Study to Assess the Safety, Tolerability, and Pharmacokinetics of E2082 in Healthy Male Subjects

Healthy Participants Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03402178
• Other study ID #: E2082-J081-001
• Status: Terminated
• Phase: Phase 1
• Start date: December 21, 2017
• Est. completion date: February 20, 2020

Study information

• Verified date: June 2021
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 118
• Est. completion date: February 20, 2020
• Est. primary completion date: February 20, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 20 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy Participants

Intervention

Drug:
• E2082
Solution (0.2 mg) or tablet (0.5 mg and 5 mg).
• Placebo
Solution (0.2 mg) or tablet (0.5 mg and 5 mg) matched to E2082.

Locations

Country	Name	City	State
Japan	Eisai Trial Site	Sumida-ku	Tokyo

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Co., Ltd.

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Cmax is the maximum observed concentration of E2082 in the plasma that is measured after a dose.	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.
Primary	Part A: Mean value of Cmax of E2082 under a fed state for the SAD Cohort 5	Cmax is the maximum observed concentration of E2082 in the plasma that is measured after a dose.	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
Primary	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	Tmax is the time at which the highest concentration of E2082 occurs.	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.
Primary	Part A: Mean value of Tmax of E2082 under fed state for the SAD Cohort 5	Tmax is the time at which the highest concentration of E2082 occurs.	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
Primary	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	AUC(0-24h) represents the total drug exposure from zero time to 24 hours after dosing.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Primary	Part A: Mean value of AUC(0-24h) under a fed state for the SAD Cohort 5	AUC(0-24h) represents the total drug exposure from zero time to 24 hours after dosing.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Primary	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	AUC(0-t) represents the total drug exposure from zero time to the time of the last quantifiable concentration.	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.
Primary	Part A: Mean value of AUC(0-t) under a fed state for the SAD Cohort 5	AUC(0-t) represents the total drug exposure from zero time to the time of the last quantifiable concentration.	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
Primary	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	AUC(0-72h) represents the total drug exposure from zero time to 72 hours after dosing.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours postdose
Primary	Part A: Mean value of AUC(0-72h) under a fed state for the SAD Cohort 5	AUC(0-72h) represents the total drug exposure from zero time to 72 hours after dosing.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours postdose
Primary	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	AUC(0-96h) represents the total drug exposure from zero time to 96 hours after dosing.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose
Primary	Part A: Mean value of AUC(0-96h) under a fed state for the SAD Cohort 5	AUC(0-96h) represents the total drug exposure from zero time to 96 hours after dosing.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose
Primary	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	AUC(0-inf) represents the total drug exposure from zero time extrapolated to infinite time.	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.
Primary	Part A: Mean value of AUC(0-inf) under a fed state for the SAD Cohort 5	AUC(0-inf) represents the total drug exposure from zero time extrapolated to infinite time.	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
Primary	Part A: Mean value of terminal elimination phase half-life (t½) of E2082 under a fasted state for the SAD Cohorts 1-10	t½ is the time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount.	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.
Primary	Part A: Mean value of t½ of E2082 under a fed state for the SAD Cohort 5	t½ is the time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount.	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
Primary	Part A: Mean value of apparent total clearance (CL/F) of E2082 under a fasted state for the SAD Cohorts 1-10	CL/F is the apparent total clearance following extravascular (example, oral) administration.	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.
Primary	Part A: Mean value of CL/F of E2082 under a fasted state for the SAD Cohort 5	CL/F is the apparent total clearance following extravascular (example, oral) administration.	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
Primary	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	The apparent volume of distribution gives information about the amount of drug distributed in body tissue rather than the plasma.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours postdose
Primary	Part A: Mean value of Vz/F of E2082 on Day 1 under a fed state for the SAD Cohort 5	The apparent volume of distribution gives information about the amount of drug distributed in body tissue rather than the plasma.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours postdose
Primary	Part B: Mean value of Cmax of E2082 for the multiple ascending dose (MAD) cohorts on Day 1	Cmax is the maximum observed concentration of E2082 in the plasma that is measured after a dose.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1
Primary	Part B: Mean value of Cmax of E2082 at steady state (Css,max) for the MAD cohorts on Day 10	Cmax is the maximum observed concentration of E2082 in the plasma that is measured after a dose.	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
Primary	Part B: Mean value of the minimum observed concentration (Cmin) of E2082 for the MAD cohorts on Day 1	Cmin is the minimum observed concentration of E2082 in the plasma that is measured after a dose.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1
Primary	Part B: Mean value of Cmin of E2082 at steady state (Css,min) for the MAD cohorts	Css,min is the minimum observed concentration of E2082 in the plasma that is measured after a dose at steady state.	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
Primary	Part B: Mean value of Tmax of E2082 for the MAD cohorts on Day 1	Tmax is the time at which the highest concentration of E2082 occurs.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1
Primary	Part B: Mean value of Tmax of E2082 at steady state (Tss,max) for the MAD cohorts	Tss,max is the time at which the highest concentration of E2082 occurs at steady state.	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
Primary	Part B: Mean value of the average steady state concentration (Css,av) of E2082 for the MAD cohorts	The average steady state concentration is calculated as AUC(0-t)/t. t is the dosing interval.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 10
Primary	Part B: Mean value of AUC(0-24h) after dosing on Day 1 for the MAD cohorts	AUC(0-24h) represents the total drug exposure from zero time to 24 hours after dosing.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1
Primary	Part B: Mean value of AUC(0-t) for the MAD cohorts	AUC(0-t) is AUC over the dosing interval on multiple dosing.	Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose of Day 10
Primary	Part B: Mean value of t½ following the last day of dosing for the MAD cohorts	t½ is the time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount.	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
Primary	Part B: Peak-trough fluctuation (PTF) for the MAD cohorts	PTF is peak to trough fluctuation at steady-state.	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
Primary	Part B: Accumulation ratio for AUC and Cmax (Rac) for the MAD cohorts	Rac (Cmax) is calculated as the ratio of drug concentrations observed during a dosing interval at steady-state divided by drug concentrations seen during the dosing interval after a single (first) dose. Rac (AUC)=steady state AUC(0-t)/single dose AUC(0- t), where t is dosing interval.	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
Primary	Part B: Mean value of apparent total clearance at steady state (CLss/F) for the MAD cohorts on Day 10	CLss/F is the apparent total clearance at steady state following extravascular (example, oral) administration. It is defined as the rate of drug elimination.	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
Primary	Part B: Mean value of Vz/F for the MAD cohorts on Day 10	Vz/F is apparent volume of distribution at terminal phase on Day 10.	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
Primary	Part B: Change from baseline in QT interval corrected for heart rate using the Fridericia formula (QTcF)		Baseline and Day 1
Primary	Part B: Change from baseline in QT interval corrected for heart rate using the Fridericia formula (QTcF)		Baseline and Day 10
Secondary	Change-from-baseline in heart rate (HR)		Baseline, Days 1 and 10
Secondary	Change from baseline in PR interval and QRS interval of the Electrocardiogram (ECG)		Baseline, Days 1 and 10
Secondary	Placebo-corrected change from baseline in HR		Baseline, Days 1 and 10
Secondary	Placebo-corrected change from baseline in QTcF, PR, QRS interval		Baseline, Days 1 and 10
Secondary	Number of participants with categorical outliers for HR, PR interval, QRS interval		Baseline up to Day 11
Secondary	Number of participants with categorical outliers defined as QTcF >450 msec, 480 msec and 500 msec at any timepoint and change-from-baseline QTcF (?QTcF) >30 msec (increased by 30 msec) and >60 msec		Baseline up to Day 11
Secondary	Number of participants with T wave morphology changes		Baseline up to Day 11
Secondary	Number of participants with U-wave presence		Baseline up to Day 11