has received at least 1 
dose of study drug, the subject will be asked to return for a final study visit, at which the 
procedures outlined in the Early Termination Visit will be completed. Every effort will be made 
to follow up with subjects who discontinue from the study prior to Visit 10 (Day 42). If subjects 
refuse to return to the clinic for the study-related assessments, a modified follow-up through, for 
example, regular telephone contact or a contact at study closure will be arranged, if agreed to by 
the subject and in compliance with local data privacy laws/practices. If the subject refuses 
follow-up, the reason for the refusal and last contact date will be documented in the eCRF and 
source documents. 
Subjects who discontinue from the study will not be replaced. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1 
Study Drugs 
Ketalar (ketamine hydrochloride injection) will be purchased from PAR Sterile Products, 870 
Parkdale Rd, Rochester, MI 48307. It will be provided as IV infusion administration. 
The Investigational Product (IP) is a capsule intended for oral administration. Each capsule 
contains DCS and lurasidone hydrochloride. Inactive ingredients include mannitol, 
croscarmellose sodium, silica dioxide, and magnesium stearate. 
 
10.2. Packaging and Labeling 
Medication will be supplied in 23 cc wide mouth HDPE bottles with screw top closure. Each 
bottle will contain 2 capsules, the required dose for either morning or evening administration, 
and desiccant to aid stability. The bottles will be packaged into a cardboard kit containing 2 
bottles for each day. Six different kit types will be available. Kit 1 will contain a 5-day titration 
pack with 10 bottles, each containing 2 capsules, for the first 5 days of the study. Kits 2 to 5 will 
contain 3-day step-up or step-down packs with 6 bottles, each containing 2 capsules. Kit 6 will 
contain a 7-day preferred dose pack with 14 bottles, each containing 2 capsules. A description of 
the 6 kit types is provided in Table 7.  


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Table 7 
NRX-101 Kits 
Kit Type 
Day 
Morning Dose 
DCS      Lurasidone 
Evening Dose 
DCS     Lurasidone 
Total Dose 
DCS        Lurasidone 
1 
350 
16.5 
0 
      16.5 
350 
33 
2 
475 
16.5 
0 
      16.5 
475 
33 
1 (7 Days) 
3 
350 
16.5 
350 
      33 
700 
49.5 
 
4 
350 
16.5 
475 
      33 
825 
49.5 
 
5 
475 
33 
475 
      33 
950 
66 
 
6 
475 
33 
475 
33 
950 
66 
 
7 
475 
33 
475 
33 
950 
66 
 
Uptitration 
for Agitation 
2 (3 Days) 
step 1  
475 
33 
475 
      66 
950 
99 
3 (3 Days) 
step 2 
475 
66 
475 
      66 
950 
132 
 
Stepdown 
for 
Somnolence 
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) 
Preferred Dose          
475 
33 
475 
       33 
950 
66 
 
The composition and physical description of each capsule is below (Table 8 
throughTable 
11 
Investigational Product (NRX-101)Identification 
 


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Table 8 
Active Capsule Composition and Physical Description  
 
Strength 
237.5/8.25 
237.5/16.5 
237.5/33 
175/8.25 
175/16.6 
0/8.25 
Size 
0el 
0el 
0el 
0 
0 
0 
Color 
Light Blue 
Swedish 
Orange 
White 
Light Blue 
Swedish 
Orange 
Light Blue 
d-Cycloserine 
242.1 mg / 
39.69% 
242.1 mg / 
39.69% 
242.1 mg / 
39.69% 
178.4 mg / 
33.66% 
178.4 mg / 
33.66% 
0 mg / 0% 
Lurasidone 
8.27 mg / 
1.56% 
16.55 mg / 
3.12% 
33.10 mg / 
6.25% 
8.27 mg / 
1.56% 
16.55 mg / 
3.12% 
8.27 mg / 
2.07% 
Mannitol 50C 
311.03 mg 
/ 50.99% 
302.75 mg / 
49.63% 
286.20 mg / 
46.92% 
300.93 mg / 
56.78% 
292.65 mg / 
55.22% 
359.17 mg / 
89.79% 
Croscarmellose 
Sodium 
39.50 mg / 
6.48% 
39.50 mg / 
6.48% 
39.50 mg / 
6.48% 
 
34.45 mg / 
6.50% 
34.45 mg / 
6.50% 
26.00 mg / 
6.50% 
Hyroxypropylmethyl 
cellulose 
E5 
(6% 
solution) 
0 mg / 0% 
0 mg / 0% 
0 mg / 0% 
0 mg / 0% 
0 mg / 0% 
4.56 mg / 
1.14% 
Silica Dioxide 
6.1 mg / 
1.0% 
6.1 
mg 
/ 
1.0% 
6.1 
mg 
/ 
1.0% 
 
5.30 mg / 
1.0% 
5.30 mg / 
1.0% 
0 mg / 0% 
Magnesium Stearate 
3.00 mg / 
0.49% 
3.00 mg / 
0.49% 
3.0 
mg 
/ 
0.49% 
2.65 mg / 
0.50% 
2.65 mg / 
0.50% 
2.00 mg / 
0.50% 
Total 
610.0 mg / 
100% 
610.0 mg / 
100% 
610.0 mg / 
100% 
530.0 mg / 
100% 
530.0 mg / 
100% 
400.0 mg / 
100% 
 


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Table 9 
Lurasidone Capsule Composition and Physical Description 
Strength 
0/8.25 
0/16.5 
0/33 
0/8.25 
0/16.6 
Size 
0el 
0el 
0el 
0 
0 
Color 
Light Blue 
Swedish 
Orange 
White 
Light Blue 
Swedish 
Orange 
Lurasidone 
8.27 mg / 
1.80% 
16.55 mg / 
3.60% 
33.10 mg / 
7.20% 
8.27 
mg 
/ 
2.07% 
16.55 mg / 
4.14% 
Mannitol 50C 
414.29 mg / 
90/06% 
406.01 mg / 
88.26% 
389.46 mg / 
84.67% 
359.17 mg / 
89.79% 
350.89 mg / 
87.72% 
Croscarmellose 
Sodium 
29.90 mg / 
6.50% 
29.90 mg / 
6.50% 
29.90 mg / 
6.50% 
26.00 mg / 
6.50% 
26.00 mg / 
6.50% 
Hyroxypropylmethyl 
cellulose 
E5 
(6% 
solution) 
5.24 mg / 
1.14% 
5.24 mg / 
1.14% 
5.24 
mg 
/ 
1.14% 
4.56 
mg 
/ 
1.14% 
4.56 
mg 
/ 
1.14% 
Magnesium Stearate 
2.30 mg / 
0.50 % 
2.30 mg / 
0.50 % 
2.30 
mg 
/ 
0.50 % 
2.00 
mg 
/ 
0.50% 
2.00 
mg 
/ 
0.50% 
Total 
460 mg / 
100% 
460 mg / 
100% 
460 
mg 
/ 
100% 
400.0 mg / 
100% 
400.0 mg / 
100% 
 
Table 10 
Placebo Capsule Composition and Physical Description 
Strength 
0/0 
0/0 
0/0 
0/0 
0/0 
Size 
0el 
0el 
0el 
0 
0 
Color 
Light Blue 
Swedish 
Orange 
White 
Light Blue 
Swedish 
Orange 
Mannitol 50C 
 
 
 
 
 
Croscarmellose 
Sodium 
 
 
 
 
 
Hyroxypropylmethyl 
cellulose 
E5 
(6% 
solution) 
 
 
 
 
 
Magnesium Stearate 
 
 
 
 
 
Total 
 
 
 
 
 


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The NRX-101 capsule is supplied in 5 strengths as described below. Matching placebos 
containing either 8.25, 16.5, or 33 mg of lurasidone and no d-cycloserine (DCS) will also be 
supplied as well as a full placebo containing no DCS or lurasidone. 


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Table 11 
Investigational Product (NRX-101)Identification 
D-cycloserine (mg) 
Lurasidone (mg) 
Capsule Color 
Capsule Size 
237.5 
33 
White 
0EL 
237.5 
16.5 
Swedish Orange 
0EL 
237.5 
8.25 
Light Blue 
0EL 
175 
16.6 
Swedish Orange 
0 
175 
8.25 
Light Blue 
0 
Each IP formulation label will include the following information: 
• Name of sponsor and address 
• Protocol number  
• Quantity of capsules 
• Storage conditions 
• Investigational drug statement (for clinical trial use only) 
• Drug packager lot number 
• Kit/Medication number 
• Contents 
• Administration statement 
• Spaces for Study Coordinator to insert: 
o Subject number 
o Date Dispensed 
When the study drug bottle is dispensed to a subject, the second panel of the label or a copy 
should be detached and affixed to the drug accountability page in the subject’s study source 
document. 
Sites will enter the subject screening ID number into the Randomization Page of the IVRS 
system, and the subject will be assigned to one of the three treatment groups. The bottle number 
Medication ID generated by the IVRS for each subject will be noted in the Randomization Page. 
Drug for each treatment day will be dispensed in 2 bottles each containing 2 capsules. Subjects 
will be instructed to take two capsules, each morning and evening.  


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10.1.1 
Storage 
Capsules will be packaged in white HDPE bottles containing desiccant with a PP closure and a 
foil induction seal. Bottles will be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 
15°C to 30°C (59°to 86°F). 
10.1.2 
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 movement records 
during the study and/or at the end of the study. 
10.1.3 
Handling and Disposal  
There are no special handling constraints for the IP. Unused IP will be returned to the CRO for 
disposal. 


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11. 
ASSESSMENT OF EFFICACY 
The primary outcome measure will be time to relapse, defined as a return to a score of >4 on the 
C-SSRS, and/or a score of 20 on the MADRS subset of the BISS. The RAC will adjudicate each 
site reported instance of relapse for compliance the protocol definition of time to relapse. 
Relapse is a time-to-event outcome reflective of this multi-component disorder. Time to relapse 
is more sensitive measure than an assessment at a fixed time. Time to relapse will be displayed 
using a Kaplan-Meier lifetable with the treatment groups compared using a two-sided Wilcoxon-
Gehan test and a proportional hazard model to include the above cited covariates.  
Titration of DCS or lurasidone within the dosing range will not be considered to be a relapse.  
All of the instruments used to measure ASIB or depression constitute serial continuous and 
ordinal outcomes which will be analyzed using MMRM, which accounts for missing data and 
early discontinuations. These instruments include the following: 
• C-SSRS (and the retrospective C-CASA component) 
• CHRT (CHRT-SR and CHRT-C) 
• BISS 
• SIBQ 
• BPRS 
The models will include treatment group, study visit, the interaction between study visit and 
treatment group, the baseline of the variable being analyzed, C-SSRS 24 hours post infusion (1, 
2), age (<25 yrs, 25-39 yrs, >40 yrs), and gender as fixed effects. The reason for missing data 
will be evaluated as a condition of MMRM analysis.  
Means, mean changes, standard deviations, and ranges will be presented separately for Stage 1 
and then for each Stage 2 treatment group over time. These endpoints will be evaluated within 
the three study treatment groups for the change from Stage 1 and Stage 2 baselines 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. 


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12. 
ASSESSMENT OF SAFETY 
12.1 
Suicidal Ideation and Clinical Management 
The documentation and proper management of suicidal ideation by sites will be documented 
with the use of the Suicidal Ideation and Behavior Questionnaire (SIBQ), completed by site 
clinicians during all visits, and by remote, independent third party raters during the screening 
period. 
Any subject who, based on the investigator’s judgment, poses an imminent risk of suicide should 
be discontinued from the study (see Section 9.2). All efforts will be taken to minimize the risk of 
suicide and the investigator will carefully monitor the subject. If during the course of the study, 
subjects show evidence of suicidal behavior, the subjects will be evaluated immediately or 
referred to their attending psychiatrist, a local emergency room, or another appropriate clinical 
setting for further evaluation to see if they are safe to continue in the study. The site will have the 
ability to direct any subject who requires emergency hospitalization to an emergency room or 
inpatient psychiatric unit that is within a 50-mile radius of the site. In addition, the subject will 
be able to contact someone at the site 24 hours a day should they have serious worsening of their 
condition. 
Suicide and attempted suicide, irrespective of the method, but occurring in connection with the 
use of IP, will be reported as AEs (all suicides are SAEs; attempted suicides can be either serious 
or non-serious AEs). 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 12.3 and 12.6.1.1. If a suicide 
attempt does not meet the criteria for an SAE, it will be considered a reportable AE and a 
Suicidal Ideation and Behavior Reportable Event Form will be completed by the investigator. 
All events of suicidal ideation and behavior will be carefully monitored. These include events of 
suicide attempts, emergence or significant worsening of suicidal ideation, completed suicides, 
and suicidal behavior. As described in Section 8.3.5.1.1, the C-SSRS and MADRS items of the 
BISS, as well as the clinician’s judgment, will be used in the assessment of suicidal risk by the 
investigator. The investigator’s clinical judgment and conclusion regarding suicidal risk will be 
documented in the SIBQ for that visit. Clinically significant (in the opinion of the site 
investigator) emergence or worsening of suicidal ideation and/or behavior will be considered 
reportable events and documented as AEs, and a Suicidal Ideation and Behavior Reportable 
Event Form will be completed and submitted to medical monitor within 24 business hours of the 
site’s knowledge of the ideation or behavior. The subject should be withdrawn from the study 
and the event will be adjudicated by the RAC as a potential endpoint event. 
If suicidal behavior meets the criteria for a SAE, according to the guidelines in Section 12.3, 
investigators are required to report the event according to the guidelines for SAEs in 
Sections 12.3 and 12.6.1.1 and submit the completed SAE form to the medical monitor within 24 


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business hours. The subject should be withdrawn from the study and the event will be 
adjudicated by the RAC as a potential endpoint event. 
The SAE Form will include the exact nature of the event and the circumstances of the subject at 
the time of the event, in addition to the usual information required to document AEs or SAEs. 
Data on all of the above will be collected on separate eCRF pages. 
The latest version of the AE dictionary, MedDRA, will be used by the CRO for the classification 
and analysis of AEs entered in the study database. For regulatory reporting, SAEs will be 
processed in the Electronic Data Capture (EDC) System and coded using MedDRA. 
If a subject (or subject’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. Pregnancy in 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. 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 subject will be discontinued from study medication. 
12.2 
Definition of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An AE does not 
necessarily have a causal relationship with 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. 
(Definition per ICH). 
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 intensity or changes in intensity 
• Whether the AE is serious or not 
• Expectedness 
• Investigator causality rating against study drug (yes or no) 
• Action taken with regard to the Investigational Product (IP) 


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• AE caused subject’s withdrawal from the study (yes or no) 
• Outcome 
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up by 
the investigator for as long as medically indicated, but without further recording in the eCRF. 
MGH CTNI or its representative retains the right to request additional information for any 
subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
12.3 
Definition of Serious Adverse Events 
The following criteria define a Serious Adverse Event: 
• 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 subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These will usually be considered serious. 
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (e.g., death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (e.g., all-cause mortality). 
In addition, the following variables will be collected for SAEs: 
• Date AE met criteria for SAE 
• Date investigator became aware of SAE 
• AE is serious due to 
• Date of hospitalization 
• Date of discharge 
• Probable cause of death 


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• Date of death 
• Autopsy performed 
• Causality assessment in relation to study procedure(s) 
• Causality assessment in relation to study drug 
• Causality assessment in relation to other medication 
• Description of AE 
Intensities will be reported for each AE in the following categories: a) Mild (awareness of sign or 
symptom, but easily tolerated); b) Moderate (discomfort sufficient to cause interference with 
normal activities); c) Severe (incapacitating, with inability to perform normal activities). 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by these criteria. An AE of severe intensity need not necessarily 
be considered serious. For example, nausea that persists for several hours may be considered 
severe nausea, but not an SAE. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but would be an SAE. 
Worsening symptoms of the primary study condition (i.e., bipolar depression) will not be 
recorded as an AE. However, if inpatient hospitalization results from worsening psychiatric 
symptoms or suicidal ideation, the hospitalization will be recorded as an SAE in the eCRF. 
Study drug abuse is an SAE, even when there are no symptoms or additional AEs, and will be 
reported according to the guidelines in Section 12.5. Misuse of IP is an AE, but is not considered 
an SAE unless accompanied by serious sequelae. 
Should an overdose of study drug occur, it must be reported in accordance with the procedures 
described in Section 12.5. An overdose associated with symptoms must be reported as an AE, 
while an overdose without associated symptoms, must be reported only on the separate Clinical 
Study Overdose Report Form. 
12.4 
Relationship to Study Drugs 
Adverse events and SAEs will be collected from the time of signature of informed consent 
throughout the treatment period. Unsolicited SAEs will be collected 30 days post last study 
treatment. 
The investigator will assess the causal relationship (i.e., the relationship to study treatment) 
between the IP and AEs, and answer “yes” or “no” to the question “Do you consider that there is 
a reasonable possibility that the event may have been caused by the investigational product?” 
Causal relationship in cases where the depression or suicidal ideation has deteriorated due to lack 
of effect will be classified as no reasonable possibility. For SAEs, causal relationship will also be 
assessed. Note that for SAEs that could be associated with any study procedure, the causal 
relationship is implied as “yes.”  


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An AE is considered unexpected if it is not listed in the IB, or the nature or severity is not 
consistent with the applicable reference in the IB. 
12.5 
Recording of Adverse Events 
AEs spontaneously reported by the subject in response to the open question from the study 
personnel: “Have you had any health problems since the previous visit?” or revealed by 
observation will be collected at each visit; classified as mild, moderate, or severe; and recorded 
in the eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a 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. 
Subjects shall be encouraged to contact the investigator or a member of the clinical site staff at 
any time between visits concerning AEs or worsening of symptoms.  
Abnormal and clinically significant lab values will be reported as AEs if they fulfill any of the 
SAE criteria or are the reason for discontinuation of treatment with the study drug. The principal 
investigator and the study biostatistician will establish the rules for what will constitute abnormal 
and clinically significant lab values based on established site-specific lab normal ranges. Adverse 
events, including abnormal lab values (clinically significant and clinically non-significant), will 
be reviewe monthly for trends by the principal investigator and the medical monitor. Should any 
abnormal lab values exceed rates described in the IB, the FDA will be notified within regulatory 
timelines. If deterioration in a laboratory value/vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result/vital sign will be considered as additional information. Wherever possible, the reporting 
investigator will use the clinical, rather than the laboratory term (e.g., anemia versus low 
hemoglobin value). In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters will be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE 
Disease progression can be considered as a worsening of a subject’s condition attributable to the 
disease for which the study drug is being studied. It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease. The development of 
worsening bipolar depression will be considered as disease progression and not an AE. Events 
(except for suicidal ideation or behavior) which are unequivocally due to disease progression 
will not be reported as an AE during the study. 
 


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12.6 
Reporting of Adverse Events 
All AEs and special reporting situations, whether serious or non-serious, will be reported from 
the time a signed and dated Informed Consent Form (ICF) is obtained until completion of the 
subject’s last study-related procedure (which may include contact for follow-up of safety). 
Serious adverse events, including those spontaneously reported to the site-investigator from the 
time a signed and dated ICF is obtained until within 30 days after the last dose of study drug, 
must be reported using the Serious Adverse Event Form. CRO will evaluate any safety 
information that is spontaneously reported by a site investigator beyond the time frame specified 
in the protocol. 
All events that meet the definition of a SAE will be reported as SAEs, regardless of whether they 
are protocol-specific assessments. 
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document and the eCRF. 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”). Investigators must record in the CRF their opinion concerning the relationship of the 
AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to CRO instructions. 
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
CRO, on behalf of the sponsor, will also report to site investigators all SAEs that are unlisted 
(unexpected) and associated with the use of the study drug. CRO will report these events to the 
designated IRB, on behalf of the sponsor. 
12.6.1 
Reporting of Serious Adverse Events 
The EDC platform will provide a mechanism for sites to report SAEs, and for the site 
investigators and medical monitor to sign off on the SAE reports. Reportable SAEs will be sent 
to the FDA by the sponsor. CRO will notify sites of reportable SAEs, as outlined in 
Section 12.6.1.1. 
When a SAE is discovered, it will be reported immediately (within 24 business hours) to the 
Medical Monitor, as described below. Serious adverse events will be reported within 24 business 
hours of the site’s knowledge of the event to the IRB (see below). 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 
site Principal Investigator will determine whether the event is study-related. All SAEs and 
reportable events will be reported within 48 business hours of [CRO] receipt of an SAE or other 
reportable event form to the sponsor, Medical Monitor, and the study site investigators. 


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12.6.1.1 Procedures for Assessing, Recording, and Reporting Adverse Events and Serious 
Adverse Events 
Throughout the duration of the study, the Investigator will closely monitor each subject for 
evidence of drug intolerance and for the development of clinical or laboratory evidence of adverse 
events.  All adverse events (expected or unexpected) which occur during the course of the study, 
whether observed by the Investigator or by the subject, and whether or not thought to be drug-
related, will be reported and followed until resolution or until they become stable. 
The description of the adverse event will include description of event, start date, stop date, 
intensity, if it was serious, relationship to test drug, change in test drug dosage, if the subject died, 
and if treatment was required. 
Events will be coded to one of the following intensity categories below: 
Severity 
Definition 
Mild 
Awareness of signs or symptoms, but no disruption of usual activity 
Moderate 
Event sufficient to affect usual activity (disturbing) 
Severe 
Event causes inability to work or perform usual activities 
(unacceptable) 
 


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Events will be coded into one of the following causality categories as defined below: 
Category 
Definition 
Unrelated 
Clearly and incontrovertibly due only to extraneous causes, and does 
not meet criteria listed under possible or probable. 
Unlikely 
Does not follow a reasonable temporal sequence from administration. 
May have been produced by the subject’s clinical state or by 
environmental factors or other therapies administered. 
Possible 
Follows a reasonable temporal sequence from administration, but 
may have been also produced by the subject’s clinical state, 
environmental factors or other therapies administered. 
Probable 
Clear-cut temporal association with administration with improvement 
on cessation of investigational medicinal product or reduction in 
dose. Reappears upon rechallenge. Follows a known pattern of 
response to the investigational medicinal product. 
Adverse events with the causality assessed as unrelated or unlikely are categorized as not related 
to study medication. 
Adverse events with the causality assessed as possible or probable are categorized as related to 
study medication and are called adverse drug reactions. 
All SAEs must be reported immediately (no more than 24 hours after becoming aware of the 
event).  The investigator must complete the SAE Report Form and notify according to the Serious 
Adverse Event Report Form Instructions.  


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13. STATISTICS 
The study analyses will be conducted in a GCP environment (ICH E6). All analyses will be pre-
specified in a Statistical Analysis (SAP) prior to beginning subject enrollment.   
13.1 
Study Design  
This is a two-stage design with two pre-defined interim looks during the second stage.  The first 
stage is a direct assignment to Ketamine while the second stage is a randomized phase for those 
subjects following a documented Ketamine response.   
13.2 
Randomization 
Following the documented observance of a therapeutic response to intravenous ketamine as 
defined by a 25% or greater reduction in the MADRS score and a score of < 3 on the C-SSRS, at 
24 hours post infusion, patients will be randomized 2:1:1 to either a fixed dose combination of 
DCS + lurasidone (NRX-101), to an identical capsule containing placebo+lurasidone, or to an 
identical capsule containing placebo. Site blocking will be used to ensure that treatment and control 
groups are balanced per site. 
13.3 
 Study Populations 
The study will have prospectively defined study populations including separate evaluability rules 
for the Ketamine treatment (Stage 1) and randomized treatment (Stage 2). 
For Stage 1, the Intent-to-Treat population will include all subjects who received the Ketamine 
infusion and they have the 24 hours post-infusion efficacy assessments.  The Per-Protocol 
population will include the subset of ITT subjects who were eligible, who had the 24 hour post-
infusion efficacy assessments within 18 to 30 hours post the start of the initial infusion, and who 
had no major protocol violations.  The Safety Population will include all subjects treated with 
Ketamine and with any post-baseline safety data. 
For Stage 2, the Intent-to-Treat population will include all subjects who received the randomized 
study treatment and have any post-baseline efficacy assessments.  The Per-Protocol population 
will include the subset of ITT subjects who were eligible, who have any post-baseline efficacy 
assessments within 1 day of scheduled visits through Day 7 and within 3 days of scheduled visits 
through Day 42, and who had no major protocol violations.  The Safety Population will include 
all subjects as treated with study treatment and with any post-baseline safety data. 
The ITT population will be used for the primary analyses.  If <5% are to be excluded from the ITT 
population, then the analysis will not be performed for the PP population.     
Every effort will be made to encourage patients to comply with the procedures and the assessments 
involved in study. Non-compliance will be tracked.  Protocol violations will be reviewed in real 
time; prospective rules will be set for exclusions from the PP population.   


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13.4 
Hypothesis Tests 
 
13.4.1 
Primary Hypotheses 
The primary study hypothesis (alternative hypothesis) is that Ketamine and experimental drug 
NRX-101 (K/N) delays the time to documented relapse as compared to both lurasidone (L) and 
placebo (P) as measured by the hazard ratio (h) versus the null hypothesis of no delay in time to 
relapse for either comparator treatment (Ketamine/lurasidone [K/L] and Ketamine/placebo [K/P]) 
as follows: 
• H0: hNRX-101 < hL and hP 
• Ha: hNRX-101 > hL and hP 
13.4.2 
Secondary Hypotheses 
The secondary study hypotheses relating to secondary ASIB and BPD endpoints (alternative 
hypotheses favoring K/N vs. K/L and K/P) are the following: 
1. K/N will favorably separate from both K/L and K/P by 72 hours, with sustained 
difference between groups thereafter. 
2. All cause discontinuation (including discontinuation for continued suicidal ideation) will 
be lower for K/N than both K/L and K/P. 
3. K/N will favorably separate from K/L and K/P starting at day 7, with sustained difference 
thereafter.   
4. Improvements within the K/N group observed at Week 2 will remain stable to end of 
study.  
5. C-SSRS scores will remain <4 for 4 weeks following treatment discontinuation (i.e. any 
“crisis” will resolve within the 6 week time period with more favorable outcomes in the 
K/N group as compared to K/L and K/P. 
13.5 
Efficacy Endpoints 
13.5.1 
Primary Efficacy Endpoint 
The primary outcome measure will be time to relapse, defined as the need to implement a new 
treatment plan (not a dose increase, decrease, or suspension) or as a return to a score of ≥4 on the C-
SSRS, and/or a score of 20 on the MADRS subset of the BISS 
13.5.2 
Secondary Efficacy Endpoints 
Additionally, symptom improvement will be evaluated by assessing changes in the secondary 
outcome measures: C-SSRS, CHRT, BISS (MADRS), and BPRS.  These measures will be 
assessed at the times specified on the Study Activity Schedule, Table 3. 
The C-SSRS (and the retrospective C-CASA component), CHRT (CHRT-SR and CHRT-C), BISS 
and BPRS (including the global severity rating) will be evaluated within and between study 


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treatment groups.  The time frame 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. Mean differences 
will be evaluated using a paired t-test with each study group and an unpaired t-test for K/N vs. K/L 
and K/P. 
 
13.5.3 
Diagnostic Metrics 
The following metrics will be evaluated at baseline: 
• MINI 7.0.2 
13.6 
Additional Endpoints 
The following additional endpoints will be recorded and analyzed for both study phases: 
• Study dose per treatment group 
• All-cause discontinuation (and reason for discontinuation) 
• Suicide rates 
• Incidence of hospitalization and ER visits for disease-related outcomes 
• Proportion of subjects who are treated with new SSRIs or have increased SSRI dosages 
• Proportion of subjects who discontinue SSRIs or have reduced SSRI dosages. 
13.7 
Safety Endpoints 
13.7.1 
Overall Adverse Events 
Separate safety analyses will be performed for the two stages for the Safety population.  Safety 
endpoints will include adverse events (AE), vital signs (VS), and relevant clinical chemistries and 
hematology parameters. 
 
The principle of treatment emergence will be employed for the analysis of AE data.  Treatment 
emergence is defined to be any event that occurred during the observation period and was not 
present at baseline, or one which represents an exacerbation of a condition present at baseline.   
 
Events emerging during Stage 1 will be counted during Stage 2 if not resolved by the start of 
randomized treatment initiation.  Unresolved adverse event outcomes at the end of Stage 2 will be 
followed for an additional seven days or until resolution, whichever occurs earlier. 
 
Adverse events will be classified by MedDRA.  For each study treatment, safety data will be 
collected and analyzed per stage or until treatment-emergent adverse events are resolved.  The 
type, incidence, timing (onset, duration), relationship, and severity of AEs will be reported for 


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treatment-emergent and SARs.  Reasons for withdrawal due to AEs will also be reported.  
Narratives will be written for every AE classified as serious or associated with death.  Safety results 
will be displayed separately for each stage and combined. 
 
Safety and tolerability will be assessed using two-sided Fisher Exact tests to compare K/N vs. K/L 
and K/P.  Mean changes from baseline will be displayed for each serum chemistry and hematology 
parameter as well as the shift; unpaired t-tests will be used to compare K/N vs. K/L and K/P; in 
addition, paired t-tests will be performed for the change from baseline for each study treatment 
group.     
13.7.2 
Other Safety Measures 
The study is being conducted in a population who would likely have been admitted to a psychiatric 
hospital, if they did not have a positive response to ketamine.  Moreover, it is expected that some 
subjects in the K/L and K/P treatment groups will have recurrence of their depression and, possibly 
suicidality. The timing and incidence of adverse findings will be compiled following planned 
surveillance of all study subjects by a designated safety monitor.  The number of such episodes 
will be evaluated using a Poisson regression model to compare study treatment groups controlling 
for C-SSRS 24 hours post infusion (1, 2), age (<25, 25-39, >40), and gender. 
 
Vital signs and ECGs will also be evaluated within and between study treatment groups.  Mean 
differences in heart rate, QRS duration, PR interval, RR interval, QT, and QTcF. QTcF intervals 
will be calculated using the Fridericia formula (Puddu et al, 1988).  The overall interpretation will 
be reported as normal or abnormal; if abnormal, then the percents clinically significant will be 
reported. Abnormal values shall not be recorded as AEs unless deemed clinically significant. 
McNemar paired comparison tests will be performed within study treatment groups for the 
abnormal percents while Fisher Exact tests will be performed between treatment groups. 
 
While symptom improvement will be evaluated by assessing changes in the secondary outcome 
measures: C-SSRS, CHRT, BISS (MADRS), SIBQ and BPRS, safety measures in the PRISE, 
CADSS and BARS (including the global severity rating) will be evaluated within and between 
study treatment groups.  The time frame 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. Mean differences 
will be evaluated using a paired t-test with each study group and an unpaired t-test for K/N vs. K/L 
and K/P. 
 
 


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13.8 
Sample Size Calculations 
13.8.1 
Allocation 
To encourage study participation, a 2:1:1 randomization will be used where at most half as many 
subjects will be assigned to the lurasidone and placebo arms as compared to the K/N study arm.  
The goal will be to have 62 subjects randomized to K/N and 31 subjects randomized to each of 
K/L and K/P for a total of 124 randomized subjects.  The randomization takes place among 
Ketamine responders once confirmed by Medical Monitor.     
13.8.2 
Stage 1 
The study goal is to achieve a total of 124 Ketamine responders for the Stage 2 evaluation.  A total 
of 192 subjects are projected to be enrolled but this number may be reached sooner if the 
cumulative effect of the Ketamine response rate exceeding 70%, if the Stage 1 loss rate being less 
than 8% (15 subjects), or if the Stage 2 loss rate being less than 8% (9 subjects). Thus, there would 
be 177 subjects who complete Stage 1 before considering Ketamine response.  The literature and 
prior experience suggests that 70% of those treated with ketamine will have an adequate reduction 
in depression and suicidality which equates to 124 Ketamine responders (177 x 0.7) who would 
be available for randomization.  More subjects will need to be enrolled if the Ketamine response 
rate was lower than 70% or the randomization refusal rate was higher than 8%, considered to be 
part of Stage 2 losses.    
13.8.3 
Stage 2 
Stage 2 will investigate the study hypotheses. The primary efficacy hypothesis is that K/N will 
delay the time to relapse relative to K/L and K/P. The goal will be to have 62 subjects 
randomized to K/N and 31 subjects randomized to K/L and K/P. These numbers are based on the 
Ketamine Responders. See Error! Reference source not found. for the total number of K/N and 
K/L subjects required to test the primary efficacy hypothesis. The sample size requirements are 
shown just for K/N and K/L. . 
The study is powered based on the number of subjects randomized to K/N vs. K/L. In order to 
achieve 90% study power with two-sided 0.05 Type I error, a total of 56 K/N subjects, 28 K/L 
subjects, and 28 K/P subjects must be evaluated for time to relapse over the full 6 weeks. This is 
based on the assumption of a 30% relapse rate in the K/N treatment group and a 70% relapse rate 
in the K/L and K/P treatment groups. A larger gap in the relapse rate is expected based on the 
literature, so this is believed to be a conservative assumption. These calculations assume a loss of 
8% during Stage 2.  
 
 
 


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Table 12 
Time to Relapse: K/N and K/L Groups Followed for 6 Weeks 
90% Power 
Reaching 
Significance 
 Test significance level, α 
0.05 
0.05 
 1 or 2 sided test? 
2 
2 
 K/L relapse-free % p1 at Week 6 
30% 
30% 
 K/N relapse-free % p2 at Week 6 
52% 
70% 
 Hazard ratio, h=ln(p1) / ln(p2) 
1.841 
3.376 
 Power ( % ) 
90 
N/A 
 Total N  
112 
112 
 Total N of relapses required, R 
48 
62 
 Total N accounting for 8% Stage 2 losses  
124 
124 
 Total N accounting for 30% K non-responders  
177 
177 
 Total N accounting for 8% Stage 1 losses  
192 
192 
The secondary efficacy hypotheses will also be evaluated using a hierarchical testing strategy 
where testing to support labeling claims continues as long as two-sided p=0.05 is reached. The 
first such hypothesis to be tested for the depression endpoints if whether K/N separates from K/L 
and K/P by 72 hours, with sustained difference between groups thereafter (see Error! Reference 
source not found.). There will be 90% power and two-sided 5% Type I error to detect a 0.754 
effect size for the comparison of the K/N against the K/L and K/P treatment groups. 
 
Table 13 
Two Group T-test: Equal Effect Sizes 
90% Power 
Reaching Significance 
 Test significance level, α 
0.05 
p=0.05 
 1 or 2 sided test? 
2 
2 
 Effect size,  = |1 - 2| /  
0.754 
0.456 
 Power ( % ) 
90 
N/A 
 Total N 
112 
112 
Next, all-cause discontinuation (including discontinuation for continued suicidal ideation) will be 
tested. The hypothesis is that the percent discontinued prior to Week 6 will be lower in K/N than 
K/L and K/P using a lifetable approach (see Error! Reference source not found.). 
 


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Table 14 
Two Group Log Rank Test: Time to All-cause Discontinuation 
90%   Power 
Reaching 
Significance 
 Test significance level, α 
0.05 
0.05 
 1 or 2 sided test? 
2 
2 
 K/L success rate p1 at Week 6 
0.225 
0.225 
 K/N success rate p2 at Week 6 
0.6 
0.43 
 Hazard ratio, h=ln(p1) / ln(p2) 
3.89 
1.77 
 Power (%) 
90 
N/A 
 Total N 
112 
112 
 Total # discontinued required, D 
60 
72 
The next hypothesis to be tested is whether K/N will separate from K/L and K/P starting at Day 
7, with sustained difference thereafter (see Error! Reference source not found.).  
The next hypothesis to be tested is whether improvements within the K/N group observed at 
Week 2 will remain stable to end of study (see Error! Reference source not found.).  


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Table 15 
One Group t-test: No Mean Change 
  
1 
2 
3 
4 
 Test significance level, a 
0.050 
0.050 
0.050 
0.050 
 1 or 2 sided test? 
2 
2 
2 
2 
 Effect size, d = |mA - m0| / s 
0.441 
0.636 
0.267 
0.384 
 Power ( % ) 
90 
90 
50 
50 
 N 
56 
28 
56 
28 
 
The last secondary hypothesis to be tested is whether C-SSRS scores will remain < baseline for 4 
weeks following treatment discontinuation (i.e., “crisis” will resolve within the 6 week time 
period with most favorable outcomes in the K/N group as compared to K/L (see Error! Reference 
source not found.). 
Table 16 
 Fisher Exact Test: Normalized C-SSRS Score Percent Scenarios 
   
1 
2 
3 
4 
 Test significance level, a 
0.050 
0.050 
0.050 
0.050 
 1 or 2 sided test? 
2 
2 
2 
2 
 Control Success %, p1 
30% 
40% 
50% 
60% 
 K/N Success %, p2 
66.7% 
76% 
84% 
91% 
 Odds ratio, y=p2(1-p1)/[p1(1-p2)] 
4.674 
4.750 
5.250 
6.741 
 Power ( % ) 
90 
90 
90 
90 
     n1 
28 
28 
28 
28 
     n2 
56 
56 
56 
56 
 Ratio: n2 / n1 
2 
2 
2 
2 
 Pairwise N = n1 + n2 
84 
84 
84 
84 
13.9 
Overall Type 1 Error Control 
The overall Type I error is two-sided 5%.  No interim analyses are planned. 
A hierarchical testing plan is in place to control Type I error to extend labeling claims in the 
following pre-defined testing order where statistical significance (two-sided p<0.05) is required 
at each step: 
1. Primary: K/N will delay time to relapse relative to K/L and K/P 
2. Secondary: K/N will separate from K/L and K/P by 72 hours, with sustained difference 
between groups thereafter 


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3. Secondary: All-cause discontinuation (including discontinuation for continued suicidal 
ideation) will be lower in K/N than K/L and K/P. 
4. Secondary: K/N will separate from K/L and K/P starting at Day 7, with sustained 
difference thereafter   
5. Secondary: Improvements within the K/N group observed at Week 2 will remain stable to 
end of study.  
13.10 
Analysis Approach 
13.10.1 Software 
All calculations will be performed using SAS statistical software, version 9.1 or later, and 
StatXact, version 10 or later.   
13.10.2 Display Formats 
All efficacy and safety data will be displayed in tables and listings.  Separate analyses will be 
performed for Stage 1, Stage 2, and for combined stages (primary efficacy endpoint).  Post-Text 
TLFs will be provided in collated electronic MS Word .rtf files (i.e. table columns and rows appear 
in MS Word Table format). 
13.10.3 Conventions 
Means, mean changes, standard deviations, and ranges will be presented separately for Stage 1 and 
then for each Stage 2 treatment group over time. These endpoints will be evaluated within the three 
study treatment groups for the change from Stage 1 and Stage 2 baselines 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. Unless otherwise specified minimum and maximum values will be reported to the 
same number of decimal places as the recorded measurements, mean and median are reported to 
one more decimal place and standard deviation one additional decimal place more than the mean. 
 
For ordinal and categorical variables, absolute and relative frequencies will be reported. Relative 
frequencies will be based on all observations and reported as percentages to one decimal place. 
Unless otherwise specified percentages will be based on the number of subjects with data and will 
not be calculated for missing categories. 
 
Adverse events, medical histories and concomitant medications will be reported on a subject and 
an event basis. The percentages will be calculated using the number of subjects in the population 
Analysis Set as the denominator. 
 


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All hypotheses will be tested at 5% (final analysis) level of significance using a two-sided test 
unless otherwise specified.   
P-values will be rounded to four decimal places. If a p-value is less than 0.0001 it will be reported 
as “<0.0001.” If a p-value is greater than 0.9999 it will be reported as “>0.9999”. 
13.10.4 General Methodology 
Time to event analyses will be performed using a Kaplan-Meier lifetable, two-sided Wilcoxon-
Gehan test, and proportional hazard models (PHREG) including the following covariates: study 
treatment,  C-SSRS 24 hours post infusion (1,2, or 3), age (<25, 25-39, >40), and gender.  The 
proportional hazard model results for the Intention-to-treat (ITT) population will be considered to 
be the primary analysis for the primary efficacy endpoint while the MMRM results for the ITT 
population will be considered to be the primary analysis for the secondary efficacy endpoints.       
All of the instruments used to measure ASIB or depression constitute serial continuous and ordinal 
outcomes which will be analyzed using Mixed-Effect Model Repeated Measure (MMRM) 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 of the variable 
being analyzed, C-SSRS 24 hours post infusion (1, 2, or 3), age (<25, 25-39, >40), and gender as 
fixed effects.  The reason for missing data will be evaluated as a condition of MMRM analysis.   
An autoregressive (AR1) variance covariance structure will be assumed for this analysis. To 
account for mis-specification of the covariance structure, the Liang and Zeger’s “sandwich” 
estimator (via the EMPIRICAL option in SAS PROC MIXED) will be used. Restricted maximum 
likelihood (REML) will be used to estimate all parameters and will be the basis for all hypothesis 
testing (SAS default).  For the primary model including the interaction term, the hypothesis test to 
perform on the fixed effects will be Type III (SAS® option htype = 3). SAS® PROC MIXED will 
be used.  
13.10.5 Primary Efficacy Endpoint 
The primary endpoint in the study will be the time to relapse measured from the day that Ketamine 
infusion was started. 
Relapse is a time to event outcome reflective of this multi-component disorder. Time to relapse is 
more sensitive measure than an assessment at a fixed time. Time to relapse will be displayed using 
a Kaplan-Meier lifetable with the treatment groups compared using a two-sided Wilcoxon-Gehan 
test and a proportional hazard model to include the above cited covariates.   
Relapse will be judged in real-time by the study physician using baseline measures of depression 
and suicidality as a guide.  


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13.10.6 Secondary Efficacy Endpoints 
All of the instruments used to measure ASIB or depression constitute serial continuous and ordinal 
outcomes which will be analyzed using MMRM, which accounts for missing data and early 
discontinuations.  These instruments are listed in Section 11. 
The models will include treatment group, study visit, the interaction between study visit and 
treatment group, the baseline of the variable being analyzed, C-SSRS 24 hours post infusion (1, 
2), age (<25 yrs, 25-39 yrs, >40 yrs), and gender as fixed effects.  The reason for missing data will 
be evaluated as a condition of MMRM analysis.  
13.10.7 Other Endpoints 
The following additional endpoints will be recorded and analyzed for both study phases: 
 
• Dose per treatment group 
• All-cause discontinuation (and reason for discontinuation) 
• Suicide rates 
• Incidence of hospitalization and ER visits for disease-related outcomes 
• Proportion of subjects who are treated with new SSRIs or have increased SSRI dosages 
• Proportion of subjects who discontinue SSRIs or have reduced SSRI dosages. 
 
Dose per treatment group will be displayed graphically over time per study treatment group.  The 
percents decreasing and increasing over time relative to starting dose will be displayed per study 
treatment group.  
 
Time to all-cause discontinuation will be displayed using a Kaplan-Meier lifetable and compared 
between treatments using a Wilcoxon-Gehan test. 
 
Suicide rates will be evaluated using a Fisher Exact test to compare K/R vs. K/L and K/P. 
 
The incidence of hospitalization and ER visits will be evaluated using a Wilcoxon Rank Sum test 
to compare each study treatment group. 
 
The proportions of subjects discontinuing SSRIs or reducing SSRI dosages will be displayed 
graphically over time per study treatment group.  The percents discontinuing SSRIs and reducing 
SSRI dosages relative to starting dose will be displayed per study treatment group.   
13.10.8 Safety Endpoints 
Separate safety analyses will be performed for Stage 1, Stage 2, and combined across stages.  


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Adverse events will be classified by MedDRA.  For each study treatment, safety data will be 
collected and analyzed while on Stage 1 or Stage 2 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.   
Planned surveillance findings according to the designated safety monitor will also be analyzed.  
Adverse event timing will be displayed graphically.  Overall incidence will be compared using a 
two-sided Fisher Exact test.  The cumulative number of such episodes will be evaluated using a 
Poisson regression model to compare study treatment groups controlling for C-SSRS 24 hours post 
infusion (1, 2), age (<25, 25-39, >40), and gender. 
Vital signs and ECGs (means and mean changes from Stage 1 and Stage 2 baselines) will also be 
evaluated within treatment groups using paired t-tests and between study treatment groups using 
unpaired t-tests.  Percents 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 percents 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. 
 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1 
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 is not limited to, 
facility details and site capabilities, past performance in similar studies, investigator, and staff 
experience, ongoing studies at the site, projected enrollment in this study, 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 CRO 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. 
Prior to subject 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 subject 
screening, the investigators and study personnel are appropriately trained and clearly understand 
the study, the investigators and study personnel accept the obligations incurred in undertaking 
this clinical investigation. 
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. 
Qualified clinical monitors or qualified contract monitors will conduct investigational site 
monitoring visits to ensure that all investigators conduct the study in compliance with the 
protocol and applicable regulations. 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 might arise. 
Periodic monitoring visits will be made in accordance with the approved monitoring plan at all 
active study sites throughout the clinical study to assure that the investigator obligations are 
fulfilled and all applicable regulations and guidelines are being followed. These visits will assure 
that the facilities are still acceptable, 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 Principal Investigator is executing all agreed activities. 
The sponsor retains the right to remove either the site-investigator or the investigational site from 
the study for issues of non-compliance with the protocol or regulatory requirements. 


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On one or more occasions, the study site may be inspected or audited by the sponsor 
representative or a third party. The investigator will be informed in advance of this visit. 
Upon completion of the clinical study (when all subjects 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 sponsor. The monitor will 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 which will be reviewed at this visit 
include: discussing retention of study files, possibility of site audits, publication policy, and 
ensuring that the investigator will notify the IRB regarding study closeout. 
14.2 
Audits and Inspections 
Subcontracts with study sites will specify that sponsor or 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. 
The Data and Safety Monitoring Board (DSMB) functions include, among others, ongoing 
assessment of masked data to determine whether any of the treatment arms show increased risk 
for AEs. The main purpose of the DSMB is to assess safety of the intervention by determining 
whether an increased number of AEs are occurring among study participants in any one of the 
treatment groups. Data will be reviewed every 4 months after the DSMB approval of the DSMB 
Charter. Frequent interim review of the data for SAEs does not require statistical adjustment for 
repeated testing or analyses. 
The Medical Monitor for this trial will be designated by sponsor/CRO. The Medical Monitor will 
review and approve the eligibility of all screened subjects, review all AEs, assess the benefits 
and risks of protocols on an ongoing basis, and work in collaboration with the IRB and RAC to 
identify safety signals and trends. 
In addition, the Medical Monitor will be available for site questions. The Medical Monitor will 
be available to sites for questions regarding inclusion/exclusion criteria, protocol conduct, and 
safety. Trained and qualified physicians will be available to provide coverage during times when 
the medical monitor is unavailable. Sites will be provided with the Medical Monitor’s cell phone 
number for emergency situations. Otherwise, sites are instructed to contact the Medical Monitor 
through email. All conversations with sites will be documented by the Medical Monitor and 
reviewed periodically by the sponsor. 
Each month the Medical Monitor will receive a listing of protocol violations for review and 
identification of possible trends.  
Serious adverse events will be reported to the CRO by the site within 24 business hours of the 
site’s knowledge of the event. For reportable unexpected and/or related SAEs, the Medical 
Monitor will contact NeuroRx within 48 business hours of the notice by the site. In addition, the 


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Medical Monitor may request individual subject records, including laboratory data, clinical 
records, and other study related data, to evaluate these events against the known safety profile of 
the study treatment and the disease. Any records sent to the Medical Monitor by the site will be 
redacted for any identifying information before transmission. The Medical Monitor may 
recommend actions including partial or complete unblinding, and/or modifying or terminating 
the study.  
Urgent Clinical Situations: During the course of the study, a subject will be reassessed for 
continued participation based on clinical judgment of the investigators. All subjects will be 
offered access to 24/7 coverage for medical emergencies through the clinical staff at each site. 
Treatment options and their risks and benefits, including continued study participation and other 
treatment options, will be sensitively explained. All study investigators have extensive clinical 
experience in the treatment of BPD and suicidal ideation, and can make the decision (while 
blinded) as to removal of subjects from the trial, particularly in the event of clinical deterioration 
or emergence/worsening of suicidal ideation. When a subject is removed from the trial based on 
clinical judgment, investigators will implement an appropriate treatment plan and arrange for 
follow-up for the subject. 
14.3 
Institutional Review Board (IRB) 
The study protocol and any amendments will be reviewed by an Institutional Review Board (IRB). 
The IRB will review the informed consent form, their updates (if any), and any written materials 
given to the subjects. A list of all IRBs and contact information will be included in the study report. 
IRB approval will be obtained and documented prior to subject enrollment and screening. Before 
study initiation, the investigator must have written and dated approval from the IRB for the 
protocol, consent form, subject recruitment materials/process (e.g., advertisements), and any 
other written information to be provided to subjects. 
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, also to be submitted to the CRO and/or sponsor, 
will be sent upon final approval of the protocol. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 
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, data sheets provided by the sponsor or other 
activities in the study, which 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 a period of time as defined by the regulatory authority for 
the country in which the investigation is conducted.  Generally, this means at least 2 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), a period of 2 
years following the date on which the entire clinical program is completed, terminated or 
discontinued or the investigational application under which the investigation is being conducted is 
terminated or withdrawn by the regulatory authorities. 
In the event the 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.  
15.2 
Reporting of Results 
The Case Report Form (CRF) is an integral part of the study and subsequent reports.  The CRF 
must be used to capture all study data recorded in the patient’s medical record.  The CRF must be 
kept current to reflect patient status during the course of the study.  Only a patient screening and 
randomization number will be used to identify the patient.   
The monitor is responsible for performing on-site monitoring at regular intervals throughout the 
study to verify adherence to the protocol; verify adherence to local regulations on the conduct of 
clinical research; and ensure completeness, accuracy, and consistency of the data entered in the 
CRF. 
The CRO will monitor completed Case Report Forms (CRFs).  A case report form will be provided 
for each screened patient. 
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in the Target e*CRF, an Internet-based electronic data collection 
system.  All details of the CRF completion and correction will be explained to the investigator.  
The management module of Target e*CRF 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).  Target e*CRF is 21CFR Part 11 compliant. 


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If the Investigator authorizes other persons to make entries in the CRF, 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.  Any outstanding entries must be completed immediately 
after the final examination.  By design, an explanation must be provided for all missing data, 
altered data, and/or out of range data. 
The completed case report form must be reviewed and signed by the Investigator named in the 
study protocol or by a designated sub investigator. 
Final monitored and audited eCRFs will be provided by the Sponsor to the sites at the end of the 
study in the format of a PDF file. 
15.3 
Confidentiality of Subject Data 
The risk of loss of privacy is judged to be minimal. Confidentiality will be maintained by 
numerically coding all data, by disguising identifying information, and by keeping all data in 
locked file drawers or on password-protected databases on password-protected and encrypted 
computers in locked offices. Subject information will be accessible only to research staff. 
Information about study participants will not leave our institution in any form that would identify 
individual subjects. Sites will enter subject data directly into the EDC system, which will be 
managed by the [CRO/data management] team. Subjects 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 of the EDC 
system will be tracked and 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. 
Pharmacogenetic information, in particular, will be coded and unlinked to individual respondent 
identifiers. The data managers, biostatistician, and study sponsor do not have access to the 
identities of subjects. That information is retained only at the clinical sites. Uses and risks related 
to data collection will be outlined in the informed consent and reviewed with the subjects. 


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16. 
ETHICAL CONSIDERATIONS 
16.1 
Ethics Review 
Anticipated benefits of the research to participants and others: This study will potentially help 
individuals with BPD and acute suicidal intention. If we discover that this intervention is 
effective, these results will lead to a full clinical development program of this treatment for BPD 
and acute suicidal intention. 
Risks to subjects relative to the anticipated benefits to research participants and others: The 
treatment has been selected with consideration of safety in mind. Additionally, adequate 
protections are in place to carefully monitor the medical wellbeing of participants. In contrast, 
the morbidity and mortality associated with BPD and suicidal ideation are known to be very 
high. 
Risks to subjects in relation to the importance of the knowledge that reasonably may be expected 
to result: The benefit to society from the development of efficacious interventions with rapid 
onset for BPD and acute suicidal ideation would be a substantial public health benefit. 
Vulnerable populations will not be included, except for adolescents ages 18 to 21. Pregnant 
women will not be included in the study. Prisoners will not be included. Subjects under the age 
of 18 years will not be included. 
16.2 
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 potential participants have demonstrated an understanding 
of the protocol, willingness to participate, and competency to consent.   
All subjects will receive monitoring for clinical deterioration, support, attention, and reassurance 
in the context of a therapeutic alliance. By definition, the target population is one in which 
subjects have not responded to available antidepressant therapies. Both active treatment and 
placebo/control groups in each trial will receive comprehensive evaluation and careful 
monitoring. Close monitoring by a trained psychiatrist is beneficial for individuals with mood 
disorders. If subjects are in need of more intensive psychiatric treatment at any time during the 
course of the trial, study personnel will assist in needed evaluation and referral to appropriate 
treatment settings. Subjects will be carefully monitored regarding depressive and other 
psychiatric symptoms. Non-responders to study treatment will be offered referrals for treatment 
at the end of the trial. 


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The investigators recognize that although DCS has been used in millions of individuals without 
report of significant safety concerns, DCS has thus far been used in 21 subjects at the 1000mg 
dose in formal studies of psychiatric illness. Therefore, the investigators will appoint a 
designated safety monitor to surveil for any safety signals that may arise in the course of the 
study.  
Lurasidone is an FDA-approved medication which is indicated in the treatment of bipolar 
depression and is a member of a class of medications (5-HT2A antagonists) that is routinely used 
in treating bipolar depression. Neither lurasidone, nor any other member of this class has 
successfully demonstrated efficacy against suicidality – in fact the medication bears a warning 
about potential suicide risk. However, its efficacy against bipolar depression is established. 
16.3 
Subject Information and Consent 
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 the potential participant has demonstrated an understanding 
of the protocol, willingness to participate and competency to consent.  
The investigator must ensure that subjects 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 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. 
All subjects will receive the consent form for the study. These documents will be read by the 
subjects and also reviewed by the subject with a clinician on the research staff prior to 
participating in the study. Any questions, concerns, or ambiguities will be clarified by the site’s 
site investigator or another study clinician prior to the subject signing consent. Subjects will sign 
informed consent and only then will begin participation in the study. 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1 
Data Capture 
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
with the investigational product or entered as a control in the investigation. 
17.2 
Retention of Records 
The investigator must retain investigational product disposition records, case report forms, and 
source documents for the maximum period required by applicable regulations and guidelines, or 
Institution procedures, and at least for 10 years. 
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, IRB, sponsor). Notice 
of such transfer will be given in writing to sponsor. 
17.3 
Use of Information and Publication Policy 
All publications will be reviewed by the sponsor for accuracy before submission to peer 
reviewed journals or scientific meetings. Abstracts should be submitted for review at least 10 
days before submission, and publications should be submitted for review at least 30 days before 
submission. The study will be posted to Clinicaltrials.gov and results reported in accordance with 
Clinicaltrials.gov guidelines. 


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18. 
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 CFR parts 50, 54, 56 and 812, 45 CFR 46, to GCP as described in ICH guideline 
E6 and to hospital Institutional Review Boards. 
 
 
 
_____________________________  
 
_____________________ 
Clinical Site Investigator Signature  
 
 
Date 
 
 
_____________________________ 
Clinical Site Investigator Printed Name 
 
 
_____________________________  
 
_____________________ 
Investigator-Sponsor Signature 
 
 
 
Date 
 
 
_____________________________ 
Investigator-Sponsor Printed Name 


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19. 
REFERENCES 
Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA, et al. 
Improvement in suicidal ideation after ketamine infusion: relationship to reductions in 
depression and anxiety. J Psychiat Res. 2014;58:161-6. 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 May;154:672-6 
Barnes TRE (2003).  The Barnes Akathisia Rating Scale - Revisited.  J Psychopharmacology.  
 
174(4), 365-370. 
Beck AT Kovacs M Weissman A. Assessment of suicidal intention: The scale of suicide ideation. 
J Consult Clin Psychology. 1979; 47: 343-352. 
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. 
Bowden, C. L., Singh, V., Thompson, P., Gonzalez, J. M., Katz, M. M., Dahl, M., Prihoda, T. J. 
and Chang, X. (2007), Development of the Bipolar Inventory of Symptoms Scale. Acta 
Psychiatrica Scandinavica, 116: 189–194. doi: 10.1111/j.1600-0447.2006.00955.x 
Bucco, T. (1970). Neurotoxic effects of cycloserine therapy in pulmonary tuberculosis of 
adolescents and young adults. Scandinavian Journal Respiratory Diseases (Supplement), 71, 
259-265. 
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. 
Desseilles M, Witte J, Chang TE, et.al. Massachusetts General Hospital SAFER Criteria for 
Clinical Trials and Research. Harvard Review of Psychiatry 2013:21(5);1-6 
DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, et al. Rapid 
resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in 
patients with treatment-resistant major depressive disorder. J Clin Psychiat. 2010;71(12):1605-
11. 
Guy, W. Clinical Global Impression (CGI) ECDEU Assessment manual for Psychopharmacology. 
Rockville, MD: U.S. Dept Health Education and Welfare 1976. 


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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. 
Kantrowitz JT, Halberstam B, Gangwisch J. Single-Dose ketamine followed by daily D-
Cycloserine in treatment-resistant bipolar depression. J Clin Psychiat. 2015;76(6):737-8. 
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. 
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. Pharmacol Biochem 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. 
Montgomery SA and Asberg M. A new depression rating scale designed to be sensitive to change. 
Br J Psychiatry 1979. 134:382–389. 
Nierenberg, A. A., Gray, S. M., & Grandin, L. D. (2001). Mood disorders and suicide. J Clin 
Psychiatry, 62 Suppl 25, 27-30. 


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Nolen-Hoeksema, S., & Morrow, J. (1991). A prospective study of depression and posttraumatic 
stress symptoms after a natural disaster: The 1989 Loma Prieta earthquake. Journal of 
Personality and Social Psychology, 61, 115–121. doi:10.1037/0022-3514.61.1.115 
Overall JE, Gorham DR, (1962). The brief psychiatric rating scale. Psychological Reports 1962 
vol. 10, pp799-812 
Pompili M, Gonda X Serafini G. Epidemiology of Suicide in Bipolar Depression. Bipolar 
Disorders. 2013;15(5):457-490. 
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. 164:1035-1043. 
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. 2:219–229. 
Reilly-Harrington NA et al (2016).  J Affective Disord, 192:  212-218. [need to add title] 
Sachdev PS, Brune M. Animal models of acute drug-induced akathisia - a review. Neurosci Behav 
R. 2000;24(3):269-77. 
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. 
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;12:71–79 
 


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20. 
APPENDICES 


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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 3 days for each episode, and 
may not be taken the day of the infusion 
starting at midnight. 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 
PPD 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. 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. 


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Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Anticonvulsants 
N 
Y 
Gabapentin, and pregabalin are allowed. 
Other anticonvulsants are not allowed, 
including lamotrigine and carbamazepine. 
Stable in dosing at least four weeks prior to 
randomization is required. 
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 is excluded. 
Antidiarrheal preparations 
Y 
N 
Only loperamide HCl (Imodium), bismuth 
subsalicylate (Pepto-Bismol), and kaolin 
preparations are allowed. 
Antifungals, systemic 
N 
Y 
— 
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.) 


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Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
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. 
Antifungal 
Y 
Y 
Itraconazole is excluded 
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 antihistamines). 
Antineoplastics/ 
Immunosuppressant agents 
N 
Yc 
Interferons, methotrexate, and other 
immunosuppressant agents are not 
allowed. Call PPD 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. 
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, indinavir, 
nelfinavir, ritonavir, saquinavir 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. 
Benzodiazepines should not be taken 
within 2 hours of infusion. 
Barbiturates 
N 
N 
Barbiturates are not allowed. 


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Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Benign prostatic hyperplasia 
treatments 
N 
Yb 
Male subjects who have symptoms of 
obstructed voiding should not be included 
in the study. Surgically or medically 
treated subjects must be asymptomatic and 
receiving a stable dosage of allowed 
medications (α-1 blockers, finasteride, or 
dutasteride) for 1 month before screening. 
Buspirone 
N 
Y 
Stable in dosing at least four weeks prior to 
randomization is allowed. 
Cough/cold preparations 
Y 
N 
Use of cough and cold preparations 
containing pseudoephedrine or 
dextromethorphan is not allowed, as are 
those containing 
phenylephrineCombination 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. 
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. 


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Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
Hormones: reproductive 
N 
Y 
Systemic hormonal contraceptives (oral 
contraceptives of estrogen and progestin 
combinations, depot injections such as 
Depo-Provera, the contraceptive implant 
Implanon, 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 3 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 not allowed 
Hypolipidemics 
N 
Yb 
Ezetimibe (Zetia) is allowed 
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. 


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Drug Name or Class 
Episodic Use 
(PRN) 
Chronic Use 
Restrictions/Comments 
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 
Proton pump inhibitors or H2 
receptor blockers 
Y 
Y 
Cimetidine 
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. 
Patients should not take benzodiazepines, 
within 2 hours of infusion 
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 
— 
Stimulants 
N 
N 
Oral or transdermal methylphenidate, 
amphetamine products or prodrugs, 
pseudoephedrine, modafinil (Provigil), and 
other medications of same category are 
notallowed 
Vaccines 
Y 
NA 
— 
a 
If being taken prior to enrolling in the study. 
b 
If being taken for at least 3 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. 
 


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Appendix 2: Assessment Tools 
 
• MINI 7.0.2 
• C-SSRS (and the retrospective C-CASA component) 
• CHRT (CHRT-SR and CHRT-C) 
• BISS 
• PRISE 
• SIBQ 
• CADSS 
• BPRS 
• BARS (including the global severity rating)