Study to Assess the Safety, Tolerability, and Pharmacokinetics of E2730

NCT03054194 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: E2730-A001-001
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

Study E2730-A001-001 is a first-in-human, sequential ascending single dose, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics (PK) of a single oral dose of E2730 in healthy participants.

Conditions

Healthy Participants

Keywords

Healthy participants; E2730; Pharmacokinetics

Outcome Measures

Primary Outcomes (20)

• Number of participants with any serious adverse event and number of participants with any non-serious adverse event

  An adverse event is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A serious adverse event is defined as any adverse event occurring at any dose that results in any of the following outcomes: results in death; is life threatening; results in inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life function; results in a congenital anomaly/birth defect; or can be defined as any other important medical event.

  up to Day 10 (Follow-up/Early Termination)

• Number of participants with an abnormal, clinically significant hematology parameter value

  Participants will fast for at least 4 hours before blood is drawn for the assessment of hematocrit, hemoglobin, platelets, red blood cell (RBC) count, and white blood cell (WBC) count with differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils). Clinical significance will be determined by the Investigator.

  Screening; Baseline; Days 2 and 5; Day 10 (Follow-up/Early Termination)

• Number of participants with an abnormal, clinically significant blood chemistry parameter value

  Participants will fast for at least 4 hours before blood is drawn for the assessment of electrolytes (chloride, potassium, sodium); liver function test parameters (alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, total bilirubin); renal function test parameters (blood urea/blood urea nitrogen, creatinine); and other parameters such as albumin, calcium, cholesterol, globulin, glucose, lactate dehydrogenase, phosphorus, total protein, triglycerides, and uric acid. Clinical significance will be determined by the Investigator.

  Screening; Baseline; Days 2 and 5; Day 10 (Follow-up/Early Termination)

• Number of participants with an abnormal, clinically significant urine value

  Urinalysis will be performed to determine abnormalities in the presence of bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, pH, protein, RBCs, specific gravity, and WBCs in urine. Clinical significance will be determined by the Investigator.

  Screening; Baseline; Days 2 and 5; Day 10 (Follow-up/Early Termination)

• Number of participants with an abnormal, clinically significant vital sign value

  Vital sign measurements (ie, systolic and diastolic blood pressure \[BP\] \[millimeters of mercury (mmHg)\], pulse \[beats per minute\], respiratory rate \[breaths per minute\], and body temperature \[centigrade\]) will be obtained in the supine position by a validated method. Clinical significance will be determined by the Investigator.

  up to Day 10 (Follow-up/Early Termination)

• Mean change from Baseline in weight

  Weight (kilograms \[kg\]) will be obtained by a validated method.

  Screening; Baseline; Day 10 (Follow-up/Early Termination)

• Number of participants with an abnormal, clinically significant electrocardiogram (ECG) parameter value

  An ECG is a record or display of a person's heartbeat produced by electrocardiography. The Holter device will be used for ECG recording. Monitoring will begin at 24 hours before dosing. Clinical significance will be determined by the Investigator.

  Screening; Baseline; up to Day 10 (Follow-up/Early Termination)

• Number of participants with an abnormal, clinically significant physical examination parameter value

  A comprehensive physical examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and lungs), abdomen, limbs, skin, and a complete neurological examination. A urogenital examination will only be required in the presence of clinical symptoms related to those regions. For abbreviated physical examinations, health status will be assessed by brief evaluation of the chest (including heart and lungs), abdomen and limbs, and other physical conditions of note. Clinical significance will be determined by the Investigator.

  Screening; Baseline; Day 5; Day 10 (Follow-up/Early Termination)

• Number of participants with an abnormal, clinically significant neurological parameter value

  Abnormalities in neurological parameters due to an increase in inhibitory neurotransmission after E2730 administration will be assessed. Clinical significance will be determined by the Investigator.

  Screening

• Mean maximum observed concentration (Cmax) for E2730 and the N-acetyl metabolite in plasma

  Cmax is defined as the maximum observed concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered. Blood samples for the determination of E2730 plasma concentrations and its N-acetyl metabolite will be collected from predose through Day 10 (216 hours postdose). Using non-compartmental analysis, plasma concentrations of E2730 and the N-acetyl metabolite will be analyzed to determine Cmax.

  Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.

• Mean time at which the highest drug concentration (tmax) occurs for E2730 and the N-acetyl metabolite in plasma

  Tmax is defined as the time from dosing to reach the maximum observed concentration a drug achieves in a specified compartment or test area of the body after the drug has been administered. Blood samples for the determination of E2730 plasma concentrations and its N-acetyl metabolite will be collected from predose through Day 10 (216 hours postdose). Using non-compartmental analysis, plasma concentrations of E2730 and the N-acetyl metabolite will be analyzed to determine tmax.

  Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.

• Mean area under the concentration-time curve from zero time to 24 hours after dosing (AUC[0-24h]) for E2730 and the N-acetyl metabolite in plasma

  AUC represents the total drug exposure over a defined period of time. Blood samples for the determination of E2730 plasma concentrations and its N-acetyl metabolite will be collected from predose through Day 10 (216 hours postdose). Using non-compartmental analysis, plasma concentrations of E2730 and the N-acetyl metabolite will be analyzed to determine AUC(0-24h).

  Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.

• Mean area under the concentration-time curve from zero time to time of last quantifiable concentration (AUC[0-t]) for E2730 and the N-acetyl metabolite in plasma

  AUC represents the total drug exposure over a defined period of time. Blood samples for the determination of E2730 plasma concentrations and its N-acetyl metabolite will be collected from predose through Day 10 (216 hours postdose). Using non-compartmental analysis, plasma concentrations of E2730 and the N-acetyl metabolite will be analyzed to determine AUC(0-t).

  Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.

• Mean area under the concentration-time curve from zero time to 72 hours after dosing (AUC[0-72h]) for E2730 and the N-acetyl metabolite in plasma

  AUC represents the total drug exposure over a defined period of time. Blood samples for the determination of E2730 plasma concentrations and its N-acetyl metabolite will be collected from predose through Day 10 (216 hours postdose). Using non-compartmental analysis, plasma concentrations of E2730 and the N-acetyl metabolite will be analyzed to determine AUC(0-72h).

  Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.

• Mean area under the concentration-time curve from zero time to 96 hours after dosing (AUC[0-96h]) for E2730 and the N-acetyl metabolite in plasma

  AUC represents the total drug exposure over a defined period of time. Blood samples for the determination of E2730 plasma concentrations and its N-acetyl metabolite will be collected from predose through Day 10 (216 hours postdose). Using non-compartmental analysis, plasma concentrations of E2730 and the N-acetyl metabolite will be analyzed to determine AUC(0-96h).

  Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.

• Mean area under the concentration-time curve from zero time extrapolated to infinite time (AUC[0-inf]) for E2730 and the N-acetyl metabolite in plasma

  AUC represents the total drug exposure over a defined period of time. Blood samples for the determination of E2730 plasma concentrations and its N-acetyl metabolite will be collected from predose through Day 10 (216 hours postdose). Using non-compartmental analysis, plasma concentrations of E2730 and the N-acetyl metabolite will be analyzed to determine AUC(0-inf).

  Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.

• Mean terminal phase half-life (t1/2) for E2730 and the N-acetyl metabolite in plasma

  Terminal half-life is the time it takes for a substance to lose half of its pharmacological, physiological, or radiologic activity. Blood samples for the determination of E2730 plasma concentrations and its N-acetyl metabolite will be collected from predose through Day 10 (216 hours postdose). Using non-compartmental analysis, plasma concentrations of E2730 and the N-acetyl metabolite will be analyzed to determine t1/2.

  Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.

• Mean apparent total clearance following extravascular (eg, oral) administration of E2730 (CL/F) in plasma

  CL/F is the rate and extent of absorption and clearance of E2730 from the plasma. Blood samples for the determination of E2730 plasma concentrations will be collected from predose through Day 10 (216 hours postdose). Using non-compartmental analysis, plasma concentrations of E2730 will be analyzed to determine CL/F. CL/F will be expressed in volume per time.

  Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.

• Mean apparent volume of distribution at terminal phase (Vz/F) for E2730 in plasma

  Volume of distribution is defined as the fluid volume that would be required to contain the amount of E2730 present in the body at the same concentration as in the plasma. Vz/F is the apparent volume of distribution at terminal phase for E2730 only. Blood samples for the determination of E2730 plasma concentrations will be collected from predose through Day 10 (216 hours postdose). Using non-compartmental analysis, plasma concentrations of E2730 will be analyzed to determine Vz/F.

  Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.

• Metabolite ratio (%) calculated as the ratio of plasma AUC(0-inf) of metabolite to parent following molar correction (MRP) for E2730 and the N-acetyl metabolite

  Metabolite ratio (%) is calculated as the ratio of plasma AUC(0-inf) of a metabolite to a parent following molar correction. Blood samples for the determination of E2730 plasma concentrations and its N-acetyl metabolite will be collected from predose through Day 10 (216 hours postdose). Using non-compartmental analysis, plasma concentrations of E2730 and the N-acetyl metabolite will be analyzed to determine the metabolite ratio.

  Day 1: predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 18 hours postdose. 24 (Day 2), 36 (Day 2), 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7), 216 hours (Day 10) postdose.

Secondary Outcomes (3)

• Mean change from Baseline in blood pressure (BP) using ambulatory BP monitoring (ABPM)

  Baseline; Day 1; Day 2

• Mean change from Baseline in heart rate using Holter monitoring

  Baseline; Day 1; Day 2

• Mean change from Baseline in corrected QT (QTc) interval using Holter monitoring

  Baseline; Day 1; Day 2

Study Arms (6)

Cohort 1: Dose 1 E2730

EXPERIMENTAL

Participants will receive Dose 1 of oral E2730 on Day 1.

Drug: E2730

Cohort 1: Matching placebo

PLACEBO COMPARATOR

Participants will receive matching oral placebo on Day 1.

Drug: Placebo

Cohort 2: Dose 2 E2730

EXPERIMENTAL

Participants will receive Dose 2 of oral E2730 on Day 1.

Drug: E2730

Cohort 2: Matching placebo

PLACEBO COMPARATOR

Participants will receive oral matching placebo on Day 1.

Drug: Placebo

Cohort 3: Dose 3 E2730

EXPERIMENTAL

Participants will receive Dose 3 of oral E2730 on Day 1.

Drug: E2730

Cohort 3: Matching placebo

PLACEBO COMPARATOR

Participants will receive oral matching placebo on Day 1.

Drug: Placebo

Interventions

E2730 DRUG

capsules

Cohort 1: Dose 1 E2730; Cohort 2: Dose 2 E2730; Cohort 3: Dose 3 E2730

Placebo DRUG

capsules

Cohort 1: Matching placebo; Cohort 2: Matching placebo; Cohort 3: Matching placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Non-smoking, male or female, age ≥18 years and ≤55 years old at the time of informed consent (note: to be considered non-smokers, participants must have discontinued smoking for at least 4 weeks before dosing)
• Body mass index (BMI) ≥18 and \<32 kilograms per meters squared (kg/m\^2) 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 (documented by a negative beta human chorionic gonadotropin \[β-hCG\] (or human chorionic gonadotropin \[hCG\]) test with a minimum sensitivity of 25 International Units per Liter \[IU/L\] or equivalent units of β-hCG \[or hCG\]). A negative urine pregnancy test is required before the administration of the first 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 3 months after study drug discontinuation.
• Evidence of disease that may influence the outcome of the study 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)
• Any history of seizures, including those experienced in childhood
• Any history of gastrointestinal surgery that may affect pharmacokinetic profiles of E2730 (eg, hepatectomy, nephrectomy, digestive organ resection) at Screening
• Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, electrocardiogram (ECG) finding, or laboratory test results that require medical treatment at Screening or Baseline
• A prolonged QT/QT corrected (QTc) interval (QC interval corrected using Fridericia's formula \[QTcF\] \>450 milliseconds) demonstrated on ECG at Screening or Baseline (based on average of triplicate ECGs). A history of risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT Syndrome) or the use of concomitant medications that prolonged the QT/QTc interval
• Left bundle branch block at Screening or Baseline
• Persistent systolic blood pressure (BP) \>130 or \<100 millimeters of mercury (mmHg) or diastolic BP \>85 or \<50 mmHg at Screening or Baseline
• Persistent heart rate less than 50 beats/min or more than 100 beats/min at Screening or Baseline

Sponsors & Collaborators

• Eisai Inc.: lead

Study Sites (1)

Eisai Trial Site

San Antonio, Texas, 78217, United States

Location

Study Design

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

Study Record Dates

• First Submitted: February 13, 2017
• First Posted: February 15, 2017
• Study Start: January 31, 2017
• Primary Completion: March 2, 2017
• Study Completion: March 2, 2017
• Last Updated: September 7, 2018

Record last verified: 2017-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)