Safety, Tolerability, and Pharmacokinetics of Oral EC5026 in Healthy Subjects

Study Overview
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Brief Summary
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This is a first-in-human study with EC5026, a new drug candidate intended to treat neuropathic pain. The purpose of the study is to provide initial safety, tolerability, and pharmacokinetics data of single ascending oral doses of EC5026 in healthy subjects.

Detailed Description
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This is a single-center, double-blind, placebo-controlled, Phase 1a single ascending dose study evaluating the safety, tolerability and pharmacokinetics of sequential doses of oral EC5026 in healthy male and female subjects. EC5026 is an inhibitor of the soluble Epoxide Hydrolase (sEH) enzyme developed as a first-in-class analgesic for the treatment of pain. This study will help refine the dosing strategy for subsequent multiple-dose studies in healthy subjects and for future clinical trials in patients with neuropathic pain. sEH is an enzyme that is downstream in the cytochrome P450 (CYP) pathway of the arachidonic acid (AA) cascade. The sEH enzyme is responsible of metabolizing a class of epoxy-fatty acids known as epoxyeicosatrienoic acids (EETs), which are potent, naturally occurring analgesics. EETs are produced at high concentrations in areas of tissue damage and inflammation, but are rapidly metabolized by the sEH enzyme into inactive compounds. Effective inhibition of sEH activity prolongs the ability of EETs to exert their analgesic activity.

Official Title
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A Single-Center, Double-Blind, Placebo-Controlled, Phase 1A Single Ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Sequential Dose Regimens of Oral EC5026 in Healthy Male and Female Subjects

Conditions
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Healthy Adults

Intervention / Treatment
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* Drug: EC5026 oral capsule
* Other: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each subject must meet all of the following criteria to be enrolled in this study: The subject is male of female 18 to 65 years, inclusive The subject is able and willing to provide written informed consent to participate in the study. The subject is considered by the investigator to be in good general health as determined by prestudy medical history, physical examination findings, clinical laboratory test results, and 12-lead electrocardiogram (ECG) results. The subject is willing and able to remain in confinement at the study unit from Day -1 to Day 5 and return to the unit at Days 7 and 14 for additional blood tests and safety evaluations. The subject has a body mass index of 19.0 to 32.0 kg/m2, inclusive, at Screening. The subject has normal blood pressure (systolic blood pressure 90 to 140 mm Hg, diastolic blood pressure 50 to 90 mm Hg), and heart rate (resting heart rate 45 to 90 beats per minute) without medication. The subject has a clinical chemistry profile including electrolytes, alkaline phosphatase (ALP), lactate dehydrogenase, creatine phosphokinase (CPK), creatinine, and urea within the normal range without medication at Screening. The subject has urinalysis results including urinary creatinine within the normal range. The subject is a nonsmoker or is willing to abstain from smoking starting 2 weeks prior to randomization and for the duration of the study. The subject is able to read, understand, and follow the study instructions. Male subjects and their female partners must agree to use double-barrier contraception during the study and for 2 months after receiving the last dose of study drug or provide proof of postmenopausal state (minimum 1 year) or surgical sterility. Male subjects must not donate sperm during the study and for 12 months after receiving the last dose of study drug. Female subjects must be nonpregnant, nonlactating, and either postmenopausal for at least 1 year, or surgically sterile for at least 3 months, or agrees to use double barrier contraception from 28 days prior to randomization and/or their last confirmed menstrual period prior to study randomization (whichever is longer) until 2 months after discharge from the clinic. Female subjects will refrain from using hormonal contraceptives for at least 28 days prior to study entry until the end of study (EOS) visit (Day 14). All female subjects of childbearing potential must have a negative pregnancy test result at Screening and baseline (Day -1). Exclusion Criteria: Subjects meeting any of the following criteria will be excluded from the study: The subject has any abnormalities in any of the following: liver function tests, CPK, or urinalysis results. Liver function tests, CPK, or urinalysis tests may be repeated at the discretion of the investigator, if necessary, to confirm any abnormalities. The subject has used any nonstudy medication(s), including low-dose aspirin for cardiovascular prophylaxis, within 1 week before administration of study drug. The subject has used chemotherapy agents or has a history of cancer, other than nonmetastatic skin cancer that has been completely excised, within 5 years prior to screening. The subject has a history of bacterial, fungal, or viral infection requiring treatment with antibiotics, antifungal agents, or antivirals within 1 month prior to randomization. The subject has a presence or history of peripheral edema within the past 5 years. The subject has a history of congestive heart failure. The subject has used drugs which are CYP inducers or inhibitors within 30 days of randomization (eg, cimetidine, paroxetine, fluoxetine, haloperidol, ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin). The subject has used any dietary aids, supplements, or foods that are known to modulate drug metabolizing enzymes (eg, St. John's wort, grapefruit juice) within 14 days of administration of study drug. The subject has difficulty in swallowing oral medications. The subject has a history of seizure disorder. The subject has serious psychosocial comorbidities as determined by the principal investigator. The subject has cognitive or psychiatric disorders, or any other condition that could interfere with compliance with study procedures and/or confinement in a study unit for 5.5 days. The subject has a history of drug or alcohol abuse within 1 year prior to Screening. The subject has used any other investigational drug within 1 month or 5 half-lives, whichever is longer, prior to randomization. The subject has used prescription drugs within 1 month or 5 half-lives, whichever is longer, prior to randomization. The subject has used over-the-counter medication excluding routine vitamins, but including mega-dose vitamin therapy, within 1 week prior to randomization. The subject has donated and/or received any blood or blood products (more than 450 mL) within 3 months prior to randomization. The subject has a presence or history of active gastrointestinal, renal, hepatic, or coagulant disorder within 1 month prior to randomization. The subject has a presence or history of esophageal or gastroduodenal ulceration within 1 month prior to randomization. The subject has a family history of significant cardiac disease (ie, sudden death in first degree relative; myocardial infarction prior to 50 years

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EC5026<br>Single Ascending Doses of oral EC5026 | Drug: EC5026 oral capsule<br>* 5 sequential cohorts of 8 subjects randomly assigned to receive single ascending oral doses of EC5026 (n=6 per cohort) or matching placebo (n=2 per cohort). Oral doses of EC5026 tested in each cohort: 0.5 mg (Cohort 1), 2 mg (Cohort 2), 8 mg (Cohort 3), 16 mg (Cohort 4), and 24 mg (Cohort 5). A blinded sentinel group of 2 subjects (1 active and 1 placebo) will be dosed at least 2 days before the remaining 6 subjects (5 active and 1 placebo) will receive blinded doses of active study drug or placebo.<br>|
| Placebo Comparator: Placebo<br>Single doses of matching oral placebo | Other: Placebo oral capsule<br>* 5 sequential cohorts of 8 subjects randomly assigned to receive single ascending oral doses of EC5026 (n=6 per cohort) or matching placebo (n=2 per cohort)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) [Safety and Tolerability] | All AEs reported or observed during the study will be recorded on the electronic case report forms (eCRF). Information to be collected includes drug treatment, type of event, time of onset, dosage, investigator-specified assessment of severity and relationship to study drug, time of resolution of the event, seriousness, any required treatment or evaluations, and outcome. Any AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent medications, or progression of disease states must also be reported. All AEs will be followed until they are resolved, stable, or judged by the investigator to be not clinically significant. The Medical Dictionary for Regulatory Activities will be used to code all AEs. A TEAE is defined as any event not present before exposure to study drug or any event already present that worsens in intensity or frequency after exposure. | 14 days | 
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Quantifiable Concentration (AUC 0-t) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | Standard noncompartmental methods will be used to determine the AUC in response to single oral doses of 0.5, 2, 8,16, and 24 mg of EC5026. The PK population will include subjects who received a single dose of EC5026 and have sufficient concentration data to support accurate estimation of at least 1 PK parameter. Subjects were excluded from the PK population when there were fewer than 3 quantifiable plasma samples. | Predose (0 hour), and at 1.25, 2.25, 4.25, 6.25, 8.25, 12.25, 24, 36, 48, 72, 84, 96, and 108 hours after dosing | 
| Maximum Observed Plasma Concentration (Cmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | Standard noncompartmental methods will be used to determine the Cmax in response to single oral doses of 0.5, 2, 8,16, and 24 mg of EC5026. The PK population will include subjects who received a single dose of EC5026 and have sufficient concentration data to support accurate estimation of at least 1 PK parameter. Subjects were excluded from the PK population when there were fewer than 3 quantifiable plasma samples. | Predose (0 hour), and at 1.25, 2.25, 4.25, 6.25, 8.25, 12.25, 24, 36, 48, 72, 84, 96, and 108 hours after dosing | 
| Time to Maximum Observed Plasma Concentration (Tmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | Standard noncompartmental methods will be used to determine the Tmax in response to single oral doses of 0.5, 2, 8,16, and 24 mg of EC5026. The PK population will include subjects who received a single dose of EC5026 and have sufficient concentration data to support accurate estimation of at least 1 PK parameter. Subjects were excluded from the PK population when there were fewer than 3 quantifiable plasma samples. | Predose (0 hour), and at 1.25, 2.25, 4.25, 6.25, 8.25, 12.25, 24, 36, 48, 72, 84, 96, and 108 hours after dosing | 
| Terminal Phase Half-life in Plasma (t1/2) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | Standard noncompartmental methods will be used to determine the t1/2 in response to single oral doses of 0.5, 2, 8,16, and 24 mg of EC5026. The PK population will include subjects who received a single dose of EC5026 and have sufficient concentration data to support accurate estimation of at least 1 PK parameter. Subjects were excluded from the PK population when there were fewer than 3 quantifiable plasma samples. | Predose (0 hour), and at 1.25, 2.25, 4.25, 6.25, 8.25, 12.25, 24, 36, 48, 72, 84, 96, and 108 hours after dosing | 
| Apparent Total Body Clearance (CL/F) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | Standard noncompartmental methods will be used to determine the CL/F in response to single oral doses of 0.5, 2, 8,16, and 24 mg of EC5026. The PK population will include subjects who received a single dose of EC5026 and have sufficient concentration data to support accurate estimation of at least 1 PK parameter. Subjects were excluded from the PK population when there were fewer than 3 quantifiable plasma samples. | Predose (0 hour), and at 1.25, 2.25, 4.25, 6.25, 8.25, 12.25, 24, 36, 48, 72, 84, 96, and 108 hours after dosing | 
| Apparent Volume of Distribution Based on the Terminal Elimination Rate Constant in Plasma (Vz/F) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | Standard noncompartmental methods will be used to determine the Vz/F in response to single oral doses of 0.5, 2, 8,16, and 24 mg of EC5026. The PK population will include subjects who received a single dose of EC5026 and have sufficient concentration data to support accurate estimation of at least 1 PK parameter. Subjects were excluded from the PK population when there were fewer than 3 quantifiable plasma samples. | Predose (0 hour), and at 1.25, 2.25, 4.25, 6.25, 8.25, 12.25, 24, 36, 48, 72, 84, 96, and 108 hours after dosing | 
| Renal Clearance (CLR) in Response to Escalating Dose Regimens of Oral EC5026 [Urine Pharmacokinetics]. | Standard noncompartmental methods will be used to determine CLR in response to single oral doses of 0.5, 2, 8,16, and 24 mg of EC5026. Subjects will be excluded from the PK population when there were fewer than 3 quantifiable plasma samples. | Urine is collected for analysis of EC5026 during the following time intervals: before dosing and 0 to 8 hours, 8 to 16 hours, 16 to 24 hours, 24 to 32 hours, 32 to 40 hours, and 40 to 48 hours after dosing | 
| Amount of Drug Excreted Unchanged in Urine Within the Time Interval 0 to 48 (Ae 0-48) in Response to Escalating Dose Regimens of Oral EC5026 [Urine Pharmacokinetics]. | Standard noncompartmental methods will be used to determine the Ae in response to single oral doses of 0.5, 2, 8,16, and 24 mg of EC5026. Subjects will be excluded from the PK population when there were fewer than 3 quantifiable plasma samples. | Urine is collected for analysis of EC5026 during the following time intervals: before dosing and 0 to 8 hours, 8 to 16 hours, 16 to 24 hours, 24 to 32 hours, 32 to 40 hours, and 40 to 48 hours after dosing | 
| Fraction of Eliminated Dose in Urine From 0 to 48 Hours (Fe 0-48%) in Response to Escalating Dose Regimens of Oral EC5026 [Urine Pharmacokinetics]. | Standard noncompartmental methods will be used to determine the Fe% in response to single oral doses of 0.5, 2, 8,16, and 24 mg of EC5026. Subjects were excluded from the PK population when there were fewer than 3 quantifiable plasma samples. | Urine is collected for analysis of EC5026 during the following time intervals: before dosing and 0 to 8 hours, 8 to 16 hours, 16 to 24 hours, 24 to 32 hours, 32 to 40 hours, and 40 to 48 hours after dosing | 
| Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | Standard noncompartmental methods will be used to determine the AUC in response to single oral doses of 0.5, 2, 8,16, and 24 mg of EC5026. The PK population will include subjects who received a single dose of EC5026 and have sufficient concentration data to support accurate estimation of at least 1 PK parameter. Subjects were excluded from the PK population when there were fewer than 3 quantifiable plasma samples. | Predose (0 hour), and at 1.25, 2.25, 4.25, 6.25, 8.25, 12.25, 24, 36, 48, 72, 84, 96, and 108 hours after dosing | 
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to 48 Hours After Dosing (AUC 0-48) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | Standard noncompartmental methods will be used to determine the AUC in response to single oral doses of 0.5, 2, 8,16, and 24 mg of EC5026. The PK population will include subjects who received a single dose of EC5026 and have sufficient concentration data to support accurate estimation of at least 1 PK parameter. Subjects were excluded from the PK population when there were fewer than 3 quantifiable plasma samples. | Predose (0 hour), and at 1.25, 2.25, 4.25, 6.25, 8.25, 12.25, 24, 36, 48 after dosing |