Diabetic Peripheral Neuropathy
Conditions
Keywords
Type 2 Diabetes, Neuropathic Pain, Peripheral Nervous System
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.
Interventions
DRUGNYX-2925
NYX-2925 is a novel small molecule that modulates the N-methyl-D-aspartate receptor (NMDAR).
DRUGPlacebo
Matching Placebo capsules.
Sponsors
Syneos Health
Aptinyx
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Treatment arms, dose levels, and randomization algorithm are masked.
Intervention model description
Subjects will be randomized to receive placebo or NYX-2925.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Numeric Rating Scale (NRS) Average Pain Intensity | From baseline (average of -7 to -1) to Week 4 (average of Days 22 through 28) | Change in the NRS score assessing average pain intensity in the past 24 hours; 0=no pain, 10=worst pain imaginable |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Numeric Rating Scale (NRS) Average Pain Intensity in Patients Who Did Not Use a Concomitant Medication at Baseline | baseline to week 4 | Change in the NRS score assessing average pain intensity in the past 24 hours for patients who did not use a concomitant medication at baseline; 0=no pain, 10=worst pain imaginable |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NYX-2925 200 mg QD NYX-2925 200 mg PO QD | 75 |
| NYX-2025 50 mg QD NYX-2925 50 mg PO QD | 77 |
| NYX-2925 10 mg QD NYX-2925 10 mg PO QD | 77 |
| Placebo QD Placebo PO QD | 72 |
| Total | 301 |
Baseline characteristics
| Characteristic | NYX-2925 200 mg QD | NYX-2025 50 mg QD | NYX-2925 10 mg QD | Placebo QD | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 20 Participants | 17 Participants | 13 Participants | 68 Participants |
| Age, Categorical Between 18 and 65 years | 57 Participants | 57 Participants | 60 Participants | 59 Participants | 233 Participants |
| DPN Disease History (years) | 3.97 years STANDARD_DEVIATION 2.723 | 3.46 years STANDARD_DEVIATION 2.632 | 3.88 years STANDARD_DEVIATION 2.528 | 3.91 years STANDARD_DEVIATION 2.373 | 3.8 years STANDARD_DEVIATION 2.565 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 30 Participants | 29 Participants | 27 Participants | 28 Participants | 114 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 47 Participants | 50 Participants | 44 Participants | 186 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 2 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants | 20 Participants | 18 Participants | 15 Participants | 70 Participants |
| Race (NIH/OMB) More than one race | NA Participants | NA Participants | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 55 Participants | 53 Participants | 55 Participants | 52 Participants | 215 Participants |
| Region of Enrollment United States | 75 participants | 77 participants | 77 participants | 72 participants | 301 participants |
| Sex: Female, Male Female | 31 Participants | 37 Participants | 32 Participants | 37 Participants | 137 Participants |
| Sex: Female, Male Male | 44 Participants | 40 Participants | 45 Participants | 35 Participants | 164 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 77 | 0 / 77 | 0 / 72 |
| other Total, other adverse events | 3 / 75 | 4 / 77 | 12 / 77 | 4 / 72 |
| serious Total, serious adverse events | 0 / 75 | 0 / 77 | 0 / 77 | 1 / 72 |
Outcome results
Primary
Numeric Rating Scale (NRS) Average Pain Intensity
Change in the NRS score assessing average pain intensity in the past 24 hours; 0=no pain, 10=worst pain imaginable
Time frame: From baseline (average of -7 to -1) to Week 4 (average of Days 22 through 28)
Population: All subjects who were included in the safety population, were randomized, and had at least 4 post-baseline daily average pain scores are included in the efficacy population. \[mixed effects repeated measures (MMRM)\]
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NYX-2925 200 mg QD | Numeric Rating Scale (NRS) Average Pain Intensity | -1.50 score on a scale | Standard Error 0.19 |
| NYX-2025 50 mg QD | Numeric Rating Scale (NRS) Average Pain Intensity | -1.61 score on a scale | Standard Error 0.19 |
| NYX-2925 10 mg QD | Numeric Rating Scale (NRS) Average Pain Intensity | -1.15 score on a scale | Standard Error 0.19 |
| Placebo QD | Numeric Rating Scale (NRS) Average Pain Intensity | -1.23 score on a scale | Standard Error 0.19 |
Secondary
Numeric Rating Scale (NRS) Average Pain Intensity in Patients Who Did Not Use a Concomitant Medication at Baseline
Change in the NRS score assessing average pain intensity in the past 24 hours for patients who did not use a concomitant medication at baseline; 0=no pain, 10=worst pain imaginable
Time frame: baseline to week 4
Population: All subjects who were included in the safety population, were randomized, and had at least 4 post-baseline daily average pain scores are included in the efficacy population. \[mixed effects repeated measures (MMRM)\]
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NYX-2925 200 mg QD | Numeric Rating Scale (NRS) Average Pain Intensity in Patients Who Did Not Use a Concomitant Medication at Baseline | -1.55 score on a scale | Standard Error 0.28 |
| NYX-2025 50 mg QD | Numeric Rating Scale (NRS) Average Pain Intensity in Patients Who Did Not Use a Concomitant Medication at Baseline | -1.62 score on a scale | Standard Error 0.26 |
| NYX-2925 10 mg QD | Numeric Rating Scale (NRS) Average Pain Intensity in Patients Who Did Not Use a Concomitant Medication at Baseline | -1.42 score on a scale | Standard Error 0.29 |
| Placebo QD | Numeric Rating Scale (NRS) Average Pain Intensity in Patients Who Did Not Use a Concomitant Medication at Baseline | -1.03 score on a scale | Standard Error 0.29 |
Post Hoc
Numeric Rating Scale (NRS) Average Pain Intensity in Subjects With DPN >= 4 Years
Change in the NRS score assessing average pain intensity in the past 24 hours in patients with DPN \>=4 years; 0=no pain, 10=worst pain imaginable
Time frame: baseline to week 4
Population: All subjects who were included in the safety population, were randomized, and had at least 4 post-baseline daily average pain scores are included in the efficacy population. \[mixed effects repeated measures (MMRM)\]
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NYX-2925 200 mg QD | Numeric Rating Scale (NRS) Average Pain Intensity in Subjects With DPN >= 4 Years | -1.19 score on a scale | Standard Error 0.27 |
| NYX-2025 50 mg QD | Numeric Rating Scale (NRS) Average Pain Intensity in Subjects With DPN >= 4 Years | -1.93 score on a scale | Standard Error 0.31 |
| NYX-2925 10 mg QD | Numeric Rating Scale (NRS) Average Pain Intensity in Subjects With DPN >= 4 Years | -1.00 score on a scale | Standard Error 0.29 |
| Placebo QD | Numeric Rating Scale (NRS) Average Pain Intensity in Subjects With DPN >= 4 Years | -0.72 score on a scale | Standard Error 0.27 |
p-value: 0.004Mixed Models Analysis