Clinical trial NCT03436849: A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ESN364 in Healthy Japanese Male and Pre- and Post-menopausal Female Subjects
Official title: Phase 1 Study of ESN364 - Placebo-controlled, Single and Multiple Oral Dose Study in Healthy Japanese Male and Healthy Japanese Pre- and Postmenopausal Female Subjects -
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Keywords: ASP2693
Pharmacodynamics
Pharmacokinetics
ESN364
Safety
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2018-02-19
Enrollment: 44
Sex: ALL
Minimum age (years): 20
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to evaluate the safety and tolerability of single and multiple oral doses of ESN364 in healthy Japanese male and pre- and post-menopausal female subjects. This study will also evaluate the pharmacokinetics (PK) of ESN364 and its metabolite, and the pharmacodynamics (PD) of ESN364 after single and multiple oral doses administration in healthy Japanese male and pre- and post-menopausal female subjects.

Detailed description: This study consists of two parts. Part 1; Single Dose (SD) and Part 2; Single and Multiple Dose (SD and MD).

Eligibility criteria: Inclusion Criteria:

* Male subject between 20 to \< 45 years of age, or female subject between 20 to \< 65 years of age.
* Body weight at screening: ≥ 50.0 kg and \< 80.0 kg for male, ≥ 40.0 kg and \< 70.0 kg for female.
* Body mass index (BMI) at screening: range of ≥ 17.6 kg/m2 and \< 26.4 kg/m2 \[BMI = Body weight (kg) ÷ {Body height (m)2}\].

Exclusion Criteria:

* Subjects who participated or are scheduled to participate in any clinical trials or post-marketing studies within 84 days prior to screening.
* Subject has had previous exposure with ESN364.
* Subject has any clinically significant history of allergic conditions prior to study drug administration.
* Subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy.
* Subject has contracted pyretic or symptomatic viral, bacterial, or fungal infection within 7 days prior to hospital admission.
* Any deviation from the normal range of blood pressure, pulse, body temperature, or routine 12-lead ECG at screening or on the day of hospital admission.
* Subjects who has any significantly abnormal results of laboratory tests at screening or on the day of hospital admission.
* Subjects who are positive for any of urinary drug abuse test or serology test at screening.
* Subject took a drug or underwent therapy within 2 weeks prior to hospital admission.
* Subjects used a drug or underwent therapy that affects sex hormones within 3 months prior to hospital admission.
* Subjects who had bilateral orchiectomy.
* Subject has used any inducer of metabolism in the 3 months prior to hospital admission.
* Subject has a history of smoking more than 10 cigarettes per day within 3 months prior to screening test.
* Subject consumes, on average, more than approximately 500 mg/day of caffeine
* Subject has a history of consuming more than 30 units of alcoholic beverages per week within 6 months prior to screening or has a history of alcoholism or drug/chemical/ substance abuse within past 2 years prior to screening.
* Subjects who conducted or is scheduled to conduct any blood donation or blood drawing.

Primary outcomes:
measure: Safety assessed by incidence of adverse events (AEs) in Part 1
timeFrame: Up to Day 12 in Part 1
measure: Safety assessed by incidence of AEs in Part 2
timeFrame: Up to Day 24 in Part 2
measure: Safety assessed by vital signs: Body temperature in Part 1
timeFrame: Up to day 12 in Part 1
measure: Safety assessed by vital signs: Body temperature in Part 2
timeFrame: Up to Day 24 in Part 2
measure: Safety assessed by vital signs: Blood pressure in Part 1
timeFrame: Up to Day 12 in Part 1
measure: Safety assessed by vital signs: Blood pressure in Part 2
timeFrame: Up to Day 24 in Part 2
measure: Safety assessed by vital signs: Pulse rate in Part 1
timeFrame: Up to Day 12 in Part 1
measure: Safety assessed by vital signs: Pulse rate in Part 2
timeFrame: Up to Day 24 in Part 2
measure: Safety assessed by laboratory test: Hematology in Part 1
timeFrame: Up to Day 12 in Part 1
measure: Safety assessed by laboratory test: Hematology in Part 2
timeFrame: Up to Day 24 in Part 2
measure: Safety assessed by laboratory test: Biochemistry in Part 1
timeFrame: Up to Day 12 in Part 1
measure: Safety assessed by laboratory test: Biochemistry in Part 2
timeFrame: Up to Day 24 in Part 2
measure: Safety assessed by laboratory test: Urinalysis in Part 1
timeFrame: Up to Day 12 in Part 1
measure: Safety assessed by laboratory test: Urinalysis in Part 2
timeFrame: Up to Day 24 in Part 2
measure: Safety assessed by standard 12-lead electrocardiogram (ECG) in Part 1
timeFrame: Up to Day 12 in Part 1
measure: Safety assessed by standard ECG in Part 2
timeFrame: Up to Day 24 in Part 2
measure: Safety assessed by ECG parameters: Heart rate in Part 1
timeFrame: Up to 24 hr after dosing in Part 1
measure: Safety assessed by ECG parameters: Heart rate in Part 2
timeFrame: Up to 24 hr after dosing on Day 10 in multiple dose (MD) of Part 2
measure: Safety assessed by ECG parameters: QT interval in Part 1
timeFrame: Up to 24 hr after dosing in Part 1
measure: Safety assessed by ECG parameters: QT interval in Part 2
timeFrame: Up to 24 hr after dosing on Day 10 in MD of Part 2
measure: Safety assessed by ECG parameters: RR interval in Part 1
timeFrame: Up to 24 hr after dosing in Part 1
measure: Safety assessed by ECG parameters: RR interval in Part 2
timeFrame: Up to 24 hr after dosing on Day 10 in MD of Part 2
measure: Safety assessed by ECG parameters: PR interval in Part 1
timeFrame: Up to 24 hr after dosing in Part 1
measure: Safety assessed by ECG parameters: PR interval in Part 2
timeFrame: Up to 24 hr after dosing on Day 10 in MD of Part 2
measure: Safety assessed by ECG parameters: QRS interval in Part 1
timeFrame: Up to 24 hr after dosing in Part 1
measure: Safety assessed by ECG parameters: QRS interval in Part 2
timeFrame: Up to 24 hr after dosing on Day 10 in MD of Part 2
measure: Safety assessed by ECG parameters: QTc interval corrected by Fridericia method (QTcF) in Part 1
timeFrame: Up to 24 hr after dosing in Part 1
measure: Safety assessed by ECG parameters: QTcF in Part 2
timeFrame: Up to 24 hr after dosing on Day 10 in MD of Part 2
measure: Safety assessed by body weight in Part 1
timeFrame: Up to Day 3 in Part 1
measure: Safety assessed by body weight in Part 2
timeFrame: Up to Day 15 in Part 2
measure: Safety assessed by menstrual cycle in pre-menopausal females
timeFrame: Up to an average of two weeks after last dosing
Secondary outcomes:
measure: Pharmacokinetics (PK) parameter for ESN364 and its metabolite: Area under the concentration-time curve (AUC) from the time of dosing to time 24 h (AUC24) in plasma
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2
measure: PK parameter for ESN364 and its metabolite: AUC from the time of dosing extrapolated to time infinity (AUCinf) in plasma
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2
measure: PK parameter for ESN364 and its metabolite: Percentage of AUCinf (AUCinf(%extrap)) in plasma
timeFrame: Up to 48 hr after dosing in Part 1
measure: PK parameter for ESN364 and its metabolite: AUC from the time of dosing to the last measurable concentration (AUClast) in plasma
timeFrame: Up to 48 hr after dosing in Part 1
measure: PK parameter for ESN364 and its metabolite: Maximum concentration (Cmax) in plasma
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PK parameter for ESN364 and its metabolite: Apparent total clearance after extra-vascular dosing (CL/F) in plasma
timeFrame: Up to 48 hr after dosing in Part 1 and after dosing on Day 10 in MD part of Part 2
measure: PK parameter for ESN364 and its metabolite: Time point prior to the time point corresponding to the first measurable (non-zero) concentration (tlag) in plasma
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PK parameter for ESN364 and its metabolite: Time of the maximum concentration： (tmax) in plasma
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PK parameter for ESN364 and its metabolite: Terminal elimination half-life (t1/2) in plasma
timeFrame: Up to 48 hr after dosing in Part 1 and after dosing on Day 10 in MD part of Part 2
measure: PK parameter for ESN364 and its metabolite: volume of distribution during the terminal elimination phase after extra-vascular dosing (Vz/F) in plasma
timeFrame: Up to 48 hr after dosing in Part 1 and after dosing on Day 10 in MD part of Part 2
measure: PK parameter for ESN364 metabolite: Metabolite to parent ratio (MPR) in plasma
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PK parameter for ESN364 and its metabolite: AUC from the time of dosing to the start of the next dosing interval (AUCtau) in plasma
timeFrame: Up to 48 hr after dosing on Day 10 in MD part of Part 2
measure: PK parameter for ESN364 and its metabolite: Peak-trough ratio (PTR) in plasma
timeFrame: Up to 48 hr after dosing on Day 10 in MD part of Part 2
measure: PK parameter for ESN364 and its metabolite: Accumulation ratio calculated using AUC (Rac(AUC)) in plasma
timeFrame: Up to 48 hr after dosing on Day 10 in MD part of Part 2
measure: PK parameter for ESN364 and its metabolite: Concentration immediately prior to dosing at multiple dosing (Ctrough) in plasma
timeFrame: Before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
measure: Pharmacodynamic (PD) endpoint for ESN364: Luteinizing hormone (LH) level in plasma
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUC12 for LH level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC24 for LH level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC48 for LH level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: Cmin for LH level
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: tmin for LH level
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUC from the Time of Dosing to the Start of the Next Dosing Interval (AUCtau) for LH level
timeFrame: Before dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: Cpredose for LH level
timeFrame: Before dosing in Part 1 and before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
measure: PD endpoint for ESN364: Follicle stimulating hormone (FSH) level in plasma
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUC12 for FSH level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC24 for FSH level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC48 for FSH level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: Cmin for FSH level
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: tmin for FSH level
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUCtau for FSH level
timeFrame: Before dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: Cpredose for FSH level
timeFrame: Before dosing in Part 1 and before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
measure: PD endpoint for ESN364: Sex hormone binding globulin (SHBG) level in plasma
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUC12 for SHBG level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC24 for SHBG level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC48 for SHBG level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: Cmin for SHBG level
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: tmin for SHBG level
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUCtau for SHBG level
timeFrame: Before dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: Cpredose for SHBG level
timeFrame: Before dosing in Part 1 and before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
measure: PD endpoint for ESN364: Total testosterone (TT) level in plasma
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUC24 for TT level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC12 for TT level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC48 for TT level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: Cmin for TT level
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: tmin for TT level
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUCtau for TT level
timeFrame: Before dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: Cpredose for TT level
timeFrame: Before dosing in Part 1 and before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
measure: PD endpoint for ESN364: Free testosterone (FT) level in plasma
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUC12 for FT level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC24 for FT level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC48 for FT level
timeFrame: Up to 48 hr after dosing in Part 1 and after first dosing in Part 2.
measure: PD endpoint for ESN364: Cmin for FT level
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: tmin for FT level
timeFrame: Up to 48 hr after dosing in Part 1, after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUCtau for FT level
timeFrame: Before dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: Cpredose for FT level
timeFrame: Before dosing in Part 1 and before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
measure: PD endpoint for ESN364: Estradiol (E) level in plasma
timeFrame: Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUC12 for E level
timeFrame: Up to 48 hr after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC24 for E level
timeFrame: Up to 48 hr after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC48 for E level
timeFrame: Up to 48 hr after first dosing in Part 2.
measure: PD endpoint for ESN364: Cmin for E level
timeFrame: Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: tmin for E level
timeFrame: Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUCtau for E level
timeFrame: Before dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: Cpredose for E level
timeFrame: Before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
measure: PD endpoint for ESN364: Progesterone (P) level in plasma
timeFrame: Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUC12 for P level
timeFrame: Up to 48 hr after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC24 for P level
timeFrame: Up to 48 hr after first dosing in Part 2.
measure: PD endpoint for ESN364: AUC48 for P level
timeFrame: Up to 48 hr after first dosing in Part 2.
measure: PD endpoint for ESN364: Cmin for P level
timeFrame: Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: tmin for P level
timeFrame: Up to 48 hr after first dosing in Part 2 and after dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: AUCtau for P level
timeFrame: Before dosing on Day 10 in MD part of Part 2
measure: PD endpoint for ESN364: Cpredose for P level
timeFrame: Before dosing on Day 2, 3, 5, 7 and 10 in MD part of Part 2
Other outcomes:
Locations:
city: Fukuoka
country: Japan
facility: Site JP00001
Study officials:
affiliation: Astellas Pharma Inc
name: Medical Director
role: STUDY_DIRECTOR
References: