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

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.

Inclusion Criteria:

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 numeric rating scale (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 of <40 kg/m^2
10. Calculated creatinine clearance of ≥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.

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.

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 investigators, 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.
6. Impaired hepatic function.
7. Known history of significant cardiovascular condition.
8. History of Huntington's disease, Parkinson's disease, Alzheimer's disease, Multiple Sclerosis, or a history of seizures, epilepsy, or strokes.
9. HIV infection, hepatitis, or other ongoing infectious disease that the investigator considers clinically significant.
10. 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 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.
11. 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.
12. Amputations of lower extremities (toe amputation is allowed).
13. 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.
14. 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 Questions 1a (only if 1b is coded YES), 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 14 based on the Sheehan - Suicidality Tracking Scale at Visit 1 or Visit 2.

Waivers to the exclusion criteria will NOT be allowed.

Treatment arms, dose levels, and randomization algorithm are masked.