A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of NYX-2925 in Subjects With Fibromyalgia
Phase: PHASE2
Conditions: Fibromyalgia
Sponsor: Aptinyx

 
A Randomized, Double-Blind, Placebo Controlled Study to 
Assess the Efficacy and Safety of NYX-2925 in Subjects with 
Fibromyalgia 
Amendment #6 
 
October 14, 2021 
NCT04147858 

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INVESTIGATIONAL PRODUCT: NYX-2925
CLINICAL PROTOCOL: NYX-2925-2005
A Randomized, Double-Blind, Placebo Controlled Study to 
Assess the Efficacy and Safety of NYX-2925 in Subjects with 
Fibromyalgia
Amendment #6
Sponsor:
Aptinyx Inc.
FINAL
IND# 129731
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/Independent Ethics Committees 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 Practice, including 
International Council for Harmonisation 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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SPONSOR SIGNATURE PAGE:
This protocol will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, the International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use E6 Guideline for Good 
Clinical Practice, and all applicable laws and regulations including, but not limited to, those 
related to data privacy and clinical study disclosure.
Aptinyx Inc.

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4.
Pain due to concurrent autoimmune, infectious, or inflammatory disease such as rheumatoid 
arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, inflammatory 
bowel disease, or other chronic widespread pain condition(s) that may confound fibromyalgia 
pain reporting.  
5. Any impairment, activity or situation that, in the judgment of the Investigator, would prevent 
satisfactory completion of the study protocol. 
6. An untreated endocrine disorder that may confound fibromyalgia assessments. 
7. History of severe renal impairment defined by currently receiving hemodialysis or peritoneal 
dialysis,or has undergone a previous renal transplant. 
8. Known history of significant cardiovascular condition, such as myocardial infarction within the 
past year, or moderate to severe congestive heart failure (New York Heart Association [NYHA] 
Class III and IV); evidence of current uncontrolled cardiac arrhythmias, angina; 
electrocardiographic evidence of acute ischemia or clinically significant conduction system 
anomalies; QTcF >450 msec (males) or >470 msec (females); or uncontrolled hypertension 
characterized by resting systolic blood pressure >160 mm Hg or resting diastolic >100 mm Hg, 
or clinically significant hypotension in the judgement of the Investigator as characterized by 
resting systolic blood pressure <90 mm Hg or resting diastolic blood pressure <60 mm Hg 
accompanied by symptoms such as lightheadedness, dizziness, and profound fatigue or signs 
such as irregular heartbeat. 
9. Resting heart rate <45 bpm or >95 bpm. 
10. History of Huntington's disease, Parkinson's disease, Alzheimer's disease, multiple sclerosis, or 
a history of seizures (with the exception of childhood febrile seizures), epilepsy, or stroke.  
11. Subject has evidence of any clinically significant, uncontrolled gastrointestinal, endocrinologic , 
hematologic, immunologic, metabolic, urologic, pulmonary (including uncontrolled, obstructive 
sleep apnea), neurologic, dermatologic, and/or other major disease (exclusive of fibromyalgia) 
that may interfere with study participation, as assessed the investigator.  
12. Positive serology test for human immunodeficiency virus (HIV) or current hepatitis B or C 
hepatitis infection, or other ongoing infectious disease that the investigator considers clinically 
significant. 
13. Concomitant use of protocol specified prohibited medications from which subject is unable to 
wash-out (see Section 8.7 of the protocol for Concomitant Medications Restrictions). 
a. Washout from excluded medication allowed only if the Investigator deems it medically 
appropriate. 
b. Washout should be completed during screening, with the last dose being at least two (2) 
weeks prior to randomization (See Section 15.1 of the protocol for Disallowed 
Analgesic and Other Medications). 
14. Sensitivity or allergy to N-methyl-D-aspartate receptor ligands including ketamine, esketamine, 
memantine, as well as amantadine, dextromethorphan, methadone, dextropropoxyphene, and/or 
ketobemidone.  
15. Use of NMDAR-binding drugs (e.g., ketamine, esketamine, memantine) as well as amantadine, 
dextromethorphan, methadone, dextropropoxyphene, and/or ketobemidone) within 30 days 
prior to dosing or during the study. 
16. Sensitivity to or intolerance to acetaminophen or associated formulation components. 

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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................1 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............17 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................22 
4. 
INTRODUCTION ......................................................................................................25 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................29 
5.1. 
Primary Objectives .....................................................................................................29 
5.2. 
Secondary Objectives .................................................................................................29 
5.3. 
Study Endpoints ..........................................................................................................29 
5.3.1. 
Efficacy Endpoints ......................................................................................................29 
5.3.2. 
: ..........................................................................................30 
5.3.3. 
Safety Endpoints .........................................................................................................30 
6. 
INVESTIGATIONAL PLAN .....................................................................................31 
6.1. 
Overall Study Design and Plan: Description ..............................................................31 
6.2. 
Scientific Rationale for Study Design ........................................................................35 
6.3. 
Justification of Dose ...................................................................................................35 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................36 
7.1. 
Subject Inclusion Criteria ...........................................................................................36 
7.2. 
Subject Exclusion Criteria ..........................................................................................37 
7.3. 
Screen Failures ............................................................................................................40 
7.4. 
Subject Withdrawal Criteria .......................................................................................40 
7.5. 
Methods of Birth Control............................................................................................40 
7.6. 
Acccurate Pain Reporting and Placebo Response Reduction Training ......................41 
8. 
STUDY TREATMENT ..............................................................................................41 
8.1. 
Dosing and Administration .........................................................................................41 
8.2. 
Study Drug Description, Appearance, Packaging, and Labeling ...............................42 
8.3. 
Preparation and Handling ...........................................................................................42 
8.4. 
Storage ........................................................................................................................42 
8.5. 
Accountability .............................................................................................................43 

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8.6. 
Treatment Compliance ................................................................................................43 
8.7. 
Concomitant and Excluded Medications ....................................................................43 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................44 
9.1. 
Screening Assessments ...............................................................................................44 
9.1.1. 
Medical History ..........................................................................................................44 
9.1.2. 
American College of Rheumatology Fibromyalgia Criteria ......................................44 
9.1.3. 
Mini-International Neuropsychiatric Interview (MINI) .............................................45 
9.2. 
Efficacy Assessments .................................................................................................45 
9.2.1. 
Numeric Rating Scale of Pain Intensity (NRS) ..........................................................45 
9.2.2. 
Daily Sleep Interference Scale (DSIS) .......................................................................45 
9.2.3. 
Fibromyalgia Impact Questionnaire  Revised (FIQR) ..............................................45 
9.2.4. 
Patient Reported Outcomes Measurement Information Systems  
Fibromyalgia PROMISFM  Fatigue Profile  Short Form .........................................45 
9.2.5. 
Patient Reported Outcomes Measurement Information Systems  
Fibromyalgia PROMISFM  Sleep Disturbance  Short Form ..................................45 
9.2.6. 
Patient Reported Outcomes Measurement Information Systems  
Fibromyalgia  PROMISFM  Physical Function  Short Form ..................................46 
9.2.7. 
.......................................................46 
9.2.8. 
Patient Global Impression of Severity (PGI-S) ..........................................................46 
9.2.9. 
Patient Global Impression of Change (PGI-C) ...........................................................46 
9.3. 
Safety Assessments .....................................................................................................46 
9.3.1. 
Safety Parameters .......................................................................................................46 
9.3.2. 
Vital Sign Measurements ............................................................................................46 
9.3.3. 
Physical Examination .................................................................................................47 
9.3.4. 
Electrocardiogram .......................................................................................................47 
9.3.5. 
Clinical Laboratory Assessments ...............................................................................47 
9.3.6. 
Sheehan Suicidality Tracking Scale (S-STS) .............................................................48 
9.3.7. 
Abuse and Diversion Assessment ...............................................................................49 
9.4. 
Safety and Pharmacovigilance ....................................................................................49 
9.4.1. 
Adverse Events  Relationship to Study Drug ...........................................................49 
9.4.2. 
Recording Adverse Events .........................................................................................50 
9.4.3. 
Reporting Adverse Events ..........................................................................................50 
9.4.3.1. 
Severity of Adverse Events ........................................................................................50 

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9.4.3.2. 
Action Taken for Adverse Events...............................................................................51 
9.4.3.3. 
Outcome for Adverse Events ......................................................................................51 
9.5. 
Serious Adverse Events ..............................................................................................51 
9.6. 
Other Reportable Events .............................................................................................53 
10. 
SCHEDULE OF PROCEDURES ..............................................................................53 
10.1. 
Visit 1 and Screening Period (Week -4 to Week -1) ..................................................53 
10.2. 
Baseline Visit: Week 0/Visit 2 ...................................................................................55 
10.3. 
Treatment Period ........................................................................................................56 
10.3.1. 
Week 2/Visit 3 ............................................................................................................56 
10.3.2. 
Week 4/Visit 4 and Week 8/Visit 5 ............................................................................57 
10.3.3. 
Week 12/Visit 6/Early Termination Visit ...................................................................58 
11. 
STOPPING CRITERIA ..............................................................................................59 
12. 
STATISTICS ..............................................................................................................60 
12.1. 
Sample Size Determination ........................................................................................60 
12.2. 
Randomization ............................................................................................................60 
12.3. 
Statistical Analysis Plan .............................................................................................60 
12.4. 
Analysis Populations ..................................................................................................60 
12.5. 
Treatment Group Comparisons ...................................................................................61 
12.6. 
Analyses of Efficacy ...................................................................................................61 
12.6.1. 
Primary Efficacy Analysis ..........................................................................................61 
12.6.2. 
Sensitivity Analysis ....................................................................................................62 
12.6.3. 
Secondary Efficacy Endpoints ....................................................................................62 
12.6.4. 
 .............................................................................................63 
12.6.5. 
Multiple Comparisons ................................................................................................63 
12.7. 
Analyses of Safety ......................................................................................................64 
12.7.1. 
Adverse Events ...........................................................................................................64 
12.7.2. 
Clinical Laboratory Tests ...........................................................................................64 
12.7.3. 
Electrocardiogram .......................................................................................................64 
12.7.4. 
Vital Sign Measurements ............................................................................................64 
12.7.5. 
Suicidal Ideation .........................................................................................................64 
12.8. 
Interim Analysis ..........................................................................................................65 
13. 
ADMINISTRATIVE ..................................................................................................65 
13.1. 
Source Documents ......................................................................................................65 

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13.2. 
Study Monitoring ........................................................................................................65 
13.3. 
Case Report Forms .....................................................................................................65 
13.4. 
Protocol Amendment(s) ..............................................................................................65 
13.5. 
Audits and Inspections ................................................................................................66 
13.6. 
Institutional Review Board .........................................................................................66 
13.7. 
Compliance with Regulatory Requirements ...............................................................66 
13.8. 
Informed Consent .......................................................................................................66 
13.9. 
Study File Management ..............................................................................................67 
13.10. 
Study Completion .......................................................................................................67 
13.11. 
Confidentiality ............................................................................................................67 
13.12. 
Compensation, Insurance, and Indemnity ..................................................................67 
13.13. 
Financial Disclosure ...................................................................................................67 
13.14. 
Records Retention .......................................................................................................67 
13.15. 
Publication Policy .......................................................................................................68 
14. 
REFERENCES ...........................................................................................................69 
15. 
APPENDICES ............................................................................................................72 
15.1. 
Guidelines / Timelines for Washing Out of Disallowed Analgesic 
Medications* ...............................................................................................................72 

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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Special Terms ...............................................................................22 
Table 3: 
Schedule of Procedures ...............................................................................................32 
 
LIST OF FIGURES 
Figure 1 
Study Design ...............................................................................................................31 
 
 

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Abbreviation  
Explanation 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
MADDERS 
Misuse, Abuse, and Diversion Drug Event Reporting System® 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini-International Neuropsychiatric Interview 
MMRM 
mixed model for repeated measures 
NF 
National Formulary 
NMDA 
N-methyl- D -aspartate 
NMDAR 
N-methyl-D-aspartate receptor 
NRS 
numeric rating scale 
NSAID(s) 
nonsteroidal anti-inflammatory drug(s) 
NYHA 
New York Heart Association 
pDPN 
painful diabetic peripheral neuropathy 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PROMISFM 
Patient Reported Outcomes Measurement Information System  Fibromyalgia 
PRR® 
Placebo Response Reduction® 
REM 
rapid eye movement 
RM 
rescue medication 
SAE 
serious adverse event 
S-STS 
Sheehan Suicidality Tracking Scale 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
TSH 
thyroid stimulating hormone 
VCT 
Verified Clinical Trials 
ULN 
upper limit of normal 

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Abbreviation  
Explanation 
USP 
United States Pharmacopeia 
Note: Abbreviations that appear only in tables or figures are defined in the appropriate tables or figures. 

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4. 
INTRODUCTION 
NYX-2925 is a novel small molecule being developed for the treatment of neuropathic pain and 
fibromyalgia. This molecule interacts with N-methyl-D-aspartate receptors (NMDARs) through 
a novel binding domain and acts as a co-agonist with glutamate. NYX-2925 appears to act at a 
binding site that is distinct from NMDAR agonists or antagonists studied to date, such as 
D-cycloserine, ketamine, MK-801, or kynurenic acid. The NYX-2925 mode of action is distinct 
from that of all existing and emerging drugs that are indicated for the treatment of neuropathic 
pain and fibromyalgia. While current medications target individual elements of pain signal 
transmission or modulation, NYX-2925 modulates multiple synaptic relays within pain circuits. 
Glutamate is the major excitatory neurotransmitter in the central nervous system and acts 
through activation of glutamate receptors. A portion of the receptors bind preferentially to 
N-methyl-D-aspartate (NMDA), and are, therefore, termed NMDARs. Unlike other glutamate 
receptors found in the brai
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or 
kainic acid receptors, the NMDARs are unique in that they have distinct binding sites for both 
glutamate and glycine, and binding by both ligands is required for receptor activation. The 
NMDARs are implicated in a number of physiological and pathological processes, including 
[Tai 2001; Mony 2009; Traynelis 2010]. 
Fibromyalgia is a chronic, debilitating, disorder typified by widespread musculoskeletal pain, 
accompanied by symptoms of fatigue, affected sleep, memory issues, and mood disorders. It is 
estimated that fibromyalgia affects 5 million people or 2 to 5% of the American adult population 
[Arnold 2012]. Women are more commonly diagnosed than men (female:male ratio is 7:1) and 
prevalence increases with age.  
Individuals suffering from fibromyalgia presently have limited treatment options available. 
Current treatment options include pregabalin, a calcium channel alpha-2-delta subunit ligand, 
and two norepinephrine and serotonin reuptake inhibitors, duloxetine and milnacipran. These 
therapies have shown some efficacy in treating fibromyalgia symptoms, although for a large 
proportion of patients, treatment is insufficient. 
Recent research suggests that the chronic widespread pain seen in fibromyalgia patients has a 
neurogenic origin. Higher levels of ascending pathway neurochemicals, including nerve growth 
factor, substance P, and brain-derived neurotrophic factor, are present in the cerebrospinal fluid 
(CSF) of fibromyalgia patients when compared to healthy controls. In addition, glutamate levels 
can be elevated in both the CSF and brain of fibromyalgia patients. Glutamate may play a central 
role by acting on NMDARs to increase the central amplification of pain perception, which is 
thought to manifest as allodynia and hyperalgesia in fibromyalgia patients [Clauw 2011]. NMDA 
receptors are thus an attractive target for fibromyalgia therapeutic drug development. 
As in fibromyalgia, the central nervous system modulates the experience of pain in people with 
neuropathic pain, with the rostroventral medial medulla [Silva 2016], the dorsal anterior 
cingulate cortex [Russo 2015], the insula, and other brain regions [Ossipov 2010] all thought to 
be involved. Neuropathic pain is caused by disease or injury of the somatosensory system as 
opposed to nociceptive pain, where the sensory system is physiologically normal [Jensen 2014]. 
While neuropathic pain can initially arise within the central or the peripheral nervous system 

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through a wide range of etiologies, central nervous system modulation of the experience of pain 
is common, regardless of the specific precipitating factors or initial location of the pain.  
Preclinical pharmacology studies support the study of NYX-2925 in both fibromyalgia and 
neuropathic pain, both of which are chronic pain syndromes involving central nervous system 
modulation of pain signals. NYX-2925 is effective in several models of neuropathic pain and has 
shown activity in the chronic unpredictable stress model of fibromyalgia. Animal models of 
neuropathic pain in which NYX-2925 was tested include the rat Bennett model of neuropathic 
pain, the rat streptozotocin model of diabetic peripheral neuropathy, and the rat Taxol® model of 
chemotherapy-induced neuropathic pain. Unlike gabapentin (150 mg/kg orally), NYX-2925 (1 to 
30 mg/kg orally) produced a rapid and long-lasting analgesia in the rat Bennett model of 
neuropathic pain without changes in locomotor activity after a single dose. Further, in the 
chronic unpredictable stress model of fibromyalgia, NYX-2925 (10 mg/kg) has been shown to 
produce mechanical analgesia. In summary, these data support testing NYX-2925 in both 
fibromyalgia and neuropathic pain. 
Pharmacokinetic studies in rats and dogs suggest that NYX-2925 is rapidly absorbed into the 
bloodstream, with time to peak plasma concentration being reached within one hour.  NYX-2925 
is rapidly eliminated from plasma, with an apparent terminal elimination half-life in the range of 
four to five hours in rats and one to two hours in dogs.  Brain exposure is approximately 5% to 
10% relative to plasma levels of NYX-2925 in rats. 
Both single-dose and daily repeat-dose toxicology studies have been performed in rats and dogs. 
The maximum tolerated dose following a single oral exposure is at least 1000 mg/kg in both rats 
and dogs. After up to 13 weeks of daily oral administration in rats and dogs, the no-observed- -
effect level (NOEL) was the highest dose tested for rats (1000 mg/kg/day) and the no-observed-
adverse-effect level (NOAEL) was 120 mg/kg/day in dogs. There were no adverse findings in 
rats. In a 42-day, repeat-dose dog study, minimal or mild changes were observed in liver 
parameters at the high dose of 180 mg/kg/day. Similar changes were observed in the 13-week, 
repeat-dose dog study at the high dose of 240 mg/kg/day: liver enzyme levels in plasma were 
increased, and microscopic examination of the liver revealed pigmented material within bile 
canaliculi and in the cytoplasm of hepatocytes. These changes in liver parameters were partially 
reversed after a two-week or four-week recovery phase. In the 13-week repeat-dose study in dog, 
these observations were considered adverse at 240 mg/kg/day; therefore, the NOAEL was 120 
mg/kg in dog. Based on the data to date, the plasma levels (exposure) of NYX-2925 at the 
NOAEL of 120 mg/kg/day in dog, the most sensitive species, is considered to be approximately 
70 and 20-fold the human dose of 50 mg and 150 mg, respectively. 
As of June 2019, the clinical development program for NYX-2925 includes two completed Phase 
1 studies in healthy volunteers, one ongoing, clinically complete Phase 1 study in healthy 
volunteers, one ongoing, clinically complete Phase 2 study in subjects with diabetic peripheral 
neuropathy (DPN), and one ongoing, clinically complete Phase 2 study in subjects with 
fibromyalgia.  NYX-2925 exposure includes 154 healthy volunteers, 301 subjects with DPN, and 
23 subjects with fibromyalgia. 
In NYX-2925-1001, a Phase 1 single and multiple ascending dose safety and tolerability study in 
healthy volunteers, pharmacokinetic analysis revealed that absorption of NYX-2925 was 
relatively rapid; peak concentrations were achieved within two hours after dosing and declined in 
a roughly monophasic manner over 24 hours. The pharmacokinetic profiles were dose-

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proportional over the dose range tested and showed minimal accumulation following once daily 
dosing for seven days. A high-fat, high-caloric meal decreased the rate of absorption and lowered 
peak plasma concentration by 10%, but had no impact on the extent of exposure, suggesting that 
the compound may be administered with or without food. The majority (approximately 60% to 
70%) of the administered dose was eliminated as unchanged NYX-2925 in the urine. Central 
nervous system exposure was confirmed, and CSF concentrations increased proportionally as the 
dose increased. 
NYX-2925-1003 was a Phase 1 randomized, double-blind, placebo-controlled, crossover study 
of the effects of NYX-2925 on sleep architecture in healthy male volunteers. Preliminary PD 
results from this study indicate that a single oral dose of 100 mg NYX-2925 in healthy subjects 
increased sleep efficiency (total sleep time) as well as non-rapid eye movement (NREM) sleep 
time without affecting rapid eye movement (REM) sleep or inducing daytime drowsiness in the 
placebo/NYX-2925 arm. 
NYX-2925-1004 was a Phase 1 double-blind, randomized, sponsor-open, parallel, placebo-
controlled exploratory study to assess the effect of multiple dose levels (10, 50, or 200 mg) of 
NYX-2925 on the brain function of healthy volunteers as measured by EEG and event-related 
potentials (ERPs). NYX 2925 was shown to acutely enhance NMDAR-dependent mismatch 
negativity (MMN) at the lowest dose tested (10 mg single dose) and quantitative 
electroencephalogram (EEG) changes along with auditory long-term plasticity changes were 
seen across the dose levels. This study also showed auditory long-term plasticity changes 3 and 7 
days after a single dose.  
In Phase 2 Study NYX-2925-2001, 301 subjects with neuropathic pain associated with DPN 
were evaluated for change in pain scores over the four-week treatment period comparing placebo 
to NYX-2925 (10, 50, or 200 mg).  Overall, there were no significant differences between 
NYX- 2925 and placebo with regard to the changes in pain scores over the four-week treatment 
period.  A numerical improvement in change in average pain intensity compared with placebo 
was observed for NYX-2925 50 mg and 200 mg, especially in subjects not taking any 
concomitant analgesic medication.  Sleep interference due to pain showed a trend toward 
improvement for NYX-2925 50 mg.  A significant (p < 0.01) improvement from baseline in 
average daily pain intensity at Weeks 3 and 4 was observed for NYX-2925 50 mg compared to 
 
A Phase 2 Study, NYX-2925-2002, was conducted in 22 women with a confirmed diagnosis of 
fibromyalgia.  In a sequential manner, all subjects were to receive daily doses of placebo, 20 mg 
NYX-2925 and 200 mg NYX-2925 for two weeks each.  At baseline and during each two-week 
treatment period, subjects underwent a series of functional magnetic resonance imaging (fMRI) 
scans, combined with proton magnetic resonance spectroscopy (1H-MRS) to measure key brain 
activity markers known to be associated with central pain perception and processing.  These 
were the primary outcome measures for this trial.  Secondary endpoints included patient reported 
outcomes of average daily pain and worst daily pain measured using a numberic rating scale 
(NRS), the impact of fibromyalgia on the subjec
ving measured by the revised 
Fibromyalgia Impact Quesionnaire (FIQR) and Patient Reported Outcomes Measurement 
Information System  Fibromyalgia (PROMISFM). At Week 6, under the 200 mg treatment 
condition, preliminary analysis of the data suggest there were significant improvements with 
NYX-2925 compared to placebo using the above measures.  Pharmacodynamic results from this 

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study revealed that NYX-2925 20 mg significantly reduced glutamate + glutamine (Glx) levels 
within the posterior insula, a region previously implicated in pain processing in fibromyalgia. 
Based on preliminary analyses, significant clinical improvements in exploratory endpoints were 
observed following treatment with NYX-2925 (week 6) compared to baseline (week 0) and 
placebo (week 2) were average daily pain (1.09-point reduction from baseline (p=0.0027) and 
0.66-point reduction vs. placebo (p=0.0072)), worst daily pain score (0.98-point reduction from 
baseline (p=0.0169) and 0.61-point reduction vs. placebo (p=0.0360)), total FIQR score (9.6-
point reduction from baseline (p=0.0085) and 6.3-point reduction vs. placebo (p=0.0135)) and 
PROMISFM Fatigue Profile total score: 5.4-point reduction from baseline (p=0.0081) and 5.6-
point reduction vs. placebo (p=0.0049). Taken together, these results warrant further clinical 
investigation of NYX-2925 in fibromyalgia. 
In addition, these data demonstrate that NYX-2925 has predictable PK, including penetration 
into the CSF and achieves PD effects as measured by changes in sleep and EEG in healthy 
volunteers and MRI and reported pain in subjects with fibromyalgia.   
Overall, NYX-2925 has been safe and well tolerated at oral doses up to 200 mg daily for up to 
four weeks.  Across the studies, there have been few severe treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs), or TEAEs leading to study discontinuation, and no 
deaths.  The most commonly reported TEAEs have been headache, diarrhea, upper respiratory 
tract infection, alanine aminotransferase increased, and arthralgia.  No subject reported a SAE 
while receiving NYX-2925.  An NYX-2925-2001 related TEAE leading to study discontinuation 
(severe headache) was reported, which occurred for a subject receiving daily NYX-2925 10 mg 
in Study NYX-2925-2001. One NYX-2925-2002 subject had an unrelated TEAE of mild 
ventricular extrasystoles leading to study discontinuation with onset during the placebo period 
and was discontinued after 1 dose of NYX-2925 20 mg. 
No clinically meaningful changes in vital sign measurements, safety 12-lead electrocardiogram 
(ECG) results, physical examination findings, Columbia-Suicide Severity Rating scale (C-
SSRS), or Sheehan Suicidality Tracking Scale (S-STS) scores have been observed after a single 
dose of NYX-2925.  Few potentially clinically significant laboratory results were observed 
during four weeks of treatment in Study NYX-2925-2001; however, these were generally 
comparable across treatment groups.  A single subject in the NYX-2925 10 mg group had 
elevated clinical laboratory results, including alanine aminotransferase increased and aspartate 
aminotransferase increased, that met investigative product stopping criteria. On the NYX-2925-
2002 study, one (4.8%) subject had a potentially clinically significant GGT result in the 
NYX-2925 200 mg period and also experienced elevated ALT and AST. These elevations 
occurred during the NXY-2925 200 mg period and declined following the end of dosing; 
however, GGT remained above the laboratory reference range at last evaluation, though trending 
downward. 
In summary, NYX-2925 has been sufficiently tested in preclinical studies for safety and 
tolerability over a wide dose range, with exposures greater than the proposed clinical doses. 
General toxicology studies in rats and dogs support clinical studies up to and including 13 weeks 
of daily doses. Clinical results to date indicate that NYX-2925 is safe and well tolerated. The 
preclinical, Phase 1 and preliminary Phase 2 clinical data support further testing for fibromyalgia 
in humans. 

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This study (NYX-2925-2005) is a randomized, double-blind, parallel-group, placebo-controlled 
study to assess the efficacy and safety of NYX-2925 in subjects with fibromyalgia. NYX-2925 
will be provided as capsules for oral administration in strengths of 50 mg NYX-2925 or 100 mg 
NYX-2925 per capsule. 
5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Primary Objectives 
The primary objectives of this study are: 
 To evaluate the efficacy of NYX 2925 taken orally once daily versus placebo for the 
treatment of fibromyalgia. 
 To assess safety and tolerability of NYX-2925 taken orally once daily 
5.2. 
Secondary Objectives 
The secondary objective of the study is: 
 To assess effects of NYX-2925 taken orally once daily versus placebo on general pain, 
sleep interference, fatigue, physical functioning, psychological state and global 
improvement. 
5.3. 
Study Endpoints 
5.3.1. 
Efficacy Endpoints 
The primary efficacy endpoint is: 
 
Change from baseline in the weekly mean of the daily Numerical Rating Scale (NRS) 
score assessing average pain intensity in the past 24 hours  
The secondary efficacy endpoints are:  
 
Global Impression of Change (PGI-C) at Week 12 
 
Change from baseline in the weekly mean of the Daily Sleep Interference Scale 
(DSIS) scores at Week 12 
 
NRS average pain intensity at Week 12 
 
NRS average pain intensity related to fibromyalgia at Week 12 
 
Change from baseline to Week 12 in the Fibromyalgia Impact Questionnaire  
Revised (FIQR) score 
 
Change from baseline to Week 12 in the Patient Reported Outcomes Measurement 
Information System  Fibromyalgia (PROMISFM) sleep disturbance score 

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Change from baseline to Week 12 in the Patient Reported Outcomes Measurement 
Information System  Fibromyalgia (PROMISFM) fatigue profile score 
 
Change from baseline to Week 12 in the Patient Reported Outcomes Measurement 
Information System  Fibromyalgia (PROMISFM) physical function score 
 
Cumulative response (percent reduction from baseline) in the weekly mean NRS 
average pain intensity at Week 12 
 
Use of rescue medication, including the proportion of subjects using rescue 
medication, the frequency and amount used 
 
Change from baseline in the weekly mean of the daily Numerical Rating Scale 
(NRS) at each week from Week 1 through Week 12 
5.3.2. 
Other Efficacy Endpoints: 
5.3.3. 
Safety Endpoints 
The safety endpoints will include adverse events, (AE), serious adverse events (SAE), 
discontinuation due to adverse events and the S-STS.  
 

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6.
INVESTIGATIONAL PLAN
6.1.
Overall Study Design and Plan: Description
This 13- to 16-week study will include a 1- to 4-week Screening Period, followed by a 12-week 
double-blind, randomized, placebo-controlled Treatment Period (Figure 1). After completion of 
the study visits, the site will contact the subjects by telephone within 7-10 days to complete a 
safety follow-up call. The Investigator, at their discretion, may ask subject to return for an 
Unscheduled Visit for any safety concerns, abnormal laboratory or ECG findings. A final call 
will be made to the subject approximately 30 days after the final visit to assess for AE closure 
and any new SAEs. The study will include up to 52 study sites in the United States.
Figure 1
Study Design

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Table 3: 
Schedule of Procedures 
Study Period 
Screening 
Baseline 
Treatment Period 
Study Week 
(Day) 
1 to 4 weeksa 
(-28 to -1) 
Week 0d 
(1 ±2) 
Week 2 
(14 ±2) 
Week 4 
(28 ±4) 
Week 8 
(56 ±4) 
Week 12b 
(84 ±4) 
Study Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Assessment 
 
 
 
 
 
 
Informed consent prior to any study procedurec 
X 
 
 
 
 
 
Assess inclusion/exclusion criteria 
X 
Xd 
 
 
 
 
APR®/PRR® training via aLearn®e e 
X 
X 
Xe 
X 
X 
 
Education on appropriate expectations for participation in a clinical 
studye 
X 
X 
X 
X 
X 
X 
Patient Global Impression of Severity (PGI-S) 
X 
X 
 
 
 
 
American College of Rheumatology (ACR) Fibromyalgia Criteria 
2016 
X 
 
 
 
 
 
Demographic characteristics (age, sex, race, and ethnicity) 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Heightw 
X 
 
 
 
 
 
Body weightx 
X 
 
 
 
 
X 
Vital sign measurements (blood pressure and pulse after sitting or 
lying supine for at least five minutes)f 
X 
X 
 
X 
X 
X 
Physical examinationg 
X 
 
 
 
 
X 
Electrocardiogram after five minutes in supine positionu 
X 
X 
 
X 
X 
X 
Urine pregnancy test for females of childbearing potential 
X 
X 
 
Xh  
Xh 
Xh 
Drug screenp 
X 
X 
 
X 
X 
X 
Obtain samples for chemistry, hematology, and urinalysisi 
X 
X 
 
X 
X 
X 
Discontinue all concomitant analgesic medicationj 
X 
 
 
 
 
 
Dispense handheld electronic diary 
X 
 
 
 
 
 
Return handheld electronic diary 
 
 
 
 
 
X 
Dispense/re-dispense rescue medication (acetaminophen) k 
X 
X 
 
X 
X 
 
Return rescue medication and perform accountabilityl 
 
X 
 
X 
X 
X 
 

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Table 3: 
Schedule of Procedures (Continued) 
Study Period  
Screening 
Baseline  
Treatment Period 
Study Week 
(Day) 
1 to 4 weeksa 
(-28 to -1) 
Week 0d 
(1 ±2) 
Week 2 
(14 ±2) 
Week 4 
(28 ±4) 
Week 8 
(56 ±4) 
Week 12b 
(84 ±4) 
Study Visit 
Visit 1 
Visit 2 
Visit 3v 
Visit 4 
Visit 5 
Visit 6 
Record average pain intensitym  and rescue medication use over past 
24 hours at bedtime for each day 
X 
X 
X 
X 
X 
X 
Randomize eligible subjects 
 
X 
 
 
 
 
Dispense study drugo 
 
X 
 
X 
X 
 
Confirm subject takes first dose of study drug (in the clinic) 
 
X 
 
 
 
 
Confirm study drug dosing each day via handheld device  
 
X 
X 
X 
X 
X 
Return study drug and assess compliancel 
 
 
X 
X 
X 
X 
Misuse, Abuse, and Diversion Drug Event Reporting System® 
(MADDERS)s 
 
 
X 
X 
X 
X 
Record Daily Sleep Interference Scale (DSIS) each morningn 
X 
X 
X 
X 
X 
X 
Assess handheld diary compliance  
 
X 
X 
X 
X 
 
MINI International Neuropsychiatric Interview (MINI) 
X 
 
 
 
 
 
Fibromyalgia Impact Questionnaire  Revised (FIQR) 
 
X 
 
X 
X 
X 
Patient Reported Outcomes Measurement Information System  
Fibromyalgia (PROMISFM)t 
 
X 
 
X 
X 
X 
Patient Global Impression of Change (PGI-C) scale 
 
 
 
X 
X 
X 
Sheehan Suicidality Tracking Scale (S-STS) 
X 
X 
Xv 
X 
X 
X 
Concomitant medications q 
X 
X 
X 
X 
X 
X 
Adverse eventsr 
X 
X 
X 
X 
X 
X 
Safety follow-up calls 
 
 
 
 
 
X y 
a Subjects will discontinue all concomitant analgesic medications taken for pain related to fibromyalgia. Duration of the period will depend upon the analgesic(s) being 
discontinued, not to exceed 4 weeks. Subjects not taking any concomitant analgesic medications at Visit 1 may directly begin Week -1 of the Screening Period.  
b 
 ET=Early Termination. Subjects who prematurely discontinue randomized treatment will have Week 12 procedures performed. Diary completion ends the night before the 
Week 12 visit. 
c  Informed consent includes an additional consent for inclusion in a secure, proprietary, research subject database to screen for protocol violators. The main informed 
consent document may be executed up to 30 days prior to the screening visit. The date the first screening related activity is 
screening date.  If the subject does not complete the screening visit within 30 days of signing the informed consent document, the subject must be reconsented.    
d Verify subject still meets all inclusion criteria and does not meet any exclusion criteria. 

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e Review of these educational materials via the aLearn portal will be repeated for all subjects at each site-based visit, with the exception of the final visit. Training at Visit 3 
is per Investigator discretion. Additional refresher training may be administered depending on findings of an ongoing blinded data review (e.g., if pain score variability is 
increased on a subject or site level). 
f 
Vital signs will include blood pressure and pulse after at least five minutes of being seated or lying supine and prior to blood sample collection. Vital signs may be repeated 
 with a minimum interval of five (5) minutes between measurements.  All vital signs should be recorded 
 
g A complete physical examination will be performed at Visit 1 and will include a comprehensive neurological examination. A brief physical examination will be performed 
at Visit 6. 
h If clinically indicated for females of childbearing potential. 
i  
Samples will be obtained following an 8-hour fast. Visit 1 tests will include HIV screening, hepatitis B screening, hepatitis C screening, and a thyroid panel (TSH, T3, T4 
and free T4).  A CRP test will be conducted on each chemistry sample collected.   
j 
Analgesic medications discontinued during the Screening Period cannot be restarted until after the Week 12 Visit has been completed (except NSAIDs taken for pain 
unrelated to FM as outlined in the protocol). 
k Subjects will be instructed to take no more than 3 g/daily (one to two 500 mg tablets every 6 hours as needed) for pain related to fibromyalgia. 
l 
Instruct study subjects to bring all used and unused study drug and rescue medication to each study visit for compliance monitoring.  At Visit 3, Study drug & rescue 
medication use and assessment of compliance will be completed by  review of daily use entries in the handheld and by subject interview. 
m Numerical Rating Scale of pain intensity (0 = no pain to 10 = worst possible pain) will be completed once daily at bedtime. Daily Sleep Interference Scale (DSIS) will be 
completed once daily upon awakening.  
n Starting after Visit 1. 
o Starting after Visit 2. Subjects will be instructed to take one capsule of study drug by mouth once daily and confirm they have taken their study drug for the day via their 
study-issued handheld device each day. 
p Urine drug screen kit for local testing. 
q  Includes prior medications taken within the last 30 days. 
r 
Adverse events 
study. Serious adverse event reporting 
will begin at the time informed consent is obtained and will end 30 days after last dose of study drug. 
s To be completed by Investigators or qualified Subinvestigators when potential abuse-
n in 
the study. 
t 
Subjects will complete the PROMISFM sleep disturbance, fatigue profile and physical function short form questionnaires.   
u  Screening ECGs will be collected in triplicate (at least two (2) minutes apart).  All other ECGs will be single ECGs. 
v Visit Three (3) will be completed by telephone or videoconference. The subject will be asked to complete the printed copy of the S-STS given to them at their Baseline 
Visit while communicating with the site staff.  The staff will review the subjects answers to the S-STS and recommend corrections, only where the form has been 
completed incorrectly.  The completed S-
and 
entered into the eCRF system.  
w  To be meassured without shoes.    
x 
To be obtained with a calibrated scale and subject must remove shoes and bulky layers of clothes. 
y 
A safety follow-up call should be completed 7-10 days after Visit 6 completion. Final safety follow-up call to be made 30 (±5 days) days after Visit 6 completion. 
Investigator may ask subject to return for Unscheduled Visit, as needed.

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6.2. 
Scientific Rationale for Study Design 
Double-blind, randomized, placebo-controlled study designs provide unbiased estimates of 
efficacy and safety. Withdrawal of all concomitant analgesic medication during the Screening 
Period is expected to reduce intersubject variability in treatment response [Katz 2005; 
Katz 2015; Data on file] Acetaminophen will be provided as rescue medication. The three-month 
duration of treatment is considered sufficient to identify clinically important and durable pain 
relief.   
Only masked versions of the protocol will be provided to study sites. The masked versions will 
obscure the probability of receiving placebo, the treatment period, and the randomization criteria 
(Section 7.1). Masking is expected to reduce variability in treatment response and to reduce the 
response to placebo.  
 
6.3. 
Justification of Dose 
The planned dose levels of NYX-2925 are 50 mg and 100 mg per day. Preliminary analysis of 
the data from the previous Phase 2 study of NYX-2925 in fibromyalgia suggest that after 
treatment with 20 mg for two weeks followed by 200 mg for two weeks, clinical effects were 
observed (see Section 4).  Over an extended time pDPN tends to become a chronic centralized 
pain condition [Schreiber 2015, Tesfaye 2013], similar to fibromyalgia. In the Phase 2 study of 
NYX-2925 in pDPN, the most consistent effects among the pre-planned and post-hoc analyses 
were observed after administration of 50 mg, and there were also effects seen at the 200 mg 
dose, although less consistently. The adverse event profile revealed no differences to placebo 
across the entire dose range in either study. Based on the presumed mechanism of action of 
NYX-2925, there is no reason to suspect that the dose range for fibromyalgia should be different 
to that for pDPN. To date no dose level between the four-fold range of 50 mg to 200 mg has 
been studied in a patient population. Therefore, to obtain a more precise understanding of the 
dose-response relationship within this range, an additional dose of 100 mg has been selected 
along with the dose strength of 50 mg to be compared to placebo for the current trial. In the 
Phase 1 single and multiple ascending dose safety, tolerability and pharmacokinetic study, the 
PK of NYX-2925 were dose proportional over the dose range tested (50  1200 mg).  The 
coefficient of variation (CV%) for exposure remained relatively low across the range (14.0% - 
31.5%).  Furthermore, a high-fat, high-caloric meal decreased the rate of absorption (delayed 
Tmax) and lowered Cmax by 10%, but had no impact on the extent of exposure (AUC values were 
comparable), suggesting NYX-2925 can be administered with or without food. 

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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Inclusion Criteria 
Inclusion Criteria: Screening  
Inclusion Criteria: Screening  
Subjects must meet ALL the following criteria to be enrolled in this study: 
1. An Institutional Review Board approved written informed consent and privacy language 
(Health Insurance Portability and Accountability Act (HIPAA)) authorization must be 
obtained from the subject prior to performing any study-related procedures. This study 
may employ electronic informed consent. Electronic or digital signatures (compliant with 
21 CFR § 11 regulations for collecting and storing digital signatures) may be captured 
informed consent supplements the interaction between the participant and the research 
staff, and it provides an opportunity for remote conduct of study activities in the setting 
of the COVID-19 Health Emergency.   
2. Subject provides separate consent to being included in a research subject database. 
3. 
 
4. Subjects must meet the following 3 conditions described in the 2016 American College of 
Rheumatology criteria for fibromyalgia [Wolfe 2016]:  
a) 
Pain Index is 4 to 6 and the Sympt
.  
b) 
 
c) Pain is generalized and present in at least 4 of 5 regions.  
5. Subject has a history of fibromyalgia that was diagnosed >1 year prior to Screening.  
6. Subject reports at least moderate pain over the last week, as assessed by PGI-S at Visit 1. 
7. Subject agrees to use only rescue medication provided reatment as needed for 
breakthrough pain related to fibromyalgia.  
8. Subject agrees not to initiate or change any non-pharmacologic interventions (including 
normal daily exercise routines, chiropractic care, physical therapy, psychotherapy, and 
massage therapy) during the study. Any ongoing non-pharmacologic intervention must be 
stable for at least 30 days prior to screening. 
9. Subject has 
2. 
10. Subject  calculated creatinine clearance is 60 mL/minute (Cockcroft-Gault formula). 
11. Absence of impaired hepatic function characterized by a previous known diagnosis of 
chronic liver disease, and/or the presence of abnormal serum total bilirubin (TBL), or 
alanine transaminase  (ALT), aspartate transaminase (AST), or alkaline 
phosphatase (ALP) >1.5x upper limit of normal (ULN) at screening. 

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12. Except as noted in criteria 10 and 11, 
clinical laboratory values are within 
normal limits or deemed not clinically significant by the Investigator. 
13. Female subjects of child bearing potential with a negative pregnancy test prior to entry 
into the study and who are practicing a highly effective method of birth control (e.g., oral 
or parenteral contraceptives, intrauterine device, barrier [condom and spermicide], 
abstinence) and who do not plan to become pregnant, breastfeed, or donate ova during the 
course of the study and for 28 days after the final administration of investigational 
product.  
14. Male subjects should use a highly effective method of birth control and refrain from 
sexual activity with female sexual partners who do not use a highly effective method of 
birth control during the study. Male subjects who are not surgically sterilized for at least 
90 days prior to screening and sexually active with female partner(s), must agree to use 
barrier contraception (condom with spermicide) during the study. Subjects must agree to 
refrain from sperm donation during the study and for 90 days after the final 
administration of investigational product. 
15. Subject has not participated in an interventional study for at least 30 days or has not taken 
investigational study medication for a period of at least 5 half-lives of the study 
medication, whichever is longer. Agrees not to participate in another interventional study 
while on treatment. Eligibility will be reviewed during the study via sponsor participation 
in a research subject database. 
16. Subject has the ability to understand the requirements of the study, abide by the study 
restrictions, as well as concomitant medications exclusions and agrees to return for the 
required assessments. 
7.2. 
Subject Exclusion Criteria 
Exclusion Criteria: 
Subjects who meets ANY of the following criteria will be excluded from the study: 
1. Lifetime history of any psychotic and/or bipolar disorder.  
2. Subjects with uncontrolled major depressive disorder or generalized anxiety disorder, in 
subjects may have been on a stable protocol allowed 
medication for greater than 60 days prior to screening) or are not expected to remain 
stable for the duration of the study. 
3. Pain due to diabetic peripheral neuropathy, post-herpetic neuralgia, traumatic injury, 
prior surgery, complex regional pain syndrome, or other source of pain that, in the 
fibromyalgia pain or require excluded therapies during the subject's study participation. 
4. Pain due to concurrent autoimmune, infectious, or inflammatory disease such as 
rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic 
arthritis, inflammatory bowel disease, or other chronic widespread pain condition(s) that 
may confound fibromyaligia pain reporting. 
5. Any impairment, activity or situation that, in the judgment of the Investigator, would 
prevent satisfactory completion of the study protocol. 

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6. An untreated endocrine disorder that may confound fibromyalgia assessments. 
7. History of severe renal impairment defined by currently receiving hemodialysis or 
peritoneal dialysis or has undergone a previous renal transplant. 
8. Known history of significant cardiovascular condition, such as myocardial infarction 
within the past year, or moderate to severe congestive heart failure (New York Heart 
Association [NYHA] Class III and IV); evidence of current uncontrolled cardiac 
arrhythmias, angina; or electrocardiographic evidence of acute ischemia or clinically 
significant conduction system anomalies; QTcF >450 msec (males) or >470 msec 
(females); or uncontrolled hypertension characterized by resting systolic blood pressure 
>160 mm Hg or resting diastolic >100 mm Hg, or clinically significant hypotension in the 
judgement of the Investigator as characterized by resting systolic blood pressure <90 mm 
Hg or resting diastolic blood pressure <60 mm Hg accompanied by symptoms such as 
lightheadedness, dizziness, and profound fatigue or signs such as irregular heartbeat. 
9. Resting pulse rate <45 bpm or >95 bpm. 
10. History of Huntington's disease, Parkinson's disease, Alzheimer's disease, multiple 
sclerosis, or a history of seizures (with the exception of childhood febrile seizures), 
epilepsy, or stroke.  
11. Subject has evidence of any clinically significant, uncontrolled gastrointestinal, 
endocrinologic, hematologic, immunologic, metabolic, urologic, pulmonary (including 
uncontrolled, obstructive sleep apnea), neurologic, dermatologic, and/or other major 
disease (exclusive of fibromyalgia) that may interfere with study participation, as 
assessed the investigator.  
12. Positive serology test for human immunodeficiency virus (HIV) or hepatitis B or C 
infection, or other ongoing infectious disease that the investigator considers clinically 
significant. 
13. Concomitant use of protocol specified prohibited medications from which subject is 
unable to wash-out (see Section 8.7 of the protocol for Concomitant Medications 
Restrictions). 
a. Washout from excluded medication allowed only if the Investigator deems it 
medically appropriate. 
b. Washout should be completed during screening, with the last dose being at least 
two (2) weeks prior to randomization (See Section 15.1 of the protocol for 
Disallowed Analgesic and Other Medications). 
14. Sensitivity or allergy to N-methyl-D-aspartate receptor ligands including ketamine, 
esketamine, amantadine, dextromethorphan, memantine, methadone, 
dextropropoxyphene and/or ketobemidone.  
15. Use of NMDAR-binding drugs (e.g., ketamine, esketamine, amantadine, 
dextromethorphan, memantine, methadone, dextropropoxyphene, and/or ketobemidone) 
within 30 days prior to dosing or during the study. 
16. Sensitivity to or intolerance to acetaminophen or associated formulation components. 

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17. Current or recent (within 12 months of screening) history of a substance use disorder 
including cannabinoid and/or alcohol use disorder as determined using the standard MINI 
version 7.0.2 for DSM-5
.  
18. a.  Positive urine drug screen for benzodiazepines or opioids inconsistent with current 
prescriptions, psychoactive cannabinoids (e.g., marijuana, THC) inconsistent with subject 
reported use, PCP, cocaine, or amphetamines at Visit 1. 
b.  Positive urine drug screen for benzodiazepines inconsistent with protocol specified 
allowed prescriptions, psychoactive cannabinoids (e.g., marijuana, THC) inconsistent 
with subject reported use, opioids, PCP, cocaine, or amphetamines at Visit 2. 
19. Hypersensitivity or intolerance to multiple medications, in the opinion of the Investigator. 
20. Meets the criteria for suicidal intent, plan and/or behavior by scoring 3 or 4 on Questions 
2 or 13, or 2 or higher on any Question 1a (only if 1b is coded YES), 3, 4, 5, 6, 7, 8, 9, 
10, 11, 12, or 14 based on the S-STS or who is at significant risk to commit suicide, as 
assessed by the investigator, at Visit 1 or Visit 2.  
21. Planned surgery during study participation. 
22. Active malignancy or a history of malignancy (except for treated non-melanoma in-situ 
skin cancer) within 5 years of screening.  
23. 
litigation.  
24. Employee, contractor, or volunteer of the study site, CRO, or Aptinyx, or relative of any 
employee, contractor, or volunteer of the study site, CRO, or Aptinyx or previous 
randomization into any clinical trial for NYX-2925. 
25. Any condition, including serious medical conditions, that could interfere with the ability 
of the subject to participate in the study or could confound study assessments. 
26. History of severe infection with COVID-19 requiring hospitalization, treatment with 
oxygen or mechanical ventilation, that may interfere with study participation, as assessed 
the investigator. 
27. Any subject with a medical history of COVID-19 infection (positive test) within the last 
two (2) months, or current symptoms consistent with COVID-19 infection (not tested), 
e.g. loss of smell, sore throat, cough or fever (2 or more symptoms at the same time), as 
assessed by the investigator. 
 
Inclusion Criteria: Randomization 
Daily pain scores and diary compliance will be transferred into the interactive response 
technology system, which will be used to assess the criteria for randomization. Subjects whose 
mean of the daily average pain intensity score during the preceding seven (7) days is within the 
protocol-defined algorithm and with adequate compliance with daily diary completion will be 
eligible for randomization. 
Waivers to the inclusion or exclusion criteria will NOT be allowed. 

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7.3. 
Screen Failures 
Subjects who sign and date the informed consent form, but who fail to meet the inclusion and do 
meet any exclusion criteria, will be considered screen failures. The reason(s) for screen failure 
must be documented by the Investigator. Screen failures may be rescreened, at the Investigator's 
discretion and will receive a new subject number. Subjects who are randomization ineligible, as 
determined by IRT, may not be rescreened.  
7.4. 
Subject Withdrawal Criteria 
Subjects who withdraw from the Treatment Period will not be replaced. Any 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 study 
requirements. Subjects who terminate early should return to the clinic for the Early Termination 
Visit. Subjects may be withdrawn from the study if any of the following criteria are met: 
 Occurrence of an adverse event, intercurrent illness, or laboratory abnormality that, in the 
opinion of the Investigator
for subject safety 
 Lack of efficacy 
 Subject withdraws consent 
 Subject noncompliance 
 Lost to follow-up 
 Pregnancy 
 Sponsor termination of study 
 An individual stopping criterion is met 
 Other 
 Other: COVID-19 
7.5. 
Methods of Birth Control 
If heterosexually active and of childbearing potential, female subjects must agree to consistently 
use a highly effective method of birth control starting at Visit 1, continuing throughout the study, 
and for 28 days after the last dose of study drug. Methods of highly effective birth control 
include: 
 Oral or parenteral contraceptives 
 Intrauterine device (either hormonal or nonhormonal type acceptable) 
 Barrier 
 Abstinence 
Female subjects must agree not to plan to become pregnant or breastfeed starting at Visit 1, 
during the study and for 28 days after the last dose of study drug. Female subjects must refrain 

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from donating ova during the study period and for 28 days after final administration of 
investigational product.  
Male subjects must use a highly effective method of birth control and refrain from sexual activity 
with female sexual partners who do not use a highly effective method of birth control starting at 
Visit 1 through the last dose of study drug. Male subjects who are not surgically sterilized for 
90 days prior to Visit 1 and are sexually active with a female partner must use a condom with 
spermicide during the study. Male subjects must refrain from sperm donation during the study 
and for 90 days after the final administration of investigational product.  
All pregnancies (female subjects and female partners of male subjects) 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-
designated Medical Monitor in a timely manner. When the newborn is healthy, further follow-up 
is not necessary.  
7.6. 
Acccurate Pain Reporting and Placebo Response Reduction Training 
Prior to recording their first pain score in the handheld diary, each subject will undergo training 
on Accurate Pain Reporting (APR®) and Placebo Response Reduction (PRR®) via an electronic 
learning management system, aLearn® [Analgesic Solutions, Wayland, MA]. Subjects will 
repeat refresher training at subsequent site based study visits, with the exception of the final visit. 
Refresher training may also be completed remotely via aLearn® at Visit 3, or anytime, per 
Investigator discretion. 
8. 
STUDY TREATMENT 
8.1. 
Dosing and Administration 
This is a double-blind study. Subjects, study personnel and the Sponsor will be blinded to study 
treatment.  
Subjects will be dispensed study drug according to the randomization schedule. A four-week 
supply of study drug will be dispensed at Weeks 0 (baseline), 4, and 8. Subjects will be 
instructed to take one capsules of study drug once daily by mouth. The first dose of study drug 
will be taken in the clinic during the Visit 2 (Week 0).  Subjects will be instructed to take study 
drug once daily throughout the study. 
Subjects will be randomized to NYX-2925 50 mg, NYX-2925 100 mg or placebo by mouth, 
once daily.  
Subjects will be dispensed three (3) bottles of acetaminophen to be used as rescue medication at 
Visit 1.  Rescue medication will be dispensed/re-dispensed at the visits identified in Table 3. 
Rescue medication will consist of 100 count bottle, 500 mg tablets of acetaminophen. Subjects 
will be instructed to take no more than 3 g/day (one to two 500 mg tablets every 6 hours as 
needed) for pain associated with fibromyalgia. Rescue medication will be provided by the 
Sponsor. Use of rescue medication should be reported daily via the study issued- handheld 
device.   

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8.2. 
Study Drug Description, Appearance, Packaging, and Labeling 
NYX-2925 is a small molecule, 
 that will be provided as capsules for oral 
administration in a strength of 50 mg and 100 mg NYX-2925 per capsule. Matching placebo 
capsules will also be provided. 
 
 
 
 
 
The study drug will be provided in bottles
bottle number, storage conditions, protocol number, Sponsor name, and 
investigational use statement. Bottles of study drug will be dispensed at Visit 2/Week 0, Visit 
4/Week 4 and Visit 5/Week 8 will include 32 capsules of NYX-2925 50 mg, NYX-2925 100 mg 
or matching placebo capsules according to the randomization schedule.   
Acetaminophen rescue medication will be provided in 100 count bottles containing 500 mg 
tablets 
tablets
number, protocol number and Sponsor name. Subjects will be instructed to take no more than 3 
g/day (one to two 500 mg tablets every 6 hours) as needed for pain related to fibromyalgia.  
Subjects will be dispensed three (3) bottles of acetaminophen to be used as rescue medication at 
Visit 1. Additional bottles of rescue medication will be dispensed as needed. 
The Sponsor will provide investigative sites with sufficient amounts of study drug and rescue 
medication to conduct the study.  
8.3. 
Preparation and Handling 
The investigative site will receive bottles of blinded study drug. The Investigator may delegate 
study drug handling to site staff who will dispense bottles of study drug for subject 
administration according to the interactive response technology system. The interactive response 
technology system is being utilized to ensure the correct distribution of blinded study drug 
according to the randomization schedule. The maintenance of treatment randomization codes 
will be maintained within the IRT system.  
The investigative site will receive bottles of acetaminophen rescue medication, and there will be 
no rescue medication preparation done at the investigative site. The Investigator may delegate 
rescue medication management to site personnel who will dispense bottles of rescue medication 
for subject administration according to the IRT system. The IRT system will be utilized to ensure 
the correct distribution of rescue medication.  
8.4. 
Storage 
Study drug should be stored in a locked, limited access location according to the label. The 
capsules should be stored at 20ºC to 25ºC, with excursions permitted between 15ºC to 30ºC. The 
investigative site should contact the Sponsor for directions regarding nonpermitted excursions. 

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Rescue medication should be stored in a locked, limited access location according to the label. 
The tablets should be stored at 20ºC to 25ºC. The investigative site should contact the Sponsor 
for direction regarding excursions.   
8.5. 
Accountability 
The Investigator or designee at the investigative site will conduct study drug accountability. The 
investigative site personnel will receive, inspect, and acknowledge condition of study drug and 
rescue medication; document the amount received, dispensed and returned; and maintain the 
study drug accountability records. A Sponsor  representative will inspect study drug and 
accountability records. Site personnel will conduct subject -level accountability, account for and 
document used/unused study drug and rescue medication, and the site will retain bottles of 
returned study drug and rescue medication in 
area.  
Upon completion or termination of the study and after Sponsor  accountability is completed, all 
used and unused study drug and containers will be returned to the depot as instructed by the 
.  All used and unused rescue medication and containers may be 
destroyed at the site or returned to the depot as instructed by the Sponsor  representative. 
8.6. 
Treatment Compliance 
Site personnel will assess subject compliance with study drug dosing and rescue medication use 
via pill count and discussion with the subject. In addition, incorrect doses will be documented. 
8.7. 
Concomitant and Excluded Medications 
Subjects will discontinue any current analgesic medicationstaken for pain related to 
fibromyalgia, with the exception of acetaminophen (rescue medication). Rescue medication may 
be taken for pain related to fibromyalgia only. Stable doses of the benzodiazepines alprazolam 
and lorazepam will be allowed for the treatment of anxiety. The benzodiazepine receptor 
agonists, zolpidem (immediate-release) and zaleplon as well as melatonin, ramelteon and low-
dose trazodone will be allowed for the treatment of sleep disturbances. Stable doses of serotonin-
specific reuptake inhibitors (SSRIs) will be allowed. Intermittment use of triptans for treatment 
of migraines is permitted.  
Concomitant use of antiepileptic drugs, gabapentinoids, mood stabilizers, nonsteroidal anti-
inflammatory drugs (NSAIDs [except cardiac preventive low dose acetylsalicylic acid]) outside 
of infrequent use for pain unrelated to fibromyalgia as described below, systemic corticosteroids, 
opioid or narcotic analgesics, muscle relaxants, tramadol, injected or topical lidocaine, injected 
or topical capsaicin, selective norepinephrine reuptake inhibitors (SNRIs), tricyclic (TCAs 
[except low-dose cyclobenzaprine]), and tetracyclic (TeCAs) antidepressants, monoamine 
oxidase inhibitors (MAOIs), psychostimulants, sodium oxybate, benzodiazepines (except 
alprazolam or lorazepam), barbiturates, or NMDA receptor ligands (e.g., ketamine, esketamine, 
amantadine, dextromethorphan [except low dose intermittent use for cough] memantine, 
methadone, dextropropoxyphene or ketobemidone) is prohibited.  
 

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A positive urine drug screen for benzodiazepines or opioids inconsistent with current 
prescriptions, psychoactive cannabinoids (e.g., marijuana, THC) inconsistent with subject 
reported use, PCP, cocaine or amphetamines is exclusionary at Visit 1. 
A positive urine drug screen for benzodiazepines inconsistent with protocol specified allowed 
prescriptions, psychoactive cannabinoids (e.g., marijuana, THC) inconsistent with subject 
reported use, opioids, PCP, cocaine or amphetamines is exclusionary at Visit 2. 
If it is questionable whether a medication(s) falls into the category of excluded medications 
named above, the Investigator should review the medication with the Sponsor prior to the 
enrollment of the subject. Washout from excluded medication for fibromyalgia is allowed only if 
the Investigator deems it is medically appropriate. The washout must be completed within the 
duration of the Screening Period with the last dose being at least two (2) weeks prior to 
randomization (See Section 15.1 of the protocol for Disallowed Analgesic and Other 
Medications).  
Subjects will be dispensed acetaminophen to be used as rescue medication and will be instructed 
to take no more than 3 g/day (one to two 500 mg tablets every 6 hours as needed) for pain related 
to fibromyalgia. Rescue medication will be provided by the Sponsor. 
For pain unrelated to fibromyalgia, subjects may use a nonsteroidal anti-inflammatory drug 
(NSAID) for up to two (2) days during a seven (7) day period.  If the need for analgesics exceeds 
this period, the patient should call the Investigator to evaluate the cause of pain and the course of 
action.  If a subject requires a NSAID for pain unrelated to fibromyalgia, the medication should 
be recorded as a concomitant medication and the adverse event must be recorded in the eCRF.   
Medications used within 30 days prior to screening through the end of treatment in this study 
must be documented in the source documents and on the corresponding electronic case report 
form (eCRF). 
9. 
STUDY ASSESSMENTS AND PROCEDURES 
9.1. 
Screening Assessments 
9.1.1. 
Medical History 
Medical history will be documented based on subject report and investigator
 
9.1.2. 
American College of Rheumatology Fibromyalgia Criteria 
The 2016 American College of Rheumatology Fibromyalgia Criteria is a patient survey that is 
used as a diagnostic tool for fibromyalgia. The diagnostic criteria for fibromyalgia are met by the 
following 3 conditions [Wolfe 2016]:  
 
 
Index is 4 to 6 and the Symptom Sever
.  
 
 
 Pain is generalized and present in at least 4 of 5 regions. 

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All subjects will be assessed for widespread pain symptoms using these criteria. 
9.1.3. 
Mini-International Neuropsychiatric Interview (MINI) 
The MINI is designed as a brief structured diagnostic interview to meet the need for a short but 
accurate structured psychiatric interview for multicenter clinical trials. The standard MINI 
version 7.0.2 for DSM-5 will be used in this study to assess the 17 most common disorders in 
mental health. The disorders investigated are the most important to identify in clinical and 
research settings.   The disorders were selected based on current prevalence rates of 0.5% or 
higher in the general population in epidemiology studies [Sheehan 1998]. 
9.2. 
Efficacy Assessments 
9.2.1. 
Numeric Rating Scale of Pain Intensity (NRS) 
The NRS of pain intensity is a unidimensional, segmented numeric version of the visual analog 
scale. A subject selects a whole number (0 to 10) that best indicates the intensity of his/her pain. 
The format consists of a horizontal line which is anchored by terms defining pain levels, where 
0 represents no pain and 10 represents worst possible pain. 
Subjects will report, at bedtime, their average pain intensity during the past 24 hours using the 
11-point NRS. 
9.2.2. 
Daily Sleep Interference Scale (DSIS) 
The DSIS was developed to quantify sleep interference due to pain. The DSIS is a single item 
measure that is completed by patients once a day (upon awakening) to accurately capture 
variability in sleep interference due to pain on a daily basis, thus minimizing recall bias. The 
DSIS has an 11-point response scale 
range from 0 (Did not interfere with sleep) to 10 (Completely interfered with sleep/unable to 
sleep due to pain). The DSIS is designed to be used in a patient daily diary that patients fill out 
upon awakening each morning [Vernon 2008].  
9.2.3. 
Fibromyalgia Impact Questionnaire  Revised (FIQR) 
The FIQR is an updated version of the Fibromyalgia Impact Questionnaire, which is an 
assessment of the physical functioning, work status, depression, anxiety, morning tiredness, pain, 
stiffness, fatigue, and well-being in fibromyalgia subjects measured over the period of one week. 
The FIQR differs from the Fibromyalgia Impact Questionnaire in that it includes questions on 
memory, tenderness, balance and environmental sensitivity as well as modified function 
questions [Bennett 2009]. 
9.2.4. 
Patient Reported Outcomes Measurement Information Systems  Fibromyalgia 
PROMISFM  Fatigue Profile  Short Form 
The PROMISFM fatigue profile is a 16-question instrument that has four 4-item short forms that 
examine the intensity of the impact of fatigue in social, cognitive, and motivation subdomains 
[Kratz 2016]. 

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9.2.5. 
Patient Reported Outcomes Measurement Information Systems  Fibromyalgia 
PROMISFM  Sleep Disturbance  Short Form  
The PROMISFM Sleep Disturbance short form is an 8-item instrument that assesses sleep 
disturbance in subjects 18 years and older [Yu 2011]. 
9.2.6. 
Patient Reported Outcomes Measurement Information Systems  Fibromyalgia  
PROMISFM  Physical Function  Short Form 
The PROMISFM physical function  short form measures the self-reported performance of 
physical activities including dexterity, walking or mobility and the ability to complete activities 
of daily living [Driban 2015].  
9.2.7. 
 
9.2.8. 
Patient Global Impression of Severity (PGI-S) 
PGI-S is a global index used to rate the severity of a specific condition (a single-state scale), on 
which (1) 
 pain , two (2) corresponds to 
and four (4) 
.   
9.2.9. 
Patient Global Impression of Change (PGI-C) 
The PGI-C allows subjects to rate the change in the disease state from study initiation to specific 
time points during the study or at the end of the study. 
overall change since beginning the study on a 7-point scale on which one (1) corresponds to 
four (4) 
 seven (7) 
  
9.3. 
Safety Assessments  
9.3.1. 
Safety Parameters 
Refer to the Table 3 (Schedule of Procedures) or Section 10 (Schedule of Procedures) for time 
points.  
9.3.2. 
Vital Sign Measurements  
Each assessment includes blood pressure and pulse after at least five (5) minutes of being seated 
or lying supine, and prior to blood sample collection. Vital signs may be repeated up to three (3) 
There should be a minimum of five (5) 
minutes of rest allotted in between measurements.  All vital signs should be recorded in the 

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eCRF system.  
9.3.3. 
Physical Examination 
A complete physical examination will include assessment of the following body systems: head, 
eyes, ears, nose, and throat, lymph nodes, neurologic, respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, dermatologic systems and extremities. 
The complete physical examination at Visit 1 will include a comprehensive neurological 
examination of the following components:  cranial nerves, muscle strength and tone, sensory 
function, coordination, gait, reflexes and mental status. 
The brief physical examination may be completed at Week 12 or the Early Termination Visit. 
For measuring weight, a calibrated scale with appropriate range and resolution will be used. 
Subjects must remove shoes and bulky layers of clothing.  
Height will be measured without shoes. 
9.3.4. 
Electrocardiogram 
Triplicate electrocardiograms will be collected at screening after five (5) minutes of supine rest 
and prior to blood sample collection, if possible. There should be a minimum of a two minute 
interval between ECGs.  The device will be a Spaulding (Spaulding Medical, West Bend, WI) 
electrocardiogram device that acquires a 12-lead electrocardiogram . The electrocardiogram data 
will submitted to the designated electrocardiogram laboratory cardiologists for measurements 
and diagnoses. 
The Investigator or qualified Subinvestigator will review all electrocardiogram interpretations 
and interval duration measurements for clinical significance. Standard electrocardiogram 
parameters will be measured. Clinically significant, abnormal 12-lead electrocardiograms should 
be repeated. Clinically significant electrocardiogram changes should be recorded as an adverse 
event.  
The Spaulding electrocardiogram device should be used for all assessments during the study 
unless it is nonoperational, in which case another electrocardiogram may be performed locally 
and transmitted to Spaulding for central reading via printout. 
9.3.5. 
Clinical Laboratory Assessments  
Blood samples for serum chemistry and hematology will be obtained after an eight-hour fast. 
The study investigator should monitor subjects during the study for signs of hepatic abnormality 
potentially meeting the stopping criteria (Section 11).  
The investigator will review clinical laboratory test results as they become available, for 
determination and documentation of clinical significance (if there are out of range values). The 
investigative site will contact the medical monitor for any liver function test results that 
potentially meet the stopping criteria. Possibly drug-related or clinically significant abnormal 
values of uncertain causality must be repeated. Persistent abnormal laboratory values should be 
Abnormal liver function tests (specified in Section 11) 
must be repeated within 48-72 hours.  

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Hematology assessments will include hemoglobin, hematocrit, red blood cell count, white blood 
cell count, differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) and 
platelet count.  
Chemistry assessments will include glucose, calcium, electrolytes (sodium, potassium, 
bicarbonate, chloride), phosphorus, blood urea nitrogen (BUN), creatinine, albumin, total 
protein, magnesium, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), lactate dehydrogenase, gamma-glutamyl transferase (GGT), albumin, 
total bilirubin, direct bilirubin, indirect bilirubin, uric acid, and C-reactive protein (CRP). A 
thyroid panel (TSH, T3, T4, and free T4) will also be collected at Visit 1. 
Qualitative urinalysis will include pH, specific gravity, glucose, ketones, protein, blood, 
leukocyte esterase, urobilinogen, nitrites, and reflex microscopy. 
Abnormal clinical laboratory tests at screening may be repeated, on a case by case basis, after 
consultation with the Medical Monitor. 
Hepatitis B screening will include both the hepatitis B surface antigen (HBsAg) and the hepatitis 
B core antibody (HBcAb) testing. If HBsAg and HBcAb are both positive, the subject is not 
eligible. Additional testing for Hepatitis B surface antibody (HBsAb) will be done in case of a 
positive test result in subjects for either HBsAg or HBcAb, but not both. Subjects positive for 
HBcAb and negative for HBsAg, but also negative for hepatitis B surface antibody are not 
eligible for entry into the study. In addition, if either HBsAg or HBcAb are positive, a 
confirmatory HBV DNA reflex test will be completed.  If the HBV DNA test is positive, the 
subject will not be eligible.    
A history of or a positive test result at Screening for the hepatitis C virus antibody indicating 
ongoing infection will result in confirmatory testing for hepatitis CmRNA. Subjects with negative 
hepatitis CmRNA will be eligible for entry into the study. 
A screening test for HIV will be completed. If the screening test for the HIV antibody is positive, 
a confirmatory test will be performed.   
Female subjects of childbearing potential will receive urine pregnancy tests (human chorionic 
gonadotropin) at Visit 1, Visit 2, and Visit 6. Testing may be performed at other visits, if 
clinically indicated. 
The urine drug panel will include benzodiazepines, psychoactive cannabinoids (e.g., marijuana, 
THC), opioids, PCP, cocaine, and amphetamines. 
9.3.6. 
Sheehan Suicidality Tracking Scale (S-STS) 
The standard version of the S-STS [Sheehan 2014] 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. 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 S-STS accommodates a wide range of time frames. In clinical trials, the frequently used 
ce the last visit
, 
.  
Suicidality identified after baseline will be recorded as an adverse event. 

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9.3.7. 
Abuse and Diversion Assessment 
Potentially aberrant drug behavior (i.e., misuse and abuse-related events) will be identified, 
assessed, and quantified using MADDERS (Analgesic Solutions, Wayland, MA), which consists of 
a set of forms completed by Investigators or qualified Subinvestigators when potential abuse-
related events are identified and upon the completion of each subject
 in the study.  
Potential abuse-related events will be adjudicated by an independent committee [Smith 2017; 
Treister 2016]. 
Any misuse and abuse-related events will be recorded as adverse events.  
9.4. 
Safety and Pharmacovigilance 
9.4.1. 
Adverse Events  Relationship to Study Drug 
An adverse event is any untoward, undesired, unplanned clinical event in the form of signs, 
symptoms, disease, or laboratory or physiological observations occurring in a human being 
participating in a clinical study with an Aptinyx study drug, regardless of causal relationship.  
Laboratory abnormalities are not considered adverse events unless they are associated with 
clinical signs or symptoms or require medical intervention. However, a laboratory abnormality 
(eg, a clinically significant change detected on clinical chemistry, hematology, or urinalysis 
results) that is independent from the underlying medical condition and requires medical or 
surgical intervention, or leads to study drug interruption or discontinuation, must be considered 
an adverse event. 
An adverse event is considered related if there is a reasonable possibility that the 
event may have been caused by the study drug under investigation (i.e., there are facts, evidence, 
or arguments to suggest possible causation). There is also a timely relationship to the 
administration of the investigational drug and the event follows a known pattern of response for 
which no alternative cause is present. 
Not Related 
 There is no reasonable possibility that the study drug under investigation may have 
caused the event. The event is obviously explained by another cause or the time of 
occurrence of the AE is not reasonably related to administration of the study medication. 
Related  
 There is a reasonable possibility that study drug under investigation caused the event (i.e., 
there are facts, evidence, or arguments to suggest possible causation). There is also a 
timely relationship to the administration of the investigational drug and the event follows 
a known pattern of response for which no alternative cause is present. 
When an assessment is not provided, the event will be treated as related for purposes of 
regulatory reporting. 

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9.4.2. 
Recording Adverse Events 
preexisting
study drug dosing and is reported as part 
al history. Pre-existing conditions should be reported as an adverse event 
only if the frequency, intensity, or character of the pre-existing condition worsens during the 
course of the study. Adverse events will be collected from the time ofstudy drug administration  
through the last day 
 
Subjects should be instructed to report all potential adverse events to the Investigator and should 
be queried in a nonleading manner, without specific prompting (e.g.
The site study staff should assess emerging symptoms of dissociative reaction similar to those 
caused by N-methyl-D-aspartate 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 adverse events. 
To avoid vague, ambiguous, or colloquial expressions, all adverse events should be recorded in 
. Each adverse event will 
also be described in terms of duration (start and stop date), severity, relationship to study drug, 
action(s) taken, and outcome. Diagnoses (rather than symptoms) should be recorded wherever 
possible. 
9.4.3. 
Reporting Adverse Events 
All adverse events must be documented, evaluated, and reported in the source documents and 
eCRF. Adverse events will be collected from the time of study drug administration through the 
last day 
 Follow-up of AEs must be conducted in 
 Ongoing adverse events should be 
followed to a satisfactory r
to report all adverse events to the Investigator. In addition, the Investigator should seek to elicit 
and as appropriate by examination. Information on all adverse events should be recorded on the 
eCRF. All clearly related signs, symptoms, and results of diagnostic procedures performed in 
relation to an adverse event should be grouped together and recorded as a single diagnosis. 
9.4.3.1. 
Severity of Adverse Events 
All adverse events will 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 adverse event occur more frequently than once a day, the 
maximum severity for the experience that day should be noted. If the severity category changes 

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over a number of days, then those changes should be recorded separately (with distinct onset 
dates). 
9.4.3.2. 
Action Taken for Adverse Events 
For each reported adverse event, an Investigator must document the action taken according to the 
following criteria: 
 No action  
 Concomitant medication  
 Hospitalization or prolongation of hospitalization 
 Study discontinued  
 Nondrug therapy 
 Other (specify) 
The Investigator must also document the action taken with study drug (as a result of a given 
adverse event) according to the following criteria: 
 Dose not changed 
 Study drug interrupted 
 Study drug withdrawn 
 Not applicable 
 Unknown 
9.4.3.3. 
Outcome for Adverse Events 
Adverse events should be followed until resolution. For each reported adverse event, 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 
9.5. 
Serious Adverse Events 
Serious adverse event reporting will begin at the time informed consent is obtained 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 email address or fax number, 
respectively: 
 
 

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A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes: 
 Death: 
adverse event. In the event of death, the 
cause of death should be recorded as the adverse event. 
 
 Is a life-threatening experience: Life-threatening adverse events include any adverse drug 
experience that, in the view of the Investigator, places the subject at immediate risk of 
death from the reaction as it occurs. It 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 
normal life 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 a serious adverse event 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 (eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or at home). 
All serious adverse events that result in death or are life threatening, regardless of causal 
relationship, must be reported to the Sponsor-designated Medical Monitor within 24 hours of the 
. A copy of the initial serious adverse event report must be received 
within one (1) business day. 
All other serious adverse events or other events reportable to the United States Food and Drug 
Administration (FDA) and/or IRB will be forwarded to the Sponsor-designated Medical Monitor 
within one (1) business day. 
Any reported cases of COVID-19 that meet the SAE criteria above should be reported as per the  
 SAE process.  
The serious adverse event report should provide as much of the required information as is 
available at the time. The following minimum information is required for reporting a serious 
adverse event: subject identification, reporting source, and an event outcome. Supplemental 
information may be transmitted using a follow-up report and should not delay the initial report. 
Aptinyx 
 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 a serious adverse event, the information 
will be treated as a serious adverse event for the purposes of this protocol. Serious adverse event 
reporting will begin at the time of consent and will end 30 days after the last dose.  
All relevant documentation pertaining to a serious adverse event (eg, additional laboratory tests, 
consultation reports, discharge summaries, and postmortem reports) will be provided to the 
Sponsor -designated Medical Monitor in a timely manner. Serious adverse events will be 

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followed until resolution or return to baseline (when worsening of a pre-existing condition is 
reported). If a serious adverse event does not return to baseline but reaches a stable situation that 
is not expected to change, this may be documented on the serious adverse event form. 
The Sponsor may break the treatment code for subjects who experience a serious adverse event 
in order to determine if the individual case or group of cases requires expedited regulatory 
reporting. Individual treatment codes will be available to limited staff who are responsible to 
break codes for reporting purposes. 
For each SAE, the Investigator and Sponsor will independently assess whether there is a 
reasonable possibility that the event may have be
-
The Sponsor will evaluate each drug-related SAE to determine if the event was unexpected. If 
the SAE is assessed to be both drug-related and unexpected, the Sponsor or designee will notify 
all Investigators, and will report it to the appropriate regulatory authorities as required by 
applicable local regulations. The Sponsor or designee will report SAEs, including narratives, to 
the U.S. FDA and local regulatory authorities as required by 21 CFR 312.32 and the 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice. The 
Investigator is responsible for notifying his/her respective IRB. 
 
9.6. 
Other Reportable Events 
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-designated Medical Monitor 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.  
10. 
SCHEDULE OF PROCEDURES 
The schedule of procedures is summarized in Table 3. 
10.1. 
Visit 1 and Screening Period (Week -4 to Week -1) 
The subject will be asked to provide written, informed consent for this study before any required 
procedures are performed. This study may employ electronic informed consent. Electronic or 
digital signatures (compliant with 21 CFR § 11 regulations for collecting and storing digital 
The use of electronic informed consent supplements the interaction between the participant and 
the research staff, and it provides an opportunity for remote conduct of study activities in the 
setting of the COVID-19 Health Emergency. Subjects will also be asked by site staff to sign an 
additional consent for their inclusion a secure, proprietary research subject database. maintained 
by Verified Clinical Trials (VCT) [Verified Clinical Trials, Garden City, NY]. The database will 
use partially identified subject inform
database. Subjects who meet any of the following criteria will not be eligible for continued 

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screening: current enrollment in another study, concurrent screening at another research site, 
violation of the required number of half-lives of the investigational product of the prior research 
study, violation of the washout period between studies, incorrect age for the NYX-2925-2005 
study, or previous randomization into a clinical trial of NYX-2925. Employees, contractors, or 
volunteers of the study site, Contract Research Organization (CRO), or Aptinyx, or relatives of 
any employee, contractor, or volunteer of the study site, CRO, or Aptinyx are not eligible to 
participate.  Serious adverse event collection begins after the informed consent is obtained and 
adverse event collection begins after study drug administration. 
There may be up to three components in the screening period for this study: 1) After providing 
informed consent, subjects will participate in a screening visit where medical history, 
concomitant medications, scales, and eligibility to participate will be assessed; 2) Subjects who 
meet eligibility requirements and are taking an analgesic medication for pain related to 
fibromyalgia will then be required to discontinue the analgesia from one to four weeks (see 
Section 15.1 of the protocol for Disallowed Analgesic and Other Medications). Subjects taking 
no concomitant analgesic medication for their fibromyalgia at Visit 1 may directly begin Week -
1 of the Screening Period; 3) During this time, subjects will be provided a handheld device to 
record their pain and rescue medication use. 
After the informed consents are signed, the following procedures and assessments should be 
completed at Visit 1: 
 Demographic characteristics (age, sex, race, and ethnicity) 
 Medical history 
 Prior (within last 30 days) and concomitant medications 
 PGI-S 
 S-STS 
 
 
 MINI 
 Adverse events  
 Confirmation that subjects meet the 2016 American College of Rheumatology criteria for 
fibromyalgia 
 Height and body weight 
 Vital signs (blood pressure and pulse after sitting or lying supine for at least five minutes) 
 Complete physical examination, including comprehensive neurological examination 
 Triplicate electrocardiograms after five (5) minutes in supine position with a minimum of 
a two minute interval between ECGs 
 Blood samples for fasting (8 hours) serum chemistry and hematology   
 Blood samples for Human immunodeficiency virus (HIV) and hepatitis screening 
 Urine sample for urinalysis 

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 Urine pregnancy test for females of childbearing potential 
 Urine drug test 
Eligible subjects who meet all inclusion and exclusion criteria will enter the 1- to 4-week 
Screening Period. The following procedures and assessments will be performed: 
 Subjects will discontinue all analgesic treatments for pain related to fibromyalgia, and 
complete daily pain diaries. The duration of their Screening Period will depend upon the 
analgesic treatment that is being discontinued, but the total duration of the Screening 
Period cannot exceed four (4) weeks (see Section 15.1 of the protocol for Disallowed 
Analgesic and Other Medications). Subjects taking no concomitant analgesic medication 
may directly begin Week -1 of the Screening Period.  
 Subjects will be provided a handheld device for pain reporting and, as a method for 
ensuring consistency and reliability of pain scoring, subjects will be instructed at all study 
visits how to record their pain score on the device and rescue medication use. Subjects 
will be educated at screening and reminded at other visits on appropriate expectations for 
their participation in a clinical study and the importance of consistently and accurately 
reporting their pain throughout the study. On each day preceding the Baseline Visit: 
(Week 0/Visit 2), subjects will record the following on the handheld device: 
o At bedtime: average pain intensity and use of rescue medication during the 
past 24 hours 
o Upon waking: DSIS 
 Subjects will be dispensed acetaminophen to be used as rescue medication and will be 
instructed to take no more than 3 g/day (one to two 500 mg tablets every 6 hours as 
needed) for pain related to fibromyalgia. 
10.2. 
Baseline Visit: Week 0/Visit 2 
At Week 0 (Visit 2), the following procedures and assessments will be performed/assessed: 
 Concomitant medication use  
 PGI-S 
 S-STS 
 Adverse events  
 Vital signs (blood pressure and pulse after sitting or lying supine for at least five minutes) 
 Electrocardiogram after five minutes in supine position 
 Blood samples for fasting (8 hours) serum chemistry and hematology 
 Urine sample for urinalysis 
 Urine pregnancy test for females of childbearing potential 
 Urine drug test 

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 Rescue medication return, assessment of appropriate use by inventory of returned tablets, 
as well as by subject interview 
 Verify eligibility with inclusion and exclusion criteria 
Pain scores reported by subjects during the Screening Period will be evaluated by the IRT system 
for raw score and for variability among scores after automated transmission of pain scores from 
the handheld devices to determine randomization eligibility.  The IRT system will notify the site 
 
Subjects who continue to meet all entry criteria and are randomized by the interactive response 
technology system will undergo the following procedures and assessments: 
 FIQR 
 PROMISFM  (sleep disturbance, fatigue profile, and physical function) 
 
 
 Dispensing of study drug  Subjects will take their first dose in the clinic. They will be 
instructed to take the study drug daily and confirm they have taken study drug in the 
handheld device each day. 
 Re-dispensing/dispensing of rescue medication  Subjects will be reminded not to exceed 
3 g/day (one to two 500 mg tablets every 6 hours as needed) for pain related to 
fibromyalgia  
 Subjects will be reminded on how to record their pain score on the device and will also 
be reminded about appropriate expectations for their participation in a clinical study and 
the importance of consistently and accurately reporting their pain intensity throughout the 
study. Refresher training of these educational materials will be repeated at each site-
based study visit via the aLearn® portal, with the exception of the final visit. On each day 
until returning to the study site, subjects will record the following on the handheld 
device: 
o At bedtime: average pain intensity and use of rescue medication during the past 
24 hours. 
o Upon waking: DSIS and confirm when study drug has been taken 
 The subject will be given a printed copy of the study specific S-STS to take home and 
complete during the Week 2 (Visit 3) telephone or videoconference visit.   
10.3. 
Treatment Period 
10.3.1. 
Week 2/Visit 3 
Week 2/Visit 3, will be conducted via telephone or videoconference.  The following procedures 
and assessments will be completed: 
 Concomitant medication use 
 S-STS  The subject will be asked to complete the printed copy of the S-STS given to 
them at their Baseline Visit while communicating with the site staff.  The staff will 
review the subject s answers to the S-STS and recommend corrections, only where the 

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form has been completed incorrectly.  The completed S-STS source document will be 
s 
chart and entered into the eCRF system.   
 Adverse events 
 Abuse and diversion assessment (MADDERS) 
 Rescue medication appropriate use assessment by review of daily use entries in the 
handheld and by subject interview 
 Study drug use and assessment of compliance by  review of daily use entries in the 
handheld and by subject interview  
 Compliance with entry into daily diary of pain intensity  
 Subjects will be instructed to take one capsule of study drug by mouth once daily  
 Subjects will be reminded not to exceed 3 g/day (one to two 500 mg tablets every 6 hours 
as needed) for pain related to fibromyalgia 
 
 Subjects will be reminded on how to record their pain on the device and will also be 
reminded about appropriate expectations for their participation in a clinical study.  
On each day until returning to the study site at Week 4/Visit4, subjects will record the 
following on the handheld device: 
o At bedtime: average pain intensity and use of rescue medication during the past 
24 hours. 
o Upon waking: DSIS and confirm when study drug has been taken 
 A subject may be asked to return to the clinic, per Investigator discretion, for additional 
study specific training or examination. Any unscheduled return to the clinic should be 
entered as an Unscheduled Visit into the eCRF and IRT systems. 
 
10.3.2. 
Week 4/Visit 4 and Week 8/Visit 5 
At Week 4/Visit 4 and Week 8/Visit 5, the following procedures and assessments will be 
performed/assessed: 
 Concomitant medication use 
 S-STS 
 Adverse events 
 Abuse and diversion assessment (MADDERS) 
 Vital signs (blood pressure and pulse after sitting or lying supine for at least five minutes) 
 Electrocardiogram after five minutes in supine position 
 Blood samples for fasting (8 hours) serum chemistry and hematology 
 Urine sample for urinalysis 

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 Urine pregnancy test, if clinically indicated for females of childbearing potential 
 Urine drug test 
 Rescue medication return, assessment of appropriate use by inventory of returned tablets, 
as well as by subject interview 
 Study drug return and assessment of compliance by inventory of returned capsules, as 
well as by subject interview  
 Compliance with entry into daily diary of pain intensity and rescue medication use 
 PGI-C 
 FIQR 
 PROMISFM (sleep disturbance, fatigue profile and physical function) 
 
 
 Dispensing of study drug  Subjects will be instructed to take one capsule of study drug 
by mouth once daily  
 Re-dispensing/dispensing of rescue medication  Subjects will be reminded not to exceed 
3 g/day (one to two 500 mg tablets every 6 hours as needed) for pain related to 
fibromyalgia 
 Subjects will be reminded on how to record their pain score on the device and will also 
be reminded about appropriate expectations for their participation in a clinical study and 
the importance of consistently and accurately reporting their pain intensity throughout the 
study. Review of these educational materials will be repeated for all subjects as refresher 
training or based on findings of an ongoing blinded data review (e.g., if pain score 
variability is increased on a subject or site level) via the aLearn® portal. On each day until 
returning to the study site at Week 8/Visit 5, subjects will record the following on the 
handheld device: 
o At bedtime: average pain intensity and use of rescue medication during the past 
24 hours. 
o Upon waking: DSIS and confirm when study drug has been taken 
10.3.3. 
Week 12/Visit 6/Early Termination Visit 
At Week 12/Visit 6, or at the time of early termination from the study, the following procedures 
and assessments will be performed/assessed: 
 Concomitant medication use 
 S-STS 
 Adverse events 
 Abuse and diversion assessment (MADDERS) 
 Vital signs (blood pressure and pulse after sitting or lying supine for at least five minutes) 
 Electrocardiogram after five (5) minutes in supine position 

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 Body weight 
 Brief physical examination 
 Blood samples for fasting (8 hours) serum chemistry and hematology 
 Urine sample for urinalysis 
 Urine pregnancy test for females of childbearing potential 
 Urine drug screen 
 Compliance with entry into daily diary of pain intensity, rescue medication use and self-
administration of study drug 
 FIQR 
 PGI-C 
 PROMISFM (sleep disturbance, fatigue profile and physical function) 
 
 
 Study drug return and assessment of compliance by inventory of returned capsules, as 
well as by subject interview  
 Rescue medication return and assessment of appropriate use by inventory of returned 
tablets, as well as by subject interview 
 Study-issued handheld device and any other study related materials returned 
 After completion of the study visits, the site will contact the subjects by telephone within 
10 days to complete a safety follow-up call.  The Investigator, at their discretion, may ask 
subject to return for an Unscheduled Visit for any safety concerns, abnormal laboratory 
or ECG findings.   
 A final call will be made to the subject approximately 30 days after the final visit to 
assess for AE closure and any new SAEs.  
11. 
STOPPING CRITERIA  
Subjects will be withdrawn from the treatment period of the study if any of the following 
laboratory results and symptoms are observed.  
 ALT or AST >8xULN   Discontinue subject treatment immediately. 
 ALT or AST >5xULN  
 ALT or AST >3xULN and (TBL >2xULN or INR >1.5)    
Discontinue treatment if result is confirmed upon retest (to be done within 48 hours or as 
soon as feasible).  
 ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
 ALT or AST >3x
eks 
 

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If an increase of serum aminotransferase of >3xULN is identified, repeat testing within 48 to 72 
hours of all four of the usual serum liver function test measures (ALT, AST, ALP, and 
TBL) should be conducted to confirm the abnormalities and to determine if they are increasing 
or decreasing.  
12. 
STATISTICS 
12.1. 
Sample Size Determination 
The planned sample size of 300 subjects will provide approximately 80% power for statistical 
testing with an overall Type I error rate of 0.05. 
12.2. 
Randomization 
Pain scores reported by subjects during the Screening Period will be evaluated by the IRT system 
for raw score and for variability among scores after transmission of pain scores from the 
handheld devices to determine randomization eligibility. Subjects whose mean of the daily 
average pain intensity score during the preceding 7 days within the protocol-defined algorithm 
and whose compliance with daily diary completion is found to be adequate will be eligible for 
randomization. The absolute pain scores and variability among scores, as well as the actual 
percentage required for diary compliance, will be masked to investigators and subjects. Subject 
eligibility for randomization into the study based on these variables will be communicated to the 
investigator via the IRT system. The 
   
12.3. 
Statistical Analysis Plan 
The planned statistical analysis methods, including procedures for accounting for missing, 
unused, and spurious data, will be described in more detail in the Statistical Analysis Plan, which 
will be finalized prior to study completion. Deviations from the original Statistical Analysis Plan 
will be described in the final clinical study report.  
Descriptive statistics for categorical variables will include the number and percent of subjects 
with each characteristic. Percentages will be based on the number of subjects with nonmissing 
values. Descriptive statistics for ordinal and continuous variables will include the number of 
subjects with nonmissing values, mean, median, standard deviation, minimum value, and 
maximum value. 
All relevant data collected in the eCRF will be shown for each subject in the individual subject 
data listings. 
12.4. 
Analysis Populations 
Safety analyses will be based on the Safety Population, defined as all subjects who receive at 
least one dose of study drug. 
Efficacy analyses will be based on the modified Intent-to-Treat Population, defined as all 
subjects in the Safety Population with at least one postbaseline assessment of the pain intensity 
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12.5. 
Treatment Group Comparisons 
The following treatment groups will be summarized in the statistical tables: 
 NYX-2925 50 mg 
 NYX-2925 100 mg 
 Placebo 
The following treatment group comparisons will be performed for efficacy: 
 NYX-2925 50 mg versus placebo 
 NYX-2925 100 mg versus placebo 
12.6. 
Analyses of Efficacy  
12.6.1. 
Primary Efficacy Analysis 
The primary efficacy analysis will be performed based on the modified Intent-to-Treat 
population. 
The primary efficacy endpoint is the change from baseline in the weekly mean of the daily NRS 
score assessing average pain intensity in the past 24 hours. The primary efficacy analysis will 
evaluate the treatment-policy estimand in the modified Intent-to-Treat population. The treatment-
policy estimand combines the improvement (reduction) from Baseline in the weekly mean of the 
daily NRS score and not discontinuing treatment early due to an AE or lack of efficacy through 
Week 12. 
The following four attributes describe the estimand that will be used to define the treatment 
effect of interest for the primary efficacy analysis: 
1. Population = Subjects meeting the protocol-specified inclusion/exclusion criteria, who 
received at least one dose of study drug and who have at least one post-baseline 
assessment of the pain intensity NRS. 
2. Subject-level outcome = Change from baseline in the weekly mean of the daily NRS 
score assessing average pain intensity in the past 24 hours 
3. Intercurrent event handling = An intercurrent event is defined as discontinuation of study 
drug due to an AE or lack of efficacy prior to Week 12. For the analysis, baseline 
Observation Carried Forward (BOCF) imputation will be used to impute data for visits 
after a patient has discontinued randomized treatment due to either of these reasons (even 
if data is present). 
4. Population-level summary measure = Difference in least squares mean change from 
baseline in the weekly mean of the daily NRS score at Week 12, comparing each dose of 
NYX-2925 to placebo. 
Any missing data at Week 12 that are not preceded by an intercurrent event (i.e., discontinuation 
of study drug due to AE or lack of efficacy) will remain as missing. 
For the primary efficacy endpoint, the daily pain intensity NRS score from the handheld device 
will be averaged for baseline after randomization. Change from baseline will be assessed for 

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treatment group difference using a mixed model for repeated measures (MMRM) with factors for 
study site, treatment, week, treatment by week interaction, and including the baseline value of 
the response variable as a covariate. Line plots displaying the mean weekly NRS scores from 
Weeks 1 through 12 for each treatment group will be generated. In these plots, the horizontal 
axis will reflect the study week and the vertical axis will reflect the average pain score. 
12.6.2. 
Sensitivity Analysis 
As a sensitivity analysis for the primary efficacy endpoint, an analysis of covariance (ANCOVA) 
model will be used to assess treatment differences. The model will include factors for study site 
and treatment and include the baseline value of the response variable as a covariate. 
Sensitivity analyses will be performed on the primary endpoint, evaluating the impact of the 
missing at random (MAR) assumption for missing data. Multiple imputation (MI) techniques 
based on Pattern Mixture Models (PMM) will be applied as the first sensitivity analysis. This 
methodology will structure data based on a missingness pattern having a monotone structure. An 
MI analysis with missing not at random (MNAR) assumption will be applied as the second 
sensitivity analysis. Placebo group based imputation will be used (i.e. the trajectories of the 
subjects with missing data on NYX-2925 are assumed to follow the placebo group after 
discontinuation).  
If the primary efficacy analysis significantly favors one or both doses of NYX-2925, a tipping 
point sensitivity analysis for the primary efficacy endpoint will be conducted. In this analysis, the 
assumption will be that that data in the NYX-2925 groups are not missing at random. A tipping 
point based assumption will be used, i.e. the trajectories of the subjects in each of the NYX-2925 
groups after withdrawal are assumed to be worse than placebo by an amount of delta. 
Successively harsher deltas will be imposed on the subjects in the NYX-2925 groups, starting 
with a mean weekly NRS score increment (increaase) of 0.5 points. The delta will be further 
increased in steps of 0.5 points (i.e., 1.0, 1.5, 2.0) until the statistical significance is lost, i.e. until 
the p-value becomes >0.05. 
12.6.3. 
Secondary Efficacy Endpoints  
The following secondary endpoints will be analyzed: 
 
Impression of Change (PGI-C) at Week 12 
 Change from baseline in the weekly mean of the Daily Sleep Interference Scale (DSIS) 
scores at Week 12 
 
average pain intensity at Week 12 
 
average pain intensity related to fibromyalgia at Week 12 
 Change from baseline to Week 12 in the Fibromyalgia Impact Questionnaire  Revised 
(FIQR) score 
 Change from baseline to Week 12 in the Patient Reported Outcomes Measurement 
Information System  Fibromyalgia (PROMISFM) sleep disturbance score 

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 Change from baseline to Week 12 in the Patient Reported Outcomes Measurement 
Information System  Fibromyalgia (PROMISFM) fatigue profile score 
 Change from baseline to Week 12 in the Patient Reported Outcomes Measurement 
Information System  Fibromyalgia (PROMISFM) physical function score  
 Cumulative response (percent reduction from baseline) in the weekly mean NRS average 
pain intensity at Week 12 
 Use of rescue medication, including the proportion of subjects using rescue medication, 
the frequency and amount used 
 Change from baseline in the weekly mean of the daily Numerical Rating Scale (NRS) at 
each week from Week 1 through Week 12 
 
12.6.4. 
Other Efficacy Analyses 
12.6.5. 
Multiple Comparisons 
The primary efficacy endpoint and primary statistical analysis are protocol specified.   
The primary efficacy endpoint and other selected efficacy endpoints will be tested (using 
MMRM as described above) to preserve the overall Type I error rate. 
There will be no other adjustments for multiple comparisons. 

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12.7. 
Analyses of Safety  
All safety summaries will be descriptive; no statistical testing will be performed. 
12.7.1. 
Adverse Events 
A TEAE is defined as an adverse event with an onset that occurs after receiving study drug, or a 
continuing adverse event diagnosed prior to the date of first dose of study drug that increases in 
severity after the start of dosing. Adverse events will be categorized by system organ class and 
preferred term with the Medical Dictionary for Regulatory Activities (MedDRA). 
Summary tables for TEAEs will include number and percent of subjects experiencing TEAEs by 
system organ class and preferred term. If a subject has more than one TEAE 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 one TEAE within a system organ class category, the subject will be 
counted only once in that system organ class category.  
The following TEAE summaries will be provided for the Treatment Period:  
 Overall summary of TEAEs  
 TEAEs by system organ class and preferred term  
 Drug-related TEAEs by system organ class and preferred term 
 TEAEs by system organ class, preferred term, and severity 
 Serious TEAEs by system organ class and preferred term 
 TEAEs leading to study drug discontinuation by system organ class and preferred term 
12.7.2. 
Clinical Laboratory Tests 
Mean changes from baseline will be summarized descriptively for each clinical laboratory 
parameter. 
Clinical laboratory results considered clinically important by the Investigator will be identified. 
Individual results for clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
outside the normal range will be flagged in the data listings.  
Clinical laboratory assessments will be conducted by a central laboratory.  
12.7.3. 
Electrocardiogram 
The interpretation of ECG and interval duration measurements by the designated ECG laboratory 
cardiologists will be reviewed by the Investigator. Clinically significant deteriorations from 
baseline will be reported and summarized as TEAEs. 
12.7.4. 
Vital Sign Measurements  
Mean change from baseline will be summarized descriptively for each vital sign. 
12.7.5. 
Suicidal Ideation 
Subjects with suicidal ideation or behavior will be identified with the S-STS.  

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12.8. 
Interim Analysis 
No interim analysis is planned for this study. 
13. 
ADMINISTRATIVE 
13.1. 
Source Documents 
Source documents are defined as the result of original observations and activities of a clinical 
investigation. Source documents may include, but are not limited to, study progress notes, e-mail 
correspondences, informed consent forms, clinical laboratory reports, medical histories, hospital 
records, and drug accountability records. All source documents will be maintained by the 
Investigator(s) and made available for inspection by Sponsor representatives, the FDA, and other 
applicable regulatory authorities. 
13.2. 
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 Council for 
Harmonisation (ICH) guidelines, Good Clinical Practice (GCP), 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. 
Aptinyx is also collecting the impact of COVID-19 on visits (e.g. incomplete or remote visits, 
dosing interruptions, changes in planned IP dispensation). 
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. 
13.3. 
Case Report Forms 
An 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 Subinvestigator listed on the FDA Form 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). 
13.4. 
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 wil
. Sites using 
a local IRB are responsible for submitting the amendment for review and approval. 

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13.5. 
Audits and Inspections 
During the course of the study or after completion of the study, each 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. 
13.6. 
Institutional Review Board 
This protocol, the informed consent document, and all relevant supporting data must be 
submitted to the IRB for approval. Institutional Review Board approval of the protocol, informed 
consent documents, any subject-facing materials, 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 adverse events or 
protocol deviations that occur during the study and meet IRB reporting requirements. 
The Investigator agrees that he/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. 
13.7. 
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. 
13.8. 
Informed Consent 
Written informed consent must be obtained from potential study subjects prior to the initiation of 
any study-related procedures. This study may employ electronic informed consent. Electronic or 
digital signatures (compliant with 21 CFR § 11 regulations for collecting and storing digital 
The use of electronic informed consent supplements the interaction between the participant and 
the research staff, and it provides an opportunity for remote conduct of study activities in the 
setting of the COVID-19 Health Emergency. The informed consent document may be executed 
up to 30 days prior to the screening visit. The date the first screening related activity is 
completed will be consider
screening visit within 30 days of signing the informed consent document, the subject must be 
reconsented. The original signed informed consent form for each participating subject shall be 
filed with records kept by the Investigator(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. If the informed consent form is revised, subjects actively participating in the study 
must be reconsented in a timely manner. 

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13.9. 
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, regulatory documents (IRB 
approvals/correspondence, study logs, FDA 1572 forms, financial disclosures, clinical study 
material records, study drug accountability records, and medical records). 
13.10. 
Study Completion 
Aptinyx requires the following data and materials be completed before a study can be considered 
terminated or completed: source documents are completed, study drug reconciliation activities 
are completed, and study procedures and assessments are source verified and completed. 
13.11. 
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 
confidentiality of personal health information, and in accordance with applicable national and/or 
local laws and regulations on personal health information protection. 
Monitors, auditors, and other authorized agents of Aptinyx, the IRB approving this research and 
applicable regulatory authorities w
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 
presen
ies will 
remain confidential. 
13.12. 
Compensation, Insurance, and Indemnity 
Information regarding compensation, insurance, and indemnity is addressed in the Clinical Trial 
Research Agreement. 
13.13. 
Financial Disclosure 
The Investigator(s) are responsible for providing financial disclosure(s) in covered clinical 
studies. Principal Investigators and Subinvestigators are required to disclose applicable financial 
information, and to promptly update Aptinyx with any relevant changes throughout the study and 
for one (1) year after study completion. 
13.14. 
Records Retention 
According to United States Investigational New Drug regulations (21 CFR 312.62), records and 
documents pertaining to the conduct of this study and the distribution of study drug including but 
not limited to source documents, eCRFs, informed consent forms, clinical laboratory test results, 
and drug inventory records will be retained. These records will be kept on file by the Principal 
Investigator for two 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 two years after the investigation has been discontinued and the FDA has been 
notified. Per ICH guidelines, documents should be retained until at least two years after the last 
approval of a marketing application in an ICH region and until there are no pending or 

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contemplated marketing applications in an ICH region, or at least two years have elapsed since 
the formal discontinuation of clinical development of the study drug. Aptinyx will notify the 
Investigator when records and documents no longer need to be retained. No study records should 
be destroyed without prior authorization. 
13.15. 
Publication Policy 
The publication policy is outlined in the Clinical Trial Agreement. 

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14. 
REFERENCES 
Arnold 2012 
Arnold LM, Clauw DJ, Dunegan LJ, Turk DC; FibroCollaborative. A 
framework for fibromyalgia management for primary care providers. Mayo 
Clin Proc. 2012 May;87(5):488-96. 
Bennett 2009 
Bennett RM, Friend R, Jones KD, Ward R, Han BK, Ross RL. The Revised 
Fibromyalgia Impact Questionnaire (FIQR): validation and psychometric 
properties. Arthritis Res Ther. 2009;11(4):R120. 
Clauw 2011 
Clauw DJ, Arnold LM, McCarberg BH; FibroCollaborative. The science of 
fibromyalgia. Mayo Clin Proc. 2011 Sep;86(9):907-11. 
Cleeland 1994 
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain 
Inventory. Ann Acad Med Singapore. 1994;23(2):129-38. 
Driban 2015 
Driban JB, Morgan N, Price LL, Cook KF, Wang C. Patient-Reported 
Outcomes Measurement Information System (PROMIS) instruments among 
individuals with symptomatic knee osteoarthritis: a cross-sectional study of 
floor/ceiling effects and construct validity. BMC Musculoskelet Disord. 
2015 Sep 14;16:253.  
Harte 2013 
Harte SE, Mitra M, Ichesco EA, et al. Development and validation of a 
pressure-type automated quantitative sensory testing system for 
point-of-care pain assessment. Med Biol Eng Comput. 2013;51(6):633-44. 
Jensen 2014 
Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: 
clinical manifestations and mechanisms. Lancet Neurol. 2014;13:924-35. 
Katz 2005 
Katz N. Methodological issues in clinical trials of opioids for chronic pain. 
Neurology. 2005;65(Suppl 4):S32 S49. 
Katz 2015 
Katz NP, Mou J, Paillard FC, Turnbull B, Trudeau J, Stoker M. Predictors 
of response in patients with postherpetic neuralgia and HIV-associated 
neuropathy treated with the 8% capsaicin patch (Qutenza). Clin J Pain. 
2015;31:859 66. 
Klinger 2017 
Klinger R, Blasini M, Schmitz J, Collocab L. Nocebo effects in clinical 
studies: hints for pain therapy. Pain Rep. 2017 Mar;2(2): e586. 
Kratz 2016 
Kratz AL, Schilling S, Goesling J, Williams DA. The PROMIS FatigueFM 
Profile: a self-report measure of fatigue for use in fibromyalgia. Qual Life 
Res. 2016 Jul;25(7):1803-13.  
Mony 2009 
Mony L, Kew JN, Gunthrope MJ, Paoletti P. Allosteric modulators of 
NR2B-containing NMDA receptors: molecular mechanisms and therapeutic 
potential. Br J Pharmacol. 2009;157:1301-17. 
Moore 2013 
Moore RA, Derry S, Wiffen PJ. Challenges in design and interpretation of 
chronic pain trials. Br J Anaesthesia 2013;111(1):38 45. 

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15. 
APPENDICES 
15.1. 
Disallowed Analgesic and Other Medications* 
Washout of the following disallowed analgesics should be completed during screening, with the 
last dose being at least 2 weeks prior to randomization. 
 Tricyclic antidepressants (TCAs) 
 Norepinephrine reuptake inhibitors (NRIs), e.g., atomoxetine (Strattera®) and bupropion 
(Wellbutrin®, Zyban®) 
 Serotonin-norepinephrine reuptake inhibitors (SNRIs), eg., milnacipran (Savella), 
duloxetine (Cymbalta®), venlafaxine (Effexor®), Desvenlafaxine (Pristiq®), 
levomilnacipran (Fetzima®) 
 Anti-epileptics, eg., gabapentin (Neurontin®) and pregabalin (Lyrica®); NMDA receptor 
ligands 
 Opioids 
 NSAIDs (except as described in section 8.7) 
 Benzodiazepines except alprazolam or lorazepam 
 Muscle relaxants 
 Acetaminophen or acetaminophen containing therapies for indications other than 
fibromyalgia 
 Topical therapies: topical capsaicin; topical/local anesthetic lidocaine 
*Any non-pharmacologic therapies or interventions for treatment of pain that are not on this list 
needs to be discussed with the Medical Monitor prior to screening (eg., nerve blocks, spinal 
stimulators, etc). 
Subjects must be stable for at least seven (7) days prior to randomization. The s
condition 
is 
 judgment. It means no significant withdrawal effects, and to be 
stable regarding their pain, i.e., subjects should not be in a flare state with much worse pain than 
before washout as is common with discontinuation of any drugs but most common with NSAIDs 
and opioids. 
Prohibited medications must not be withdrawn for participation in this study when prescribed for 
a condition other than pain.