Clinical trial NCT03402178: Study to Assess the Safety, Tolerability, and Pharmacokinetics of E2082 in Healthy Male Subjects
Official title: A Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Dose Studies to Assess the Safety, Tolerability, and Pharmacokinetics of E2082 in Healthy Male Subjects
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Healthy Participants
Keywords: E2082
male
single ascending dose
multiple ascending dose
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2018-01-18
Enrollment: 118
Sex: MALE
Minimum age (years): 20
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will be conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of single ascending oral doses of E2082 in healthy Japanese adult and elderly male participants, and to evaluate the safety, tolerability, and PK of multiple ascending oral doses of E2082 in healthy Japanese and Caucasian adult male participants.


Eligibility criteria: Inclusion Criteria:

Participants must meet all of the following criteria to be included in this study:

* Non-smoking, age ≥20 years and \<55 years old adult male (Cohorts 1 to 9 of Part A and all cohorts of Part B), or age ≥55 years and ≤85 years old elderly male (only Cohort 10 of Part A) at the time of informed consent. To be considered non-smokers, participants must have discontinued smoking for at least 4 weeks before dosing.
* Body mass index ≥18 and \<30 kilograms per meters squared at Screening

Exclusion Criteria:

Participants who meet any of the following criteria will be excluded from this study:

* Evidence of disease that may influence the outcome of the study within 4 weeks before dosing; example, 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 gastrointestinal surgery that may affect pharmacokinetic profiles of E2082, example, hepatectomy, nephrectomy, and digestive organ resection
* Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, electrocardiogram finding, or laboratory test results that require medical treatment at Screening

Primary outcomes:
measure: Part A: Mean value of the maximum observed concentration (Cmax) of E2082 under a fasted state for the single ascending dose (SAD) Cohorts 1-10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later.
measure: Part A: Mean value of Cmax of E2082 under a fed state for the SAD Cohort 5
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose
measure: Part A: Mean value of the time at which the highest plasma concentration (Tmax) of E2082 occurs under a fasted state for the SAD Cohorts 1-10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later.
measure: Part A: Mean value of Tmax of E2082 under fed state for the SAD Cohort 5
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose
measure: Part A: Mean value of the area under the concentration-time curve from zero time to 24 hours after dosing (AUC[0-24h]) under a fasted state for the SAD Cohorts 1-10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose
measure: Part A: Mean value of AUC(0-24h) under a fed state for the SAD Cohort 5
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose
measure: Part A: Mean value of AUC from zero time to the time of the last quantifiable concentration (AUC[0-t]) under a fasted state for the SAD Cohorts 1-10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later.
measure: Part A: Mean value of AUC(0-t) under a fed state for the SAD Cohort 5
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose
measure: Part A: Mean value of AUC from zero time to 72 hours after dosing (AUC[0-72h]) under a fasted state for the SAD Cohorts 1-10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours postdose
measure: Part A: Mean value of AUC(0-72h) under a fed state for the SAD Cohort 5
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours postdose
measure: Part A: Mean value of AUC from zero time to 96 hours after dosing (AUC[0-96h]) under a fasted state for the SAD Cohorts 1-10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose
measure: Part A: Mean value of AUC(0-96h) under a fed state for the SAD Cohort 5
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose
measure: Part A: Mean value of AUC from zero time extrapolated to infinite time (AUC[0-inf]) under a fasted state for the SAD Cohorts 1-10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later.
measure: Part A: Mean value of AUC(0-inf) under a fed state for the SAD Cohort 5
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose
measure: Part A: Mean value of terminal elimination phase half-life (t½) of E2082 under a fasted state for the SAD Cohorts 1-10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later.
measure: Part A: Mean value of t½ of E2082 under a fed state for the SAD Cohort 5
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose
measure: Part A: Mean value of apparent total clearance (CL/F) of E2082 under a fasted state for the SAD Cohorts 1-10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), and 168 (Day 8) hours postdose for all cohorts. Additionally, 240 (Day 11) and 336 (Day 15) hours postdose for Cohort 4 or later.
measure: Part A: Mean value of CL/F of E2082 under a fasted state for the SAD Cohort 5
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 168 (Day 8), 240 (Day 11), and 336 (Day 15) hours postdose
measure: Part A: Mean value of the apparent volume of distribution at terminal phase of E2082 on Day 1 (Vz/F) under a fasted state for the SAD Cohorts 1-10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours postdose
measure: Part A: Mean value of Vz/F of E2082 on Day 1 under a fed state for the SAD Cohort 5
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours postdose
measure: Part B: Mean value of Cmax of E2082 for the multiple ascending dose (MAD) cohorts on Day 1
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1
measure: Part B: Mean value of Cmax of E2082 at steady state (Css,max) for the MAD cohorts on Day 10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10
measure: Part B: Mean value of the minimum observed concentration (Cmin) of E2082 for the MAD cohorts on Day 1
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1
measure: Part B: Mean value of Cmin of E2082 at steady state (Css,min) for the MAD cohorts
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10
measure: Part B: Mean value of Tmax of E2082 for the MAD cohorts on Day 1
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1
measure: Part B: Mean value of Tmax of E2082 at steady state (Tss,max) for the MAD cohorts
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10
measure: Part B: Mean value of the average steady state concentration (Css,av) of E2082 for the MAD cohorts
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 10
measure: Part B: Mean value of AUC(0-24h) after dosing on Day 1 for the MAD cohorts
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1
measure: Part B: Mean value of AUC(0-τ) for the MAD cohorts
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose of Day 10
measure: Part B: Mean value of t½ following the last day of dosing for the MAD cohorts
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10
measure: Part B: Peak-trough fluctuation (PTF) for the MAD cohorts
timeFrame: Predose at Days 1, 2, 6, 10, 12, 13, and 14. 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1. 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10
measure: Part B: Accumulation ratio for AUC and Cmax (Rac) for the MAD cohorts
timeFrame: Predose at Days 1, 2, 6, 10, 12, 13, and 14. 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1. 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10
measure: Part B: Mean value of apparent total clearance at steady state (CLss/F) for the MAD cohorts on Day 10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10
measure: Part B: Mean value of Vz/F for the MAD cohorts on Day 10
timeFrame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168, 240, and 336 hours postdose of Day 10
measure: Part B: Change from baseline in QT interval corrected for heart rate using the Fridericia formula (QTcF)
timeFrame: Baseline and Day 1
measure: Part B: Change from baseline in QT interval corrected for heart rate using the Fridericia formula (QTcF)
timeFrame: Baseline and Day 10
Secondary outcomes:
measure: Change-from-baseline in heart rate (HR)
timeFrame: Baseline, Days 1 and 10
measure: Change from baseline in PR interval and QRS interval of the Electrocardiogram (ECG)
timeFrame: Baseline, Days 1 and 10
measure: Placebo-corrected change from baseline in HR
timeFrame: Baseline, Days 1 and 10
measure: Placebo-corrected change from baseline in QTcF, PR, QRS interval
timeFrame: Baseline, Days 1 and 10
measure: Number of participants with categorical outliers for HR, PR interval, QRS interval
timeFrame: Baseline up to Day 11
measure: Number of participants with categorical outliers defined as QTcF >450 msec, 480 msec and 500 msec at any timepoint and change-from-baseline QTcF (ΔQTcF) >30 msec (increased by 30 msec) and >60 msec
timeFrame: Baseline up to Day 11
measure: Number of participants with T wave morphology changes
timeFrame: Baseline up to Day 11
measure: Number of participants with U-wave presence
timeFrame: Baseline up to Day 11
Other outcomes:
Locations:
city: Sumida-ku
country: Japan
facility: Eisai Trial Site
state: Tokyo
Study officials:
References: