A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of NYX-2925 in Subjects With Neuropathic Pain Associated With Diabetic Peripheral Neuropathy
Phase: PHASE2
Conditions: Diabetic Peripheral Neuropathic Pain
Sponsor: Aptinyx

 
 
A Randomized, Double-Blind, Placebo Controlled Study to Assess the Efficacy and 
Safety of NYX-2925 in Subjects with Neuropathic Pain Associated with Diabetic 
Peripheral Neuropathy 
Amendment #7 
25 June 2021 
NCT04146896 

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INVESTIGATIONAL PRODUCT: NYX-2925 
CLINICAL PROTOCOL: NYX-2925-2008
A Randomized, Double-Blind, Placebo Controlled Study to 
Assess the Efficacy and Safety of NYX-2925 in Subjects with 
Neuropathic Pain Associated with Diabetic Peripheral 
Neuropathy
Amendment #7
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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and Other Medications). The discontinuation of analgesic medication(s) will be managed by the Principal 
Investigator or designee at the investigative site, as applicable. Subjects taking no concomitant analgesic 
medication for their painful diabetic neuropathy at Visit 1 may directly begin Week -1 of the Screening 
Period 
During Visit 1, eligible subjects will be provided a handheld device, and as a method for ensuring 
consistency and reliability of pain scoring, subjects will be instructed at all study visits on how to record 
their pain and rescue medication use on the device. Subjects will also be educated at screening (APR® and 
PRR® training [Analgesic Solutions, Wayland, MA] ) via the aLearn® electronic learning management 
system and provided refresher training in that portal at all site-based study visits, with the exception of the 
final visit.  Subjects will be reminded at all visits of appropriate expectations around their participation in a 
clinical study and the importance of consistently and accurately reporting their pain throughout the study. 
An ongoing blinded data review (e.g., if pain score variability is increased on a subject or site level) will be 
conducted to monitor these metrics [Analgesic Solutions, Wayland, MA]. 
Subjects will be dispensed acetaminophen to be used as rescue medication (RM) and will be instructed to 
take no more than 2 g /day (one to two 500 mg tablets every 6 hours as needed up to 4 tablets total) for DPN 
related pain.  
For pain unrelated to DPN, 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 DPN, the medication should be recorded as a concomitant medication and the adverse event 
must be recorded in the eCRF.   
Beginning at Week - 1, DPN related pain intensity and rescue medication use will be recorded in the study-
issued handheld device daily at bedtime. Subjects will enter their average pain intensity, worst pain 
intensity, average pain upon walking, and total rescue medication use during the past 24 hours. Pain 
intensity will be recorded using an 11-point NRS, with 0 being no pain and 10 being the worst pain 
imaginable. Every morning upon awakening, subjects will complete the Daily Sleep Interference Scale 
(DSIS) via their study-issued handheld device. 
The following scales will be completed at the Screening Visit (Visit 1): MNSI, MDT, PGI-S and S-
STS. 
Screening Period: Week -1 (as needed) 
Subjects taking no concomitant analgesic medication for their painful diabetic neuropathy at Visit 1 may 
directly begin Week -1 of the Screening Period. 
Baseline Visit: Week 0/Visit 2 
At Visit 2 (Baseline Visit), study personnel will verify eligibility with the inclusion and exclusion criteria 
when the subjects are on site and perform safety assessments prior to randomization. 
The appropriate use of rescue medication will be assessed by inventory of the returned tablets, as well as by 
subject interview. Subjects will be asked a nonleading question to assess potential adverse events. Use of 
concomitant medications will be documented. Additional procedures during Visit 2 will include the S-STS, 
an ECG, and vital signs (blood pressure and pulse after sitting or lying supine for at least five (5) minutes). 
Blood (8 hour fast) samples will be collected for hematology, serum chemistry, and urine sample will be 
collected for urinalysis testing. Subjects will undergo drug screens using a local urine testing kit. Subjects 
who test positive for benzodiazepines inconsistent with protocol specified allowed prescriptions, 
psychoactive cannabinoids (e.g., marijuana, THC) inconsistent with subject reported use, opioids, PCP, 
cocaine or amphetamines, will not be allowed to continue in the study. Female subjects of childbearing 
potential will be tested for pregnancy using a local urine testing kit and will be counseled to continue using 
highly effective contraception.  
Pain scores reported by subjects during the Screening Period will be evaluated by the interactive response 

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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................... 1 
INVESTIGATOR SIGNATURE PAGE: ....................................................................................... 2 
SPONSOR SIGNATURE PAGE: ................................................................................................... 3 
PROCEDURES IN CASE OF EMERGENCY.............................................................................. 4 
1. 
SYNOPSIS ..................................................................................................................... 5 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ........... 16 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................... 21 
4. 
INTRODUCTION ....................................................................................................... 23 
5. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................. 26 
5.1. 
Primary Objective .......................................................................................................... 26 
5.2. 
Secondary Objective ...................................................................................................... 26 
5.3. 
Study Endpoints............................................................................................................. 26 
5.3.1. 
Efficacy Endpoints ........................................................................................................ 26 
5.3.2. 
 .............................................................................................. 27 
5.3.3. 
Safety Endpoints ............................................................................................................ 27 
6. 
INVESTIGATIONAL PLAN ..................................................................................... 27 
6.1. 
Overall Study Design and Plan: Description ................................................................. 27 
6.2. 
Scientific Rationale for Study Design ........................................................................... 39 
6.3. 
Justification of Dose ...................................................................................................... 39 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................ 39 
7.1. 
Subject Inclusion Criteria .............................................................................................. 39 
7.2. 
Subject Exclusion Criteria ............................................................................................. 41 
7.3. 
Screen Failures .............................................................................................................. 43 
7.4. 
Subject Withdrawal Criteria .......................................................................................... 43 
7.5. 
Methods of Birth Control .............................................................................................. 44 
7.6. 
Accurate Pain Reporting and Placebo Response Reduction Training .......................... 44 

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8. 
STUDY TREATMENT ............................................................................................... 44 
8.1. 
Dosing and Administration............................................................................................ 44 
8.2. 
Study Drug and Rescue Medication Description, Appearance, Packaging, and Labeling
 ....................................................................................................................................... 45 
8.3. 
Preparation and Handling .............................................................................................. 45 
8.4. 
Storage ........................................................................................................................... 46 
8.5. 
Accountability ............................................................................................................... 46 
8.6. 
Treatment Compliance .................................................................................................. 46 
8.7. 
Concomitant and Excluded Medications ....................................................................... 46 
9. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................... 47 
9.1. 
Screening Assessments .................................................................................................. 47 
9.1.1. 
Medical History ............................................................................................................. 47 
9.1.2. 
Masquerading Disorders Tool ....................................................................................... 47 
9.1.3. 
Michigan Neuropathy Screening Instrument ................................................................. 48 
9.2. 
Efficacy Assessments .................................................................................................... 48 
9.2.1. 
Numeric Rating Scale of Pain Intensity ........................................................................ 48 
9.2.2. 
Patient Global Impression of Change ............................................................................ 48 
9.2.3. 
Norfolk Quality of Life Questionnaire  Diabetic Neuropathy (QOL-DN) .................. 48 
9.2.4. 
Daily Sleep Interference Scale ...................................................................................... 49 
9.2.5. 
Brief Pain Inventory for Diabetic Peripheral Neuropathy ............................................. 49 
9.2.6. 
Patient Global Impression of Severity (PGI-S) ............................................................. 49 
9.2.7. 
Pain Catastrophizing Scale (PCS) ................................................................................. 49 
9.3. 
Safety Assessments ....................................................................................................... 49 
9.3.1. 
Safety Parameters .......................................................................................................... 49 
9.3.2. 
Vital Sign Measurements .............................................................................................. 50 
9.3.3. 
Physical Examination .................................................................................................... 50 
9.3.4. 
Electrocardiogram ......................................................................................................... 50 
9.3.5. 
Clinical Laboratory Assessments .................................................................................. 50 
9.3.6. 
Sheehan-Suicidality Tracking Scale .............................................................................. 51 

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9.3.7.
Abuse and Diversion Assessment ................................................................................. 52
9.4. 
Safety and Pharmacovigilance ...................................................................................... 52 
9.4.1. 
Adverse Events  Relationship to Study Drug .............................................................. 52 
9.4.2. 
Recording Adverse Events ............................................................................................ 52 
9.4.3. 
Reporting Adverse Events ............................................................................................. 53 
9.5. 
Serious Adverse Events ............................................................................................... 54 
9.5. 
Other Reportable Events ................................................................................................ 56 
10. 
SCHEDULE OF PROCEDURES .............................................................................. 56 
10.1. 
Visit 1 and Screening Period (Week -4 to Week -1) ..................................................... 56 
10.2. 
Baseline Visit: Week 0/Visit 2 ...................................................................................... 58 
10.3. 
Treatment Period ........................................................................................................... 59 
10.3.1. 
Week 2/Visit 3 ............................................................................................................... 59 
10.3.2. 
Week 4/Visit 4 ............................................................................................................... 60 
10.3.3. 
Week 8/Visit 5 ............................................................................................................... 61 
10.3.4. 
Week 12/Visit 6/Early Termination .............................................................................. 62 
11. 
STOPPING CRITERIA .............................................................................................. 63 
12. 
STATISTICS ............................................................................................................... 63 
12.1. 
Sample Size ................................................................................................................... 63 
12.2. 
Randomization ............................................................................................................... 63 
12.3. 
Statistical Analysis Plan ................................................................................................ 64 
12.4. 
Analysis Populations ..................................................................................................... 64 
12.5. 
Treatment Group Comparisons ..................................................................................... 64 
12.6. 
Analyses of Efficacy...................................................................................................... 64 
12.6.1. 
Primary Efficacy Endpoint ............................................................................................ 64 
12.6.2. 
Secondary Efficacy Endpoints ...................................................................................... 66 
12.6.3. 
 ................................................................................................ 66 
12.6.4. 
Multiple Comparisons ................................................................................................... 67 
12.7. 
Analyses of Safety ......................................................................................................... 67 
12.7.1. 
Adverse Events .............................................................................................................. 67 

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12.7.2.
Clinical Laboratory Tests .............................................................................................. 67
12.7.3. 
Electrocardiogram ......................................................................................................... 68 
12.7.4. 
Vital Sign Measurements .............................................................................................. 68 
12.7.5. 
Suicidal Ideation ............................................................................................................ 68 
12.8. 
Interim Analysis ............................................................................................................ 68 
13. 
ADMINISTRATIVE ................................................................................................... 68 
13.1. 
Source Documents ......................................................................................................... 68 
13.2. 
Study Monitoring........................................................................................................... 68 
13.3. 
Electronic Case Report Forms (eCRF) .......................................................................... 68 
13.4. 
Protocol Amendment(s) ................................................................................................. 69 
13.5. 
Audits and Inspections .................................................................................................. 69 
13.6. 
Institutional Review Board ............................................................................................ 69 
13.7. 
Compliance with Regulatory Requirements .................................................................. 69 
13.8. 
Informed Consent .......................................................................................................... 69 
13.9. 
Study File Management ................................................................................................. 70 
13.10. 
Study Completion .......................................................................................................... 70 
13.11. 
Confidentiality ............................................................................................................... 70 
13.12. 
Compensation, Insurance, and Indemnity ..................................................................... 70 
13.13. 
Financial Disclosure ...................................................................................................... 70 
13.14. 
Records Retention ......................................................................................................... 71 
13.15. 
Publication Policy .......................................................................................................... 71 
14. 
REFERENCES ............................................................................................................ 72 
15. 
APPENDICES ............................................................................................................. 74 
15.1. 
Disallowed Analgesic and Other Medications* ............................................................ 74 
 
 
 

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LIST OF TABLES 
Table 1 
Emergency Contact Information .................................................................................... 4 
Table 2 
Abbreviations and Special Terms ................................................................................ 21 
Table 3 
Schedule of Procedures ................................................................................................ 35 
 
LIST OF FIGURES 
 
Figure 1 
Study Design ................................................................................................................ 28 

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Abbreviation or specialist term 
Explanation 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MDT 
Masquerading Disorders Tool 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
MNSI 
Michigan Neuropathy Screening Instrument 
NF 
National Formulary 
NMDAR 
N-methyl-D-aspartate receptor 
NOAEL 
no-observed-adverse-effect level 
NOEL 
no-observed-effect level 
NRS 
Numeric Rating Scale 
NYHA 
New York Heart Association 
PCS 
Pain Catastrophizing Scale 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PRR® 
Placebo Response Reduction® 
QOL-DN 
Norfolk Quality of Life Questionnaire - Diabetic Neuropathy 
SAE 
serious adverse event 
S-STS 
Sheehan-Suicidality Tracking Scale 
TBL 
total bilirubin 
T3 
Triiodothyronine 
T4 
Thyroxine 
TEAE 
treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
TSH 
thyroid stimulating hormone 
VCT 
Verified Clinical Trials 
ULN 
upper limit of normal 
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 small molecule interacts with N-methyl-D-aspartate receptors (NMDARs) 
through a novel binding domain and acts as 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, and are, therefore, termed NMDARs. Unlike other glutamate receptors 
found 
-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 anxiety, cognition, 
Tai 2001; Mony 2009; 
Traynelis 2010]. 
The central nervous system modulates the experience of pain in people with neuropathic pain, with 
the rostroventralmedial 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 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. The prevalence of neuropathic pain is 
approximately 8% in the population in the United States [Gilron 2015; Toth 2013; Bouhassira 
2008]. Individuals suffering from neuropathic pain, irrespective of the underlying disorder, 
currently have limited treatment options available. 
Current treatment options predominantly include antidepressants and antiepileptics. These 
therapies have shown some efficacy in treating neuropathic pain symptoms, although for a large 
proportion of patients, treatment is insufficient. 
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. 

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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 1 hour. NYX-2925 is 
rapidly eliminated from plasma, with an apparent terminal elimination half-life in the range of 4 to 
5 hours in rats and 1 to 2 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 August 2020, the clinical development program for NYX-2925 includes 3 completed Phase 1 
studies in healthy volunteers, 1 completed Phase 2 study in subjects with diabetic peripheral 
neuropathy (DPN), 1 completed Phase 2 study in subjects with fibromyalgia. NYX-2925 exposure 
in these studies includes 154 healthy volunteers, 229 subjects with DPN, and 22 subjects with 
fibromyalgia. There is also one ongoing Phase 2 study in subjects with fibromyalgia. 
In Phase 2 Study NYX-2925-2001, 300 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). NYX-2925 did not significantly affect average pain scores in adult 
subjects with neuropathic pain associated with DPN. However, numerical improvements in pain 
intensity were observed in subjects taking NYX-2925 compared with placebo, especially for subjects 
with long-standing disease who were not using a 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 placebo in the pos
 
Exploratory efficacy analyses of NYX-2925 (20 and 200 mg) compared to placebo have also been 
performed in Phase 2 Study NYX-2925-2002 in 22 subjects with fibromyalgia. Clinically 
meaningful and nominally statistically significant improvements were observed in pain, fatigue, the 
overall intensity of fibromyalgia symptoms and their impact on function. NYX-2925 demonstrated 
antinociceptive activity in neuroimaging evaluations. Pharmacodynamic results from this study 
revealed that NYX-2925 reduced glutamate + glutamine (Glx) levels within the posterior insula, a 
region previously implicated in pain processing in fibromyalgia. 

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Pharmacokinetic analysis revealed that absorption of NYX-2925 was relatively rapid; peak 
concentrations were achieved within 2 hours after dosing and declined in a roughly monophasic 
manner over 24 hours. The pharmacokinetic profiles were dose-proportional over the dose range 
tested and showed minimal accumulation following once daily dosing for 7 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. 
Overall, NYX-2925 appears to be safe and well tolerated at oral doses up to 200 mg daily for up 
to 4 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, arthralgia, abdominal distension, anxiety, and 
eructation. 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 NYX2925 20 mg. 
No clinically meaningful changes in vital sign measurements, safety 12-lead electrocardiogram 
(ECG) results, physical examination findings or suicidality have been observed after a single 
dose of NYX-2925. Few potentially clinically significant laboratory results were observed during 
4 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 Phase 2 clinical data support further testing in patients with painful 
peripheral diabetic neuropathy. 
This study (NYX-2925-2008) is a randomized, double-blind, placebo-controlled study to assess 
the efficacy and safety of NYX-2925 in subjects with neuropathic pain associated with diabetic 
peripheral neuropathy. NYX-2925 will be provided as capsules for oral administration in a 
strength of 50 mg NYX-2925 per capsule. 
 

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5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Primary Objective 
The primary objective of this study is: 
 To evaluate the efficacy of NYX-2925 50 mg QD versus placebo in treating neuropathic 
pain associated with diabetic peripheral neuropathy. 
 To assess the safety and tolerability of NYX-2925 50 mg QD. 
5.2. 
Secondary Objective 
The secondary objective of the study is: 
 To assess the effects of NYX-2925 50 mg QD versus placebo on pain characteristics, 
sleep interference, 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 Numeric Rating Scale (NRS) score assessing 
average pain intensity related to DPN in the past 24 hours. 
The secondary efficacy endpoints are: 
 Change from baseline in the weekly mean of the Daily Sleep Interference Scale (DSIS) 
scores at Week 12. 
 Percentage of 
 Patient Global 
Impression of Change (PGI-C) at Week 12. 
 
from baseline in the weekly mean 
NRS average pain intensity related to DPN at Week 12. 
 
average pain intensity related to DPN at Week 12. 
 Change from baseline to Week 12 in Norfolk Quality of Life Questionnaire  Diabetic 
Neuropathy (QOL-DN) score.  
 Use of rescue medication, including the proportion of subjects using rescue medication, 
the frequency and amount used. 
 Cumulative response (percent reduction from baseline) in the weekly mean NRS average 
pain intensity at Week 12 
 Change from baseline in the weekly mean of the daily Numerical Rating Scale (NRS) at 
each week from Week 1 through Week 12 

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5.3.2. 
Other Efficacy Endpoints 
5.3.3. 
Safety Endpoints 
The safety endpoints will include adverse events and serious adverse events, discontinuation due 
to AE and the S-STS. 
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; 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 37 study sites in the United States. 
 

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Figure 1
Study Design
Visit 1 and Screening Period: (Week -4 to Week -1)
Upon Institutional Review Board (IRB) approval of the protocol, 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 signatures) may be captured 
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 to provide an additional consent for their 
inclusion in 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 information to r
Subjects who meet any of the following criteria will not be eligible for continued 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-2925-2008 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.
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 any analgesic medications for their 
pain related to diabetic peripheral neuropathy will then be required to discontinue the analgesic 
medication. Subjects taking no concomitant analgesic medication for their painful diabetic 

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neuropathy at Visit 1 may directly begin Week -1 of the Screening Period. The last dose of any 
prohibited analgesic must be at least two (2) weeks prior to randomization. 
3) During this time, subjects will be provided a handheld device to record their pain and rescue 
medication use. Prior to recording their first pain score in the handheld device, 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 with Type 2 diabetes who have been on stable antidiabetic medication for at least one 
(1) month (or have stable glycemic control with diet and exercise alone) and who have been 
diagnosed with DPN in the lower extremities for at least four (4) years (DPN in the upper 
extremities is not exclusionary) will be screened for diabetic peripheral neuropathy using the 
Michigan Neuropathy Screening Instrument (MNSI) and the Masquerading Disorders Tool 
(MDT). Subjects must have presence of pain due to diabetic neuropathy for at least 6 months 
prior to screening. Subjects 
moderate pain  over the last week, as assessed 
by the Patient Global Impression of Severity (PGIS) at the screening visit. Additional procedures 
during Visit 1 will include the completion of the Sheehan-Suicidality Tracking Scale (S-STS); 
serious adverse event collection which will begin from the time of informed consent is obtained 
through 30 days after the last dose of study drug, demographic characteristics, and medical 
history (including history of Type 2 diabetes and history of painful DPN, prior (within the last 30 
days) and concomitant medications, complete physical examination (with comprehensive 
neurological examination), triplicate electrocardiograms (ECGs [three separate ECGs]), with a 
minimum of a two minute interval), vital signs (blood pressure and pulse after sitting or lying 
supine for at least five (5) minutes), height, body weight, and collection of blood (8 hour fast) 
samples for hematology, serum chemistry, hemoglobin A1c (HbA1c), triglycerides, human 
immunodeficiency virus (HIV) screening, hepatitis screening, and urine sample will be collected 
for urinalysis. Vital signs may be repeated up to three (3) times at screening, per the 
with the final measurement of vital signs being entered into the eCRF system. All subjects will 
undergo urine drug screens using a local urine testing kit. Subjects who test positive for 
benzodiazepines or opioids inconsistent with current prescriptions, psychoactive cannabinoids 
(e.g., marijuana, THC) inconsistent with subject reported use, PCP, cocaine or amphetamines, 
will not be eligible for the study. Female subjects of childbearing potential will be tested for 
pregnancy using a local urine testing kit and will be counseled to begin or continue using highly 
effective contraception. 
Eligible subjects who meet all entry criteria will enter a 1 to 4-week Screening Period, during 
which they will discontinue all their analgesic treatments, including those being taken for 
neuropathic pain associated with diabetic peripheral neuropathy. The duration of the Screening 
Period will depend upon the analgesic treatment that is being discontinued (see Section 15.1 of 
the protocol for Disallowed Analgesic and Other Medications). The discontinuation of analgesic 
medication(s) will be managed by the Principal Investigator or designee at the investigative site, 
as applicable. Subjects not taking concomitant analgesic medications at Visit 1 may directly 
begin Week -1 of the Screening Period. 
During Visit 1, eligible subjects will be provided a handheld device, 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 and rescue medication use on the device. Each subject will undergo 

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educational training on Accurate Pain Reporting (APR®) and Placebo Response Reduction 
(PRR®) via an electronic learning management system, aLearn® [Analgesic Solutions, 
Wayland, MA] Subjects will be educated at screening and reminded at other study visits on 
appropriate expectations around their participation in a clinical study and the importance of 
consistently and accurately reporting their pain throughout the study. This training is mandatory 
prior to randomization and at each site-based visit, with the exception of the final visit. An 
ongoing data review (e.g., if pain score variability is increased on a subject or site level) will be 
conducted to monitor these metrics [Analgesic Solutions, Wayland, MA]. 
Subjects will be dispensed acetaminophen to be used as rescue medication and will be instructed 
to take no more than 2 g /day (one to two 500 mg tablets every 6 hours as needed up to 4 tablets 
total) for DPN related pain. 
For pain unrelated to DPN, 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 DPN, the medication should be recorded as a 
concomitant medication and the adverse event must be recorded in the eCRF. Beginning at Week 
-1, DPN related pain intensity and rescue medication use will be recorded in the study-issued 
handheld device daily at bedtime. Subjects will enter their average pain intensity, worst pain 
intensity, average pain upon walking, and total rescue medication use during the past 24 hours. 
Pain intensity will be recorded using an 11-point NRS, with 0 being no pain and 10 being the 
worst pain imaginable. Every morning upon awakening, subjects will complete the Daily Sleep 
Interference Scale (DSIS) via their study-issued handheld device. 
The following scales will be completed at the Screening Visit (Visit 1): MNSI, MDT, PGI-S and 
S-STS. 
Screening Period: Week -1 (as needed) 
Subjects taking no concomitant analgesic medication for their painful diabetic neuropathy at 
Visit 1 may directly begin Week -1 of the Screening Period. 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.  
Baseline Visit: Week 0/Visit 2 
At the Visit 2 (Baseline Visit), study personnel will verify eligibility with the inclusion and 
exclusion criteria when the subjects are on site and perform safety assessments prior to 
randomization. 
The appropriate use of rescue medication will be assessed by inventory of the returned tablets, as 
well as by subject interview. Subjects will be asked a nonleading question to assess potential 
adverse events. Use of concomitant medications will be documented. Additional procedures 
during Visit 2 will include the S-STS, an ECG, and vital signs (blood pressure and pulse after 
sitting or lying supine for at least five (5) minutes). Blood (8 hour fast) samples will be collected 
for hematology, serum chemistry, and urine sample will be collected for urinalysis testing. 
Subjects will undergo drug screens using a local urine testing kit. Subjects who test positive for 
benzodiazepines inconsistent with protocol specified allowed prescriptions, psychoactive 
cannabinoids (e.g., marijuana, THC) inconsistent with subject reported use, PCP, opioids, 

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cocaine or amphetamines, will not be allowed to continue in the study. Female subjects of 
childbearing potential will be tested for pregnancy using a local urine testing kit and will be 
counseled to continue using highly effective contraception. 
Pain scores reported by subjects during the Screening Period will be evaluated by the interactive 
response technology (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 seven (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 IRT system will 
provided. 
Eligible subjects will be randomized to receive either doses of oral NYX-2925 50 mg or placebo 
daily for 12 weeks. Investigators and subjects will be both blinded to treatment allocation and 
masked to the randomization criteria. Subjects will be dispensed a four-week supply of study 
drug and instructed to take one (1) capsule by mouth once daily. The first dose of study drug will 
be taken in the clinic during Visit 2 (Week 0). Subjects will be instructed to take study drug daily 
throughout the study. Acetaminophen will be dispensed/re-dispensed for use as rescue 
medication for DPN related pain; and instructions on not to exceed 2 g/day (one to two 500 mg 
tablets every 6 hours as needed up to 4 tablets total) will be reinforced. 
Adverse events will be collected from the time of study drug administration through the last day 
. 
Subjects will be instructed to continue entering their average pain intensity, worst pain intensity, 
average pain upon walking, and usage of rescue medication over the past 24 hours into their 
study-issued handheld device every night. Every morning upon awakening, subjects will 
complete the DSIS and confirm they have taken their study drug in the past 24 hours via their 
study-issued handheld device. Pain diary compliance will be reviewed by the study staff, and 
reporting instructions will be reinforced. Subjects will be reminded of appropriate expectations 
around their participation in a clinical study and the importance of consistently and accurately 
reporting their pain intensity throughout the study. Each subject will undergo educational 
training on Accurate Pain Reporting (APR®) and Placebo Response Reduction (PRR®) via an 
electronic learning management system, aLearn® [Analgesic Solutions, Wayland, MA].Review 
of these educational materials will be repeated for all subjects within the aLearn® platform at 
each site-based visit, with the exception of the final visit. An ongoing blinded data review (e.g., 
if pain score variability is increased on a subject or site level) will be conducted to monitor these 
metrics [Analgesic Solutions, Wayland, MA]. 
The following scales will be completed at the Baseline Visit (Visit 2): Brief Pain Inventory for 
Diabetic Peripheral Neuropathy (BPI-DPN), the Norfolk Quality of Life Questionnaire - Diabetic 
Neuropathy (QOL-DN), Patient Global Impression of Severity (PGI-S)Pain Catastrophizing 
Scale (PCS) and Sheehan  Suicidality Tracking Scale (S-STS). 

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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.   
Treatment Period: Week 2/Visit 3 
Subjects will be contacted by the clinic study staff via telephone or videoconference at the end of 
Week 2 (Visit 3) for assessment of compliance with study drug, rescue medication use and diary 
entries. The appropriate use of study drug and rescue medication will be assessed by subject 
interview. Subjects will be instructed to take one capsule of study drug by mouth once daily. 
Rescue medication, if required should not exceed 2g/day (one to two 500 mg tablets every 6 
hours as needed up to 4 tablets total for DPN related pain. 
Pain diary compliance will be reviewed by the study staff, and reporting instructions will be 
reinforced. Adverse events will again be assessed by asking the subjects a nonleading question. 
Misuse and abuse-related events will be assessed using the Misuse, Abuse, and Diversion Drug 
Event Reporting System® (MADDERS [Analgesic Solutions, Wayland, MA]). Use of 
concomitant medications will be documented.  
The subject will be asked to complete the printed copy of the S-STS given to them at their 
answers to the S-STS and recommend corrections, only where the form has been completed 
incorrectly.  The completed S- STS source document will be mailed back to the clinic or returned 
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 visit should be entered as 
an Unscheduled Visit in the eCRF and IRT systems. 
Subjects will be instructed to continue entering their average pain intensity, worst pain intensity, 
average pain upon walking, and rescue medication use over the past 24 hours into their study-
issued handheld device every night. Every morning upon awakening, subjects will complete the 
DSIS and confirm they have taken their study drug in the past 24 hours via their study-issued 
handheld device. Subjects will be reminded of appropriate expectations around their participation 
in a clinical study and the importance of consistently and accurately reporting their pain 
throughout the study.  
Review of these educational materials will be repeated for all subjects within the aLearn® 
platform at each site-based visit, with the exception of the final visit. An ongoing blinded data 
review (e.g., if pain score variability is increased on a subject or site level) will be conducted to 
monitor these metrics [Analgesic Solutions, Wayland, MA]. 
The following scales to be completed at Week 2 (Visit 3) visit via telephone or videoconference: 
S-STS. 
Treatment Period: Week 4/Visit 4 
Subjects will return to the clinic at the end of Week 4 (Visit 4) for assessment of compliance 
with study drug and rescue medication use. The appropriate use of study drug and rescue 
medication will be assessed by inventory of the returned study drug and rescue medication, as 
well as by subject interview. Subjects will be dispensed a four-week supply of study drug. 

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Subjects will be instructed to take one capsule of study drug by mouth once daily.  Rescue 
medication will be dispensed/re-dispensed to the subject with instructions not to exceed 2g/day 
(one to two 500 mg tablets every 6 hours as needed up to 4 tablets total) for DPN related pain. 
Pain diary compliance will be reviewed by the study staff, and reporting instructions will be 
reinforced. Adverse events will be elicited by asking the subject a nonleading question. Misuse 
and abuse-related events will be assessed using MADDERS (Analgesic Solutions, Wayland, 
MA). Use of concomitant medications will be documented. Additional procedures during Visit 4 
will include S-STS and vital signs (blood pressure and pulse after sitting or lying supine for at 
least five (5) minutes). Blood (8 hour fast) samples will be collected for hematology, serum 
chemistry, and urine sample will be collected for urinalysis testing. Subjects will undergo drug 
screens using a local urine testing kit. Subjects who test positive for benzodiazepines inconsistent 
with protocol specified allowed prescriptions, psychoactive cannabinoids (e.g., marijuana, THC) 
inconsistent with subject reported use, PCP, opioids, cocaine or amphetamines, will not be 
allowed to continue in the study. Female subjects will be tested for pregnancy using a local urine 
testing kit, if clinically indicated for females of childbearing potential. Female subjects of 
childbearing potential will be counseled to continue using highly effective contraception. 
Subjects will be instructed to continue entering their average pain intensity, worst pain intensity, 
average pain upon walking, and rescue medication use over the past 24 hours into their study-
issued handheld device every night and to complete the DSIS and confirm they have taken their 
study drug in the past 24 hours via their study-issued handheld device in morning. Subjects will 
be reminded of appropriate expectations around their participation in a clinical study and the 
importance of consistently and accurately reporting their pain throughout the study. Review of 
these educational materials will be repeated for all subjects within the aLearn portal at each site-
based visit, with the exception of the final visit. An ongoing blinded data review (e.g., if pain 
score variability is increased on a subject or site level) will be conducted to monitor these metrics 
[Analgesic Solutions, Wayland, MA]. 
The following scales will be completed at Week 4 (Visit 4): BPI-DPN, Patient Global 
Impression of Change (PGI-C), QOL-DN and S-STS. 
Treatment Period: Week 8/Visit 5 
Subjects will return to the clinic at the end of Week 8 (Visit 5) for assessment of compliance 
with study drug and rescue medication use. The appropriate use of study drug and rescue 
medication will be assessed by inventory of the returned study drug and rescue medication, as 
well as by subject interview. Subjects will be dispensed a four-week supply of study drug. 
Subjects will be instructed to take one capsule of study drug by mouth once daily. Rescue 
medication will be dispensed/re-dispensed to the subject with instructions not to exceed 2g/day 
(one to two 500 mg tablets every 6 hours as needed up to 4 tablets total) for DPN related pain. 
Pain diary compliance will be reviewed by the study staff, and reporting instructions will be 
reinforced. Adverse events will be elicited by asking the subject a nonleading question. Misuse 
and abuse-related events will be assessed using MADDERS (Analgesic Solutions, Wayland, 
MA). Use of concomitant medications will be documented. 
Additional procedures during Visit 5 will include S-STS and vital signs (blood pressure and 
pulse after sitting or lying supine for at least five (5) minutes). ECG would be conducted. Blood (8 

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hour fast)) samples will be collected for hematology, serum chemistry, and urine sample will be 
collected for urinalysis testing. Subjects will undergo drug screens using a local urine testing kit. 
Subjects who test positive for benzodiazepines inconsistent with protocol specified allowed 
prescriptions, psychoactive cannabinoids (e.g., marijuana, THC) inconsistent with subject 
reported use, PCP, opioids, cocaine or amphetamines, will not be allowed to continue in the 
study. Female subjects will be tested for pregnancy using a local urine testing kit, if clinically 
indicated for females of childbearing potential. Female subjects of childbearing potential will be 
counseled to continue using highly effective contraception. 
Subjects will be instructed to continue entering their average pain intensity, worst pain intensity, 
average pain upon walking, and rescue medication use over the past 24 hours into their study-
issued handheld device every night. Every morning upon awakening, subjects will complete the 
DSIS and confirm they have taken their study drug in the past 24 hours via their study-issued 
handheld device. Subjects will be reminded of appropriate expectations around their participation 
in a clinical study and the importance of consistently and accurately reporting their pain 
throughout the study. Review of these educational materials will be repeated for all subjects at 
each site-based visit, with the exception of the final visit. An ongoing blinded data review (e.g., 
if pain score variability is increased on a subject or site level) will be conducted to monitor these 
metrics [Analgesic Solutions, Wayland, MA]. 
The following scales will be completed at Week 8 (Visit 5): PGI-C and S-STS. 
Treatment Period: Week 12/Visit 6 or Early Termination Visit 
During Week 12 (Visit 6) or Early Termination Visit, subjects will return to the clinic for 
assessment of compliance with study drug and rescue medication use. The appropriate use of 
study drug and rescue medication will be assessed by inventory of the returned study drug and 
rescue medication, as well as by subject interview. Subjects will return the study-issued handheld 
device and other materials to the study site. Pain diary compliance will be reviewed by the study 
staff. Adverse events will be assessed by asking the subjects a nonleading question. Misuse and 
abuse-related events will be assessed using MADDERS (Analgesic Solutions, Wayland, MA). 
Use of concomitant medications will be documented. Additional procedures during Visit 6/Early 
Termination Visit will include S-STS and vital signs (blood pressure and pulse after sitting or 
lying supine for at least five (5) minutes). Body weight will be measured, a brief physical 
examination performed, and ECG would be conducted. Blood (8 hour fast) samples will be 
collected for hematology, serum chemistry, HbA1c, and urine sample will be collected for 
urinalysis testing. Female subjects of childbearing potential will be tested for pregnancy using a 
local urine testing kit. Subjects will a undergo drug screens using a local urine testing kit. 
The following scales will be completed at the Week 12 (Visit 6)/Early Termination Visit: BPI- 
DPN, PGI-C, QOL-DN, PCS and S-STS. 
A safety follow-up telephone call will be made to the subject within 7-10 days and then 
approximately 30 days after week 12/final visit to assess for any AE/SAE closure and any newly 
reported SAEs. 
The schedule of assessments is provided in Table 3. 

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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 0 
(1± 2)b 
Week 2 
(14 ± 2) 
Week 4 
(28 ± 4) 
Week 8 
(56 ± 4) 
Week 12/ 
ETb 
(84 ± 4) 
Study Visit 
Visit 1 
Visit 2 
Visit 3w 
Visit 4 
Visit 5 
Visit 6 
Assessment 
 
 
 
 
 
 
Informed consent prior to any study procedurec 
X 
 
 
 
 
 
Assess inclusion/exclusion criteria 
X 
X d 
 
 
 
 
APR®/PRR® training via aLearn®e  
X 
X 
X 
X 
X 
 
Education on appropriate expectations around 
participation in a clinical studye 
X 
X 
X 
X 
X 
 
Michigan Neuropathy Screening Instrument (MNSI) 
X 
 
 
 
 
 
Masquerading Disorders Tool (MDT) 
X 
 
 
 
 
 
Demographic characteristics (age, sex, race, and ethnicity) 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Heightt 
X 
 
 
 
 
 
Body weight t,u 
X 
 
 
 
 
X 
Vital signs (blood pressure and pulse after sitting or lying 
supine for at least 5 minutes) f 
X 
X 
 
X 
X 
X 
Physical examination g 
X 
 
 
 
 
X 
Triplicate electrocardiograms (3 separate ECGs) with a 
minimum of 2 mins gap between each ECG.V 
X 
 
 
 
 
 
Electrocardiogram (ECG) after at least 5 minutes in 
supine position 
 
X 
 
 
X 
X 
Urine pregnancy test for females of childbearing potentialh 
X 
X 
 
X 
X 
X 
Urine Drug screens i 
X 
X 
 
X 
X 
X 
Obtain samples for hematology, chemistry, and urinalysis j 
X j 
X 
 
X 
X 
X j 
Discontinue all concomitant analgesic medicationsk 
X 
 
 
 
 
 
Dispense handheld electronic diary 
X 
 
 
 
 
 

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Study Period Screening 
Baseline 
Treatment Period 
Study Week 
(Day) 
1 to 4 
weeksa 
(-28 to -1) 
Week 0 
(1± 2)b 
Week 2 
(14 ± 2) 
Week 4 
(28 ± 4) 
Week 8 
(56 ± 4) 
Week 12/ 
ETb  
(84 ± 4) 
Study Visit 
Visit 1 
Visit 2 
Visit 3w 
Visit 4 
Visit 5 
Visit 6 
Return handheld electronic diary 
 
 
 
 
 
X 
Dispense/re-dispense rescue medication (acetaminophen) l 
X 
X 
 
X 
X 
 
Return rescue medication and perform accountability m 
 
X 
 
X 
X 
X 
Record average pain intensity, worst pain intensity, average 
pain upon walking and rescue medication use over past 24 
hours at bedtime for each day n 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Record Daily Sleep Interference Scale (DSIS) each 
morning o 
X 
X 
X 
X 
X 
X 
Assess handheld diary compliance 
 
X 
X 
X 
X 
X 
Randomize eligible subjects 
 
X 
 
 
 
 
Dispense study drug 
 
X 
 
X 
X 
 
First dose of study drug (in the clinic) 
 
X 
 
 
 
 
Confirm daily study drug dosing in past 24 hours each  
morningp 
 
X 
X 
X 
X 
X 
Return study drug and assess compliancem 
 
 
 
X 
X 
X 
Pain Catastrophizing Scale (PCS) 
 
X 
 
 
 
X 
Brief Pain Inventory for Diabetic Peripheral Neuropathy 
(BPI- DPN) 
 
X 
 
X 
 
X 
Norfolk Quality of Life Questionnaire  Diabetic 
Neuropathy (QOL-DN) 
 
X 
 
X 
 
X 
Patient Global Impression of Severity (PGI-S) 
X 
X 
 
 
 
 
Patient Global Impression of Change (PGI-C) 
 
 
 
X 
 X 
X 
Sheehan-Suicidality Tracking Scale (S-STS) 
X 
X 
Xw 
X 
X 
X 
Misuse, Abuse, and Diversion Drug Event Reporting 
System® (MADDERS) r 
 
 
X 
X 
X 
X 
Concomitant medications 
Xq 
X 
X 
X 
X 
X 
Adverse eventsS  
X 
X 
X 
X 
X 
X 
Safety follow-up calls 
 
 
 
 
 
Xx 

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a) Subjects will discontinue all concomitant analgesic medications taken for pain related to diabetic peripheral neuropathy. 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 completed 
 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. 
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. An ongoing blinded data review (e.g., if pain score variability is increased on a subject or site 
level) will be conducted to monitor these metrics [Analgesic Solutions, Wayland, MA]. 
f) 
Vital signs will include blood pressure and pulse after sitting or lying supine for at least five (5) minutes, and prior to blood sample collection. Vital 
 with a minimum interval of five (5) minutes between 
measurements
s, with the final measurement of vital signs being entered into the 
eCRF system. 
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 the Visit 6/Early Termination Visit. 
h) If clinically indicated for females of childbearing potential. 
i) 
Urine drug screen kit for local testing. 
j) 
Samples will be obtained following an 8 hour fast. Visit 1 tests will include HbA1c, triglycerides, HIV screening, hepatitis B screening, hepatitis C 
screening, CRP, and a thyroid panel (TSH, T3, T4 and free T4). Visit 6 (Week 12)/Early Termination Visit tests will include HbA1c. A CRP test will be 
conducted on each chemistry sample collected.    
k) Analgesic medications discontinued during the Screening Period cannot be restarted until after the Week 12 visit. 
l) 
Subjects will be instructed to take no more than 2 g/daily (one to two 500 mg tablets every 6 hours as needed up to 4 tablets total) for DPN related pain. 
m) Instruct study participants to bring all used and unused study drug and rescue medication to each visit for compliance monitoring. 
n) Numeric Rating Scale of pain intensity (0 = no pain to 10 = worst pain imaginable) will be completed once daily at bedtime. DSIS will be completed 
upon waking. 
o) Starting after Visit 1. 
p) 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 
in past 24 hours via their study-issued handheld device upon awakening in morning. 
q) Includes prior medications taken within the last 30 days. 
r) 
To be completed by Investigators or qualified Sub-investigators when potential abuse-related events are identified and upon completion of each 
 study. 

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s) 
Adverse events will be collected 
 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.. 
t) 
BMI will be calculated based on height and body weight. 
u) Weight to be obtained with a calibrated scale with appropriate range and resolution.  Subject must remove shoes and bulky layers of clothes 
v) Screening ECGs will be collected in triplicate (at least two (2) minutes apart).  All other ECGs will be single ECGs. 
w) 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 
 answers to the S-STS and recommend corrections, only 
where the form has been completed incorrectly.  The completed S STS source document will be mailed back to the clinic or returned at the next study visit 
 
x) 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 medications during the Screening Period is 
expected to reduce intersubject variability in treatment response [Katz 2005; Katz 2015; Data on 
file]. The three-month duration of treatment is considered sufficient to identify clinically important 
pain relief. As described in Section 4, although NYX-2925 did not meet the primary endpoint in 
the prior Phase 2 study, the observed trends toward improved changes in average pain intensity 
suggest that NYX-2925 has the potential to mitigate neuropathic pain in patients who are not using 
a concomitant analgesic medication and with long-
 
Only masked versions of the protocol will be provided to study sites. The masked versions will 
obscure the probability of receiving placebo 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 
In the first Phase 2 study, the most consistent effects of NYX-2925 were observed at the 50 mg 
dose in pre-planned and post-hoc analyses, as described in Section 4. The adverse event profile 
revealed no differences to placebo across the entire dose range. Thus, 50 mg has been selected to 
be compared to placebo for the current study. In the Phase 1 single and multiple ascending dose 
safety, tolerability and pharmacokinetic study, 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. 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Inclusion Criteria 
Inclusion Criteria: Screening 
Subjects must meet ALL the following criteria to be enrolled in this study: 
1. An Institutional Review Board (IRB) 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. 
2. Consent to being included in a research subject database. 
3. 
 age. 
4. Diagnosis of Type 2 Diabetes. 
5. At least moderate pain intensity over the last week as assessed by PGI-S at Visit 1. 
6. 
 1). 
7. Stable use of diabetic medications beginning 1 month prior to Visit 1 (adequate glycemic 
control with diet and exercise alone is also permitted). 
8. 
 
(DPN in the upper extremities is not exclusionary). 

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9. Presence of pain due to diabetic neuropathy for at least 6 months prior to screening. 
10. Total s
4 on the Michigan Neuropathy Screening Instrument. 
11. 
2. 
12. Absence of impaired hepatic function. Impaired hepatic function is characterized by a 
previous known diagnosis of chronic liver disease, and/or 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. 
13. Cal
 (Cockcroft-Gault formula). 
14. Fasting triglycerides <600 mg/dL. 
15. Except as noted in criteria 12-14 above, clinical laboratory values must be within normal 
limits, or deemed not clinically significant by the Investigator. 
16. 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. 
17. 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. 
18. Has not participated in an interventional study for at least 30 days or has not taken 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. 
19. Ability to understand the requirements of the study, abide by the study restrictions, as well 
as concomitant medications exclusions, and agree to return for the required assessments. 
20. 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. 
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 criteria will NOT be allowed. 

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7.2. 
Subject Exclusion Criteria 
Subjects who meet ANY of the following criteria will be excluded from the study. 
1. Current diagnosis of major psychiatric disorder (including schizophrenia and/or bipolar 
disorder), including subjects who have required an antipsychotic (e.g., aripiprazole, 
asenapine, cariprazine, clozapine, lurasidone, olanzapine, quetiapine, risperidone, 
ziprasidone) or mood stabilizer (e.g., lithium, carbamazepine, lamotrigine valproate) for a 
psychiatric condition in the past year, or subjects who have had a major depressive episode 
(MDE) in the past 6 months. Subjects with major depressive disorder (MDD), generalized 
anxiety disorder (GAD) or panic disorder who have been on stable medication for the past 3 
months (and are expected to remain stable for the duration of the study) and whose 
condition is currently well-controlled may be included. 
2. Pain that cannot be clearly differentiated from, or could interfere with, the assessment of 
peripheral diabetic neuropathy, as measured by the Masquerading Disorders Tool at Visit 1. 
3. Neurologic disorders unrelated to diabetic neuropathy (e.g., phantom limb from 
amputation), skin condition in the area of neuropathy that could alter sensation (e.g., plantar 
ulcer), or other painful conditions (e.g., arthritis) that, in the judgment of the investigator, 
could interfere with reporting of pain due to diabetic neuropathy. 
4. History of hypoglycemia that disturbed consciousness, or ketoacidosis requiring 
hospitalization within past 3 months. 
5. History of severe renal impairment defined by renal dialysis or peritoneal dialysis, or has 
undergone renal transplant. 
6. 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 or 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. 
7. Pulse rate <45 bpm or >90 bpm. 
8. 
sclerosis, or a history of seizures (with the exception of childhood febrile seizures), 
epilepsy, or stroke. 
9. Positive serology test result for HIV or current hepatitis B or C infection, or other ongoing 
infectious disease that the investigator considers clinically significant. 
10. 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. 

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b.   Washout period should be completed during screening, with last dose being at least two 
(2) weeks prior to randomization (See Section 15.1 of the protocol for Disallowed 
Analgesic and Other Medications). 
11. Current or recent (within 12 months of screening) history of a substance use disorder 
including cannabinoid use disorder.  
12.  
a. Visit 1: 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. Visit 2: Positive urine drug screen for benzodiazepines inconsistent with protocol 
specified allowed prescriptions, psychoactive cannabinoids (e.g., marijuana, THC) 
inconsistent with subject reported use, PCP, opioids, cocaine, or amphetamines at Visit 
2. 
13. Sensitivity to, allergy to, or concomitant use of N-methyl-D-aspartate receptor ligands 
including ketamine, esketamine, amantadine, dextromethorphan, memantine, methadone, 
dextropropoxyphene, lamotrigine, and/or ketobemidone. 
14. Use of NMDAR-binding drugs (e.g., ketamine, esketamine, amantadine, dextromethorphan, 
memantine, methadone, dextropropoxyphene, lamotrigine, and/or ketobemidone) within 30 
days prior to dosing or during the study. Use of high concentration capsaicin patch within 3 
months prior to screening; use of lidocaine patch within 1 month prior to screening.  
15. Sensitivity to or intolerance to acetaminophen or associated formulation components. 
16. Hypersensitivity or intolerance to multiple medications, in the opinion of the investigator. 
17. Amputations of lower extremities (toe(s) amputation is allowed). 
18. 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. 
19. Planned surgery during study participation. 
20. Active malignancy or a history of malignancy (except for treated non-melanoma in-situ 
skin cancer) within 5 years of screening. 
21. 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.  
22. 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. Presence of an 
exclusionary masquerading disorder in the Masquerading Disorders Tool (MDT) 
assessment.  
23. 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 diabetes) that may interfere with study participation, as assessed the 
investigator.  

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24. Previous randomization in current or previous NYX-2925 clinical trials. 
25. 
 
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.  
Waivers to the exclusion criteria will NOT be allowed. 
7.3. 
Screen Failures 
Subjects who sign and date the informed consent forms, but who fail to meet the inclusion and 
exclusion criteria, will be considered screen failures. Reason(s) for screen failure must be 
documented by the Investigator. Screen failures may be rescreened, at the 
 discretion. 
Subjects who are randomization ineligible may not be rescreened. Rescreened subjects will be 
assigned new subject numbers. 
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 
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 
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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 from 
donating ova during the study period and for 28 days after the 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 
days prior to Visit 1 and are sexually active with a female partner must use a condom with 
spermicide during the study. 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. 
Accurate 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 capsule of study drug once daily by mouth. The first dose of study drug will be taken in 
the clinic during Visit 2 (Week 0). Subjects will be instructed to take study drug once daily 
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Subject will be randomized to doses of NYX-2925 50 mg or placebo by mouth, once daily.  
Subjects will also be dispensed one (1) bottle of acetaminophen to be used as rescue medication at 
visit 1. Rescue medication will be dispense/re-dispensed at the visits identified in Table 3. 
Rescue medication will consist of 500 mg tablets of acetaminophen. Subjects will be instructed to 
take one to two 500 mg tablets every 6 hours as needed up to 4 tablets total for DPN related pain, 
not to exceed 2 g/day. Rescue medication will be provided by the Sponsor. Rescue medication use 
should be reported daily via the study issued- handheld device. 
8.2. 
Study Drug and Rescue Medication 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 NYX-2925 per capsule. Matching placebo capsules will also be provided. 
 
 
 
 
 
-2925 Oral Capsules or 
Placebo to Match , capsule count, bottle number, storage conditions, protocol number, instructions 
for use, a space for subject number, Sponsor name, and investigational use statement. Bottles of 
study drug dispensed at Visit 2/Week 0, Visit 4/Week 4 and Visit 5/Week 8 will contain 32 
capsules of NYX-2925 50 mg or matching placebo capsules according to the randomization 
schedule. 
Acetaminophen rescue medication will be provided in bottles containing 500 mg tablets of 
bottle number, protocol number, 
a space for subject number and Sponsor name. Subjects will be instructed to take no more than 2 
g/daily (one to two 500 mg tablets every 6 hours and up to 4 tablets total) as needed for DPN 
related pain. Subjects will be dispensed 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, and there will be no study drug 
preparation done at the investigative site. The Investigator may delegate study drug management to 
site personnel who will dispense kits of study drug for subject administration according to the IRT 
system. The IRT system will be 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 

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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. 
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 
directions regarding excursions. 
8.5. 
Accountability 
The Investigator or designee at the investigative site will conduct study drug accountability for 
study drug and rescue medication. 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 rescue medication accountability records. Site personnel 
will conduct subject-level accountability, account for and document used containers/unused study 
drug and rescue medication, and the site will retain containers of returned study drug and rescue 
 
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 Sponsor 
representative. All used and unused rescue medication and containers may be destroyed at the site 
or returned to the depot 
 
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 medications, taken for neuropathic pain associated 
with diabetic peripheral neuropathy, with the exception of acetaminophen (rescue medication). 
Rescue medication may be taken for DPN related pain only. Subjects may continue their 
antidiabetic medications. Adjustment of diabetic medications may be made, as necessary, for the 
provider. Stable doses of the benzodiazepines alprazolam or 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.  Intermittent 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 DPN as described below, systemic corticosteroids, opioid or 

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narcotic analgesics, muscle relaxants, tramadol, injected or topical lidocaine, injected or topical 
capsaicin, norepinephrine reuptake inhibitors (NRIs), serotonin-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.  
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 or 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 DPN 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 2 g/day (one to two 500 mg tablets every 6 hours as needed up to 4 tablets total) 
for DPN related pain. Rescue medication will be provided by the Sponsor. 
For pain unrelated to DPN, 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 DPN, the medication should be recorded as a 
concomitant medication and the adverse event must be recorded in the eCRF. 
Medications used 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 
 
9.1.2. 
Masquerading Disorders Tool 
The Masquerading Disorders Tool (Analgesic Solutions, Wayland, MA) is a screening instrument 
to help identify subjects with disorders that masquerade as painful diabetic peripheral neuropathy, 
tunnel syndrome. The screening instrument consists of symptom screening questions and an in-
clinic 
results of this assessment tool are provisional, with the final decision based on the clinical 
judgment of the Investigator. 

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9.1.3. 
Michigan Neuropathy Screening Instrument 
The Michigan Neuropathy Screening Instrument (MNSI) is a 15-item, self-administered 
questionnaire and a 5-item clinician-administered lower extremity examination that includes 
inspection of vibratory sensation and ankle reflexes. It can be used to assess distal symmetrical 
peripheral neuropathy in diabetes [Herman 2012]. 
9.1.3.1. 
MNSI Modified Scoring 
On the self-
6, 8 12, 14 15 are each 
sponses to questions 7 and 13 each count as one point. On the 
lower extremity examination, responses for the left and right feet were combined for the following 
measures of the examination: ulceration, ankle reflex, vibration perception at great toe, and 
monofilament.  Ulceration was scored as one point if present in either lower extremity.  Ankle 
reflex was scored as 0.5 point if present/reinforcement in one lower extremity and one point if 
absent in one or both lower extremities.  Vibration was scored as 0.5 point if decreased in one 
lower extremity and one point if absent in one or both lower extremities. Monofilament was scored 
as 0.5 point if reduced in one lower extremity and one point if absent in one or both lower 
extremities.  (Appearance from the clinical examination is not scored.) 
The self-administered questionnaire has a maximum score of 15 points, and the clinical 
examination has a maximum score of 4 points, resulting in a total maximum possible score on the 
MNSI of 19 points [Herman 2012]. 
9.2. 
Efficacy Assessments 
9.2.1. 
Numeric Rating Scale of Pain Intensity 
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 that is anchored by terms defining pain levels, where 
0 represents no pain and 10 represents worst pain imaginable. 
Subjects will report at bedtime their average pain intensity, worst pain intensity, and average pain 
upon walking during the past 24 hours, using the 11-point NRS. 
9.2.2. 
Patient Global Impression of Change 
The PGI-C is a 7-point scale that allows subjects to rate the change in the disease state from study 
impression of overall change since beginning the study [Guy W 1976]. 
9.2.3. 
Norfolk Quality of Life Questionnaire  Diabetic Neuropathy (QOL-DN) 
The Norfolk QOL-DN is a 47-item, subject-reported questionnaire designed to measure the 
relationship between symptomatic diabetic neuropathy and quality of life from the perspective of 
the patient. It is composed of 2 parts: questions related to symptoms experienced by the patient and 
questions related to the impact of the patient's neuropathy on activities of daily life. A factor 
analysis performed on the Norfolk QOL-DN separated the questions into 5 domains: activities of 
daily living, symptoms, small fiber neuropathy, large fiber neuropathy, and autonomic neuropathy. 
The QOL-DN is sensitive to the different features of diabetic neuropathy including small fiber, 
large fiber, and autonomic nerve function [Vinik 2005]. 

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9.2.4. 
Daily Sleep Interference Scale 
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-
much your pain has interfered with your sleep durin
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]. 
9.2.5. 
Brief Pain Inventory for Diabetic Peripheral Neuropathy 
The BPI-DPN is a patient-completed numeric rating scale that assesses the severity of pain 
(Severity scale), its impact on daily functioning (Interference scale), and other aspects of pain (e.g., 
location of pain, relief from medications). A modified version of the BPI-DPN, including the 4-
item pain Severity scale (Worst Pain, Least Pain, Average Pain, and Pain Now) and the 7-item pain 
Interference scale (General Activity, Mood, Walking Ability, Normal Work, Relations With 
Others, Sleep, Enjoyment of Life) has been validated in patients with painful diabetic peripheral 
neuropathy) and distinguishes between pain due to diabetic peripheral neuropathy and pain due to 
for Interference. The 4 Severity items and the 7 Interference items can also each be averaged to 
form 2 composite scores, the Pain Severity Index and the Pain Interference Index [Zelman 2005]. 
9.2.6. 
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 
 [Guy W 1976]. 
9.2.7. 
Pain Catastrophizing Scale (PCS) 
The PCS is a 13-item instrument that assesses the state of mind of patients in pain through a 
comprehensive evaluation instrument that encompasses the different perspectives on 
catastrophizing. Factor analyses of the PCS have shown that catastrophizing can be viewed as a 
. The PCS instructions ask 
participants to reflect on past painful experiences, and to indicate the degree to which they 
experienced each of 13 thoughts or feelings when experiencing pain, on 5-point scales with the end 
points (0) not at all and (4) all the time. The PCS total score is computed by summing responses to 
all 13 items. PCS total scores range from 0  52. The PCS subscales are computed by summing the 
responses to rumination, magnification, and helplessness items [Sullivan 1995]. 
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. 

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9.3.2. 
Vital Sign Measurements 
Each assessment includes blood pressure and pulse after sitting or lying supine for at least five (5) 
minutes and prior to blood sample collection. Vital signs may be repeated up to three (3) times at 
There should be a minimum of five (5) minutes of rest 
allotted in between measurements. 
documents, with the final measurement of vital signs being entered into the 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, and dermatologic systems; and extremities. 
The complete physical examination at Visit 1 will include a comprehensive neurological 
examination of the following: cranial nerves, muscle strength and tone, sensory function, 
coordination, gait, reflexes, and mental status. 
A brief physical examination will be completed at Week 12/Early Termination. 
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 ECGs with a minimum of a two minute interval between each ECG will be collected at 
screening, and a standard 10-second ECG will be collected at baseline, week 8 and week 12/ET 
after at least five (5) minutes of supine rest and prior to blood sample collection, if possible. The 
device will be a Spaulding (Spaulding Medical, West Bend, WI) electrocardiogram (ECG) device 
that acquires a 12-lead ECG. The ECG data will be submitted to the designated ECG laboratory 
cardiologists for measurements and diagnoses.  
The Principal Investigator or qualified Sub-investigator will review all ECG interpretations and 
interval duration measurements for clinical significance. Standard ECG parameters will be 
measured. Clinically significant, abnormal 12-lead ECGs should be repeated. Clinically significant 
ECG changes should be recorded as an adverse event. 
The Spaulding ECG device should be used for all assessments during the study unless it is non- 
operational, in which case another ECG may be performed locally and transmitted to Spaulding for 
central reading via printout. 
9.3.5. 
Clinical Laboratory Assessments 
Blood samples for hematology and chemistry will be obtained after an 8-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 followed at 

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Section 11) must be 
repeated within 48-72 hours. 
Hematology assessments will include hemoglobin, hematocrit, red blood cell count, white blood 
cell count, differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), and 
platelet count. Hemoglobin A1c will be assessed at Visit 1 and Visit 6/Early Termination. 
Chemistry assessments will include glucose, calcium, electrolytes (sodium, potassium, bicarbonate, 
chloride), phosphorus, blood urea nitrogen (BUN), creatinine, creatinine clearance, 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). 
Triglycerides and a thyroid panel (TSH, T3, T4, and free T4) will also be measured 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 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. 
If the screening test for HIV antibody is positive, confirmatory test may be performed. 
-human chorionic 
gonadotropin) at Visit 1, Visit 2, and Visit 6. Testing may be performed at other visits, if clinically 
indicated. 
The urine drug screen will include benzodiazepines, psychoactive cannabinoids (e.g., 
marijuana,THC), PCP, opioids, cocaine and amphetamines. 
9.3.6. 
Sheehan-Suicidality Tracking Scale 
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 studies, the frequently used 
. 
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, which consists of a set of forms completed by 
Investigators or qualified Subinvestigators when potential abuse-related events are identified and 
-related events will 
be adjudicated by an independent committee [Smith 2017; Treister 2016]. 
Any misuse and abuse-related event will be recorded as an adverse event. 
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 (e.g., a 
clinically significant change detected on clinical chemistry, hematology, or urinalysis results) that 
is independent from the underlying medical condition and that requires medical or surgical 
intervention, or leads to study drug interruption or discontinuation, must be considered an adverse 
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 the 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. 
9.4.2. 
Recording Adverse Events 
-
-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.  

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Subjects should be instructed to report all potential adverse events to the Investigator and should be 
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 
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 accordance 
 Ongoing adverse events should be followed to a 
satisfactory resolution in the Invest
adverse events to the Investigator. In addition, the Investigator should seek to elicit any clinical or 
propriate 
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 
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 

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 Hospitalization or prolongation of hospitalization 
 Study discontinuation 
 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. Serious adverse events are reported to the Sponsor or 
designee using the provided form by email or fax to the following email address or fax number, 
respectively: 
 
 
 
 
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes: 
 
n outcome and is NOT the adverse event. In the event of death, the 
 unknown. 
 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 

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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 
 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 1 of the outcomes listed previously (e.g., 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 
within 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 1 business day. 
Any reported cases of COVID-19 that meet the SAE criteria above should be reported as per the 
 defined 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 (e.g., additional diagnostic 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 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 
-
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 

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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. 
9.5. 
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 in 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 infor
 
Subjects who meet any of the following criteria will not be eligible for continued 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-2925-2008 study, or previous 
randomization into a clinical trial of NYX-2925. Employees, contractors, or volunteers of the study 
site, 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 collect 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 diabetic peripheral 
neuropathy will then be required to dis
weeks (see Section 15.1 of the protocol for  Disallowed Analgesic and Other Medications). 
Subjects taking no concomitant analgesic medication for their painful diabetic neuropathy 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.  

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Prior to recording their first pain score in the handheld device, each subject will undergo 
educational training on Accurate Pain Reporting (APR®) and Placebo Response Reduction (PRR®) 
via an electronic learning management system, aLearn® [Analgesic Solutions, Wayland, MA]. 
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, including history of Type 2 diabetes and history of painful DPN 
 Prior (within last 30 days) and concomitant medications 
 S-STS 
 Adverse events 
 Confirmation of diabetic peripheral neuropathy by the following assessments: 
 MNSI 
 MDT 
 PGI-S 
 Height and body weight 
 Vital signs (blood pressure and pulse after sitting or lying supine for at least five (5) 
minutes) 
 Complete physical examination, including comprehensive neurological examination 
 Triplicate ECG after at least five (5) minutes in supine position with a minimum of a two 
minute interval between ECGs 
 Fasting (8 hours) blood samples for hematology, serum chemistry, triglycerides, HbA1c, 
and a thyroid panel (TSH, T3, T4 and free T4) 
 Blood samples for screening for HIV, hepatitis B and hepatitis C 
 Urine sample for urinalysis 
 Urine pregnancy test for females of childbearing potential 
 Urine drug screen 
Eligible subjects who meet all the inclusion criteria and none of the 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 neuropathic pain associated with 
diabetic peripheral neuropathy, 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 4 weeks (see Section 15.1 of the 
protocol for Disallowed Analgesic and Other Medications). Subjects already 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 

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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: 
 At bedtime: average pain intensity, worst pain intensity, average pain upon walking, 
and rescue medication use during the past 24 hours 
 Upon waking: DSIS 
 Subjects will be dispensed acetaminophen to be used as rescue medication and will be 
instructed to take no more than 2 g/day (one to two 500 mg tablets every 6 hours as needed 
up to 4 tablets total) for DPN related pain. 
10.2. 
Baseline Visit: Week 0/Visit 2 
At Week 0/Visit 2 (Baseline Visit), the following procedures and assessments will be 
performed/assessed prior to randomization: 
 Concomitant medication use 
 PGI-S 
 S-STS 
 Adverse events 
 Vital signs (blood pressure and pulse after sitting or lying supine for at least 5 minutes)  
 ECG after at least five (5) minutes in supine position 
 Fasting (8 hours) blood samples for hematology and serum chemistry 
 Urine sample for urinalysis 
 Urine pregnancy test for females of childbearing potential 
 Urine drug screen 
 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 transmission of pain scores from the handheld 
devices to determine randomization eligibility. The IRT system will notify the site if the subject is 
 provided. 
Subjects who continue to meet all entry criteria and are randomized by the IRT system will 
undergo the following procedures and assessments: 
 BPI-DPN 
 QOL-DN 
 PCS 

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 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 past 24 
hours in the handheld device upon awakening in morning. 
 Re-dispensing/dispensing of rescue medication  Subjects will be reminded not to exceed 2 
g/day (one to two 500 mg tablets every 6 hours as needed up to 4 tablets total) for DPN 
related pain. 
 Subjects will be reminded of 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 at each site-
based study visit, with the exception of the final visit. An ongoing blinded data review 
(e.g., if pain score variability is increased on a subject or site level) will be conducted to 
monitor these metrics [Analgesic Solutions, Wayland, MA]. On each day until returning to 
the study site at Week 4/Visit 4, subjects will record the following on the handheld device: 
 At bedtime: average pain intensity, worst pain intensity, average pain upon walking, 
and rescue medication use during the past 24 hours. 
 Upon waking: DSIS, confirm they have taken study drug. 
 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 
 answers to the S-STS and recommend corrections, only where the form has been 
completed incorrectly.  The completed S STS source document will be mailed back to the 
eCRF system.  Adverse events 
 MADDERS 
 Rescue medication appropriate use assessment by review of daily use entries in the 
handheld diary as well as by subject interview 
 Study drug use and assessment of compliance by review of daily use entries in the 
handheld diary, as well as by subject interview 
 Study drug use and assessment of compliance by review of daily use entries in the 
handheld diary and by subject interview Compliance with entry into daily diary of pain 
intensity, rescue medication use, and study drug administration 
 Subjects will be instructed to take one capsule of study drug by mouth once daily.  

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 Subjects will be reminded not to exceed 2 g/day (one to two 500 mg tablets every 6 hours 
as needed up to 4 tablets total) for DPN related pain. 
 Subjects will be reminded of how to record their pain on the device and will also be 
reminded about appropriate expectations for their participation in a clinical study. Review 
of these educational materials will be repeated for all subjects within the aLearn® portal at 
each site-based study visit, with the exception of the final visit. An ongoing blinded data 
review (e.g., if pain score variability is increased on a subject or site level) will be 
conducted to monitor these metrics [Analgesic Solutions, Wayland, MA]. On each of day 
until returning to the study site at Week 4 (Visit 4), subjects will record the following on 
the handheld device: 
 At bedtime: average pain intensity, worst pain intensity, average pain upon walking, 
and rescue medication use during the past 24 hours 
 Upon waking: DSIS and confirm they have taken study drug 
 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 
At Week 4/Visit 4, the following procedures and assessments will be performed/assessed: 
 Concomitant medication use 
 S-STS 
 Adverse events 
 MADDERS 
 Vital signs (blood pressure and pulse after sitting or lying supine for at least five (5) 
minutes) 
 Fasting (8 hours) blood samples for serum chemistry and hematology 
 Urine sample for urinalysis 
 Urine pregnancy test, if clinically indicated for females of childbearing potential 
 Urine drug screen 
 BPI-DPN 
 PGI-C 
 QOL-DN 
 Rescue medication return and 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, rescue medication use, and study 
drug administration 

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 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 2 
g/day (one to two 500 mg tablets every 6 hours as needed up to 4 tablets total) for DPN 
related pain 
 Subjects will be reminded of 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 at each site-
based visit, at each site-based visit, with the exception of the final visit. An ongoing 
blinded data review (e.g., if pain score variability is increased on a subject or site level) will 
be conducted to monitor these metrics [Analgesic Solutions, Wayland, MA]. On each of 
day until returning to the study site at Week 8 (Visit 5), subjects will record the following 
on the handheld device: 
 At bedtime: average pain intensity, worst pain intensity, average pain upon walking, 
and rescue medication use during the past 24 hours 
 Upon waking: DSIS and confirm they have taken their study drug Subjects will be 
instructed to return to the study site at Week 8 (Visit 5). 
10.3.3. 
Week 8/Visit 5 
At Week 8/Visit 5, the following procedures and assessments will be performed/assessed: 
 Concomitant medication use 
 S-STS 
 Adverse events 
 MADDERS 
 Vital signs (blood pressure and pulse after sitting or lying supine for at least five (5) 
minutes) 
 ECG after at least five (5) minutes in supine position 
 Fasting (8 hours) blood samples for serum chemistry and hematology 
 Urine sample for urinalysis 
 Urine pregnancy test, if clinically indicated for females of childbearing potential 
 Urine drug screen 
 Compliance with entry into daily diary of pain intensity, rescue medication use, and study 
drug administration 
 Rescue medication return and 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 

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 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 2 
g/day (one to two 500 mg tablets every 6 hours as needed up to 4 tablets total) for DPN 
related pain 
 Subjects will be reminded of how to record their pain on the device and will also be 
reminded about appropriate expectations for their participation in a clinical study. Review 
of these educational materials will be repeated for all subjects at each site-based visit, with 
the exception of the final visit. An ongoing blinded data review (e.g., if pain score 
variability is increased on a subject or site level) will be conducted to monitor these metrics 
[Analgesic Solutions, Wayland, MA]. On each of day until returning to the study site at 
Week 12 (Visit 6), subjects will record the following on the handheld device: 
 At bedtime: average pain intensity, worst pain intensity, average pain upon walking, 
and rescue medication use during the past 24 hours 
 Upon waking: DSIS and confirm they have taken their study drug Subjects will be 
instructed to return to the study site at Week 12 (Visit 6). 
10.3.4. 
Week 12/Visit 6/Early Termination 
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 
 MADDERS 
 Body weight 
 Vital signs (blood pressure and pulse after sitting or lying supine for at least five (5) 
minutes) 
 Brief physical examination 
 ECG after at least five (5) minutes in supine position 
 Fasting (8 hours) blood samples for serum chemistry and hematology, including HbA1c 
 Urine sample for urinalysis 
 Urine pregnancy test for females of childbearing potential 
 Urine drug screen 
 BPI-DPN 
 PGI-C 
 QOL-DN 
 PCS 

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 Compliance with entry into daily diary of pain intensity, rescue medication use, and study 
drug administration 
 Rescue medication return and 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 
 Study-issued handheld device and other equipment/documents return 
 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 newly reported 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
 
If an increase of serum aminotransferase of >3xULN is identified, repeat testing within 48 to 72 
hours of all four of the usual serum measures (ALT, AST, ALP, and TBL) should  conducted to 
confirm the abnormalities and to determine if they are increasing or decreasing. 
12. 
STATISTICS 
12.1. 
Sample Size 
The planned sample size is a total of 204 randomized subjects. This will provide approximately 
80% power using 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 

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intensity score during the preceding seven (7) days is within the protocol-defined algorithm and 
whose compliance with daily diary completion is 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 
No other information will be provided. 
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 percentage 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 non-missing 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 NRS. 
12.5. 
Treatment Group Comparisons 
The following treatment groups will be summarized in the statistical tables: 
 NYX-2925 50 mg 
 Placebo 
The following treatment group comparisons will be performed for efficacy: 
 NYX-2925 50 mg versus placebo 
12.6. 
Analyses of Efficacy 
12.6.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in the weekly mean NRS score 
assessing average pain intensity related to DPN in the past 24 hours. 
12.6.1.1. Primary Efficacy Analysis 
The primary efficacy analysis will be performed based on the modified Intent-to-Treat population. 

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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 weekly mean of the daily average pain intensity NRS score 
from the handheld device will be averaged for baseline after randomization. Change from baseline 
will be assessed for treatment group differences 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. 
12.6.1.2. 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 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).  

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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 (increase) 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. 
12.6.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will be tested: 
 Change from baseline in the weekly mean of the Daily Sleep Interference Scale (DSIS) 
scores at Week 12. 
 
Impression of Change (PGI-C) at Week 12. 
 
NRS average pain intensity related to DPN at Week 12. 
 
e weekly mean NRS 
average pain intensity related to DPN at Week 12. 
 Change from baseline to Week 12 in the Norfolk Quality of Life Questionnaire - Diabetic 
Neuropathy (QOL-DN) score. 
 Use of rescue medication, including the proportion of subjects using rescue medication, the 
frequency and amount used 
 Cumulative response (percent reduction from baseline) in the weekly mean NRS average 
pain intensity at Week 12 
 Change from baseline in the weekly mean of the daily Numerical Rating Scale (NRS) at 
each week from Week 1 through Week 12 
12.6.3. 
Other Efficacy Analyses 

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12.6.4. 
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) in a hierarchical manner to preserve the overall Type I error rate. 
There will be no adjustment for multiple comparisons for other efficacy endpoints. 
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 percentage of subjects experiencing TEAEs 
by system organ class and preferred term. If a subject has more than 1 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 1 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: 
 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 change 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. 

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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. 
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 diagnostic reports, medical histories, hospital 
records, and study 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. 
Electronic Case Report Forms (eCRF) 
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 designated Sub-investigator 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 

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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 
local IRB are responsible for submitting the amendment for review and approval. 
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 documents, and all relevant supporting data must be submitted 
to the Institutional Review Board (IRB) for approval. IRB approval of the protocol, informed 
consent documents, and any subject-facing materials 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. Subjects will also be asked to provide an additional consent for 
their inclusion in a secure, proprietary research subject database maintained by Verified Clinical 

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Trials (VCT) [Verified Clinical Trials, Garden City, NY]. The informed consent document may be 
executed up to 30 days prior to the screening visit. The date the first screening related activity is 
complet
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 must be reconsented with the IRB-approved 
revised ICF in a timely manner. 
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, 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 will be grant
medical records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the subjects, to the extent permitted by the law and regulations. In any 
presentation of th
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. 

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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 2 years after a marketing application is approved for the drug for the indication for 
which it is being studied. If no application is filed or approved, these records must be kept for 2 
years after the investigation has been discontinued and the FDA has been notified. Per ICH 
application in an ICH region and until there are no pending or contemplated marketing applications 
have elapsed since the formal discontinuation of clinical 
development of the study drug. Aptinyx will notify the Investigator in writing when records and 
documents no longer need to be retained. No study records should be destroyed without prior 
written authorization. 
13.15. 
Publication Policy 
The publication policy is outlined in the Clinical Trial Agreement. 

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14. 
REFERENCES 
Bouhassira 2008 
Bouhassira D, Lantéri-Minet M, Attal N, et al. Prevalence of chronic 
pain with neuropathic characteristics in the general population. Pain. 
2008;136:380-7. 
Gilron 2015 
Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis 
and treatment. Mayo Clin Proc. 2015;90(4):532-45. 
Guy W 1976 
Guy W (ed). ECDEU Assessment Manual for Psychopharmacology. 
Rockville, MD: US Department of Health, Education, and Welfare 
Public Health Service Alcohol, Drug Abuse, and Mental Health 
Administration, 1976  
Herman 2012 
Herman WH, Pop-Busui R, Braffett BH, et al. Use of the Michigan 
Neuropathy Screening Instrument as a measure of distal symmetrical 
peripheral neuropathy in Type 1 diabetes: results from the Diabetes 
Control and Complications Trial/Epidemiology of Diabetes Interventions 
and Complications. Diabet Med. 2012;29:937-44. 
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, et al. 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. 
Mony 2009 
Mony L, Kew JN, Gunthrope MJ, et al. Allosteric modulators of NR2B- 
containing NMDA receptors: molecular mechanisms and therapeutic 
potential. Br J Pharmacol. 2009;157:1301-17. 
Ossipov 2010 
Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin 
Invest. 2010;120(11):3779-87. 
Russo 2015 
Russo JF, Sheth SA. Deep brain stimulation of the dorsal anterior 
cingulate cortex for the treatment of chronic neuropathic pain. Neurosurg 
Focus. 2015;38(6):E11. 
Sheehan 2014 
Sheehan DV, Giddens JM, Sheehan IS. Status update on the Sheehan-
Suicidality Tracking Scale (S-STS) 2014. Innov Clin Neurosci. 2014;11(9-
10):93 140. 
Silva 2016 
Silva M, Costa-Pereira JT, Martins D, et al. Pain modulation from the 
brain during diabetic neuropathy: uncovering the role of the 
rostroventromedial medulla. Neurobiol Dis. 2016;96:346-56. 
Smith 2017 
Smith SM, Jones JK, Katz NP, et al. Measures that identify prescription 
medication misuse, abuse, and related events in clinical trials: ACTTION 
critique and recommended considerations. J Pain. 2017;18(11):1287-94. 

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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) [e.g., duloxetine (Cymbalta®), 
milnacipran (Savella), venlafaxine (Effexor®), desvenlafaxine (Pristiq®), levomilnacipran 
(Fetzima®)],
 Anti-epileptics, e.g., 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 DPN 
 Topical therapies: topical capsaicin; topical/local anesthetic lidocaine 
*Any non-pharmacologic therapies or interventions for treatment of pain that are not on this list 
must be discussed with the Medical Monitor prior to screening (e.g., nerve blocks, spinal 
stimulators, etc). 
Subjects must be stable for at least seven (7) days prior to randomization. 
 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.