Clinical trial NCT04044664
Conditions: Post-Traumatic Stress Disorder
Sponsor: Aptinyx
Start date: 2019-01-25; Completion date: 2020-08-05
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the safety, tolerability, and response profile of NYX-783 in a Post-Traumatic Stress Disorder population.

Detailed description:
The study will be a 10 to 12-week study, including a 1 to 3-week screening Period, followed by a double-blind, randomized, placebo-controlled, parallel-group Treatment Period, and a 1-week follow-up Period. Subjects eligible for the study will be randomized to receive either NYX-783 (4-weeks) or placebo (4 or 8-weeks).

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Placebo oral capsule intervention 2: NYX-783
Intervention descriptions: intervention 1: Matching placebo capsules. intervention 2: NYX-783 is a small molecule that modulates the N-methyl-D-aspartate receptor (NMDAR).

Protocol documents:
Prot_000.pdf: 
NCT 04044664 
NYX-783-2004 
A Study to Evaluate the Safety and Efficacy of NYX-783 in 
Subjects with Post-Traumatic Stress Disorder 
Protocol 
01 May 2020 


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INVESTIGATIONAL DRUG: NYX-783 
CLINICAL PROTOCOL: NYX-783-2004 
A Study to Evaluate the Safety and Efficacy of NYX-783 in 
Subjects with Post-Traumatic Stress Disorder 
 
Sponsor: Aptinyx Inc. 
 
 
 
 
 
 
IND Number: 135011 
 
This document is a confidential communication from Aptinyx Inc. Acceptance of this document constitutes 
an agreement by the recipient(s) that no information contained herein will be published or disclosed 
without prior written approval from Aptinyx Inc., except that this document may be disclosed to 
appropriate Institutional Review Boards (IRBs) under the condition that they are also required to maintain 
confidentiality. 


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INVESTIGATOR SIGNATURE PAGE 
The signature of the investigator below constitutes his/her approval of this protocol and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol as specified in both the clinical and administrative sections, including all statements 
regarding confidentiality. This study will be conducted in compliance with the protocol and all 
applicable regulatory requirements, in accordance with Good Clinical Practices (GCPs), including 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) Guidelines, and in general conformity with the most recent version of the 
Declaration of Helsinki. 
 
Principal Investigator 
 
 
 
 
Printed Name 
 
 
 
 
 
 
Signature
Date


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APPROVAL PAGE:
Aptinyx Inc.
_____________________________
_________________________
 
_____________________________
__________________________




















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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ..............................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
4. 
LIST OF ABBREVIATIONS.....................................................................................18 
5. 
INTRODUCTION ......................................................................................................21 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................24 
6.1. 
Criteria for Evaluation ................................................................................................25 
6.1.1. 
Efficacy Criteria ..........................................................................................................25 
6.1.2. 
Safety Criteria .............................................................................................................25 
6.1.3. 
Exploratory Criteria ....................................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design and Plan: Description ..............................................................27 
7.2. 
Scientific Rationale for Study Design ........................................................................33 
7.2.1. 
Subject Population Rationale ......................................................................................33 
7.3. 
Justification of Dose ...................................................................................................34 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................36 
8.1. 
Subject Inclusion Criteria ...........................................................................................36 
8.2. 
Subject Exclusion Criteria ..........................................................................................36 
8.3. 
Screen Failures ............................................................................................................39 
8.4. 
Subject Withdrawal Criteria .......................................................................................39 
8.5. 
Methods of Birth Control............................................................................................40 
9. 
SCHEDULE OF PROCEDURES ..............................................................................41 
9.1. 
Screening Period (Day -21 to -7) ................................................................................41 
9.2. 
Day -7 (±3 days) .........................................................................................................42 
9.3. 
Stage 1: Day 1 .............................................................................................................42 
9.4. 
Week 2, Day 14 (±3 days) ..........................................................................................43 
9.5. 
Stage 2: Week 4, Day 28 (±3 days) ............................................................................43 
9.6. 
Week 6, Day 42 (±3 days) ..........................................................................................44 
9.7. 
Week 8, Day 56 (±3 days) ..........................................................................................45 


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9.8. 
Early Termination Visit ..............................................................................................46 
9.9. 
Safety Follow-up Visit (7 days post-therapy ±3 days) ...............................................47 
10. 
STUDY TREATMENT ..............................................................................................48 
10.1. 
Dosing and Administration .........................................................................................48 
10.2. 
Randomization and Blinding ......................................................................................48 
10.3. 
Treatment Compliance ................................................................................................49 
10.4. 
Concomitant Medications ...........................................................................................49 
10.5. 
Study Drug Discontinuation .......................................................................................50 
11. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................51 
11.1. 
Study Drug ..................................................................................................................51 
11.2. 
Study Drug Packaging and Labeling ..........................................................................51 
11.3. 
Study Drug Storage .....................................................................................................51 
11.4. 
Study Drug Preparation ..............................................................................................51 
11.5. 
Study Drug Accountability .........................................................................................51 
12. 
STUDY ASSESSMENTS ..........................................................................................53 
12.1. 
Psychiatric Rating Scales/Outcome Measures/Test(s) ...............................................53 
12.1.1. 
Structured Clinical Interview for DSM-5 (SCID-5-CT) ............................................53 
12.1.2. 
SAFER Remote Interview ..........................................................................................53 
12.2. 
Clinical Measures .......................................................................................................53 
12.2.1. 
Clinician Administered PTSD Scale for DSM-5 (CAPS-5) .......................................53 
12.2.2. 
Hospital and Anxiety Depression Scale (HADS) .......................................................54 
12.2.3. 
PTSD Checklist for DSM-5 (PCL-5) .........................................................................54 
12.2.4. 
Clinical Global Impressions-Severity (CGI-S) ...........................................................54 
12.2.5. 
Pittsburgh Sleep Quality Index (PSQI) .......................................................................54 
12.2.6. 
Pittsburgh Sleep Quality Index Addendum (PSQI-A) ................................................54 
12.2.7. 
55 
12.2.8. 
55 
12.2.9. 
Dissociative Experiences Scale-II (DES-II) ...............................................................55 
12.2.10. 
Life Events Checklist for DSM-5 (LEC-5) ................................................................55 
12.2.11. 
Symbol Coding from the Brief Assessment of Cognition (BAC Symbol 
Coding) .......................................................................................................................55 
12.3. 
Exploratory Assessments ............................................................................................55 
12.3.1.1. 
Pharmacogenomics (PGX) and Biomarkers ...............................................................55 


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12.3.2. 
Plasma Concentrations ................................................................................................56 
12.4. 
Safety Assessments .....................................................................................................56 
12.4.1. 
Demographics and Medical History ...........................................................................56 
12.4.2. 
Vital Sign Measurements ............................................................................................56 
12.4.3. 
Physical Examination (PE) .........................................................................................56 
12.4.4. 
12-lead Electrocardiogram ..........................................................................................57 
12.4.5. 
Clinical Laboratory Assessments ...............................................................................57 
12.4.6. 
Sheehan Suicidality Tracking Scale (S-STS) .............................................................58 
12.5. 
Adverse Events and Serious Adverse Events .............................................................58 
12.5.1. 
Definition of an Adverse Event ..................................................................................58 
12.5.2. 
Definition of a Serious Adverse Event .......................................................................58 
12.5.3. 
Adverse Event Reporting ............................................................................................59 
12.5.4. 
Serious Adverse Event Reporting ...............................................................................59 
12.5.5. 
Relationship to Study Drug ........................................................................................60 
12.5.6. 
Severity of Adverse Events ........................................................................................61 
12.5.7. 
Action Taken for Adverse Events...............................................................................61 
12.5.8. 
Outcome for Adverse Events ......................................................................................62 
12.5.9. 
Other Reportable Events .............................................................................................62 
13. 
STOPPING RULES AND SAFETY MONITORING ...............................................63 
13.1. 
Stopping Rules for Individual Subjects ......................................................................63 
13.2. 
Stopping Rules for Study ............................................................................................63 
13.3. 
Data and Safety Monitoring Board (DSMB) ..............................................................63 
14. 
STATISTICAL METHODS .......................................................................................65 
14.1. 
General Principles of Statistical Analysis...................................................................65 
14.2. 
Sample Size Determination ........................................................................................65 
14.3. 
Analysis Populations ..................................................................................................65 
14.4. 
Analysis of Efficacy Variables ...................................................................................65 
14.4.1. 
Methods of Analysis ...................................................................................................65 
14.4.1.1. 
Primary Efficacy Endpoint Analysis ..........................................................................66 
14.4.1.2. 
Secondary Efficacy Endpoints Analyses ....................................................................66 
14.4.1.3. 
Exploratory Efficacy Endpoints Analyses ..................................................................66 
14.4.2. 
Handling of Missing Data ...........................................................................................67 
14.4.3. 
Supportive Analyses ...................................................................................................67 


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14.5. 
Subject Disposition .....................................................................................................67 
14.6. 
Demographic/Baseline Data .......................................................................................67 
14.6.1. 
Demographics and Other Baseline Characteristics .....................................................67 
14.6.2. 
Other Baseline Data ....................................................................................................67 
14.7. 
Study Drug Exposure ..................................................................................................67 
14.8. 
Inclusion/Exclusion Criteria .......................................................................................67 
14.9. 
Efficacy Data Listings ................................................................................................68 
14.10. 
Analysis of Safety .......................................................................................................68 
14.10.1. 
Adverse Events ...........................................................................................................68 
14.10.2. 
Clinical Laboratory Tests ...........................................................................................68 
14.10.3. 
Electrocardiogram .......................................................................................................68 
14.10.4. 
Vital Sign and Weight Measurements ........................................................................68 
14.10.5. 
S-STS ..........................................................................................................................68 
14.10.6. 
Other Safety Data .......................................................................................................69 
14.11. 
Interim Analysis ..........................................................................................................69 
15. 
ADMINISTRATIVE ..................................................................................................70 
15.1. 
Source Documents ......................................................................................................70 
15.2. 
Study Monitoring ........................................................................................................70 
15.3. 
Case Report Forms .....................................................................................................70 
15.4. 
Protocol Amendment(s) ..............................................................................................70 
15.5. 
Audits and Inspections ................................................................................................70 
15.6. 
Institutional Review Board (IRB) ...............................................................................71 
15.7. 
Compliance with Regulatory Requirements ...............................................................71 
15.8. 
Informed Consent .......................................................................................................71 
15.9. 
Study File Management ..............................................................................................71 
15.10. 
Study Completion .......................................................................................................71 
15.11. 
Confidentiality ............................................................................................................71 
15.12. 
Compensation, Insurance, and Indemnity ..................................................................72 
15.13. 
Financial Disclosure ...................................................................................................72 
15.14. 
Records Retention .......................................................................................................72 
15.15. 
Publication Policy .......................................................................................................72 
16. 
REFERENCES ...........................................................................................................73 
17. 
APPENDIX A: MAYO TBI SEVERITY CLASSIFICATION SYSTEM ................78 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Special Terms ...............................................................................18 
Table 3: 
Study Objectives and Endpoints .................................................................................24 
Table 4: 
Schedule of Assessments ............................................................................................30 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................29 
 
 








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5. 
INTRODUCTION 
NYX-783 
is an orally bioavailable, small molecule 
 being developed 
for the treatment of post-traumatic stress disorder (PTSD). This new molecular entity is a 
modulator of the N-methyl-D-aspartate receptor (NMDAR), and acts as a co-agonist to glutamate 
at the NMDAR. The NMDARs are a large family of ionotropic glutamate receptors found 
predominantly in the central nervous system (CNS). (Hollmann 1994, Paoletti 2007)  
Glutamate, the physiologic agonist at NMDAR, is the major excitatory neurotransmitter in the 
CNS. NMDARs are tetrameric, mixed ion channels (i.e., Ca+2, Na+, and K+) containing two 
glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits. There are a number 
of variants of the glycine binding subunits and four gene products of the glutamate subunits 
referred to as GluN2A, GluN2B, GluN2C, and GluN2D. Full activation of NMDA receptors 
requires the simultaneous binding of both co-agonists, glycine and glutamate. (Hansen 2017)  
Unlike NMDAR antagonists, which block or inhibit the NMDAR, and unlike D-cycloserine 
(DCS, an NMDAR partial agonist), which mediates its effects through binding at the GluN1 
glycine co-agonist site, NYX-783 modulates the NMDAR by binding to a unique modulatory 
site. NYX-783 binding to this novel site triggers altered receptor conformation, resulting in 
activity at all four GluN2 subtypes (GluN2A, GluN2B, GluN2C, and GluN2D). NMDAR-
mediated synaptic plasticity is thought to be a primary mechanism in the formation of new 
memories and NMDA receptor subunits have differential roles in fear acquisition and extinction.  
PTSD is a common and often severe condition that is evoked by a terrifying event, either 
personally experienced or witnessed by the individual. (APA 2013) Most people exposed to 
severe traumatic events may have temporary difficulty adjusting and coping, but with time 
symptoms get better. In PTSD, symptoms such as re-experiencing traumatic event, avoidance, 
numbing and elevated arousal show no spontaneous improvement, with symptoms lasting for 
months or even decades, and interfering with daily functioning and interpersonal relationships. 
(Almli 2014) The lifetime prevalence of PTSD is about 8% in the general population, but occurs 
in much higher proportions in special populations at higher risk for exposure to trauma. 
(Kilpatrick 2013, Almli 2014) A meta-analysis of 33 studies found that the prevalence of PTSD 
in service members returning from deployment in Afghanistan and Iraq was 23%. (Fulton 2015) 
PTSD is associated with significant psychological and physical burden on the individual level, 
and economic burdens from societal aspects. (Ellis 2018)  
PTSD, according to the DSM-5 diagnostic criteria, is characterized by 4 major symptom clusters 
following a traumatic event. The symptom categories cover: 1) intrusive symptoms: traumatic 
event persistently re-experienced through unwanted upsetting memories, nightmares, flashbacks, 
emotional distress after exposure to traumatic reminders, physical activity after exposure to 
traumatic reminders; 2) avoidance symptoms, including trauma-related thoughts or feelings and 
trauma-related external reminders; 3) negative alterations in cognition and mood (examples 
include inability to recall key features of the trauma, overly negative thoughts and assumptions 
about oneself or the world, exaggerated blame of self or others for causing the trauma, negative 
affect, decreased interest in activities, feeling isolated, or difficulty experiencing positive affect); 
and 4) alterations of  arousal and reactivity symptoms incorporating irritability or aggression, 
risky or destructive behavior, hypervigilance, heightened startle reaction, difficulty 


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concentrating, or difficulty sleeping. In addition, DSM-5 
al recurrently experiences depersonalization and/or 
derealization. (APA 2013)  
Beyond the core mental symptom categories of PTSD, impairments have been identified in a 
number of domains of cognitive functioning, including working memory, executive functions, 
sustained attention, and processing speed. (Twamley 2009, Kanagaratnam 2007, Samuelson 
2006)  
In a meta-analysis of data from 21 placebo-controlled trials, selective serotonin re-uptake 
inhibitors (SSRIs) were found to be superior to placebo in the treatment of PTSD, but the effect 
size was small (standardized mean difference = -0.23). (Hoskins 2015) Currently, two SSRIs, 
sertraline and paroxetine, have been approved by FDA for treatment of PTSD. Fluoxetine and 
venlafaxine also have shown efficacy in reducing PTSD symptoms in placebo -controlled 
clinical trials. (Hoskins 2015) Overall, however, response rates with SSRIs have rarely exceeded 
60%, and less than 20-30% of subjects have been shown to achieve full remission. (Berger 2009) 
The premise of this trial stems from the role of NMDARs in a number of physiological and 
pathological processes, including PTSD (Steckler 2012, Sherin 2011, Ravindran 2009) and 
affected cognitive domains. (Gonzalez 2015, Tsai 2016) The key element of PTSD is a pervasive 
sense of impending danger, fearfulness, and heightened arousal in situations where no actual 
threat or danger is present. (Pole 2007) Persistent fear memory may be the result of enhanced 
fear acquisition, impaired fear extinction, and/or deficiencies in contextual processing. 
(Garfinkel 2014)   
NMDARs have been shown to regulate fear acquisition and extinction due to their role in 
synaptic development and plasticity. (Radulovic 2018, Luchkina 2018) Further, there appears to 
be differential roles for the NMDAR receptor subtypes. For example, GluN2A receptor subunit 
activation may have a role in the formation and/or stabilization of new learned fear responses, 
whereas GluN2B receptor activation may be involved with the suppression/extinction of learned 
fear responses. (Dalton 2012)  
NYX-783 has exhibited efficacy in several pre-clinical models of PTSD symptoms. Specifically, 
in a model of intrusive fear memory, a single oral dose of NYX-783 (1 mg/kg) facilitated 
extinction of conditioned fear similarly to a single dose of the positive control DCS (15 mg/kg 
given subcutaneously). When contextual fear memory was measured 14 days after the original 
conditioning session, spontaneous recovery of freezing behavior was observed in rats previously 
treated with DCS. Importantly, no spontaneous recovery of freezing behavior was observed in 
rats previously treated with NXY-783. Thus, a single treatment with NYX-783 reduced freezing 
in a rat model of intrusive fear memory when measured either proximal or remote to fear 
conditioning. Additionally, in an assay that measures affective state (heterospecific rough-and-
tumble play), NYX-783 increased the number of rat hedonic ultrasonic vocalizations across a 
broad dose range. NYX-783 also decreased rat immobility in the Porsolt forced swim assay, 
which exhibits high predictive validity for antidepressant activity. These data may be significant 
given the widespread use of antidepressants to treat PTSD symptoms. 
Safety pharmacology studies indicate that NYX-783 has low potential for off-target 
pharmacology. NYX-783 had no significant activity in a panel of 80 receptor-binding assays that 
included gamma-aminobutyric acid (GABA), opiate, serotonin, and tachykinin receptors, ion 


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channels, and transporters. NYX-783 was inactive in modulating human ether-à-go-go-related 
gene (hERG) activity and had no effect on hemodynamic or ECG parameters in male isolated 
guinea pig hearts (Langendorff method) up to 
µM.  
In general, NYX-783 was well-tolerated after single oral doses up to and including 600 mg/kg in 
rats and 1000 mg/kg in dogs. In a 91-day repeat-dose study, NYX-783 was well tolerated at all 
dose levels, and the no-observed-adverse-effect-level (NOAEL) in rats was the highest dose 
tested, 500 mg/kg. In the daily repeat-dose, 91-day dog toxicology study, NYX-783 was 
evaluated at doses of 2, 6, and 20 mg/kg. There were notable changes in liver parameters at 6 and 
20 mg/kg; the liver-associated findings at 6 mg/kg were considered non-adverse and recovered 
after a 4-week drug holiday. Also, at the 20 mg/kg dose, elevations in serum levels of liver 
enzymes, primarily ALT, were observed. The liver-associated findings at 20 mg/kg were 
considered adverse and did not recover. Therefore, the NOAEL in dog was 6 mg/kg/day. All 
adverse observations occurred at doses in excess of the planned clinical doses.   
 Results are available from all 70 subjects in the Phase 1, first-in-human study of NYX-783 
(NYX-783-1002) in which healthy male and female subjects were enrolled. In this study, safety 
and pharmacokinetics of single doses (10, 50, 200, and 600 mg) and multiple doses (once daily 
for 7 days of 2, 50, and 200 mg) of NYX-783 were evaluated. Seventy subjects were included in 
the safety population and 54 active-treated subjects were included in the PK population. NYX-
783 was safe and well-tolerated at the studied doses. No grade 3, grade 4, or serious adverse 
events were reported. Further, there were no laboratory results or ECG findings reported as 
adverse events. There were 2 unrelated adverse events (emesis and viral gastroenteritis) that lead 
to withdrawal from the study. There were 2 mild adverse events (headache and fatigue) that the 
investigator considered possibly related to NYX-783. A maximum tolerated dose was not 
reached in the study. 
The PK data from study NYX-783-1002 have shown that following oral administration of 2 to 
600 mg, NYX-783 was rapidly absorbed and Cmax was reached within 1 to 2 hours post dose. 
Concentrations declined in a roughly monophasic manner over 24 hours, and a roughly biphasic 
manner over 48 hours after 7 days of dosing. NYX-783 had a t1/2 of approximately 4 hours and 
demonstrated dose-proportional PK with minimal accumulation following QD dosing for 7 days. 
Data suggests that NYX-783 can be administered with or without food, and, plasma exposures to 
NYX-783 in the elderly cohort were comparable. The majority (50-60%) of the administered 
dose of NYX-783 was excreted unchanged in the urine. CSF samples were obtained in subjects 
taking a single 50 mg dose of NYX-783. NYX-783 crossed the blood brain barrier, with CSF 
concentrations at 4 and 8 hours approximately 12% to 14% of plasma Cmax at the same dose 
level.  
 






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6.1.3. 
Exploratory Criteria  
 
 
 
 
   


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan: Description 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
outpatient study of approximately 12 weeks duration (Screening: 3 weeks; Treatment: 8 weeks; 
Follow-up: 1 week). In this study, a sequential parallel comparison design (SPCD) will be used 
to examine the efficacy and safety of oral NYX-783 compared to placebo in the treatment of 
PTSD symptoms. On Day 1, approximately 156 eligible subjects will be randomized to receive 
placebo, NYX-783 50 mg QD, or NYX-783 10 mg QD in a 4:1:1 ratio, respectively (Figure 1). 
Placebo non-responders (CAPS-5 total score reduction from baseline [Day 1] 35% and CAPS-5 
total score 
 at Week 4) and placebo responders identified during Stage 1 (Week 1-4) will then 
be then re-randomized in a blinded fashion to placebo, NYX-783 50 mg QD or NYX-783 10 mg 
QD in Stage 2 (Weeks 4-8) in a 3:2:2 ratio. Subjects who received active treatment during Stage 
1 will receive placebo in Stage 2, thus providing information about the maintenance effect of 
NYX-783 treatment after re-randomization to placebo. Subjects who complete the study will 
have received either 4 weeks of NYX-783 50 mg QD or 10 mg QD (and 4 weeks of placebo) or 
8 weeks of placebo. The sample size estimate is based on an assumption of 15% dropout during 
period 1, and 11 % dropout rate in period 2. 
All potential study participants must provide written informed consent before initiating any 
protocol-specified procedures. A 2-step approach will be used to identify the study population 
during the Screening period:   
1) Screening visit (Days -28 to -14). Potential subjects will be screened for the presence of 
PTSD using the self-report PCL-5, with the Life Events Checklist for DSM-5 (LEC-5) being 
used to assess the nature of the primary traumatic event. Subjects with a PCL-5 severity score 
38 will be interviewed by an investigative site clinician or trained mental health professional 
using the Structured Interview for DSM-5 (SCID-5-CT) to exclude comorbidities. The CAPS-5 
will be used to confirm the diagnosis of PTSD and to identify the primary traumatic event. The 
severity of PTSD symptoms within the past month will be assessed based on the CAPS-5; a 
CAPS-5 total 
 Other screening procedures will include 
demographics, medical history, vital sign measurements, PE, height, weight, ECG, laboratory 
samples (chemistry, hematology, urinalysis, drug screen), suicidality, and concomitant 
medication information. Other clinical measures will be used to assess sleep quality, cognitive 
effects, and mood and anxiety symptoms.  
2) SAFER interview (Day -14 ± 3 days). Subjects who meet the diagnostic criteria at the 
Screening visit will then participate in telephone-based interview (SAFER interview) to confirm 
the diagnosis of PTSD and review potential comorbidities and study exclusion criteria. Those 
subjects meeting the diagnostic and selection criteria will be eligible for proceeding to the 
randomization visit. 
On Day 1, eligible subjects will be randomized to receive NYX-783 50 mg QD, NYX-783 10 mg 
QD, or matching placebo. Assessments on Day 1 will include vital signs, ECG, weight, 
laboratory samples (pharmacogenomics [optional], plasma concentration, RNA (optional), 
chemistry, hematology, urinalysis and drug screen), suicidality, and concomitant medication 
review. Clinical measures will be used to assess severity of PTSD symptoms, sleep quality, 


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cognitive effects, and mood and anxiety symptoms. Study drug will be administered at the 
investigative site on Day 1 and dispensed for subsequent outpatient administration. 
At the follow-up visits on Weeks 2, 4, 6, and 8/early termination, PTSD severity in the past week 
will be assessed by the investigative site using the CAPS-5 and PCL-5. Other clinical measures 
will be used to assess sleep quality, cognitive effects, mood, and anxiety symptoms. Safety 
assessments will also be performed at these visits and at the safety follow-up visit, which occurs 
approximately 7 days after the last dose of study drug. 
Blood samples for evaluating plasma concentrations will be collected at Week 4 and Week 
8/early termination. Blood samples for pharmacogenomic (PGX) testing will be collected on Day 
1 for those subjects who have signed consent to participate in this exploratory analysis. Optional 
blood samples for biomarker (RNA) testing will be collected on Day 1, Week 4, and Week 
8/early termination.  
Safety throughout the entire study will be assessed by adverse events, vital sign measurements, 
weight, PE, ECG testing, clinical laboratory testing, and the Sheehan Suicidality Tracking Scale 
(S-STS) instrument.  
Rater qualification, training, and surveillance will be centrally monitored during the study. 
A Data and Safety Monitoring Board (DSMB) will perform periodic reviews of available safety 
data to ensure it is safe to proceed. 
 
 
 
 
 








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l) 
Stage 2 dosing begins on the day after the Week 4 visit. 
m) Includes concurrent medical and psychiatric history. 
n) 
 
o) Use interactive response technology for study drug dispensing. 
p) 7 days post-therapy. 
q) Clinical labs should be fasted except for screening. 
r) 
Only if required for adverse event follow-up. 
s) 
Rating based on the past month 
t) 
Rating based on the past week 
u) Use since last visit  version after screening. 
v) Women of childbearing potential. 
w) Remote visit (optional.  Only if necessary, due to COVID-19 health emergency) 
x) Visit window is ± 7 days. 
 
 
 
 
 


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7.2. 
Scientific Rationale for Study Design 
This Phase 2, proof-of-concept, placebo-controlled study uses a sequential parallel comparison 
design (SPCD), which is appropriate due to the short active treatment phases (two 4-week 
double-blind treatment periods) and the expected relatively meaningful placebo response rate. 
The purpose of conducting this exploratory study is to investigate the safety and tolerability of 
NYX-783 in a PTSD population, and to characterize the response profile of NYX-783 for the 
treatment of PTSD symptoms evaluated by the intrusion, avoidance, negative alterations in 
cognition and mood, and arousal & reactivity subscores as well as CAPS-5 total score. The 
results from this study will be utilized to inform the future NYX-783 development plans.   
The SPCD is an adaptive design that allows for re-randomization of placebo subjects (both 
"non-responders" 
initial stage of the study to placebo or active 
treatment in a subsequent stage of the trial. In this study, d
-
population 
of Stage 1 arms [1 = placebo], [2 = NYX-783 50 mg QD], [3 = NYX 783 10 mg QD] and the 
 non-
in Stage 2 arms [7 = placebo], [8 = NYX-783 50 
mg QD], [9 = NYX 783 10 mg QD] are pooled to yield a single p-value for treatment 
comparison. Estimation of the treatment effect is enhanced by using data from the two study 
stages (Tamura 2011), and the SPCD design is appropriate for earlier stage trials, such as 
moderately-sized Phase 2 studies. (Tamura 2011, Baer 2013) The SPCD design aims to increase 
the probability of demonstrating a treatment effect, especially if the Stage 1 placebo response 
rate is high. (Chen 2011) The design reduces the impact of placebo response and thus improves 
the power of the study, which in turn allows for an adequately powered proof-of-concept trial 
with a smaller sample size and mitigation of the untoward effect of a placebo response. (Baer 
2013) All efficacy analyses will be evaluated at the 0.10, one-
-sided is 
appropriate because the primary objective of the study is to demonstrate that NYX-783 is 
superior to placebo in reducing the severity of PTSD symptoms. 
Beyond the primary objective, an SPCD can address useful exploratory aspects. In this study, for 
example, by providing information about the maintenance effect of NYX-783 treatment after re-
randomization of subjects initially allocated to one of the active treatment arms [2] and [3] to 
placebo arms [10] and [11]. The re-randomization of both placebo-responders and placebo 
non--responders from Stage 1 will characterize the response profile of subjects with initial high 
vs. low placebo response rate in Stage 2 drug treatment arms [5], [6] vs. [8], [9] respectively.  
Altered gene expression associated with PTSD has been characterized in peripheral blood 
samples collected from civilian and military populations in clinical trials. (Banerjee 2017) 
Analysis of RNA, including microRNA (miRNA) and/or messenger RNA (mRNA), provides a 
new opportunity to understand the biological pathways underlying PTSD, with the potential to 
establish biomarker-driven subgroups within the PTSD diagnosis, and/or to serve as a platform 
for pre-clinical mechanistic studies (Glatt 2013).  
7.2.1. 
Subject Population Rationale 
The goal of the study is to recruit subjects with a clearly identifiable primary traumatic event 
during adulthood.  


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Inclusion criterion #2 clarifies that subjects with delayed-onset PTSD (i.e., the full diagnostic 
criteria for PTSD are not met until at least 6 months after the event, although the onset and 
expression of some symptoms may be immediate) (APA 2013) will be allowed to enter into the 
study if the full diagnostic criteria for PTSD according to the DSM-5 are met at least 6 months 
prior to screening.  
In delayed-onset PTSD, which occurs in about 25% of PTSD cases, (Utzon-Frank 2014) subjects 
might have experienced subthreshold PTSD symptoms after the trauma. Potentially, some 
additional trauma then impairs 
the index traumatic event. 
Consequently, subthreshold PTSD symptoms become more severe and evolve into clinically 
manifest PTSD. For inclusion into the study, at least 6 months of clinically manifest PTSD must 
be present prior to screening (inclusion criterion #2), with no further traumas in that same 6-
month period (exclusion criterion #4).  
Subjects meeting inclusion criteria #2, #3 and #4 enrich the study with a moderate-to-severe 
PTSD population. A score of 38 or higher on PCL-5 indicates likely PTSD in both civilian and 
veteran populations. (Blevins 2015, Hoge 2014) The timeframe associated with the primary 
traumatic event as defined by inclusion criterion #2 is designed to minimize spontaneous 
remission during the study, while exclusion criteria #1, #3, and #4 control for significant 
chronicity of the disease and minimize Axis-II disorders overlapping with associated complex 
traumas in childhood. Exclusion criterion #1 reduces the variability of the study population by 
excluding subjects with complex PTSD. Subjects with complex PTSD typically present with 
psychological symptoms related to prolonged, repeated trauma, and these are often present in 
addition to the more typical symptoms of PTSD, including changes in self-concept and response 
to stressful events. Alt
the 
DSM-5, this protocol helps navigate identification of complex PTSD based on trauma type, age 
of subject when exposed to trauma, and certain phenotype (i.e., if affect dysregulation and 
interpersonal dysfunction are primary over other core PTSD symptoms).  
Exclusion criteria #6, #7, #9, #14, and #16 minimize disease comorbidities, and #5 minimizes 
TBI consequences associated with the primary traumatic event. The purpose of exclusion criteria 
#10, #11, #12, and #13 is to exclude subjects taking psychoactive drugs due to either their 
potential influence on PTSD symptoms (different classes of antidepressants, sleep inducers with 
long half-life) or potential interference with NYX-783 influencing the effect of NMDA 
modulation on sleep architecture, interference with  the  pharmacology of NYX-783 (i.e., there is 
a possible interaction between gabapentinoids [pregabalin, gabapentin], interaction with and 
certain NMDA receptor complexes). (Chen 2018)  
7.3. 
Justification of Dose 
The planned dose levels in this study are NYX-783 50 mg/day and 10 mg/day. Based on the 
preliminary PK results of the Phase 1, first-in-human study in healthy male and female 
volunteers (NYX-783-1002), the maximum plasma concentration (Cmax) of NYX-783 50 mg is 
expected to be approximately 0.8 g/mL. Total exposure (area under the plasma-concentration 
curve [AUC0-24]) is expected to be approximately 5.0 
.  
In the contextual fear conditioning test, NYX-783, when administered to rats as a single oral 
dose of 1 mg/kg, facilitated fear extinction learning on extinction Days 1-4 and prevented the 


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re-consolidation of fear memory when retested on Day 14 compared to vehicle. At this 
pharmacologically-active dose (1 mg/kg) in rats, the plasma Cmax 
 
In addition, a single dose of NYX-783 in the fear conditioning stress model provided a long-term 
effect, preventing freezing behavior after one dose of drug in rodents and preventing recovery of 
fear after 14 days. One objective of this Phase 2 study is to confirm that the observed preclinical 
long -lasting effects are translatable to humans, i.e., once daily (QD) administration provides 
long-lasting benefits. 
The pharmacologic effects of NYX-783 are currently believed to be driven primarily by Cmax.  
Thus, the dose planned for the current clinical study is expected to result in human plasma 
concentrations that are within the Cmax range that was associated with positive effects on -fear 
extinction measures. 
The 50 mg dose is 1/12th of the maximum single dose (600 mg) and 25% of the maximum 
multiple dose (200 mg) given once daily for 7 days in the Phase 1 trial (NYX-783-1002), which 
were safe and well-tolerated. The 600 mg single dose as well as the 200 mg multiple dose were 
associated with PK exposures (Cmax and AUC) below the NOAEL for both the dog and rat in the 
Good Laboratory Practice toxicology studies. In the Phase 1 trial, NYX-783 had a terminal 
elimination half-life (t½) of approximately 4 hours and demonstrated no accumulation with once 
daily dosing over 7 days. In all single-dose groups, approximately 57% of the administered dose 
was recovered as NYX-783 in the urine. Based on the available preclinical and preliminary 
clinical safety and PK data, the 10 and 50 mg dose strengths selected for this study are expected 
to be safe and well-tolerated. 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Male and female subjects between the ages of 18 to 65 years (inclusive) at the time of 
signing the informed consent. 
2. A primary diagnosis of PTSD (DSM-5 criteria, APA 2013) according to the CAPS-5 and 
SCID-5-CT, with the primary traumatic event occurring 12 months prior to screening. 
NOTE: In cases 
delayed--onset 
must be 
present for at least 6 months prior to screening. 
3. PCL-5 38 at screening. 
4. CAPS-5 total score 
 at screening. 
5. Qualified to participate according to the SAFER interview. 
6. Female subjects of childbearing potential must have a negative serum pregnancy test at 
screening and be practicing an adequate method of birth control (e.g., oral or parenteral 
contraceptives, intrauterine device, barrier, abstinence). Subjects may not be breastfeeding or 
plan to become pregnant or donate ova during the study and for 30 days after the last dose of 
study drug. 
7. Male subjects who are sexually active with female partner(s) must agree to the following 
during the study and for 30 days after the last dose of study drug: a) use an acceptable 
method of birth control (condom with spermicide or surgical sterilization) and b) refrain from 
sexual activity with female partners who do not use an acceptable method of birth control. 
Barrier contraception (condom with spermicide) must be used by all male subjects who are 
not surgically sterilized at least 90 days prior to screening. Male subjects must also agree to 
refrain from sperm donation during the study and until 30 days after the last dose of study 
drug. 
8. Ability to understand the requirements of the study, provide written informed consent, abide 
by the study restrictions, and agree to return for the required assessments. 
9. Willing to use a smartphone-based video recording technology for monitoring compliance 
with study drug administration. 
10. The subject has a stable social situation 
, e.g. no changes are expected 
during the course of the study in work, marital, or accommodation status. 
8.2. 
Subject Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Complex PTSD, defined as a condition that may develop following exposure to an event 
or series of events of an extreme and prolonged or repetitive nature of which the subject 
experienced as extremely threatening or horrific and from which escape was difficult or 


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impossible (e.g., torture, slavery, genocide campaigns, prolonged domestic violence, 
repeated childhood sexual or physical abuse). If affect dysregulation and interpersonal 
dysfunction that are primary over other core PTSD symptoms, 
opinion, they should be considered as exclusionary criteria. NOTE: Non-interpersonal 
trauma (e.g. motor vehicle accident, mass transportation accident, domestic fire, mass 
shooting survivor) prior to 18 years of age are not exclusionary, and, the trauma can be 
considered the primary traumatic event (index trauma). 
2. Trauma focused psychotherapies including, prolonged exposure therapy, cognitive 
behavioral therapy, eye movement desensitization and reprocessing therapy (EMDR) 
within 30 days prior to screening or during the study. 
3. Primary traumatic event occurred prior to 2001. 
4. Primary traumatic event was followed by further major traumatic life episodes in the 6 
months prior to screening. 
5. Primary traumatic event was associated with traumatic brain injury (TBI) categorized as 
Moderate-to Severe TBI, according to the Mayo TBI Severity Classification System. 
(Malec 2007) (See Appendix A) 
6. Substance use disorder within the 6 months prior to screening. Use of any illicit drugs of 
abuse during the study period is prohibited.  
7. History of alcohol abuse within the 6 months prior to screening. NOTE: Up to an average 
of 1 drink/day is allowed during the study.  
8. Positive screen for alcohol or drugs of abuse, including phencyclidine, barbiturates, 
benzodiazepines, opiates, methadone, cocaine, cannabinoids, and amphetamines at 
screening or Day 1. Subjects who have a positive screen for cannabinoids or other 
medically prescribed drugs of abuse at screening, must have a negative screen at Day 1 
and agree not to use during the study. 
9. Any history of schizophrenia or other psychotic disorder, bipolar disorder, psychosis, or 
other Axis 1 disorder (except for major depressive disorder or anxiety disorders that 
followed exposure to the trauma or an anxiety disorder that showed a worsening after 
trauma). Anxiety disorders (such as selective mutism, specific phobia, social anxiety 
disorder, panic disorder, agoraphobia, and generalized anxiety disorder) are exclusionary 
only if the diagnosis preceded the primary traumatic event, and, the subject was seeking 
and received treatment for the symptoms prior to the primary traumatic event. NOTE: A 
current secondary diagnosis of major depressive disorder without full remission is not 
exclusionary; if treated, the dose of a permitted antidepressant must be stable for at least 
30 days prior to screening and expected to continue during the study. 
10. Clozapine use or electroconvulsive therapy within the 12 months prior to screening or 
during the study.  
11. Current use of medications with primarily CNS activity (e.g., antipsychotics, 
anticonvulsant drugs [including gabapentinoids], psychostimulants, 
benzodiazepines, methylphenidate, doxazosin, prazosin, clonidine, first-
generation sedating H1 antihistamines, quetiapine, eszopiclone, zolpidem 
extended-release, or any other sedative-hypnotic medications) within 3 days prior 
to screening or during the study. NOTE: Use of certain non-benzodiazepine sleep 


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inducers (e.g., zolpidem immediate-release [up to 10 mg at bedtime], zaleplon 
[up to 20 mg at bedtime]), melatonin, or ramelteon for sleep are allowed. 
12. Use of nefazodone, selective serotonin reuptake inhibitors (SSRIs, such as 
fluoxetine, sertraline, escitalopram, citalopram, paroxetine), serotonin and 
norepinephrine reuptake inhibitors (SNRIs, such as desvenlafaxine, duloxetine, 
venlafaxine), reversible and non-reversible  monoamine oxidase inhibitors (such 
as selegiline, phenelzine, tranylcypromine), tricyclic antidepressants (such as 
amitriptyline, imipramine, nortriptyline), noradrenergic and specific serotonergic 
antidepressant (NaSSA) mirtazapine, serotonin modulator and stimulator 
antidepressants (such as vilazodone or vortioxetine), or the norepinephrine, 
serotonin and dopamine reuptake inhibitor bupropion within 30 days (90 days for 
fluoxetine) prior to screening or during the study. NOTE: Subjects on stable 
3
therapy during the study with no expected change in dose. 
13. Treatment with an injectable depot neuroleptic within 90 days prior to screening 
or during the study. 
14. Subjects who meet the criteria for suicidal intent, plan and/or behavior on the S-STS at 
screening or Day 1. These criteria are a score of 3 or 4 on questions 2 or 13, or 2 or 
higher on any of the following questions: 1a (only if 1b is coded YES), 3, 4, 5, 6, 7, 8, 9, 
10, 11, 12, or 14. 
15. In the process of litigating for compensation for a psychiatric disorder. Subjects who are 
in the process of applying for medical or VA benefits and/or those who have settled a 
disability claim prior to enrollment in the trial are eligible.  
16. 
seizures (history of childhood febrile seizures are not exclusionary), epilepsy, or stroke. 
17. History of allergy, sensitivity, or intolerance to N-methyl-D-aspartate receptor (NMDAR) 
ligands, including ketamine, dextromethorphan, memantine, methadone, 
dextropropoxyphene, or ketobemidone, as well as current use of such agents. 
18. Received an investigational drug product or device within 30 days (or 5 half-lives, 
whichever is longer for a drug product) of dosing. 
19. Previously received NYX-783. 
20. 
(males) or 470 (females) milliseconds (msec) or an ECG that is not suitable for QT 
measurements (e.g., poorly defined termination of T-
 
21. A known familial history or known presence of long QT syndrome, or a known history of 
past or current clinically significant arrhythmias or ischemic heart disease. 
22. Body mass index >35 kg/m2 at screening. 
23. 
 at screening. 
24. Uncontrolled Type I or Type II diabetes mellitus or uncontrolled hypertension. 
25. Estimated creatinine clearance <60 mL/minute calculated by the Cockcroft-Gault 
equation at screening or history of renal disease, as assessed by the investigator or the 
sponsor-designated medical monitor. 


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26. Known diagnosis of a current infectious disease, including human immunodeficiency 
virus infection, hepatitis, or other ongoing infectious disease that the investigator 
considers clinically significant.   
27. Current evidence of dysplasia or history of malignancy (including lymphoma and 
leukemia) in the last 5 years, with the exception of successfully treated non-metastatic 
basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the 
cervix. 
28. History of gastrointestinal disease or surgery (except simple appendectomy or hernia 
repair), leading to impaired drug absorption. 
29. Known abnormal laboratory results, ECG results, medical history or concurrent 
conditions which, in the opinion of the investigator or sponsor, would preclude safe study 
participation or interfere with study procedures/assessments. 
30. Uncorrected hypothyroidism or hyperthyroidism. NOTE: subjects with compensated 
hypothyroidism, with normal thyroid-stimulating hormone levels may be enrolled. 
31. Impaired hepatic function characterized by a previous known diagnosis of chronic liver 
disease and/or the presence of direct bilirubin >1.5x, or, alanine transaminase, aspartate 
transaminase, alkaline phosphatase, or gamma-glutamyl transferase >2x the upper limit 
of normal at screening. 
32. Current borderline personality disorder, antisocial personality disorder, or other 
personality disorder (e.g. subject showed pervasive pattern of disregard for and violation  
of the rights of others, or subject has had previous repetitive suicidal behavior [including 
aborted, interrupted or ineffective suicide attempts, gestures], self-mutilating behavior, or 
with study participation. 
33. Use of NMDAR-binding drugs (e.g., ketamine, dextromethorphan, memantine, 
methadone, lamotrigine, esketamine) within 60 days prior to dosing or during the study. 
34. 3,4-Methylenemetamphetamine (MDMA)-assisted psychotherapy within 90 days prior to 
screening or during the study. 
35. Expected to initiate any psychotherapy during the study. 
8.3. 
Screen Failures 
Subjects who sign and date the ICF but who fail to meet the inclusion and exclusion criteria are 
considered screen failures. Reason(s) for screen failure must be documented by the investigator 
and provided to the sponsor in a timely fashion. Subjects may be rescreened if the investigator 
considers rescreening appropriate. If a screened subject is not eligible for randomization, the 
primary reason for failure should be recorded on the applicable eCRF. The primary reason for 
screen failure should be recorded according to one of the following categories: did not meet 
inclusion criteria; did meet exclusion criteria; protocol violation or subject noncompliance 
(specify); lost to follow-up; withdrew consent; other (specify). 
8.4. 
Subject Withdrawal Criteria 
A subject may withdraw consent at any point during the study. The investigator may discontinue 
a subject at any time if it is deemed medically appropriate, or for subject noncompliance with 


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study requirements. Subjects who withdraw will not be replaced. For subjects who are lost to 
follow-up (i.e., those subjects whose status is unclear because of failure to appear for study visits 
without stating an intention to withdraw), the investigator should document in the source 
documents steps taken to contact the subject. Subjects are to be withdrawn from the study if any 
of the following criteria are met: 
 Occurrence of an AE, intercurrent illness, or laboratory abnormality which, in the opinion of 
the investigator
safety. 
 Withdrawal of informed consent 
 Noncompliance with protocol procedures 
 Lost to follow-up 
 Pregnancy 
 Study termination by the sponsor 
 Other:  COVID-19 site response 
8.5. 
Methods of Birth Control 
Female subjects of childbearing potential who are sexually active with a male partner must 
practice one of the following methods of birth control during the study and for 30 days after the 
last dose of study drug. 
 Oral or parenteral contraceptives 
 Intrauterine device (either hormonal or non-hormonal type acceptable) 
 Barrier (condom, contraceptive sponge, diaphragm, or cervical cap with spermicide) 
 Abstinence 
Females not of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy, or tubal ligation) or who are post-menopausal 
(amenorrhea) for at least 2 years. 
Female subjects of childbearing potential must have a negative pregnancy test at screening and 
Day 1. 
Male subjects who are not surgically sterilized must agree to use an acceptable method of birth 
control and refrain from sexual activity with female sexual partners who do not use an acceptable 
method of birth control during the study and for 30 days after the last dose of study drug. Male 
subjects who are not surgically sterilized for at least 90 days prior to screening, and who are 
sexually active with a female partner, must agree to use barrier contraceptives (condom with 
spermicide) during the study and for 30 days after the last dose of study drug. Male subjects must 
also agree to refrain from sperm donation during the study and until 30 days after the last dose of 
study drug. 


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9. 
SCHEDULE OF PROCEDURES 
9.1. 
Screening Period (Day -28 to -14) 
 Informed consent form (ICF) must be signed before any protocol-directed procedures are 
performed. A separate ICF for optional pharmacogenomics (PGX) and PAX blood sampling 
will also be administered at the screening visit. 
 Inclusion/exclusion criteria 
 Demographics and habits (alcohol and/or illicit drug use, employment history, smoking 
history, and index traumatic event) 
 Medical and psychiatric history (including non-pharmacologic interventions) 
 PTSD diagnosis, according to DSM-5 (SCID-5-CT to exclude co-morbidities and CAPS-5 to 
diagnose PTSD)  
 LEC-5 (part of PCL-5 with LEC-5 and Criterion A) 
 S-STS (last month version) 
 Vital sign measurements (after at least 5 minutes of rest, sitting or supine) 
 Height (calculate BMI) 
 Body weight (calculate BMI) 
 PE  
 ECG (after at least 5 minutes supine rest) 
 Laboratory tests: 
o Clinical chemistry (calculate estimated creatinine clearance) 
o Hematology 
o HIV, hepatitis B surface antigen, hepatitis C antibody 
o Serum pregnancy test for women of childbearing potential 
o Drug and alcohol screen (serum) 
o Urinalysis 
 Clinical measures: 
o CAPS-5  
o PCL-5 (last month version) 
o HADS 
o CGI-S 
o PSQI 
o PSQI-A 


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o
 
 Prior and concomitant medications 
 SAEs (collection begins after ICF signed) 
9.2. 
Day -14 (±3 days) 
Subjects who meet eligibility criteria according to the PCL-5 ( 38), SCID-5-CT, and CAPS-5 
(total score 
) at screening will complete a SAFER remote phone interview. Those subjects 
confirmed to have met the study diagnostic and selection criteria as determined during the 
SAFER interview are then eligible to proceed in the study.  
9.3. 
Stage 1: Day 1  
 Medical and psychiatric history updates (if applicable) 
 Inclusion/exclusion criteria 
 S-STS (since last visit version) 
 Vital signs (after at least 5 minutes of rest, sitting or supine) 
 Body weight 
 ECG (after at least 5 minutes supine rest) 
 Concomitant medications 
 Laboratory tests 
o Clinical chemistry (fasted) 
o Hematology 
o 
 
 
 
o Pregnancy test (urine) for women of childbearing potential 
o Drug (urine) and alcohol screen (breathalyzer) 
o Urinalysis 
 Clinical measures (all measures except for CAPS-5 are not required if last measurement is 
within 14 days prior to Day 1)  
o CAPS-5 
o PCL-5 
o HADS 
o CGI-S 
o PSQI 
o PSQI-A 


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o 
 
o DES-II 
o BAC-Symbol Coding 
 Randomization  
 Study drug dispensing, dose administration (in clinic and after completion of above-noted 
study procedures), and compliance monitoring 
o Medication adherence and reminder system training 
 AEs (serious and non-serious) 
9.4. 
Week 2, Day 14 (±7 days) 
 S-STS (since last visit version) 
 Vital sign measurements (after at least 5 minutes of rest, sitting or supine) 
 Body weight 
 Laboratory tests: clinical chemistry (fasted) 
 Clinical outcome measures 
o CAPS-5 
o PCL-5 
o HADS 
o PSQI 
o PSQI-A 
o CGI-S 
 Study drug accountability, compliance review, and dispensing 
o Medication adherence and reminder system review 
 Concomitant medications 
 AEs (serious and non-serious) 
9.5. 
Stage 2: Week 4, Day 28 (±3 days) 
Study drug (including extra kit) dispensed in Stage 1 may not be re-dispensed and/or 
administered in Stage 2. 
 S-STS (since last visit version) 
 Vital signs (after at least 5 minutes of rest, sitting or supine) 
 Body weight 
 PE  
 ECG (after at least 5 minutes supine rest) 
 Laboratory tests 


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o Clinical chemistry (fasted) 
o Hematology 
o Plasma concentration blood sample 
o RNA (miRNA, mRNA) PAXgene® blood sample (optional) 
o Pregnancy test (urine) for women of childbearing potential 
o Drug (urine) and alcohol screen (breathalyzer) 
o Urinalysis 
 Clinical measures 
o CAPS-5 
o PCL-5 
o HADS 
o CGI-S 
o PSQI 
o PSQI-A 
o BAC-Symbol Coding 
o 
 
o DES-II 
 Randomization (for Stage 2) 
 Study drug accountability, compliance review, and dispensing (for next day dosing) 
o Medication adherence and reminder system review 
 Concomitant medications 
 AEs (serious and non-serious) 
9.6. 
Week 6, Day 42 (±7 days)  
 S-STS (since last visit version) 
 Vital signs (after at least 5 minutes of rest, sitting or supine) 
 Body weight 
 Laboratory tests: clinical chemistry (fasted) 
 Clinical outcome measures 
o CAPS-5 
o PCL-5 
o HADS 


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o PSQI 
o PSQI-A 
o CGI-S 
 Study drug accountability, compliance review, and dispensing  
o Medication adherence and reminder system review 
 Concomitant medications 
 AEs (serious and non-serious) 
9.7. 
Week 8, Day 56 (±3 days) 
 S-STS (since last visit version) 
 Vital signs (after at least 5 minutes of rest, sitting or supine) 
 Body weight 
 PE 
 ECG (after at least 5 minutes supine rest) 
 Laboratory tests 
o Clinical chemistry (fasted) 
o Hematology 
o Plasma concentration blood sample 
o 
 
o Drug and alcohol screen (serum) 
o Pregnancy test (urine) for women of childbearing potential 
o Urinalysis 
 Clinical outcome measures 
o CAPS-5 
o PCL-5 
o HADS 
o CGI-S 
o PSQI 
o PSQI-A 
o BAC-Symbol Coding 
o 
 
o DES-II 
o 
 


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 Study drug accountability and compliance review 
o Medication adherence system review and retrieval of device (if applicable)  
 Concomitant medications 
 AEs (serious and non-serious) 
9.8. 
Early Termination Visit 
 S-STS (since last visit version) 
 Vital signs (after at least 5 minutes of rest, sitting or supine) 
 Body weight 
 PE 
 ECG (after at least 5 minutes supine rest) 
 Laboratory tests 
o Clinical chemistry (fasted) 
o Hematology 
o Plasma concentration blood sample 
o 
 
o Drug and alcohol screen (serum) 
o Pregnancy test (urine) for women of childbearing potential 
o Urinalysis 
 Clinical measures 
o CAPS-5 
o PCL-5 
o HADS 
o CGI-S 
o PSQI 
o PSQI-A 
o BAC-Symbol Coding 
o 
 
o DES-II 
o 
 
 Study drug accountability and compliance review 
o Medication adherence system review and device retrieval (if applicable) 
 Concomitant medications 


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 AEs (serious and non-serious) 
9.9. 
Safety Follow-up Visit (7 days post-therapy ±3 days) 
The following safety assessments are to be performed only if required for AE follow-up: 
 Vital signs (after at least 5 minutes of rest, sitting or supine)  
 Body weight 
 PE 
 ECG (after at least 5 minutes supine rest) 
 Laboratory tests 
o Clinical chemistry (fasted) 
o Hematology 
o Urinalysis 
The following assessments are to be performed for all subjects at this visit: 
 Concomitant medications 
 AEs (serious and non-serious) 
 
 
9.10 
Remote Visits 
 
In the event that a subject cannot be physically present at the investigational site (due to the 
COVID-19 health emergency) within the time window of their scheduled visits, the following 
assessments will be completed remotely through videoconference or phone call with site staff: 
 Reporting of AEs 
 concomitant medication 
 the evaluation of suicidality (SSTS), and the  
 administration of the CAPS-5 
Remote assessments can only be done for Week 2, Week 6, and Safety Follow-up visits. The 
mode of assessment will be captured in the clinical database. Baseline, Week 4 (re-
randomization) and Final Visit Week 8/ET must be completed at the site. The rest of the safety 
procedures such as blood and urine sampling, vital signs, ECG and physical exam must be done 
within 7 days of the remote assessment. Instances of remote assessment will be collected in the 
database. If these safety procedures cannot be completed in that timeframe, the subject may have 
to be discontinued from the study. Please consult with the 
Medical Monitor as these 
issues arise. 
 


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10. 
STUDY TREATMENT 
10.1. 
Dosing and Administration 
The first dose of study drug in Stage 1 will be administered orally at the investigative site with 
water and supervised by blinded clinic personnel who will perform hand and mouth checks to 
confirm dosing. Subsequent study drug administration will be on an outpatient basis. Stage 2 
dosing begins the day after the Week 4 visit. 
Subjects will be instructed to take 1 capsule per day with water. The capsules should be 
swallowed whole and not opened. 
Study drug provided at each visit will be sufficient to last until the next planned visit. 
 
 
 
 
 
 
 
 
 
 
 
  
All study drug dispensed to the subject must be recorded in the eCRF and accountability logs. 
Subjects will be instructed to return all used and unused blister cards, including the extra blister 
card, at each subsequent study visit for accountability.  
10.2. 
Randomization and Blinding 
The study will be conducted as a placebo-controlled, double-blind study. The randomization 
schedule will be produced by the authorized sponsor designee.  
On Day 1, subjects will be randomized to receive placebo, NYX-783 50 mg QD, or NYX-783 10 
mg QD in a 4:1:1 ratio, respectively. Placebo responders and placebo non-responders (CAPS-5 
total score reduction from baseline 35% and total CAPS-5 total 
identified at the completion of Stage 1 (Weeks 1-4) in a blinded fashion; then, each group (i.e., 
placebo responders and placebo non-responders) will be re-randomized in a blinded fashion to 
placebo, NYX-783 50 mg QD, NYX-783 10 mg QD in a 3:2:2 ratio, respectively, for Stage 2 
(Weeks 4-8) treatment. Subjects who received active treatment during Stage 1 will receive 
placebo in Stage 2.  
The authorized investigative site personnel will obtain blinded kit assignments using an 
interactive response technology (IRT) system. The blinded dose information may only be 
obtained by the investigator (or designee) in an emergency, where the information may have an 
impact on further treatment decisions or aid in the emergency treatment of the subject. Every 
effort must be made to contact the sponsor prior to unblinding. 


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10.3. 
Treatment Compliance 
Blinded clinic personnel will observe dosing on Day 1 to ensure subject compliance. A 
smartphone--based video recording technology platform will be utilized for monitoring 
compliance with study drug administration. The platform uses artificial intelligence on 
smartphones to confirm medication ingestion. Additionally, built-in reminders and a 
communication system may allow for real-time intervention in case of study drug interruptions. 
Use of the platform will be required for all subjects. The platform will be provided to subjects 
preloaded onto a smartphone, or subjects will download the platform onto his/her personal 
mobile device during a study visit. Video recordings will be encrypted and transmitted to a 
secure centralized location for further analyses, including testing for duplicate enrollment at 
other investigative sites. The captured data and video will be reviewable through a roles and 
restricted system ensuring privacy of information. The system is compliant with the Health 
Insurance Portability and Accountability Act (HIPAA), which protects the privacy and security 
of healthcare information. Phone numbers of the subjects may also be collected and stored in an 
encrypted manner. Storing the phone numbers will allow for direct communication with subjects, 
including automated messaging from the Platform device and contact by healthcare providers or 
other monitoring personnel. At no time is the phone number visible to healthcare providers or 
sponsor monitoring personnel. 
Investigative site personnel will also perform compliance calculations based on returned study 
drug. Noncompliance (missed doses) or partially administered doses must be documented in the 
eCRF. 
10.4. 
Concomitant Medications 
Concomitant medications used within 30 days prior to dosing and through the end-of-study 
assessments at the final follow-up visit must be documented on the concomitant medications 
eCRF. Additionally, use of any of the below medications within 90-day before Screening 
restrictions  must be documented on the eCRF.  
The investigator (or designee) should instruct subjects to notify the study site about any new 
medications taken after the start of the study drug and prior to study discontinuation.  
The following medication is prohibited within 12 months prior to screening and during the study: 
 Clozapine 
The following medications are prohibited within 30 days (90 days for fluoxetine) prior to 
screening and through the entire study period:  
 Nefazodone 
 Monoamine oxidase inhibitors such as selegiline, phenelzine, tranylcypromine 
 SSRIs and SNRIs such as fluoxetine, sertraline, escitalopram, citalopram, paroxetine, 
desvenlafaxine, duloxetine, venlafaxine 
 Tricyclic antidepressants such as amitriptyline, imipramine, nortriptyline 
 NaSSA mirtazapine 


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 Serotonin modulator and stimulator antidepressants such as vilazodone or 
vortioxetine 
 Norepinephrine, serotonin and dopamine reuptake inhibitor bupropion 
Initiation of current therapy with the following medications is prohibited within 30 days prior 
to Screening or during the study:  
 Other allowed antidepressants   
 
 
However, 
is 
opinion) for at least 30 days prior to the start of screening and no change of dose occurs 
during the screening, treatment, or follow-up periods of the study.  
Medications with primarily CNS activity are prohibited within 3 days prior to screening and 
through the entire study period. Examples of these medications include the following:  
 Conventional or atypical antipsychotics, anticonvulsant drugs (including 
gabapentinoids), or psychostimulants  
 Benzodiazepines 
 Methylphenidate  
 Doxazosin 
 Prazosin 
 Clonidine 
 First generation sedating H1 antihistamines 
 Quetiapine 
 Eszopiclone 
 Zolpidem extended-release  
 Other sedative-hypnotics 
Use of certain non-benzodiazepine sleep inducers (e.g., zolpidem immediate-release [up to 10 
mg at bedtime], zaleplon [up to 20 mg at bedtime]), melatonin, or ramelteon for sleep are 
allowed. NOTE: the non-benzodiazepine sleep inducers should be administered as a single dose 
immediately before bedtime and may not be re-administered during the night.  
Use of NMDAR-binding drugs (e.g., ketamine, dextromethorphan, memantine, methadone, 
lamotrigine, esketamine) may not be used within 60 days prior to dosing or during the study. 
Exceptions to these specifications must be approved by the sponsor designated medical monitor. 
10.5. 
Study Drug Discontinuation 
Study drug must be discontinued for a given subject if the investigator determines that 
continuing it would result in a significant risk for that subject. Please also refer to protocol-
specified Subject Withdrawal Criteria (see Section 8.4). 


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11. 
STUDY DRUG MATERIALS AND MANAGEMENT 
11.1. 
Study Drug 
NYX-783 is formulated for this study as 50 mg, and 10 mg capsules for oral administration. 
Matching placebo capsules for oral administration are also provided.  
 
 
 
   
 
11.2. 
Study Drug Packaging and Labeling 
Study drug will be packaged in kits containing blister cards of blinded NYX-783 50 mg, NYX-
783 10 mg or placebo capsules. 
 
 
 
 
 
. The labels will include, but will not be limited to, kit number, 
capsule count, storage conditions, sponsor name, and investigational use statement. The sponsor 
will provide the investigative site with sufficient amounts of study drug to conduct the study. 
11.3. 
Study Drug Storage 
Study drug should be stored in a locked, limited-access location according to label and under the 
direct responsibility of the investigator or designated pharmacist or clinic site staff. The capsules 
should be stored at 20º-25ºC with excursions permitted between 15º-30ºC. The investigative site 
should contact the sponsor for directions regarding non-permitted excursions. 
11.4. 
Study Drug Preparation 
The investigator may delegate study drug handling and accountability as appropriate. An 
interactive response technology (IRT) will specify to investigative site personnel which study 
drug kit to dispense. 
 
. Refer to the Product Pharmacy Manual and/or IRT manual for additional 
instruction. The pharmacy manual includes instructions for registering product complaints, if 
required. 
11.5. 
Study Drug Accountability 
The investigator may delegate study drug accountability as appropriate. The investigative site 
personnel will receive, inspect, acknowledge study drug condition, document amount 
received/dispensed/returned, dispense, acknowledge shipments as instructed, and maintain study 
drug accountability records. A sponsor representative will inspect the study drug and 
accountability records. Site personnel will dispense (and administer if required) study drug to 
subjects, account for and document used/unused study drug, and return any unused study drug (if 


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applicable) to unblinded pharmacy personnel. Only subjects enrolled in this clinical study and 
eligible to receive treatment are to receive study drug material. 
Upon completion or termination of the study, and after sponsor accountability is completed, all 
used and unused supplies must be returned or destroyed as instructed by sponsor representative. 


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12. 
STUDY ASSESSMENTS  
12.1. 
Psychiatric Rating Scales/Outcome Measures/Test(s) 
Investigative sites will be required to identify and provide clinical raters with suitable experience 
and training to conduct interviews and/or clinician-rated scales. Remote rater qualification, 
certification, training, and surveillance will be required for all investigative site clinical raters. 
Enrollment may not begin at an investigative site until a clinical rater has been informed by the 
sponsor and/or designee that qualification, training, and/or certification requirements have been 
satisfied. If a clinical rater changes during the study, new rater(s) must complete qualification, 
training, and certification requirements and be deemed acceptable by the sponsor and/or designee 
prior to completing interviews and/or scales. Information from diagnostic interviews, 
medical/psychiatric and/or medication history, and rating scales may be requested by the sponsor 
or designee for data review and/or rater surveillance activities. 
12.1.1. 
Structured Clinical Interview for DSM-5 (SCID-5-CT) 
The Structured Clinical Interview for DSM-5, Clinical Trials Version (SCID-5-CT) is a semi-
structured interview guide for making the major DSM-5 diagnoses. It is administered by a 
clinician or trained mental health professional who is familiar with DSM-5 classification and 
diagnostic criteria. (APA 2013) 
The SCID-5-CT modules will support assessing the mental disorders-related eligibility criteria.   
12.1.2. 
SAFER Remote Interview 
The SAFER remote interview is an independent psychologist- or psychiatrist-administered 
interview to assess whether a subject is appropriate for a study by confirming eligibility criteria. 
The acronym stands for the 
 to the following criteria: State versus trait; 
Assessability; Face validity; Ecological validity; and Rule of 3 Ps (pervasive, persistent, and 
pathological). (Desseiles 2013) The interview is intended to increase the quality of the study by 
restricting the sample to a more homogenously defined PTSD population. As such, the SAFER 
interview can help in the selection of subjects who are good candidates for assessment of a 
treatment effect by minimizing the risk that factors unrelated to treatment will influence 
outcomes. The SAFER interview will be completed with the subject by phone.   
12.2. 
Clinical Measures 
12.2.1. 
Clinician Administered PTSD Scale for DSM-5 (CAPS-5) 
The CAPS-5 is a 30-item structured interview for diagnosis and assessment of PTSD (Weathers 
2017). In addition to assessing the severity and frequency of the 20 DSM-5 PTSD symptoms, 
questions target the onset and duration of symptoms, subjective distress, impact of symptoms on 
social and occupational functioning, improvement in symptoms since a previous CAPS-5 
interview, overall response validity, overall PTSD severity, and specifications for the 
dissociative subtype (depersonalization and derealization). CAPS-5 total symptom severity score 
is calculated by summing severity scores for the 20 DSM-5 PTSD symptoms. Similarly, CAPS-5 
symptom cluster severity scores are calculated by summing the individual item severity scores 
for symptoms corresponding to a given DSM-5 cluster: Criterion B, intrusions (items 1-5); 


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Criterion C, avoidance (items 6-7); Criterion D, negative alterations in cognitions and mood 
(items 8-14); and, Criterion E, alterations in arousal and reactivity (items 15-20). The assessor 
combines information on frequency and intensity of an item into a single severity rating (0-4) for 
each of the 20 DSM-5 PTSD symptoms, with a maximum possible score of 80 points. A higher 
score corresponds to more severe PTSD. (APA 2013) 
12.2.2. 
Hospital and Anxiety Depression Scale (HADS) 
The HADS is a self-assessment tool consisting of two subscales, one for anxiety (HADS-A) and 
one for depression (HADS-D). (Zigmond 1983, Bjelland 2002) Each subscale consists of 7 items 
that are scored from 0-3, for a maximum score of 21 for either anxiety or depression; higher 
scores represent more severe anxiety or depression.  
12.2.3. 
PTSD Checklist for DSM-5 (PCL-5) 
The PCL-5 is a 20-item self-report measure that assesses PTSD symptoms experienced over the 
last week or month according to DSM-5 criteria. Items assess symptoms across 4 symptom 
clusters of PTSD (re-experiencing, negative mood, avoidance, and hyperarousal) on a 0-4 point 
Likert scale. Total scores range from 0-80. The 
should be used after 
screening. 
12.2.4. 
Clinical Global Impressions-Severity (CGI-S) 
The CGI-S scale assesses the global severity of illness and change in clinical condition over 
time, and subjects are rated from 1 (normal, not at all ill) to 7 (among the most extremely ill 
subjects). (Guy 1976). 
12.2.5. 
Pittsburgh Sleep Quality Index (PSQI) 
The PSQI (Buysse 1989) is a questionnaire to assess sleep quality and disturbances over a 1-
month time interval. A total of 19 items are self-rated, 15 objective (about frequency of sleep 
disturbances and subjective sleep quality) and 4 subjective (typical bedtime, wake-up time, sleep 
latency and sleep duration) items. These 19 items generate 7 component scores: subjective sleep 
quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of 
sleeping medication, and daytime dysfunction, each of which ranges from 0: no difficulty to 3: 
severe difficulty. The PSQI Global Score is generated by addition of the 7 individual component 
scores and ranges from 0 to 21. A global score >5 indicates significant sleep disturbance. The 
additional 5 items rated by the bedpartner or roommate will not be collected for this trial. 
12.2.6. 
Pittsburgh Sleep Quality Index Addendum (PSQI-A) 
The PSQI-A (Germain 2005) is a self-report instrument to assess disruptive nocturnal behavior 
(DNB) in PTSD subjects, according to the following 7 types of behaviors:  1) hot flashes, 2) 
general nervousness, 3) memories or nightmares of traumatic experience, 4) severe anxiety or 
panic, not related to traumatic memories, 5) bad dreams, not related to traumatic memories, 6) 
episodes of terror or screaming during sleep without fully awakening and 7) episodes of acting 
out dreams, such as kicking, punching, running, or screaming. Each DNB is rated on a scale of 0-
3 (0: not in the past month, 1: less than once a week, 2: once or twice a week, and 3: three or 
more times a week), with a global score range of 0-21. 


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12.2.9. 
Dissociative Experiences Scale-II (DES-II) 
The Dissociative Experiences Scale-II (DES-II) (Carlson 1993) is a 28 item, self-report 
questionnaire that measures a wide variety of dissociative experiences, from normal (e.g., day-
dreaming) to pathological (depersonalization). Subjects rate the percentage of time they have the 
experience, from 0% to 100% (in increments of 10). 
12.2.10. 
Life Events Checklist for DSM-5 (LEC-5)   
The LEC-5 (Weathers 2013) is a 17-item self-reporting tool to screen 
 
12.2.11. 
Symbol Coding from the Brief Assessment of Cognition (BAC Symbol Coding) 
The Brief Assessment of Cognition (BACS, Keefe et al., 2004) is a pen-and-paper cognitive 
assessment used in hundreds of research studies and clinical trials. A tablet-based version of the 
BACS, the BAC App, was validated in 2016 to allow standardized presentation of task 
instructions and stimuli, audio-recording of responses, and automatized scoring and data 
management (Atkins et. al., 2016). BAC Symbol Coding is delivered on the Pathway tablet and 
offers a sensitive measure of processing speed. Participants are provided a key and asked to fill 
in the corresponding numbers beneath a series of symbols as quickly as possible within 90 
seconds. The assessment takes approximately 3-5 minutes to complete, including instructions 
and practice.   
12.3. 
Exploratory Assessments 
 
 
 
 
 


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12.4. 
Safety Assessments 
Refer to the Schedule of Assessments (Table 4) or schedule of procedures section (Section 9.0) 
for time points. All abnormal or out-of-range safety results will be reviewed by an investigator 
for clinical significance. Possibly drug-related or clinically-relevant abnormal results of 
uncertain causality must be repeated. Ongoing abnormal findings should be followed at the 
discretion of the investigator. 
12.4.1. 
Demographics and Medical History 
Date of birth, sex, Hispanic ethnicity, race, smoking status, reproductive status, employment 
status, alcohol consumption, and index traumatic event will be collected. A complete medical 
and psychiatric history should include whether the subject has any significant conditions or 
diseases relevant to the condition/disease under study. The index traumatic event is the primary 
traumatic event that led to the initial development of PTSD symptoms; year of event should be 
collected. Any ongoing medical or psychiatric conditions present at the time of informed consent 
are to be documented as medical history, including clinically significant laboratory results, ECG 
findings, PE abnormalities/symptoms, or psychiatric symptoms noted during the screening 
period. The condition (i.e., diagnosis) should be described wherever possible. 
12.4.2. 
Vital Sign Measurements 
Each assessment includes blood pressure, respiration rate, heart rate (HR), and oral body 
temperature, taken after at least 5 minutes of rest (seated or supine). Height and weight will also 
be collected. Vital signs may be repeated for eligibility determination. 
12.4.3. 
Physical Examination (PE)  
The Investigator (or qualified designee) will perform a routine, thorough PE that includes an 
assessment of the eyes, ears, nose, throat, and extremities as well as a dermatological 


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examination and assessment of the respiratory, cardiovascular, gastrointestinal, and 
musculoskeletal systems.  
12.4.4. 
12-lead Electrocardiogram 
The ECG will include all 12 standard leads. Standard ECG parameters, including HR, RR, PR, 
corrected QT (QTc) intervals, and QRS duration, will be measured. 
All ECGs should be collected after at least 5 minutes supine rest. Clinically significant, abnormal 
ECGs should be repeated. Any clinically significant ECG change should be recorded as an AE.  
ECGs may be repeated for eligibility determination. 
12.4.5. 
Clinical Laboratory Assessments  
The investigator will review clinical laboratory test results as they become available for 
determination and documentation of clinical significance, if there are any out-of-range values. 
Abnormal laboratory results at Screening may be repeated for eligibility determination. Possibly 
drug-related or clinically-relevant abnormal values of uncertain causality must be repeated. 
Ongoing abnormal laboratory 
  
All women of child-bearing potential will receive serum pregnancy tests (ß-HCG) and urine 
pregnancy tests.  
Hepatitis and HIV screen includes: HIV, hepatitis B surface antigen, and hepatitis C antibody. 
Hematology includes: White blood cell count with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils); hemoglobin; hematocrit; mean corpuscular volume (MCV); 
mean corpuscular hemoglobin (MCH); MCH concentration (MCHC); mean platelet volume 
(MPV); red blood cell count; red cell distribution width (RDW), and platelet count. 
Clinical chemistry includes electrolytes (bicarbonate, calcium, chloride, phosphorus, potassium, 
sodium, magnesium), enzymes (ALP, AST, ALT, lactate dehydrogenase, gamma-glutamyl 
transferase), and other tests (albumin, bilirubin [total], direct bilirubin, indirect bilirubin, 
creatinine, glucose, protein [total], blood urea nitrogen, thyroid stimulating hormone [at 
screening only], and uric acid). 
Qualitative urinalysis includes appearance, color, pH, specific gravity, glucose, ketones, protein, 
blood, leukocyte esterase, urobilinogen, bilirubin, and nitrites. Microscopy will include red blood 
cells, white blood cells, epithelial cells, casts, and bacteria. 
Standard blood and urine drug panel includes analysis for benzodiazepines, opiates, cocaine, 
cannabinoids, amphetamines, barbiturates, methadone, and phencyclidine. Serum and alcohol 
breathalyzer testing will also be performed. The screening period may be extended to ensure 
washout, if needed, between screening and Day 1. 
An estimated creatinine clearance will be calculated. 
Refer to the laboratory sample collection, handling, and shipping specifications for additional 
instruction. 


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12.4.6. 
Sheehan Suicidality Tracking Scale (S-STS) 
The standard version of the S-STS (Sheehan 2014[a]) is a 16-item scale that assesses the 
seriousness of suicidality phenomena on a Likert-type scale (0 to 4) ranging from 0 = 
to 
.  It also assesses the frequency of key phenomena and the overall time spent in 
suicidality. The standard version is available in identical clinician- and subject-rated formats. 
The tool is to be administered via interview with the subject (by a trained operator/interviewer).  
If possible, the same interviewer should be used throughout the study for the same subject.  The 
S-STS accommodates a wide range of timeframes. In clinical trials, the frequently used variants 
the past day.   
The S-STS maps to both the Columbia Suicide Severity Rating Scale (Giddens 2014) and to all 
categories in the FDA Draft Guidance documents of both 2010 and 2012 and provides coverage 
for all suicidal phenomena presented in the draft FDA guidance. The S-STS has been studied and 
validated against other instruments used for the assessment of suicidality and been shown to 
provide at least equal sensitivity to detecting suicidal ideation and behavior. (Sheehan 2014 [b]) 
NOTE: Suicidality identified after baseline will be recorded as an AE. 
12.5. 
Adverse Events and Serious Adverse Events 
12.5.1. 
Definition of an Adverse Event  
An AE is any untoward, undesired, or unplanned clinical event in the form of signs, symptoms, 
disease, or laboratory or physiological observations associated with the use of an intervention in 
humans participating in a clinical study, regardless of causal relationship.  
Pre-existing conditions (i.e., ones that are present before study drug dosing) should be reported 
as an AE only if the frequency, intensity, or character of the condition worsens during the study. 
(Note: Pre-existing conditions are reported during the Screening period 
medical history.) 
Laboratory or ECG abnormalities are not considered AEs unless they are associated with clinical 
signs or symptoms or require medical intervention. However, a laboratory abnormality (e.g., a 
clinically significant change detected on clinical chemistry, coagulation, hematology, urinalysis) 
that is independent from the underlying medical condition and requires medical/surgical 
intervention or leads to study drug interruption or discontinuation, must be considered an AE. 
12.5.2. 
Definition of a Serious Adverse Event 
An SAE is any AE occurring at any dose that results in any of the following outcomes: 
 Death  
 
 Is a life-threatening experience  
Life-threatening AEs include any adverse drug experience, which, in the view of the 
investigator, places the subject at immediate risk of death from the reaction as it occurs. It 


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does not include a reaction that, had it occurred in a more serious form, might have caused 
death. 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in a persistent or significant disability/incapacity   
Disability is defined as a substantial disruption in a 
functions. 
 Results in a congenital anomaly/birth defect 
 Additionally, important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed previously (e.g., an allergic bronchospasm requiring 
intensive treatment in an emergency room or at home). 
12.5.3. 
Adverse Event Reporting 
Adverse events will be collected from the time of study drug administration through the last day 
 Follow-up of AEs must be conducted in accordance 
ice.  
All AEs must be documented, evaluated, and reported in the source documents and electronic 
case report forms (eCRFs), and include the following information: duration (start and stop dates 
or if continuing at final visit), severity, relationship to study drug, action(s) taken, outcome, and 
whether it constitutes a serious adverse event (SAE). Diagnoses (rather than symptoms) should 
be recorded wherever possible. To avoid vague, ambiguous, or colloquial expressions, all AEs 
should be r
 
recorded as AEs 
unless there is a clinically significant safety concern (e.g., serious adverse event). 
Subjects should be instructed to report all potential AEs to the investigator. Subjects should also 
be queried in a non-leading manner, without specific prompting (e.g.
 
about all potential AEs. The site study staff should assess emerging symptoms of dissociative 
reaction similar to those caused by NMDA antagonists, including memory impairment, 
disturbance in time, body or environmental perception, stilted speech, emotional withdrawal, 
impaired coordination, motor retardation, bizarre reasoning or illusory experiences in any 
sensory perception, or confused state; such symptoms may be captured as AEs. 
12.5.4. 
Serious Adverse Event Reporting 
Serious adverse event (SAE) reporting will begin from the time of informed consent and will end 
30 days after the last dose of study drug. SAEs must be reported to the sponsor or designee using 
the provided form either by email or fax to the following address or telephone number, 
respectively: 


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All SAEs that result in death or are life threatening, regardless of causal relationship, must be 
reported to the sponsor or designee within 24 
of the initial SAE report must be received within one (1) business day. 
All other SAEs or other events reportable to FDA and/or institutional review board (IRB) will be 
forwarded to the sponsor or designee within one (1) business day. 
The SAE report should provide as much of the required information as is available at the time. 
The following minimum information is required for reporting an SAE: subject identification, 
reporting source, and event outcome. Supplemental information may be transmitted using a 
follow-up report and should not delay the initial report. Aptinyx (or its authorized representative) 
may contact the investigational site to solicit additional information or to follow-up on the event. 
If there is any doubt whether the information constitutes an SAE, the information will be treated 
as an SAE for the purposes of this protocol.  
All relevant documentation pertaining to an SAE (additional laboratory tests, consultation 
reports, discharge summaries, postmortem reports, etc.) will be provided to the sponsor or 
designee in a timely manner. Serious AEs will be followed until resolution or return to baseline 
(when worsening of a pre-existing condition is reported). If an SAE does not return to baseline 
but reaches a stable situation that is not expected to change, this should be documented on the 
SAE form.  
12.5.5. 
Relationship to Study Drug 
For each reported AE/SAE, the investigator must assess the relationship to study drug using the 
following categories: 
Unrelated 
 Does not follow a known response pattern to the suspect study drug (if response pattern is 
previously known). 
 Can clearly be explained by the known 
modes of therapy administered to the subject. 
Unlikely Related 
 The temporal sequence from dosing of the study drug suggests that a relationship is unlikely. 
 Follows a response pattern that is unlike that of the suspect study drug (if response pattern is 
previously known). 
 
r modes of therapy 
administered to the subject. 
Possibly Related 
 Follows a reasonable temporal sequence from dosing of the study drug.  
 May follow a known response pattern to the suspect study drug (if response pattern is 
previously known). 
 
administered to the subject. 


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Probably Related 
 Follows a reasonable temporal sequence from dosing of the study drug.  
 
or any other modes of therapy administered to the subject. 
 Is confirmed by improvement on stopping or slowing dosing of the study drug, if applicable. 
When an assessment is not provided, the event will be treated as Possibly Related for purposes of 
regulatory reporting. 
12.5.6. 
Severity of Adverse Events 
All AEs must be assessed for severity, using the following general grading scale: 
Mild: Transient or mild discomfort (< 48 hours); no medical intervention/therapy required. 
 
Moderate: Mild to moderate limitation in activity  some assistance may be needed; no or 
minimal medical intervention/therapy required. 
 
Severe: Marked limitation in activity  some assistance usually required; medical 
intervention/therapy, required hospitalization possible. 
 
Life-threatening: Extreme limitation in activity  significant assistance required; significant 
medical intervention/therapy required, hospitalization or hospice care probable. 
 
When changes in the severity of an AE occur more frequently than once a day, the maximum 
severity for the experience that day should be noted. If the severity category changes over a 
number of days, then those changes should be recorded separately (with distinct onset dates). 
12.5.7. 
Action Taken for Adverse Events 
For each reported AE, the action taken must be evaluated and recorded on the eCRF according to 
the following criteria: 
 No action taken 
 Concomitant medication taken 
 Hospitalization or prolongation of hospitalization 
 Discontinued study 
 Non-drug therapy 
 Other (specify) 
The investigator must also document on the eCRF the action taken with study drug (as a result of 
a given AE) according to the following criteria: 
 Dose not changed  
 Study drug withdrawn 


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 Not applicable 
 Unknown 
12.5.8. 
Outcome for Adverse Events 
For each reported AE, the investigator must document the outcome according to the following 
criteria: 
 Fatal 
 Not recovered/ not resolved 
 Recovered/ resolved 
 Recovered/ resolved with sequelae 
 Recovering/ resolving 
 Unknown 
12.5.9. 
Other Reportable Events 
Reports of overdose (with or without an AE), abuse, dependency, inadvertent or accidental 
exposure, pregnancy, and unexpected therapeutic benefit should be forwarded in the same time 
frame as an SAE. Overdose occurs when a subject is dosed or has taken a dose greater than the 
intended or scheduled dose specified by the protocol.  
All pregnancies occurring during the study must be followed for information regarding the 
course of pregnancy, delivery, and condition of the newborn. Follow-up should be provided by 
the investigator to the sponsor in a timely manner. When the newborn is healthy, further follow-
up is not necessary. Male subjects must inform the investigator if their partner becomes pregnant 
during the study. Female subjects of childbearing potential and female partners of male subjects 
must use an acceptable method of birth control during the participation in this study. 


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13. 
STOPPING RULES AND SAFETY MONITORING 
13.1. 
Stopping Rules for Individual Subjects 
Any subject may withdraw consent at any point during the study. The investigator can 
discontinue a subject at any time if it is deemed medically appropriate, or for subject 
noncompliance with study requirements. Subjects will be withdrawn from the study if any of the 
following criteria are met: 
 Occurrence of an AE, intercurrent illness, or laboratory abnormality which, in the opinion of 
safety 
 Repeated results (i.e., values are confirmed by repeat testing as soon as feasible) showing any 
of one following laboratory findings:   
  T
  
 ALT or AST >3 x ULN 
 
 
 
 
upper quadrant pain, or tenderness, fever, rash, or eosinophilia (>5%) 
 
 
 
(msec) that was not present on the corresponding baseline ECG, or a QT/QTc interval >60 
msec over the corresponding baseline value. The QT interval should be corrected by 
. 
13.2. 
Stopping Rules for Study 
The DSMB will review safety data at regular intervals, as outlined in the DSMB charter. If the 
individual stopping criteria are met for five or more subjects receiving one of the treatment 
regimens with active study drug, dosing should be stopped based on unblinded review of data by 
the DSMB. The DSMB should assess the potential increase of risks associated with psychiatric 
symptoms, such as change in suicidality measured by the S-STS and change in dissociative 
symptoms measured by the DES-II. The study may be terminated or suspended if new 
concerning information regarding the safety of the study drug appears during the conduct of the 
study. 
13.3. 
Data and Safety Monitoring Board (DSMB) 
The sponsor or designee will appoint a Data and Safety Monitoring Board (DSMB) for the 
periodic review of available study data. The DSMB is an independent group of experts that 
advises the sponsor and the study investigators. The members of the DSMB serve in an 
individual capacity and provide their expertise and recommendations. The primary 
responsibilities of the DSMB are to (1) periodically review and evaluate the accumulated study 
data for participant safety, study conduct and progress, and (2) make recommendations to the 
sponsor concerning the continuation, modification, or termination of the trial. The DSMB 


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considers study-specific data as well as relevant background knowledge about the disease, test 
agent, or patient population under study. The DSMB is responsible for defining its deliberative 
processes, including event triggers that would call for an unscheduled review, stopping 
guidelines, unmasking (unblinding), and voting procedures prior to initiating any data review. 
The DSMB is also responsible for maintaining the confidentiality of its internal discussions and 
activities as well as the contents of reports provided to it. Refer to the DSMB charter for 
additional details. 
 
 
 
 


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14. 
STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be finalized before study data are 
unblinded. Additional statistical analyses other than those described in this protocol may be 
performed if deemed appropriate and will be described in the SAP. 
14.1. 
General Principles of Statistical Analysis 
Categorical data will be summarized using counts and percentages. Continuous data will be 
summarized using descriptive statistics (number of subjects, mean, standard deviation [SD], 
median, minimum, and maximum). Unless otherwise specified, tests of treatment effects will be 
conducted using one-
10. 
14.2. 
Sample Size Determination 
Response to treatment will be measured using the CAPS-5 score change from baseline to Week 4 
(Stage 1) and from Week 4 to Week 8 (Stage 2). If the effect size of NYX-783 is in line with the 
effect sizes observed in similar historical studies, this study is powered at approximately 80% to 
reject the null hypothesis at a one-sided 
10 level for any single specified efficacy 
comparison. The sample size estimate assumes a 15% dropout during stage 1 and 11% dropout 
during stage 2. The sample size may be adjusted if the actual dropout rate exceeds this 
assumption. 
14.3. 
Analysis Populations  
Intention-to-treat (ITT): The ITT population will consist of all randomized subjects. Subjects 
in the ITT population will be analyzed according to the treatment they are assigned at 
randomization. The primary efficacy analysis will be performed on the ITT population. Unless 
otherwise specified, all other efficacy analyses also will be conducted on the ITT population.  
Efficacy data for the 50 mg QW group will be summarized and shown in the listings but will not 
be included in the formal efficacy comparisons between treatment groups. 
NOTE: Any additional study populations for analysis of efficacy will be defined in the SAP. 
Safety Population: The safety population consists of all randomized subjects who receive at 
least one dose of study drug (active or placebo). Subjects in the safety population will be 
analyzed according to the treatment they actually received. Unless otherwise specified, all safety 
analyses will be conducted on the Safety population. 
14.4. 
Analysis of Efficacy Variables 
14.4.1. 
Methods of Analysis 
Treatment arms [1 = placebo], [2 = NYX-783 50 mg QD], [3 = NYX-783 10 mg QD] and [7 = 
placebo], [8 = NYX-783 50 mg QD], [9 = NYX-783 10 mg QD] will be analyzed for the primary 
and secondary efficacy variables. Treatment arms [4 = placebo], [5 = NYX-783 50 mg QD], [6 = 
NYX-783 10 mg QD], [10 = placebo], and [11 = placebo] will be utilized for exploratory 
efficacy analyses to keep integrity of the trial. 


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14.4.1.1. Primary Efficacy Endpoint Analysis 
The ITT population will be the primary efficacy analysis population. The data from the NYX-
783 treatment groups (using both Stage 1 and Stage 2) will be used for the comparison to 
placebo. This consists of subjects (randomized to placebo and NYX-783 from treatment arms 
[1], [2] and [3] for Stage 1 and treatment arms [7], [8], and [9] for Stage 2.  
will be evaluated using the weighted combination of the estimated 
treatment effects from the stage-
 The 
MMRM models will include variables for treatment group, visit, treatment-by-visit interaction 
term, baseline CAPS-5 score and baseline-by-visit interaction. An unstructured covariance 
matrix will be used. In the case of non-convergence, alternative covariance structures will be 
used. The sequence of alternative covariance structures will be specified in the SAP. The 
Kenward-Roger approximation will be used to adjust the denominator degrees of freedom. The 
treatment effect will be assessed as the differences in least-squares mean (LS mean) changes 
from baseline to Week 4 (Stage 1) and from Week 4 to Week 8 (Stage 2) for the NYX-783 50 
mg QD, NYX-783 10 mg QD, and placebo groups, pooled across Stages 1 and 2 using 
Stage 1/Stage 2. 
Subgroup analyses will be conducted with visit, treatment, investigator, treatment-by-visit 
interaction, the corresponding baseline score, and the baseline-by-visit interaction  and, if 
applicable  the corresponding change from screening to baseline will be included in the model.  
14.4.1.2. Secondary Efficacy Endpoints Analyses 
The ITT population also will be utilized for analysis of the secondary efficacy endpoints. 
Analysis of change from baseline in the secondary efficacy variables, including PCL-5, HADS-
A, HADS-D, PSQI, PSQI-A, CGI-S and BAC symbol coding will use similar MMRM models to 
those used for analysis of the primary efficacy analysis, and include baseline severity score as a 
covariate. 
In addition to comparing the individual active dose groups vs. placebo, similar analyses using 
analogous models will be done using the combined QD dose groups vs. Placebo.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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Further efficacy analysis details will be provided in the SAP. 
14.4.2. 
Handling of Missing Data 
analyses to support the primary efficacy analysis will be described in the SAP. 
14.4.3. 
Supportive Analyses 
Sensitivity analysis of the primary endpoint may be conducted using alternative weights for the 
stage-wise treatment effects. The population(s) to be evaluated in the sensitivity analysis will be 
defined in the SAP. Additional post-hoc analyses may be completed. 
14.5. 
Subject Disposition 
The summary of subject enrollment and disposition will display the number of subjects who are 
included in each analysis population and number of subjects who completed the study vs. 
discontinued early from the study. Specific reasons for discontinuation will be summarized 
according to the reasons listed on the eCRF. All subject disposition data and analysis population 
details will be presented in the data listings. 
14.6. 
Demographic/Baseline Data 
14.6.1. 
Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristic data including gender, age, height, weight, and 
BMI will be summarized using descriptive statistics. Categorical data for race and ethnicity will 
be summarized by counts and percentages. Similar descriptive statistics will be used to 
summarize the baseline clinical and other efficacy outcome characteristics. 
Treatment differences in subject 
test for categorical variables and Type III sums of squares analysis of variance (ANOVA) for 
continuous variables.  
The demographics and other baseline characteristics summaries will be provided for both the 
safety and ITT populations by treatment groups and overall. Data listings will be provided for all 
demographics and baseline characteristics data. 
14.6.2. 
Other Baseline Data 
Medical history, prior medications, and any other baseline data collected will be presented in 
separate data listings by the subject number. 
14.7. 
Study Drug Exposure 
All study drug dosing information collected on the eCRF will be summarized and presented in 
the data listings. 
14.8. 
Inclusion/Exclusion Criteria 
All inclusion/exclusion criteria not met will be presented in separate data listings by subject 
number. 


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14.9. 
Efficacy Data Listings 
Supporting data related to the efficacy and exploratory assessments will be presented in separate 
data listings by subject number, study stage, and treatment assignment. 
14.10. 
Analysis of Safety  
The safety population will be used for the analysis of all safety variables. 
14.10.1. 
Adverse Events 
Adverse events will be categorized by system organ class (SOC) and preferred term with the 
Medical Dictionary for Regulatory Activities. Summary tables for TEAEs will include numbers 
and percentages of subjects experiencing AEs by SOC and preferred term. If a subject has more 
than 1 AE that codes to the same preferred term, the subject will be counted only once for that 
preferred term. Similarly, if a subject has more than 1 AE within an SOC category, the subject 
will be counted only once in that SOC category. The following summary tables will be included 
in the clinical study report for each treatment and overall: summary of AEs, relationship of AEs 
to study drug, severity of AEs, SAEs, and AEs leading to study drug discontinuation. 
Data listings will be provided for all AEs, AEs leading to study drug discontinuation, and SAEs. 
14.10.2. 
Clinical Laboratory Tests 
Individual results of clinical laboratory tests from hematology, serum chemistry, and urinalysis 
that are outside of the normal range will be flagged in the data listings. Results and change from 
baseline will be summarized by treatment arm and scheduled visit using descriptive statistics for 
numeric parameters and counts and percentages for categorical parameters. 
Clinical laboratory data will be presented in the data listings. 
14.10.3. 
Electrocardiogram 
Results and change from baseline will be summarized by treatment and scheduled visit and time 
point using descriptive statistics (number of subjects, mean, SD, median, minimum, and 
maximum) for each ECG parameter assessment. All ECG data will be provided in the data 
listings. 
14.10.4. 
Vital Sign and Weight Measurements 
Results and change from baseline will be summarized by treatment and scheduled visit and time 
point using descriptive statistics (number of subjects, mean, standard deviation, median, 
minimum, and maximum) for each measurement. All vital sign and weight data will be provided 
in the data listings. 
14.10.5. 
S-STS 
Data collected for S-STS will be summarized by dose group and visit/time point. Change from 
baseline, if applicable, will also be calculated and summarized in the same manner. All S-STS 
data will be provided in the data listings.  


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14.10.6. 
Other Safety Data 
Physical examination findings, concomitant medications and other safety data will be presented 
in the data listings. 
14.11. 
Interim Analysis 
No interim analyses are planned for this study.  


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15. 
ADMINISTRATIVE 
15.1. 
Source Documents 
Source documents are defined as original observations and activities of a clinical investigation. 
Source documents may include, but are not limited to, study progress notes, e-mail 
correspondences, ICFs, clinical laboratory reports, medical histories, hospital records, and drug 
accountability records. All source documents must be maintained by the investigator(s) and 
made available for inspection by sponsor representatives, the FDA, and other applicable 
regulatory authorities. 
15.2. 
Study Monitoring 
Site visits will be conducted by an authorized sponsor representative (site monitor) to inspect 
study data, source documents, and eCRFs in accordance with International Conference for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, 
good clinical practices (GCPs), and local regulations or guidelines. The monitor will inspect the 
study data at regular intervals throughout the study to verify adherence to the protocol as well as 
completeness, consistency, and accuracy of study data. 
The investigator will permit sponsor representatives, its third-party vendors, the FDA, and/or 
respective health authorities to inspect facilities and records relevant to this study. 
15.3. 
Case Report Forms 
An electronic CRF (eCRF) will be used to record all subject data required in this protocol. The 
eCRF must be completed by designated and trained study personnel. The eCRF will be signed by 
the principal investigator or a sub-investigator listed on the Form FDA 1572. It is the 
responsibility of the principal investigator to ensure the eCRFs are completed and submitted to 
Aptinyx (or designee) in an accurate and timely manner. The processing of eCRFs will include 
an audit trail (to include changes made, reason for change, date of change and person making the 
change). 
15.4. 
Protocol Amendment(s) 
If a protocol has been filed with regulatory agencies or submitted to an IRB and requires 
changes, a protocol amendment must be written. The sponsor will make changes to the protocol. 
All amendments will be submitted to the IRB by the investigative site for review and approval. 
15.5. 
Audits and Inspections 
During the study, or after completion of the study, the study site may be subject to an audit by an 
Aptinyx Quality Assurance Auditor (or an auditor appointed by Aptinyx or its authorized 
representative) and/or an inspector from the FDA and/or other regulatory authority. Every 
attempt will be made to notify the investigator in writing in advance of the audit. If the 
investigator receives notification of a regulatory inspection for a different study during the 
clinical conduct for this study, the investigator must notify the sponsor. 


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15.6. 
Institutional Review Board (IRB) 
This protocol, the informed consent document, and all relevant supporting data must be 
submitted to the IRB for approval. IRB approval of the protocol, informed consent document, 
and any advertisement used to recruit study subjects must be obtained before the study may be 
initiated. The IRB must comply with requirements set forth in the Code of Federal Regulations 
(CFR) part 56. 
The investigator is responsible for keeping the IRB advised of the progress of the study, changes 
to research activity, unanticipated problems involving risk to human subjects or others, and any 
changes made to the protocol as deemed appropriate, but in any case, at least once a year. The 
investigator is also responsible for notifying the IRB of any significant AEs or protocol 
deviations that occur during the study and meet IRB reporting requirements. 
The investigator agrees that he or she will not make any changes in the research without IRB 
approval, except where necessary to eliminate apparent immediate hazards to human subjects, as 
referenced in 21 CFR 312.66. 
15.7. 
Compliance with Regulatory Requirements 
This study will be conducted in compliance with the protocol and all regulatory requirements, in 
accordance with GCP, including ICH Guidelines, and in general conformity with the most recent 
version of the Declaration of Helsinki. 
15.8. 
Informed Consent 
Written signed informed consent must be obtained from potential study participants prior to the 
initiation of non-routine study-related tests. The original signed ICF for each participating 
subject must be filed with records kept by the investigators(s). A copy of the signed informed 
consent document must be provided to the subject. If applicable, written consent will be obtained 
using a certified translation. ICF revisions must be obtained in a timely manner. 
15.9. 
Study File Management 
The investigator is responsible for ensuring that the study files are maintained. The study file will 
include, but is not limited to, source documents, correspondence, and regulatory documents (IRB 
approvals/correspondence, study logs, FDA 1572 forms, financial disclosures, clinical study 
material records, study drug accountability records, and medical records). 
15.10. 
Study Completion 
Aptinyx requires the following data and materials be completed before a study can be considered 
terminated or completed: source documents, study drug reconciliation activities, study 
procedures and assessments are source verified. 
15.11. 
Confidentiality 
Personal study subject data collected and processed for the purposes of this study should be 
managed by the investigator and his/her staff with adequate precautions to ensure the 


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confidentiality of personal health information (PHI), and in accordance with applicable national 
and/or local laws and regulations on PHI protection. 
Monitors, auditors, and other authorized agents of Aptinyx, the IRB approving this research, and 
medical records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the subjects, to the extent permitted by the law and regulations. In any 
presentation of the results of this study at meetings or in publicati
remain confidential. 
15.12. 
Compensation, Insurance, and Indemnity 
Information regarding compensation, insurance, and indemnity is addressed in the Clinical Trial 
Agreement. 
15.13. 
Financial Disclosure 
The investigator(s) are responsible for providing financial disclosure(s) in covered clinical 
studies. Principal investigators and sub-investigators are required to disclose applicable financial 
information, and to promptly update Aptinyx with any relevant changes throughout the study and 
for 1 year after study completion. 
15.14. 
Records Retention 
According to US Investigational New Drug regulations (21 CFR 312.62), records and documents 
pertaining to the conduct of this study and the distribution of study drugs including, but not 
limited to, source documents, case report forms, ICFs, clinical laboratory test results, and drug 
inventory records must be retained. These records will be kept on file by the principal 
investigator for 2 years after a marketing application is approved for the drug for the indication 
for which it is being studied. If no application is filed or approved, these records must be kept for 
2 years after the investigation has been discontinued and the FDA has been notified. Per ICH 
guidelines, documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. Aptinyx will notify the investigator when 
records and documents no longer need to be retained. No study records should be destroyed 
without prior authorization. 
15.15. 
Publication Policy 
The publication policy is outlined in the Clinical Trial Agreement. 


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16. 
REFERENCES 
Almli 2014 
Almli LM, Fani N, Smith AK, Ressler KJ. Genetic approaches to 
understanding post-traumatic stress disorder. Int J 
Neuropsychopharmacol. 2014;17:355-370. 
APA 2013 
American Psychiatric Association. Diagnostic and Statistical Manual of 
Mental Disorders. 5th ed. American Psychiatric Publishing: Arlington, 
VA; 2013.  
Atkins 2017 
Atkins, A.S., Tseng, T., Vaughan, A., Twamley, E.W., Harvey, P; 
Narasimhan, M.; Patterson, T. & Keefe, R.S.E. (2017). Validation of 
the tablet-administered Brief Assessment of Cognition (BAC Symbol 
Coding).  Schizophr Res 2017;181, 100 106. 
Baer 2013 
Baer L, and Ivanova A. When should the sequential parallel 
comparison design be used in clinical trials? Clin Invest. 2013;3:823-
833. 
Banerjee 2017 
Banerjee SB, Morrison FG , and Ressler KJ: Genetic approaches for the 
study of PTSD: Advances and challenges. Neurosci Lett. 2017 May 10; 
649: 139 146
Berger 2009 
Berger W, Mendlowicz MV, Marques-Portella C, Kinrys G, Fontenelle 
LF, Marmar CR, Figueira I. Pharmacologic alternatives to 
antidepressants in posttraumatic stress disorder: a systematic review. 
Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:169-80. 
Bjelland 2002 
Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the 
Hospital Anxiety and Depression Scale. An updated literature review. J 
Psychosom Res. 2002;52:69-77. 
Blevins 2015 
Blevins CA, Weathers FW, Davis MT, Witte TK, Domino JL. The 
Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5): 
Development and Initial Psychometric Evaluation. J Trauma Stress. 
2015;28:489-498. 
Buysse 1989 
Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The 
Pittsburgh Sleep Quality Index: a new instrument for psychiatric 
practice and research. Psychiatry Res. 1989;28:193-213. 
Carlson 1993 
Carlson EB, Putnam FW. An update on the Dissociative Experience 
Scale. Dissociation. 1993;6:16-27. 






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PTSD prevalence using DSM-IV and DSM-5 criteria. J Trauma Stress. 
2013;26:537-47. 
Luchkina 2018 
Luchkina NV, Bolshakov VY. Mechanisms of fear learning and 
extinction: synaptic plasticity-fear memory connection. 
Psychopharmacology (Berl). 2018 Nov 10. [epub ahead of print] 
Malec 2007 
Malec JF, Brown AW, Leibson CL, Flaada JT, Mandrekar JN, Diehl 
NN, Perkins PK. The Mayo Classification System for traumatic brain 
injury severity. Journal of Neurotrauma. 2007;9:1417-1424. 
Paoletti 2007 
Paoletti P, Neyton J. NMDA receptor subunits: function and 
pharmacology. Curr Opin Pharmacol. 2007;7:39-47. 
Pole 2007 
Pole N. The psychophysiology of posttraumatic stress disorder: a meta-
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Radulovic 2018 
Radulovic J, Ren LY, Gao C. N-Methyl D-aspartate receptor subunit 
signaling in fear extinction. Psychopharmacology (Berl). 2018 Sep 20. 
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Ravindran 2009 
Ravindran LN, Stein MB.  Pharmacotherapy of PTSD: premises, 
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Samuelson 2006 
Samuelson KW, Neylan TC, Metzler TJ, Lenoci M, Rothlind J, Henn-
Haase C, Choucroun G, Weiner MW. Marmar CR. Neuropsychological 
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Neuropsychology. 2006;20:716-726. 
Sheehan 2014 [a] 
Sheehan DV, Giddens JM, Sheehan IS. Status update on the 
Sheehan-Suicidality Tracking Scale (S-STS) 2014. Innov Clin 
Neurosci. 2014;11(9-10):93-140. 
Sheehan 2014 [b] 
Sheehan DV, Alphs LD, Mao L, et al. Comparative validation of the S-
STS, the ISST-Plus, and the C-SSRS for assessing the Suicidal 
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Neurosci. 2014;11(9-10):32-46. 
Sheehan 2008 
Sheehan KH, Sheehan DV. Assessing treatment effects in clinical trials 
with the discan metric of the Sheehan Disability Scale. Int Clin 
Psychopharmacol. 2008;23:70-83. 
Sherin 2011 
Sherin JE, Nemeroff CB.  Post-traumatic stress disorder: the 
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Steckler 2012 
Steckler T, Risbrough V. Pharmacological treatment of PTSD  
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Tamura 2011 
Tamura RN, Huang X, Boos DD. Estimation of treatment effect for the 
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Tsai GE. Ultimate translation: developing therapeutics targeting on the 
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Weathers, FW, Litz BT, Keane, TM, Palmieri, PA, Marx BP, Schnurr 
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Utzon-Frank N, Breinegaard N, Bertelsen M, Borritz M, Eller NH, 
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Zigmond AS, Snaith RP. The hospital anxiety and depression scale. 
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17. 
APPENDIX A: MAYO TBI SEVERITY CLASSIFICATION 
SYSTEM 
A.  Classify as Moderate-Severe (Definite) TBI if one or more of the following criteria apply:  
1. Death due to this TBI 
2. Loss of consciousness of 30 minutes or more 
3. Post-traumatic anterograde amnesia of 24 hours or more 
4. Worst Glasgow Coma Scale full score in first 24 hours <13 (unless invalidated upon 
review, e.g., attributable to intoxication, sedation, systemic shock)  
5. One or more of the following present: 
 Intracerebral hematoma 
 Subdural hematoma 
 Epidural hematoma 
 Cerebral contusion 
 Hemorrhagic contusion 
 Penetrating TBI (dura penetrated) 
 Subarachnoid hemorrhage 
 Brain Stem injury 
B. If none of criteria A apply, classify as Mild (Probable) TBI if one or more of the following 
criteria apply: 
1. Loss of consciousness of momentary to less than 30 minutes  
2. Post-traumatic anterograde amnesia of momentary to less than 24 hours  
3. Depressed, basilar or linear skull fracture (dura intact) 
C. If none of Criteria A or B apply, classify as Symptomatic (Possible) TBI if one or more of 
the following symptoms are present: 
 Blurred vision 
 Confused (mental state changes) 
 Dazed 
 Dizziness 
 Focal neurologic symptoms 
 Headache 
 Nausea 
 
 

SAP_001.pdf: 
NCT04044664 
NYX-783-2004 
A Study to Evaluate the Safety and Efficacy of NYX-783 in 
Subjects with Post-Traumatic Stress Disorder 
SAP 
18 Sept 2020 


 
Version Final 1.1    |    18-Sep-2020    |    
 
 Page 1 of 33 
Sponsor 
Aptinyx 
Protocol Title: 
A Study to Evaluate the Safety and Efficacy of NYX-783 in 
Subjects with Post-Traumatic Stress Disorder 
Protocol Number: 
NYX-783-2004 
 
 
Document Version: 
Final 1.1 
Document Date: 
18SEP2020 
Approvals 


 
Version Final 1.1    |    18-Sep-2020    |    
 
 Page 2 of 33 
Document History 
Version 
Date 
Author 
Description 
Final 1.0 
04AUG2020 
 Initial Version 
Final 1.1 
18SEP2020 
 
-
-Add COVID-19 impact analysis
-Update on compliance


 
Version Final 1.1    |    18-Sep-2020    |    
 
 Page 3 of 33 
Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
List of Tables .................................................................................................................................. 4 
1.
Overview ............................................................................................................................. 5 
2.
Study Objectives and Endpoints ......................................................................................... 5 
2.1. 
Study Objectives ........................................................................................................... 5 
2.1.1. Primary Objective ......................................................................................................... 5 
2.1.2. Secondary Objectives.................................................................................................... 6 
2.1.3. Exploratory Objectives ................................................................................................. 6 
2.2. 
Study Endpoints ............................................................................................................ 7 
2.2.1. Efficacy Endpoints ........................................................................................................ 7 
2.2.2. Safety Endpoints ........................................................................................................... 8 
3.
Overall Study Design and Plan ........................................................................................... 8 
3.1. 
Overall Design .............................................................................................................. 8 
3.2. 
Sample Size and Power ................................................................................................. 8 
3.3. 
Study Population ........................................................................................................... 8 
3.4. 
Treatments Administered .............................................................................................. 8 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................... 8 
3.6. 
Blinding and Unblinding............................................................................................... 9 
3.7. 
Schedule of Events ........................................................................................................ 9 
4.
Statistical Analysis and Reporting .................................................................................... 12 
4.1. 
Introduction ................................................................................................................. 12 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 12 
5.
Analysis Populations ......................................................................................................... 13 
6.
General Issues for Statistical Analysis .............................................................................. 14 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 14 
6.1.1. Baseline ....................................................................................................................... 14 
6.1.2. Adjustments for Covariates......................................................................................... 14 
6.1.3. Handling of Dropouts or Missing Data ....................................................................... 14 
6.1.4. Derived Variables ....................................................................................................... 15 
7.
Study Patients/Subjects and Demographics ...................................................................... 19 
7.1. 
Disposition of Patients/Subjects and Withdrawals ..................................................... 19 
7.2. 
Protocol Violations and Deviations ............................................................................ 19 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 20 
7.4. 
Exposure and Compliance .......................................................................................... 20 


 
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8.
Efficacy Analysis .............................................................................................................. 21 
8.1. 
Primary Efficacy Analysis .......................................................................................... 21 
8.1.1. CAPS-5 ....................................................................................................................... 21 
8.1.2. run;Primary Efficacy- Sensitivity Analysis ............................................................. 22 
8.2. 
Secondary Efficacy Analysis ...................................................................................... 23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.
Safety and Tolerability Analysis ....................................................................................... 24 
9.1. 
Adverse Events ........................................................................................................... 24 
9.2. 
Adverse Events of Interest .......................................................................................... 25 
9.2.1. Adverse Events Leading to Discontinuation of Study ................................................ 25 
9.2.2. Deaths and Serious Adverse Events ........................................................................... 26 
9.3. 
S-STS .......................................................................................................................... 26
9.4. 
Clinical Laboratory Evaluations ................................................................................. 26 
9.5. 
Vital Signs and Physical Examination ........................................................................ 27 
9.6. 
Electrocardiograms ..................................................................................................... 28 
9.7. 
Concomitant Medication ............................................................................................. 28 
10.
Other Planned Analysis..................................................................................................... 29 
10.1. Pharmacokinetic Analysis ........................................................................................... 29 
10.2. COVID-19 Assessment Impact................................................................................... 29 
11.
Changes from Protocol Planned Analysis......................................................................... 29 
12.
References ......................................................................................................................... 30 
13.
Tables, Listings, and Figures ............................................................................................ 31 
14.
Appendix 1: PSQI Derivation ........................................................................................... 32 
List of Tables 
Table 1: Schedule of Events ......................................................................................................... 10 
Table 2 PCS criteria for lab tests .................................................................................................. 26 
Table 3 PCS criteria for vital signs ............................................................................................... 27 


 
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1.
Overview
This statistical analysis plan (SAP) describes the planned analysis and reporting for Aptinyx 
protocol number NYX-783-2004 (A Study to Evaluate the Safety and Efficacy of NYX-783 in 
Subjects with Post-Traumatic Stress Disorder), dated 01-May-2020 amendment 3. Reference 
materials for this statistical plan include the protocol and the accompanying sample data 
collection documents. Operational aspects related to collection and timing of planned clinical 
assessments are not repeated in this SAP unless relevant to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials1. All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association2 and the Royal Statistical Society3, 
for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to any 
unblinded inferential or descriptive analysis of data pertaining to Aptinyx’s study NYX-783-
2004. 
2.
Study Objectives and Endpoints
2.1. 
Study Objectives 
The overarching goal of this exploratory study is to investigate the safety and tolerability of 
NYX-783 in a Post-Traumatic Stress Disorder (PTSD) population, and to characterize the 
response profile of PTSD symptoms to NYX-783 treatment, as assessed by the intrusion, 
avoidance, and negative alterations in cognition and mood, and arousal & reactivity subscores as 
well as the total score on the Clinician-Administered PTSD Scale for the Diagnostic and 
Statistical Manual of Mental Disorders, 5th edition (CAPS-5)  
2.1.1. 
Primary Objective 
The primary objective is to assess the effects of NYX-783 compared to placebo on reducing the 
severity of PTSD symptoms as measured by the Clinician-Administered PTSD Scale for the 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition (CAPS-5).  


 
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2.1.2. 
Secondary Objectives 
The secondary objectives are 

To assess the effect of NYX-783 compared to placebo in the following outcomes: a)
change in symptoms of PTSD as measured by the PTSD-Checklist for DSM-5 (PCL-5),
b) change in sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI)
Global Score, and c) change in cognitive function as measured by the Symbol Coding
from the Brief Assessment of Cognition (BAC Symbol Coding).

To assess the effect of NYX-783 compared to placebo in the change in global clinical
severity of PTSD symptoms as measured by the Clinical Global Impressions-Severity
(CGI-S) scale.

To compare NYX-783 vs. placebo in the change in levels of anxiety and depression as
measured by the Hospital Anxiety and Depression Scale (HADS).

To assess the safety and tolerability of NYX-783 compared to placebo.
2.1.3. 
Exploratory Objectives 
The exploratory objectives are 


 
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2.2. 
Study Endpoints 
2.2.1. 
Efficacy Endpoints 
2.2.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the change in CAPS-5 total score and subscores 
following 4 weeks of treatment in each respective Stage (Stage 1 [baseline to Week 4] and Stage 
2 [Week 4 to Week 8]) .The primary endpoint will be evaluated using the weighted combination 
of the estimated treatment effects from stage-specific models. 
2.2.1.2. 
Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints of this study include the following 

Change in symptoms of PTSD as measured by the PCL-5 following 4 weeks of treatment
in each respective Stage (Stage 1 [baseline to Week 4] and Stage 2 [Week 4 to Week 8])

Change in sleep quality as measured by the PSQI Global Score and the PSQI Addendum
for PTSD (PSQI-A) Global Score following 4 weeks of treatment in each respective
Stage (Stage 1 [baseline to Week 4] and Stage 2 [Week 4 to Week 8])

Change in cognitive function as measured by the Symbol Coding from BAC Symbol
Coding following 4 weeks of treatment in each respective Stage (Stage 1 [baseline to
Week 4] and Stage 2 [Week 4 to Week 8])

Change in CGI-S following 4 weeks of treatment in each respective Stage

Change in Hospital and Anxiety Depression Scale for Anxiety (HADS-A) and Hospital
and Anxiety Depression Scale for Depression (HADS-D) subscores following 4 weeks of
treatment in each respective Stage (Stage 1 [baseline to Week 4] and Stage 2 [Week 4 to
Week 8])
2.2.1.3. 
Exploratory Efficacy Endpoint(s) 
The exploratory efficacy endpoint of this study include the following: 


 
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2.2.2. 
Safety Endpoints 
2.2.2.1. 
Secondary Safety and Tolerability Endpoint(s) 
Safety and tolerability endpoints for this study will be based on: incidences of adverse events 
(AEs) and any changes in vital signs, physical examination findings (including weight), 12-lead 
ECG results, clinical laboratory values, and suicidality assessments (Sheehan Suicidality 
Tracking Scale [STS-S]). 
3.
Overall Study Design and Plan
3.1. 
Overall Design 
3.2. 
Sample Size and Power 
Response to treatment will be measured using the CAPS-5 score change from baseline to Week 4 
(Stage 1) and from Week 4 to Week 8 (Stage 2). If the effect size of NYX-783 is in line with the 
effect sizes observed in similar historical studies, this study is powered at approximately 80% to 
reject the null hypothesis at a one-sided α = 0.10 level for any single specified efficacy 
comparison. The sample size estimate (n=156) assumes a 15% dropout during Stage 1 and 11% 
dropout during Stage 2, based on the treatment comparisons specified for Amendment 2 of the 
protocol. The sample size may be adjusted if the actual dropout rate exceeds this assumption; 
patients randomized based on earlier protocol versions will be included in data listings, but will 
not be included in data summaries or inferential analyses. 
3.3. 
Study Population 
The study population consists of adult subjects diagnosed with Post-Traumatic Stress Disorder 
(PTSD). The goal of the study is to recruit subjects with a clearly identifiable primary traumatic 
event during adulthood. 
3.4. 
Treatments Administered 
NYX-783 is formulated for this study as 50 mg, and 10 mg capsules for oral administration. 
Matching placebo capsules for oral administration are also provided. The study will be 
conducted as a placebo-controlled, double-blind study. The Treatment period will be conducted 
in 2 Stages to examine the efficacy and safety of NYX-783 compared to placebo in the treatment 
of PTSD symptoms.  
3.5. 
Method of Assigning Subjects to Treatment Groups 
On Day 1, subjects will be randomized to receive placebo, NYX-783 50 mg QD, or NYX-783 10 mg 
QD in a 4:1:1 ratio, respectively. Placebo responders and placebo non-responders (CAPS-5 total 
score reduction from baseline ≤35% and total CAPS-5 total score ≥26 at Week 4) will be identified at 
the completion of Stage 1 (Weeks 1-4) in a blinded fashion; then, each group (i.e., placebo 
responders and placebo non-responders) will be re-randomized in a blinded fashion to placebo, 
NYX-783 50 mg QD, NYX-783 10 mg QD in a 3:2:2 ratio, respectively, for Stage 2 (Weeks 4-8) 


 
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treatment. Subjects who received active treatment during Stage 1 will receive placebo in Stage 2. 
Figure 1: Study Design 
Figure from protocol Section 7.1 Overall Study Design and Plan: Description. 
3.6. 
Blinding and Unblinding 
The study will be conducted as a placebo-controlled, double-blind study.  The authorized 
investigative site personnel will obtain blinded kit assignments using an interactive response 
technology (IRT) system. The blinded dose information may only be obtained by the investigator (or 
designee) in an emergency, where the information may have an impact on further treatment decisions 
or aid in the emergency treatment of the subject. 
3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 1 


 
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Table 1: Schedule of Events 


 
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4.
Statistical Analysis and Reporting
4.1. 
Introduction
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, 
and graphical representations will be performed primarily using SAS (release 9.4 or 
higher).  
Continuous (quantitative) variable summaries will include the number of subjects (n) 
with non-missing values, mean, standard deviation (SD) (or standard error (SE) if 
appropriate), median, minimum, and maximum. Confidence intervals (CIs) will be added 
if appropriate.  
Categorical (qualitative) variable summaries will be based on frequencies and 
percentages.  
Unless stated otherwise, efficacy data for endpoints included in mixed effects repeated 
measures model (MMRM) analyses (groups [1], [2], [3], [7], [8], and [9]) will be 
summarized by visit and treatment group (Placebo, NYX-783 10 mg QD, NYX-783 50 
mg QD) to allow for summary data treatment comparisons as per model inference.  
Efficacy data for Stage 2 groups [4], [5], [6], [10], and [11] will be presented separately. 
Unless stated otherwise, safety data will be summarized by Stage and treatment group 
(Placebo [as Placebo Only and Placebo Stage 2, separately], NYX-783 10 mg QD, NYX-
783 50 mg QD); data presented by visit will be displayed based on the treatment group 
which applies at onset for AEs/collection date. 
The minimum and maximum will be reported with the same degree of precision (i.e., the 
same number of decimal places) as the observed data. Measures of location (mean and 
median) will be reported to 1 degree of precision more than the observed data and 
measures of spread (SD, SE) will be reported to 2 degrees of precision more than the 
observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all statistical tests will be conducted at a 0.10 significance 
level using one-sided tests and p-values will be reported. Corresponding 80% CIs (the 
interpretation of which is equivalent to a one-sided 90% CI when restricted to a single 
bound) will be presented. 
4.2. 
Interim Analysis and Data Monitoring 
No interim analyses for review of efficacy are planned for this study. 
Data and Safety Monitoring Board (DSMB) will be responsible for the periodic review of 
available study data. Refer to the DSMB Charter for additional details of deliveries and 
timings of DSMB meetings. 


 
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5.
Analysis Populations
The following analysis populations are planned for this study. As per protocol, the 50mg 
QW group will not be included in analysis population. Main efficacy and safety data for 
those subjects will be listed.  

Safety Population (SAF): The SAF consists of all randomized subjects who
receive at least one dose of study drug (active or placebo). SAF inclusion and
reporting will be evaluated separately for each Stage so there will be a safety set
defined for Stage 1 (randomized subjects who receive at least one dose of study
drug (active or placebo) during Stage 1 and a safety set defined for Stage 2
(randomized subjects who receive at least one dose of study drug (active or
placebo) during Stage 2). Subjects in the SAF will be analyzed according to the
treatment they actually received. For definition of actual treatment see Section
6.1.4. Unless otherwise specified, all safety analyses will be conducted on the
Safety Population.

Intent-To-Treat (ITT) Population: The ITT Population will consist of all
randomized subjects. Subjects in the ITT Population will be analyzed according to
the treatment they are assigned at randomization. The primary efficacy analysis
will be performed on the ITT Population. Unless otherwise specified, all other
efficacy analyses also will be conducted on the ITT Population.  Subject data for
each Stage is included in ITT analyses based on the availability of randomization
assignments. As efficacy results are also presented by Stage, an ITT Stage 1
population will be created (all randomized subjects) and an ITT Stage 2
population will be created (all randomized subjects entering Stage 2).

Modified Intent-To-Treat (mITT) Population: The mITT Population will
consist of all ITT subjects who received at least 2 weeks of study drug and had at
least one post-dose measurement of CAPS-5 (CAPS-5 questionnaire must be
complete.) Subjects in the mITT Population will be analyzed according to the
treatment they are assigned at randomization. This analysis population will serve
as sensitivity analysis for primary efficacy analysis. As efficacy results are also
presented by Stage, a mITT Stage 1 population will be created (all mITT subjects)
and a mITT Stage 2 population will be created (all mITT subjects entering Stage
2).

Per-Protocol Population (PP): The PP Population will consist of all ITT
Population subjects who do not incur a major protocol violation that would
challenge the validity of their data (including compliance assessment).  This
population will be used to evaluate the sensitivity of the primary efficacy analysis.
For the same reason as ITT population, a PP Stage 1 population (subjects from
ITT without any major protocol deviation) and a PP Stage 2 population (subjects
from ITT without any major protocol deviation entering Stage 2) will be created.


 
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6.
General Issues for Statistical Analysis
6.1. 
Statistical Definitions and Algorithms
6.1.1. 
Baseline 
The last non-missing observation recorded prior to the first dose of study drug (NYX-783 
or placebo) will be used as the baseline observation for all calculations of change from 
baseline for Stage 1 data. For purposes of safety evaluation, subjects that are re-
randomized in Week 4, the last non-missing observation before Week 4 will be used as 
baseline for Stage 2 data, with exception of groups [4] and [7] as referenced in Figure 1.   
Changes from baseline for these groups will be based on the Stage 1 baseline given their 
study intervention remained unchanged.   
For purposes of efficacy analyses, baseline values for Stage 2 data within all groups [4], 
[5], [6], [7], [8], [9], [10], and [11] will be based on the last assessment prior to first dose 
of study drug in Stage 2. 
6.1.2. 
Adjustments for Covariates 
The primary efficacy endpoint will be evaluated using the weighted combination of the 
estimated treatment effects from the Stage-specific mixed models for repeated measures 
(MMRM). The MMRM models will include variables for treatment group, visit, 
treatment-by-visit interaction term, baseline CAPS-5 score and baseline-by-visit 
interaction. 
6.1.3. 
Handling of Dropouts or Missing Data 
Missing efficacy data will be handled using MMRM’s maximum likelihood method. No 
additional imputation is planned to be performed. 
In general, there will be no substitutions made to accommodate missing data points. All 
data recorded on the case report form (CRF) will be included in data listings that will 
accompany the clinical study report. 
6.1.3.1. 
Handling of Missing Date Values 
Partial or Missing Dates 
The following conventions will be used to impute missing portions of dates for AEs.  An 
AE with missing or incomplete start dates will be reported as treatment emergent for both 
Stages unless data provided clearly indicates an onset as occurring within a particular 
Stage (e.g. a month specific to Stage 1) or outside of the treatment-emergent period (e.g. 
year provided is prior to first dose of study drug) as defined in Section 6.1.4.   
Partially available concomitant medication dates will be handled similarly with respect to 
identifying use as concomitant as defined in Section 9.7. 


 
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6.1.3.2. 
Imputation Methods and Sensitivity Analysis  
Observed cases, without imputation, will be used for the majority of analyses. 
If the relationship of an AE is missing, it will be considered possibly-related unless the 
event is not considered treatment-emergent as defined in Section 9.1. Missing AE 
severity will be coded as severe.  
6.1.4. 
Derived Variables 

Actual treatment received: After unblinding, all blister cards dispensed will be
unblinded. Actual treatment will be defined by stage as the higher dose received
at least one time (one capsule) during the corresponding stage (50mg > 10mg >
Placebo).

CAPS-5 (Clinician Administered PTSD Scale for DSM-5) = The CAPS-5 is a 30-
item structured interview for diagnosis and assessment of PTSD. CAPS-5 scores
are derived at data-management level. CAPS-5 total symptom severity score is
calculated by summing severity scores for the 20 DSM-5 PTSD symptoms.
Similarly, CAPS-5 symptom cluster severity scores (subscores) are calculated by
summing the individual item severity scores for symptoms corresponding to a
given DSM-5 cluster: Criterion B, intrusions (items 1-5); Criterion C, avoidance
(items 6-7); Criterion D, negative alterations in cognitions and mood (items 8-14);
and, Criterion E, alterations in arousal and reactivity (items 15-20).
The assessor combines information on frequency and intensity of an item into a
single severity rating (0-4) for each of the 20 DSM-5 PTSD symptoms, with a
maximum possible score of 80 points. A higher score corresponds to more severe
PTSD.

PCL-5 (PTSD Checklist for DSM-5) = The PCL-5 is a 20-item self-report
measure that assesses PTSD symptoms experienced over the last week or month
according to DSM-5 criteria. PCL-5 score is derived at data-management level.
Items assess symptoms across 4 symptom clusters of PTSD (re-experiencing,
negative mood, avoidance, and hyperarousal) on a 0-4 point Likert scale. Total
scores range from 0-80. The “since last week” version should be used after
screening.  A higher score corresponds to more severe PTSD. PCL-5 response is
defined as decrease (from baseline) of 10 points at the end of each stage (week
4/week 8) [6].If total sore is missing at one time point (Week4/Week8) then
response will be set to missing. If patient early terminated and assessment at
Week 4 or Week 8 missing then patient will be a non-responder. Baseline defined
as in section 6.1.1.

PSQI= The Pittsburgh Sleep Quality Index (PSQI) 8 is a questionnaire to assess
sleep quality and disturbances over a 1-month time interval. The score and
subscores on this scale are derived by biostatistics. A total of 19 items are self-rated,
15 objective (about frequency of sleep disturbances and subjective sleep quality) and
4 subjective (typical bedtime, wake-up time, sleep latency and sleep duration) items.
These 19 items generate 7 component scores: subjective sleep quality, sleep


 
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latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping 
medication, and daytime dysfunction, each of which ranges from 0: no difficulty to 
3: severe difficulty. A global score >5 indicates significant sleep disturbance. The 
algorithm to calculate PSQI score is detailed in Appendix 1: PSQI Derivation. If 
response to any of these 19 items (except question 5J, if response to 5J is missing 
then it can be imputed to 0)) is missing, then PSQI score for that subject will be 
null.  

PSQIA= This is the addendum to the PSQI assessment assessing disruptive
nocturnal behavior (DNB) in PTSD subjects based on 7 types of behaviors: 1) hot
flashes, 2) general nervousness, 3) memories or nightmares of traumatic
experience, 4) severe anxiety or panic, not related to traumatic memories, 5) bad
dreams, not related to traumatic memories, 6) episodes of terror or screaming
during sleep without fully awakening and 7) episodes of acting out dreams, such as
kicking, punching, running, or screaming. Each DNB is rated on a scale of 0-3 (0:
not in the past month, 1: less than once a week, 2: once or twice a week, and 3:
three or more times a week), with a global score range of 0-21. Lower scores
represent less disruptive behavior.  PSQIA and is calculated by biostatistics in the
following way:
o
Calculate number of non-missing monthly behavior scores responses. Call
this count PSQIACNT. If PSQIACNT >=6 then PSQIA score =
(PSQIASUM/PSQIACNT)*7 else set value to null. The score can range
from 0 to 21.

BAC Symbol Coding (Symbol Coding from the Brief Assessment of Cognition) =
The Brief Assessment of Cognition (BACS) is a pen-and-paper cognitive
assessment. BAC Symbol Coding is delivered on a Pathway tablet and offers a
sensitive measure of processing speed. Participants are provided a key and asked to
fill in the corresponding numbers beneath a series of symbols as quickly as possible
within 90 seconds. The assessment takes approximately 3-5 minutes to complete,
including instructions and practice. The measure represents the correct number of
numerals (0-110); a higher count reflects a higher function.

CGI-S (Clinical Global Impressions-Severity) = The CGI-S scale assesses the
global severity of illness and change in clinical condition over time, and subjects
are rated from 1 (normal, not at all ill) to 7 (among the most extremely ill
subjects).

HADS (Hospital and Anxiety Depression Scale) =The HADS is a self-assessment
tool consisting of two subscales, one for anxiety (HADS-A) and one for
depression (HADS-D). Each subscale consists of 7 items that are scored from 0-3,
for a maximum score of 21 for either anxiety or depression; higher scores
represent more severe anxiety or depression. HADS score are derived by
biostatistics. HADS-A and HADS-D total scores will be computed only if the 7
items in each subscale are complete.


 
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

DES-II (Dissociative Experiences Scale-II) =The Dissociative Experiences Scale-
II (DES-II) is a 28 item, self-report questionnaire that measures a wide variety of
dissociative experiences, from normal (e.g., day-dreaming) to pathological
(depersonalization). The DES-II score is derived by data-management. Subjects
rate the percentage of time they have the experience, from 0% to 100% (in
increments of 10), the score is the sum of the individual items divided by 28. DES-
II total score will be computed only if all the 28 individual questions are non-
missing.

 
 
 
 
 
 
 
 
 

Sheehan Suicidality Tracking Scale (S-STS) = The standard version of the S-STS
is a 16-item scale that assesses the seriousness of suicidality phenomena on a
Likert-type scale (0 to 4) ranging from 0 = “not at all” to 4 = “extremely.” The S-
STS score will be derived by data-management. The S-STS accommodates a wide
range of timeframes. In clinical trials, the frequently used variants are “in the past
week”, “in the past month”, “since the last visit”, “lifetime look back”, and “in the
past day.” In this study, during screening, "in the past month" version is used. For
all the other visits "since the last visit" version of the S-STS is used.

Subjects with high S-STS scores- Subjects with a score of 3 or 4 on any questions
2, 3, 4, 5, 6, 7, 8 or 13 in the S-STS questionnaire will be flagged.


 
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
Placebo Non-responder = A Placebo Non-responder must satisfy the following
criteria.
o
Randomized to placebo in Stage 1 of the study
o
Week 4 whose CAPS-5 total score reduction from baseline [Day 1] ≤35%
and Week 4 CAPS-5 total score is ≥ 26

Change from baseline = value at current visit– value at baseline (as defined in
Section 6.1.1).

TEAE = this is any adverse event with an onset date on or after first dose of study
drug through 7 days after last dose of study drug. The Stage in which an event is
considered treatment emergent will also be determined based on the relative onset
timing against the first dose of Stage-specific study drug. Adverse Events with an
onset during the 7 days after end of Stage 2 will be part of Stage 2.

Duration of reported treatment period (years):  For displays of TEAEs, it may be
necessary to standardize rates of events due to variable treatment reporting periods.
For Stage-specific reporting, durations are computed based on (the date of the last
dose of study drug - the date of the first dose of Stage-specific study drug + 1).

Treatment Related AEs= For each reported AE/SAE, the investigator assesses the
relationship to study drug and categorize them into the following categories: Not
Related = Unrelated and Unlikely Related, Related = Possibly Related and Probably
Related). If an assessment is missing, then it will be treated as Related.

Sexual Abuse= this is used to flag subjects who were victims of sexual abuse. If the
medical history term preferred term is ‘Sexual Abuse’ or ‘Victim of Sexual Abuse’
then those subjects will be flagged as victim of sexual abuse.

Time since start of Trauma (months) = date of randomization - date of index
traumatic event (from medical history mhterm equals PTSD or POST
TRAUMATIC STRESS DISORDER)

High Avoidance Scores= Subjects with scores >=3 in Q6 or Q7 or Q13, avoidance
related 
questions 
in 
CAPS-5 
questionniare 
will 
be 
flagged. 
Data
Adjustments/Handling/Conventions
All collected data will be presented in listings. Data not subject to analysis according to 
this plan will not appear in any tables or graphs but will be included only in the data listings. 
All P values will be displayed in four decimals and rounded using standard scientific 
notation (e.g., 0.XXXX). If a p value less than 0.0001 occurs it will be shown in tables as 
<0.0001. 


 
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Adverse events will be coded using the MedDRA version 21.1 thesaurus. 
7.
Study Patients/Subjects and Demographics
Unless specified otherwise, summaries defined in this section will be presented by Stage 
based on treatment groups defined in Section 4.1 and in total within each reporting 
period. 
7.1. 
Disposition of Patients/Subjects and Withdrawals 
The summary of subject enrollment and disposition will display the number of subjects 
who are screen failures (Stage 1), the number and percentage of subjects randomized, 
treated, completed and discontinued in each Stage. Specific reasons for discontinuation 
will be summarized according to the reasons listed on the eCRF. Percentages will be 
calculated based on randomized subjects in each Stage and overall. 
The number of subjects enrolled, screen failures, randomized, treated and entering Stage 
2 will be also tabulated by site.  This summary will be reproduced Over All Stages.  
For each stage and overall, each analysis population will be described. 
All subject disposition data and analysis population details will be presented in data 
listings.  Screen failure data will also be listed. 
7.2. 
Protocol Violations and Deviations 
Prior to database lock, the protocol deviations will be reviewed for the following reasons: 

Standard study terminology deviation categories assigned

Severity (major versus minor) assigned

If a subject should be excluded from the PP population
Documentation will be put into place around the determination of patient population prior 
to lock and unblinding. 
After database lock it may be determined that additional protocol deviations occurred, but 
could not be known prior to database lock. For example, a subject receiving study drug 
for the wrong treatment arm (i.e., a treatment arm other than the one they were 
randomized to). As a result, any additional protocol deviations found after database lock 
will be included with previous protocol deviations and documented separately to ensure 
timing of deviation is identified. 
A subject listing will include the planned treatment arm, deviation category, protocol 
deviation, occurrence date with the corresponding study day, severity (major versus 
minor), and if the protocol deviation resulted in excluding a subject from the PP 
population. A frequency distribution table will be created to summarize only major 
protocol deviations by the assigned deviation categories. 


 
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7.3. 
Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristic data including gender, age, height, weight 
and BMI will be summarized using descriptive statistics. For the continuous variables, 
the number of non-missing values and the mean, standard deviation, minimum, median 
and maximum will be tabulated.  
Categorical data for age group, race, sex, ethnicity, family status, education and 
employment will be summarized by counts and percentages.  
Time since start of PTSD (months) will be summarized. Similar descriptive statistics will 
be used to summarize the baseline clinical measures such as CAPS-5, PCL-5, HADS, 
CGI-S, PSQI and PSQI-A.  
Treatment differences in subject characteristics at baseline (based on Stage 1 treatment 
groups), will be assessed using Chi-square test (or Fisher’s exact test in case Chi-square 
does not fit the data) for categorical variables and Type III sums of squares analysis of 
variance (ANOVA) for continuous variables. For continuous variables, in case normality 
is not assessed a Kruskall-Wallis test will be performed.  
These analyses will be performed on both the ITT Population using assigned treatment 
and SAF Population using actual treatment received for Stage 1 and Stage 2. For SAF 
Stage 1 analysis, actual treatment received during Stage 1 will be used for treatment 
group. For SAF Stage 2 analysis, actual treatment received during Stage 2 will be used 
for treatment group and placebo will be splitted in Placebo Only and Placebo Stage 2. 
The number and percentage of subjects reporting types of medical histories will be 
tabulated by MedDRA system organ class and preferred term (coded using MedDRA 
v.21.1). This analysis will be conducted by Stage 1 treatment groups for the SAF.
All baseline characteristics data, including medical and disease history, as well as 
diagnosis information, will be reported in data listings. 
7.4. 
Exposure and Compliance 
The first dose of study drug in Stage 1 will be administered orally at the investigative 
site. Subsequent study drug administration will be conducted on an outpatient basis. 
Stage 2 dosing begins the day after the Week 4 visit. Subjects will be instructed to take 1 
capsule per day with water. A digital video dosing verification system for self-
administration of investigational product (AiCure) was used to track capsule ingestion, 
and day and time of self-administration. This system is independent from EDC so a 
spreadsheet containing its information will be included in the statistical analysis of 
compliance. Cumulative counts for the total number of capsules dispensed; taken; 
returned and lost; subject compliance; as well as the duration of treatment will be 
summarized by actual treatment received (placebo [regardless of Stage 1 assignment], 
NYX-783 10 QD, and NYX-783 50 QD. The percentage of subjects who were compliant 
in each Stage will also be presented based on the SAF population. A subject will be 
considered compliant if between 80% and 120% of their expected dose had been taken. 
Exposure and compliance data will be listed. 


 
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8.
Efficacy Analysis
Unless specified otherwise, all efficacy analyses will be based on the ITT Population by 
treatment group (Placebo, NYX-783 50 mg and NYX-783 10 mg). 
8.1. 
Primary Efficacy Analysis 
The sequential parallel comparison design (SPCD) is an adaptive design that allows for 
re-randomization of placebo subjects (both "non-responders" and “responders”) from an 
initial stage of the study to placebo or active treatment in a subsequent stage of the trial. 
In this study, data from the “all-comers” population of Stage 1 arms [1 = placebo], [2 = 
NYX-783 50 mg QD], [3 = NYX 783 10 mg QD] and the subpopulations of “placebo 
non-responders” in Stage 2 arms [7 = placebo], [8 = NYX-783 50 mg QD], [9 = NYX 
783 10 mg QD] are pooled to yield a single p-value for treatment comparison. 
8.1.1. 
CAPS-5 
The primary efficacy endpoint is change in CAPS-5 total score and subscores following 4 
weeks of treatment in each respective Stage (Stage 1 [baseline to Week 4] and Stage 2 
[Week 4 to Week 8]). Changes from baseline for specific visits and treatment groups will 
be used for the comparison of NYX-783 to placebo as described in Section 6 (for 
specification of visit alignment) and Section 6.1.1 (for information on baseline 
derivations). Modeled data will consist of change from baseline data through Week 4 for 
all of those randomized to treatment arms 1, 2 or 3 for Stage 1; and change from Week 4 
assessment data for subjects randomized to arms 7, 8, or 9 for Stage 2.   
The primary efficacy endpoint will be evaluated using the weighted combination of the 
estimated treatment effects from the Stage-specific mixed models for repeated measures 
(MMRM). The MMRM models will include variables for treatment group, visit, 
treatment-by-visit interaction term, baseline CAPS-5 score as covariate, and baseline-by-
visit interaction. An unstructured covariance matrix will be used. If the model fails to 
converge with an unstructured covariance matrix other structures will be tried and the 
structure with the lowest corrected Akaike information criterion (AICC) will be used for 
the analysis. Full details will be included in the CSR. The Kenward-Roger approximation 
will be used to adjust the denominator degrees of freedom.  
The treatment effect will be assessed as the differences in least-squares mean (LS mean) 
changes from baseline to Week 4 (Stage 1) and from Week 4 to Week 8 (Stage 2) for the 
NYX-783 50 mg QD, NYX-783 10 mg QD, and placebo groups defined in Section 8.1. A 
pairwise comparison will be made between each of the NYX-783 arms and placebo.  
The treatment effect will be pooled across Stages 1 and 2 using pre-specified 0.6/0.4 
weighting for Stage 1/Stage 2.  
Combined inference is computed using the weighted linear combination of stage-wise 
test statistics4: 


 
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𝑍𝐶𝑜𝑚𝑏𝑖𝑛𝑒𝑑= 
0.6𝛿1̂ + 0.4𝛿2
̂ 
√0.62𝑉𝑎𝑟(𝛿1̂ ) + 0.42𝑉𝑎𝑟(𝛿2
̂)
Where, 𝛿1̂  is the estimated Stage 1 treatment effect and 𝛿2
̂ is the estimated Stage 2
treatment effect. The combined test statistic 𝑍𝑐𝑜𝑚𝑏𝑖𝑛𝑒𝑑 is used to compute the overall one 
sided treatment effect p-value.  
LS means, 80% CIs (the interpretation of which is equivalent to a one-sided 90% CI 
when restricted to a single bound), and SEs for the mean CAPS-5 scores by visit and 
treatment group within each Stage will be estimated based on the separate MMRM 
models. This inferential analysis will also be performed for estimation of the following 
mean CAPS-5 treatment differences within each Stage: 
•
placebo vs NYX-783 10mg QD
•
placebo vs NYX-783 50mg QD
•
placebo vs NYX-783 10mg QD + NYX-783 50mg QD
One-sided P-values for these Stage-specific differences will be reported based on 
individual t-tests but no formal statistical inferences are planned for these results. 
These analyses will be repeated for each subscore. 
Descriptive statistics for observed CAPS-5 total score, subscores and their relative 
changes from baseline will also be tabulated by study visit and treatment group as 
described in Section 4.1 for the groups specified in Section 8.1.  
CAPS-5 scores will also be presented graphically by treatment at each visit based on 
mean plots. 
The following pseudo SAS code will be used to implement the MMRM analyses 
proc mixed data=xxx ; 
 class trt avisit subjid; 
 model change = trt avisit trt*avisit caps5b caps5b*avisit 
/ s ddfm=kenwardroger 
 repeated avisit /subject = subjid type=un; 
 lsmeans avisit * trt / diff=all cl alpha=0.2 
run; 
8.1.2. Primary Efficacy- Sensitivity Analysis 
The following sensitivity analyses will be performed to assess the robustness of the 
results of the primary analyses and to test the assumptions of the MMRM model: 

The primary efficacy analyses will be repeated using the PP Population.


 
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
The primary efficacy analyses will be repeated using the mITT Population.

The treatment effect will be pooled across Stages 1 and 2 using 0.5/0.5 weighting
for Stage 1/Stage 2.
8.2. 
Secondary Efficacy Analysis
PCL-5 total score, PSQI score, PSQI-A score, BAC symbol coding, CGI-S scale, HADS-A 
scale, and HADS-D scale, will be analyzed based on the methods described in Section 8.1.1, 
using the endpoint appropriate baseline covariate.  
8.3. 
Exploratory Efficacy Analyses 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.5. 
Subgroup Analyses  
The primary efficacy endpoint will be described on the following subgroups 
1. Gender
2. Race (White, Non-white)
3. Time Since Trauma (≤ median and > median) , date of trauma from medical


 
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history where mhterm equals PTSD, POST TRAUMATIC STRESS DISORDER 
4. Marital Status (Married, Not Married)
5. Trauma type(Sexual Abuse (from medical history where preferred term in
“Sexual Abuse”,” Victim of Sexual Abuse)  vs. other)
6. Taken Pain Medication during study () at any point in the study (Yes, No). The
list of concomitant medications will be reviewed prior to database lock and pain
medications of interest will be identified for this analysis.
7. PSQI Sleeping Status (Good Sleeper total score <=5, Poor Sleeper total score >5)
at baseline (Day 1 only)
8. HADS-A and HADS-D Score categories (normal (0-7), borderline abnormal (8-
10) and abnormal (>=11))
9. Subjects with and without AEs of interest at any point during the study (Yes, No)
10. Subjects with high avoidance scores- Subjects with score 3,4 in avoidance
categories of CAPS5 Q6,7 or distant from other people, Q13.
9.
Safety and Tolerability Analysis
Safety will be evaluated from reported AEs, changes in clinical laboratory values, changes 
in vital signs, electrocardiogram (ECG) and physical examination results.  Safety data will 
be summarized by stage and group as described in Section 4.1. 
All safety analyses will be performed on the SAF. 
9.1. 
Adverse Events 
The number, percentage and incidence rate of subjects reporting treatment emergent AEs 
(TEAEs), grouped by MedDRA system organ class (SOC) and preferred term (PT) 
(coded using MedDRA v21.1), will be tabulated by Stage, and treatment group. In the 
case of multiple occurrences of the same TEAE within the same subject and Stage, a 
subject will only be counted once for each PT or SOC.  Similar methods will be used to 
provide summaries further reported by severity and relationship. In the summaries 
reporting severity and relationship to study medication the event with the maximum 
severity and strongest relationship will be reported, respectively. For these analyses, 
missing severity and relationship will be imputed as described in Section 6.1.3.2. 
The frequency, percentage, and incidence rate of subjects reporting TEAEs, will be 
reported as described for the following summaries: 

TEAEs by SOC and PT

TEAEs by SOC, PT, and maximum severity

Treatment-related TEAEs by SOC and PT

Treatment-related TEAEs by SOC, PT, and maximum severity
An overall summary of TEAEs, TEAEs leading to discontinuation of study, serious 
TEAEs, Severe or life-threatening TEAEs, and fatal AEs will be reported.  This summary 
will also be reported for treatment-related TEAEs.  Overall summaries for TEAEs and 


 
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treatment-related TEAEs by maximum severity will also be provided. The number of 
total events at each level of TEAE reporting will also be used in the calculation of 
incidence rate per subject-years of study participation given the specified Stage and 
reporting treatment period (total events/total patient-years included in the reported 
treatment period).  In general, the duration of the reported treatment period is based on 
the amount of time a subject has taken the assigned drug within each Stage of reporting 
for a specified treatment; this is described in more detail in Section 6.1.4. 
Missing and partially missing AE start and/or stop dates will be used to determine TEAE 
status for reporting, according to the specifications described in Section 6.1.5. 
In the AE data listings, all AEs will be displayed. AEs that are not treatment-emergent 
will be flagged. 
9.2. 
Adverse Events of Interest 
The following are AEs of interest. 

Suicidality (ideation or attempt)

Abuse and/or dependency events (drug & alcohol)

Dissociative experience events

Depression (or worsening depression)
The following AEs are also of potential clinical interest 

Eating disorder

Nightmares (or worsening nightmares)

Anxiety (or worsening anxiety)

Panic attack

Self-injurious behavior

Aggressive behavior toward others

Negative social events (e.g. loss of job, separation from significant other)
A summary of incidence rates (frequencies and percentages) by SOC, and preferred term 
will be prepared for all adverse event of interest listed above. The summary will be 
presented for each Stage as described in Section 9.1. 
9.2.1. 
Adverse Events Leading to Discontinuation of Study 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to 
discontinuation of study, by SOC, and preferred term will be prepared. The summary will 
be presented by each Stage, as described in Section 9.1. No inferential statistical tests will 
be performed. 
A data listing of AEs leading to withdrawal/discontinuation of study will also be 
provided, displaying details of the event(s) captured on the CRF. 


 
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9.2.2. 
Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
Serious adverse events will be listed and tabulated by SOC and PT; the summary will be 
presented by each Stage, as described in Section 9.1. A summary of fatal TEAEs will also 
be provided. 
9.3. 
S-STS
Data collected for S-STS will be summarized using descriptive statistics. Change from 
baseline will also be calculated and summarized in the same manner. All S-STS data will 
be provided in the data listings. 
A summary of subjects with a score of 3 or 4 on questions 2 to 8 and 13 will be presented 
by stage and treatment group.  
9.4. 
Clinical Laboratory Evaluations 
Laboratory test results from hematology, serum chemistry, and urinalysis will be 
summarized descriptively (counts and percentages for categorical parameters) by treatment 
group, Stage and time point as both observed values and change from baseline values. 
Proportion of subjects with values < LLN and >ULN by treatment group, Stage and time 
point will be presented in summary tables. 
The number of subjects with clinical laboratory values below, within, or above the normal 
range in relation to baseline will be tabulated for each clinical laboratory analyte by Stage 
and treatment group (bi-directional shift table) and visit. For those shift table, the most 
extreme post-baseline value will be used. 
Urine drug screen, alcohol test and urine pregnancy test results will be presented in listings. 
Potentially Clinically Significant (PCS) Laboratory Tests are defined as below  
Table 2 PCS criteria for lab tests 
Serum Chemistry 
Alkaline Phosphatase (ALP) 
> 2 x ULN
Serum Chemistry 
Alanine Aminotransferase (ALT) 
> 3 x ULN
Serum Chemistry 
Aspartate Aminotransferase (AST) 
> 3 x ULN
Serum Chemistry 
Blood Urea Nitrogen (BUN) 
> 1.5 x ULN
Serum Chemistry 
Creatinine 
>1.5 x Baseline or > 1.5 x ULN
Serum Chemistry 
Gamma-Glutamyl Transferase (GGT) 
> 3 x ULN
Serum Chemistry 
Lactate Dehydrogenase (LDH) 
> 3 x ULN


 
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Serum Chemistry 
Total Bilirubin 
> 2 x ULN
Hematology 
White Blood Cell Count 
≤ 2.8 10^9/L 
Hematology 
Absolute Neutrophils Count 
<1.5 10^9/L 
Frequency distributions of the clinical laboratory tests of interest listed above will 
summarized for PCS values at any post-baseline visit. 
Evaluation of potential Drug-Induced Serious Hepatotoxicity (eDISH) will also be done 
by plot. 
9.5. 
Vital Signs and Physical Examination 
Descriptive summaries of actual values and changes from baseline will be calculated for 
supine systolic blood pressure, supine diastolic blood pressure, heart rate, respiratory rate, 
oral body temperature and weight by dose treatment  group and visit/time point.   
: 
PCS criteria for vital signs are listed below 
Table 3 PCS criteria for vital signs 
Supine Systolic Blood Pressure 
≤90 and decrease ≥20 mm Hg;  ≥180 and 
increase ≥20 mm Hg 
Supine Diastolic Blood Pressure 
≤50 and decrease ≥15 mm Hg;  ≥105 and 
increase ≥15 mm Hg 
Supine Heart Rate 
≤50 and decrease ≥15 bpm;  ≥120 and 
increase ≥15 bpm 
Body Weight 
Change(increase or decrease) from 
Baseline ≥7%  
Respiratory Rate 
<12 and >20 per minute 
Frequency distributions of the vital signs of interest listed above will summarized for PCS 
values at any post-baseline visit. 
Physical Examinations will be listed. 


 
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9.6. 
Electrocardiograms 
Descriptive summaries will be presented for ECG measures of PR interval, QRS interval, 
QT interval, QTc interval (both correction methods), and HR. These summaries will be 
presented by treatment group, Stage and visit. 
The number and percentage of patients/subjects with normal and abnormal investigator 
reported ECG results will be summarized by visit and treatment group.  An outlier 
analysis using QTcF will also be done based on these standard criteria. If the change from 
baseline QTcF values are > 30 or 60 msec, or if QTcF post baseline values are >450, 470 
or 500. This will be done by Stage and Over All. Shift tables for results (normal, 
abnormal CS, abnormal NCS) from baseline to post-baseline visits will be presented by 
body system, treatment group, Stage and visit. 
Bazett’s correction (QTcB) and Fridericia’s correction (QTcF) will be derived as follows: 
Bazett’s Correction (QTcb) 
RR
QT
QTc
m
b
sec

Fridericia’s Correction (QTcf) 
3
sec
RR
QT
QTc
m
f 
Where: Relative Rate: RR = 60 / HR 
HR = Heart Rate obtained from the ECG. 
9.7. 
Concomitant Medication 
The number and percentage of subjects using prior and concomitant medications will be 
grouped by ATC Level 4 and preferred name (coded based on Sept 2018 version of 
World Health Organization Drug Coding Dictionary [WHODD], and tabulated by stage 
and treatment group. In the case of multiple uses of the same medication within the same 
subject, each subject will only be counted once for each preferred name. Prior 
medications will be presented separately from concomitant medications. Medications that 
started prior to the first dose of study drug (Stage 1) will be considered prior medications 
whether or not they were stopped prior to the first dose of study drug. If a medication 
starts prior to the first dose and continues after the first dose of study drug, it will be 
considered both prior and concomitant.  A medication will be determined as concomitant 
for each Stage if taken at any time during the reported timeframe.   
Prior medications will be reported by Stage 1 treatment groups only.  Concomitant 
medications will be reported for each Stage. If the use of concomitant medication starts in 
Stage 1 and ends after Stage 2 dose administration start date, it will be reported in Stage 1 
and Stage 2 summary tables. Incidences will be displayed by treatment group.  For 


 
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reporting in each Stage, subjects will be reported by the treatment received in their 
respective Stage. 
10.
Other Planned Analysis
 
 
 
10.2. COVID-19 Assessment Impact 
To address the impact of COVID-19 on evaluating the efficacy of the trial, the following 
approach will be implemented: 
-
First describing the population : randomized date, visits missed, visits done
remotely, restriction due to COVID-19 by visit.Restriction due to COVID-19 is
defined as first day to stay at home, it will be defined by state.
-
Second a sensivity analysis on efficacy endpoints CAPS-5, PCL-5, PSQI score,
HADS will be run. The main MMRM model will be run adding the COVID-19
restriction variable to evaluate impact of this covariate on treatment difference
estimates. This covariate will be a time-varying covariate.
-
A listings of all patient impacted by COVID-19 will be produced.
11.
Changes from Protocol Planned Analysis
-
Add mITT population for sensitivity analysis of primary efficacy.
-
Add responder analysis for PCL-5.
-
Add analysis for several subgroups
-
Comparison of active treatment groups together is not relevant in this exploratory
analysis without having any results on the comparison versus Placebo.
-
Add COVID-19 Assessment Impact Analysis


 
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12.
References
1. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee
on Professional Ethics, April 2016.
http://www.amstat.org/about/ethicalguidelines.cfm
2. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014.
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf.
3. US Federal Register. (1998) International Conference on Harmonization; Guidance
on Statistical Principles for Clinical Trials. Department of Health and Human
Services: Food and Drug Administration [Docket No. 97D-0174]. Federal Register
Volume 63, Number 179, pages 49583-49598. September 16, 1998.
4. Chen Y, Yang Y, Hung HM, Wang S. Evaluation of performance of some enrichment
designs dealing with high placebo response in psychiatric clinical trials. Contemp
Clin Trials. 2011;32:592-604.
5. Fava M, Evins A, E, Dorer D, J, Schoenfeld D, A: The Problem of the Placebo
Response in Clinical Trials for Psychiatric Disorders: Culprits, Possible Remedies,
and a Novel Study Design Approach. Psychother Psychosom 2003;72:115-127.
6. Weathers, F.W., Litz, B.T., Keane, T.M., Palmieri, P.A., Marx, B.P., & Schnurr, P.P.
(2013). The PTSD Checklist for DSM-5 (PCL-5). Scale available from the National
Center for PTSD at www.ptsd.va.gov.
7.
8. Buysse, Daniel J., et al. "The Pittsburgh Sleep Quality Index: a new instrument for
psychiatric practice and research." Psychiatry res28.2 (1989): 193-213.


 
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13.
Tables, Listings, and Figures
All listings, tables and graphs will have a header showing the sponsor company name and 
protocol and a footer showing the version of SAS, the file name and path, and the source 
of the data (CRF page or listing number). 
In general, one listing will be produced per CRF domain. All listings will be sorted by 
treatment, site, and subject number. All calculated variables will be included in the 
listings. 
In all listings a blank line will be placed between each subject. Within a data listing, if an 
item appears line after line (e.g., repetition of subject number), then only the first 
occurrence will be displayed. 
In data listings, the information for one subject will be kept on one page if at all possible, 
rather than splitting a subject’s information across pages. 
All tables, listings are described in the NYX-783-2004 SAP Shells latest document. 


 
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14.
Appendix 1: PSQI Derivation
In order to calculate the PSQI total score first the following 7 variables need to be derived 
PSQIDURAT, PSQIDISTB, PSQILATEN, PSQIDAYDYS, PSQIHSE, PSQISLPQUAL, 
PSQIMEDS (noted as Q1A-Q1G in Section 6.1.4). All of them are added to give PSQI total 
score. 
PSQIDURAT- DURATION OF SLEEP 
IF Q4 ≥ 7, THEN set value to 0 
IF Q4 < 7 and ≥ 6, THEN set value to 1 
IF Q4 < 6 and ≥ 5, THEN set value to 2 
IF Q4 < 5, THEN set value to 3 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQIDISTB - SLEEP DISTURBANCE 
IF Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j (IF Q5JCOM is null or Q5j is null, 
set the value of Q5j to 0) = 0, THEN set value to 0 
IF Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j (IF Q5JCOM is null or Q5j is null, 
set the value of Q5j to 0) ≥ 1 and ≤ 9, THEN set value to 1 
IF Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j (IF Q5JCOM is null or Q5j is null, 
set the value of Q5j to 0) > 9 and ≤ 18, THEN set value to 2 
IF Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j (IF Q5JCOM is null or Q5j is null, 
set the value of Q5j to 0) > 18, THEN set value to 3 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQILATEN - SLEEP LATENCY 
First, recode Q2 into Q2new thusly: 
IF Q2 ≥ 0 and ≤ 15, THEN set value of Q2new to 0 
IF Q2 > 15 and ≤ 30, THEN set value of Q2new to 1 
IF Q2 > 30 and ≤ 60, THEN set value of Q2new to 2 
IF Q2 > 60, THEN set value of Q2new to 3  
Next 
IF Q5a + Q2new = 0, THEN set value to 0 
IF Q5a + Q2new ≥ 1 and ≤ 2, THEN set value to 1 
IF Q5a + Q2new ≥ 3 and ≤ 4, THEN set value to 2 
IF Q5a + Q2new ≥ 5 and ≤ 6, THEN set value to 3 


 
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Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQIDAYDYS- DAY DYSFUNCTION DUE TO SLEEPINESS 
IF Q8 + Q9 = 0, THEN set value to 0 
IF Q8 + Q9 ≥ 1 and ≤ 2, THEN set value to 1 
IF Q8 + Q9 ≥ 3 and ≤ 4, THEN set value to 2 
IF Q8 + Q9 ≥ 5 and ≤ 6, THEN set value to 3 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQIHSE- SLEEP EFFICIENCY 
Diffsec = Difference in seconds between day and time of day Q1 and day Q3 
Diffhour = Absolute value of diffsec / 3600 
newtib =IF diffhour > 24, then newtib = diffhour – 24 
IF diffhour ≤ 24, THEN newtib = diffhour 
(NOTE, THE ABOVE JUST CALCULATES THE HOURS BETWEEN GNT (Q1) AND GMT 
(Q3)) 
tmphse = (Q4 / newtib) * 100 
IF tmphse ≥ 85, THEN set value to 0 
IF tmphse < 85 and ≥ 75, THEN set value to 1 
IF tmphse < 75 and ≥ 65, THEN set value to 2 
IF tmphse < 65, THEN set value to 3 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQISLPQUAL- OVERALL SLEEP QUALITY 
Q6 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQIMEDS- NEED MEDS TO SLEEP 
Q7 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQI TOTAL 
PSQIDURAT + PSQIDISTB + PSQILATEN + PSQIDAYDYS + PSQIHSE + PSQISLPQUAL 
+ PSQIMEDS
Minimum Score = 0 (better); Maximum Score = 21 (worse) 
Interpretation: TOTAL ≤ 5 associated with good sleep quality 
TOTAL > 5 associated with poor sleep quality