Novel Soluble Epoxide Hydrolase Inhibitor for Neuropathic Pain in Patients with Spinal Cord Injury

The goal of this clinical trial is to evaluate safety and tolerability of multiple oral doses of EC5026 in male and female patients with neuropathic pain due to spinal cord injury. The main question it aims to answer is whether EC5026 is safe and well tolerated in SCI patients with neuropathic pain. In addition, this trial will also study the effects of EC5026 on pain.

Researchers will compare EC5026 to placebo.

Participants will be asked to:

* Take EC5026 or placebo in a masked fashion, once daily, for 14 consecutive days.
* Undergo physical exams, vital signs assessments, ECGs, and blood draws
* Complete assessments of pain, sleep, functional status, and perception of change

EC5026 has been shown to be effective in preclinical pain models of pain, including inflammatory and neuropathic pain subtypes. Three Phase 1 studies of EC5026 have been conducted in healthy volunteers; a Phase 1a Single Ascending Dose (SAD) study, a Phase 1a Fed-Fasted study, and a Phase 1b Multiple Ascending Dose (MAD) study. The Phase 1b MAD study evaluated the safety, tolerability, and PK of 2 sequential ascending dose regimens of oral EC5026, administered once daily for 7 consecutive days, in healthy volunteers. The present study will evaluate the safety and tolerability, as well as target engagement and pharmacodynamics, of EC5026 administered as multiple doses in subjects with neuropathic pain due to spinal cord injury.

Eligibility Criteria:
Inclusion Criteria:

Each subject must meet all of the following criteria to be enrolled in this study:

1. Male and female United States Veterans 18 and older.
2. Subjects must be willing to provide written informed consent to participate in the study.
3. Subjects must be able to provide own transportation to study site every day for the duration of the study.
4. Subjects must have a complete or incomplete C2-T12 SCI of at least 12 months duration, with below-level neuropathic pain identified by the International Spinal Cord Injury Pain (ISCIP) classification criteria.
5. Subjects must have completed a minimum of 6 of the 7 daily assessments for average and worst daily pain prior to final screening, using an 11-point numerical rating scale (NRS) for average daily pain intensity, and the arithmetic average daily SCI neuropathic pain score must be ≥4 and ≤9, with a standard deviation less than or equal to 1.2.

   Daily pain assessment screenings will be done over the phone with the study coordinator after informed consent is obtained.
6. Subjects must be in overall stable condition, as determined by pre-study medical history, physical examination, clinical laboratory tests, and 12-lead ECG measurements.
7. Subjects must have normal or not clinically significant clinical laboratory test results, as determined by the study investigator, including coagulation panel, blood cell counts, comprehensive metabolic panel analytes, and creatinine clearance (60 cm3/min or greater). Clinical laboratory tests results that are consistent with known, stable comorbidities will be allowed as long as the comorbidities do not represent an exclusion criteria per se.
8. Subjects must have a negative screening for HIV, Hepatitis C, and Hepatitis B within 30 days of randomization.
9. Subjects must have a negative urinary drug screen (UDS) for illicit drugs (marihuana/THC are allowed) and serum ethanol level \<80 mg/dL.
10. Male subjects who are not surgically sterile (vasectomized) and their female sexual partners must agree to use contraception during the study period and for 2 months afterward.
11. Male subjects must not donate sperm during the study and for 12 months after receiving the last dose of study drug.
12. Female subjects must be non-pregnant, non-lactating, and either postmenopausal for at least 1 year, or surgically sterile (bilateral tubal ligation ('clipping or tying tubes' or hysterectomy) for at least 3 months, or they must agree to use a highly effective contraception method (less than 1 pregnancy per 100 people using the method for one year), from 28 days and/or their last confirmed menstrual period prior to study enrollment (whichever is longer) until 2 months after clinic discharge.

Exclusion Criteria:

Subjects meeting any of the following criteria will be excluded from the study:

1. Ventilator-dependent subjects, with the exception of nocturnal use of CPAP or BiPAP.
2. Subjects with pain that is not present every day (chronic) or where the pain description does not have a classic neuropathic phenotype.
3. Subjects with other chronic neuropathic pain conditions, including painful diabetic neuropathy, HIV-associated neuropathic pain, chemotherapy or ethanol-associated neuropathy.
4. Subjects with other pain syndromes that may confound assessment or self-evaluation of the SCI neuropathic pain.
5. Subjects with only negative symptoms, defined as numbness without clear evidence of spontaneous pain, either constant or episodic.
6. Subjects using opioid medications on a regular basis or pro re nata (PRN). Non-opioid pain medications will be allowed if at a fixed stable dose for more than 1 month prior to Screening with no anticipation of the dose changing during the study, and if they do not interfere with the subject's ability to rate pain as per Investigator's discretion. Allowed non-opioid medications include gabapentin, pregabalin, duloxetine, acetaminophen, ibuprofen, celecoxib, meloxicam, other antidepressants including amitriptyline and other antiepileptics, as well as topical capsaicin and topical lidocaine.
7. Subjects with active Hepatitis A, Hepatitis B and/or Hepatitis C.
8. Subjects with any clinically unstable or significant cardiovascular (including acute coronary syndrome within the prior year to Screening), renal, hepatic, respiratory, gastrointestinal, hematological, endocrine, or infectious disease (including HIV infection).
9. Subjects with clinically significant abnormalities on screening vital signs, laboratory tests, and/or ECG. Subjects with poor venous access will also be excluded.
10. Subjects with a history of disorders of the hypothalamic-pituitary-adrenal axis, including adrenal insufficiency and Cushing's.
11. Subjects who have used chemotherapy agents, or who have a personal history of cancer or cancer in first degree relatives suggestive of elevated cancer risk, other than nonmetastatic skin cancer that has been completely excised, within 5 years prior to Screening.
12. Subjects with a history of bacterial, fungal, or viral infection requiring treatment with antibiotics, antifungal agents, or antivirals within 1 month prior to randomization.
13. Subjects who have used (within 14 days of randomization) or plan on using during the duration of the study any prescription or over-the-counter drugs that are moderate-strong CYP3A4 inducers or inhibitors.
14. Subjects who have used (within 14 days of randomization) or plan on using during the duration of the study any dietary aids, supplements, or foods that are moderate-strong CYP3A4 inhibitors (e.g., grapefruit juice).
15. Subjects with difficulty in swallowing oral medications.
16. Subjects with serious psychosocial comorbidities as determined by the Investigator.
17. Subjects with current cognitive or major psychiatric disorders, or any other condition that could interfere with compliance with study procedures.
18. Subjects with a positive drug or alcohol test (\>80 mg/dL) during Screening and/or admission (a positive THC test will be allowed as long as it consists of minimal social use, per discretion of Investigator), or with a recent history of binge drinking within 1 week of randomization.
19. Subjects who have used any other investigational drug within 1 month prior to enrollment. If the investigational drug is known to have a long half life, a longer washout period will be done.
20. Subjects with a presence or history of active gastrointestinal disorder, including esophageal or gastroduodenal ulceration, or renal, hepatic, or coagulant disorder within 1 month prior to enrollment.
21. Subjects with a family history of significant cardiac disease (i.e., sudden death in first degree relative; myocardial infarction before the age of 50).
22. Subjects with confirmed COVID-19, or suspected COVID-19 (e.g., developed symptoms of a respiratory infection such as cough, sore throat, shortness of breath, or fever, but did not get tested for COVID-19) within 30 days of randomization.
23. Subjects who have received a COVID-19 vaccine within 30 days of randomization or are planning on receiving it during the study duration.
24. Subjects who are not Veterans