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

Keywords

• E2082
• male
• single ascending dose
• multiple ascending dose

Study arms

• Experimental
  E2082

  E2082 will be administered as a solution (0.2 milligram \[mg\]), a 0.5 mg tablet, and a 5 mg tablet. Part A: Cohort 1 participants will receive a single dose of a 0.2 mg E2082 solution, and participants in Cohorts 2 to 4, respectively, will receive a single dose of 0.5 mg, 1 mg, or 2.5 mg E2082 tablets under fasted conditions. Cohort 5 participants will receive a single dose of 5 mg E2082 under fasted conditions, and then they will receive 5 mg E2082 under fed conditions after washout. Participants in Cohorts 6 to 10, respectively, will receive 10 mg (adult participants), 15 mg, 25 mg, 40 mg, or 10 mg (elderly participants) E2082 tablets under fasted conditions. Part B: Participants in Cohorts 1 to 4, respectively, will receive 2.5 mg, 5 mg, 10, or 15 mg tablets once daily for 10 days. E2082 will be administered under fasted conditions on Day 1 and Day 10 and under fed conditions during Day 2 to Day 9.

  Drug: E2082

• Placebo comparator
  E2082-matched placebo

  Matched placebo will be administered as a solution (0.2 mg), a 0.5 mg tablet, and a 5 mg tablet. Part A: Cohort 1 participants will receive a single dose of a 0.2 mg matched placebo solution, and participants in Cohorts 2 to 4, respectively, will receive a single dose of 0.5 mg, 1 mg, or 2.5 mg matched placebo tablets under fasted conditions. Cohort 5 participants will receive a single dose of 5 mg matched placebo under fasted conditions, and then they will receive 5 mg matched placebo under fed conditions after washout. Participants in Cohorts 6 to 10, respectively, will receive 10 mg (adult participants), 15 mg, 25 mg, 40 mg, or 10 mg (elderly participants) matched placebo tablets under fasted conditions. Part B: Participants in Cohorts 1 to 4, respectively, will receive 2.5 mg, 5 mg, 10, or 15 mg matched placebo tablets once daily for 10 days. Matched placebo will be administered under fasted conditions on Day 1 and Day 10 and under fed conditions during Day 2 to Day 9.

  Drug: Placebo

Interventions

• DrugE2082

  Solution (0.2 mg) or tablet (0.5 mg and 5 mg).

• DrugPlacebo

  Solution (0.2 mg) or tablet (0.5 mg and 5 mg) matched to E2082.

Primary outcomes

1. 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.

   Time frame: 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.

2. 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.

   Time frame: 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

3. 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.

   Time frame: 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.

4. 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.

   Time frame: 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

5. 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.

   Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose

6. 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.

   Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose

7. 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.

   Time frame: 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.

8. 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.

   Time frame: 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

9. 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.

   Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours postdose

10. 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.

    Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours postdose

11. 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.

    Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose

12. 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.

    Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose

13. 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.

    Time frame: 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.

14. 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.

    Time frame: 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

15. 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.

    Time frame: 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.

16. 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.

    Time frame: 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

17. 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.

    Time frame: 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.

18. 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.

    Time frame: 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

19. 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.

    Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours postdose

20. 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.

    Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours postdose

21. 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.

    Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1

22. 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.

    Time frame: 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

23. 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.

    Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1

24. 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.

    Time frame: 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

25. 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.

    Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1

26. 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.

    Time frame: 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

27. 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-τ)/τ. τ is the dosing interval.

    Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 10

28. 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.

    Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose of Day 1

29. Part B: Mean value of AUC(0-τ) for the MAD cohorts

    AUC(0-τ) is AUC over the dosing interval on multiple dosing.

    Time frame: Predose and 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose of Day 10

30. 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.

    Time frame: 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

31. Part B: Peak-trough fluctuation (PTF) for the MAD cohorts

    PTF is peak to trough fluctuation at steady-state.

    Time frame: 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

32. 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-τ)/single dose AUC(0- τ), where τ is dosing interval.

    Time frame: 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

33. 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.

    Time frame: 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

34. 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.

    Time frame: 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

35. Part B: Change from baseline in QT interval corrected for heart rate using the Fridericia formula (QTcF)

    Time frame: Baseline and Day 1

36. Part B: Change from baseline in QT interval corrected for heart rate using the Fridericia formula (QTcF)

    Time frame: Baseline and Day 10

Secondary outcomes

1. Change-from-baseline in heart rate (HR)

   Time frame: Baseline, Days 1 and 10

2. Change from baseline in PR interval and QRS interval of the Electrocardiogram (ECG)

   Time frame: Baseline, Days 1 and 10

3. Placebo-corrected change from baseline in HR

   Time frame: Baseline, Days 1 and 10

4. Placebo-corrected change from baseline in QTcF, PR, QRS interval

   Time frame: Baseline, Days 1 and 10

5. Number of participants with categorical outliers for HR, PR interval, QRS interval

   Time frame: Baseline up to Day 11

6. 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

   Time frame: Baseline up to Day 11

7. Number of participants with T wave morphology changes

   Time frame: Baseline up to Day 11

8. Number of participants with U-wave presence

   Time frame: Baseline up to Day 11