Clinical trial NCT03054194: Study to Assess the Safety, Tolerability, and Pharmacokinetics of E2730
Official title: A Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of E2730
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Participants
Keywords: Healthy participants
E2730
Pharmacokinetics
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2017-02-15
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Study E2730-A001-001 is a first-in-human, sequential ascending single dose, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics (PK) of a single oral dose of E2730 in healthy participants.


Eligibility criteria: Inclusion Criteria:

* Non-smoking, male or female, age ≥18 years and ≤55 years old at the time of informed consent (note: to be considered non-smokers, participants must have discontinued smoking for at least 4 weeks before dosing)
* Body mass index (BMI) ≥18 and \<32 kilograms per meters squared (kg/m\^2) at Screening

Exclusion Criteria:

* Clinically significant illness that requires medical treatment within 8 weeks or a clinically significant infection that requires medical treatment within 4 weeks of dosing
* Females who are breastfeeding or pregnant at Screening or Baseline (documented by a negative beta human chorionic gonadotropin \[β-hCG\] (or human chorionic gonadotropin \[hCG\]) test with a minimum sensitivity of 25 International Units per Liter \[IU/L\] or equivalent units of β-hCG \[or hCG\]). A negative urine pregnancy test is required before the administration of the first dose per cohort.
* Females of childbearing potential who:

  * Had unprotected sexual intercourse within 30 days before study entry and do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double barrier method \[such as condom plus diaphragm with spermicide\] or have a vasectomized partner with confirmed azoospermia but hormonal contraceptives are not permitted) throughout the entire study period and for 28 days after study drug discontinuation
  * Are currently abstinent, and do not agree to use a double barrier method (as described above) or refrain from sexual activity during the study period or for 28 days after study drug discontinuation

NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).

* Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception throughout the study period or for 28 days after study drug discontinuation). No sperm donation is allowed during the study period or for 3 months after study drug discontinuation.
* Evidence of disease that may influence the outcome of the study within 4 weeks before dosing (eg, psychiatric disorders and disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system, or participants who have a congenital abnormality in metabolism)
* Any history of seizures, including those experienced in childhood
* Any history of gastrointestinal surgery that may affect pharmacokinetic profiles of E2730 (eg, hepatectomy, nephrectomy, digestive organ resection) at Screening
* Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, electrocardiogram (ECG) finding, or laboratory test results that require medical treatment at Screening or Baseline
* A prolonged QT/QT corrected (QTc) interval (QC interval corrected using Fridericia's formula \[QTcF\] \>450 milliseconds) demonstrated on ECG at Screening or Baseline (based on average of triplicate ECGs). A history of risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT Syndrome) or the use of concomitant medications that prolonged the QT/QTc interval
* Left bundle branch block at Screening or Baseline
* Persistent systolic blood pressure (BP) \>130 or \<100 millimeters of mercury (mmHg) or diastolic BP \>85 or \<50 mmHg at Screening or Baseline
* Persistent heart rate less than 50 beats/min or more than 100 beats/min at Screening or Baseline
* History of myocardial infarction, ischemic heart disease, or cardiac failure at Screening
* History of clinically significant arrhythmia or uncontrolled arrhythmia
* Known history of clinically significant drug allergy at Screening or Baseline
* Known history of food allergies or presently experiencing significant seasonal or perennial allergy at Screening or Baseline
* Known to be human immunodeficiency virus positive at Screening
* Active viral hepatitis (A, B, or C) as demonstrated by positive serology at Screening
* History of drug or alcohol dependency or abuse within the 2 years before Screening, or those who have a positive drug test (including cannabinoids) or alcohol test at Screening or Baseline
* Intake of caffeinated beverages or food within 72 hours before dosing
* Intake of nutritional supplements, juice, and herbal preparations or other foods or beverages that may affect the various drug-metabolizing enzymes and transporters (eg, alcohol, grapefruit, grapefruit juice, grapefruit-containing beverages, apple or orange juice, vegetables from the mustard green family \[eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussel's sprouts, mustard\], and charbroiled meats) within 1 week before dosing
* Intake of herbal preparations containing St. John's Wort within 4 weeks before dosing
* Use of prescription drugs within 4 weeks before dosing
* Intake of over-the-counter (OTC) medications within 2 weeks before dosing
* Currently enrolled in another clinical study or used any investigational drug or device within 30 days or 5 half-lives, whichever is longer, preceding informed consent
* Receipt of blood products within 4 weeks, or donation of blood within 8 weeks, or donation of plasma within 1 week of dosing
* Engagement in strenuous exercise within 2 weeks before check-in (eg, marathon runners, weight lifters)

Primary outcomes:
measure: Number of participants with any serious adverse event and number of participants with any non-serious adverse event
timeFrame: up to Day 10 (Follow-up/Early Termination)
measure: Number of participants with an abnormal, clinically significant hematology parameter value
timeFrame: Screening; Baseline; Days 2 and 5; Day 10 (Follow-up/Early Termination)
measure: Number of participants with an abnormal, clinically significant blood chemistry parameter value
timeFrame: Screening; Baseline; Days 2 and 5; Day 10 (Follow-up/Early Termination)
measure: Number of participants with an abnormal, clinically significant urine value
timeFrame: Screening; Baseline; Days 2 and 5; Day 10 (Follow-up/Early Termination)
measure: Number of participants with an abnormal, clinically significant vital sign value
timeFrame: up to Day 10 (Follow-up/Early Termination)
measure: Mean change from Baseline in weight
timeFrame: Screening; Baseline; Day 10 (Follow-up/Early Termination)
measure: Number of participants with an abnormal, clinically significant electrocardiogram (ECG) parameter value
timeFrame: Screening; Baseline; up to Day 10 (Follow-up/Early Termination)
measure: Number of participants with an abnormal, clinically significant physical examination parameter value
timeFrame: Screening; Baseline; Day 5; Day 10 (Follow-up/Early Termination)
measure: Number of participants with an abnormal, clinically significant neurological parameter value
timeFrame: Screening
measure: Mean maximum observed concentration (Cmax) for E2730 and the N-acetyl metabolite in plasma
timeFrame: Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.
measure: Mean time at which the highest drug concentration (tmax) occurs for E2730 and the N-acetyl metabolite in plasma
timeFrame: Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.
measure: Mean area under the concentration-time curve from zero time to 24 hours after dosing (AUC[0-24h]) for E2730 and the N-acetyl metabolite in plasma
timeFrame: Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.
measure: Mean area under the concentration-time curve from zero time to time of last quantifiable concentration (AUC[0-t]) for E2730 and the N-acetyl metabolite in plasma
timeFrame: Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.
measure: Mean area under the concentration-time curve from zero time to 72 hours after dosing (AUC[0-72h]) for E2730 and the N-acetyl metabolite in plasma
timeFrame: Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.
measure: Mean area under the concentration-time curve from zero time to 96 hours after dosing (AUC[0-96h]) for E2730 and the N-acetyl metabolite in plasma
timeFrame: Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.
measure: Mean area under the concentration-time curve from zero time extrapolated to infinite time (AUC[0-inf]) for E2730 and the N-acetyl metabolite in plasma
timeFrame: Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.
measure: Mean terminal phase half-life (t1/2) for E2730 and the N-acetyl metabolite in plasma
timeFrame: Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.
measure: Mean apparent total clearance following extravascular (eg, oral) administration of E2730 (CL/F) in plasma
timeFrame: Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.
measure: Mean apparent volume of distribution at terminal phase (Vz/F) for E2730 in plasma
timeFrame: Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.
measure: Metabolite ratio (%) calculated as the ratio of plasma AUC(0-inf) of metabolite to parent following molar correction (MRP) for E2730 and the N-acetyl metabolite
timeFrame: Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.
Secondary outcomes:
measure: Mean change from Baseline in blood pressure (BP) using ambulatory BP monitoring (ABPM)
timeFrame: Baseline; Day 1; Day 2
measure: Mean change from Baseline in heart rate using Holter monitoring
timeFrame: Baseline; Day 1; Day 2
measure: Mean change from Baseline in corrected QT (QTc) interval using Holter monitoring
timeFrame: Baseline; Day 1; Day 2
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: Eisai Trial Site
state: Texas
Study officials:
References: