Clinical trial NCT04676685: A Study to Assess the Safety and Tolerability of E2730 After Multiple Dose and the Food Effect After Single Dose in Healthy Participants
Official title: A Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose and Single Dose Food Effect Study to Assess the Safety, Tolerability, and Pharmacokinetics of E2730 in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: E2730
Healthy participants
Pharmacokinetics
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2020-12-21
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The primary purpose of the study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of E2730 of multiple ascending oral doses in healthy adult participants and to assess the differences in PK, safety, and tolerability of E2730 between healthy Japanese and non-Japanese participants following multiple doses. This study will also determine the effect of food on PK of E2730.


Eligibility criteria: Inclusion Criteria:

1. Non-smoking, healthy male or female, age greater than or equal to (\>=) 18 years and \<55 years old at the time of informed consent. To be considered non-smokers, Participants must have discontinued smoking for at least 4 weeks before dosing
2. Japanese Participants must have been born in Japan of Japanese parents and Japanese grandparents, must have lived no more than 5 years outside of Japan, and must not have changed their life style or habits, including diet, while living outside of Japan
3. Body mass index (BMI) \>=18 and \<30 kilograms per meter square (kg/m\^2) at Screening

Exclusion Criteria:

1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin \[β-hCG\] test). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug
2. Females of childbearing potential who:

   * Within 28 days before study entry, did not use a highly effective method of contraception, which includes any of the following:
   * Total abstinence (if it is their preferred and usual lifestyle)
   * An intrauterine device or intrauterine hormone-releasing system (IUS)
   * A contraceptive implant
   * An oral contraceptive (Participant must have been on a stable dose of the same oral contraceptive product for at least 28 days before dosing and must agree to stay on the same dose of the oral contraceptive throughout the study and for 28 days after study drug discontinuation)
   * Have a vasectomized partner with confirmed azoospermia
   * Do not agree to use a highly effective method of contraception throughout the entire study period and for 28 days after study drug discontinuation
3. Males who have not had a successful vasectomy (confirmed azoospermia) if their female partners meet the exclusion criteria above (that is, the female partners are of childbearing potential and are not willing to use a highly effective contraceptive method throughout the study period and for 5 times the half-life of the study drug plus 90 days after study drug discontinuation)
4. Clinically significant illness that requires medical treatment within 8 weeks or a clinically significant infection that requires medical treatment within 4 weeks of dosing
5. 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
6. Any history of gastrointestinal surgery that may affect PK profiles of E2730, example, hepatectomy, nephrectomy, and digestive organ resection
7. Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, ECG finding, or laboratory test results that require medical treatment at Screening
8. A prolonged QT interval of the ECG/Corrected QT interval (QT/QTc) (QTcF greater than \[\>\] 450 milliseconds \[ms\]) demonstrated by a repeated ECG at Screening or Baseline (based on average of triplicate ECGs). A history of risk factors for torsade de pointes (example, heart failure, hypokalemia, family history of long QT Syndrome) or the use of concomitant medications that prolonged the QT/QTc interval
9. Persistent systolic BP \>139 or \<90 millimeter of mercury (mmHg) or diastolic BP \>89 or \<50 mmHg at Screening or Baseline
10. Heart rate \<45 beats/minute or \>100 beats/minute at Screening or Baseline
11. Any lifetime history of suicidal ideation or any lifetime history of suicidal behavior as indicated by the Columbia-Suicide Severity Rating Scale (C-SSRS) or equivalent scale or via interview with a psychiatrist
12. Any lifetime history of psychiatric disease (including but not limited to depression or other mood disorders, bipolar disorder, psychotic disorders, including schizophrenia, panic attacks, anxiety disorders ). The absence of a history of psychiatric disease should be documented by a checklist in the electronic case report form (eCRF)
13. Any current psychiatric symptoms as indicated by a standard screening tool
14. Any suicidal ideation with intent with or without a plan at Screening or within 6 months of Screening (that is, answering "Yes" to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS)
15. Any lifetime suicidal behavior (per the Suicidal Behavior Section of the C-SSRS)
16. Known history of clinically significant drug allergy at Screening
17. Known history of food allergies or presently experiencing significant seasonal or perennial allergy at Screening
18. Known to be human immunodeficiency virus (HIV) positive at Screening
19. Active viral hepatitis (A, B, or C) and syphilis as demonstrated by positive serology at Screening
20. History of drug or alcohol dependency or abuse, or those who have a positive drug test at Screening or Baseline
21. Exposure within the last 14 days to an individual with confirmed or probable corona virus disease 2019 (COVID-19) or symptoms within the last 14 days that are on the most recent Centers for Disease Control and Prevention (CDC) list of COVID symptoms or any other reason to consider the participants at potential risk for an acute COVID-19 infection
22. Currently enrolled in another clinical study or used any investigational drug or device within 28 days or 5 half-lives, whichever is longer, preceding informed consent
23. Receipt of blood products within 4 weeks, or donation of blood within 8 weeks, or donation of plasma within 1 week of dosing
24. Any personal or family history of seizures (including febrile seizures) or epilepsy or episode of unexplained loss of consciousness
25. Any history of neurological or other medical conditions which in the opinion of the investigator has the potential to reduce seizure threshold (example, history of head concussion, traumatic brain injury, alcohol abuse, substance abuse, developmental abnormalities in the brain)
26. Any epileptiform discharges on resting EEG (including during hyperventilation and photo-stimulation)

Primary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: Screening up to Day 32 (approximately 60 days)
measure: Part A, Cmax: Maximum Observed Plasma Concentration for E2730
timeFrame: Day 1: 0-24 hours; Day 18: 0-336 hours
measure: Part A, Css,min: Minimum Observed Plasma Concentration at Steady State for E2730
timeFrame: Time Frame: Day 18: 0-24 hours
measure: Part A, tmax: Time at Which the Highest Drug Plasma Concentration Occurs for E2730
timeFrame: Day 1: 0-24 hours; Day 18: 0-336 hours
measure: Part A, Css,av: Average Steady State Plasma Concentration at Steady State for E2730
timeFrame: Time Frame: Day 18: 0-24 hours
measure: Part A, AUC(0-24h): Area Under the Plasma Concentration-time Curve From Zero Time to 24 Hours After Dosing for E2730
timeFrame: Day 1: 0-24 hours; Day 18: 0-24 hours
measure: Part A, t1/2: Terminal Elimination Phase Half-life Following Last day of Dosing for E2730
timeFrame: Day 18: 0-336 hours
measure: Part A, PTF: Peak-trough Fluctuation for E2730
timeFrame: Day 18: 0-24 hours
measure: Part A, Rac: Accumulation Ratio for Cmax and AUC for E2730
timeFrame: Day 1: 0-24 hours; Day 18: 0-24 hours
measure: Part A, CLss/F: Apparent Total Clearance Following Extravascular Administration at Steady State for E2730
timeFrame: Day 18: 0-336 hours
measure: Part A, Vz/F: Apparent Volume of Distribution at Terminal Phase
timeFrame: Day 18: 0-336 hours
measure: Part B, Cmax: Maximum Observed Plasma Concentration for E2730
timeFrame: Day 1: 0-288 hours; Day 22: 0-288 hours
measure: Part B, tmax: Time at Which the Highest Drug Plasma Concentration Occurs for E2730
timeFrame: Day 1: 0-288 hours; Day 22: 0-288 hours
measure: Part B, AUC(0-24h): Area Under the Plasma Concentration-time Curve From Zero Time to 24 Hours After Dosing for E2730
timeFrame: Day 1: 0-24 hours; Day 22: 0-24 hours
measure: Part B, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to Time of Last Quantifiable Concentration for E2730
timeFrame: Day 1: 0-288 hours; Day 22: 0-288 hours
measure: Part B, AUC(0-72h): Area Under the Plasma Concentration-time Curve From Zero Time to 72 Hours After Dosing for E2730
timeFrame: Day 1: 0-72 hours; Day 22: 0-72 hours
measure: Part B, AUC(0-inf): Area Under the Plasma Concentration-time Curve From Zero Time Extrapolated to Infinite Time for E2730
timeFrame: Day 1: 0-288 hours; Day 22: 0-288 hours
measure: Part B, t1/2: Terminal Elimination Phase Half-life for E2730
timeFrame: Day 1: 0-288 hours; Day 22: 0-288 hours
measure: Part A: Geometric Mean Ratio of Cmax Between the Healthy Japanese and non-Japanese Participants for E2730
timeFrame: Day 1: 0-24 hours; Day 18: 0-336 hours
measure: Part A: Geometric Mean Ratio of AUC(0-24) Between the Healthy Japanese and non-Japanese Participants for E2730
timeFrame: Day 1: 0-24 hours; Day 18: 0-24 hours
measure: Part B: Geometric Mean Ratio of Cmax Between the Fasted and fed State for E2730
timeFrame: Day 1: 0-288 hours; Day 22: 0-288 hours
measure: Part B: Geometric Mean Ratio of AUC(0-t) Between the Fasted and fed State for E2730
timeFrame: Day 1: 0-288 hours; Day 22: 0-288 hours
measure: Part B: Geometric Mean Ratio of AUC(0-72h) Between the Fasted and fed State for E2730
timeFrame: Day 1: 0-72 hours; Day 22: 0-72 hours
measure: Part B: Geometric Mean Ratio of AUC(0-inf) Between the Fasted and fed State for E2730
timeFrame: Day 1: 0-288 hours; Day 22: 0-288 hours
Secondary outcomes:
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline, Day 32
measure: Change From Baseline in Heart Rate (HR)
timeFrame: Baseline, Day 32
measure: Placebo Corrected Change From Baseline in SBP and DBP
timeFrame: Baseline, Day 32
measure: Placebo Corrected Change From Baseline in HR
timeFrame: Baseline, Day 32
measure: Number of Participants With Categorical Outliers for SBP and DBP
timeFrame: Baseline up to Day 32
measure: Change From Baseline in QT Interval by Fridericia (QTcF)
timeFrame: Baseline, Day 32
measure: Change From Baseline in PR Interval of the ECG (PR), QRS Interval of the ECG (QRS)
timeFrame: Baseline, Day 32
measure: Placebo Corrected Change From Baseline in QTcF, PR and QRS
timeFrame: Baseline, Day 32
measure: Number of Participants With Categorical Outliers for QTcF, HR, PR, and QRS
timeFrame: Baseline, Day 32
measure: Number of Participants With T-wave Morphology Changes
timeFrame: Baseline up to Day 32
measure: Number of Participants With Presence of Abnormal U-wave
timeFrame: Baseline up to Day 32
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: Collaborative Neuroscience Research, LLC.
state: California
Study officials:
References: