A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E2027 in Healthy Subjects

NCT02873156 | Completed Phase 1 FDA Drug

• 1 other identifier: E2027-A001-002
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of multiple ascending oral doses of E2027 in healthy participants.

Conditions

Healthy Subjects

Keywords

E2027; Healthy participants; Pharmacokinetics; Pharmacodynamics

Outcome Measures

Primary Outcomes (12)

• Maximum drug concentration (Cmax)

  Blood samples will be collected on Day 1 at predose and postdose 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours; Day 14 (at predose and postdose 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours); and Day 15 (24 hours postdose from Day 14).

  Day 1 and Day 14

• Mean predose drug concentration (Cmin)

  Predose on Days 2, 4, 6, 8, 10, 12, 13, and 14

• Mean time to reach maximum (peak) drug concentration (tmax)

  Blood samples will be collected on Day 1 at predose and postdose 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18 and 24 hours; Day 14 (at predose and postdose 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours); and Day 15 (24 hours postdose from Day 14).

  Day 1 and Day 14

• Mean area under the concentration-time curve from zero time to 24 hours postdose (AUC(0-24h))

  Blood samples will be collected on Day 1 at predose and postdose 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18 and 24 hours; Day 14 (at predose and postdose 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours); and Day 15 (24 hours postdose from Day 14).

  Day 1 and Day 14

• Mean area under the concentration-time curve from zero time extrapolated to infinity (AUC(0-inf))

  Blood samples will be collected on Day 14 (at predose and postdose 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours) and Day 15 (24 hours postdose from Day 14).

  Day 14

• Mean terminal elimination half-life (t1/2)

  Blood samples will be collected on Day 14 (at predose and postdose 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours) and Day 15 (24 hours postdose from Day 14).

  Day 14

• Average steady state drug concentration (Css,av)

  Blood samples will be collected on Day 14 (at predose and postdose 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours) and Day 15 (24 hours postdose from Day 14).

  Day 14

• Mean apparent clearance at steady state (CLss/F)

  Blood samples will be collected on Day 14 (at predose and postdose 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours) and Day 15 (24 hours postdose from Day 14).

  Day 14

• Mean apparent volume of distribution at steady state (Vss/F)

  Blood samples will be collected on Day 14 (at predose and postdose 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours) and Day 15 (24 hours postdose from Day 14).

  Day 14

• Mean accumulation ratio (Rac) (Day 14: Day 1) for AUC(0-24h), Cmax and Cmin

  Day 1 at predose and postdose 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18 and 24 hours; Day 14 (at predose and postdose 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours); and Day 15 (24 hours postdose from Day 14)

  Day 1 and Day 14

• Mean peak-trough fluctuation ratio (PTF)

  Blood samples will be collected on Day 14 (at predose and postdose 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours) and Day 15 (24 hours postdose from Day 14).

  Day 14

• Mean ratio of cerebrospinal fluid (CSF) : plasma concentrations

  Day -2 (time-matched to the Day 13 lumbar puncture [LP]) and Day 13 (predose)

Secondary Outcomes (2)

• Percentage change from Baseline in pharmacodynamic measure

  Day -2 (baseline with no drug) to Day 13 (on drug)

• Change from baseline in Observed Fridericia's Correction Formula (QTcF)

  Days -1, 1, and 14

Study Arms (2)

E2027

EXPERIMENTAL

Four sequential cohorts of healthy participants (≥50 years and ≤85 years old) will be treated with multiple ascending doses of E2027 up to the maximum tolerated dose (MTD). A total of 6 participants per cohort will be randomized to E2027.Proposed doses of E2027 are: * Part A Cohort 1: 50 mg (1 × 50 mg capsule) * Cohort 2: 100 mg (2 × 50 mg capsules) * Cohort 3: 200 mg (4 × 50 mg capsules) * Cohort 4: 400 mg (8 × 50 mg capsules) * Cohort 6: 25 mg (5 × 5 mg capsules) Part B * Cohort 5: 400 mg (8 × 50 mg capsule) Part C: • Cohort 7: 50 mg (1 × 50 mg capsules) Part D: * Cohort 8: 5 mg (1 × 5 mg capsules) * Cohort 9: 10 mg (2 × 5 mg capsules)

Drug: E2027

Placebo

PLACEBO COMPARATOR

Four sequential cohorts of healthy participants (≥50 years and ≤85 years old) will be treated with multiple ascending doses of E2027 matched placebo up to the MTD. A total of 2 participants per cohort will be randomized to E2027 matched placebo.

Drug: E2027 matched placebo

Interventions

E2027 DRUG

Participants will receive E2027 capsules, orally once daily (QD) on Days 1 to 14 after an overnight fast of at least 10 hours. E2027 will be administered orally with 240 milliliter (mL) (8 fluid ounces) of water.

E2027

E2027 matched placebo DRUG

Participants will receive E2027 matched placebo capsules, orally once daily (QD) on Days 1 to 14 after an overnight fast of at least 10 hours. E2027 matched placebo will be administered orally with 240 mL (8 fluid ounces) of water.

Placebo

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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 \[beta (ß)-hCG\] (or human chorionic gonadotropin \[hCG\]) test with a minimum sensitivity of 25 International Unit per Liter (IU/L) or equivalent units of ß-hCG \[or hCG\]). A negative urine pregnancy test is required before the administration of the 1st 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 28 days after study drug discontinuation
• Medical conditions which are not adequately and stably controlled on stable doses of medications or which, in the clinical opinion of the Principal Investigator (PI), may interfere with study procedures or participant safety 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). Participants with the following stable medical conditions, adequately controlled with stable doses of concomitant medications, need not be excluded if in the opinion of the PI, their conditions do not compromise participant safety or study procedures:
• hypertension without cerebrovascular or cardiovascular complications, controlled on not more than 1 antihypertensive drug
• hyperlipidemia without cerebrovascular or cardiovascular complications, controlled with diet or monotherapy medication
• mild, localized diseases of the skin, respiratory tract which do not require systemic medication treatment and without systemic complications
• mild, localized diseases of the eyes which are not symptomatic and do not require systemic medication treatment and without systemic complications
• osteoarthritis which does not require opioids for treatment of pain
• History of cerebrovascular disease (including transient ischemic attack or stroke)
• Any history of abdominal surgery that may affect pharmacokinetic (PK) profiles of E2027 (eg, hepatectomy, nephrectomy, digestive organ resection) at Screening or Baseline
• Any other clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, electrocardiogram (ECG) finding, or laboratory test results that requires medical treatment at Screening or Baseline

Sponsors & Collaborators

• Eisai Inc.: lead

Study Sites (1)

California Clinical Trials Medical Group

Glendale, California, 91206, United States

Location

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 16, 2016
• First Posted: August 19, 2016
• Study Start: August 10, 2016
• Primary Completion: November 29, 2017
• Study Completion: November 29, 2017
• Last Updated: September 7, 2018

Record last verified: 2017-11

Locations

US (1)