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Completed

NCT Number: NCT02415790

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

This first-in-human study, designed to assess the safety, tolerability, and pharmacokinetics (PK) of single oral ascending doses of E2027, will be administered to healthy adult participants to determine the maximum tolerated dose (MTD). Thereafter, the pharmacodynamic (PD) effects of single doses of E2027 on elevation of cerebrospinal fluid (CSF) cyclic guanidine monophosphate (cGMP) in healthy adult participants will be evaluated across a broad dose range, to establish the PK/PD relationship.

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Key information

Conditions

Healthy Participants

Age range

18 year–85 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Paraxel International

Glendale, California, United States

About this study

The study will consist of 4 parts, Parts A, B, C, and D. Part A is a single ascending dose (SAD) clinical pharmacology for evaluation of safety, tolerability, and PK characteristics up to the MTD in healthy adult (greater than or equal to 18 years and less than or equal to 50 years old). In Part B, the PK and PD effects of E2027 on CSF cGMP are evaluated in healthy adult (greater than or equal to 18 years and less than or equal to 50 years old). Participants in 2nd cohort of Part B will participate in the evaluation of food effect in Treatment Period 2. In Part C, the design is similar to Part A. This healthy elderly cohort (greater than or equal to 65 years and less than or equal to 85 years old) will provide bridging PK, safety, and tolerability data on E2027 compared to younger healthy participants in Part A and Part B. Part D will be conducted in healthy Japanese adult participants (greater than or equal to 20 years and less than or equal to 50 years old) and is designed to bridge the PK, safety, and tolerability data of E2027 between Japanese and non-Japanese participants. All parts of the study will have 2 phases: the Prerandomization Phase and the Randomization Phase. The Prerandomization Phase will consist of a Screening Period and a Baseline Period during which each participant's study eligibility will be determined and baseline assessments will be conducted. The Randomization Phase will consist of the Treatment Period and a Follow-Up Period. During the Treatment Period, participants will be randomized to receive a single oral dose of either E2027 or placebo matching E2027.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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)

Treatment and study plan

E2027

Drug

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

Drug

E2027 matching placebo capsule will be administered.

Primary outcomes

  1. Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Time frame: From screening up to 10 days

  2. 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)

    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.

  3. 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)

    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.

  4. 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)

    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.

  5. 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)

    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.

  6. 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)

    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.

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

Sponsors and collaborators

Lead sponsor

Eisai Inc.

Industry

Registry information

Official study title

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

Important dates

Study start
2015
Primary completion
2016
Study completion
2016
First posted
Apr 14, 2015
Registry last updated
Mar 8, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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