- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02415790
Study to Assess the Safety, Tolerability, Pharmacokinetics of E2027 in Healthy Adult and Elderly Subjects, and the Pharmacodynamics in Healthy Adult Subjects
A 4-Part, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics of E2027 in Healthy Adult, Elderly and Japanese Subjects, and the Pharmacodynamics in Healthy Adult Subjects
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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California
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Glendale, California, United States
- Paraxel International
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Part A and B only:
Nonsmoking, male or female, age greater than or equal to 18 years and less than or equal to 50 years old at the time of informed consent
Part C only:
Nonsmoking, male or female, age greater than or equal to 65 years and less than or equal to 85 years old at the time of informed consent
Part D only:
- Nonsmoking, male or female, age greater than or equal to 20 years and less than or equal to 50 years old at the time of informed consent
- Born in Japan to Japanese parents and grandparents of Japanese descent
- Been living outside Japan for less than 5 years
Lifestyle, including diet, has not changed significantly since leaving Japan
All parts:
- Body mass index (BMI) greater than or equal to 18 and less than or equal to 30 kg/m2 at Screening
Exclusion Criteria:
- 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
If 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
- Are currently abstinent, and do not agree to use a double barrier method or refrain from sexual activity
- Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above. No sperm donation is allowed during the study period or for 28 days after study drug discontinuation.
- Evidence of disease that may influence the outcome of the study within 4 weeks before dosing
- Any history of abdominal surgery that may affect PK profiles of E2027
- Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, ECG finding, or laboratory test results that requires medical treatment at Screening or Baseline
- A prolonged QT/QTc interval (QTc greater than 450 ms) demonstrated on ECG at Screening or Baseline
- Persistent systolic blood pressure greater than 130 mmHg or diastolic blood pressure greater than 85 mm Hg at Screening or Baseline (Parts A, B, and D)
- Persistent systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mm Hg at Screening or Baseline (Part C)
- Heart rate less than 50 or more than 100 beats/min at Screening or Baseline
- History of prolonged QT/QTc interval
- Left bundle branch block
- History of myocardial infarction or active ischemic heart disease
- History of clinically significant arrhythmia or uncontrolled arrhythmia
- Known history of clinically significant drug allergy at Screening or Baseline
- Known history of food allergies or presently experiencing significant seasonal or perennial allergy at Screening or Baseline
- Known to be human immunodeficiency virus (HIV) positive at Screening
- Active viral hepatitis (A, B or C) as demonstrated by positive serology at Screening
- History of drug or alcohol dependency or abuse within the 2 years before Screening, or those who have a positive urine drug or alcohol test at Screening or Baseline
- Intake of caffeinated beverages or food within 72 hours before dosing
- Intake of nutritional supplements, juice, and herbal preparations or other foods or beverages that may affect the various drug metabolizing enzymes and transporters within 1 week before dosing
- Intake of herbal preparations containing St. John's Wort within 4 weeks before dosing
- Use of prescription drugs within 4 weeks before dosing
- Intake of over-the-counter (OTC) medications within 2 weeks before dosing
- Currently enrolled in another clinical trial or used any investigational drug or device within 30 days (or 5 half-lives, whichever is longer) preceding informed consent
- Engagement in strenuous exercise within 2 weeks before check-in (eg, marathon runners, weight lifters, etc.)
- Any contraindication to continuous CSF sampling via indwelling lumbar catheter (Part B only)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Part A: PK of E2027 in healthy adults
Part A consists of 6 sequential cohorts of healthy adults.
There will be 8 participants in each cohort, with 6 participants randomized to E2027 and 2 participants to placebo.
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Part A: E2027 capsules will be administered orally in doses of 10 mg to 1200 mg in Part A and in Part B, C, and D at doses not exceeding the highest dose achieved in Part A.
E2027 matching placebo capsule will be administered.
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Experimental: Part B: PK and PD of E2027 in healthy adults
Part B consists of 4 sequential cohorts of healthy adult participants.
There will be 8 participants in the 1st cohort, with 6 participants randomized to E2027 and 2 participants to placebo.
In the 2nd to 4th cohorts, there will be 7 participants in each cohort, with 6 participants randomized to E2027 and 1 participant to placebo.
Participants in the 2nd cohort will then receive placebo/the same dose of E2027 again after their washout period in the fed state for the evaluation of food effect.
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Part A: E2027 capsules will be administered orally in doses of 10 mg to 1200 mg in Part A and in Part B, C, and D at doses not exceeding the highest dose achieved in Part A.
E2027 matching placebo capsule will be administered.
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Experimental: Part C: PK of E2027 in elderly cohorts
In Part C, 1 cohort of 8 healthy elderly participants will be enrolled, with 6 participants randomized to E2027 and 2 participants to placebo.
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Part A: E2027 capsules will be administered orally in doses of 10 mg to 1200 mg in Part A and in Part B, C, and D at doses not exceeding the highest dose achieved in Part A.
E2027 matching placebo capsule will be administered.
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Experimental: Part D: PK of E2027 in healthy Japanese adults
In Part D, there will be 3 cohorts of 7 healthy adult Japanese participants, with 6 participants randomized to E2027 and 1 participant to placebo.
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Part A: E2027 capsules will be administered orally in doses of 10 mg to 1200 mg in Part A and in Part B, C, and D at doses not exceeding the highest dose achieved in Part A.
E2027 matching placebo capsule will be administered.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: From screening up to 10 days
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From screening up to 10 days
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Plasma PK assessments of E2027 and its metabolites for Part A, Part B, Part C, and Part D - Cmax (maximum drug concentration)
Time Frame: Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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For participants in Part B of the 2nd cohort only, samples will also be collected on the following days of Treatment Period 2: Day 1 at predose and postdose 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 18 hours.
Participants will receive a single oral dose of the same study drug that they received in the previous treatment period, but after a high-fat meal.
|
Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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Plasma PK assessments of E2027 and its metabolites for Part A, Part B, Part C, and Part D - tmax (time to reach maximum (peak) concentration following drug administration)
Time Frame: Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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For participants in Part B of the 2nd cohort only, samples will also be collected on the following days of Treatment Period 2: Day 1 at predose and postdose 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 18 hours.
Participants will receive a single oral dose of the same study drug that they received in the previous treatment period, but after a high-fat meal.
|
Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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Plasma PK assessments of E2027 and its metabolites for Part A, Part B, Part C, and Part D - AUC (area under the concentration-time curve)
Time Frame: Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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For participants in Part B of the 2nd cohort only, samples will also be collected on the following days of Treatment Period 2: Day 1 at predose and postdose 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 18 hours.
Participants will receive a single oral dose of the same study drug that they received in the previous treatment period, but after a high-fat meal.
|
Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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Plasma PK assessments of E2027 and its metabolites for Part A, Part B, Part C, and Part D - t1/2 (terminal elimination half-life following last dose)
Time Frame: Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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For participants in Part B of the 2nd cohort only, samples will also be collected on the following days of Treatment Period 2: Day 1 at predose and postdose 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 18 hours.
Participants will receive a single oral dose of the same study drug that they received in the previous treatment period, but after a high-fat meal.
|
Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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Plasma PK assessments of E2027 and its metabolites for Part A, Part B, Part C, and Part D - CL/F (Apparent total clearance following extravascular (eg, oral) administration)
Time Frame: Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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Plasma PK assessments of E2027 and its metabolites for Part A, Part B and Part C - AUC Metabolite Ratio (Metabolite to E2027 ratio for AUC(0-inf) following molecular weight correction) For participants in Part B of the 2nd cohort only, samples will also be collected on the following days of Treatment Period 2: Day 1 at predose and postdose 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 18 hours. Participants will receive a single oral dose of the same study drug that they received in the previous treatment period, but after a high-fat meal. |
Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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Plasma PK assessments of E2027 and its metabolites for Part A, Part B, Part C, and Part D - Vz/F (Apparent volume of distribution at terminal phase)
Time Frame: Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
|
For participants in Part B of the 2nd cohort only, samples will also be collected on the following days of Treatment Period 2: Day 1 at predose and postdose 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 18 hours.
Participants will receive a single oral dose of the same study drug that they received in the previous treatment period, but after a high-fat meal.
|
Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (parts A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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Plasma PK assessments of E2027 and its metabolites for Part A, Part B, Part C, and Part D - AUC Metabolite Ratio (Metabolite to E2027 ratio for AUC following molecular weight correction)
Time Frame: Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (part A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
|
For participants in Part B of the 2nd cohort only, samples will also be collected on the following days of Treatment Period 2: Day 1 at predose and postdose 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 18 hours.
Participants will receive a single oral dose of the same study drug that they received in the previous treatment period, but after a high-fat meal.
|
Day 1 at predose and postdose 0.5 (30 minutes) to 18 hours, postdose on Day 2 (24 and 36 hours (part A, B, C, D) and 30 hours (part B only), Day 3 (48 hours), Day 4 (72 hours), Day 5, (96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 10 (216 hours)
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Urine PK assessments of E2027 and its metabolites for Part A and Part C - Ae (cumulative amount of drug excreted in urine up to 96 hours postdose)
Time Frame: Day 1 to Day 5 postdose at 0 to 4 hours and greater than 4 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours and 72 to 96 hours
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Day 1 to Day 5 postdose at 0 to 4 hours and greater than 4 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours and 72 to 96 hours
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Urine PK assessments of E2027 and its metabolites for Part A and Part C - CLR (renal clearance)
Time Frame: Day 1 to Day 5 postdose at 0 to 4 hours and greater than 4 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours and 72 to 96 hours
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Day 1 to Day 5 postdose at 0 to 4 hours and greater than 4 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours and 72 to 96 hours
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CSF PK assessments of E2027 and its metabolites for Part B - Cmax (maximum drug concentration)
Time Frame: At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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CSF PK assessments of E2027 and its metabolites for Part B - tmax (time to reach maximum (peak) concentration following drug administration)
Time Frame: At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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CSF PK assessments of E2027 and its metabolites for Part B - AUC (area under the concentration-time curve from zero time extrapolated to infinite time)
Time Frame: At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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CSF PK assessments of E2027 and its metabolites for Part B - t1/2 (terminal elimination half-life following last dose)
Time Frame: At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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CSF PK assessments of E2027 and its metabolites for Part B - CSF:plasma ratio (ratio of AUC for CSF:plasma)
Time Frame: At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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PD assessments for Part B - change from baseline in CSF cGMP
Time Frame: At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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PD assessments for Part B - Amax (maximum change (%) of CSF cGMP concentration compared to baseline at a single time point within 30 hours postdose)
Time Frame: At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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PD assessments for Part B - tAmax (time at which Amax occurs for CSF cGMP)
Time Frame: At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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PD assessments for Part B - AUAC(-3 - 0 h) (area under the CSF cGMP concentration x time curve from time - 3 h to 0 h)
Time Frame: At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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PD assessments for Part B - AUAC(0 -30 h) (Area under the CSF cGMP concentration x time curve from time 0 h to 30 h)
Time Frame: At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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PD assessments for Part B -Delta AUAC(0 - 30 h) (Change (%) in AUAC averaged over 30 hours postdose relative to baseline AUAC averaged over 3 h predose for CSF cGMP, i.e. (AUAC(0 - 30 h)/30 minus AUAC(-3 - 0 h)/3)/(AUAC(-3 - 0 h)/3)
Time Frame: At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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At -3, - 2, -1 hours, predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours
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Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Other Study ID Numbers
- E2027-A001-001
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