Clinical trial NCT03219320
Conditions: Diabetic Peripheral Neuropathy
Keywords: Type 2 Diabetes Neuropathic Pain Peripheral Nervous System
Sponsor: Aptinyx
Start date: 2017-06-27; Completion date: 2018-11-02
Enrollment: 301 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy of multiple dose levels of NYX-2925 versus placebo in treating the neuropathic pain associated with Diabetic Peripheral Neuropathy.

Detailed description:
This is a randomized, double-blind, parallel-group, placebo-controlled, multiple-dose study to assess the efficacy and safety of NYX-2925 in subjects with neuropathic pain associated with diabetic peripheral neuropathy.

The study will be a 6 to 9-week study, including a 1 to 4-week (dependent on duration of washout period) Screening Period, followed by a 4-week double-blind, randomized, placebo-controlled Treatment Period, and a 1-week Follow Up Period. Subjects eligible for the study will randomize to receive either NYX-2925 or placebo for 4 weeks.

Arms: arm 1: Up to 300 subjects: Placebo arm 2: Up to 300 subjects: Multiple dose levels of NYX-2925 daily for 28 days
Interventions: intervention 1: NYX-2925 intervention 2: Placebo
Intervention descriptions: intervention 1: NYX-2925 is a novel small molecule that modulates the N-methyl-D-aspartate receptor (NMDAR). intervention 2: Matching Placebo capsules.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
INVESTIGATIONAL PRODUCT: NYX-2925 
CLINICAL PROTOCOL: NYX-2925-2001 
A Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled, Multiple-Dose Study to Assess the 
Efficacy and Safety of NYX-2925 in Subjects with 
Neuropathic Pain Associated with Diabetic Peripheral 
Neuropathy 
Amendment #3 
Sponsor: 
Aptinyx Inc. 
1801 Maple Avenue, Suite 4300 
Evanston, IL 60201 
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 (IRBs/IECs) under the condition that they are also required to maintain 
confidentiality. 
NCT03219320


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




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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
24-Hour Emergency Medical Contact 
Medical Monitor 
   
Serious Adverse Event Reporting Information 
Email:
 


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1 
SYNOPSIS 
IND# 129731 
Name of Sponsor Company: 
Aptinyx Inc. 
Name of investigational product: 
NYX-2925 
Name of active ingredient: 
(2S, 3R)-3-hydroxy-2((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide 
Title of Study:  
A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multiple-Dose Study to Assess the 
Efficacy and Safety of NYX-2925 in Subjects with Neuropathic Pain Associated with Diabetic 
Peripheral Neuropathy 
Principal Investigator:  
To be determined 
Study center(s):  
Approximately 35 centers in the United States 
Studied period (years):  
Estimated date first patient enrolled: July 2017 
Estimated date last patient completed: November 2018 
Phase of development:  
2 
Objectives:  
Primary objective: 
 
To evaluate the efficacy of multiple dose levels of NYX-2925 versus placebo in treating 
the neuropathic pain associated with diabetic peripheral neuropathy  
Secondary objectives: 
 
To assess the effects of multiple dose levels of NYX-2925 versus placebo on pain 
characteristics, sleep interference, health status, psychological state, and global 
improvement 
 
To assess the safety and tolerability of multiple dose levels of NYX-2925 


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Methodology: 
Study Design 
The study will be a 6- to 9-week study, including a 1-to 4-week Screening Period, followed by a 
4-week double-blind, randomized, placebo-controlled Treatment Period, and a 1-week Follow Up 
Period. 
 
Screening Period (Week -4 to -1) 
The subjects will be asked to provide informed consent for this study before any required procedures 
are performed. Subjects will also be required to sign an additional consent for their inclusion in a 
subject registry database. The database will use partially-identified subject information to review 
subjects’ research study history within a proprietary, secure platform. 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 since the 
last research study, violation of the washout period between studies, or incorrect age for the NYX-
2925-2001 study. Employees, contractors and volunteers of the study site, or relatives of any 
employees, contractors and volunteers of the study site are not eligible to participate. 
 
Subjects with Type 2 diabetes who have been on stable antidiabetic medication for at least 1 month (or 
have stable glycemic control with diet and exercise alone) and who have been suffering from painful 
diabetic peripheral neuropathy in the lower extremities for at least 6 months but not more than 10 years 
will be screened for diabetic peripheral neuropathy using the Michigan Neuropathy Screening 
Instrument and the Masquerading Disorders Tool. Subjects must have a score of ≥4 and ≤9 on the 11-
point Numerical Rating Scale (NRS) for average pain over the past 24 hours at Visit 1. Subjects will be 
assessed for widespread pain symptoms using the American College of Rheumatology Fibromyalgia 
Criteria. Additional procedures during Visit 1 will include the administration of the Hospital Anxiety 
and Depression Scale (HADS), completion of the Sheehan Suicidality Tracking Scale (S-STS), adverse 
event collection which will begin at the time of informed consent, demographic characteristics, medical 
history including concomitant medications, complete physical examination (with comprehensive 
neurological examination), 5-minute electrocardiogram, vital signs (sitting blood pressure and pulse), 
height, body weight, and collection of blood and urine samples for chemistry, Human 
immunodeficiency virus (HIV), hepatitis, triglycerides, hematology (including HbA1c), and urinalysis. 
All subjects will undergo urine drug and alcohol screen using a local urine testing kit and breathalyzer, 
respectively. Subjects who test positive for marijuana, opioids, benzodiazepines inconsistent with 
current prescriptions, or alcohol 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 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 except 1 (if applicable) of their pharmacologic analgesic treatments for 
neuropathic pain associated with diabetic peripheral neuropathy, and complete daily pain diaries. The 
duration of the Screening Period will depend upon the analgesic treatment that is being discontinued. 
The only allowed analgesics for painful diabetic peripheral neuropathy may not be an N-methyl-D-
aspartate receptor ligand, must be non-opioid and non-sedative, and must not interfere with subjects’ 
pain reporting. The allowed analgesic must have been taken for at least 1 month (30 days) prior to Visit 
1, and subjects must be on a stable fixed dose that is not expected to change during the study.  Subjects 
already taking no more than 1 allowed concomitant analgesic medication at Visit 1 may directly begin 
Week -1 of the Screening Period. 
 


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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 Visits 1 through 3 on how to 
record their pain on the device. Subjects will also be educated at Visits 1 through 3 on 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 may be 
repeated for some or all subjects depending on findings of an ongoing blinded data review (e.g., if pain 
score variability is increased on a subject or site level). 
 
Subjects will be dispensed acetaminophen to be used as rescue medication, and will be instructed to 
take no more than 2 g/daily (one to two 500-mg caplets every 4 to 6 hours as needed) for DPN pain. 
 
Beginning immediately after Visit 1, 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, pain on walking, and whether rescue medication was used 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. 
 
Screening Period (Week -1) 
The investigative site staff will contact study subjects by telephone weekly through Week -1 to 
reinforce the reporting instructions (i.e., diary completion) and to assess adverse events. Subjects will 
be asked a non-leading question to inquire about potential adverse events, “Have you experienced any 
new or changed symptoms since we last asked/since last week?” Subjects taking no more than 1 
allowed concomitant analgesic medications at Visit 1 may directly begin Week -1 of the Screening 
Period. 
 
Baseline Visit (Week 0) 
At Visit 2 (Baseline Visit), study personnel will verify eligibility with the inclusion and exclusion 
criteria when the subjects are on site, and prior to randomization. Pain scores reported by subjects 
during the Screening Period will be evaluated by the interactive response technology system for raw 
score and for variability among scores after transmission of pain scores from the handheld devices to 
determine randomization eligibility The interactive response technology system will notify the site if 
the subjects is “Eligible” or “Not eligible.” No other information will be provided. 
 
Subjects whose mean of the daily average pain intensity score during the preceding 7 (±1) days is 
within the protocol-defined algorithm and with adequate compliance with daily diary completion will 
be eligible for randomization. The absolute pain score 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 interactive response technology system. 
 
Subjects will again be asked a non-leading question to assess potential adverse events.  Use of 
concomitant medications will be documented. Vital signs (blood pressure and pulse) will be measured 
after sitting for 5 minutes and a 5-minute electrocardiogram will be performed. Medical history will be 
updated and a brief physical examination performed. Blood and urine samples will be collected for 
chemistry, hematology, and urinalysis testing. Subjects will undergo drug and alcohol screen using a 
local urine testing kit and breathalyzer, respectively. Subjects who test positive for marijuana, opioids, 


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benzodiazepines inconsistent with current prescriptions, or alcohol, 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.  
 
Eligible subjects will be randomized to receive either NYX-2925 or placebo for 4 weeks. Investigators 
and subjects will be masked to the randomization allocation. 
 
Subjects will be dispensed a 2-week supply of investigational product and instructed to take 2 capsules 
by mouth once daily. Subjects will also be re-dispensed acetaminophen to use as rescue medication for 
DPN pain; instructions not to exceed 2 g/day will be reinforced. The appropriate use of rescue 
medication will be assessed by inventory of the returned caplets, as well as by subject interview. 
 
Subjects will be instructed to continue entering their average pain intensity, worst pain intensity, pain 
upon walking, and whether they used rescue medication over the past 24 hours into their study-issued 
handheld devices every night. Every morning upon awakening, subjects will complete the DSIS via 
their study-issued handheld device. Pain diary compliance will be reviewed at each study visit by the 
study staff, and reporting instructions will be reinforced. 
 
Quantitative sensory testing will be done using the Bedside Sensory Testing Kit. The following scales 
will be completed at the Baseline Visit: Brief Pain Inventory for Diabetic Peripheral Neuropathy 
(BPI-DPN), the Short-Form McGill Pain Questionnaire version 2 (SF-MPQ-2), the Norfolk Quality of 
Life Questionnaire - Diabetic Neuropathy (QOL-DN), the HADS, the Insomnia Severity Index, and the 
S-STS.  
 
One week following the Week 0 visit, subjects will be contacted by telephone for an assessment of 
adverse events and to reinforce diary completion. Adverse events will be assessed by asking the subject 
a non-leading question. 
 
Treatment Period: Week 2 
Subjects will return to the clinic at the end of Week 2 for assessment of compliance with study 
medication, use of rescue medication, and be dispensed the final 2-week supply of investigational 
product and rescue medication for DPN pain. Pain diary compliance will be reviewed by the study 
staff, and reporting instructions will be reinforced. Adverse events will be assessed by asking the 
subject a non-leading question. Use of concomitant medications will be documented. Vital signs 
(sitting blood pressure and pulse) will be measured. Blood samples will be collected for liver function 
testing. 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, pain upon walking, and rescue medication use over the past 24 hours into their study-issued 
handheld devices every night. Every morning upon awakening, subjects will complete the DSIS via 
their study-issued handheld device.  
 
Scales to be completed at the Week 2 visit include the Patient Global Impression of Change (PGI-C), 
the S-STS, and the Insomnia Severity Index.  
 
One week following the Week 2 visit, subjects will be contacted by telephone for an assessment of 
adverse events and to reinforce diary completion. 


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Treatment Period: Week 4/Early Termination 
During the Week 4 or Early Termination Visit, subjects will be evaluated for compliance with study 
medication, and return all materials and unused study medication/rescue medication to the study site. 
The study-issued handheld device will be returned. Pain diary compliance will be reviewed by the 
study staff. Adverse events will be assessed by asking the subject a non-leading question. Use of 
concomitant medications will be documented. Vital signs (sitting blood pressure and pulse) and body 
weight will be measured, brief physical examination performed, and subjects will undergo a 5-minute 
electrocardiogram. Blood and urine samples will be collected for chemistry, hematology, and urinalysis 
testing. Female subjects of childbearing potential will be tested for pregnancy using a local urine 
testing kit. Subjects will undergo drug and alcohol screen using a local urine testing kit and 
breathalyzer, respectively. 
 
Scales to be completed at the Week 4/Early Termination Visit include BPI-DPN, PGI-C, SF-MPQ-2, 
HADS, QOL-DN, Insomnia Severity Index, and S-STS. 
 
7 Days Post-Treatment Follow Up Visit (Week 5) 
Subjects will return to the study site 7 days following the Week 4/Early Termination visit to assess 
adverse events and concomitant medication use. The adverse event assessment will include any serious 
adverse events that were ongoing at the time of study completion, and whether any ongoing adverse 
events had progressed to becoming serious. Blood samples will be collected for liver function testing.  
 
Number of subjects (planned and analyzed):  
Approximately 300 subjects enrolled by a randomized method with a pre-specified number of subjects 
per treatment arm.  


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Diagnosis and main criteria for inclusion:  
Inclusion Criteria: Screening  
1. An Institutional Review Board-approved written informed consent and privacy language 
(Health Insurance Portability and Accountability Act) authorization must be obtained from the 
subject prior to performing any study related procedures. 
2. Subjects who consent to being included in a subject registry database. 
3. Male and female subjects ≥18 and ≤75 years of age. 
4. Subjects with a diagnosis of Type 2 Diabetes. 
5. Subjects with a score of ≥4 and ≤9 on the 11-point NRS for average pain intensity over the past 
24 hours at Visit 1. 
6. Hemoglobin A1c (HbA1c) ≤11% (measured at Visit 1). 
7. Stable use of diabetic medications beginning 1 month prior to Visit 1. (Adequate glycemic 
control with only diet and exercise is also permitted.) 
8. Subjects with diabetic peripheral neuropathy, of symmetrical nature and in lower extremities 
for ≥6 months to ≤10 years, and diagnosed by a score of ≥3 on Michigan Neuropathy 
Screening Instrument. 
9. Body mass index <40 kg/m2. 
10. Calculated creatinine clearance ≥60 mL/minute (Cockcroft-Gault formula). 
11. Clinical laboratory values must be within normal limits or deemed not clinically significant by 
the investigator and sponsor-designated medical monitor.  
12. Female subjects must either: 
 
Be of non-childbearing potential: 
o Post-menopausal (defined as at least 1 year without any menses) prior to Visit 1; or 
o Documented as surgically sterile. 
 
Or, if of childbearing potential: 
o Agree not to try to become pregnant during the study and for 28 days after the final 
administration of investigational product;  
o Have a negative urine pregnancy test at Visit 1; and  
o If heterosexually active, agree to consistently use 2 forms of highly effective birth 
control (at least 1 of which must be a barrier method) starting at Visit 1 and 
continuing throughout the study period and for 28 days after the final 
administration of investigational product. 
13. Female subjects must agree not to breastfeed starting at Visit 1 and continuing throughout the 
study period and for 28 days after the final administration of investigational product. 
14. Female subjects must not donate ova starting at Visit 1 and continuing throughout the study 
period and for 28 days after the final administration of investigational product. 
15. Male subjects must refrain from sperm donation starting at Visit 1 and continuing throughout 
the study period and for 90 days after the final administration of investigational product.  
16. Male subjects who are not surgically sterilized for at least 90 days, and sexually active with a 
female partner, must use a condom with spermicide during the study, and for 90 days after the 
last dose of investigational product. 
17. Has not participated in an interventional study for at least 30 days. 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. 


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18. 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. 
 
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 7 (±1) 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. 
Exclusion Criteria: 
1. Subjects who have a current diagnosis of a major psychiatric disorder (including schizophrenia, 
bipolar disorder, or panic disorder), including those who have required an antipsychotic or 
mood stabilizer (e.g., lithium, carbamazepine, 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) or generalized anxiety disorder (GAD) who 
have been on stable medication for the past 3 months (and are expected to remain stable for the 
duration of the trial) and whose condition is currently well-controlled may be included 
2. Subjects who have 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. Subjects with history of severe renal impairment defined by renal dialysis or peritoneal 
dialysis, or who have undergone renal transplant. 
6. Impaired hepatic function characterized by a previous known diagnosis of chronic liver 
disease, and/or the presence of abnormal serum total bilirubin, or alanine transaminase (ALT), 
aspartate transaminase (AST), or alkaline phosphatase >1.5 x upper limit of normal (ULN) at 
screening.  
7. Known history of significant cardiovascular condition, such as myocardial infarction or 
congestive heart failure; evidence of current uncontrolled cardiac arrhythmias, angina, or 
electrocardiographic evidence of acute ischemia; or active conduction system abnormalities; 
QTcF >450 msec (males) or >470 msec (females), or uncontrolled hypertension characterized 
by resting systolic blood pressure values >140 mm Hg or resting diastolic >90 mm Hg. 
8. Heart rate <45 bpm or >90 bpm. 
9. Fasting triglycerides >250 mg/dL. 
10. History of Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, Multiple Sclerosis, 
or a history of seizures, epilepsy, or strokes.  
11. HIV infection, hepatitis, or other ongoing infectious disease that the investigator considers 
clinically significant.  


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12. Concomitant use of antiepileptic drugs, non-steroidal anti-inflammatory drugs (except cardiac 
preventive acetylsalicylic acid), opioids, muscle relaxants, dextromethorphan (except low dose 
intermittent use for cough), tramadol, topical lidocaine, topical capsaicin, and selective 
norepinephrine reuptake inhibitors. Subjects are allowed to enter with a maximum of 1 allowed 
analgesic medication for neuropathic pain that has been taken at a stable dose for at least 1 
month (30 days) prior to Visit 1. Allowed analgesics may not be N-methyl-D-aspartate receptor 
ligands, must be non-opioid and non-sedative, and must not interfere with subjects’ pain 
reporting. Tricyclic antidepressants may be continued if designated as the single analgesic 
medication for the treatment of pain. 
13. History of or current substance abuse disorder as defined by Diagnostic and Statistical Manual 
of Mental Disorders - Fifth Edition. 
14. Recreational and/or medicinal marijuana use within the past 6 months. 
15. Positive urine drug screen for marijuana, opioids, benzodiazepines inconsistent with current 
prescriptions, or breathalyzer test for alcohol at Visit 1. 
16. Positive urine drug screen for marijuana, opioids, benzodiazepines inconsistent with current 
prescriptions, or breathalyzer test for alcohol at Visit 2. 
17. Sensitivity to, allergy to, or concomitant use of N-methyl-D-aspartate receptor ligands 
including ketamine, amantadine, dextromethorphan (except low dose intermittent use for 
cough), memantine, methadone, dextropropoxyphene, and/or ketobemidone.  
18. Amputations of lower extremities (toe amputation is allowed). 
19. 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. 
20. Subjects with hypersensitivity to multiple medications, in the opinion of the investigator. 
21. Subjects who meet 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 at Visit 1 or Visit 2.   
 
Waivers to the exclusion criteria will NOT be allowed. 
Test product, dose and mode of administration, batch number:  
NYX-2925, oral capsules, 2 capsules once daily by mouth.  
Reference therapy, dose and mode of administration, batch number:  
Placebo, oral capsules, 2 capsules once daily by mouth 
Rescue medication 
Acetaminophen, up to 2 g/day, as needed for DPN pain. To be dispensed beginning at Visit 1 and 
re-dispensed throughout the entire study. 
Duration of Study 
Screening: One to 4 weeks of analgesic medication washout. 
Maintenance: Four weeks of blinded treatment with either NYX-2925 or placebo. 
Follow-Up: Assessment of LFTs, adverse events and concomitant medications 1 week following the 
Week 4/Early Termination Visit. 


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Criteria for evaluation: 
Efficacy: 
Primary Efficacy Endpoint: 
 
Change in the NRS score assessing average pain intensity in the past 24 hours from baseline 
(average of Days -7 to -1) to Week 4 (average of Days 22 through 28) 
Secondary Efficacy Endpoint 
 
Change in the mean NRS score for daily worst pain intensity from baseline (average of Days -7 
to -1) to Week 4 (average of Days 22 through 28) 
 
Change in the mean NRS score assessing average pain intensity in the past 24 hours from 
baseline (average of Days -7 to -1) to each week of treatment (average of Days 1 through 7, 
Days 8 through 14, and Days 15 through 21) 
 
Change in the mean NRS score assessing average pain upon walking intensity in the past 
24 hours from baseline (average of Days -7 to -1) to each week of treatment (average of Days 1 
through 7, Days 8 through 14, Days 15 through 21, and Days 22 through 28) 
 
PGI-C at Weeks 2 and 4 
 
Change in published subscale scores of the SF-MPQ-2 from baseline (Visit 2) to Week 4 
 
Change in published subscale scores of the QOL-DN from baseline (Visit 2) to Week 4 
 
Change in the Insomnia Severity Index from baseline (Visit 2) to Week 2 and Week 4 
 
Change in published subscale scores of the HADS from baseline (Visit 2) to Week 4 
 
Change in the mean DSIS score from baseline (average of Days -7 to -1) to each week of 
treatment (average of Days 1 through 7, Days 8 through 14, Days 15 through 21, and Days 22 
through 28) 
 
Change in the BPI-DPN from baseline (Visit 2) to Week 4 
Safety: 
 
Adverse event monitoring 
 
Physical examination 
 
Vital signs 
 
5-minute electrocardiogram 
 
Clinical laboratory test results 
 
S-STS 
Exploratory 
 
Use of rescue medication 
 
Percent of subjects achieving ≥30% and ≥50% pain reduction on the NRS average pain 
intensity from baseline (average of Days -7 to -1) to Week 4 (average of Days 22 through 28) 
 
Number of days to the first ≥30% reduction and first ≥50% reduction in the NRS average pain 
intensity 
 
Number of days to sustained pain reduction 


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Sample Size: 
The planned sample size is a total of 300 randomized subjects. This sample size will provide 
approximately 80% power for a 2-sided t-test with Type I error of 0.048. 
Statistical methods: 
Safety analyses will be based on the Safety Population, which is defined as all subjects who receive at 
least 1 dose of investigational product. Efficacy analyses will be based on the modified Intent-to-Treat 
Population, which is defined as all subjects in the Safety Population with at least 1 post baseline 
assessment of the pain intensity NRS. 
For the primary efficacy endpoint, the daily pain intensity NRS score from the handheld device will be 
averaged for baseline (Days -7 to -1) and Week 4 (Days 22 to 28) after randomization. Change from 
baseline to Week 4 will be assessed for treatment group differences with an analysis of covariance with 
fixed factors for study site and treatment, with baseline value as a covariate. As a sensitivity analysis, a 
mixed model repeated measures analysis of variance will be used to assess treatment differences. The 
model will include factors for study site, treatment, week, and the treatment-by-week interaction, with 
baseline value as a covariate. 
Change in the mean NRS score assessing average pain intensity in the past 24 hours from baseline 
(average of Days -7 to -1) to each week of treatment will be assessed for treatment group differences 
with an analysis of covariance with fixed factors for study site and treatment, with baseline value as a 
covariate. Change from baseline for the PGI-C, SF-MPQ-2, QOL-DN, Insomnia Severity Index, 
HADS, DSIS, BPI-DPN will be analyzed similarly. 
The use of rescue medication and percent of subjects meeting responder criteria will be summarized 
descriptively. 
The number of days to the first ≥30% reduction and first ≥50% reduction in the NRS average pain 
intensity will be assessed for treatment group differences with the log-rank test.  
Adverse events will be categorized by system organ class and preferred term with the Medical 
Dictionary for Regulatory Activities. Summary tables for treatment-emergent adverse events (TEAEs) 
will include number and percent of subjects experiencing TEAEs by system organ class and preferred 
term. 
Mean change in clinical laboratory and vital signs from baseline (Visit 2) to Week 4 (Visit 4) will be 
summarized descriptively. Clinical laboratory results considered clinically important by the 
investigator will be identified. Subjects with suicidal ideation or behavior will be identified with the 
S-STS. 
 


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2 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................1 
1 
SYNOPSIS ...................................................................................................................5 
2 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............15 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................20 
4 
INTRODUCTION ......................................................................................................21 
5 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................25 
5.1 
Primary Objective .......................................................................................................25 
5.2 
Secondary Objectives .................................................................................................25 
5.3 
Study Endpoints ..........................................................................................................25 
5.3.1 
Efficacy Endpoints ......................................................................................................25 
5.3.2 
Safety Endpoints .........................................................................................................26 
5.3.3 
Exploratory Efficacy Endpoints .................................................................................26 
6 
INVESTIGATIONAL PLAN .....................................................................................27 
6.1 
Overall Study Design and Plan: Description ..............................................................27 
6.2 
Scientific Rationale for Study Design ........................................................................35 
6.3 
Justification of Dose ...................................................................................................35 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................37 
7.1 
Subject Inclusion Criteria ...........................................................................................37 
7.2 
Subject Exclusion Criteria ..........................................................................................38 
7.3 
Screen Failures ............................................................................................................40 
7.4 
Subject Withdrawal Criteria .......................................................................................40 
7.5 
Methods of Birth Control............................................................................................40 
8 
STUDY TREATMENT ..............................................................................................42 
8.1 
Dosing and Administration .........................................................................................42 
8.2 
Investigational Product Description, Appearance, Packaging, and Labeling .............42 
8.3 
Preparation and Handling ...........................................................................................42 
8.4 
Storage ........................................................................................................................43 
8.5 
Accountability .............................................................................................................43 
8.6 
Treatment Compliance ................................................................................................43 


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8.7 
Concomitant and Excluded Medications ....................................................................43 
9 
STUDY ASSESSMENTS AND PROCEDURES ......................................................45 
9.1 
Screening Assessments ...............................................................................................45 
9.1.1 
Masquerading Disorders Tool ....................................................................................45 
9.1.2 
Michigan Neuropathy Screening Instrument ..............................................................45 
9.1.3 
Bedside Sensory Testing Kit ......................................................................................45 
9.1.4 
American College of Rheumatology Fibromyalgia Criteria ......................................45 
9.2 
Efficacy Assessments .................................................................................................45 
9.2.1 
Numeric Rating Scale of Pain Intensity (NRS) ..........................................................45 
9.2.2 
Patient Global Impression of Change (PGI-C) ...........................................................46 
9.2.3 
Short-Form McGill Pain Questionnaire, version 2 (SF-MPQ-2) ...............................46 
9.2.4 
Norfolk Quality of Life Questionnaire – Diabetic Neuropathy (QOL-DN) ...............46 
9.2.5 
Hospital Anxiety and Depression Scale (HADS) .......................................................46 
9.2.6 
Insomnia Severity Index .............................................................................................46 
9.2.7 
Daily Sleep Interference Scale (DSIS) .......................................................................47 
9.2.8 
Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) .......................47 
9.3 
Safety Assessments .....................................................................................................47 
9.3.1 
Safety Parameters .......................................................................................................47 
9.3.2 
Vital Sign Measurements ............................................................................................47 
9.3.3 
Physical Examination .................................................................................................47 
9.3.4 
Electrocardiogram .......................................................................................................48 
9.3.5 
Clinical Laboratory Assessments ...............................................................................48 
9.3.6 
Sheehan Suicidality Tracking Scale (S-STS) .............................................................49 
9.4 
Safety and Pharmacovigilance ....................................................................................49 
9.4.1 
Adverse Events – Relationship to Investigational Product .........................................49 
9.4.2 
Recording Adverse Events .........................................................................................50 
9.4.3 
Reporting Adverse Events ..........................................................................................51 
9.4.3.1 
Severity of Adverse Events ........................................................................................51 
9.4.3.2 
Action Taken for Adverse Events ...............................................................................51 
9.4.3.3 
Outcome for Adverse Events ......................................................................................52 
9.5 
Serious Adverse Events ..............................................................................................52 
9.6 
Other Reportable Events .............................................................................................53 
10 
SCHEDULE OF PROCEDURES ..............................................................................55 


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10.1 
Screening Period (Week -4 to -1) ...............................................................................55 
10.2 
Baseline (Week 0) .......................................................................................................56 
10.3 
Treatment Period (Week 2 and Week 4) ....................................................................57 
10.3.1 
Week 2 (Visit 3) ..........................................................................................................57 
10.3.2 
Week 4 (Visit 4)/Early Termination ...........................................................................58 
10.4 
Follow-Up Period (7 Days Post-Treatment) ...............................................................59 
11 
STOPPING CRITERIA ..............................................................................................60 
12 
STATISTICS ..............................................................................................................61 
12.1 
Sample Size Determination ........................................................................................61 
12.2 
Randomization ............................................................................................................61 
12.3 
Statistical Analysis Plan .............................................................................................61 
12.4 
Analysis Populations ..................................................................................................61 
12.5 
Analyses of Efficacy ...................................................................................................62 
12.5.1 
Primary Efficacy Endpoint .........................................................................................62 
12.5.1.1 
Primary Efficacy Analysis ..........................................................................................62 
12.5.1.2 
Sensitivity Analysis ....................................................................................................62 
12.5.2 
Other Efficacy Endpoints ...........................................................................................62 
12.5.3 
Multiple Comparisons ................................................................................................62 
12.6 
Analyses of Safety ......................................................................................................62 
12.6.1 
Adverse Events ...........................................................................................................63 
12.6.2 
Clinical Laboratory Tests ...........................................................................................63 
12.6.3 
Electrocardiogram .......................................................................................................63 
12.6.4 
Vital Sign Measurements ............................................................................................63 
12.6.5 
Suicidal Ideation .........................................................................................................64 
12.7 
Interim Analysis ..........................................................................................................64 
13 
ADMINISTRATIVE ..................................................................................................65 
13.1 
Source Documents ......................................................................................................65 
13.2 
Study Monitoring ........................................................................................................65 
13.3 
Case Report Forms .....................................................................................................65 
13.4 
Protocol Amendment(s) ..............................................................................................65 
13.5 
Audits and Inspections ................................................................................................65 
13.6 
Institutional Review Board .........................................................................................66 
13.7 
Compliance with Regulatory Requirements ...............................................................66 


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13.8 
Informed Consent .......................................................................................................66 
13.9 
Study File Management ..............................................................................................66 
13.10 
Study Completion .......................................................................................................66 
13.11 
Confidentiality ............................................................................................................66 
13.12 
Compensation, Insurance, and Indemnity ..................................................................67 
13.13 
Financial Disclosure ...................................................................................................67 
13.14 
Records Retention .......................................................................................................67 
13.15 
Publication Policy .......................................................................................................67 
14 
REFERENCES ...........................................................................................................68 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ....................................................................4 
Table 2: 
Abbreviations and Special Terms ................................................................20 
Table 3: 
Schedule of Procedures ................................................................................32 
 
LIST OF FIGURES 
Figure 1: 
Study Design ................................................................................................31 
 


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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and special terms are used in this study protocol. 
Table 2: 
Abbreviations and Special Terms  
Abbreviation or specialist term 
Explanation 
AUC 
Area Under the Plasma Concentration versus Time Curve 
BPI-DPN 
Brief Pain Inventory for Diabetic Peripheral Neuropathy 
CFR 
Code of Federal Regulations 
Cmax 
Plasma Concentration 
CSF 
Cerebrospinal fluid 
DSIS 
Daily Sleep Interference Scale 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
GAD 
Generalized Anxiety Disorder 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HbA1c 
Hemoglobin A1c; glycated hemoglobin 
HCV RNA 
Hepatitis C Virus-Ribonucleic Acid 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
MDD 
Major Depressive Disorder 
MDE 
Major Depressive Episode 
NF 
National Formulary 
NMDA 
N-methyl-D-aspartate 
NMDAR 
N-methyl-D-aspartate receptor 
NRS 
Numerical Rating Scale 
PGI-C 
Patient Global Impression of Change 
QOL-DN 
Norfolk Quality of Life Questionnaire - Diabetic Neuropathy 
SF-MPQ-2 
Short-Form McGill Pain Questionnaire version 2 
S-STS 
Sheehan Suicidality Tracking Scale 
TEAE 
Treatment-emergent adverse events 
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. NYX-2925 is an N-methyl-D-aspartate receptor (NMDAR) functional glycine-site 
partial agonist, and at low concentrations of endogenous agonist (glycine or D-serine), 
NYX-2925 partially activates NMDAR. 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 of existing 
and emerging drugs that are indicated for the treatment of neuropathic pain and fibromyalgia. 
While current medications target individual elements of pain signal transmission or modulation, 
NYX-2925 modulates multiple synaptic relays within pain circuits. 
Glutamate is the major excitatory neurotransmitter in the central nervous system and acts 
through activation of glutamate receptors. A portion of the receptors bind preferentially to 
N-methyl-D-aspartate (NMDA), and are therefore, termed NMDARs. Unlike other glutamate 
receptors found in the brain, such as α-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, learning, stroke, schizophrenia, Parkinson’s disease, and neuropathic pain 
(Traynelis 2010, Mony 2009, Tai 2001). 
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 been shown to be effective 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 


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the chronic unpredictable stress model of fibromyalgia, NYX-2925 (10 mg/kg) has been shown 
to produce mechanical analgesia. In summary, these data support testing NYX-2925 in both 
fibromyalgia and neuropathic pain. 
Pharmacokinetic studies have been performed in rats and dogs, and suggest that NYX-2925 is 
rapidly absorbed into the bloodstream, and time to peak plasma concentration is reached within 
1 hour. NYX-2925 is rapidly eliminated from plasma with an apparent terminal elimination 
half-life in the range of 1 to 2 hours. Brain exposure is approximately 5% to 10% relative to 
plasma levels of NYX-2925. 
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 6 weeks of daily oral doses, the no-observed-adverse-effect levels were the 
highest doses tested (180 mg/kg in dogs and 480 mg/kg in rats). There were no adverse findings 
in either species. The plasma levels (exposure) of NYX-2925 at the highest doses in these studies 
are considered to be at least 50- to 100-fold the projected human therapeutic dose.   
NYX-2925 has been administered to humans. The first-in-human study (NYX-2925-1001), for 
which results are available, was a combined single and multiple ascending dose, placebo-
controlled study in healthy volunteers that also includes food-effect, cerebrospinal fluid (CSF), 
and elderly cohorts.  
In the single dose portion of the study, single doses of NYX-2925 were administered orally. Five 
ascending dose groups (50 mg, 150 mg, 400 mg, 800 mg, and 1200 mg) and an elderly cohort 
(300 mg) with 8 subjects each (6 on active drug, 2 on placebo in each group) were dosed. Seven 
days after the initial dose, the 400 mg dose group received a second repeated dose (6 active drug, 
1 placebo) to examine the effect of food on plasma drug concentrations. A CSF cohort (50 mg) 
was also completed with 6 subjects receiving NYX-2925. In 7 dose groups or cohorts, 29 males 
and 25 females were enrolled. A total of 52 of the 54 single dose subjects completed the study. 
Two subjects randomized to placebo discontinued study participation. One subject was lost to 
follow-up and 1 subject discontinued due to physician decision (related to subject 
noncompliance). One subject in the elderly cohort receiving 300 mg experienced a treatment-
emergent adverse event (TEAE) which was not considered related to NYX-2925. Five subjects 
in the CSF cohort receiving 50 mg experienced at least one TEAE, one of which (procedural 
headache) was deemed related to NYX-2925. One subject receiving placebo experienced a 
TEAE. There were no TEAEs reported for clinical laboratories, safety electrocardiograms, or 
vital signs.     
In the multiple ascending dose phase, there were three ascending dose groups (150, 600 and 900 
mg) with 8 subjects in each dose group; 6 received active drug and 2 received placebo for up to 7 
days. There were also 6 subjects in the CSF cohort who were dosed with NYX-2925 300 mg (no 
placebo control) and 5 completed the study. A total of 15 males and 15 females were enrolled. 
Study medication was given once daily for up to 7 days. Two subjects in the CSF cohort 
discontinued study participation, 1 due to other (related to subject noncompliance) and 1 due to 
protocol violation. All subjects in 150 mg, 600 mg, and 900 mg dose groups received all 7 doses 
of study medication. Twelve subjects (1 NYX-2925 150 mg, 3 NYX-2925 600 mg, 1 NYX-2925 
900 mg, 2 placebo, and 5 NYX-2925 300 mg CSF cohort) reported at least 1 TEAE. There was 
one subject in the 150 mg dose group with urinary retention assessed as unrelated by the 
investigator, and possibly related by the sponsor. There was 1 subject with at least 1 study drug 


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related TEAE (flatulence and bloating) in the 600 mg dose group, 1 placebo subject with at least 
1 study drug related TEAE (fatigue and lethargy), and 1 CSF cohort subject with at least 1 study 
drug related TEAE (headache). No grade 3 or higher TEAEs, serious TEAEs, or TEAEs leading 
to study discontinuation were reported. No individual preferred adverse event term was reported 
for more than 1 subject in the 150 mg, 600 mg, or 900 mg dose groups. In the CSF cohort, 3 
subjects reported procedural headache, 5 subjects reported procedural pain, and 2 subjects 
reported vomiting. There were no TEAEs reported for clinical laboratories, safety 
electrocardiograms, or vital signs. 
Concerning cardiovascular safety, a thorough analysis of ECGs demonstrated that NYX-2925 
did not increase QTc at any dose up to 1200 mg.  The maximum geometric mean peak plasma 
concentration (Cmax) (20.1 μg/ml) was well above the expected exposure in clinical care.  There 
were no clinically significant changes in HR, PR and QRS or in ECG diagnostic statements. 
The pharmacokinetics of NYX-2925 in humans are similar to the pharmacokinetics in rats and 
dogs. Pharmacokinetic analysis revealed that absorption of NYX-2925 was relatively rapid and 
peak concentrations were achieved within 2 hours after dosing and declined in a roughly 
monophasic manner over 24 hours. The pharmacokinetics were dose proportional over the dose 
range tested (within the variability) and showed minimal accumulation following once per day 
dosing for 7 days. A high-fat, high-caloric meal decreased the rate of absorption (delayed Tmax), 
lowered Cmax by 10%, but had no impact on the extent of exposure (area under the plasma 
concentration versus time curve [AUC] values were comparable), 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. The central nervous 
system exposure was confirmed from the CSF concentration time profile in both CSF dose 
groups. The CSF concentrations increased proportionally as the dose increased. 
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 support clinical studies up to and including 6 weeks of daily doses. 
Results from the first-in-human study indicate that NYX-2925 is safe and well-tolerated in the 
male and female healthy volunteers dosed to date at single doses up to 1200 mg, and multiple 
doses up to 900 mg given daily for 7 days. The preclinical and phase 1 clinical data support 
further testing in humans. 
In addition to the current trial, there are 2 other ongoing clinical studies with NYX-2925. NYX-
2925-1003 is a phase 1, double-blind, placebo-controlled, pilot, crossover study to assess the 
effects of NYX-2925 on sleep architecture as assessed by polysomnography in healthy male 
subjects aged 40-55 when their bedtime is advanced by 3 hours in a sleep laboratory. Also 
ongoing is study NYX-2925-2002, in subjects with fibromyalgia. The primary objective of this 
study is to determine whether NYX-2925 modulates central nervous system activity in key pain 
neural circuitry, consistent with the potential to provide analgesia in subjects with fibromyalgia, 
as assessed by neuroimaging methods. Secondarily, this study will provide a preliminary 
characterization of the safety of NYX-2925 in subjects with fibromyalgia. 
Further, there is planned study; a phase 1, double-blind, randomized, sponsor-open, parallel, 
placebo-controlled exploratory study to assess the effect of multiple dose levels of NYX-2925 on 


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the brain function of healthy volunteers as measured by electroencephalogram and event related 
potentials.  
To date, one serious adverse event, cholelithiasis requiring inpatient hospitalization, has been 
reported in the clinical development program for NYX-2925, that being in the current study, 
NYX-2925-2001. The event is considered not related to NYX-2925. 
This study (NYX-2925-2001) is a randomized, double-blind, placebo-controlled, multiple-dose 
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. 


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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 multiple dose levels of 
NYX-2925 versus placebo in treating the neuropathic pain associated with diabetic peripheral 
neuropathy. 
5.2 
Secondary Objectives 
Secondary objectives of the study are to assess the: 
 Effects of multiple dose levels of NYX-2925 versus placebo on pain characteristics, sleep 
interference, health status, psychological state, and global improvement. 
 Safety and tolerability of multiple dose levels of NYX-2925. 
5.3 
Study Endpoints 
5.3.1 
Efficacy Endpoints 
The primary endpoint is the change in the numerical rating scale (NRS) score assessing average 
pain intensity in the past 24 hours from baseline (average of Days -7 to -1) to Week 4 (average of 
Days 22 through 28).  
Secondary efficacy endpoints include: 
 Change in the mean NRS score for daily worst pain intensity from baseline (average of 
Days -7 to -1) to Week 4 (average of Days 22 through 28)  
 Change in the mean NRS score assessing average pain intensity in the past 24 hours from 
baseline (average of Days -7 to -1) to each week of treatment (average of Days 1 through 
7, Days 8 through 14, and Days 15 through 21) 
 Change in the mean NRS score assessing average pain upon walking intensity in the past 
24 hours from baseline (average of Days -7 to -1) to each week of treatment (average of 
Days 1 through 7, Days 8 through 14, Days 15 through 21, and Days 22 through 28) 
 Patient Global Impression of Change (PGI-C) at Weeks 2 and 4 
 Change in published subscale scores of the Short-Form McGill Pain Questionnaire 
version 2 (SF-MPQ-2) from baseline (Visit 2) to Week 4 
 Change in published subscale scores of the Norfolk Quality of Life Questionnaire - 
Diabetic Neuropathy (QOL-DN) from baseline (Visit 2) to Week 4  
 Change in the Insomnia Severity Index from baseline (Visit 2) to Week 2 and Week 4 
 Change in published subscale scores of the Hospital Anxiety and Depression Scale 
(HADS) from baseline (Visit 2) to Week 4  


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 Change in the mean Daily Sleep Interference Scale (DSIS) score from baseline (average 
of Days -7 to -1) to each week of treatment (average of Days 1 through 7, Days 8 through 
14, Days 15 through 21, and Days 22 through 28) 
 Change in the Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) from 
baseline (Visit 2) to Week 4 
5.3.2 
Safety Endpoints 
The safety endpoints will include adverse events, vital signs, physical examination findings, 
electrocardiograms, clinical laboratory results, and the Sheehan Suicidality Tracking Scale 
(S-STS).  
5.3.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include: 
 Use of rescue medication  
 Percent of subjects achieving ≥30% and ≥50% pain reduction on the NRS average pain 
intensity from baseline (average of Days -7 to -1) to Week 4 (average of Days 22 through 
28) 
 Number of days to the first ≥30% reduction and first ≥50% reduction in the NRS average 
pain intensity 
 Number of days to sustained pain reduction 


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6 
INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan: Description 
The study will be a 6- to 9-week study, including a 1- to 4-week Screening Period, followed by a 
4-week double-blind, randomized, placebo-controlled Treatment Period, and a 1-week 
Follow-Up Period (Figure 1). The schedule of assessments is provided in Table 3. The study will 
include approximately 35 study sites in the United States. 
Screening Period (Week -4 to -1) 
Upon Institutional Review Board (IRB) approval of the protocol, subjects will be asked to 
provide informed consent for this study before any required procedures are performed. Subjects 
will also be required to sign an additional consent for their inclusion in a subject registry 
database. The database will use partially-identified subject information to review subjects’ 
research study history within a proprietary, secure platform. 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 since the last research study, violation of the washout period between studies, or 
incorrect age for the NYX-2925-2001 study. Employees, contractors and volunteers of the study 
site, or relatives of any employees, contractors and volunteers of the study site are not eligible for 
study participation. 
Subjects with Type 2 diabetes who have been on stable antidiabetic medication for at least 
1 month (or have stable glycemic control with diet and exercise alone) and who have been 
suffering from painful diabetic peripheral neuropathy in the lower extremities for at least 6 
months but not more than 10 years will be screened for diabetic peripheral neuropathy using the 
Michigan Neuropathy Screening Instrument and the Masquerading Disorders Tool. Subjects 
must have a score of ≥4 and ≤9 on the 11-point NRS for average pain over the past 24 hours at 
Visit 1. Subjects will be assessed for widespread pain symptoms using the American College of 
Rheumatology Fibromyalgia Criteria. Additional procedures during Visit 1 will include the 
administration of the HADS, completion of the S-STS, adverse event collection which will begin 
at the time of informed consent, demographic characteristics, medical history including 
concomitant medications, complete physical examination (with comprehensive neurological 
examination), 5-minute electrocardiogram, vital signs (sitting blood pressure and pulse after 5 
minutes), height, body weight, and collection of blood and urine samples for chemistry, HIV, 
hepatitis, and triglycerides, hematology (including HbA1c), and urinalysis. All subjects will 
undergo urine drug and alcohol screen using a local urine testing kit and breathalyzer, 
respectively. Subjects who test positive for marijuana, opioids, benzodiazepines inconsistent 
with current prescriptions, or alcohol 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 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 except 1(if applicable) of their pharmacologic analgesic 
treatments for neuropathic pain associated with diabetic peripheral neuropathy, and complete 
daily pain diaries. The duration of the Screening Period will depend upon the analgesic treatment 


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that is being discontinued. The only allowed analgesic for painful diabetic peripheral neuropathy 
may not be an N-methyl-D-aspartate receptor ligands, must be non-opioid and non-sedative, and 
must not interfere with subjects’ pain reporting (Section 8.7). The allowed analgesics must have 
been taken for at least 1 month (30 days) prior to Visit 1, and subjects must be on a stable fixed 
dose that is not expected to change during the study.  
The discontinuation of all (but 1 allowed, as applicable) analgesic medications will be managed 
by the principal investigator at the investigative site. Subjects already taking no more than 
1 allowed concomitant analgesic medication 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, and subjects will be instructed at Visits 1 
through 3 on how to record their pain on the device 
 
 Subjects will also be educated at Visits 1 through 3 on 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 may be repeated for some 
or all subjects depending on findings of an ongoing blinded data review (e.g., if pain score 
variability is increased on a subject or site level). 
Subjects will be dispensed acetaminophen to be used as rescue medication, and will be instructed 
to take no more than 2 g/daily (one to two 500-mg caplets every 4 to 6 hours as needed) for DPN 
pain. 
Beginning immediately after Visit 1, 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, pain on walking, and whether rescue medication was used 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 DSIS via their study-issued handheld device.  
 
Screening Period (Week -1) 
The investigative site staff will contact study subjects by telephone weekly through Week -1 to 
reinforce the reporting instructions (i.e., diary completion) and to assess adverse events. Subjects 
will be asked a non-leading question to inquire about potential adverse events, “Have you 
experienced any new or changed symptoms since we last asked/since last week?” Subjects taking 
no more than 1 allowed concomitant analgesic medication at Visit 1 may directly begin Week -1 
of the Screening Period. 
 
 
 


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Baseline (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 prior to randomization. Pain scores reported 
by subjects during the Screening Period will be evaluated by the interactive response technology 
system for raw score and for variability among scores after transmission of pain scores from the 
handheld devices to determine eligibility. The interactive response technology system will notify 
the site if the subject is “Eligible” or “Not eligible”. No other information will be provided. 
Subjects whose mean of the daily average pain intensity score during the preceding 7 (±1) days 
is within the protocol-defined algorithm (Section 12.2) and with adequate compliance with daily 
diary completion will be eligible for randomization. The absolute pain score and variability 
among scores, as well as the actual percentage required for diary compliance, will be masked to 
investigators and subjects. The appropriate use of rescue medication will be assessed by 
inventory of the returned caplets, as well as by subject interview. Subject eligibility for 
randomization into the study based on these variables will be communicated to the investigator 
via the interactive response technology system. 
Subjects will again be asked a non-leading question to assess potential adverse events, for 
example, “Have you experienced any new or changes symptoms since we last asked/since your 
last visit?” Use of concomitant medications will be documented. Vital signs (blood pressure and 
pulse) will be measured after sitting for 5 minutes and a 5-minute electrocardiogram will be 
performed. Medical history will be updated and a brief physical examination performed. Blood 
and urine samples will be collected for chemistry, hematology, and urinalysis testing. Subjects 
will undergo drug and alcohol screen using a local urine testing kit and breathalyzer, 
respectively. Subjects who test positive for marijuana, opioids, benzodiazepines inconsistent 
with current prescriptions, or alcohol, 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.  
Eligible subjects will be randomized to receive either NYX-2925 or placebo for 4 weeks. 
Investigators and subjects will be masked to the randomization allocation. 
Subjects will be dispensed a 2-week supply of investigational product and instructed to take 
2 capsules by mouth once daily. Subjects will also be re-dispensed acetaminophen to use as 
rescue medication for DPN pain; instructions not to exceed 2 g/day will be reinforced.  
Subjects will be instructed to continue entering their average pain intensity, worst pain intensity, 
pain upon walking, and whether they used rescue medication over the past 24 hours into their 
study-issued handheld devices every night. Every morning upon awakening, subjects will 
complete the DSIS via their study-issued handheld device. Pain diary compliance will be 
reviewed at each study visit by the study staff, and reporting instructions will be reinforced. 
Quantitative sensory testing will be done using the Bedside Sensory Testing Kit. The following 
scales will be completed at the Baseline Visit: BPI-DPN, the SF-MPQ-2, the QOL-DN, the 
HADS, the Insomnia Severity Index, and the S-STS.  
One week following the Week 0 visit, subjects will be contacted by telephone for an assessment 
of adverse events and to reinforce diary completion. Adverse events will be assessed by asking 
the subject a non-leading question.  


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Treatment Period (Week 2, Visit 3) 
Subjects will return to the clinic at the end of Week 2 for assessment of compliance with study 
medication, use of rescue medication, and be dispensed the final 2-week supply of 
investigational product and rescue medication for DPN pain. Pain diary compliance will be 
reviewed by the study staff, and reporting instructions will be reinforced. Adverse events will be 
assessed by asking the subject a non-leading question; for example, “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?” Use of concomitant 
medications will be documented. Vital signs (sitting blood pressure and pulse after 5 minutes) 
will be measured. Blood samples will be collected for liver function testing. 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, 
pain upon walking, and rescue medication use over the past 24 hours into their study-issued 
handheld devices every night. Every morning upon awakening, subjects will complete the DSIS 
via their study-issued handheld device.  
Scales to be completed at the Week 2 visit include the PGI-C, the S-STS, and the Insomnia 
Severity Index. 
One week following the Week 2 visit, subjects will be contacted by telephone for an assessment 
of adverse events and to reinforce diary completion.  
 
Treatment Period (Week 4/Early Termination, Visit 4) 
During the Week 4 or Early Termination Visit, subjects will be evaluated for compliance with 
study medication, and return all materials and unused study medication/rescue medication to the 
study site. The study-issued handheld device will be returned. Pain diary compliance will be 
reviewed by the study staff. Adverse events will be assessed by asking the subject a non-leading 
question; for example, “Have you experienced any new or changed symptoms since we last 
asked/since your last visit?” Use of concomitant medications will be documented. Vital signs 
(sitting blood pressure and pulse after 5 minutes) and body weight will be measured, brief 
physical examination performed, and subjects will undergo a 5-minute electrocardiogram. Blood 
and urine samples will be collected for chemistry, hematology, and urinalysis testing. Female 
subjects of childbearing potential will be tested for pregnancy using a local urine testing kit. 
Subjects will undergo drug and alcohol screen using a local urine testing kit and breathalyzer, 
respectively. 
Scales to be completed at the Week 4/Early Termination Visit include BPI-DPN, PGI-C, 
SF-MPQ-2, HADS, QOL-DN, Insomnia Severity Index, and S-STS.  
 
Follow-Up Visit (Week 5/7 days Post-Treatment, Visit 5) 
Subjects will return to the study site 7 days following the Week 4/Early Termination visit to 
assess adverse events and concomitant medication use. The adverse event assessment will 
include any serious adverse events that were ongoing at the time of study completion, and 


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whether any ongoing adverse events had progressed to becoming serious. Blood samples will be 
collected for liver function testing. 
 
 
Figure 1: 
Study Design 
Follow-up
Wk -4
Wk 4
Wk 5/ 
End Study
Wk -1
Wk 0/ 
Baseline
Washout of 
analgesic for pDPN
(As Applicable)
Daily Pain Score
Screening
n = 300
Randomization 
Eligibility 
Assessment
Treatment Period
NYX-2925 or Placebo
 
pDPN = painful diabetic peripheral neuropathy; Wk = week 


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Table 3: Schedule of Procedures 
Study Period 
Screening 
Baseline 
Treatment 
Follow-Up 
Study Week 
(Day) 
1 to 4 weeksa 
(-28 to -1) 
Week 0 
(1)b 
Week 2 
(14 ± 2) 
Week 4c 
(28 ± 2) 
Week 5 
(35 ± 2) 
Study Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Assessment 
 
 
 
 
 
Informed consent prior to any study procedure 
X 
 
 
 
 
Assess inclusion/exclusion criteria 
X 
X 
 
 
 
Instructions on reporting pain 
X 
X 
X 
 
 
Education on appropriate expectations around participation in a clinical studyd 
X 
X 
X 
 
 
Michigan Neuropathy Screening Instrument 
X 
 
 
 
 
Masquerading Disorders Tool 
X 
 
 
 
 
Bedside Sensory Testing Kit 
 
X 
 
 
 
American College of Rheumatology Fibromyalgia Criteria 
X 
 
 
 
 
Demographic characteristics (age, sex, race, and ethnicity) 
X 
 
 
 
 
Medical history 
X 
update 
 
 
 
Height 
X 
 
 
 
 
Body weight 
X 
 
 
X 
 
Vital sign measurements (sitting)e 
X 
X 
X 
X 
 
Physical examinationf 
X 
X 
 
X 
 
5-minute electrocardiogram after 5 minutes in supine position 
X 
X 
 
X 
 
Urine pregnancy test for females of childbearing potential 
X 
X 
 
X 
 
HIV and hepatitis testsg 
X 
 
 
 
 
Drug and alcohol screenh 
X 
X 
 
X 
 
Obtain samples for serum chemistry, hematology, and urinalysisi 
X 
X 
Xi 
X 
Xi 
Discontinue all but 1 concomitant analgesic medication 
Xj 
 
 
 
 
Record average pain intensity over past 24 hoursk 
 
 
 
 
 
Dispense handheld electronic diary 
 
X 
 
 
 
 
Return handheld electronic diary 
 
 
 
X 
 
Dispense rescue medication (acetaminophen)l 
X 
X 
X 
 
 
Return rescue medication and perform accountabilitym 
 
X 
X 
X 
 


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Study Period 
Screening 
Baseline 
Treatment 
Follow-Up 
Study Week 
(Day) 
1 to 4 weeksa 
(-28 to -1) 
Week 0 
(1)b 
Week 2 
(14 ± 2) 
Week 4c 
(28 ± 2) 
Week 5 
(35 ± 2) 
Study Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Record average pain intensity, worst pain intensity, pain upon walking,k and 
rescue medication use over past 24 hours at bedtime for each day 
X 
X 
X 
 
 
Record Daily Sleep Interference Scale (DSIS) each morning 
X 
X 
X 
 
 
Phone call to reinforce diary instructionsn 
X 
X 
X 
X 
 
Assess pain and diary compliance  
 
X 
X 
X 
 
Randomize eligible subjects 
 
X 
 
 
 
Dispense investigational product  
 
X 
X 
 
 
Return investigational product and assess compliancem 
 
 
X 
X 
 
Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) 
 
X 
 
X 
 
Short-Form McGill Pain Questionnaire (SF-MPQ-2) 
 
X 
 
X 
 
Norfolk Quality of Life Questionnaire – Diabetic Neuropathy (QOL-DN) 
 
X 
 
X 
 
Insomnia Severity Index  
 
X 
X 
X 
 
Hospital Anxiety and Depression Scale (HADS) 
X 
X 
 
X 
 
Patient Global Impression of Change (PGI-C) scale 
 
 
X 
X 
 
Sheehan Suicidality Tracking Scale (S-STS) 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
Adverse eventso 
X 
X 
X 
X 
X 
a) Subjects will discontinue all but 1 allowed concomitant pharmacologic analgesic medication. Duration of the period will depend upon the analgesic 
treatment(s) being discontinued (not to exceed 4 weeks). Subjects taking no more than 1 allowed concomitant analgesic medication at Visit 1 may directly 
begin Week -1 of the Screening Period. 
b) Visit window for Baseline Visit is 6 to 10 days after start of Week -1 
c) Subjects who prematurely discontinue randomized treatment will have Week 4 procedures performed. 
d) Review of these educational materials may be repeated for some or all subjects or depending on findings of an ongoing blinded data review (e.g., if pain 
score variability is increased on a subject or site level). 
e) Vital signs will include blood pressure and pulse after at least 5 minutes of being seated, and prior to blood sample collection. 
f) 
A complete physical examination will be performed at Visit 1 and a brief physical examination will be performed at Visits 2 and 4. The physical 
examination at Visit 1 will include a comprehensive neurological examination. 
g) If the screening hepatitis C antibody test result is reactive, a nucleic acid test for hepatitis C virus-ribonucleic acid (HCV RNA) should be performed for 
confirmation of chronic infection. If the screening HIV test is positive, a confirmatory Western Blot test should be performed to confirm HIV status. 
h) Urine drug screen and alcohol breathalyzer.  


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i) 
Samples will be obtained following an 8-hour fast. The Week 2 and Week 5 samples will only be analyzed for liver function tests and no fasting will be 
required. HbA1c will be collected at Screening (Visit 1) only. 
j) 
Analgesic medications discontinued during the Screening Period cannot be restarted until after the Week 4 visit. 
k) Numerical Rating Scale of pain intensity (0 = no pain to 10 = worst pain imaginable) will be completed once daily at bedtime. At Visit 1, average pain 
intensity over the past 24 hours will be recorded onto device by site personnel.  
l) 
Subjects will be instructed to take no more than 2 g/daily (one to two 500-mg caplets every 4 to 6 hours as needed) for pain. 
m) Instruct study participants to bring all used and unused investigational product and rescue medication to each visit for compliance monitoring. 
n) Phone call will be made weekly during weeks with no study visits, to reinforce diary completion.  
o) Weekly phone calls will be made during weeks with no study visits, to assess adverse events.  


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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 but 1 concomitant analgesic medication during the 
Screening Period is expected to reduce inter-subject variability in treatment response (Katz 2005, 
Katz 2015). The 1-month duration of treatment is considered sufficient to identify clinically 
important pain relief. 
Only masked versions of the informed consent and protocol will be provided to study sites. The 
masked versions will obscure the number of dose groups (i.e., 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 
Multiple dose levels of NYX-2925 are planned. No dose is more than 1/6th of the maximum 
single dose (1200 mg) given in phase 1, which was safe and well-tolerated. Further, no dose is 
more than 2/9th of the maximum multiple dose (900 mg) given once daily for 7 days in phase 1, 
which was safe and well-tolerated. Both the 1200 mg single dose and the 900 mg multiple dose 
were associated with pharmacokinetic exposures (maximum concentration and area under the 
concentration curve) below the no-observed-adverse-effect levels for both the dog and rat in the 
Good Laboratory Practice toxicology studies. NYX-2925 has a terminal elimination half-life of 4 
to 5 hours and demonstrated no accumulation with once daily dosing over 7 days in phase 1. This 
is consistent with pharmacokinetic data in rats and dogs, following much higher doses over six 
weeks. Approximately 65% of the NYX-2925 dose is eliminated as unchanged drug in the urine. 
Thus, no drug accumulation is expected in this study. Both male and female subjects were 
included in the phase 1 studies and provide adequate support for studying both female and male 
subjects with neuropathic pain, when using appropriate contraception precautions. Thus, the 
selected dose strengths chosen for this study are well supported by the available preclinical and 
clinical safety and pharmacokinetic data. The 28-day duration of exposure to NYX-2925 in this 
study is supported by the general toxicology studies in rats and dogs, comprising 42 and 55 daily 
doses, respectively. 
The dose strengths of NYX-2925 planned for this study are expected to produce maximum 
plasma concentrations ranging from approximately 170 to 3400 ng/mL. These levels 
approximate the plasma maximum concentration associated with efficacy in the rat Bennett, 
Taxol®, and streptozotocin models. In those pharmacology models, analgesia was observed at 
doses between 1 and 30 mg/kg, corresponding to maximum plasma concentrations levels of 210 
to 4500 ng/mL, respectively. Brain exposure in humans, as measured in CSF, is anticipated to 
approximate the CSF levels measured in rats at analgesic doses. Additionally, the anticipated 
CSF levels in humans should be 3- to 6-orders of magnitude greater than the NYX-2925 
concentration associated with half-maximal response at the NMDAR target.  
Preclinical data support daily dosing as sufficient to result in efficacy in pain syndromes. First, 
when given to rats, NYX-2925 enhances hippocampal long-term potentiation at 24 hours and as 
much as 1 week following a single-oral dose. This enhancement of synaptic plasticity is a 
probable mechanism for the long duration of effects in the pain models. Following a single oral 
dose in the rat Bennett model of neuropathic pain, analgesic activity was consistently seen at 


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24 hours post-dose, and in some experiments at 1 week post-dose. In a rat Bennett model 
experiment that included gabapentin as a positive control, gabapentin was active only at the 
1-hour time point. In the rat Taxol® model of chemotherapy-induced neuropathy, NYX-2925 was 
active at both 24 hours and 1 week after administration of a single dose, whereas the positive 
control, bupivacaine, was active only at the 1-hour testing interval. Gabapentin (150 mg/kg 
orally) was inactive in this model. Finally, in the rat model of streptozotocin-induced diabetic 
neuropathy, NYX-2925 analgesic activity was also evident at 24 hours and 1 week following a 
single dose. Given that the mean elimination half-life of NYX-2925 in the rat is approximately 
2 hours, these data indicate that the analgesic activity of NYX-2925, which is consistently 
present for 24 hours after a single dose and often present for a week, persists beyond the 
presence of drug in the rat. Along with the corresponding 1-week persistence of effects on the 
enhancement of synaptic plasticity, the proposed underlying mechanism of drug action, the rat 
pain model data support the idea that NYX-2925 effects will persist for at least 24 hours 
following a single dose in humans. Taken together, these preclinical data support daily dosing in 
humans. 


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7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Subject Inclusion Criteria 
Inclusion Criteria: Screening  
1. An IRB-approved written informed consent and privacy language (Health Insurance 
Portability and Accountability Act) authorization must be obtained from the subject prior 
to performing any study-related procedures. 
2. Subjects who consent to being included in a subject registry database.  
3. Male and female subjects ≥18 and ≤75 years of age. 
4. Subjects with a diagnosis of Type 2 diabetes. 
5. Subjects with a score of ≥4 and ≤9 on the 11-point NRS for average pain intensity over 
the past 24 hours at Visit 1. 
6. Hemoglobin A1c (HbA1c) ≤11% (measured at Visit 1). 
7. Stable use of diabetic medications beginning 1 month prior to Visit 1. (Adequate 
glycemic control with only diet and exercise is also permitted).  
8. Subjects with diabetic peripheral neuropathy, of symmetrical nature and in lower 
extremities for ≥6 months to ≤10 years, and diagnosed by a score of ≥3 on the Michigan 
Neuropathy Screening Instrument. 
9. Body mass index <40 kg/m2. 
10. Calculated creatinine clearance ≥60 mL/minute (Cockcroft-Gault formula). 
11. Clinical laboratory values must be within normal limits or deemed not clinically 
significant by the investigator and sponsor-designated medical monitor.  
12. Female subjects must either:  
 Be of non-childbearing potential: 
o Post-menopausal (defined as at least 1 year without any menses) prior to Visit 1; 
or 
o Documented as surgically sterile. 
 Or, if of childbearing potential: 
o Agree not to try to become pregnant during the study and for 28 days after the 
final administration of investigational product;  
o Have a negative urine pregnancy test at Visit 1; and  
o If heterosexually active, agree to consistently use 2 forms of highly effective birth 
control (at least 1 of which must be a barrier method) starting at Visit 1 and 
continuing throughout the study period and for 28 days after the final 
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13. Female subjects must agree not to breastfeed starting at Visit 1 and continuing throughout 
the study period and for 28 days after the final administration of investigational product. 
14. Female subjects must not donate ova starting at Visit 1 and continuing throughout the 
study period and for 28 days after the final administration of investigational product. 
15. Male subjects must refrain from sperm donation starting at Visit 1 and continuing 
throughout the study period and for 90 days after the final administration of 
investigational product.  
16. Male subjects who are not surgically sterilized for at least 90 days, and sexually active 
with a female partner, must use a condom with spermicide during the study, and for 
90 days after the last dose of investigational product. 
17. Has not participated in an interventional study for at least 30 days. 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. 
18. 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. 
Inclusion Criteria: Randomization 
Daily pain scores and diary compliance will be transferred into the interactive response 
technology system, which will assess the criteria for randomization. Subjects whose mean of the 
daily average pain intensity score during the preceding 7 (±1) 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. 
7.2 
Subject Exclusion Criteria 
1. Subjects who have a current diagnosis of major psychiatric disorder (including 
schizophrenia, bipolar disorder, or panic disorder), including those who have required an 
antipsychotic or mood stabilizer (e.g., lithium, carbamazepine, 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) or 
generalized anxiety disorder (GAD) who have been on stable medications for the past 3 
months (and are expected to remain stable for the duration of the trial) and whose 
condition is currently well-controlled may be included. 
2. Subjects who have 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. 


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4. History of hypoglycemia that disturbed consciousness, or ketoacidosis requiring 
hospitalization within past 3 months. 
5. Subjects with history of severe renal impairment defined by renal dialysis or peritoneal 
dialysis, or who have undergone renal transplant. 
6. Impaired hepatic function characterized by a previous known diagnosis of chronic liver 
disease, and/or the presence of abnormal serum total bilirubin, or alanine transaminase 
(ALT), aspartate transaminase (AST), or alkaline phosphatase >1.5 x upper limit of 
normal (ULN) at screening.  
7. Known history of significant cardiovascular condition, such as myocardial infarction or 
congestive heart failure; evidence of current uncontrolled cardiac arrhythmias, angina, or 
electrocardiographic evidence of acute ischemia; or active conduction system 
abnormalities; QTcF >450 msec (males) or >470 msec (females), or uncontrolled 
hypertension characterized by resting systolic blood pressure values >140 mm Hg or 
resting diastolic >90 mm Hg. 
8. Heart rate <45 bpm or >90 bpm. 
9. Fasting triglycerides >250 mg/dL. 
10. History of Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, Multiple 
Sclerosis, or a history of seizures, epilepsy, or strokes.  
11. Human immunodeficiency virus (HIV) infection, hepatitis, or other ongoing infectious 
disease that the investigator considers clinically significant.  
12. Concomitant use of antiepileptic drugs, non-steroidal anti-inflammatory drugs (except 
cardiac preventive acetylsalicylic acid), opioids, muscle relaxants, dextromethorphan 
(except low dose intermittent use for cough), tramadol, topical lidocaine, topical 
capsaicin, and selective norepinephrine reuptake inhibitors. Subjects are allowed to enter 
with a maximum of 1 allowed analgesic medication for neuropathic pain that has been 
taken at a stable dose for at least 1 month (30 days) prior to Visit 1. Allowed analgesics 
may not be N-methyl-D-aspartate receptor ligands, must be non-opioid and non-sedative 
and must not interfere with subjects’ pain reporting (Section 8.7). Tricyclic 
antidepressants may be continued if designated as the single analgesic medication for the 
treatment of pain. 
13. History of or current substance abuse disorder as defined by Diagnostic and Statistical 
Manual of Mental Disorders - Fifth Edition.  
14. Recreational and/or medicinal marijuana use within the past 6 months. 
15. Positive urine drug screen for marijuana, opioids, benzodiazepines inconsistent with 
current prescriptions, or breathalyzer test for alcohol at Visit 1. 
16. Positive urine drug screen for marijuana, opioids, any benzodiazepines inconsistent with 
current prescriptions, or breathalyzer test for alcohol at Visit 2. 
17. Sensitivity to, allergy to, or concomitant use of N-methyl-D-aspartate receptor ligands 
including ketamine, amantadine, dextromethorphan (except low dose intermittent use for 
cough), memantine, methadone, dextropropoxyphene, and/or ketobemidone.  
18. Amputations of lower extremities (toe amputation is allowed). 


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19. 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. 
20. Subjects with hypersensitivity to multiple medications, in the opinion of the investigator. 
21. Subjects who meet 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 at Visit 1 or Visit 2.   
Waivers to the exclusion criteria will NOT be allowed. 
7.3 
Screen Failures 
Subjects who sign and date the informed consent form, but who fail to meet the inclusion and 
exclusion criteria, are considered screen failures. Reason(s) for screen failure must be 
documented by the investigator and provided to the sponsor in a timely fashion. Screen failures 
who had failed due to not meeting criteria under Protocol Amendment 2 may be rescreened with 
Sponsor approval. No other subjects may be rescreened. 
7.4 
Subject Withdrawal Criteria 
Subjects who withdraw from the Treatment Period will not be replaced. Any subject may 
withdraw consent at any point during the study. The investigator may discontinue a subject at 
any time if it is deemed medically appropriate, or for subject noncompliance with study 
requirements. Subjects who terminate early should return to the clinic for the Early Termination 
visit. Subjects may be withdrawn from the study if any of the following criteria are met: 
 Occurrence of an adverse event, intercurrent illness, or laboratory abnormality that, in the 
opinion of the investigator, warrants the subject’s permanent withdrawal from the study 
for subject safety 
 Lack of efficacy 
 Subject withdraws consent 
 Subject noncompliance 
 Lost to follow-up 
 Pregnancy 
 Sponsor termination of study 
 An individual stopping criteria is met 
7.5 
Methods of Birth Control 
If heterosexually active, female subjects must agree to consistently use 2 forms of highly 
effective birth control (at least 1of which must be a barrier method) starting at Visit 1 and 
continuing throughout the study period and for 28 days after the final administration of 
investigational product. Methods of highly effective birth control include: 
 Oral or parenteral contraceptives 


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 Intrauterine device (either hormonal or non-hormonal type acceptable) 
 Barrier 
Female subjects must agree not to breastfeed starting at Visit 1 and continuing throughout the 
study period and for 28 days after the final administration of investigational product. Female 
subjects must not donate ova starting at Visit 1 and continuing throughout the study period and 
for 28 days after the final administration of investigational product.  
Male subjects must refrain from sperm donation starting at Visit 1 and continuing throughout the 
study period and for 90 days after the final administration of investigational product. Male 
subjects who are not surgically sterilized for at least 90 days, and sexually active with a female 
partner, must use a condom with spermicide during the study, and for 90 days after the last dose 
of investigational product. 


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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 blinded investigational product according to the randomization 
schedule. Investigational product will be dispensed at the Week 0 (Baseline) and Week 2 visits; 
at each of the 2 visits, subjects will receive a 2-week supply of investigational product. Subjects 
will be instructed to take 2 capsules of investigational product once daily by mouth.  
Randomized treatment will be: 
NYX-2925 by mouth once daily for 4 weeks, or 
Placebo by mouth once daily for 4 weeks 
Subjects will also be dispensed 1 bottle of acetaminophen to be used as rescue medication at the 
visits identified in Table 3. Rescue medication will consist of 500 mg caplets of acetaminophen. 
Subjects will be instructed that up to 2 g/day of rescue medication are allowed and should be 
reported daily via their study-issued handheld device. 
8.2 
Investigational Product Description, Appearance, Packaging, and 
Labeling 
NYX-2925 is a small molecule ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-
diazaspiro[3.4]octan-2-yl)butanamide), that will be provided as capsules for oral administration. 
Matching placebo capsules will also be provided. 
The oral formulation of the investigational product comprises inert United States Pharmacopeia 
(USP)-grade excipients in a capsule made of hydroxyl-propyl cellulose. The content of the 
capsule is a dry blend of NYX-2925, microcrystalline cellulose, National Formulary (NF), 
pregelatinized starch, NF, and magnesium stearate USP. 
Matching placebo capsules will contain only the inactive ingredients listed previously. 
The investigational product will be provided in a blister-pack kit. The labels will include 
“NYX-2925 Oral Capsules or Placebo to Match”, capsule count, kit number, storage conditions, 
retest date, sponsor name, and investigational use statement. Each kit of investigational product 
will include 18 capsules (nine 2-capsule rows) of either matching placebo capsules or NYX-2925 
capsules according to the randomization schedule. The investigational product will be packaged 
in a way that each dose will be 2 capsules/row. 
The sponsor will provide investigative sites with sufficient amounts of investigational product to 
conduct the study.   
8.3 
Preparation and Handling 
The investigative site will receive blister pack kits of blinded investigational product, and there 
will be no investigational product preparation done at the investigative site. The investigator may 


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delegate investigational product handling to site staff who will dispense kits of investigational 
product for subject administration according to the interactive response technology system. The 
interactive response technology system is being utilized to ensure the correct distribution of 
blinded investigational product according to the randomization schedule. The maintenance of 
treatment randomization codes will be maintained within the interactive response technology 
system.  
8.4 
Storage 
Investigational product 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 non-permitted 
excursions. 
8.5 
Accountability 
The investigator or designee at the investigative site will conduct investigational product 
accountability. The investigative site personnel will receive, inspect, and acknowledge condition 
of investigational product; document the amount received, dispensed and returned, and will 
dispense, and maintain the investigational product accountability records. A sponsor 
representative will inspect investigational product and accountability records. Site personnel will 
conduct subject level accountability, account for and document used/unused investigational 
product, and retain kits of returned investigational product to the investigative site’s limited 
access storage facility.  
Upon completion or termination of the study, and after sponsor accountability is completed, all 
used and unused supplies will be returned or destroyed as instructed by sponsor representative. 
8.6 
Treatment Compliance 
Site personnel will assess subject compliance with investigational product dosing. In addition, 
incorrect or partially administered doses will be documented. 
8.7 
Concomitant and Excluded Medications 
Subjects will discontinue all except 1 of their analgesic treatments for neuropathic pain 
associated with diabetic peripheral neuropathy. The allowed analgesic medication for 
neuropathic pain may not be an N-methyl-D-aspartate receptor ligand, must be non-opioid and 
non-sedative, and must not interfere with the subject’s pain reporting. The allowed analgesic 
must have been taken for at least 1 month (30 days) prior to Visit 1, and subjects must be on a 
stable fixed dose that is not expected to change during the study. Subjects may continue their 
antidiabetic medications.  
Concomitant use of antiepileptic drugs, non-steroidal anti-inflammatory drugs (except cardiac 
preventive acetylsalicylic acid), opioids, muscle relaxants, dextromethorphan (except low dose 
intermittent use for cough), tramadol, topical lidocaine, topical capsaicin, and selective 
norepinephrine reuptake inhibitors is prohibited. Tricyclic antidepressants may be continued if 
designated as the single analgesic medication for the treatment of pain. Concomitant use of the 
following N-methyl-D-aspartate receptor ligands; ketamine, amantadine, dextromethorphan 


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(except low dose intermittent use for cough), memantine, methadone, dextropropoxyphene, 
and/or ketobemidone is prohibited. Recreational or medicinal use of marijuana is prohibited. 
Subjects will be dispensed acetaminophen to be used as rescue medication, and will be instructed 
to take no more than 2 g/daily (one to two 500-mg caplets every 4 to 6 hours as needed) for DPN 
pain. Rescue medication will be provided by the sponsor. 
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 is allowed only if the investigator 
deems it is medically appropriate. The washout period must cover 5 half-lives of the drug and 
must be completed within the duration of the Screening Period. 
Concomitant medications used within 30 days prior to screening and through the follow-up visit 
must be documented in the source documents and on the corresponding electronic case report 
form (eCRF). 


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9 
STUDY ASSESSMENTS AND PROCEDURES 
9.1 
Screening Assessments 
9.1.1 
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, such as Morton’s neuroma, peripheral vascular disease, Achilles tendonitis, arthritis, 
and tarsal tunnel syndrome. The screening instrument consists of symptom screening questions, 
and an in-clinic history and examination to target the nature and etiology of the subject’s 
peripheral pain. The results of this assessment tool are provisional, with the final decision based 
on the clinical judgment of the investigator. 
9.1.2 
Michigan Neuropathy Screening Instrument 
The Michigan Neuropathy Screening Instrument is a 15-item, self-administered questionnaire 
and a 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 
Bedside Sensory Testing Kit 
The Bedside Sensory Testing Kit (Analgesic Solutions, Wayland, MA) is used to assess a 
subject’s sensory profile to allow phenotypic identification of subgroups of subjects with painful 
diabetic peripheral neuropathy who might respond differently to a given treatment. The kit 
consists of multiple sensory instruments that are applied to different peripheral anatomic sites to 
evaluate the following phenomena: extent of damage of low threshold mechanoreceptive small 
fibers in the feet, dynamic mechanical allodynia, punctate hyperalgesia, high threshold 
mechanoreceptive function, and cold allodynia. 
9.1.4 
American College of Rheumatology Fibromyalgia Criteria 
The 2010 American College of Rheumatology Fibromyalgia Criteria is a clinician-administered 
survey that is used as a diagnostic tool for fibromyalgia. The diagnostic criteria for fibromyalgia 
are met by the following 3 conditions:  
 Widespread Pain Index ≥7 and Symptom Severity Score ≥5, or the Widespread Pain 
Index is 3 to 6 and the Symptom Severity Score is ≥9;  
 Symptoms have been present at a similar level for at least 3 months; and 
 Subject does not have a disorder that would otherwise explain the pain (Wolfe 2010). 
9.2 
Efficacy Assessments 
9.2.1 
Numeric Rating Scale of Pain Intensity (NRS) 
The NRS of pain intensity is a unidimensional, segmented numeric version of the visual analog 
scale. A subject selects a whole number (0 to 10) that best indicates the intensity of his/her pain. 


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The format consists of a horizontal line which 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 pain upon 
walking during the past 24 hours, using the 11-point NRS. 
9.2.2 
Patient Global Impression of Change (PGI-C) 
The PGI-C is a 7-point scale that allows subjects to rate the change in the disease state from 
study initiation to specific time points during the study or at the end of the study. It provides the 
subject’s impression of overall change since beginning the study. 
9.2.3 
Short-Form McGill Pain Questionnaire, version 2 (SF-MPQ-2) 
The SF-MPQ-2 measures the sensory, affective, and evaluative qualities of pain, including 
symptoms relevant to neuropathic pain. The tool includes visual analogue as well as verbal rating 
scales of pain intensity on a total of 22 neuropathic and non-neuropathic pain descriptors that are 
each evaluated on a 10-point numerical rating scale (Dworkin 2009).  
9.2.4 
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). 
9.2.5 
Hospital Anxiety and Depression Scale (HADS) 
The HADS is a self-reported screening tool for anxiety and depression in non-psychiatric clinical 
populations.  The scale consists of 14 items (7 each for anxiety and depression), each rated on a 
4-point scale ranging from 0 (not at all) to 3 (very often). Responses are based on the relative 
frequency of symptoms over the preceding week. Possible scores range from 0 to 21 for each 
subscale. An analysis of scores on the two subscales supported the differentiation of each mood 
state into four ranges: ‘non cases’ (scores 0-7), ‘mild cases’ (scores 8-10), ‘moderate cases’ 
(scores 11-15), and ‘severe cases’ (scores 16 or higher) (Zigmond 1983). 
9.2.6 
Insomnia Severity Index 
The ISI is a 7-item self-report questionnaire assessing the nature, severity, and impact of 
insomnia. The usual recall period is the “last month” and the dimensions evaluated are: severity 
of sleep onset, sleep maintenance and early morning awakening problems, sleep dissatisfaction, 
interference of sleep difficulties with daytime functioning, noticeability of sleep problems by 
others, and distress caused by the sleep difficulties. A 5-point Likert scale is used to rate each 
item (e.g., 0 = no problem; 4 = very severe problem), yielding a total score ranging from 0 to 28. 
The total score is interpreted as follows: absence of insomnia (0–7); sub-threshold insomnia 
(8-14); moderate insomnia (15–21); and severe insomnia (22–28) (Bastien 2001). 


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9.2.7 
Daily Sleep Interference Scale (DSIS) 
The DSIS was developed to quantify sleep interference due to pain. The DSIS is a single-item 
measure that is completed by patients once a day (upon awakening) to accurately capture 
variability in sleep interference due to pain on a daily basis, thus minimizing recall bias. The 
DSIS has an 11-point response scale that asks patients to ‘‘Select the number that best describes 
how much your pain has interfered with your sleep during the past 24 hours.’’ Response options 
range from 0 (Did not interfere with sleep) to 10 (Completely interfered with sleep / unable to 
sleep due to pain). The DSIS is designed to be used in a patient daily diary that patients fill out 
upon awakening each morning (Vernon 2008).  
9.2.8 
Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) 
The BPI 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, 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), which distinguishes between pain due to DPN and pain due to other causes. Each 
BPI item uses a 0-10 numeric rating scale anchored at zero for “no pain” and 10 for “pain as bad 
as you can imagine” for Severity, and “does not interfere” to “completely interferes” 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). 
9.3 
Safety Assessments  
9.3.1 
Safety Parameters 
Refer to the Table 3 (Schedule of Procedures) or Section 10 (Schedule of Procedures) for time 
points.  
9.3.2 
Vital Sign Measurements  
Each assessment includes blood pressure and pulse after at least 5 minutes of being seated, and 
prior to blood sample collection. Vital signs may be repeated after 20 minutes for eligibility 
assessments. 
9.3.3 
Physical Examination 
A complete or brief physical examination will be performed as specified in the schedule of 
procedures table. A complete physical examination will include assessment of the following 
body systems: head, eyes, ears, nose, and throat; lymph nodes; neurologic; respiratory; 
cardiovascular; gastrointestinal; musculoskeletal; dermatologic; and extremities. 
The physical examination at Visit 1 will include a comprehensive neurological examination. The 
brief physical examination will be completed per investigator discretion. 
Body weight and height will be measured at selected visits (Table 3). 


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9.3.4 
Electrocardiogram 
Electrocardiograms (5-minute duration) will be collected after 5 minutes of supine rest and prior 
to blood sample collection, if possible. The device will be a Spaulding electrocardiogram device 
that acquires a 12-lead electrocardiogram continuously at each time point for up to 5 minutes. 
The 5 minutes of electrocardiogram data will be converted into a summary electrocardiogram 
(simulated 10-second electrocardiogram) for each electrocardiogram time point and submitted to 
the designated electrocardiogram laboratory cardiologists for measurements and diagnoses as 
though it were a standard 10-second electrocardiogram. Electrocardiograms may be repeated for 
eligibility assessments.  
The investigator or qualified sub-investigator will review all electrocardiogram interpretations 
and interval duration measurements for clinical significance. Standard electrocardiogram 
parameters will be measured. Clinically significant, abnormal 12-lead electrocardiograms should 
be repeated. Clinically significant electrocardiogram changes should be recorded as an adverse 
event.  
The Spaulding electrocardiogram device should be used for all assessments during the study 
unless it is non-operational, in which case another electrocardiogram may be performed locally 
and transmitted to Spaulding for central reading via printout. 
9.3.5 
Clinical Laboratory Assessments  
Blood samples for serum chemistry and hematology will be obtained after an 8-hour fast, except 
for the Week 2 and Week 5 liver function tests. 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 relevant abnormal 
values of uncertain causality must be repeated. Persistently abnormal laboratory values should be 
followed at the investigator’s discretion. Clinical labs may be repeated for eligibility 
assessments. Abnormal liver function tests (specified in section 11) must be repeated within 48-
72 hours. 
Hematology assessments will include total white blood cell count, differential (neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils), hemoglobin, hematocrit, red blood cell 
count, platelet count and HbA1c (at Visit 1). 
Serum chemistry assessments will include electrolytes (bicarbonate, calcium, chloride, 
phosphorous, potassium, sodium, and magnesium), enzymes (alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, lactate dehydrogenase, and gamma-glutamyl 
transferase), and other (albumin, total bilirubin, direct bilirubin, indirect bilirubin, creatinine, 
glucose, triglycerides (at screening), total protein, blood urea nitrogen, and uric acid). 
Qualitative urinalysis will include pH, specific gravity, glucose, ketones, protein, blood, 
leukocyte esterase, urobilinogen, nitrites, and reflex microscopy. 


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All women of childbearing potential will receive urine pregnancy tests (ß-human chorionic 
gonadotropin).   
The urine drug panel will include cannabinoids, opioids, and benzodiazepines; an alcohol screen 
will also be performed with a breathalyzer.  
Hepatitis and HIV screen includes: Hepatitis B surface antigen, hepatitis C antibody, and HIV. If 
the screening hepatitis C antibody test result is reactive, a nucleic acid test for HCV RNA should 
be performed for confirmation of chronic infection. If the screening HIV test is positive, a 
confirmatory Western Blot test should be performed to confirm HIV status. 
9.3.6 
Sheehan Suicidality Tracking Scale (S-STS) 
The standard version of the S-STS (Sheehan 2014[2]) 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” 
(0) to 4 = “extremely”. It also assesses the frequency of key phenomena and the overall time 
spent in suicidality. The standard version is available in identical clinician- and subject-rated 
formats. The S-STS accommodates a wide range of time frames. In clinical trials, the frequently 
used variants are “in the past week”, “in the past month”, “since the last visit”, “lifetime look 
back”, and “in the past day”.  
The S-STS maps to both the C-CASA, and to all of the categories in the FDA Draft Guidance 
documents of both 2010 and 2012, and in addition provides coverage for all suicidal phenomena 
presented in the draft FDA guidance. The S-STS has been studied and validated against other 
instruments used for the assessment of suicidality in a study, and been shown provide at least 
equal sensitivity to detecting suicidal ideation and behavior (Sheehan 2014 [1]). 
Suicidality identified after baseline will be recorded as an adverse event. 
9.4 
Safety and Pharmacovigilance 
9.4.1 
Adverse Events – Relationship to Investigational Product 
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 investigational product, regardless of causal 
relationship. A pre-existing condition is one that is present before investigational product dosing 
and is reported as part of the subject’s medical history. Pre-existing conditions should be 
reported as an adverse event only if the frequency, intensity, or character of the pre-existing 
condition worsens during the course of the study. 
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, coagulation, hematology, 
urinalysis) that is independent from the underlying medical condition and that requires medical 
or surgical intervention, or leads to investigational product interruption or discontinuation, must 
be considered an adverse event. 


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For each reported adverse event, an investigator must assess the relationship to investigational 
product using the following scale: 
Unrelated 
 Does not follow a known response pattern to the suspect investigational product (if 
response pattern is previously known). 
 Can clearly be explained by the known characteristics of the subject’s clinical state or 
other modes of therapy administered to the subject. 
Unlikely Related 
 The temporal sequence from dosing of the investigational product suggests that a 
relationship is unlikely. 
 Follows a response pattern that is unlike that of the suspect investigational product (if 
response pattern is previously known). 
 Could be reasonably explained by the subject’s clinical state or other modes of therapy 
administered to the subject. 
Possibly Related 
 Follows a reasonable temporal sequence from dosing of the investigational product.  
 May follow a known response pattern to the suspect investigational product (if response 
pattern is previously known). 
 Could also be reasonably explained by the subject’s clinical state or other modes of 
therapy administered to the subject. 
Probably Related 
 Follows a reasonable temporal sequence from dosing of the investigational product.  
 Could not be reasonably explained by the known characteristics of the subject’s clinical 
state or any other modes of therapy administered to the subject. 
 Is confirmed by improvement on stopping or slowing dosing of the investigational 
product, if applicable. 
When an assessment is not provided, the event will be treated as possibly related for purposes of 
regulatory reporting. 
9.4.2 
Recording Adverse Events 
A “pre-existing” condition is one that is present before investigational product dosing and is 
reported as part of the subject’s medical history. Pre-existing conditions should be reported as an 
adverse event only if the frequency, intensity, or character of the pre-existing condition worsens 
during the course of the study. Adverse events will be collected from the time the informed 
consent is signed to the end of the subject’s participation in the study. 
Subjects should be instructed to report all potential adverse events to the investigator, and, 
queried in a non-leading manner, without specific prompting (e.g., “How are you feeling?”). The 
site study staff should assess emerging symptoms of dissociative reaction similar to those caused 


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by NMDA antagonists including memory impairment, disturbance in time, body or 
environmental perception, stilted speech, emotional withdrawal, impaired coordination, motor 
retardation, bizarre reasoning or illusory experiences in any sensory perception, or confused 
state; such symptoms may be captured as adverse events. 
To avoid vague, ambiguous, or colloquial expressions, all adverse events should be recorded in 
standard medical terminology rather than in the subject’s own words. Each adverse event will 
also be described in terms of duration (start and stop date), severity, relationship to 
investigational product, 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 event collection begins after the subject has completed the informed consent and 
continues until the subject’s participation in the study ends. Ongoing adverse events should be 
followed to a satisfactory resolution in the investigator’s opinion. Subjects should be instructed 
to report all adverse events to the investigator. In addition, the investigator should seek to elicit 
any clinical or objective reactions by specific questioning (e.g., “How have you been feeling?”) 
and as appropriate by examination. Information on all adverse events should be recorded on the 
eCRF. All clearly related signs, symptoms, and results of diagnostic procedures performed in 
relation to an adverse event should be grouped together and recorded as a single diagnosis.   
9.4.3.1 
Severity of Adverse Events 
All adverse events will be assessed for severity, using the following general grading scale: 
Mild: Transient or mild discomfort (<48 hours); no medical intervention/therapy required. 
Moderate: Mild to moderate limitation in activity – some assistance may be needed; no or 
minimal medical intervention/therapy required. 
Severe: Marked limitation in activity, some assistance usually required; medical 
intervention/therapy, required hospitalization possible. 
Life threatening: Extreme limitation in activity, significant assistance required; significant 
medical intervention/therapy required, hospitalization, or hospice care probable. 
When changes in the severity of an adverse event occur more frequently than once a day, the 
maximum severity for the experience that day should be noted. If the severity category changes 
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 taken 
 Concomitant medication taken 
 Hospitalization or prolongation of hospitalization 


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 Discontinued study 
 Nondrug therapy 
 Other (specify) 
The investigator must also document the action taken in regards to investigational product (as a 
result of a given adverse event) according to the following criteria: 
 Dose not changed 
 Investigational product interrupted 
 Investigational product 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 events are reported to the sponsor-designated medical monitor using the Aptinyx 
provided form by email or fax at: 
 
 
 
 
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes: 
 Death: “Death” is an outcome and is NOT the adverse event. In the event of death, 
the cause of death should be recorded as the adverse event. The only exception is 
“sudden death” when the cause is unknown. 
 Is a life-threatening experience: Life-threatening adverse events include any adverse 
drug experience, which, in the view of the investigator, places the subject at 
immediate risk of death from the reaction as it occurs. It 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 


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 Results in a persistent or significant disability/incapacity: Disability is defined as a 
substantial disruption in a person’s ability to conduct normal life functions. 
 Results in a congenital anomaly/birth defect 
 Additionally, important medical events that may not result in death, be life 
threatening, or require hospitalization may be considered a serious adverse event 
when, based upon appropriate medical judgment, they may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed 
previously. Example: 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 
site’s knowledge of the event. A copy of the initial serious adverse event report must be received 
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. 
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 (additional laboratory tests, 
consultation reports, discharge summaries, postmortem reports, etc.) 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 required expedited regulatory 
reporting. Individual treatment codes will be available to limited staff who are responsible to 
break codes for reporting purposes. 
All serious adverse events will be reported to the FDA. 
9.6 
Other Reportable Events 
Reports of overdose (with or without an adverse event), abuse, dependency, inadvertent or 
accidental exposure, pregnancy, and unexpected therapeutic benefit should be forwarded in the 
same timeframe as a serious adverse event. Overdose occurs when a subject is dosed or has taken 


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a dose greater than the intended or scheduled dose specified by the protocol. All pregnancies 
occurring during the study must be followed for information regarding the course of pregnancy, 
delivery, and condition of the newborn. Follow-up should be provided by the investigator to the 
sponsor-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. Female subjects of childbearing potential and female partners of male 
subjects must use an acceptable method of birth control during the participation in this study.  


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10 
SCHEDULE OF PROCEDURES 
The schedule of procedures is summarized in Table 3 . 
10.1 
Screening Period (Week -4 to -1) 
The subject will be asked to provide informed consent for this study before any required 
procedures are performed. Subjects will also be asked to sign an additional consent for their 
inclusion in a subject registry database. Adverse event collection will begin at the time of 
informed consent. 
After the informed consents are signed, the following procedures and assessments should be 
completed at Visit 1: 
 Confirmation of diabetic peripheral neuropathy by the following assessments: 
o Michigan Neuropathy Screening Instrument  
o Masquerading Disorders Tool 
o American College of Rheumatology Fibromyalgia Criteria 
 NRS for average pain intensity over the past 24 hours  
 Demographic characteristics (age, sex, race, and ethnicity) 
 Medical history 
 Prior (within last 30 days) and concomitant medications 
 Height and body weight 
 Sitting vital signs (blood pressure and pulse after 5 minutes) 
 Complete physical examination, including comprehensive neurological examination 
 Electrocardiogram after 5 minutes in supine position 
 Urine pregnancy test for females of childbearing potential 
 Urine drug test 
 Breathalyzer test for alcohol 
 Blood samples for fasting (8 hours) serum chemistry HIV, hepatitis B surface antigen, 
hepatitis C antibody, triglycerides, and hematology (including HbA1c) 
 Urine sample for urinalysis 
 HADS 
 S-STS 
 Adverse events 


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Eligible subjects who meet all inclusion and exclusion criteria will enter the 1- to 4-week 
Screening Period. The following procedures and assessments will be performed: 
 Subjects who are taking more than 1 analgesic medication will discontinue all but 
1 of the medications as allowed by the protocol before the start of daily pain and sleep 
evaluations. The duration of their Screening Period will depend on the time required 
to discontinue analgesic medications, but the total duration of the Screening Period 
cannot exceed 4 weeks. Subjects who are taking no more than 1 allowed analgesic 
medication will begin daily pain and sleep evaluations at bedtime immediately after 
Visit 1 (i.e., will begin Week -1). 
 Subjects will be provided a handheld device, and as a method for ensuring 
consistency and reliability of pain scoring, instructed on how to record their pain on 
the device 
 Subjects 
will also be educated on appropriate expectations around their participation in a 
clinical study 
 
 On each of the days preceding Visit 2 (Baseline Visit), subjects will record the 
following on the handheld device: 
o At bedtime: average pain intensity, worst pain intensity, pain on walking, and 
use of rescue medication during the past 24 hours 
o Upon waking: DSIS 
 Subjects will be dispensed acetaminophen to be used as rescue medication, and will 
be instructed to take no more than 2 g/daily (one to two 500-mg caplets every 4 to 
6 hours as needed) for DPN pain. 
 The investigative site staff will contact study subjects by telephone weekly until and 
including Week -1 to reinforce the reporting instructions (7±2 days prior to Visit 2) 
and assess adverse events. 
10.2 
Baseline (Week 0) 
At Visit 2 (Baseline Visit), the following procedures and assessments will be performed: 
 Medical history update 
 Concomitant medication use assessed 
 Rescue medication supplies returned, appropriate use assessed, and 
compliance/accountability performed 
 Adverse events assessed 
 Sitting vital signs (blood pressure and pulse after 5 minutes) 
 Brief physical examination 
 Electrocardiogram after 5 minutes in supine position 
 Urine pregnancy test for females of childbearing potential 
 Urine drug test 


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 Breathalyzer test for alcohol 
 Urine sample for urinalysis 
 Bedside Sensory Testing Kit 
 Pain scores reported by subjects during the Screening Period and diary compliance 
evaluated by the interactive response technology system for raw score and for variability 
among scores by automated transmission of pain scores from the handheld devices 
Subjects who continue to meet all entry criteria and are randomized by the interactive response 
technology system will undergo the following procedures and assessments: 
 Blood samples for fasting (8 hours) serum chemistry and hematology 
 HADS 
 S-STS 
 BPI-DPN 
 SF-MPQ-2 
 QOL-DN 
 Insomnia Severity Index 
 Investigational product dispensed 
 Rescue medication dispensed 
Subjects will be reminded on how to record their pain on the device 
 
Subjects will also be reminded about appropriate 
expectations around their participation in a clinical study
 
 Review of these educational materials may be repeated for 
some or all subjects depending on findings of an ongoing blinded data review (e.g., if pain score 
variability is increased on a subject or site level. On each day until returning to the study site at 
Week 2, subjects will record the following on the handheld device: 
 At bedtime: average pain intensity, worst pain intensity, pain on walking, and use of 
rescue medication during the past 24 hours. 
 Upon waking: DSIS 
The investigative site staff will contact study subjects by telephone one week following Week 0 
to reinforce the diary completion and assess adverse events. 
Subjects will be instructed to return to the study site at Week 2. 
10.3 
Treatment Period (Week 2 and Week 4) 
10.3.1 
Week 2 (Visit 3) 
At Visit 3, the following procedures and assessments will be performed: 


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 Concomitant medication use assessed 
 Adverse events assessed 
 Sitting vital signs (blood pressure and pulse after 5 minutes) 
 Serum chemistry for liver function testing (only) 
 PGI-C 
 Insomnia Severity Index 
 Rescue medication supplies returned, appropriate use assessed, and 
compliance/accountability performed 
 Investigational product and supplies returned and compliance/accountability performed 
 Compliance with entry of pain intensity and rescue medication into daily diary 
 Investigational product dispensed 
 Rescue medication dispensed 
Subjects will be reminded on how to record their pain on the device 
 
Subjects will also be reminded about appropriate 
expectations around their participation in a clinical study 
 
 Review of these educational materials may be repeated for 
some or all subjects depending on findings of an ongoing blinded data review (e.g., if pain score 
variability is increased on a subject or site level. On each of day until returning to the study site 
at Week 4, subjects will record the following on the handheld device: 
 At bedtime: average pain intensity, worst pain intensity, pain on walking, and use of 
rescue medication during the past 24 hours. 
 Upon waking: DSIS 
The investigative site staff will contact study subjects by telephone one week following Week 0 
to reinforce the diary completion and assess adverse events. 
Subjects will be instructed to return to the study site at Week 4. 
10.3.2 
Week 4 (Visit 4)/Early Termination 
At Visit 4, or at the time of early termination from the study, the following procedures and 
assessments will be performed: 
 Concomitant medication use assessed 
 Adverse events assessed 
 Body weight 
 Sitting vital signs (blood pressure and pulse after 5 minutes) 
 Brief physical examination 
 Electrocardiogram after 5 minutes in supine position 


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 Urine pregnancy test for females of childbearing potential 
 Urine drug test 
 Breathalyzer test for alcohol 
 Blood samples for fasting (8 hours) serum chemistry and hematology 
 Urine sample for urinalysis 
 BPI-DPN 
 SF-MPQ-2 
 QOL-DN 
 Insomnia Severity Index 
 HADS 
 PGI-C 
 S-STS 
 Rescue medication supplies returned, appropriate use assessed, and 
compliance/accountability performed 
 Investigational product and supplies returned and compliance/accountability performed 
 Study-issued handheld device returned 
 Compliance with entry of pain intensity and rescue medication into daily diary 
Subjects will be instructed to return to the study site after 7 days. 
10.4 
Follow-Up Period (Week 5/7 Days Post-Treatment) 
Subjects will return to the study site 7 days following the Week 4/Early Termination visit to 
assess adverse events and concomitant medication use. The adverse event assessment will 
include any serious adverse events that were ongoing at the time of study completion, and 
whether any ongoing adverse events had progressed to becoming serious. Blood samples will be 
collected for liver function testing. 
 


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11 
STOPPING CRITERIA  
Subjects will be withdrawn from the treatment period of the study if any of the following criteria 
are met. Repeat testing must be completed within 48-72 hours: 
Repeated results (i.e. values confirmed by repeat testing): 
 Serum total bilirubin ≥ 2.5 mg/dL, or 
 Subject meets one of the following criteria 
 ALT or AST >3 x ULN, or 
 ALT or AST ≥ 3 x ULN, and total  bilirubin ≥ 2 x ULN, or 
 ALT or AST ≥ 3 x ULN, with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain, or tenderness, fever, rash, or 
eosinophilia (>5%), or 
 Alkaline phosphatase ≥ 2x ULN. 


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12 
STATISTICS 
12.1 
Sample Size Determination 
The planned sample size is 300 randomized subjects. This sample size will provide 
approximately 80% power for a 2-sided t-test with Type I error of 0.048.  
12.2 
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 7 (±1) days is within the 
protocol-defined algorithm and with adequate compliance with daily diary completion will be 
eligible for randomization. 
Eligible subjects will be randomized to receive either NYX-2925 or placebo for 4 weeks in a 
pre-specified allocation. The randomization will be stratified by study site. 
12.3 
Statistical Analysis Plan 
The planned statistical analysis methods, including procedures for accounting for missing, 
unused, and spurious data, will be described in more detail in the Statistical Analysis Plan, which 
will be finalized prior to study completion. Deviations from the original Statistical Analysis Plan 
will be described in the final clinical study report.  
Descriptive statistics for categorical variables will include the number and percent of subjects 
with each characteristic. Percentages will be based on the number of subjects with non-missing 
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, which is defined as all subjects who 
receive at least 1 dose of investigational product. 
Efficacy analyses will be based on the modified Intent-to-Treat Population, which is defined as 
all subjects in the Safety Population with at least 1 post baseline assessment of the pain intensity 
NRS. 


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12.5 
Analyses of Efficacy  
12.5.1 
Primary Efficacy Endpoint 
12.5.1.1 
Primary Efficacy Analysis 
For the primary efficacy endpoint, the daily pain intensity NRS score from the handheld device 
will be averaged for baseline (Days -7 to -1) and Week 4 (Days 22 to 28) after randomization. 
Change from baseline to Week 4 will be assessed for treatment group differences with an 
analysis of covariance with fixed factors for study site and treatment, with baseline value as a 
covariate. 
12.5.1.2 
Sensitivity Analysis 
For the primary efficacy endpoint, the daily pain intensity NRS score from the handheld device 
will be averaged for baseline (Days -7 to -1) and each week (Days 1 to 7, Days 8 to 14, Days 15 
to 21, and Days 22 to 28) after randomization. A mixed model repeated measures analysis of 
variance will be used to assess treatment differences. The model will include factors for study 
site, treatment, week, and the treatment-by-week interaction, with baseline value as a covariate. 
12.5.2 
Other Efficacy Endpoints 
Change in the mean NRS score assessing average pain intensity in the past 24 hours from 
baseline (average of Days -7 to -1) to each week of treatment (average of Days 1 through 7, 
Days 8 through 14, and Days 15 through 21) will be assessed for treatment group differences 
with an analysis of covariance with fixed factors for study site and treatment, with baseline value 
as a covariate. Change from baseline for the PGI-C, SF-MPQ-2, QOL-DN, Insomnia Severity 
Index, HADS, DSIS, BPI-DPN will be analyzed similarly. 
The use of rescue medication and percent of subjects meeting responder criteria (≥30% reduction 
and first ≥50% reduction in the NRS average pain intensity) will be summarized descriptively. 
The number of days to the first ≥30% reduction and first ≥50% reduction in the NRS average 
pain intensity and the number of days to sustained pain reduction will be assessed for treatment 
group differences with the log-rank test. Subjects who fail to achieve the target reduction will be 
censored at the end of their final week with NRS pain intensity measurements. 
12.5.3 
Multiple Comparisons 
The primary efficacy endpoint and primary statistical analysis are protocol-specified. A Type I 
error of 0.005 will be allocated to the interim analysis (if applicable) and a Type I error of 0.048 
will be allocated to the final analysis (Fleming 1984). There will be no adjustment for multiple 
treatment group comparisons in this phase 2 study. 
12.6 
Analyses of Safety  
All safety summaries will be descriptive; no statistical testing will be performed. 


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12.6.1 
Adverse Events 
A TEAE is defined as an adverse event with an onset that occurs after receiving investigational 
product, or a continuing adverse event diagnosed prior to the date of first dose of investigational 
product, which 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. 
Summary tables for TEAEs will include number and percent of subjects experiencing TEAEs by 
system organ class and preferred term. If a subject has more than 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 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 for the Screening Period and Treatment Period 
(including Follow-Up):  
 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 and TEAEs leading to investigational product discontinuation will be identified. 
12.6.2 
Clinical Laboratory Tests 
Mean change from baseline (Visit 2) to Week 4 (Visit 4) will be summarized descriptively for 
each analyte. 
Clinical laboratory results considered clinically important by the investigator will be identified. 
Individual results for clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
outside the normal range will be flagged in the data listings.  
Clinical laboratory assessments will be conducted by the following central laboratory: 
  
  
  
  
  
12.6.3 
Electrocardiogram 
The interpretation of electrocardiogram and interval duration measurements by the designated 
electrocardiogram laboratory cardiologists will be reviewed by the investigator. Clinically 
significant deteriorations from baseline will be reported and summarized as TEAEs. 
12.6.4 
Vital Sign Measurements  
Change from baseline to each scheduled measurement will be summarized descriptively. 
Baseline will be defined as the last evaluation prior to dosing with investigational product on 
Day 1. 


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12.6.5 
Suicidal Ideation 
Subjects with suicidal ideation or behavior will be identified with the S-STS.  
12.7 
Interim Analysis 
One interim analysis may be conducted after approximately 50% of subjects (i.e., approximately 
150 subjects) have completed Visit 4. Based on the interim analysis, 1 or more dose groups of 
NYX-2925 could be discontinued and the total sample size re-estimated. A Type I error of 0.005 
would be allocated to the interim analysis. Complete details of the interim analysis would be 
provided in a separate analysis plan. It is not anticipated that the interim analysis would lead the 
Sponsor to decide to terminate the trial, although such a decision, made for any reason, would be 
made after consultation with FDA. 


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13 
ADMINISTRATIVE 
13.1 
Source Documents 
Source documents are defined as the result of original observations and activities of a clinical 
investigation. Source documents may include, but are not limited to, study progress notes, e-mail 
correspondences, informed consent forms, clinical laboratory reports, medical histories, hospital 
records, and drug accountability records. All source documents will be maintained by the 
investigator(s) and made available for inspection by sponsor representatives, the FDA, and other 
applicable regulatory authorities. 
13.2 
Study Monitoring 
Site visits will be conducted by an authorized sponsor representative (site monitor) to inspect 
study data, source documents, and eCRFs in accordance with International Conference on 
Harmonisation (ICH) guidelines, good clinical practices (GCPs), and local regulations or 
guidelines. The monitor will inspect the study data at regular intervals throughout the study to 
verify adherence to the protocol, as well as completeness, consistency, and accuracy of study 
data. 
The investigator will permit sponsor representatives, its third party vendors, the FDA, and/or 
respective health authorities to inspect facilities and records relevant to this study. 
13.3 
Case Report Forms 
An eCRF will be used to record all subject data required in this protocol. The eCRF must be 
completed by designated and trained study personnel. The eCRF will be signed by the principal 
investigator or a subinvestigator listed on the FDA Form 1572. It is the responsibility of the 
principal investigator to ensure the eCRFs are completed and submitted to Aptinyx (or designee) 
in an accurate and timely manner. The processing of eCRFs will include an audit trail (to include 
changes made, reason for change, date of change and person making the change). 
13.4 
Protocol Amendment(s) 
If a protocol has been filed with regulatory agencies or submitted to an IRB and requires 
changes, a protocol amendment must be written. The sponsor will make changes to the protocol. 
All amendments will be sent to a central IRB on the study sites’ behalf, if applicable. Sites using 
a 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. 


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13.6 
Institutional Review Board 
This protocol, the informed consent document, and all relevant supporting data must be 
submitted to the IRB for approval. Institutional Review Board approval of the protocol, informed 
consent document, any subject-facing materials, and any advertisement used to recruit study 
subjects must be obtained before the study may be initiated. The IRB must comply with 
requirements set forth in the Code of Federal Regulations (CFR) part 56. 
The investigator is responsible for keeping the IRB advised of the progress of the study, changes 
to research activity, unanticipated problems involving risk to human subjects or others, and any 
changes made to the protocol as deemed appropriate, but in any case, at least once a year. The 
investigator is also responsible for notifying the IRB of any significant adverse events or 
protocol deviations that occur during the study, and meet IRB reporting requirements. 
The investigator agrees that he or she will not make any changes in the research without IRB 
approval, except where necessary to eliminate apparent immediate hazards to human subjects, as 
referenced in 21 CFR 312.66. 
13.7 
Compliance with Regulatory Requirements 
This protocol 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 participants prior to the 
initiation of non-routine study-related tests. The original signed informed consent form for each 
participating subject shall be filed with records kept by the investigators(s). A copy of the signed 
informed consent document must be provided to the subject. If applicable, written consent will 
be obtained using a certified translation. If the informed consent form is revised, subjects must 
be re-consented 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, investigational product 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, investigational product 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 


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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 granted direct access to the study subjects’ original 
medical records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the subjects, to the extent permitted by the law and regulations. In any 
presentation of the results of this study at meetings or in publications, the subjects’ identity will 
remain confidential. 
13.12 
Compensation, Insurance, and Indemnity 
Information regarding compensation, insurance, and indemnity is addressed in the Clinical Trial 
Research Agreement. 
13.13 
Financial Disclosure 
The investigator(s) are responsible for providing financial disclosure(s) in covered clinical 
studies. Principal investigators and subinvestigators are required to disclose applicable financial 
information, and to promptly update Aptinyx with any relevant changes throughout the study and 
for 1 year after study completion. 
13.14 
Records Retention 
According to United States Investigational New Drug regulations (21 CFR 312.62), records and 
documents pertaining to the conduct of this study and the distribution of investigational products 
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 guidelines, documents should be retained until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. Aptinyx will notify 
the investigator when records and documents no longer need to be retained. No study records 
should be destroyed without prior authorization. 
13.15 
Publication Policy 
The publication policy is outlined in the Clinical Trial Agreement. 


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14 
REFERENCES 
 
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Fleming TR, Harrington DP, O'Brien PC. Designs for group sequential 
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Gilron 2015 
Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and 
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Herman 2012 
Herman WH, Pop-Busul R, Braffett BH. et al. Use of the Michigan 
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peripheral neuropathy in Type 1 diabetes: results from the Diabetes 
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and Complications. Diabet Med. 2012;29:937-44. 
Jensen 2014 
Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: 
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Katz 2005 
Katz N. Methodological issues in clinical trials of opioids for chronic 
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Katz NP, Mou J, Paillard FC, Turnbull B, Trudeau J, Stoker M. Predictors 
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Mony 2009 
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SAP_001.pdf: 
Statistical Analysis Plan 
A Randomized, Double-Blind, Parallel-Group, Placebo 
Controlled, Multiple-Dose Study to Assess the Efficacy and 
Safety of NYX-2925 in Subjects with Neuropathic Pain 
Associated with Diabetic Peripheral Neuropathy 
Sponsor: 
Aptinyx Inc. 
1801 Maple Avenue, Suite 4300 
Evanston, IL 60201 
Clinical Protocol No.: 
NYX-2925-2001 
Study Phase: 
2 
Investigational Product: 
NYX-2925 
Prepared by: 
Date: 
December 14, 2018 
SAP Version: 
Final Version 1.0 
Protocol Version: 
Amendment #3/February 28, 2018 
Confidential and Proprietary Information 
NCT03219320


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Aptinyx Inc. 
Protocol No.: NYX-2925-2001 
Statistical Analysis Plan (SAP) 
Confidential 
Page 3 of 69 
December 14, 2018 
Table of Contents 
1.
List of Abbreviations and Special Terms .............................................................................................. 7 
2.
Introduction ........................................................................................................................................... 9 
3.
Study Objectives ................................................................................................................................. 10 
3.1 
Primary Objective ....................................................................................................................... 10 
3.2 
Secondary Objectives .................................................................................................................. 10 
4.
Study Overview .................................................................................................................................. 10 
4.1 
Study Drug Treatment Arms ....................................................................................................... 10 
4.2 
Subject Randomization ............................................................................................................... 11 
4.3 
Number of Subjects ..................................................................................................................... 11 
4.4 
Sample Size Considerations ........................................................................................................ 11 
4.5 
Study Design ............................................................................................................................... 11 
4.6 
Unblinding Study Drug Treatment Procedures ........................................................................... 11 
4.7 
Analyses Changes from the Protocol .......................................................................................... 12 
5.
General Statistical Principles .............................................................................................................. 12 
5.1 
Key Definitions ........................................................................................................................... 12 
5.1.1 Day 1/Date of First Dose ............................................................................................................ 12 
5.1.2 Study Day.................................................................................................................................... 12 
5.1.3 Not Reported ............................................................................................................................... 12 
5.1.4 Baseline and Post-Baseline Values ............................................................................................. 13 
5.1.5 Change from Baseline ................................................................................................................. 13 
5.1.6 Percent Change from Baseline .................................................................................................... 13 
5.2 
Treatment Group Comparisons ................................................................................................... 13 
5.3 
Conventions ................................................................................................................................ 14 
5.3.1 Descriptive Statistics ................................................................................................................... 14 
5.3.2 Frequency Distributions .............................................................................................................. 14 
5.3.3 Shift Tables ................................................................................................................................. 14 
5.3.4 Safety Data Statistical Inference ................................................................................................. 15 
5.3.5 Efficacy Data Statistical Inference .............................................................................................. 15 
5.3.5.1 
P-values ................................................................................................................................... 15
5.3.5.2 
Analysis of Covariance Model ................................................................................................ 15 
5.3.5.3 
Mixed Effects Repeated Measures Model .............................................................................. 16 
5.3.5.4 
Time-to-Event Analyses ......................................................................................................... 16 
5.3.5.5 
Frequency Distribution Tests .................................................................................................. 17 


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5.4 
Analysis Visits ............................................................................................................................ 18 
5.4.1 Safety Analysis Visits ................................................................................................................. 18 
5.4.2 Efficacy NRS Pain Intensity Scores Analysis Visits .................................................................. 19 
5.4.3 Efficacy DSIS Analysis Visits .................................................................................................... 20 
5.4.4 Other Efficacy Data Analysis Visits ........................................................................................... 20 
5.5 
Data Imputations ......................................................................................................................... 21 
5.5.1 Character Values in Numeric Data ............................................................................................. 21 
5.5.2 Missing Analysis Values ............................................................................................................. 21 
5.5.3 Missing or Partial Dates .............................................................................................................. 22 
5.6 
Multiplicity Adjustments and Type I Error ................................................................................. 22 
5.7 
By-Center Analyses .................................................................................................................... 23 
5.8 
Subpopulation Analyses .............................................................................................................. 23 
6. 
Analysis Populations ........................................................................................................................... 23 
6.1 
Safety Population ........................................................................................................................ 23 
6.2 
Efficacy Population ..................................................................................................................... 24 
6.3 
PP Population .............................................................................................................................. 25 
7. 
Disposition, Baseline, and Other Characteristics ................................................................................ 25 
7.1 Subject Disposition ............................................................................................................................. 25 
7.2 Demographics and Disease History .................................................................................................... 26 
7.3 Subject Inclusion and Exclusion Criteria ............................................................................................ 26 
7.4 Medical History .................................................................................................................................. 28 
7.5 Questionnaire/Scale Assessments only at Screening or Baseline ....................................................... 28 
7.5.1 Masquerading Disorders Tool............................................................................................................. 29 
7.5.2 Michigan Neuropathy Screening Instrument ...................................................................................... 29 
7.5.3 American College of Rheumatology Fibromyalgia Criteria ............................................................... 30 
7.5.4 Bedside Sensory Testing Kit ............................................................................................................... 30 
8. 
Study Drug Exposure, Rescue Medication, and Other Medications ................................................... 31 
8.1 
Study Drug Accountability ......................................................................................................... 31 
8.2 
Study Drug Exposure .................................................................................................................. 32 
8.3 
Rescue Medication ...................................................................................................................... 33 
8.4 
Prior and Concomitant Medications ........................................................................................... 34 
9. 
Efficacy Analyses ............................................................................................................................... 34 
9.1 
Primary Efficacy Data ................................................................................................................. 34 
9.1.1 Primary Efficacy Endpoint.......................................................................................................... 35 
9.1.2 Primary Efficacy Endpoint Analysis ........................................................................................... 35 


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9.1.3 Primary Efficacy Endpoint Sensitivity Analyses ........................................................................ 35 
9.2 
Secondary Efficacy Data and Endpoints ..................................................................................... 37 
9.2.1 NRS Score Assessing Worst Pain Intensity in the Past 24 Hours ............................................... 37 
9.2.2 Change in the Mean NRS Score Assessing Average Pain Intensity in the Past 24 Hours at 
Weeks 1, 2, 3, and 4 ................................................................................................................................ 38 
9.2.3 NRS Score Assessing Average Pain upon Walking Intensity in the Past 24 Hours ................... 38 
9.2.4 Patient Global Impression of Change (PGI-C) ........................................................................... 38 
9.2.5 Short-Form McGill Pain Questionnaire, version 2 (SF-MPQ-2) ................................................ 39 
9.2.6 Norfolk Quality of Life Questionnaire - Diabetic Neuropathy (QOL-DN) ................................ 40 
9.2.7 Insomnia Severity Index (ISI) ..................................................................................................... 42 
9.2.8 Hospital Anxiety and Depression Scale (HADS) ....................................................................... 42 
9.2.9 Daily Sleep Interference Scale (DSIS) ........................................................................................ 43 
9.2.10 
Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) ................................... 43 
9.3 
Exploratory Efficacy Endpoints .................................................................................................. 45 
9.3.1 Use of Rescue Medication Subgroup Analyses .......................................................................... 45 
9.3.2 Responder Status Endpoints........................................................................................................ 45 
9.3.3 Number of Days to Responder Status ......................................................................................... 46 
9.3.4 Number of Days to Sustained Pain Reduction ............................................................................ 46 
9.4 
Summary of Efficacy Analyses ................................................................................................... 47 
10. Safety Analyses ................................................................................................................................... 48 
10.1 
Adverse Events ........................................................................................................................... 48 
10.2 
Clinical Laboratory Tests ............................................................................................................ 50 
10.3 
Vital Sign Measurements ............................................................................................................ 52 
10.4 
12-Lead Electrocardiogram (ECG) ............................................................................................. 52 
10.5 
Physical Examinations ................................................................................................................ 53 
10.5.1 
Complete and Brief Physical Examinations ............................................................................ 53 
10.5.2 
Neurological Examination ...................................................................................................... 53 
10.6 
Other Safety Analyses ................................................................................................................. 54 
10.6.1 
Sheehan Suicidality Tracking Scale (S-STS) .......................................................................... 54 
10.6.2 
Body Weight ........................................................................................................................... 55 
10.6.3 
Other Reportable Events ......................................................................................................... 55 
11. Other Analyses .................................................................................................................................... 56 
11.1 Protocol Deviations ............................................................................................................................. 56 
12. Interim Analyses ................................................................................................................................. 56 
13. List of Planned CSR Tables, Figures, and Listings in Section 14 ...................................................... 56 
14. List of Planned CSR Appendices in Section 16.2 ............................................................................... 62 


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15. References ........................................................................................................................................... 64 
Appendix I: Schedule of Procedures ........................................................................................................... 67 
 
 
 
 


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1. List of Abbreviations and Special Terms 
∑ 
Sum of All 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BPI-DPN 
Brief Pain Inventory for Diabetic Peripheral Neuropathy 
BMI 
Body Mass Index 
BOCF 
Baseline Observation Carried Forward 
C-CASA 
Columbia Classification Algorithm of Suicide Assessment 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTMS 
Clinical Trial Management System 
DPN 
Diabetic Peripheral Neuropathy 
DSIS 
Daily Sleep Interference Scale 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDC 
Electronic Data Capture 
eDISH 
Evaluation of Drug-Induced Serious Hepatotoxicity 
eDT 
Electronic Data Transfer 
EMA 
European Medicines Agency 
ET 
Early Termination 
FDA 
Food and Drug Administration 
HADS 
Hospital Anxiety and Depression Scale 
HbA1c 
Hemoglobin A1c; Glycated Hemoglobin 
HCV RNA 
Hepatitis C Virus-Ribonucleic Acid 


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HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonisation 
ISI 
Insomnia Severity Index 
LOCF 
Last Observation Carried Forward 
MD 
Medicinae Doctor 
M.S. 
Master of Science Degree 
N/A 
Not Applicable 
NRS 
Numerical Rating Scale 
NYX-2925 
Aptinyx’s Investigational Study Drug 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDT 
Masquerading Disorders Tool 
MMRM 
Mixed Effects Repeated Measures 
OREs 
Other Reportable Events 
PCS 
Potentially Clinically Significant 
PDF 
Portable Document Format (supported by Adobe® Acrobat®) 
PGI-C 
Patient Global Impression of Change 
PhD 
Doctor of Philosophy 
PI 
Principal Investigator 
PP 
Per Protocol 
PT 
Preferred Term 
QOL-DN 
Norfolk Quality of Life Questionnaire - Diabetic Neuropathy 
SAP 
Statistical Analysis Plan 
SAS® 
FDA Recommended Statistical Software 
SF-MPQ-2 
Short-Form McGill Pain Questionnaire, version 2 
SOC 
System Organ Class 
SS 
Symptom Severity 


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S-STS 
Sheehan Suicidality Tracking Scale 
Sub-I 
Sub-Principal Investigator 
TEAE 
Treatment-Emergent Adverse Event 
TFL’s 
Tables, Figures, and Listings 
ULN 
Upper Limit of Normal 
WHO-DD 
World Health Organization Drug Dictionary 
WPI 
Widespread Pain Index 
2. Introduction 
This statistical analysis plan (SAP) describes the planned statistical analysis and reporting of the 
clinical study protocol titled “A Randomized, Double-Blind, Parallel-Group, Placebo Controlled, 
Multiple-Dose Study to Assess the Efficacy and Safety of NYX-2925 in Subjects with Neuropathic 
Pain Associated with Diabetic Peripheral Neuropathy” dated on February 28, 2018, amendment #3.   
The structure and content of this SAP provides sufficient detail to meet the requirements identified by 
the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and International 
Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals 
for Human Use: Guidance on Statistical Principles in Clinical Trials[1].  All work planned and 
reported for this SAP will follow internationally accepted guidelines, published by the American 
Statistical Association[2] and the Royal Statistical Society[3], for statistical practice.   
The purposes of this SAP are to: 
• 
Outline the types of analyses and presentations of data that will form the basis for drawing 
conclusions to the study objectives and hypotheses outlined in the protocol 
• 
Explain in detail how the data will be handled and analyzed, adhering to commonly accepted 
standards and practices for Good Statistical Practice 
All analyses described in this plan are considered a priori analyses in that they have been defined 
prior to locking the study database.  The planned analyses identified in this SAP may be included in 
clinical study reports (CSR), regulatory submissions, or future manuscripts.  Also, post-hoc 
exploratory analyses not identified in this SAP may be performed to further examine study data.  Any 
post-hoc or unplanned exploratory analyses performed will be clearly identified as such in the final 
CSR. 
The following documents were reviewed in preparation of this SAP: 
• 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
The reader of this SAP is encouraged to also read the clinical study protocol and other identified 
documents for details on the planned conduct of this study.  Operational aspects related to collection 
and timing of planned clinical assessments are not repeated in this SAP unless relevant to the planned 
analyses. 
3. Study Objectives 
3.1 Primary Objective 
The primary objective of this study is to evaluate the efficacy of multiple dose levels of NYX-2925 
versus placebo in treating the neuropathic pain associated with diabetic peripheral neuropathy. 
3.2 Secondary Objectives 
Secondary objectives of the study are to assess the: 
• 
Effects of multiple dose levels of NYX-2925 versus placebo on pain characteristics, sleep 
interference, health status, psychological state, and global improvement; 
• 
Safety and tolerability of multiple dose levels of NYX-2925. 
4. Study Overview 
4.1 Study Drug Treatment Arms 
Subjects will be dispensed blinded investigational product according to the randomization schedule.  
Investigational product will be dispensed at the Week 0 (Baseline) and Week 2 visits; at each of the 2 
visits, subjects will receive a 2-week supply of investigational product.  All capsules are identical in 
appearance and the strengths are placebo, 10 mg, 50 mg, and 100 mg.  
 
 
 
There will be 4 study drug treatment arms: 
• 
10 mg of NYX-2925 by mouth once daily for 4 weeks 
• 
50 mg of NYX-2925 by mouth once daily for 4 weeks 
• 
200 mg of NYX-2925 by mouth once daily for 4 weeks 
• 
Placebo by mouth once daily for 4 weeks 
 
 


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4.2 Subject Randomization 
At the Baseline visit, average daily pain scores and diary compliance will be transferred into the 
interactive response technology system, which will be used to assess the following criteria for 
randomization[4]: 
 
 
 
 
 
 
 
 
 
Eligible subjects will be randomized to receive either NYX-2925 10 mg daily, NYX-2925 50 mg 
daily, NYX-2925 200 mg daily, or placebo for 4 weeks in a 1:1:1:1 allocation.  The randomization 
will be stratified by study site. 
4.3 Number of Subjects 
The protocol for this study planned on enrolling approximately 300 subjects with a randomized 
1:1:1:1 method with approximately 75 subjects per treatment arm listed in Section 4.1.  The study 
will include approximately 35 study sites in the United States. 
4.4 Sample Size Considerations 
The planned sample size is 75 randomized subjects per group for a total of 300 randomized subjects. 
The mean and standard deviation for reduction in pain from baseline for placebo and active drug were 
estimated from publicly available sources on duloxetine, pregabalin, gabapentin, and oxycodone. The 
mean difference from placebo based on higher dose groups (duloxetine ≥60 mg once daily and 
pregabalin ≥300 mg) was estimated at 1.05.  The standard deviation was estimated as 2.25. 
A sample size of 75 subjects per group will provide approximately 80% power for a 2-sided t-test 
with Type I error of 0.05[5] when the mean difference from placebo is 1.05 and the standard deviation 
is 2.25. 
4.5 Study Design 
The study will be a 6- to 9-week study, including a 1- to 4-week Screening Period, followed by a 
4-week double-blind, parallel treatment, randomized, placebo-controlled Treatment Period, and a 
1-week Follow-Up Period.  The schedule of assessments is provided in in Appendix I. 
4.6 Unblinding Study Drug Treatment Procedures 
This is a double-blind study and therefore, the treatments assigned to each subject must remain 
blinded for analysis purposes until after database lock (not for safety concerns).  Prior to database 
lock, this SAP will be signed off and considered final.  After the electronic database has been locked, 
the treatment randomization codes will be unblinded and the analyses described in this SAP may be 
created.  


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4.7 Analyses Changes from the Protocol 
In Section 9.2.5 of the protocol, ‘moderate cases’ (scores 11-15), and ‘severe cases’ (scores 16 or 
higher) were categories defined for Hospital Anxiety and Depression Scale (HADS) based on 
Zigmond 1983[22].  However, more recent ranges are defined as ‘moderate cases’ (scores 11-14), and 
‘severe cases’ (scores 15 or higher) based on Snaith 1994[21]. 
In Section 12.4 of the protocol, it mentions that the modified Intent-to-Treat Population will be used 
for the efficacy analyses.  This will be replaced with the Efficacy Population. 
In Section 12.5 of the protocol, it mentions that treatment groups 200 mg combined with 50 mg of 
NYX-2925 will be provided in the summary tables.  This specific grouping of multiple treatments 
will not be performed in this planned statistical analysis. 
In Section 12.6.1.1 of the protocol, it states that study site will be used as a fixed factor in the analysis 
of covariance.  Study site will not be included in the any statistical models due to low enrolling sites.  
Some study sites will not have all four treatment arms assigned to randomized subjects and this can 
affect some statistical models.  The rest of the analyses stated in the protocol support the analyses 
planned in this SAP. 
Section 12.8 of the protocol mentioned that a potential interim analysis would be conducted, but after 
additional consideration no formal interim analyses will actually be performed for this study.  The 
sample size was calculated using a 0.048 Type I error, but the same results were based on a 0.05 Type 
I error without having an interim analysis. 
5. General Statistical Principles 
5.1 Key Definitions 
The following items below are standard terminologies discussed throughout the SAP. 
5.1.1 Day 1/Date of First Dose 
Day 1 is also referred to in the protocol and CRF as Visit 2, Baseline Visit, and Week 0.   
The date of first dosing of study drug is not collected on the CRF because subjects are given study 
drug to administer themselves.  Therefore, it will be assumed that Day 1 is the same day as the first 
dosing day of study drug for subjects in the safety population later described in the SAP in Section 
6.1. 
5.1.2 Study Day 
Study day will be calculated in reference to Day 1 stated above in Section 5.1.1.  For assessments 
conducted on or after the Day 1 date, study day is calculated as the assessment date – Day 1 date + 1.  
For assessments conducted before the Day 1 date, study day is calculated as the assessment date – 
Day 1 date.  There is no Study Day 0 in this study. 
5.1.3 Not Reported 
A not reported value may be displayed in a listing, summary statistics table, frequency table, shift 
table, etc.  The not reported record could be due to a missed sample/measurement/assessment, missed 
visit, unable to calculate a value, or withdrawal from the study early. 


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5.1.4 Baseline and Post-Baseline Values 
Unless otherwise specified, the baseline value is defined as the last measurement/assessment 
collected/derived on Day 1 or screening.  Unless otherwise specified, post-baseline values are defined 
as collected/derived measurements/assessments after Day 1. 
For specific questionnaire assessments, missing responses on Day 1 will not be substituted for 
screening values for the baseline specific questionnaires.  If the total score cannot be calculated at 
Day 1, then the screening visit will be used if the total score can be calculated at screening.  If the 
total score cannot be calculated for both screening and Day 1 visits, then the latest individual values 
and subscale scores will be used for the baseline.  All questions within a specific questionnaire will be 
paired together in an analysis visit for the baseline records. 
5.1.5 Change from Baseline 
If both post-baseline and baseline values are present/imputed, then change from baseline is defined as 
each post-baseline value – baseline value.  Otherwise the change from baseline will not be reported. 
5.1.6 Percent Change from Baseline 
If the baseline value is not equal to zero or missing and the change from baseline value is 
present/imputed, then the percent change from baseline is defined as 100 x (change from baseline / 
baseline) and is rounded off to 1 number after the decimal point.  Otherwise the percent change from 
baseline will not be reported. 
5.2 Treatment Group Comparisons 
The following treatment groups will be summarized in the statistical tables: 
• 
200 mg of NYX-2925 
• 
50 mg of NYX-2925 
• 
10 mg of NYX-2925 
• 
All Doses of NYX-2925 
• 
Placebo 
• 
Not Randomized and Not Treated 
o This will only be displayed for the analysis population table that presents subjects 
screened, but were not randomized and were not dispensed study drug. 
• 
All Subjects 
o This will only be displayed for the analysis population, subject disposition, and 
demographics tables. 
Efficacy data subject listings will be presented by the planned randomized treatment arm each subject 
was assigned to.  All other subject listings will be presented by the actual treatment arm if they 
received study drug. 
 
 


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The following treatment group comparisons will be performed for efficacy: 
• 
200 mg of NYX-2925 versus Placebo 
• 
50 mg of NYX-2925 versus Placebo 
• 
200 mg combined with 50 mg of NYX-2925 versus Placebo 
o This pooled treatment group will only be displayed for the primary efficacy endpoint. 
• 
10 mg of NYX-2925 versus Placebo 
5.3 Conventions 
All tables, figures, listings, and analyses stated in this SAP will be generated using SAS® software 
version 9.4 or later. 
In the event for subjects screened more than once for the study, the latest data collected will be used 
for all tables, figures, listings, and analyses stated in this SAP.  For example, a subject may have 
deemed a screen failure, but specific changes in the protocol amendment #3 for the inclusion and 
exclusion criteria may allow certain past screen-failed subjects to be enrolled in the study.  More 
details are stated in Section 7.3. 
5.3.1 Descriptive Statistics 
Descriptive statistics (the number of subjects [n], mean, standard deviation [SD], median, minimum, 
maximum, and not reported) will be used to summarize continuous variables.  Means will be 
presented to one more decimal place than the recorded data.  Medians will be presented using the 
same number of decimal places as the recorded data unless the calculated median results in an 
additional decimal place ending in “5” (i.e. 5 & 7 = 6, 5 & 8 = 6.5, etc.).  Standard deviations will be 
presented to two more decimal places than the recorded data.  Minimum and maximum values will be 
presented using the same number of decimal places as the recorded data. 
For data reporting 3 or more numbers after the decimal point (i.e. urinalysis specific gravity), the 
descriptive statistics for mean, standard deviation, median, minimum, and maximum will all be 
reported to the same precision as the data was collected.  For data reporting 2 numbers after the 
decimal point, the descriptive statistics for standard deviation will be reported as 3 numbers after the 
decimal place (same as the mean). 
5.3.2 Frequency Distributions 
Frequency distributions (count [n], percentage of subjects [%], and not reported) will be used to 
summarize categorical or qualitative variables.  In general, the denominator for the percentage 
calculation will be based upon the total number of subjects in the study population for the treatment 
groups for that particular time point assessment.  Records that are missing or not done will be 
displayed as “Not Reported” and will not be factored into the percentage calculation, unless otherwise 
specified.  Percentages will be presented to a maximum of one number after the decimal place. 
5.3.3 Shift Tables 
Shift tables (count [n], percentage of subjects [%], and not reported) will be used to summarize 
categorical or qualitative variables just like frequency distributions, but will also factor in a change in 
time.  For this study, shift tables will include a shift from the baseline analysis visit to each post-
baseline analysis visit.  If a categorical value is missing or not done at baseline and/or at a post-
baseline visit, “Not Reported” will be presented in the shift table.  Only observed records at both 


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baseline and each post-baseline visit will be factored into the percentage calculation, unless otherwise 
specified.  Percentages will be presented to a maximum of one number after the decimal place. 
Planned shift tables in the SAP will be discussed in their respective data sections.  Categorical values 
that will be presented in the shift tables will be pre-defined (i.e. “Low”, “Normal”, “High”, and “Not 
Done”). 
5.3.4 Safety Data Statistical Inference 
All safety data summaries will use descriptive statistics, frequency distributions, and/or shift tables.  
No formal statistical testing will be performed with the safety data. 
5.3.5 Efficacy Data Statistical Inference 
5.3.5.1 P-values 
P-values will be reported out and rounded off to 4 numbers after the decimal point (i.e. “0.####).  
Any p-values that are > 0.9999 will be reported as “>.9999” in the tables.  Any p-values that are < 
0.0001 will be reported as “<.0001” in the tables. 
5.3.5.2 Analysis of Covariance Model 
Using the change from baseline as a dependent variable, an analysis of covariance (ANCOVA) model 
with treatment (200 mg of NYX-2925, 50 mg of NYX-2925, 10 mg of NYX-2925, and Placebo) as 
the main effect and the baseline value as a covariate will be used to compare treatment groups at an 
individual analysis visit[4].  The comparison of the NYX-2925 versus placebo will be assessed by 
forming the least squares means estimate of each particular NYX-2925 treatment groups stated in 
Section 5.2 and comparing them to the placebo group.  The Kenward-Roger approximation will be 
used to estimate denominator degrees of freedom.  Here is the SAS® code: 
PROC MIXED DATA=ADAM ORDER=DATA METHOD=REML; 
 
CLASS TRTP; 
 
MODEL CHG = BASE TRTP / DDFM=KENWARDROGER; 
 
LSMEANS TRTP / DIFF CL ALPHA=0.05; 
 
/* -1 = Placebo; 0 = 10 mg of NYX-2925; 0.5 = 200 mg and 50 mg of NYX-2925 */ 
 
LSMESTIMATE “200 mg and 50 mg of NYX-2925 versus Placebo” TRTP 0 0.5 0.5 -1 / CL; 
RUN; 
The following ANCOVA model statistics for each treatment group will be presented in an analysis 
table: 
• 
n = the number of records for that treatment or pooled treatment group 
• 
Least Squares Mean for the treatment groups 
• 
Standard Error for the treatment groups 
• 
Least Squares Mean Difference for the NYX-2925 treatment groups versus Placebo 
• 
Standard Error Difference for the treatment groups versus Placebo 
• 
95% Confidence Interval for the Difference for the treatment groups versus Placebo 
• 
P-value for the Difference for the treatment groups versus Placebo 


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5.3.5.3 Mixed Effects Repeated Measures Model 
A mixed effects repeated measures (MMRM) model will be used for modeling analyses over time 
with each post-baseline analysis visit[4].  The dependent variable will be the change from baseline and 
the model will include treatment (200 mg of NYX-2925, 50 mg of NYX-2925, 10 mg of NYX-2925, 
and Placebo), analysis visit, treatment-by-analysis visit interaction, the baseline value as a covariate, 
and subject as a random effect.  The comparison of the NYX-2925 versus placebo will be assessed by 
forming the least squares means estimate of each particular NYX-2925 treatment groups stated in 
Section 5.2 and comparing them to the placebo group at each post-baseline analysis visit.  An 
unstructured covariance structure will be used to model the within-subject errors.  The Kenward-
Roger approximation will be used to estimate denominator degrees of freedom.  Here is the SAS® 
code: 
PROC MIXED DATA=ADAM ORDER=DATA METHOD=REML; 
 
CLASS USUBJID TRTP AVISITN; 
 
MODEL CHG = BASE TRTP AVISITN TRTP*AVISITN / DDFM=KENWARDROGER; 
 
REPEATED / TYPE=UN SUBJECT=USUBJID R; 
 
LSMEANS TRTP*AVISITN / DIFF CL ALPHA=0.05; 
RUN; 
In case of convergence issues, other covariance structures will be used including (but not limited to) 
autoregressive (AR (1)), compound symmetry (CS), and variance components (VC) to find the 
covariance structure with the best fit.  The fit statistics will be compared for all covariance structures; 
the structure with the smallest Akaike information criterion will be retained as the preferred model. 
The following MMRM model statistics for each treatment group at every post-baseline analysis visit 
will be presented in an analysis table: 
• 
n = the number of records for that treatment or pooled treatment group at that analysis visit 
• 
Least Squares Mean for the treatment groups 
• 
Standard Error for the treatment groups 
• 
Least Squares Mean Difference for the NYX-2925 treatment groups versus Placebo 
• 
Standard Error Difference for the treatment groups versus Placebo 
• 
95% Confidence Interval for the Difference for the treatment groups versus Placebo 
• 
P-value for the Difference for the treatment groups versus Placebo 
Each dependent variable and the particular analysis visit(s) will be described in the efficacy analyses 
Section 9 that will be used in a MMRM model. 
5.3.5.4 Time-to-Event Analyses 
The post-baseline study day at which the pre-defined responder status occurs will be used in the 
analysis of number of days to responder status analyses.  If a subject never reaches the pre-defined 
responder status then the number of days will be censored at Day 28 or the day of the last particular 
efficacy assessment, whichever is earliest.  Number of days to responder status will be analyzed by 
the Cox proportional hazards model with the baseline mean NRS score pain intensity score of interest 
as a covariate[4].  The adjusted hazard ratio, 95% CI, and a p-value will be provided from the model 


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for each NYX-2925 treatment groups versus Placebo.  The n (%) of subjects who are considered a 
responder as well as the n (%) of censored observations will be presented for each treatment group.   
Here is the SAS® Code: 
PROC PHREG DATA=ADAM; 
 
CLASS TRTP; 
 
MODEL AVAL*CNSR(1) = TRTP BASEPAIN / RISKLIMITS=WALD; 
RUN; 
Additionally, the Kaplan-Meier method[4] will be analyzed for the probability plots only.  The same 
censoring technique will be used as stated in the Cox proportional hazards model.  Here is the SAS® 
Code: 
PROC LIFETEST DATA=ADAM CONFTYPE=LINEAR METHOD=KM ALPHA=0.05; 
 
TIME AVAL*CNSR(1); 
 
STRATA TRTP; 
RUN; 
The specific number of days to responder statuses calculated will be described in Section 9.3.3 and 
the number of days to sustained pain reduction in Section 9.3.4 of the SAP. 
5.3.5.5 Frequency Distribution Tests 
Frequency distributions that have two responses (i.e. yes/no) and compare two different treatment 
groups (i.e. active versus placebo) may use a chi-square test for reporting a p-value.  This is referred 
to as a 2x2 table.  If the expected cells counts for any of the 2x2 tables are not ≥ 5, then Fisher’s exact 
test will be used instead.  Each p-value using Fisher’s exact test will be denoted in any summary 
table. 
Odds ratio and relative risk estimates will be provided when chi-square or Fisher’s exact test p-values 
are reported in summary tables[4].  Both the odds ratio and relative risk estimates will be based on the 
“yes” responders of the active treatment as the numerator compared to the placebo treatments as the 
denominator in these estimates.  95% confidence intervals will also be provided for both odds ratio 
and relative risk estimates.  Here is the SAS® code: 
PROC FREQ DATA=ADAM; 
 
WEIGHT COUNT; 
 
/* where # is based on the type of responder criterion in CRIT#FLN */ 
 
TABLES TRTP*CRIT#FLN / FISHER CHISQ RELRISK; 
 
ODS OUTPUT Freq.Table1.RelativeRisks=ODDSRATIO(WHERE=(Statistic="Odds Ratio")); 
 
ODS OUTPUT Freq.Table1.RelativeRisks=RELRISK(WHERE=(Statistic="Relative Risk 
(Column 1)")); 
RUN; 


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5.4 Analysis Visits 
Analysis visits are determined based on the collected/derived data for the study that will be used for 
listings and statistical analyses.  In some events, there may be differences in visits depending on the 
data used for statistical summaries and as a result analysis visits are defined.  For example, data for 
efficacy versus safety may have different methods for defining the analysis visits.  The subsections 
below represent the analysis visits that will be used to support the analyses in this SAP. 
In the event more than one record is collected/derived within an analysis visit, the non-missing record 
with the date closest to the target day will be selected.  If there is a tie between two dates between the 
target date, then the first date will be used.  Unless otherwise specified in Sections 9 and 10, if more 
than one non-missing record occurs on the same date, then the first planned scheduled result will be 
used. 
Clinical laboratory tests will also consider lowest, highest, and most abnormal post-baseline results as 
additional analyses.  More details are provided in Section 10.2. 
5.4.1 Safety Analysis Visits 
Each safety analyses section will state which analysis visits will be used in their respective summary 
tables.  All collected/derived records will be included in the appendix listings. 
Protocol and/or CRF Term 
Analysis Visit (Target Day) 
Study Day Window 
Visit 1/Screening/Weeks -4 to -1 
Screening (-28) 
≤ Day -1 
Visit 2/Baseline/Week 0 
Day 1 (1) 
Only Day 1 
N/A 
Baseline(a) (N/A) 
≤ Day 1 
N/A 
Unscheduled Week 1 (N/A) 
Day 2 to Day 9 
Visit 3/Week 2 
Week 2 (14) 
Day 10 to Day 18 
N/A 
Week 2/ET(b) (14) 
Day 10 to Day 18 
N/A 
Unscheduled Week 3 (N/A) 
Day 19 to Day 23 
Visit 4/Week 4 
Week 4 (28) 
Day 24 to Day 32 
N/A 
Week 4/ET(c) (28) 
Day 24 to Day 32 
Visit 4/Early Termination 
Early Termination(b,c) (N/A) 
Day 2 or Later 
Visit 5/Week 5/Follow-Up 
Follow-Up(d) (35) 
Day 33 to Day 39 
N/A 
Repeat Follow-Up(e) (N/A) 
Any Repeat Follow-
Up Visits 
N/A 
Last Post-Baseline Visit(f) (N/A) 
Day 2 or Later 
N/A 
Overall Post-Baseline Visits(g) (N/A) 
Day 2 or Later 
(a) Baseline definition described in Section 5.1.4. 
(b) For listings, the Week 2/ET visit will be displayed if it can be mapped within the Day 10 to Day 18 
study day window for Week 2 and there was not a scheduled Week 2 visit.  Otherwise, Early 


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Termination will be displayed in the listing.  For analysis purposes for displaying the analysis visits, 
Week 2/ET will be pooled with Week 2 data. 
(c) For listings, the Week 4/ET visit will be displayed if it can be mapped within the Day 24 to Day 32 
study day window for Week 4 and there was not a scheduled Week 4 visit.  Otherwise, Early 
Termination will be displayed in the listing.  For analysis purposes for displaying the analysis visits, 
Week 4/ET will be pooled with Week 4 data. 
(d) Subjects will return to the study site 7 days following the Week 4/Early Termination visit to assess 
adverse events and concomitant medication use.  The adverse event assessment will include any 
serious adverse events that were ongoing at the time of study completion, and whether any ongoing 
adverse events had progressed to becoming serious.  Blood samples will be collected for liver 
function testing. 
(e) If subjects return after the Follow-Up visit for a repeat assessment, that visit and any additional 
visits will be identified as a Repeat Follow-Up visit. 
(f) This considers the last post-baseline values collected/derived for a particular set of data (including 
unscheduled and repeated measurements/assessments). 
(g) This is used for combining all post-baseline data.  Examples of this are used for study drug 
accountability, compliance, treatment exposure, and rescue medication. 
5.4.2 Efficacy NRS Pain Intensity Scores Analysis Visits 
These analysis visits are for the daily diary data when the study-issued handheld devices where 
provided on Visit 1 (screening) until the devices are returned on the Week 4 or Early Termination 
visit. 
Protocol and/or CRF Term 
Analysis Visit 
Study Day Window 
Visit 1/Screening/Weeks -4 to -1 
Screening(a) 
≤ Day -8 
Visit 1/Screening/Weeks -4 to -1 
Baseline 
Day -7 to Day -1 
Visit 2/Baseline/Week 0 
Week 1 
Day 1 to Day 7 
Visit 3/Week 2 
Week 2 
Day 8 to Day 14 
N/A 
Week 3 
Day 15 to Day 21 
Visit 4/Week 4 
Week 4 
Day 22 to Day 28 
N/A 
After Day 28(b) 
Day 29 or Later 
(a) Screening values will be displayed in listings, but not included summary tables. 
(b) Data collected after Day 28 will be displayed in listings, but not included summary tables with an 
analysis visit. 
 
 


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5.4.3 Efficacy DSIS Analysis Visits 
These analysis visits are for the daily diary data when the study-issued handheld devices where 
provided on Visit 1 (screening) until the devices are returned on the Week 4 or Early Termination 
visit. 
Protocol and/or CRF Term 
Analysis Visit 
Study Day Window 
Visit 1/Screening/Weeks -4 to -1 
Screening(a) 
≤ Day -7 
Visit 1/Screening/Weeks -4 to -1 
Visit 2/Baseline/Week 0 
Baseline 
Day -6 to Day 1 
N/A 
Week 1 
Day 2 to Day 8 
Visit 3/Week 2 
Week 2 
Day 9 to Day 15 
N/A 
Week 3 
Day 16 to Day 22 
Visit 4/Week 4 
Week 4 
Day 23 to Day 29 
N/A 
After Day 29(b) 
Day 30 or Later 
(a) Screening values will be displayed in listings, but not included summary tables. 
(b) Data collected after Day 29 will be displayed in listings, but not included summary tables with an 
analysis visit. 
5.4.4 Other Efficacy Data Analysis Visits 
Each efficacy analyses section will state which analysis visits that will be used in the summary tables.  
All collected/derived records will be included in the appendix listings. 
Protocol and/or CRF Term 
Analysis Visit (Target Day) 
Study Day Window 
Visit 1/Screening/Weeks -4 to -1 
Screening (-28) 
≤ Day -1 
Visit 2/Baseline/Week 0 
Day 1 (1) 
Only Day 1 
N/A 
Baseline(a) (N/A) 
≤ Day 1 
N/A 
Unscheduled Week 1 (N/A) 
Day 2 to Day 10 
Visit 3/Week 2 
Week 2 (14) 
Day 11 to Day 17 
N/A 
Week 2/ET(b) (14) 
Day 11 to Day 17 
N/A 
Unscheduled Week 3 (N/A) 
Day 18 to Day 24 
Visit 4/Week 4 
Week 4 (28) 
Day 25 to Day 31 
N/A 
Week 4/ET(c) (28) 
Day 25 to Day 31 
Visit 4/Early Termination 
Early Termination(b,c) (N/A) 
Day 2 or Later 
N/A 
Last Post-Baseline Visit(d) (N/A) 
Day 2 or Later 
(a) Baseline definition described in Section 5.1.4. 


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(b) For listings, the Week 2/ET visit will be displayed if it can be mapped within the Day 11 to Day 17 
study day window for Week 2 and there was not a scheduled Week 2 visit.  Otherwise, Early 
Termination will be displayed in the listing.  For analysis purposes for displaying the analysis visits, 
Week 2/ET will be pooled with Week 2 data. 
(c) For listings, the Week 4/ET visit will be displayed if it can be mapped within the Day 25 to Day 31 
study day window for Week 4 and there was not a scheduled Week 4 visit.  Otherwise, Early 
Termination will be displayed in the listing.  For analysis purposes for displaying the analysis visits, 
Week 4/ET will be pooled with Week 4 data. 
(d) This considers the last post-baseline values collected/derived for a particular set of data (included 
unscheduled and repeated measurements/assessments). 
5.5 Data Imputations 
Standard methods described below will be used for imputing missing data and character values in 
numeric collected parameter data. 
5.5.1 Character Values in Numeric Data 
Characters such as “<, >, and/or =” may be included in some parameter data values that are supposed 
to be collected in a numeric format.  This is most commonly seen in laboratory data.  Analysis values 
for results with “<=” or “>=” will be analyzed with those characters stripped from the collected result 
(i.e. “<=1.030” = “1.030” and “>=100” = “100”). 
Analysis values with only “<” will be handled using these methods: 
• 
For precision data collected with at least one number after the decimal point, the analysis 
value will be the numeric value minus 1 extra precision unit (i.e. “<0.1” = “0.09”). 
• 
For whole numbers collected and the value reported as “<0” then the analysis value will be 0. 
• 
For other whole numbers collected, the analysis value will be the numeric value minus 1. 
Analysis values with only “>” will be handled using these methods: 
• 
For precision data collected with at least one number after the decimal point, the analysis 
value will be the numeric value plus 1 extra precision unit (i.e. “>5.25” = “5.251”). 
• 
For whole numbers collected, the analysis value will be the numeric value plus 1. 
Documentation of how to handle other unplanned characters found in the data for numeric parameter 
results will be described in the ADaM Analysis Data Reviewer’s Guide. 
For listing purposes, the collected results will be displayed in the CSR listings and appendices (i.e. 
“<5.0” over “4.99”). 
5.5.2 Missing Analysis Values 
Unless otherwise specified, missing analysis values will not be imputed for the safety data in this 
SAP.  Specific efficacy missing data imputations are described in the sensitivity analyses in Section 
9.1.3.  No other standard imputations of missing efficacy data will be applied unless it is described 
later in the SAP in the respective data section. 
 
 


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5.5.3 Missing or Partial Dates 
Adverse Event Start Dates: 
• 
Method 1 – Earliest Possible Start Date: 
o If any combination of the year, month, and/or day are missing then the start date will 
be set to the earliest possible date that is ≥ to the screening date. 
• 
Method 2 – Latest Possible Start Date: 
o If any combination of the year, month, and/or day are missing then the start date will 
be set to the latest possible date that is ≤ to the latest possible adverse event end date.  
If the adverse event is ongoing after the final visit for the subject, then the final visit 
date will be used. 
Prior/Concomitant Medications Start Dates: 
• 
Method 1 – Earliest Possible Start Date: 
o If any combination of the year, month, and/or day are missing then the start date will 
be set to the earliest possible date that is ≥ to the subject’s date of birth. 
• 
Method 2 – Latest Possible Start Date: 
o If any combination of the year, month, and/or day are missing then the start date will 
be set to the latest possible date that is ≤ to the latest possible medication end date.  If 
the medication is ongoing after the final visit for the subject, then the final visit date 
will be used. 
Adverse Event and Prior/Concomitant Medications End Dates: 
• 
Method 1 – Earliest Possible End Date: 
o If any combination of the year, month, and/or day are missing then the end date will 
be set to the earliest possible date that is ≥ to the earliest possible adverse 
event/medication start date. 
• 
Method 2 – Latest Possible End Date: 
o If any combination of the year, month, and/or day are missing then the end date will 
be set to the latest possible date that is ≤ to the subject’s final visit date.  If the 
adverse event/medication is ongoing after the final visit for the subject, then the final 
visit date will be used. 
Medical History Disease Onset Dates: 
• 
If year is missing, then the date will not be imputed. 
• 
If both the month and day are missing, then the date will be imputed as July 1st with the year 
collected.  However, if this imputed date is ≥ to the screening date then the imputed date will 
be the screening date minus 1 day. 
• 
If only the day is missing, then the date will be imputed as the 15th with the year and month 
collected.  However, if this imputed date is ≥ to the screening date then the imputed date will 
be the screening date minus 1 day. 
5.6 Multiplicity Adjustments and Type I Error 
No formal adjustments for multiplicity will be performed for this phase 2 study.  All p-values will be 
tested using alpha at the 0.05 level, two-tailed. 


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As an exploratory procedure, multiple comparisons for the primary endpoint may be performed, using 
Hochberg’s procedure[6].  Only the individual NYX-2925 treatment arms versus Placebo would use 
this method.  The Type I error would be set at 0.05.  A nested testing procedure is used after the p-
values are ranked from largest to smallest.  These are the 3 steps that would be followed: 
• 
Step 1:  if the largest observed p-value is ≤ 0.05, then statistical significance would be 
declared for all 3 comparisons. 
• 
Step 2:  if the largest observed p-value is > 0.05, then the remaining 2 comparisons would be 
tested against 0.05 / 2 = 0.025.  If the second largest observed p-value is ≤ 0.025, then 
statistical significance would be declared for the 2 smallest p-value comparisons. 
• 
Step 3:  if the second largest observed p-value is > 0.025, then the last comparison would be 
tested against 0.05 / 3 = 0.017.  If the smallest observed p-value is ≤ 0.017, then statistical 
significance would be declared only for the smallest p-value comparison. 
5.7 By-Center Analyses 
The study includes 39 study sites in the United States.  Some study sites will not have all four 
treatment arms assigned to randomized subjects.  Only the primary efficacy data described in Section 
9.1 will be summarized using descriptive statistics by study site. No other by-center analyses will be 
planned in this SAP.  Study site will not be included as a covariate in any statistical models. 
5.8 Subpopulation Analyses 
Only the primary efficacy data described in Section 9.1 will be summarized using descriptive 
statistics by the follow subpopulations: 
• 
Age Groups: 
o 18-55 
 
A majority of the subjects enrolled in the study are ≥ 45 years old. 
o 56-65 
o 66-75  
• 
Gender:  Female; Male 
• 
Race:  White; Black or African American; Other 
• 
Ethnicity:  Hispanic or Latino; Not Hispanic or Latino 
• 
Concomitant Analgesic Medications at Baseline[4]:  Yes or No 
o Additionally, the primary endpoint for mean change from baseline to Week 4 will be 
summarized with the same ANCOVA model described in Section 5.3.5.2 based on 
two separate ANCOVA models by subjects using or not using 1 concomitant 
analgesic medication at baseline and throughout the duration of the study. 
6. Analysis Populations 
Subjects who screened for the study, but were excluded from any of the analysis populations below, 
will have the reasons why presented in a subject listing and frequency distribution tables. 
6.1 Safety Population 
All subjects who were dispensed study drug during the baseline visit and did not return all the study 
drug in their next visit will be in the safety population.  It will be assumed that these subjects in the 


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safety population have taken at least one dose of study drug.  Study drug is not referring to rescue 
medication that was dispensed at screening or at any other visits. 
Subjects in the safety population will be used for all analyses of safety data and will be analyzed 
based on the actual treatment received in the study.  In the event subjects received study drug with 
multiple study drug treatments by mistake in the study, the following analyses will be updated: 
• 
Latest Treatment and Lowest NYX-2925 Dose Given: 
o If 10 mg was the lowest NYX-2925 dose given, then that will be used for the 
remainder of the study after that study drug has been dispensed. 
o If 50 mg was the lowest NYX-2925 dose given, then that will be used for the 
remainder of the study after that study drug has been dispensed. 
o If 200 mg or placebo was given, then NYX-2925 200 mg will be used for the 
remainder of the study after that study drug has been dispensed. 
o This method will be applied to data regarding:  adverse events, concomitant 
medications, study drug accountability, study drug exposure, and rescue medication. 
o For example, if a subject received placebo for weeks 1-2 and then received a kit for 
NYX-2925 50 mg, then 2 different safety treatment arms would be assigned for this 
subject.  Safety data mentioned above in weeks 1-2 would be counted in the placebo 
group and any time after receiving NYX-2925 50 mg will be counted in the NYX-
2925 50 mg group. 
• 
Lowest NYX-2925 Treatment: 
o Placebo will not be used. 
o Each subject will only be counted in one NYX-2925 treatment group (10 mg, 50 mg, 
or 200 mg). 
o This method will be applied to all safety data not mentioned above (i.e. clinical 
laboratory tests, vital sign measurements, electrocardiogram, physical examinations, 
etc.). 
6.2 Efficacy Population 
The efficacy population will be based on subjects included in the safety population, were randomized, 
and have at least 4 post-baseline daily scores for the NRS assessment score assessing average pain 
intensity in the past 24 hours or at least one post-baseline visit (Week 2, Week 4, or Early 
Termination).  
Subjects will be excluded from the efficacy population in the event a subject is given study drug by 
mistake without being randomized.  This will also be classified as a major protocol violation.  
Subjects in the efficacy population will be analyzed based on the planned treatment they were 
randomized to in the study.  The efficacy population will be the primary analysis population used for 
this study. 
 
 


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6.3 PP Population 
The Per Protocol (PP) population will be based on all subjects in the efficacy population and the 
following criteria: 
• 
Subjects received the same study drug throughout the duration of the study; 
• 
Subjects received the same study drug to which they were randomized; 
• 
Subjects met the randomization inclusion criteria described in Section 7.1 of the protocol; 
• 
Subjects did not use any of the prohibited concomitant medications listed in Section 8.7 of 
the protocol; 
• 
Subjects who have an overall study drug treatment compliance between 80% and 125%; 
• 
Subjects have an observed mean NRS score assessing average pain intensity in the past 24 
hours calculated within the Week 4 efficacy analysis visit window. 
Subjects in the PP population will be defined based on a review of the relevant data by the Sponsor 
prior to database lock.  However, subjects dispensed the wrong treatment arm (i.e., a treatment arm 
other than the one they were randomized to) will be removed from the PP population.  Subjects in the 
PP population will be analyzed based on the planned treatment they were randomized to in the study. 
7. Disposition, Baseline, and Other Characteristics 
7.1 Subject Disposition 
All subjects who were screened in the study will be summarized in a frequency distribution table by 
their following status after the baseline visit where the denominator will be the number of subjects 
screened: 
• 
Randomized and Treated 
• 
Randomized and Not Treated 
• 
Not Randomized, but Treated 
• 
Not Randomized and Not Treated 
Any subjects “Not Randomized and Not Treated” will be subcategorized for the following reasons 
collected on the CRF:  randomization ineligible, does not meet inclusion/exclusion criteria, withdrew 
consent, adverse event, protocol non-compliance, lost to follow-up, pregnancy, sponsor terminated 
the study, and other.  Some reasons may have more than one reason collected on the CRF.  If the 
subject meets all the criteria, but is ineligible for study drug treatment arm randomization then 
“randomization ineligible” will be used in the tables and listings.  “Other” will be displayed on the 
tables if collected on the CRF and no other standardized term may be used. 
In the event for subjects screened more than once for the study, the latest screening data collected will 
be used for all subject disposition tables and listings if they were randomized and/or given study 
treatment.  Otherwise, the earliest screening data collected will be used for subjects not randomized or 
given study treatment. 
Frequency distributions of the subjects who completed Visit 4 will be summarized.  Furthermore, 
frequency distributions for the subjects who discontinued prematurely will be summarized along with 
the primary reason for withdrawal or discontinuation collected on the CRF. 
The subject disposition listing(s) will include all subjects with the following data:  treatment arm, 
protocol amendment version, date informed consent signed, date of completing Visit 4 or 


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discontinuing from the study, date of last dose of study drug (if applicable), study completion status, 
and primary reason for study discontinuation (if applicable), and the date of the follow-up visit or 
reason why it was not done.  Subjects who received study drug will have their calculated study days 
presented next to the dates in parentheses. 
7.2 Demographics and Disease History 
Demographics and baseline characteristics will be summarized for the safety, efficacy, and PP 
populations.  Descriptive statistics will be calculated for the following continuous demographic and 
baseline characteristic variables at screening:  age, height, weight, and body mass index (BMI).  
Frequency distributions will be tabulated for the following categorical demographic variables:  sex, 
childbearing potential, race, and ethnicity. 
Disease history for both DPN – Lower Extremities and Type II Diabetes will be summarized based on 
the number of years in the demographics and baseline characteristics table.  Each disease events will 
be provided in the medical history subject listing, but not summarized in the medical history table. 
The number of years for each disease be calculated as the (number of days from the onset date to the 
latest signed informed consent date) / 365.25 and is rounded off by one number after the decimal 
point.  For partial dates collected, the imputation history date described in Section 5.5.3 will be used. 
Subject listings will include the treatment arm, subject’s date of birth, and all continuous/categorical 
variables listed above. 
7.3 Subject Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria will be provided in a subject listing where each subject number not 
meeting each criterion will be displayed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Inclusion/ 
Exclusion 
Number 
Amendment #2 
Amendment #3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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In order for a subject to be randomized, the subject’s mean NRS score assessing average pain 
intensity in the past 24 hours and diary compliance will be used to assess the following inclusion 
criteria for randomization: 
 
 
 
 
 
 
 
 
Subject listings will include the treatment arm, protocol amendment version(s), was the subject 
rescreened (yes/no), and inclusion/exclusion criteria numbers not met.  Subjects will be given “Screen 
Fail” as the treatment arm unless the subject was randomized to a study treatment.  Any subjects that 
may have been randomized to a study treatment in error due to failure to pass the inclusion/exclusion 
criteria will be reported as protocol deviations.  The numbers of the inclusion/exclusion criteria not 
met will list the protocol amendment version number and a brief description of the 
inclusion/exclusion criteria.  Subject’s meeting all inclusion/exclusion criteria, at screening but failing 
the inclusion criteria for randomization will not be given a number.  Therefore, only “Randomization 
Ineligible” will be presented in the subject disposition tables and listings. 
7.4 Medical History 
Medical history data will be mapped using the Medical Dictionary for Regulatory Activities 
(MedDRA, version 19.0 to system organ class (SOC), and preferred term (PT).  This data will be 
summarized in a frequency distribution.  Subjects may have more than one medical history record per 
SOC and PT.  At each level of subject summarization, a subject will be counted once if he/she reports 
one or more medical history record at that specific level.  Subjects must have a medical history of 
both DPN – Lower Extremities and Type II Diabetes in order to be eligible for the study.  Therefore, 
these events will not be counted in the medical history frequency distribution table, but a footnote will 
be added that all subjects had both DPN – Lower Extremities and Type II Diabetes in the safety 
population.  A frequency distribution table will be displayed by the safety treatment arms and all 
subjects even though the medical history information was collected prior to dispensing study drug. 
Additionally, collected data on the CRF will be listed by subject, safety treatment arm, verbatim body 
system, verbatim medical condition/procedure, onset date, and ongoing status/end date. 
7.5 Questionnaire/Scale Assessments only at Screening or Baseline 
These screening questionnaires/scales will be provided in separate individual subject listings.  Details 
of data summarized in one overall questionnaire/scale assessments only at screening or baseline table 
will be mentioned in the following subsections. 


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7.5.1 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, such 
as Morton’s neuroma, peripheral vascular disease, Achilles tendonitis, arthritis, and tarsal tunnel 
syndrome.  The screening instrument consists of symptom screening questions, and an in-clinic 
history and examination to target the nature and etiology of the subject’s peripheral pain.  The results 
of this assessment tool are provisional, with the final decision based on the clinical judgment of the 
investigator. 
The Masquerading Disorders Tool (MDT) contains 15 sections, where sections 1-14 are comprised of 
1-3 questions with each question having a yes or no response.  The overall MDT assessment in 
section 15 will be included in a frequency distribution table: 
• 
Masquerading Disorder Not Present 
• 
Masquerading Disorder Present 
• 
Masquerading Disorder Present; Painful Diabetic Neuropathy as Dominant Pain 
7.5.2 Michigan Neuropathy Screening Instrument 
The Michigan Neuropathy Screening Instrument is a 15-item, self-administered questionnaire and a 
lower extremity examination that includes inspection of vibratory sensation and ankle reflexes.  It can 
be used to assess distal symmetrical peripheral neuropathy in diabetes[7]. 
The history portion of the Michigan Neuropathy Screening Instrument answered by the subjects 
contains 15 questions with each question having a yes or no response.  Each yes response has a 
numeric value of 1 and 0 is assigned to no responses.  The History Total Score is the sum of all 15 
questions with values ranging from 0 to 15.  No missing values will be imputed. 
The physical assessment portion of the Michigan Neuropathy Screening Instrument will be completed 
by a study site health professional and is assessed individually for the right and left feet.  Each foot 
has the following assessment with following numeric scores: 
• 
Appearance of Feet – Normal:  Yes = 0; No = 1 
• 
Ulceration:  Absent = 0; Present = 1 
• 
Ankle Reflexes:  Present = 0; Present/Reinforcement = 0.5; Absent = 1 
• 
Vibration Perception at Great Toe:  Present = 0; Decreased = 0.5; Absent = 1 
• 
Monofilament:  Normal = 0; Reduced = 0.5; Absent = 1 
A subscale score is determined for both the right and left feet individually.  The subscale scores range 
from 0 to 5 and no missing values will be imputed.  The Physical Assessment Total Score will be the 
sum of both the right and left subscale scores if they are both calculated.  Other details are collected if 
the appearance of the foot is not normal:  deformities; dry skin, callus; infection; fissure; and other 
specify.  That data collected will be presented in subject listings, but is not part of the numeric 
subscale and total scores. 
Both the Michigan Neuropathy Screening Instrument History Total Score and Physical Assessment 
Total Score will be summarized using descriptive statistics in a table. 


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7.5.3 American College of Rheumatology Fibromyalgia Criteria 
The 2010 American College of Rheumatology Fibromyalgia Criteria is a clinician-administered 
survey that is used as a diagnostic tool for fibromyalgia.  The diagnostic criteria for fibromyalgia are 
met by the following 3 conditions:  
• 
Widespread Pain Index ≥7 and Symptom Severity Score ≥5, or the Widespread Pain Index is 
3 to 6 and the Symptom Severity Score is ≥9;  
• 
Symptoms have been present at a similar level for at least 3 months; and 
• 
Subject does not have a disorder that would otherwise explain the pain[8]. 
The Widespread Pain Index (WPI) is a score comprised of 19 areas where subjects experienced pain 
within the last week with a yes or no response for each area.  Each individual yes response has a 
numeric value of 1 and 0 is assigned to each no response.  The WPI score will have values ranging 
from 0 to 19.  If any of the individual area responses are missing, the WPI score will not be 
calculated.  Here are the 19 areas that will be assessed: 
• 
Shoulder Girdle, Left; Shoulder Girdle, Right; Upper Arm, Left; Upper Arm, Right; Lower 
Arm, Left; Lower Arm, Right; Hip (Buttock, Trochanter), Left; Hip (Buttock, Trochanter), 
Right; Upper Leg, Left; Upper Leg, Right; Lower Leg, Left; Lower Leg, Right; Jaw, Left; 
Jaw, Right; Chest; Abdomen; Upper Back; Lower Back; and Neck 
The Symptom Severity (SS) Score is based on 4 questions with each question having a numeric score 
ranging from 0 to 3.  If all 4 questions are given a numeric score, then the Symptom Severity Score 
will range from 0 to 12.  If any of the individual scores are missing, the Symptom Severity Score will 
not be calculated. 
Both the Widespread Pain Index score and Symptom Severity Score will be summarized using 
descriptive statistics in a table.  Additionally, counts and percentages will be presented for subjects 
reaching these responses for these categories[8]: 
• 
Widespread Pain Index ≥7 and Symptom Severity Score ≥5 
• 
Widespread Pain Index is 3 to 6 and Symptom Severity Score ≥9 
7.5.4 Bedside Sensory Testing Kit 
The Bedside Sensory Testing Kit (Analgesic Solutions, Wayland, MA) is used to assess a subject’s 
sensory profile to allow phenotypic identification of subgroups of subjects with painful diabetic 
peripheral neuropathy who might respond differently to a given treatment.  The kit consists of 
multiple sensory instruments that are applied to different peripheral anatomic sites to evaluate the 
following phenomena:  extent of damage of low threshold mechanoreceptive small fibers in the feet, 
dynamic mechanical allodynia, punctate hyperalgesia, high threshold mechanoreceptive function, and 
cold allodynia. 
The Bedside Sensory Testing Kit is comprised of 5 sections and individual tests within each section 
will be completed by the study site principal investigator (PI) or sub-principal investigator (Sub-I): 
• 
Neuropen® Test - Low Threshold Mechanoreceptive Function 
o 10 locations will be selected with test having a yes or no response. 
o Each “yes” response will be scored as a 1 with the total score being the sum of the 10 
location with scores ranging from 0 to 10. 


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o This will be summarized using descriptive statistics in a table. 
• 
Foam Brush Test - Dynamic Mechanical Allodynia 
o NRS scoring based on an 11-point numerical rating scale/Likert scale ranging from 0 
to 10 will be assessed once for each of these locations: 
 
Foot 
 
Shin 
 
Thigh 
o These 3 scores will be summarized using descriptive statistics in a table. 
• 
Safety Pin Test - Punctate Hyperalgesia 
o NRS scoring based on an 11-point numerical rating scale/Likert scale ranging from 0 
to 10 will be assessed 5 times for each of these locations: 
 
Foot 
 
Shin 
 
Thigh 
o If at least 3 scores are collected for an area, the mean score will be calculated and 
rounded off by one number after the decimal point. 
o These 3 mean scores will be summarized using descriptive statistics in a table. 
o The foot, shin, and thigh locations will also be asked once, “Was the pin sharp?” with 
a yes or no response.  This data will be summarized by counts and percentages for the 
responses. 
• 
Von Frey Filament Test - Temporal Summation 
o NRS scoring based on an 11-point numerical rating scale/Likert scale ranging from 0 
to 10 will be assessed 5 times for each of these locations: 
 
Foot 
 
Shin 
 
Thigh 
o The change between the first and last scores will be calculated for each area (last 
score – first score). 
o This change score will be summarized using descriptive statistics in a table. 
• 
Tuning Fork Test - Cold Allodynia 
o NRS scoring based on an 11-point numerical rating scale/Likert scale ranging from 0 
to 10 will be assessed once for each of these locations: 
 
Foot 
 
Shin 
 
Thigh 
o These 3 scores will be summarized using descriptive statistics in a table. 
8. Study Drug Exposure, Rescue Medication, and Other Medications 
8.1 Study Drug Accountability 
Subjects will be dispensed blinded study drug according to the randomization schedule at visits Week 
0 (Baseline) and Week 2.  In the event the subject comes in for an unscheduled visit prior to Week 4, 
they may be dispensed additional blinded study drug.  
 
 


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The following data will be collected and derived at each start and end to the study drug accountability 
visit intervals: 
Parameter 
Origin/Derivation 
Capsules Dispensed Amount 
CRF 
Capsules Returned Amount 
CRF 
Expected Number of 
Capsules Taken 
Derived:  (Date Returned – Date Dispensed + 1) x 2 (where the 
maximum would be 36 because 36 capsules are issued at each 
dispensing visit) 
Estimated Number of 
Capsules Taken 
Derived:  Number of Capsules Dispensed Amount – Number of 
Capsules Returned Amount 
Treatment Compliance (%) 
Derived:  100 x Estimated Number of Capsules Taken / Expected 
Number of Capsules Taken (rounded off by one number after the 
decimal point) 
The Overall Treatment Compliance (%) will be calculated as: 
• 
100 x ∑ (Estimated Number of Capsules Taken at All Visits) / ∑ (Expected Number of 
Capsules Taken at All Visits) and rounded off by one number after the decimal point 
A subject will be classified as being compliant with study drug administration if their calculated 
compliance by analysis visit and overall is between 80% and 125%, inclusive.  Descriptive statistics 
will be summarized for treatment compliance by returning analysis visits Week 2, Week 4, and 
Overall.  The following categorical ranges will be summarized in a table for those same analysis visits 
and overall: 
• 
<80%, 80-125%, >125%, and Not Reported 
Any study drug not returned during a subject’s visit where study drug compliance is assessed will 
assume that all of that study drug was taken by the subject for analysis purposes.  No adjustments will 
be made even if comments are documented on the CRF that stated lost samples were reported by the 
subjects.  All study drug accountability comments will be provided in a subject listing.  If a subject 
does not return study drug after being dispensed study drug, then the study drug returned and overall 
treatment compliance will be set to missing. 
8.2 Study Drug Exposure 
The study will be packaged in a way that each dose will be 2 capsules/row, with the following blinded 
configuration for each treatment arm: 
 
 
 
 
 
 
 
 
Due to the nature of this study and data collection, it will be assumed each capsule taken by the 
subjects will have equal treatment weight for study drug compliance and exposure.  After database 
lock and when the study drug treatment is unblinded, each kit number assigned to a subject will be 


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verified that correct treatment arm was given based on the randomization schedule.  Any incorrect 
treatment arm kit given where the estimated number of capsules taken defined in Section 8.1 is 
greater than zero, will be defined as a major protocol deviation.  Study drug exposure will be listed 
and summarized based on the treatment arm subjects received.  Any combinations of different 
treatment arms may be identified (i.e. receiving 50 mg of NYX-2925 dose for kit and receiving 200 
mg of NYX-2925 dose for another kit). 
The number of study days of study drug exposure will be summarized using descriptive statistics 
based on the date of the last dose of study drug collected in the subject disposition CRF page.  If the 
last dose of study drug was not collected in the subject disposition CRF page, the last date of study 
drug returned will be used as the estimated date.  If a subject does not return study drug after being 
dispensed study drug and the date of the last dose of study drug was not collected, then the number of 
study days will be set to missing. 
8.3 Rescue Medication 
Subjects will also be dispensed 1 bottle of acetaminophen to be used as rescue medication at visits 
Screening, Week 0 (Baseline), and Week 2.  Each bottle will contain either 100 or 175 caplets and 
this amount will be collected on the CRF.  Rescue medication will consist of 500 mg caplets of 
acetaminophen.  Subjects will be instructed that up to 2 g/day of rescue medication are allowed and 
should be reported daily via their study issued handheld device. 
The following data will be collected and derived at each start and end to the rescue medication 
accountability visit intervals: 
Parameter 
Origin/Derivation 
Caplets Dispensed Amount 
CRF 
Caplets Returned Amount 
CRF 
Estimated Number of Days 
Taken 
Derived:  Date Returned – Date Dispensed + 1 (where the 
maximum would be the number of caplets issued at each dispensing 
visit) 
Estimated Number of 
Caplets Taken 
Derived:  Number of Caplets Dispensed Amount – Number of 
Caplets Returned Amount 
Average Rescue Medication 
Taken (g/day) 
Derived:  0.5 x Estimated Number of Caplets Taken / Estimated 
Number of Days Taken (rounded off by two numbers after the 
decimal point) 
The Overall Post-Baseline Average Rescue Medication Taken (g/day) will be calculated as: 
• 
0.5 x ∑ (Estimated Number of Caplets Taken After Dispensed at the Baseline Visit) / 
Number of Study Days at the Week 4/Early Termination Visit (rounded off by two numbers 
after the decimal point) 
Descriptive statistics will be summarized for average rescue medication taken (g/day) by returning 
analysis visits Baseline, Week 2, Week 4, and Overall Post-Baseline. 
Any rescue medication not returned during a subject’s visit where rescue medication accountability is 
assessed will be set to missing for analysis purposes.  If the caplets returned amount was collected as 


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zero on the CRF and the CRF collected a comment that the rescue medication bottle was not returned, 
then the caplets returned amount will be set to missing for analysis purposes. 
8.4 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD), version 03-2016 and will be classified according to the default Anatomical 
Therapeutic Chemical (ATC) classification system code (up to 4 levels), WHO-DD Drug Name, and 
Preferred Term (PT). 
Due to the nature of this study, the date and time of first dose of study drug was not collected on the 
CRF.  Therefore, the following algorithm will be used to determine prior medications: 
• 
Earliest Possible Medication Start Date ≤ Baseline Visit Date 
The following algorithm will be used to determine concomitant medications: 
• 
Latest Possible Medication Stop Date ≥ Baseline Visit Date 
Depending on the start and stop dates of the medication, it is possible for a medication to be classified 
as both prior and concomitant. 
Prior and concomitant medications will be summarized by the ATC Class Level 3 category (or Level 
2 if there is not an applicable Level 3 category) and PT.  Subjects may have more than one 
medication per ATC category and PT.  At each level of subject summarization, a subject will be 
counted once if he/she reports one or more medications at that specific level.  The prior medication 
frequency distribution table will be displayed by the safety treatment arms and all subjects even 
though the prior medication information was collected prior to dispensing study drug. 
Concomitant medications identified on the CRF as the 1 protocol allowed analgesic medication will 
be repeated in an additional subject listing and summary table. 
9. Efficacy Analyses 
In the event efficacy data was collected more than once within the same day, the latest complete set of 
assessment data will be used for the analyses.  All unused multiple assessments for efficacy collected 
within the same date will be presented in the subject listings.  Any efficacy assessments that were 
collected more than once within the same day will be documented in the SDTM Study Data 
Reviewer’s Guide. 
9.1 Primary Efficacy Data 
The primary efficacy data for this study is the NRS score assessing average pain intensity in the past 
24 hours.  Daily collected pain scores are based on an 11-point numerical rating scale/Likert scale 
ranging from 0 to 10.  Where 0 represents no pain and 10 is the worst pain imaginable[9]. 
 
 


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The mean NRS score assessing average pain intensity in the past 24 hours will be calculated for the 
analysis visits described in Section 5.4.2[4]: 
• 
Baseline (average of Study Days -7 to -1) 
• 
Week 1 (average of Study Days 1 to 7) 
• 
Week 2 (average of Study Days 8 to 14) 
• 
Week 3 (average of Study Days 15 to 21) 
• 
Week 4 (average of Study Days 22 to 28) 
The mean baseline visit will be calculated if at least 6 of the study days have a reported pain score.  
This is a requirement in order to be eligible for being randomized to a study drug treatment arm.  
There will need to at least 4 daily pain scores collected within a post-baseline analysis visit in order to 
calculate the mean pain score for that visit. 
Each mean analysis visit score will take on values ranging from 0 to 10 and will be rounded off by 
one number after the decimal point.  Data prior to Study Day -7 or after Study Day 28 will not be 
used in the mean calculated scores.  No missing data imputations will be used for these observed 
means, but Section 9.1.3 will explain imputation methods used for sensitivity analyses. 
The actual means, change from baseline, and percent change from baseline at each analysis visit will 
be summarized using descriptive statistics.  The same descriptive statistics table will be additionally 
provided by each study site, age groups, gender, race, ethnicity, and subjects using or not using at 
least 1 concomitant analgesic medication at Baseline.  All data collected and derived will be 
presented in subject listings. 
9.1.1 Primary Efficacy Endpoint 
The primary endpoint is based on the change in mean NRS score assessing average pain intensity in 
the past 24 hours from baseline to Week 4. 
9.1.2 Primary Efficacy Endpoint Analysis 
The primary endpoint for mean change from baseline to Week 4 will be summarized with the same 
ANCOVA model described in Section 5.3.5.2.  Additionally, 2 ANCOVA models will be provided 
for subjects using or not using at least 1 concomitant analgesic medication at Baseline[4]. 
9.1.3 Primary Efficacy Endpoint Sensitivity Analyses 
Missing values that occurred between Study Day 1 through Day 28 for individual NRS scores 
assessing average pain intensity in the past 24 hours will be imputed in sensitivity analysis.  Any 
missing data for individual scores not collected at Baseline (Study Day -7 through Day -1) will not be 
imputed.  The following 3 imputation methods will be applied: 
• 
Method 1[10]:  Model-Based using SAS® procedures PROC MI and PROC MIANALYZE 
o Individual missing scores will imputed 5 times[11] with a random seed number of 
8743216514. 
o The Markov chain Monte Carlo method will be used to compute full imputations 
using the following variables:  planned treatment arm and scores at Study Day 1 
through Day 28. 
 


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• 
Method 2[4]:  Last Observation Carried Forward (LOCF) 
o Individual missing scores will use the last individual study day value that was 
collected and will continue to carry that forward until an observed score was 
collected. 
o If Day 1 is missing, then the mean baseline value will be used (not just the Study Day 
-1 score). 
• 
Method 3[4]:  Baseline Observation Carried Forward (BOCF) 
o Individual missing scores will use the mean baseline value calculated. 
Once the missing data has been imputed based on one of the following methods, the post-baseline 
analysis visits will be recalculated if they could not be calculated before.  For example, if a subject 
has observed scores collected for Days 22, 23, 24, and 25 then the observed Week 4 analysis visit 
mean was already calculated.  As a result, imputed Days 26, 27, and 28 will not be used in calculation 
for the Week 4 analysis visit. 
No descriptive statistics tables will be created for any of these imputation methods.  The mean change 
from baseline results in Methods 2 (LOCF) and 3 (BOCF) will be summarized with the same 
ANCOVA model stated in Section 9.1.2. 
The mean change from baseline results in Method 1 (Model-Based) will be summarized into 5 
individual ANCOVA models stated in Section 9.1.2 based on the imputation number.  From there the 
ANCOVA statistics will be analyzed in PROC MIANALYZE to produce overall statistics for: 
• 
n = the number of records for that treatment or pooled treatment group 
• 
Least Squares Mean for the treatment groups 
• 
Standard Error for the treatment groups 
• 
Least Squares Mean Difference for the NYX-2925 treatment groups versus Placebo 
• 
Standard Error Difference for the treatment groups versus Placebo 
• 
95% Confidence Interval for the Difference for the treatment groups versus Placebo 
• 
P-value for the Difference for the treatment groups versus Placebo 
Here is the SAS® code for Method 1: 
PROC MI DATA=ADAM NIMPUTE=5 SEED=8743216514 MINIMUM=0 MAXIMUM=10 
OUT=ADAM_IMPUTE; 
 
CLASS TRTP; 
MCMC INITIAL = EM; 
 
VAR TRTP BASE CHG1 -- CHG28; 
RUN; 
PROC MEANS; 
 
BY _IMPUTATION_ AVISIT; 
 
VAR CHG; 
 
OUTPUT OUT=ADAM_IMPUTE_MEANS MEAN=CHG; 
RUN; 


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ODS OUTPUT PARAMETERESTIMATES=MIXPARMS; 
PROC MIXED DATA=ADAM_IMPUTE_MEANS ORDER=DATA METHOD=REML; 
 
BY _IMPUTATION_; 
 
CLASS TRTP; 
 
MODEL CHG = BASE TRTP / DDFM=KENWARDROGER; 
 
LSMEANS TRTP / DIFF CL ALPHA=0.05; 
 
/* -1 = Placebo; 0 = 10 mg of NYX-2925; 0.5 = 200 mg and 50 mg of NYX-2925 */ 
 
LSMESTIMATE “200 mg and 50 mg of NYX-2925 versus Placebo” TRTP 0 0.5 0.5 -1 / CL; 
RUN; 
PROC MIANALYZE PARMS=MIXPARMS ALPHA=0.05 MULT; 
 
CLASS TRTP; 
 
MODELEFFECTS INTERCEPT TRTP; 
RUN; 
9.2 Secondary Efficacy Data and Endpoints 
Additional efficacy data is stated below that will be collected for this study and how it will be 
analyzed.  Specific secondary efficacy endpoints are described how they will be derived for each 
analysis visit. 
9.2.1 NRS Score Assessing Worst Pain Intensity in the Past 24 Hours 
The collection method of the NRS score assessing worst[10] pain intensity in the past 24 hours is the 
same as the primary efficacy data described in Section 9.1 for the NRS score assessing average pain 
intensity in the past 24 hours.  The study-issued handheld devices were not programmed with logic 
checks to flag instances in which subjects might have mistakenly reported their worst pain intensity 
scores as being less than their average pain intensity scores.  However, rather than assume these to be 
self-evident errors and thus correct them, such scores will be analyzed based on the actual values 
collected. 
The secondary endpoints of interest with this data is the change in the mean score from baseline to 
each analysis week of treatment (Weeks 1, 2, 3, and 4).  The same analyses methods will be applied 
to the NRS score assessing worst pain intensity in the past 24 hours as described in Sections 9.1, 
9.1.1, and 9.1.2.  No imputation methods for missing data will be applied for this secondary endpoint. 
The actual means, change from baseline, and percent change from baseline will be summarized using 
descriptive statistics.  ANCOVA analyses using the mean change from baseline will be provided for 
Weeks 1, 2, 3, and 4 as described in Section 5.3.5.2.  A MMRM model will be analyzed for all post-
baseline analysis visits (Weeks 1, 2, 3, and 4) for the mean change from baseline as described in 
Section 5.3.5.3. 


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9.2.2 Change in the Mean NRS Score Assessing Average Pain Intensity in the Past 
24 Hours at Weeks 1, 2, 3, and 4 
This is the same data described in Section 9.1 for the NRS score assessing average pain intensity in 
the past 24 hours.  The secondary endpoints of interest with this data is the change in the mean score 
from baseline to each analysis week of treatment (Weeks 1, 2, and 3).  The same analyses methods 
will be applied to Weeks 1, 2, and 3 as described in Section 9.1.2 for Week 4. 
ANCOVA analyses using the mean change from baseline will be provided for individual models for 
Weeks 1, 2, and 3 as described in Section 5.3.5.2.  A MMRM model will be analyzed for all post-
baseline analysis visits (Weeks 1, 2, 3, and 4) for the mean change from baseline as described in 
Section 5.3.5.3.  No imputation methods for missing data will be applied for the MMRM model. 
9.2.3 NRS Score Assessing Average Pain upon Walking Intensity in the Past 24 
Hours 
The collection method of the NRS score assessing average pain upon walking intensity in the past 24 
hours is the same as the method for the primary efficacy data described in Section 9.1 for the NRS 
score assessing average pain intensity in the past 24 hours.  The secondary endpoints of interest with 
this data is the change in the mean score from baseline to each analysis week of treatment (Weeks 1, 
2, 3, and 4).  The same analyses methods will be applied to the NRS score assessing average pain 
upon walking intensity in the past 24 hours as described in Sections 9.1, 9.1.1 and 9.1.2.  No 
imputation methods for missing data will be applied for these secondary endpoints. 
The actual means, change from baseline, and percent change from baseline at each analysis visit will 
be summarized using descriptive statistics.  ANCOVA analyses using the mean change from baseline 
will be provided for individual models for Weeks 1, 2, 3, and 4 as described in Section 5.3.5.2.  A 
MMRM model will be analyzed for all post-baseline analysis visits (Weeks 1, 2, 3, and 4) for the 
mean change from baseline as described in Section 5.3.5.3. 
9.2.4 Patient Global Impression of Change (PGI-C) 
The PGI-C is a 7-point Likert scale that allows subjects to rate the change in the disease state from 
study initiation to specific time points during the study or at the end of the study.  It provides the 
subject’s impression of overall change since beginning the study.  Below are the numeric values 
assigned in the 7-point scale along with categorical values and analysis categorical values[4]: 
Numeric Value 
Categorical Value 
Analysis Categorical Value 
1 
Very Much Improved 
Improved 
2 
Much Improved 
Improved 
3 
Minimally Improved 
Minimally Improved to Worse 
4 
No Change 
Minimally Improved to Worse 
5 
Minimally Worse 
Minimally Improved to Worse 
6 
Much Worse 
Minimally Improved to Worse 
7 
Very Much Worse 
Minimally Improved to Worse 
Missing 
Missing 
Minimally Improved to Worse 


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The secondary endpoints of interest are the actual collected values at Weeks 2 and 4.  The last post-
baseline visit for each subject will also by summarized.  There is no baseline collection due to the 
nature of this data being the change after receiving study drug. 
Descriptive statistics will be provided using the numeric value data for each analysis visit.  A 
frequency distribution will be created for each analysis visit based on the collected categorical values.  
The analysis categorical values stated above will be summarized by frequency distributions, odds 
ratio, and relative risk analyses described in Section 5.3.5.5. 
9.2.5 Short-Form McGill Pain Questionnaire, version 2 (SF-MPQ-2) 
The SF-MPQ-2 measures the sensory, affective, and evaluative qualities of pain, including symptoms 
relevant to neuropathic pain.  The tool includes visual analogue as well as verbal rating scales of pain 
intensity on a total of 22 neuropathic and non-neuropathic pain descriptors that are each evaluated on 
a 10-point numerical rating scale/Likert scale ranging from 0 to 10[12].  Where 0 represents none and 
10 is worst possible. 
The following questions that make up each published summary scale score[13]: 
• 
Continuous Descriptors: 
o Throbbing Pain, Cramping Pain, Gnawing Pain, Aching Pain, Heavy Pain, and 
Tender 
• 
Intermittent Descriptors: 
o Shooting Pain, Stabbing Pain, Sharp Pain, Splitting Pain, Electric-Shock Pain, and 
Piercing 
• 
Neuropathic Descriptors: 
o Hot-Burning Pain, Cold-Freezing Pain, Pain Caused by Light Touch, Itching, 
Tingling or ‘Pins and Needles’, and Numbness 
• 
Affective Descriptors: 
o Tiring-Exhausting, Sickening, Fearful, and Punishing-Cruel 
Each of the 4 summary scale scores will be calculated by the mean if more than 50% of the responses 
are available for the calculation.  For example, the Continuous Descriptors summary scale score will 
need at least 4 of the 6 components available in order to calculate the mean.  If all the 4 summary 
scale scores can be calculated, then the total pain score is computed by averaging the non-rounded 4 
individual summary scale scores.  If at least one summary scale score is missing, the total pain score 
will be set to missing.  Each mean summary scale and total pain score will take on values ranging 
from 0 to 10 and will be rounded off by one number after the decimal point. 
The secondary endpoints of interest with this data are the published summary scales and total pain 
scores change from baseline to Week 4.  Subjects will be instructed to answer each question based on 
the pain and related symptoms they felt during the past week, so responses should be interpreted as 
cumulative over that time period.  The SF-MPQ-2 will be assessed at the Baseline and Week 4/Early 
Termination visits. 
The actual means and change from baseline will be summarized using descriptive statistics.  
ANCOVA analyses using the change from baseline to Week 4 will be provided for the published 
summary scales and total pain scores.  The change from baseline to last post-baseline visit for each 
subject will also by summarized. 


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9.2.6 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 subject and 
questions related to the impact of the subject’s neuropathy on activities of daily life.  As a 
comprehensive questionnaire it addresses the entire spectrum of neuropathy including the 
concentration of symptoms in the extremities, subtle loss of function such as fine motor impairments 
and sensory changes, unique problems with proprioception and balance, and autonomic symptoms 
that are not captured in existing instruments.  An initial biographical page collects twelve health-
related background history items, which are not scored.  These are followed by 35 scored questions - 
numbered items comprising the entire scale[14].  Lower scores represent a better quality of life.  Each 
individual question concerns particular functions or symptoms related to the following 5 subscale 
domains[15, 16]: 
• 
Symptoms: 
o Questions 1-7 for Symptoms in the following Categories:  Numbness; Tingling, Pins 
and Needles; Electric Shocks; Other Unusual Sensations; Superficial Pain; Deep 
Pain; Weakness 
 
5 Possible Responses:  Feet, Legs, Hands, Arm, or None 
 
For “None” selected, a score of 0 will be assigned to that question.  
Otherwise, a score of each location response selected will be assigned a value 
of 1.  As a result, each question may have a score of 0 or 1 for each location, 
with a total maximum of 4. 
o Question 9:  “In the past 4 weeks, has the touch of bed sheets, clothes, or wearing 
shoes bothered you?” 
 
5-point Likert scale ranging from 0 (“Not a problem”) to 4 (“Severe 
problem”) 
 
The symptoms subscale score is the sum of the 8 questions with scores 
ranging from 0 to 32. 
• 
Activities of Daily Living (ADLs): 
o Questions 12, 22, 23, 25, and 26 
 
5-point Likert scale ranging from 0 (“Not a problem”) to 4 (“Severe 
problem”) 
 
The ADLs subscale score is the sum of the 5 questions with scores ranging 
from 0 to 20. 
• 
Small Fiber Neuropathy: 
o Questions 10, 16, 17, and 18 
 
5-point Likert scale ranging from 0 (“Not a problem”) to 4 (“Severe 
problem”) 
o The small fiber neuropathy subscale score is the sum of the 4 questions with scores 
ranging from 0 to 16. 
• 
Physical Functioning/Large Fiber Neuropathy: 
o Questions 8, 11, 13-15, and 24 
 
5-point Likert scale ranging from 0 (“Not a problem”) to 4 (“Severe 
problem”) 
 


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o Questions 27-30 and 33-35 
 
5-point Likert scale ranging from 0 (“Not at all”) to 4 (“Severely”) 
o Question 31 
 
Excellent = -2; Very Good = -1; Good = 0; Fair = 1; Poor = 2 
o Question 32 
 
Much Better = -2; Somewhat Better = -1; About the Same = 0; Somewhat 
Worse = 1; Much Worse = 2 
o The physical functioning/large fiber neuropathy subscale score is the sum of the 15 
questions with scores ranging from -4 to 56. 
• 
Autonomic Neuropathy: 
o Questions 19, 20, and 21 
 
5-point Likert scale ranging from 0 (“Not a problem”) to 4 (“Severe 
problem”) 
o The autonomic neuropathy subscale score is the sum of the 3 questions with scores 
ranging from 0 to 12. 
If 4 or more (>10%) responses are missing from the 35 questions, then the subject will be excluded 
from the Norfolk QOL-DN analyses.  If 3 or fewer responses are missing, then the following data 
imputations will be performed: 
• 
If any missing questions occurred during the Baseline visit, then the mean score for all 
subjects in at that specific study site will be used to impute missing questions. 
• 
If any missing questions occurred during a post-baseline visit, then the mean score for all 
subjects in that specific randomized treatment group will be used to impute missing 
questions. 
The Total Quality of Life Score will be calculated by the sum of all the 35 questions stated above in 
the subscale domains with the total score ranging from -4 to 136.  
The questionnaire has been validated using factor analysis and its psychometric properties defined.  It 
has tested at the 90th percentile for reliability, sensitivity and specificity. It correlates with other 
measures of neuropathy, most strongly with the total neuropathy score (TNS) (r=0.53, p=0.0001) and 
then with the neuropathy score in the lower limbs (NIS-LL+7) (r=0.27, P=0.0005), but not with 
individual indices of electrophysiology or quantitative sensory testing.  Of the QOL subscales, 
Activities of Daily Living (ADLs) were the greatest contributors to the total neuropathy score.  
Norfolk QOL-DN has been used in major neuropathy clinical trials for diabetic neuropathy. 
The secondary endpoints of interest with this data is the published subscale domains and total scores 
change from baseline to Week 4.  The Norfolk QOL-DN is sensitive to the different features of 
diabetic neuropathy including small fiber, large fiber, and autonomic nerve function.  Subjects will be 
instructed to rate most items over the last 4 weeks, so responses should be interpreted as cumulative 
over that time period.  Not merely an inventory of the subject’s status at the moment of filling out the 
questionnaire.  The Norfolk QOL-DN will be assessed at the Baseline and Week 4/Early Termination 
visits. 
The actual means and change from baseline will be summarized using descriptive statistics.  
ANCOVA analyses using the mean change from baseline will be provided for Week 4.  The change 
from baseline to last post-baseline visit for each subject will also by summarized. 


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All 35 individual question responses, calculated subscale domain scores, and the total score will be 
presented in subject listings.  All other health-related questions answered on the front page of the 
questionnaire will be presented in subject listings, but not in summary tables. 
9.2.7 Insomnia Severity Index (ISI) 
The ISI is a 7-item self-report questionnaire assessing the nature, severity, and impact of insomnia.  
The usual recall period is the “last month” and the dimensions evaluated are: severity of sleep onset, 
sleep maintenance and early morning awakening problems, sleep dissatisfaction, interference of sleep 
difficulties with daytime functioning, noticeability of sleep problems by others, and distress caused by 
the sleep difficulties.  A 5-point Likert scale is used to rate each item (i.e. 0 = none; 4 = very severe).  
The categorical responses are slightly different for some of the questions, but the numeric scores 
remained the same from 0 to 4.  If all questions are answered, then the total score will be calculated 
by the sum of all the responses ranging from 0 to 28.  If any of the 7 questions are missing, then the 
total score will be set to missing.  The total score is interpreted as follows[17, 18]: 
• 
Absence of Insomnia (0-7) 
• 
Sub-Threshold Insomnia (8-14) 
• 
Moderate Insomnia (15–21) 
• 
Severe Insomnia (22–28) 
The secondary endpoints of interest with this data is the total score change from baseline to Week 2 
and Week 4.  Subjects will be instructed to answer each question based their sleep patterns in the last 
2 weeks, so responses should be interpreted as cumulative over that time period.  The ISI will be 
assessed at the Baseline, Week 2, and Week 4/Early Termination visits. 
The total score actual means and change from baseline will be summarized using descriptive 
statistics.  ANCOVA analyses using the mean change from baseline will be provided for individual 
models for Weeks 2 and 4.  The change from baseline to last post-baseline visit for each subject will 
also by summarized.  The 4 interpreted total score categorical values will be summarized in a 
frequency distribution table and a shift table. 
9.2.8 Hospital Anxiety and Depression Scale (HADS) 
The HADS is a self-reported screening tool for anxiety and depression in non-psychiatric clinical 
populations.  The scale consists of 14 items (7 each for anxiety and depression), each rated on a 4-
point scale ranging from 0 to 3 (i.e. 0 = not at all; 3 = most of the time).  The categorical responses 
are slightly different for some of the questions, but the numeric scores remained the same from 0 to 3.  
Responses are based on the relative frequency of symptoms over the preceding week[19].   
When a HADS questionnaire is partially incomplete, the individual subscale scores are estimated by 
assuming that the missing item(s) have a value equal to the average of those in existence, provided 
that no more than 3 items of a subscale are missing[20].  The individual imputed missing scores will 
use the specific subscale mean score and will be rounded off to the nearest whole number.  If an 
individual subscale score is missing 4 or more items, then that subscale score will be set to missing.  
A total score adding the anxiety and depression subscale scores for HADS will not be calculated. 
 
 


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Possible scores range from 0 to 21 for each subscale.  An analysis of scores on the 2 subscales 
supported the differentiation of each mood state into 4 ranges[21]: 
• 
Normal Cases (Scores 0-7) 
• 
Mild Cases (Scores 8-10) 
• 
Moderate Cases (Scores 11-14) 
• 
Severe Cases (Scores 15-21) 
The secondary endpoints of interest with this data is the published subscale and total scores change 
from baseline to Week 4.  Subjects will be instructed to answer each question based how they have 
felt in the past week, so responses should be interpreted as cumulative over that time period.  The 
HADS will be assessed at the Screening, Baseline, and Week 4/Early Termination visits. 
The actual means and change from baseline will be summarized using descriptive statistics.  
ANCOVA analyses using the mean change from baseline will be provided for Week 4.  The change 
from baseline to last post-baseline visit for each subject will also by summarized.  The 4 interpreted 
categorical values for each subscale will be summarized in a frequency distribution table and a shift 
table. 
9.2.9 Daily Sleep Interference Scale (DSIS) 
The collection method of the Daily Sleep Interference Scale (DSIS) score has data that is similar to 
the primary efficacy data described in Section 9.1 for the NRS score assessing average pain intensity 
in the past 24 hours.  However, the study days are shifted by one day based on the analysis visits 
described in Section 5.4.3 due to the scores are based on sleep from the previous study day: 
• 
Baseline (average of Study Days -6 to 1) 
• 
Week 1 (average of Study Days 2 to 8) 
• 
Week 2 (average of Study Days 9 to 15) 
• 
Week 3 (average of Study Days 16 to 22) 
• 
Week 4 (average of Study Days 23 to 29) 
Daily collected scores and are based on an 11-point numerical rating scale/Likert scale ranging from 0 
to 10.  Where 0 represents “did not interfere with sleep” and 10 is “completely interfered with 
sleep/unable to sleep” due to pain[23]. 
The secondary endpoints of interest with this data is the change in the mean score from baseline to 
each analysis week of treatment (Weeks 1, 2, 3, and 4).  The same analyses methods will be applied 
to the Daily Sleep Interference Scale (DSIS) score as described in Sections 9.1, 9.1.1 and 9.1.2.  No 
imputation methods for missing data will be applied for these secondary endpoints. 
The actual means and change from baseline at each analysis visit will be summarized using 
descriptive statistics.  ANCOVA analyses using the mean change from baseline will be provided for 
individual models for Weeks 1, 2, 3, and 4 as described in Section 5.3.5.2.  A MMRM model will be 
analyzed for all post-baseline analysis visits (Weeks 1, 2, 3, and 4) for the mean change from baseline 
as described in Section 5.3.5.3. 
9.2.10 Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) 
The BPI 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, 


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relief from medications).  A modified version of the BPI, 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, which 
distinguishes between pain due to DPN and pain due to other causes.  Each BPI item uses a 0 to 10 
numeric rating scale anchored at zero for “no pain” and 10 for “pain as bad as you can imagine” for 
Severity, and “does not interfere” to “completely interferes” for Interference[24]. 
If at least 3 of the 4 Severity items have a reported score, then the Pain Severity Index will be the 
calculated mean.  Otherwise, the Pain Severity Index will be set to missing.  If at least 4 of the 7 
Interference items have a reported score, then the Pain Interference Index will be the calculated mean.  
Otherwise, the Pain Interference Index will be set to missing.  The Pain Severity Index and the Pain 
Interference Index will be referred to as composite scores[25]. 
The study-issued handheld devices were not programmed with logic checks to flag instances in which 
subjects might have mistakenly reported their worst pain intensity scores as being less than their 
average pain intensity scores.  However, rather than assume these to be self-evident errors and thus 
correct them, such scores will be analyzed based on the actual values collected.  Also, the least pain in 
the last 24 hours scores may be greater than the worst pain in the last 24 hours and/or right now pain 
scores.  Edit checks were not applied in the handheld devices for the subject’s confusion of the three 
scores.  The Pain Severity Index score equally distributes all these three scores and the average pain 
score.  Therefore, the Pain Severity Index score is not impacted by any of these scores being 
transposed.  As a result the scores will be analyzed based on the values collected. 
The 2 composite scores will take on values ranging from 0 to 10 and will be rounded off by one 
number after the decimal point.  A total pain score for BPI-DPN will not be calculated. 
The secondary endpoints of interest with this data is the 2 composite scores change from baseline to 
Week 4.  Subjects will be instructed to answer each question based their pain at the time or within the 
last 24 hours.  The BPI-DPN will be assessed at the Baseline and Week 4/Early Termination visits. 
The actual means and change from baseline will be summarized using descriptive statistics.  
ANCOVA analyses using the mean change from baseline described in Section 5.3.5.2 will be 
provided for individual models for Week 4.  The change from baseline to last post-baseline visit for 
each subject will also by summarized. 
BPI-DPN question 8, “In the last 24 hours, how much relief have pain treatments or medications 
provided?  Please circle the one percentage that most shows how much relief you have received.” will 
be collected on the CRF and has values that range from 0% (no relief) to 100% (complete relief).  
This question will be included in the descriptive statistics, but not in the ANCOVA analyses. 
BPI-DPN question 1, “Throughout our lives, most of us have had pain from time to time (such as 
minor headaches, sprains, and toothaches).  Have you had pain other than these everyday kinds of 
pain today?” is a categorical response (yes/no).  This data will be presented in a subject listing, but 
not summarized in a table. 
BPI-DPN question 2, “On the diagram, shade in the areas where you feel pain.  Put an X on the area 
that hurts the most.” will be provided in subject listings, be not in any summary tables.  BPI-DPN 
question 7, “What treatments or medications are you receiving for your pain?” was not collected in 
the eDT because this was included in the prior and/or concomitant medications collected on the CRF. 


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9.3 Exploratory Efficacy Endpoints 
9.3.1 Use of Rescue Medication Subgroup Analyses 
Boxplots will be produced for each treatment arm side-by-side for the mean change from baseline 
NRS scores assessing average pain intensity in the past 24 hours versus the average rescue medication 
taken (g/day) at the following analysis visits: 
• 
Baseline (average of Study Days -7 to -1) 
o Versus Rescue Medication from Screening to Baseline 
• 
Week 1 (average of Study Days 1 to 7) 
o Versus Rescue Medication from Baseline to Week 2 
• 
Week 2 (average of Study Days 8 to 14) 
o Versus Rescue Medication from Baseline to Week 2 
• 
Week 3 (average of Study Days 15 to 21) 
o Versus Rescue Medication from Week 2 to Week 4 
• 
Week 4 (average of Study Days 22 to 28) 
o Versus Rescue Medication from Week 2 to Week 4 
Scatter plots will also be produced for each analysis listed above for the mean change from baseline 
NRS scores assessing average pain intensity in the past 24 hours versus the average rescue medication 
taken (g/day). 
Daily rescue medication taken will be collected in the daily diary data for each subject.  If a subject 
recorded the use of rescue medication, then the NRS score for that specific day will be set to the mean 
baseline value calculated for the NRS scores assessing average pain intensity in the past 24 hours.  
Otherwise, the individual NRS scores assessing average pain intensity in the past 24 hours will 
remain the same value as collected.  As an additional exploratory analysis, mean NRS score assessing 
average pain intensity in the past 24 hours will be recalculated for the post-baseline analysis visits 
described in Section 5.4.2: 
• 
Week 1 (average of Study Days 1 to 7) 
• 
Week 2 (average of Study Days 8 to 14) 
• 
Week 3 (average of Study Days 15 to 21) 
• 
Week 4 (average of Study Days 22 to 28) 
ANCOVA analyses using the mean change from baseline will be provided for Weeks 1, 2, 3, and 4 as 
described in Section 5.3.5.2.  These results compared to the analyses stated in Sections 9.1.2 and 9.2.2 
will assist in determining the impact use of rescue medication. 
9.3.2 Responder Status Endpoints 
Different efficacy responder statuses will be defined based on the following methods[4, 10]: 
• 
Responder at ≥30% Pain Reduction: 
o Subjects achieving ≥30% pain reduction on the mean NRS score assessing average 
pain intensity in the past 24 hours from baseline to Week 4 analysis visit and the 
subjects must complete the study.  Subjects who do not have an analysis visit Week 4 
mean NRS score assessing average pain intensity in the past 24 hours will be set to a 
non-responder. 


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• 
Responder at ≥50% Pain Reduction: 
o Subjects achieving ≥50% pain reduction on the mean NRS score assessing average 
pain intensity in the past 24 hours from baseline to Week 4 analysis visit and the 
subjects must complete the study.  Subjects who do not have an analysis visit Week 4 
mean NRS score assessing average pain intensity in the past 24 hours will be set to a 
non-responder. 
• 
Responder at ≥30% Pain Reduction and Week 4 PGI-C Improved Score: 
o Subjects achieving ≥30% pain reduction on the mean NRS score assessing average 
pain intensity in the past 24 hours from baseline to Week 4 analysis visit and the 
subjects must complete the study.  Subjects who do not have an analysis visit Week 4 
mean NRS score assessing average pain intensity in the past 24 hours will be set to a 
non-responder. 
o In addition, to be classified as “responders” subjects must have an analysis visit 
Week 4 PGI-C score of 1 (Very Much Improved) or 2 (Much Improved).  Otherwise, 
those subjects will be set to non-responders. 
The percent change from baseline that is ≤ -30.0% is equivalent to ≥30% pain reduction.  Subjects 
with a calculated mean NRS score assessing average pain intensity in the past 24 hours at analysis 
visit Week 4 will be provided in a figure based on their percent change from baseline values.  The 
horizontal axis displays a range of percentage-reductions from baseline at Week 4 in the mean NRS 
score assessing average pain intensity in the past 24 hours and the vertical axis displays the 
percentage of subjects achieving each of those levels of improvement.  The horizontal axis will range 
from 0% to 100% in percentage-reductions and will not plot subjects with percentages below 0% (i.e. 
subjects that showed worse pain at Week 4 and the percentage change from baseline > 0%). 
Frequency distributions, odds ratio, and relative risk analyses described in Section 5.3.5.5 will be 
used to summarize the responder status endpoints. 
9.3.3 Number of Days to Responder Status 
The number of days[4] to responder status will consider any 4 consecutive days between Study Day 1 
and 28.  If any of the 4-day means for NRS score assessing average pain intensity in the past 24 hours 
at show a ≥30% pain reduction, then the first study day within the 4-day interval will be the number 
of days to responder status.  Individual scores on the first study day within the 4-day interval may be 
missing or <30% pain reduction as long as the 4-day mean is ≥30%.  A maximum of 1 missing value 
may be present in the mean calculation if at least 3 scores are present.   
The number of days using ≥50% pain reduction will also be calculated using the same methods.  The 
number of days to responder status will be based on the observed daily pain scores and will not use 
any imputation methods for missing data described in Section 9.1.3.  Cox proportional hazards 
modeling analyses described in Section 5.3.5.4 will be used for the number of days in each responder 
definition.  Additionally, a Kaplan-Meier probability plot will be created for each planned treatment 
arm and number of days to responder status. 
9.3.4 Number of Days to Sustained Pain Reduction 
If a subject reaches a responder status at any point of the study as defined in Section 9.3.3, the 
following additional conditions will also need to be met in order for the subject to be considered as 
sustaining pain reduction: 


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• 
At least 8 days from the onset of the response to the last collected pain score that is ≤ Study 
Day 28. 
o Study Day 21 is the latest possible day for sustained pain reduction if the study day 
NRS score assessing average pain intensity in the past 24 hours was collected. 
• 
The responder status endpoint of interest stated in Section 9.3.2 must by met at the Week 4 
analysis visit. 
o Responder at ≥30% Pain Reduction 
o Responder at ≥50% Pain Reduction 
• 
Once the responder status has been met, the remainder of the study days after the last day in 
the 4-day interval until Study Day 28 will calculate the overall remaining mean for NRS 
score assessing average pain intensity in the past 24 hours.  If the overall remaining mean 
score shows a pain reduction ≥ to the responder status (i.e. ≥30% or ≥50%), then this criteria 
of the sustained pain reduction will be met. 
A frequency distribution of these categories will be summarized: 
• 
≥30% Pain Reduction Status 
o Never Reached 
o Reached, but did not Sustain 
o Reached and Sustained at Mean Analysis Visit Week 4 (Responder Endpoint) 
• 
≥50% Pain Reduction Status 
o Never Reached 
o Reached, but did not Sustain 
o Reached and Sustained at Mean Analysis Visit Week 4 (Responder Endpoint) 
The number of days of onset to sustained pain reduction will be summarized using descriptive 
statistics.  The same Cox proportional hazards modeling analyses and Kaplan-Meier probability plot 
described in Section 9.3.3 will be applied to sustained pain reduction data.  The number of days to 
sustained pain reduction will be based on the observed daily pain scores and will not use any 
imputation methods for missing data described in Section 9.1.3. 
9.4 Summary of Efficacy Analyses 
The table below describes the p-value analyses preformed on the different types of efficacy data for 
this study: 
Efficacy Data 
ANCOVA 
Repeated 
Measures 
Hazard 
Modeling 
Chi-
Square 
Mean Change from Baseline NRS Score Assessing 
Average Pain Intensity in the Past 24 Hours at Week 4 
X 
 
 
 
Mean Change from Baseline NRS Score Assessing 
Average Pain Intensity in the Past 24 Hours at Weeks 1, 
2, 3, and 4 
X 
X 
 
 
Mean Change from Baseline NRS Score Assessing 
Worst Pain Intensity in the Past 24 Hours at Week 4 
X 
 
 
 


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Efficacy Data 
ANCOVA 
Repeated 
Measures 
Hazard 
Modeling 
Chi-
Square 
Mean Change from Baseline NRS Score Assessing 
Worst Pain Intensity in the Past 24 Hours at Weeks 1, 2, 
3, and 4 
X 
X 
 
 
Mean Change from Baseline NRS Score Assessing 
Average Pain upon Walking Intensity in the Past 24 
Hours at Week 4 
X 
 
 
 
Mean Change from Baseline NRS Score Assessing 
Average Pain upon Walking Intensity in the Past 24 
Hours at Weeks 1, 2, 3, and 4 
X 
X 
 
 
PGI-C 
 
 
 
X 
SF-MPQ-2 
X 
 
 
 
Norfolk QOL-DN 
X 
 
 
 
ISI 
X 
 
 
 
HADS 
X 
 
 
 
DSIS 
X 
X 
 
 
BPI-DPN 
X 
 
 
 
Responder Status Endpoints 
 
 
 
X 
Number of Days to Responder Status 
 
 
X 
 
Number of Days to Sustained Pain Reduction 
 
 
X 
 
10. Safety Analyses 
10.1 Adverse Events 
Treatment-emergent adverse events (TEAEs) will be those occurring during or after administration of 
the first dose of study drug until 30 days after the final dose of study drug.  Due to the nature of this 
study, the date and time of first dose of study drug was not collected on the CRF.  Therefore, the 
following algorithm will be used to determine if the adverse events are treatment-emergent: 
• 
Earliest Possible AE Start Date ≥ Baseline Visit and Study Drug Dispensation and 
• 
Latest Possible AE Start Date ≤ 30 Days After the Final Dose of Study Drug 
Adverse events that started on the Baseline Visit (Study Day 1) that are the result of abnormal 
clinically significant electrocardiograms (ECGs) or clinical laboratory tests collected prior to study 
drug dispensation will not be considered TEAEs. 


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The following System Organ Class (SOC) AEs for abnormal clinically significant clinical laboratory 
tests will be reviewed to determine if the AE is not treatment-emergent: 
• 
Investigations 
• 
Infections and infestations (with the Preferred Term = “Urinary tract infection”) 
AEs that started prior to first dosing of study drug, but become worse in severity after receiving study 
drug will be considered treatment-emergent.  The determination of whether or not an adverse event is 
classified as “treatment emergent” (i.e. TEAE) is not dictated by the classification of “relationship to 
study drug” collected on the CRF, but rather by the temporal relationship of the adverse event to the 
administration of study drug. 
A related study drug TEAE is defined as any TEAE with at least a possible relationship to the study 
drug as assessed by the investigator or that is missing the assessment of causal relationship whose 
relationship to the study drug could not be ruled out.  Relationships of “possibly related”, “probably 
related”, or missing are collected on the CRF, then those adverse events will be considered related 
study drug TEAEs.  If the “unrelated” or “unlikely related” are collected on the CRF, then those 
adverse events will be considered not related study drug TEAEs. 
Severity is assigned to each adverse event collected on the CRF.  Maximum severity has the 
following order: “life threatening”, “severe”, “moderate”, and “mild” as possible collection options 
on the CRF.  A missing severity will be treated as “unknown” for analysis purposes. 
All adverse events will be coded and summarized by System Organ Class (SOC) and Preferred Term 
(PT) based on Medical Dictionary for Regulatory Activities (MedDRA) version 19.0 coding 
dictionary.  This data will be summarized in a frequency distribution.  Subjects may have more than 
one TEAE record per SOC and PT.  At each level of subject summarization, a subject will be counted 
once if he/she reports one or more TEAE record at that specific level.  For tables summarized by SOC 
and PT, the events will be displayed in the order of descending frequency counts for all treatments by 
SOC and then PT within SOC. 
The number of subjects with at least one of the following adverse events, percentages for each 
category by treatment, and the number of total events will be included in an overall treatment-
emergent adverse events summary table: 
• 
Any TEAEs 
• 
Related TEAEs 
• 
Maximum Severity TEAEs 
• 
Serious TEAEs 
• 
Related, Serious TEAEs 
• 
TEAEs Leading to Study Discontinuation 
• 
Related TEAEs Leading to Study Discontinuation 
• 
TEAEs Leading to Death 
Summaries including the number of subjects and percentages of the following adverse events by SOC 
and PT will be provided: 
• 
Any TEAEs 
• 
Related TEAEs 
• 
Maximum Severity TEAEs 


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• 
Serious TEAEs 
• 
TEAEs Leading to Study Discontinuation 
Additionally, TEAEs will be summarized by descending frequency counts of PT for all treatments.  
All adverse event data collected will be provided in subject listings.  Subset subject listings will also 
be provided by serious treatment-emergent adverse events and deaths; by treatment-emergent adverse 
events leading to study discontinuation; any adverse events that are not considered to be treatment-
emergent; by serious adverse events and deaths that are not considered to be treatment-emergent; and 
by adverse events leading to study discontinuation that are not considered to be treatment-emergent. 
10.2 Clinical Laboratory Tests 
Clinical laboratory tests for hematology, serum chemistry, and urinalysis will be summarized: 
• 
Observed results at all analysis visits (Screening, Baseline, Week 2, Week 4, Follow-up, Last 
Post-Baseline Visit, Lowest Post-Baseline Result, Highest Post-Baseline Result, and Most 
Abnormal Post-Baseline Result) 
o Descriptive statistics for numeric results 
 
Most Abnormal Post-Baseline Result will be removed 
o Frequency distributions for the categorical results  
 
Lowest and Highest Post-Baseline Result will be removed 
• 
Change from baseline for numeric results at all post-baseline analysis visits (Week 2, Week 
4, Follow-up, Last Post-Baseline Visit, Lowest Post-Baseline Result, and Highest Post-
Baseline Result) 
• 
Shift tables for abnormalities from baseline to post-baseline visits 
o Numeric Results:  Low, Normal, and High 
 
Shift tables will be presented by each post-baseline analysis visit, the overall 
lowest post-baseline result (scheduled or unscheduled), and the overall 
highest post-baseline result (scheduled or unscheduled).  
o Categorical Results:  Normal and Abnormal 
 
Shift tables will be presented by each post-baseline analysis visit and the 
overall most abnormal post-baseline result (scheduled or unscheduled). 
Hematology assessments will include total white blood cell count, differential (neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils), hemoglobin, hematocrit, red blood cell count, 
platelet count, and HbA1c.  HbA1c will be collected and analyzed at Screening (Visit 1) only. 
Serum chemistry assessments will include electrolytes (bicarbonate, calcium, chloride, phosphorous, 
potassium, sodium, and magnesium), enzymes (alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, lactate dehydrogenase, and gamma-glutamyl transferase), and other 
(albumin, total bilirubin, direct bilirubin, indirect bilirubin, creatinine, calculated creatinine clearance 
(Cockcroft-Gault formula), glucose, triglycerides, total protein, blood urea nitrogen, and uric acid).  
Calculated creatinine clearance and triglycerides will be collected/calculated and analyzed at 
Screening (Visit 1) only.  Only serum chemistry tests at Week 2 and the follow-up visits are planned 
to be collected and analyzed for these 6 liver function tests (alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, and indirect bilirubin).  
No fasting for these liver function serum chemistry tests will be required, as is required for glucose 
and triglycerides. 


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Urinalysis will include pH, specific gravity, glucose, ketones, protein, blood, leukocyte esterase, 
urobilinogen, nitrites, and reflex microscopy. 
Other clinical laboratory tests for hematology, serum chemistry, and urinalysis collected that are not 
stated above will be included in subject listings, but not in the summary tables. 
Potentially Clinically Significant (PCS) Clinical Laboratory Tests: 
Clinical Laboratory 
Category 
Clinical Laboratory Test 
PCS Threshold 
Serum Chemistry 
Alkaline Phosphatase (ALP) 
> 2 x ULN 
Serum Chemistry 
Alanine Aminotransferase (ALT) 
> 3 x ULN 
Serum Chemistry 
Aspartate Aminotransferase (AST) 
> 3 x ULN 
Serum Chemistry 
Blood Urea Nitrogen (BUN) 
> 1.5 x ULN 
Serum Chemistry 
Creatinine 
>1.5 x Baseline or > 1.5 x ULN 
Serum Chemistry 
Gamma-Glutamyl Transferase (GGT) 
> 3 x ULN 
Serum Chemistry 
Lactate Dehydrogenase (LDH) 
> 3 x ULN 
Serum Chemistry 
Total Bilirubin 
> 2 x ULN 
Hematology 
White Blood Cell Count 
≤ 2.8 10^9/L 
Hematology 
Absolute Neutrophils Count 
< 1.5 10^9/L 
Frequency distributions of the clinical laboratory tests of interest listed above will summarized for 
potentially clinically significant (PCS) values at individual analysis visits and any post-baseline visit. 
eDISH (evaluation of Drug-Induced Serious Hepatotoxicity)[26] plots will be created for the following 
highest post-baseline laboratory test values versus highest post-baseline total bilirubin values: 
• 
Alkaline Phosphatase (ALP) versus Total Bilirubin 
• 
Alanine Aminotransferase (ALT) versus Total Bilirubin 
• 
Aspartate Aminotransferase (AST) versus Total Bilirubin 
The peak post-baseline ALP, ALT, AST, and total bilirubin values will each be divided by their 
respective upper limit of normal (ULN) range.  Those individual ALP, ALT, and AST transformed 
values will be plotted against transformed total bilirubin values to help identify the following[27]: 
• 
Hy’s Law Range:  ALP, ALT, or AST > 3 x ULN and Total Bilirubin > 2 x ULN 
• 
Hyperbilirubinemia:  ALP, ALT, or AST ≤ 3 x ULN and Total Bilirubin > 2 x ULN 
• 
Temple’s Corollary Range:  ALP, ALT, or AST > 3 x ULN and Total Bilirubin ≤ 2 x ULN 
 
 


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The following additional laboratory tests collected will be provided in subject listings only: 
• 
Urine Pregnancy Tests 
o All women of childbearing potential 
• 
Serology Tests: 
o HIV, Hepatitis B Virus Surface Antigen, and Hepatitis C Virus Antibody Tests 
o If the screening hepatitis C antibody test result is reactive, a nucleic acid test for 
HCV RNA should be performed for confirmation of chronic infection. 
o If the screening HIV test is positive, a confirmatory Western Blot test should be 
performed to confirm HIV status. 
• 
Urine Drug Screen Tests 
o Cannabinoids, Opioids, and Benzodiazepines 
• 
Alcohol Breathalyzer Screen Tests 
The clinical laboratory test results will be listed and accompanied by normal ranges when provided; 
values outside the normal ranges will be flagged.  All abnormal clinical laboratory test results for 
hematology, serum chemistry, and urinalysis will be provided in a subject listing.  In the event any 
clinical laboratory samples were collected more than once with different requisition numbers within 
the same date and time, the most abnormal results followed by the greatest change from baseline will 
used in the summary tables.  All samples will be reported in the subject listings and these will be 
documented in the SDTM Study Data Reviewer’s Guide. 
10.3 Vital Sign Measurements 
Systolic blood pressure (mmHg), diastolic blood pressure (mmHg), and pulse rate (bpm) will be 
assessed at analysis visits Screening, Baseline, Week 2, Week 4, and Last Post-Baseline Visit.  
Observed vital signs and changes from baseline will be summarized for the vital signs using 
descriptive statistics. 
10.4 12-Lead Electrocardiogram (ECG) 
Electrocardiogram (ECG) parameters will be measured at Screening, Baseline, and Week 4/Early 
Termination.  Descriptive statistics of observed values and changes from baseline will be summarized 
for: 
• 
ECG Mean Heart Rate (beats/min) 
• 
RR Interval (msec) 
• 
PR Interval (msec) 
• 
QRS Duration (msec) 
• 
QTcF Interval (msec) 
QT Interval and QTcB Interval will be collected and provided in subject listings, but not included in 
the summary tables.  The interpretation of ‘Normal’, ‘Abnormal, not clinically significant’, and 
‘Abnormal, clinically significant’ will be summarized at each analysis visit.  A shift table of these 
interpretations will be provided from baseline to Week 4 and Last Post-Baseline Visit. 
 
 


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Frequency distributions of the QTcF Interval will be displayed for abnormally high values that are 
greater than their baseline value at any post-baseline visit and the following data cuts: 
• 
> 450 msec and > Baseline Value 
• 
> 470 msec and > Baseline Value 
• 
> 500 msec and > Baseline Value 
Additionally, the change from baseline frequency distributions of the QTcF Interval will displayed for 
the following data cuts: 
• 
> 30 msec 
• 
> 60 msec 
10.5 Physical Examinations 
10.5.1 Complete and Brief Physical Examinations 
A complete physical examination will be given to subjects at the screening visit.  The following 8 
pre-defined areas will be assessed with the option to examine other areas as well: 
• 
HEENT (Head, Eyes, Ears, Nose, and Throat); Lymph Nodes; Respiratory; Cardiovascular; 
Gastrointestinal; Musculoskeletal; Dermatologic; and Extremities 
• 
Additional Other Specified Areas (no specific limit) 
o The body system will be specified on the CRF and will be standardized in the subject 
listings. 
Responses may be “Normal”, “Abnormal”, or “Not Done” for each of the 8 pre-defined areas.  If 
another body system is entered on the CRF, only “Normal” or “Abnormal” responses will be 
collected.  If any response was “Abnormal” then the abnormality will be specified on the CRF.  If 
either all the assessments or individual assessments are marked as “Not Done” then the reason not 
done will be entered on the CRF. 
A brief physical examination will be given at the Baseline, Week 4/Early Termination, and 
potentially during any unscheduled visits.  The following question will be answered by the 
investigator, “Were there any clinically significant changes observed since the previous Physical 
Exam?”  If the answer is “No” then no other data will be collected.  For “Yes” responses, any specific 
body system(s) that changed will have the details entered on the CRF. 
All complete and brief physical examinations will be provided in subject listings.  An additional 
listing will be provided for any changes from normal to abnormal in any area that occurred at any 
post-baseline visit.  No summary tables will be provided. 
10.5.2 Neurological Examination 
A complete neurological examination will be given to subjects only at the screening visit.  The 
following 7 neurological areas will be assessed: 
• 
Cranial Nerves; Muscle Strength & Tone; Sensory Function; Coordination; Gait; Reflexes; 
and Mental Status 
Responses may be “Normal”, “Abnormal”, or “Not Done” for each of the 7 neurological areas.  If any 
response was “Abnormal” then the abnormality will be specified on the CRF.  If either all the 


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assessments or individual assessments are marked as “Not Done” then the reason not done will be 
entered on the CRF. 
Results collected will be presented in a subject listing, but not summarized in a table. 
10.6 Other Safety Analyses 
10.6.1 Sheehan Suicidality Tracking Scale (S-STS) 
The standard version of the S-STS[28] is a 16-item scale that assesses the seriousness of suicidality 
phenomena on a Likert-type scale (0 to 4) ranging from 0 = “not at all” to 4 = “extremely”.  It also 
assesses the frequency of key phenomena and the overall time spent in suicidality.  The standard 
version is available in identical clinician- and subject-rated formats.  The S-STS accommodates a 
wide range of time frames.  In clinical trials, the frequently used variants are “in the past week”, “in 
the past month”, “since the last visit”, “lifetime look back”, and “in the past day”.  
The S-STS maps to both the C-CASA, and to all of the categories in the FDA Draft Guidance 
documents of both 2010 and 2012, and in addition provides coverage for all suicidal phenomena 
presented in the draft FDA guidance.  The S-STS has been studied and validated against other 
instruments used for the assessment of suicidality in a study, and been shown provide at least equal 
sensitivity to detecting suicidal ideation and behaviors[29].  Suicidality identified after baseline will be 
recorded as an adverse event. 
The total score is the sum of all 16 questions and with values ranging from 0 to 64[29, 30].  The 
response for Question 1a will be used in the total score (not the Yes/No responses for Questions 1 or 
1b).  If Question 14 has a score ≥ 1, then Question 15 will be filled out.  The maximum score for 
“How serious was each attempt?” in Question 15 will be used in the total score.  If Question 12 has a 
score ≥ 1, then Question 16 will be filled out.  The maximum score for “How serious was each 
preparation?” in Question 16 will be used in the total score.  If Questions 15 and/or 16 do not need to 
be filled out, then those responses will be set to zero.  No other missing values will be imputed and if 
any of the first 14 questions are missing, then the total score will be set to missing. 
Two additional subscale scores will be calculated[30]: 
• 
Suicidal Ideation: 
o If Question 5 has an individual score ≤ 1, then the suicidal ideation subscale score is 
the sum of questions 2, 3, 4, and 5. 
o If Question 5 has an individual score > 1, then the suicidal ideation subscale score is 
the sum of questions 2, 3, and 4.The suicidal ideation subscale score ranges from 0 to 
13.  If any of those 4 questions are missing, then the suicidal ideation subscale score 
will be set to missing. 
• 
Suicidal Behaviors: 
o If Question 5 has an individual score > 1, then the suicidal behaviors subscale score 
is the sum of questions 6, 7a, 8, and 5. 
o If Question 5 has an individual score ≤ 1, then the suicidal behaviors subscale score 
is the sum of questions 6, 7a, and 8. 
o The suicidal behaviors subscale score ranges from 0 to 16.  If any of those 4 
questions are missing, then the suicidal behaviors subscale score will be set to 
missing. 


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The actual and change from baseline for the 16 individual item scores, suicidal ideation subscale 
score, suicidal behaviors subscale score, and total score will be summarized using descriptive 
statistics.  Analysis visits Screening, Baseline, Week 2, Week 4, and Last Post-Baseline Visit will be 
summarized in a table.  In the event the S-STS data was assessed more than once within the same day, 
and the results differ, the worst individual assessment from each questionnaire data will be used for 
this table.  Any S-STS assessments that were collected more than once within the same day will be 
documented in the SDTM Study Data Reviewer’s Guide.  All numeric data and other character results 
collected will be presented in a subject listing. 
Abnormally high post-baseline results will be additionally provided in a separate subject listing for 
each of the 16 questions with the following criteria: 
• 
Scores of 3 “Very” or 4 “Extremely” 
o Questions 2 or 13 
• 
Scores of 2 “Moderately”, 3 “Very”, or 4 “Extremely” 
o Question 1a (only if Question 1b is as “Yes”) 
o Questions 3-12 and 14 
o Any Score ≥ 2 for Questions 15 and 16 (more than one response may be present for 
each question) 
A frequency distribution table will summarize if a subject has at least one of those abnormally high 
results listed above for each post-baseline visit and overall. 
10.6.2 Body Weight 
The subject’s body weight (in kg units) will be summarized using descriptive statistics at the 
Screening, Baseline, Week 4, and Last Post-Baseline Visit analysis visits.  The actual, change from 
baseline, and percent change from baseline results will be displayed in the descriptive statistics. 
Subjects experiencing a ≥ 7% weight gain[31] during their last post-baseline visit will be flagged in a 
subject listing and summarized in a frequency distribution table. 
Individual subject body weight data will be listed by the original results and units collected; as well as 
the results in kg units.  If the data was collected in pounds, then the conversion factor will be weight 
in pounds x 0.454 and rounded off by one number after the decimal point.  This conversion for weight 
to kg units will be derived in the eDC (electronic data capture) system. 
10.6.3 Other Reportable Events 
Other Reportable Events (OREs) are defined as reports of overdose (with or without an adverse 
event), abuse, dependency, inadvertent or accidental exposure, pregnancy, and unexpected therapeutic 
benefit should be forwarded in the same timeframe as a serious adverse event.  Overdose occurs when 
a subject is dosed or has taken a dose greater than the intended or scheduled dose specified by the 
protocol. 
Details and occurrences of OREs will be collected separately in a pharmacovigilance database and 
will be presented in a subject listing, but not summarized in a table. 


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11. Other Analyses 
11.1 Protocol Deviations 
Protocol deviations are collected during the study in the clinical trial management system (CTMS).  
Prior to database lock, the protocol deviations will be reviewed for the following reasons: 
• 
Standard study terminology deviation categories assigned 
• 
Severity (major versus minor) assigned 
• 
If a subject should be excluded from the PP population 
After database lock it may be determined that additional protocol deviations occurred, but could not 
be known prior to database lock.  For example, a subject receiving study drug for the wrong treatment 
arm (i.e., a treatment arm other than the one they were randomized to).  As a result, any additional 
protocol deviations found after database lock will be included with previous protocol deviations.  
A subject listing will include the planned treatment arm, deviation category, protocol deviation, 
occurrence date with the corresponding study day, severity (major versus minor), and if the protocol 
deviation resulted in excluding a subject from the PP population.  A frequency distribution table will 
be created to summarize only major protocol deviations by the assigned deviation categories. 
12. Interim Analyses 
Section 12.8 of the protocol mentioned that a potential interim analysis was being conducted, but after 
additional consideration no formal interim analyses will actually be performed for this study. 
13. List of Planned CSR Tables, Figures, and Listings in Section 14 
The following are planned summary tables, figures, and listings (TFL’s).  TFL’s will be numbered 
according to the nomenclature used to support the CSR in Section 14.  The final TFL numbering may 
be different from the SAP.  No amendment will be made for changes in TFL numbering.  All titles, 
footnotes, and headers specified in the mock TFL shells will be displayed in the produced output 
unless otherwise specified.  Notes to programmers will not be included in the TFL’s.  There will be a 
footnote in all TFL’s that includes the SAS® version number, company creating the output, program 
name, the date/time that the output was produced, and the dataset(s) referenced for the output.  
Additional footnotes may be added to help explain/support particular data values that are not 
displayed in the mock TFL shells.  A separate mock TFL shells document will be created to support 
the appearances of these planned TFL’s. 
Number 
Population* 
TFL: Title 
14.1 Disposition, Demographic, and Baseline Data Summary Tables 
14.1.1 
All Subjects 
Table: Analysis Populations 
14.1.2.1 
Safety* 
Table: Subject Disposition 
14.1.2.2 
Efficacy* 
Table: Subject Disposition 
14.1.2.3 
PP 
Table: Subject Disposition 
14.1.3.1 
Safety* 
Table: Demographics and Baseline Characteristics 
14.1.3.2 
Efficacy* 
Table: Demographics and Baseline Characteristics 


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Number 
Population* 
TFL: Title 
14.1.3.3 
PP 
Table: Demographics and Baseline Characteristics 
14.1.4 
Safety 
Table: Medical History by System Organ Class and Preferred Term 
14.1.5 
Safety 
Table: Prior Medications by ATC Class and Preferred Term 
14.1.6 
Safety* 
Table: Questionnaire/Scale Assessments only at Screening or 
Baseline 
14.2 Efficacy Data Summary Tables and Figures 
14.2.1 Primary Efficacy Data 
14.2.1.1.1 
Efficacy* 
Table: Mean Change and Percent Change from Baseline NRS Score 
Assessing Average Pain Intensity in the Past 24 Hours 
14.2.1.1.2 
PP 
Table: Mean Change and Percent Change from Baseline NRS Score 
Assessing Average Pain Intensity in the Past 24 Hours 
14.2.1.1.3 
Efficacy 
Table: Mean Change and Percent Change from Baseline NRS Score 
Assessing Average Pain Intensity in the Past 24 Hours (by Study 
Site) 
14.2.1.1.4 
Efficacy 
Table: Mean Change and Percent Change from Baseline NRS Score 
Assessing Average Pain Intensity in the Past 24 Hours (by Age 
Groups) 
14.2.1.1.5 
Efficacy 
Table: Mean Change and Percent Change from Baseline NRS Score 
Assessing Average Pain Intensity in the Past 24 Hours (by Gender) 
14.2.1.1.6 
Efficacy 
Table: Mean Change and Percent Change from Baseline NRS Score 
Assessing Average Pain Intensity in the Past 24 Hours (by Race) 
14.2.1.1.7 
Efficacy 
Table: Mean Change and Percent Change from Baseline NRS Score 
Assessing Average Pain Intensity in the Past 24 Hours (by Ethnicity) 
14.2.1.1.8 
Efficacy* 
Table: Mean Change and Percent Change from Baseline NRS Score 
Assessing Average Pain Intensity in the Past 24 Hours (by 
Concomitant Analgesic Medications) 
14.2.1.1.9 
Efficacy 
Figure: Mean Change from Baseline NRS Score Assessing Average 
Pain Intensity in the Past 24 Hours 
14.2.1.2.1.1 
Efficacy* 
Table: Analysis of Covariance Model for Mean Change from 
Baseline NRS Score Assessing Average Pain Intensity in the Past 24 
Hours (Observed Data) 
14.2.1.2.1.2 
PP 
Table: Analysis of Covariance Model for Mean Change from 
Baseline NRS Score Assessing Average Pain Intensity in the Past 24 
Hours (Observed Data) 


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Number 
Population* 
TFL: Title 
14.2.1.2.2 
Efficacy 
Table: Analysis of Covariance Model for Mean Change from 
Baseline NRS Score Assessing Average Pain Intensity in the Past 24 
Hours (Model-Based Missing Data Imputation) 
14.2.1.2.3 
Efficacy 
Table: Analysis of Covariance Model for Mean Change from 
Baseline NRS Score Assessing Average Pain Intensity in the Past 24 
Hours (LOCF Missing Data Imputation) 
14.2.1.2.4 
Efficacy 
Table: Analysis of Covariance Model for Mean Change from 
Baseline NRS Score Assessing Average Pain Intensity in the Past 24 
Hours (BOCF Missing Data Imputation) 
14.2.1.2.5 
Efficacy 
Table: Analysis of Covariance Model for Mean Change from 
Baseline NRS Score Assessing Average Pain Intensity in the Past 24 
Hours (BOCF Rescue Medication Data Imputation) 
14.2.1.2.6 
Efficacy* 
Table: Analysis of Covariance Model for Mean Change from 
Baseline NRS Score Assessing Average Pain Intensity in the Past 24 
Hours (Concomitant Analgesic Medications) 
14.2.1.3.1 
Efficacy 
Table: Mixed Effects Repeated Measures Model for Mean Change 
from Baseline NRS Score Assessing Average Pain Intensity in the 
Past 24 Hours 
14.2.1.3.2 
PP 
Table: Mixed Effects Repeated Measures Model for Mean Change 
from Baseline NRS Score Assessing Average Pain Intensity in the 
Past 24 Hours 
14.2.1.4.1 
Efficacy* 
Table: Responder Status Endpoints Based on Mean NRS Score 
Assessing Average Pain Intensity in the Past 24 Hours 
14.2.1.4.2 
Efficacy 
Figure: Percentage-Reduction from Baseline at Week 4 for Mean 
NRS Score Assessing Average Pain Intensity in the Past 24 Hours 
14.2.1.5.1 
Efficacy 
Table: Number of Days to Responder Status Based on Mean NRS 
Score Assessing Average Pain Intensity in the Past 24 Hours 
14.2.1.5.2 
Efficacy 
Figure: Probability of Number of Days to Responder Status Based on 
Mean NRS Score Assessing Average Pain Intensity in the Past 24 
Hours 
14.2.1.6.1 
Efficacy 
Table: Number of Days to Sustained Pain Reduction Based on Mean 
NRS Score Assessing Average Pain Intensity in the Past 24 Hours 
14.2.1.6.2 
Efficacy 
Figure: Probability of Number of Days to Sustained Pain Reduction 
Based on Mean NRS Score Assessing Average Pain Intensity in the 
Past 24 Hours 
14.2.1.7.1 
Efficacy 
Figure: Boxplots of Weekly Mean Change from Baseline NRS Score 
Assessing Average Pain Intensity in the Past 24 Hours and Average 
Rescue Medication Taken (g/day) 


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Number 
Population* 
TFL: Title 
14.2.1.7.2 
Efficacy 
Figure: Scatter Plots of Weekly Mean Change from Baseline NRS 
Score Assessing Average Pain Intensity in the Past 24 Hours and 
Average Rescue Medication Taken (g/day) 
14.2.2 – 14.2.10 Secondary Efficacy Data 
14.2.2.1 
Efficacy* 
Table: Mean Change and Percent Change from Baseline NRS Score 
Assessing Worst Pain Intensity in the Past 24 Hours 
14.2.2.2 
Efficacy* 
Table: Analysis of Covariance Model for Mean Change from 
Baseline NRS Score Assessing Worst Pain Intensity in the Past 24 
Hours 
14.2.2.3 
Efficacy 
Table: Mixed Effects Repeated Measures Model for Mean Change 
from Baseline NRS Score Assessing Worst Pain Intensity in the Past 
24 Hours 
14.2.2.4 
Efficacy 
Figure: Mean Change from Baseline NRS Score Assessing Worst 
Pain Intensity in the Past 24 Hours 
14.2.3.1 
Efficacy* 
Table: Mean Change and Percent Change from Baseline NRS Score 
Assessing Average Pain upon Walking Intensity in the Past 24 Hours 
14.2.3.2 
Efficacy* 
Table: Analysis of Covariance Model for Mean Change from 
Baseline NRS Score Assessing Average Pain upon Walking Intensity 
in the Past 24 Hours 
14.2.3.3 
Efficacy 
Table: Mixed Effects Repeated Measures Model for Mean Change 
from Baseline NRS Score Assessing Average Pain upon Walking 
Intensity in the Past 24 Hours 
14.2.3.4 
Efficacy 
Figure: Mean Change from Baseline NRS Score Assessing Average 
Pain upon Walking Intensity in the Past 24 Hours 
14.2.4.1 
Efficacy* 
Table: Descriptive Statistics for Patient Global Impression of Change 
14.2.4.2 
Efficacy 
Table: Frequency Distributions for Patient Global Impression of 
Change 
14.2.5.1 
Efficacy 
Table: Change from Baseline Short-Form McGill Pain Questionnaire 
14.2.5.2 
Efficacy 
Table: Analysis of Covariance Model for Change from Baseline 
Short-Form McGill Pain Questionnaire 
14.2.6.1 
Efficacy 
Table: Change from Baseline Norfolk Quality of Life Questionnaire - 
Diabetic Neuropathy 
14.2.6.2 
Efficacy 
Table: Analysis of Covariance Model for Norfolk Quality of Life 
Questionnaire - Diabetic Neuropathy 
14.2.7.1 
Efficacy 
Table: Change from Baseline Insomnia Severity Index 
14.2.7.2 
Efficacy 
Table: Frequency Distributions for Insomnia Severity Index 


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Number 
Population* 
TFL: Title 
14.2.7.3 
Efficacy 
Table: Shifts from Baseline Insomnia Severity Index 
14.2.7.4 
Efficacy 
Table: Analysis of Covariance Model for Insomnia Severity Index 
14.2.8.1 
Efficacy* 
Table: Change from Baseline Hospital Anxiety and Depression Scale 
14.2.8.2 
Efficacy* 
Table: Frequency Distributions for Hospital Anxiety and Depression 
Scale 
14.2.8.3 
Efficacy 
Table: Shifts from Baseline Hospital Anxiety and Depression Scale 
14.2.8.4 
Efficacy* 
Table: Analysis of Covariance Model for Hospital Anxiety and 
Depression Scale 
14.2.9.1 
Efficacy 
Table: Mean Change and Percent Change from Baseline Daily Sleep 
Interference Scale in the Past 24 Hours 
14.2.9.2 
Efficacy 
Table: Analysis of Covariance Model for Mean Change from 
Baseline Daily Sleep Interference Scale in the Past 24 Hours 
14.2.9.3 
Efficacy 
Table: Mixed Effects Repeated Measures Model for Mean Change 
from Baseline Daily Sleep Interference Scale in the Past 24 Hours 
14.2.9.4 
Efficacy 
Figure: Mean Change from Baseline Daily Sleep Interference Scale 
in the Past 24 Hours 
14.2.10.1 
Efficacy 
Table: Change from Baseline Brief Pain Inventory for Diabetic 
Peripheral Neuropathy 
14.2.10.2 
Efficacy 
Table: Analysis of Covariance Model for Brief Pain Inventory for 
Diabetic Peripheral Neuropathy 
14.3 Safety and Other Data Summary Tables, Figures, and Listings 
14.3.1 Adverse Event Tables 
14.3.1.1 
Safety* 
Table: Overall Summary of Treatment-Emergent Adverse Events 
14.3.1.2 
Safety* 
Table: Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
14.3.1.3 
Safety 
Table: Treatment-Emergent Adverse Events by Preferred Term 
14.3.1.4 
Safety 
Table: Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
14.3.1.5 
Safety 
Table: Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Maximum Severity 
14.3.1.6 
Safety 
Table: Serious Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
14.3.1.7 
Safety 
Table: Treatment-Emergent Adverse Events Leading to 
Discontinuation by System Organ Class and Preferred Term 


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Number 
Population* 
TFL: Title 
14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events 
14.3.2.1 
Safety* 
Listing: Serious Treatment-Emergent Adverse Events and Deaths 
14.3.2.2 
Safety 
Listing: Serious Adverse Events and Deaths Not Considered 
Treatment-Emergent 
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events 
N/A 
N/A 
Provided by Clinical, if applicable 
14.3.4 Abnormal Laboratory Value Listings 
14.3.4 
Safety* 
Listing: Abnormal Clinical Laboratory Results 
14.3.5 Safety and Other Data Tables, Figures, and Listings 
14.3.5.1.1.1 
Safety 
Table: Change from Baseline Clinical Laboratory Results for 
Hematology 
14.3.5.1.1.2 
Safety 
Table: Shifts from Baseline Clinical Laboratory Results for 
Hematology 
14.3.5.1.2.1 
Safety 
Table: Change from Baseline Clinical Laboratory Results for Serum 
Chemistry (Liver Function Tests) 
14.3.5.1.2.2 
Safety 
Table: Change from Baseline Clinical Laboratory Results for Serum 
Chemistry (Non-Liver Function Tests) 
14.3.5.1.2.3 
Safety 
Table: Shifts from Baseline Clinical Laboratory Results for Serum 
Chemistry (Liver Function Tests) 
14.3.5.1.2.4 
Safety 
Table: Shifts from Baseline Clinical Laboratory Results for Serum 
Chemistry (Non-Liver Function Tests) 
14.3.5.1.3.1 
Safety 
Table: Change from Baseline Clinical Laboratory Results for 
Urinalysis (Numeric Data) 
14.3.5.1.3.2 
Safety 
Table: Frequency Distributions for Clinical Laboratory Results for 
Urinalysis (Categorical Data) 
14.3.5.1.3.3 
Safety 
Table: Shifts from Baseline Clinical Laboratory Results for 
Urinalysis (Numeric Data) 
14.3.5.1.3.4 
Safety 
Table: Shifts from Baseline Clinical Laboratory Results for 
Urinalysis (Categorical Data) 
14.3.5.1.4 
Safety* 
Table: Potentially Clinically Significant Clinical Laboratory Results 
14.3.5.1.5 
Safety* 
Figure: eDISH Plots of Clinical Laboratory Results versus Total 
Bilirubin 
14.3.5.2 
Safety 
Table: Change from Baseline Vital Sign Measurements 
14.3.5.3.1 
Safety 
Table: Change from Baseline Electrocardiogram Parameter Results 


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Number 
Population* 
TFL: Title 
14.3.5.3.2 
Safety 
Table: Frequency Distributions for Electrocardiogram Interpretations 
14.3.5.3.3 
Safety 
Table: Shifts from Baseline Electrocardiogram Interpretations 
14.3.5.3.4 
Safety* 
Table: Frequency Distributions for Abnormally High QTcF Interval 
Results 
14.3.5.4 
Safety 
Table: Study Drug Treatment Compliance and Exposure 
14.3.5.5 
Safety 
Table: Rescue Medication 
14.3.5.6.1 
Safety 
Table: Concomitant Medications by ATC Class and Preferred Term 
14.3.5.6.2 
Safety 
Table: Concomitant Analgesic Medications by ATC Class and 
Preferred Term 
14.3.5.7 
Safety 
Listing: Change to Abnormal Post-Baseline Physical Examinations 
14.3.5.8.1 
Safety 
Table: Change from Baseline Sheehan Suicidality Tracking Scale 
14.3.5.8.2 
Safety 
Table: Frequency Distributions for Abnormal Post-Baseline Sheehan 
Suicidality Tracking Scale Results 
14.3.5.8.3 
Safety 
Listing: Abnormal Post-Baseline Sheehan Suicidality Tracking Scale 
Results 
14.3.5.9 
Safety 
Table: Body Weight (kg) 
14.3.5.10 
Safety 
Table: Major Protocol Deviations 
* Denotes a table that will be provided in the topline analyses after database lock. 
14. List of Planned CSR Appendices in Section 16.2 
The following are planned appendix listings used to support the CSR in Section 16.2.  All subjects 
will be provided regardless of their randomized/treated status.  The same details mentioned in the 
planned TFL’s in Section 13 will be applied to the planned appendices. 
Number 
Appendix Title 
16.2.1 Subject Discontinuations/Completions 
16.2.1.1 
Subject Disposition 
16.2.1.2 
Screen Failures and Subjects Not Randomized 
16.2.2 Protocol Deviations 
16.2.2.1 
Protocol Deviations 
16.2.2.2 
Subjects Dosed Incorrectly with Study Drug 
16.2.3 Subject Populations and Excluded Reasons 
16.2.3 
Analysis Populations 


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Number 
Appendix Title 
16.2.4 Demographic Data and Other Baseline Characteristics 
16.2.4.1 
Demographics and Baseline Characteristics 
16.2.4.2 
Inclusion and Exclusion Criteria 
16.2.4.3 
Medical History 
16.2.4.4 
Masquerading Disorders Tool (MDT) 
16.2.4.5 
Michigan Neuropathy Screening Instrument 
16.2.4.6 
Bedside Sensory Testing Kit 
16.2.4.7 
2010 American College of Rheumatology Fibromyalgia Criteria 
16.2.5 Compliance and Drug Concentration Data 
16.2.5.1 
Study Drug Accountability 
16.2.5.2 
Rescue Medication Accountability 
16.2.6 Individual Efficacy Response Data 
16.2.6.1 
Numeric Rating Scale of Pain Intensity in the Past 24 Hours 
16.2.6.2 
Patient Global Impression of Change (PGI-C) 
16.2.6.3 
Short-Form McGill Pain Questionnaire (SF-MPQ-2) 
16.2.6.4 
Norfolk Quality of Life Questionnaire - Diabetic Neuropathy (QOL-DN) 
16.2.6.5 
Insomnia Severity Index (ISI) 
16.2.6.6 
Hospital Anxiety and Depression Scale (HADS) 
16.2.6.7 
Daily Sleep Interference Scale (DSIS) 
16.2.6.8 
Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) 
16.2.6.9 
Number of Days to Responder Status and Sustained Pain Reduction 
16.2.7 Adverse Events Data 
16.2.7.1 
Adverse Events 
16.2.7.2 
Treatment-Emergent Adverse Events Leading to Study Discontinuation 
16.2.7.3 
Adverse Events Not Considered Treatment-Emergent 
16.2.7.4 
Adverse Events Leading to Study Discontinuation that are Not Considered 
Treatment-Emergent 
16.2.8 Individual Laboratory Safety Data 
16.2.8.1 
Clinical Laboratory Results for Hematology 
16.2.8.2 
Clinical Laboratory Results for Serum Chemistry 


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Number 
Appendix Title 
16.2.8.3 
Clinical Laboratory Results for Urinalysis 
16.2.8.4 
Clinical Laboratory Results for Urine Pregnancy Tests 
16.2.8.5 
Clinical Laboratory Results for Serology 
16.2.8.6 
Clinical Laboratory Results for Urine Drug Screens 
16.2.8.7 
Clinical Laboratory Results for Alcohol Breathalyzer Screens 
16.2.9 Other Safety and Clinical Assessment Data 
16.2.9.1.1 
Prior and Concomitant Medications 
16.2.9.1.2 
Concomitant Analgesic Medications 
16.2.9.2 
Vital Sign Measurements 
16.2.9.3 
12-Lead Electrocardiogram (ECG) 
16.2.9.4.1 
Physical Exanimations 
16.2.9.4.2 
Neurological Exanimation 
16.2.9.5 
Sheehan Suicidality Tracking Scale (S-STS) 
16.2.9.6 
Body Weight 
16.2.9.7 
Other Reportable Events (OREs) 
15. References 
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Principles for Clinical Trials. Department of Health and Human Services: Food and Drug 
Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, pages 49583-
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Guidelines/Efficacy/E9/Step4/E9_Guideline.pdf 
[2] American Statistical Association. Ethical Guidelines for Statistical Practice. Prepared by the 
Committee on Professional Ethics, 07 August 1999. 
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[3] Royal Statistical Society. The Royal Statistical Society: Code of Conduct, August 1993. 
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[4] Rice ASC, Dworkin RH, McCarthy TD, et al. EMA401, an orally administered highly selective 
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[5] Fleming TR, Harrington DP, O'Brien PC. Designs for group sequential tests. Control Clin Trials. 
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[6] Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful 
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[7] Herman WH, Pop-Busul 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. https://www.ncbi.nlm.nih.gov/pubmed/22417277 
[8] Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary 
diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 
(Hoboken). 2010;62:600-10. https://www.ncbi.nlm.nih.gov/pubmed/20461783 
[9] Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in 
chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001 
Nov;94(2):149-58. https://www.ncbi.nlm.nih.gov/pubmed/11690728 
[10] Guidance for Industry. Analgesic Indications: Developing Drug and Biological Products. U.S. 
Department of Health and Human Services, Food and Drug Administration, Center of Drug 
Evaluation and Research (CDER). 2014 Feb. https://www.fda.gov/downloads/drugs/ 
guidancecomplianceregulatoryinformation/guidances/ucm384691.pdf 
[11] Sterne, JAC, White IR, Carlin JB. Multiple imputation for missing data in epidemiological and 
clinical research: potential and pitfalls. BMJ. 2009; 338: b2393. 
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[12] Dworkin RH, Turk DC, Revicki DA, et al. Development and initial validation of an expanded and 
revised version of the Short-Form McGill Pain Questionnaire (SF-MPQ-2). Pain. 2009;144:35-
42. https://www.ncbi.nlm.nih.gov/pubmed/19356853 
[13] Lovejoy TI, Turk DC, Morasco BJ. Evaluation of the Psychometric Properties of the Revised 
Short-Form McGill Pain Questionnaire (SF-MPQ-2). J Pain. 2012 Dec; 13(12): 1250–1257. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513374/ 
[14] Vinik EJ, Hayes RP, Oglesby A, et al. The development and validation of the Norfolk QOL-DN, 
a new measure of patients’ perception of the effects of diabetes and diabetic neuropathy. Diabetes 
Technol Therap. 2005;7:497-508. https://www.ncbi.nlm.nih.gov/pubmed/15929681 
[15] Adams D, Gonzalez‑Duarte A, O’Riordan WD, et al. Patisiran, an RNAi Therapeutic, for 
Hereditary Transthyretin Amyloidosis. The New England Journal of Medicine. 2018;379:11-21.  
[16] Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen Treatment for Patients with 
Hereditary Transthyretin Amyloidosis. The New England Journal of Medicine. 2018;379:22-31. 
[17] Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome 
measure for insomnia research. Sleep Med. 2001;2:297-307. 
https://www.ncbi.nlm.nih.gov/pubmed/11438246 
[18] Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: Psychometric 
Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011 May 1; 
34(5): 601–608. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079939/ 
[19] Snaith RP. The Hospital Anxiety and Depression Scale. Health Qual Life Outcomes. 2003; 1: 29. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC183845/ 
[20] Jörngarden A, Wettergen L, von Essen L. Measuring health-related quality of life in adolescents 
and young adults: Swedish normative data for the SF-36 and the HADS, and the influence of age, 


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gender, and method of administration. Health Qual Life Outcomes 2006; 4: 91. 
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[21] Snaith RP, Zigmond AS. HADS: Hospital Anxiety and Depression Scale. Windsor, NFER 
Nelson. 1994. 
[22] Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 
1983;67:361-70. 
[23] Vernon MK, Brandenberg NA, Alvir JMJ, Griesing T, Revicki DA. Reliability, validity and 
responsiveness of the daily sleep interference scale among diabetic peripheral neuropathy and 
postherpetic neuralgia patients. J Pain Symptom Mgt. 2008;36:54-68. 
https://www.ncbi.nlm.nih.gov/pubmed/18411009 
[24] Zelman DC, Gore M, Dukes E, et al. Validation of a modified version of the Brief Pain Inventory 
for painful diabetic peripheral neuropathy. J Pain Symptom Manage. 2005;29:401-10. 
https://www.ncbi.nlm.nih.gov/pubmed/15857744 
[25] Cleeland C. The Brief Pain Inventory User Guide. 2009. 
[26] Watkins PB, Desai M, Berkowitz SD, et al. Evaluation of drug-induced serious hepatotoxicity 
(eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban 
after total hip or knee replacement surgery. Drug Saf. 2011 Mar 1;34(3):243-52. 
https://www.ncbi.nlm.nih.gov/pubmed/21332248 
[27] Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. U.S. 
Department of Health and Human Services, Food and Drug Administration, Center of Drug 
Evaluation and Research (CDER), Center of Biologics Evaluation and Research (CBER). 2009 
Jul. https://www.fda.gov/downloads/guidances/UCM174090.pdf 
[28] Sheehan DV, Alphs LD, Lian M, et al. Comparative validation of the S-STS, the ISST-Plus, and 
the C-SSRS for assessing the Suicidal Thinking and Behavior FDA 2012 Suicidality Categories. 
Innov Clin Neurosci. 2014;11(9-10):32-46. https://www.ncbi.nlm.nih.gov/pubmed/25520887 
[29] Sheehan DV, Giddens JM, Sheehan IS. Status update on the Sheehan Suicidality Tracking Scale 
(S-STS) 2014. Innov Clin Neurosci. 2014;11:93–140. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267803/ 
[30] Coric V, Stock EG, Pultz J, Marcus R. Sheehan Suicidality Tracking Scale (Sheehan-STS): 
Preliminary Results from a Multicenter Clinical Trial in Generalized Anxiety Disorder. 
Psychiatry (Edgmont). 2009 Jan; 6(1): 26–31. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719443/ 
[31] Pfizer. Review of Clinical Data. Generic Drug Name: Sertraline. NDA: 19-839, 20-990. 2003 Sep 
3. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources 
/UCM411352.pdf 
 


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Appendix I: Schedule of Procedures 
 
Study Period 
Screening 
Baseline 
Treatment 
Follow-Up 
Study Week 
(Day) 
1 to 4 weeksa 
(-28 to -1) 
Week 0 
(1)b 
Week 2 
(14 ± 2) 
Week 4c 
(28 ± 2) 
Week 5 
(35 ± 2) 
Study Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Assessment 
 
 
 
 
 
Informed consent prior to any study procedure 
X 
 
 
 
 
Assess inclusion/exclusion criteria 
X 
X 
 
 
 
Instructions on reporting pain 
X 
X 
X 
 
 
Education on appropriate expectations around participation in a clinical studyd 
X 
X 
X 
 
 
Michigan Neuropathy Screening Instrument 
X 
 
 
 
 
Masquerading Disorders Tool 
X 
 
 
 
 
Bedside Sensory Testing Kit 
 
X 
 
 
 
American College of Rheumatology Fibromyalgia Criteria 
X 
 
 
 
 
Demographic characteristics (age, sex, race, and ethnicity) 
X 
 
 
 
 
Medical history 
X 
Update 
 
 
 
Height 
X 
 
 
 
 
Body weight 
X 
 
 
X 
 
Vital sign measurements (sitting)e 
X 
X 
X 
X 
 
Physical examinationf 
X 
X 
 
X 
 
5-minute electrocardiogram after 5 minutes in supine position 
X 
X 
 
X 
 
Urine pregnancy test for females of childbearing potential 
X 
X 
 
X 
 
HIV and hepatitis tests g 
X 
 
 
 
 
Drug and alcohol screenh 
X 
X 
 
X 
 
Obtain samples for serum chemistry, hematology, and urinalysisi 
X 
X 
Xi 
X 
Xi 
Discontinue all but 1 concomitant analgesic medication 
Xj 
 
 
 
 
Record average pain intensity over past 24 hoursk 
X 
 
 
 
 
Dispense handheld electronic diary 
X 
 
 
 
 


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Study Period 
Screening 
Baseline 
Treatment 
Follow-Up 
Study Week 
(Day) 
1 to 4 weeksa 
(-28 to -1) 
Week 0 
(1)b 
Week 2 
(14 ± 2) 
Week 4c 
(28 ± 2) 
Week 5 
(35 ± 2) 
Study Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Return handheld electronic diary 
 
 
 
X 
 
Dispense rescue medication (acetaminophen)l 
X 
X 
X 
 
 
Return rescue medication and perform accountabilitym 
 
X 
X 
X 
 
Record average pain intensity, worst pain intensity, pain upon walking,k and 
rescue medication use over past 24 hours at bedtime for each day 
X 
X 
X 
 
 
Record Daily Sleep Interference Scale (DSIS) each morning 
X 
X 
X 
 
 
Phone call to reinforce diary instructionsn 
X 
X 
X 
X 
 
Assess pain and diary compliance  
 
X 
X 
X 
 
Randomize eligible subjects 
 
X 
 
 
 
Dispense investigational product  
 
X 
X 
 
 
Return investigational product and assess compliancem 
 
 
X 
X 
 
Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) 
 
X 
 
X 
 
Short-Form McGill Pain Questionnaire (SF-MPQ-2) 
 
X 
 
X 
 
Norfolk Quality of Life Questionnaire – Diabetic Neuropathy (QOL-DN) 
 
X 
 
X 
 
Insomnia Severity Index  
 
X 
X 
X 
 
Hospital Anxiety and Depression Scale (HADS) 
X 
X 
 
X 
 
Patient Global Impression of Change (PGI-C) scale 
 
 
X 
X 
 
Sheehan Suicidality Tracking Scale (S-STS) 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
Adverse eventso 
X 
X 
X 
X 
X 
a) Subjects will discontinue all but 1 allowed concomitant pharmacologic analgesic medication. Duration of the period will depend upon the analgesic 
treatment(s) being discontinued, not to exceed 4 weeks. Subjects taking no more than 1 allowed concomitant analgesic medication at Visit 1 may directly 
begin Week -1 of the Screening Period. 
b) Visit window for Baseline Visit is 6 to 10 days after start of Week -1. 
c) Subjects who prematurely discontinue randomized treatment will have Week 4 procedures performed. 


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d) Review of these educational materials may be repeated for some or all subjects or depending on findings of an ongoing blinded data review (e.g., if pain 
score variability is increased on a subject or site level). 
e) Vital signs will include blood pressure and pulse after at least 5 minutes of being seated, and prior to blood sample collection. 
f) 
A complete physical examination will be performed at Visit 1 and a brief physical examination will be performed at Visits 2 and 4. The physical 
examination at Visit 1 will include a comprehensive neurological examination.  
g) If the screening hepatitis C antibody test result is reactive, a nucleic acid test for hepatitis C virus-ribonucleic acid (HCV RNA) should be performed for 
confirmation of chronic infection. If the screening HIV test is positive, a confirmatory Western Blot test should be performed to confirm HIV status. 
h) Urine drug screen and alcohol breathalyzer.  
i) 
Samples will be obtained following an 8-hour fast. The Week 2 and Week 5 samples will only be analyzed for liver function tests and no fasting will be 
required. HbA1c will be collected at Screening (Visit 1) only. 
j) 
Analgesic medications discontinued during the Screening Period cannot be restarted until after the Week 4 visit. 
k) Numerical Rating Scale of pain intensity (0 = no pain to 10 = worst pain imaginable) will be completed once daily at bedtime. At Visit 1, average pain 
intensity over the past 24 hours will be recorded onto device by site personnel.  
l) 
Subjects will be instructed to take no more than 2 g/daily (one to two 500-mg caplets every 4 to 6 hours as needed) for pain. 
m) Instruct study participants to bring all used and unused investigational product and rescue medication to each visit for compliance monitoring. 
n) Phone call will be made weekly through during weeks with no study visits, to reinforce diary completion. 
o) Weekly phone calls will be made during weeks with no study visits, to assess adverse events.