Healthy Adults
Conditions
Brief summary
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
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.
Interventions
DRUGEC5026 oral capsule
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.
OTHERPlacebo oral capsule
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)
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
EicOsis Human Health Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Each subject must meet all of the following criteria to be enrolled in this study: 1. The subject is male of female 18 to 65 years, inclusive 2. The subject is able and willing to provide written informed consent to participate in the study. 3. 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. 4. 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. 5. The subject has a body mass index of 19.0 to 32.0 kg/m2, inclusive, at Screening. 6. 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. 7. 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. 8. The subject has urinalysis results including urinary creatinine within the normal range. 9. 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. 10. The subject is able to read, understand, and follow the study instructions. 11. 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. 12. Male subjects must not donate sperm during the study and for 12 months after receiving the last dose of study drug. 13. 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: 1. 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. 2. The subject has used any nonstudy medication(s), including low-dose aspirin for cardiovascular prophylaxis, within 1 week before administration of study drug. 3. 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. 4. 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. 5. The subject has a presence or history of peripheral edema within the past 5 years. 6. The subject has a history of congestive heart failure. 7. 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). 8. 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. 9. The subject has difficulty in swallowing oral medications. 10. The subject has a history of seizure disorder. 11. The subject has serious psychosocial comorbidities as determined by the principal investigator. 12. 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. 13. The subject has a history of drug or alcohol abuse within 1 year prior to Screening. 14. The subject has used any other investigational drug within 1 month or 5 half-lives, whichever is longer, prior to randomization. 15. The subject has used prescription drugs within 1 month or 5 half-lives, whichever is longer, prior to randomization. 16. The subject has used over-the-counter medication excluding routine vitamins, but including mega-dose vitamin therapy, within 1 week prior to randomization. 17. The subject has donated and/or received any blood or blood products (more than 450 mL) within 3 months prior to randomization. 18. The subject has a presence or history of active gastrointestinal, renal, hepatic, or coagulant disorder within 1 month prior to randomization. 19. The subject has a presence or history of esophageal or gastroduodenal ulceration within 1 month prior to randomization. 20. The subject has a family history of significant cardiac disease (ie, sudden death in first degree relative; myocardial infarction prior to 50 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) [Safety and Tolerability] | 14 days | 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. |
| 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]. | 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 | 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. |
| Maximum Observed Plasma Concentration (Cmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 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 | 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. |
| Time to Maximum Observed Plasma Concentration (Tmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 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 | 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. |
| Terminal Phase Half-life in Plasma (t1/2) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 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 | 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. |
| Apparent Total Body Clearance (CL/F) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 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 | 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. |
| 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]. | 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 | 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. |
| Renal Clearance (CLR) in Response to Escalating Dose Regimens of Oral EC5026 [Urine Pharmacokinetics]. | 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 | 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. |
| 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]. | 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 | 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. |
| 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]. | 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 | 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. |
| 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]. | 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 | 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. |
| 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]. | Predose (0 hour), and at 1.25, 2.25, 4.25, 6.25, 8.25, 12.25, 24, 36, 48 after dosing | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| EC5026 0.5 mg Single 0.5 mg dose of oral EC5026 | 6 |
| EC5026 2 mg Single 2 mg dose of oral EC5026 | 6 |
| EC5026 8 mg Single 8 mg dose of oral EC5026 | 6 |
| EC5026 16 mg Single 16 mg dose of oral EC5026 | 6 |
| EC5026 24 mg Single 24 mg dose of oral EC5026 | 6 |
| Placebo Single dose of matching oral placebo | 10 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | EC5026 0.5 mg | Total | Placebo | EC5026 24 mg | EC5026 16 mg | EC5026 8 mg | EC5026 2 mg |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 40.5 years | 36.0 years | 45.0 years | 37.5 years | 42.0 years | 28.0 years | 33.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 17 Participants | 4 Participants | 5 Participants | 3 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 23 Participants | 6 Participants | 1 Participants | 3 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 14 Participants | 4 Participants | 0 Participants | 1 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 26 Participants | 6 Participants | 6 Participants | 5 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 6 participants | 40 participants | 10 participants | 6 participants | 6 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 22 Participants | 5 Participants | 4 Participants | 4 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 18 Participants | 5 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 10 |
| other Total, other adverse events | 2 / 6 | 4 / 6 | 2 / 6 | 4 / 6 | 4 / 6 | 3 / 10 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 10 |
Outcome results
Primary
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.
Time frame: 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
Population: All urine concentrations were below the limit of quantification for the EC5026 0.5 and 2 mg dose groups.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EC5026 8 mg | 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]. | 0.0127 mg | Geometric Coefficient of Variation 65.9 |
| EC5026 16 mg | 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]. | 0.0210 mg | Geometric Coefficient of Variation 86.2 |
| EC5026 24 mg | 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]. | 0.0487 mg | Geometric Coefficient of Variation 70.9 |
Primary
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.
Time frame: 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
Population: Values for CL/F were excluded from summary statistics when %AUCextrap was \>20%. Plasma concentrations following EC5026 0.5 mg were below the limit of quantification for all subjects at all time points. For 2 subjects in the EC5026 2 mg dose group, plasma concentrations were quantifiable in fewer than 3 samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EC5026 8 mg | Apparent Total Body Clearance (CL/F) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 2.23 L/h | Standard Deviation 0.56 |
| EC5026 16 mg | Apparent Total Body Clearance (CL/F) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 2.35 L/h | Standard Deviation 0.52 |
| EC5026 24 mg | Apparent Total Body Clearance (CL/F) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 2.62 L/h | Standard Deviation 0.54 |
Primary
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.
Time frame: 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
Population: Plasma concentrations following EC5026 0.5 mg were below the limit of quantification for all subjects at all time points. For 2 subjects in the EC5026 2 mg dose group, plasma concentrations were quantifiable in fewer than 3 samples. Values for Vz/F were excluded from summary statistics when %AUCextrap was \>20.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EC5026 8 mg | 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]. | 178 liters | Standard Deviation 21 |
| EC5026 16 mg | 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]. | 146 liters | Standard Deviation 34.5 |
| EC5026 24 mg | 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]. | 153 liters | Standard Deviation 40.2 |
Primary
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.
Time frame: 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
Population: Plasma concentrations following EC5026 0.5 mg were below the limit of quantification for all subjects at all timepoints. For 2 subjects in the EC5026 2 mg dose group, plasma concentrations were quantifiable in fewer than 3 samples. These subjects were excluded from the PK population. Values for AUC0 inf were excluded from summary statistics when %AUCextrap was \>20%.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EC5026 8 mg | 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]. | 3690 ng*h/mL | Geometric Coefficient of Variation 26.3 |
| EC5026 16 mg | 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]. | 6960 ng*h/mL | Geometric Coefficient of Variation 22.1 |
| EC5026 24 mg | 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]. | 9310 ng*h/mL | Geometric Coefficient of Variation 21.1 |
Primary
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.
Time frame: Predose (0 hour), and at 1.25, 2.25, 4.25, 6.25, 8.25, 12.25, 24, 36, 48 after dosing
Population: Plasma concentrations following EC5026 0.5 mg were below the limit of quantification for all subjects at all timepoints. For 2 subjects in the EC5026 2 mg dose group, plasma concentrations were quantifiable in fewer than 3 samples. These subjects were excluded from the PK population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EC5026 2 mg | 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]. | 119 ng*h/mL | Geometric Coefficient of Variation 59.7 |
| EC5026 8 mg | 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]. | 1870 ng*h/mL | Geometric Coefficient of Variation 7.9 |
| EC5026 16 mg | 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]. | 4450 ng*h/mL | Geometric Coefficient of Variation 14.7 |
| EC5026 24 mg | 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]. | 6130 ng*h/mL | Geometric Coefficient of Variation 13.4 |
Primary
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.
Time frame: 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
Population: Plasma concentrations following EC5026 0.5 mg were below the limit of quantification for all subjects at all timepoints. For 2 subjects in the EC5026 2 mg dose group, plasma concentrations were quantifiable in fewer than 3 samples. These subjects were excluded from the PK population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EC5026 2 mg | 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]. | 258 ng*h/mL | Geometric Coefficient of Variation 145.4 |
| EC5026 8 mg | 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]. | 3450 ng*h/mL | Geometric Coefficient of Variation 28.4 |
| EC5026 16 mg | 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]. | 6780 ng*h/mL | Geometric Coefficient of Variation 23.1 |
| EC5026 24 mg | 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]. | 9030 ng*h/mL | Geometric Coefficient of Variation 22.1 |
Primary
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.
Time frame: 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
Population: All urine concentrations were below the limit of quantification for the EC5026 0.5 and 2 mg groups.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EC5026 8 mg | 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]. | 0.159 percentage of eliminated dose | Geometric Coefficient of Variation 65.9 |
| EC5026 16 mg | 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]. | 0.132 percentage of eliminated dose | Geometric Coefficient of Variation 86.2 |
| EC5026 24 mg | 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]. | 0.203 percentage of eliminated dose | Geometric Coefficient of Variation 70.9 |
Primary
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.
Time frame: 14 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EC5026 0.5 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment-Related TEAE | 0 Participants |
| EC5026 0.5 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment Emergent Adverse Event (TEAE) | 2 Participants |
| EC5026 0.5 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Adverse Events | 2 Participants |
| EC5026 2 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Adverse Events | 4 Participants |
| EC5026 2 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment Emergent Adverse Event (TEAE) | 4 Participants |
| EC5026 2 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment-Related TEAE | 0 Participants |
| EC5026 8 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment-Related TEAE | 0 Participants |
| EC5026 8 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Adverse Events | 3 Participants |
| EC5026 8 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment Emergent Adverse Event (TEAE) | 2 Participants |
| EC5026 16 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment Emergent Adverse Event (TEAE) | 4 Participants |
| EC5026 16 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Adverse Events | 6 Participants |
| EC5026 16 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment-Related TEAE | 0 Participants |
| EC5026 24 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Adverse Events | 4 Participants |
| EC5026 24 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment Emergent Adverse Event (TEAE) | 4 Participants |
| EC5026 24 mg | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment-Related TEAE | 0 Participants |
| Placebo | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Adverse Events | 5 Participants |
| Placebo | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment-Related TEAE | 0 Participants |
| Placebo | Incidence of Adverse Events (AEs) [Safety and Tolerability] | Any Treatment Emergent Adverse Event (TEAE) | 3 Participants |
Primary
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.
Time frame: 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
Population: Plasma concentrations following EC5026 0.5 mg were below the limit of quantification for all subjects at all time points. For 2 subjects in the EC5026 2 mg dose group, plasma concentrations were quantifiable in fewer than 3 samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EC5026 2 mg | Maximum Observed Plasma Concentration (Cmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 4.69 ng/mL | Geometric Coefficient of Variation 45.8 |
| EC5026 8 mg | Maximum Observed Plasma Concentration (Cmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 82.7 ng/mL | Geometric Coefficient of Variation 11.1 |
| EC5026 16 mg | Maximum Observed Plasma Concentration (Cmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 220 ng/mL | Geometric Coefficient of Variation 16.2 |
| EC5026 24 mg | Maximum Observed Plasma Concentration (Cmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 301 ng/mL | Geometric Coefficient of Variation 14.6 |
Primary
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.
Time frame: 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
Population: All urine concentrations were below the limit of quantification for the EC5026 0.5 and 2 mg dose groups.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| EC5026 8 mg | Renal Clearance (CLR) in Response to Escalating Dose Regimens of Oral EC5026 [Urine Pharmacokinetics]. | 0.00679 L/h | Geometric Coefficient of Variation 64.8 |
| EC5026 16 mg | Renal Clearance (CLR) in Response to Escalating Dose Regimens of Oral EC5026 [Urine Pharmacokinetics]. | 0.00473 L/h | Geometric Coefficient of Variation 76.7 |
| EC5026 24 mg | Renal Clearance (CLR) in Response to Escalating Dose Regimens of Oral EC5026 [Urine Pharmacokinetics]. | 0.00794 L/h | Geometric Coefficient of Variation 58.7 |
Primary
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.
Time frame: 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
Population: Plasma concentrations following EC5026 0.5 mg were below the limit of quantification for all subjects at all time points. For 2 subjects in the EC5026 2 mg dose group, plasma concentrations were quantifiable in fewer than 3 samples. Given that plasma concentrations for the 2 mg dose group were near the limit of quantification, the estimates for t½ should be viewed with caution.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EC5026 2 mg | Terminal Phase Half-life in Plasma (t1/2) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 143 hours | Standard Deviation 63.3 |
| EC5026 8 mg | Terminal Phase Half-life in Plasma (t1/2) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 59.1 hours | Standard Deviation 19 |
| EC5026 16 mg | Terminal Phase Half-life in Plasma (t1/2) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 44.8 hours | Standard Deviation 14 |
| EC5026 24 mg | Terminal Phase Half-life in Plasma (t1/2) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 41.8 hours | Standard Deviation 14.6 |
Primary
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.
Time frame: 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
Population: Plasma concentrations following EC5026 0.5 mg were below the limit of quantification for all subjects at all time points. For 2 subjects in the EC5026 2 mg dose group, plasma concentrations were quantifiable in fewer than 3 samples.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EC5026 2 mg | Time to Maximum Observed Plasma Concentration (Tmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 1.25 hours |
| EC5026 8 mg | Time to Maximum Observed Plasma Concentration (Tmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 1.25 hours |
| EC5026 16 mg | Time to Maximum Observed Plasma Concentration (Tmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 1.25 hours |
| EC5026 24 mg | Time to Maximum Observed Plasma Concentration (Tmax) in Response to Escalating Dose Regimens of Oral EC5026 [Plasma Pharmacokinetics]. | 1.25 hours |