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

NCT02415790 | Completed Phase 1

• 1 other identifier: E2027-A001-001
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Healthy Participants

Keywords

E2027; Healthy Adult and Elderly Subjects; Pharmacokinetics/Pharmacodynamics

Outcome Measures

Primary Outcomes (21)

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

  From screening up to 10 days

• Plasma PK assessments of E2027 and its metabolites for Part A, Part B, Part C, and Part D - Cmax (maximum drug concentration)

  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)

• 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)

  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)

• 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)

  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)

• 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)

  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)

• 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)

  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)

• 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)

  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)

• 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)

  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)

• 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)

  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

• Urine PK assessments of E2027 and its metabolites for Part A and Part C - CLR (renal clearance)

  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

• CSF PK assessments of E2027 and its metabolites for Part B - Cmax (maximum drug concentration)

  At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours

• CSF PK assessments of E2027 and its metabolites for Part B - tmax (time to reach maximum (peak) concentration following drug administration)

  At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours

• 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)

  At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours

• CSF PK assessments of E2027 and its metabolites for Part B - t1/2 (terminal elimination half-life following last dose)

  At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours

• CSF PK assessments of E2027 and its metabolites for Part B - CSF:plasma ratio (ratio of AUC for CSF:plasma)

  At predose (0 hour), and postdose at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 and 30 hours

• PD assessments for Part B - change from baseline in CSF cGMP

  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

• PD assessments for Part B - Amax (maximum change (%) of CSF cGMP concentration compared to baseline at a single time point within 30 hours postdose)

  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

• PD assessments for Part B - tAmax (time at which Amax occurs for CSF cGMP)

  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

• 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)

  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

• 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)

  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

• 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)

  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

Study Arms (4)

Part A: PK of E2027 in healthy adults

EXPERIMENTAL

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.

Drug: E2027; Drug: E2027 matching placebo

Part B: PK and PD of E2027 in healthy adults

EXPERIMENTAL

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.

Drug: E2027; Drug: E2027 matching placebo

Part C: PK of E2027 in elderly cohorts

EXPERIMENTAL

In Part C, 1 cohort of 8 healthy elderly participants will be enrolled, with 6 participants randomized to E2027 and 2 participants to placebo.

Drug: E2027; Drug: E2027 matching placebo

Part D: PK of E2027 in healthy Japanese adults

EXPERIMENTAL

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.

Drug: E2027; Drug: E2027 matching placebo

Interventions

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.

Part A: PK of E2027 in healthy adults; Part B: PK and PD of E2027 in healthy adults; Part C: PK of E2027 in elderly cohorts; Part D: PK of E2027 in healthy Japanese adults

E2027 matching placebo DRUG

E2027 matching placebo capsule will be administered.

Part A: PK of E2027 in healthy adults; Part B: PK and PD of E2027 in healthy adults; Part C: PK of E2027 in elderly cohorts; Part D: PK of E2027 in healthy Japanese adults

Eligibility Criteria

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

You may qualify if:

• 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

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
• 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

Sponsors & Collaborators

• Eisai Inc.: lead

Study Sites (1)

Paraxel International

Glendale, California, United States

Location

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 11, 2015
• First Posted: April 14, 2015
• Study Start: July 1, 2015
• Primary Completion: June 1, 2016
• Study Completion: July 1, 2016
• Last Updated: March 8, 2017

Record last verified: 2017-03

Locations

US (1)