Clinical trial NCT02368912: A Study to Assess the Safety, Tolerability and Effects of Single and Multiple Ascending Doses of ASP1707 in Healthy Male and Pre-menopausal Female Subjects, Including a Comparison of the Effects Under Fasted and Fed Conditions in Healthy Young Male Subjects
Official title: A Double Blind, Randomized, Placebo-controlled, Ascending Single and Multiple Oral Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ASP1707 in Healthy Young and Elderly Male Subjects and in Healthy Pre-menopausal Female Subjects Including an Open-label Comparison of Pharmacokinetics Under Fasted and Fed Conditions in Healthy Young Male Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pharmacokinetics of ASP1707
Pharmacodynamics of ASP1707
Keywords: Phase 1
ASP1707
Dose escalation
Food effect
Maximum tolerated dose (MTD)
Healthy subjects
Single ascending dose
Multiple ascending dose
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2015-02-23
Enrollment: 176
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This study consists of four parts:

Part 1 is a randomized, double-blind, placebo-controlled, single ascending dose study in healthy young male subjects to evaluate the safety, tolerability pharmacokinetics (PK) and effect on certain hormones and if possible to determine the highest well-tolerated dose of ASP1707 in healthy young male subjects under fasted conditions.

Part 2 is an open label, randomized crossover, single dose study to determine the effect of food on the pharmacokinetics of ASP1707and effect on certain hormones in healthy young male subjects.

Part 3 is a randomized, double-blind, placebo-controlled, multiple ascending dose study to evaluate the safety, tolerability and pharmacokinetics (PK) of ASP1707 in healthy elderly men and healthy premenopausal females, and to determine the effect on certain hormones in males. Age and gender is also evaluated.

Part 4 is a randomized, double-blind, placebo-controlled, parallel, multiple dose study to evaluate the safety, tolerability and PK of ASP1707, and its effect on certain hormones in healthy pre-menopausal female subjects.

Detailed description: Part 1 comprises 7 dose groups of 8 healthy young male subjects. ASP1707 or matching placebo ( 3 to 1 ratio) is given as a single dose under fasted conditions.

The first group receives the lowest dose while the last group receives the highest dose.

Part 2 (Food-Effect) The group consists of 12 healthy young male subjects who receive two separate doses of ASP1707 under fasted or fed conditions. Half of the subjects are dosed first under fasted condition and half of them had first an FDA high-fat breakfast. Subjects receive the alternate treatment on the second occasion. Dosing is separated by at least 7 days or 7 times t1/2 (terminal elimination half-life) as assessed from Part 1.

Part 3 Comprises 4 dose groups of 12 healthy elderly men each, and two groups of 12 healthy premenopausal women. The latter are dosed ASP1707 or placebo in parallel to the 4 male groups. Subjects are fasted or fed depending on observations from Part 2.

Dose levels are defined after evaluating interim safety, tolerability and PK and PD results from Part 1. A lower maximum dose is used in women than in men, based on preclinical data. Dose escalation in the men is independent from dose escalation in the women. Women and men receive once-daily dosing;

Part 4 includes 4 groups, 1 placebo and 3 for ASP1707, each with 9 pre-menopausal women. Subjects in each dose group receive a fixed daily dose. Subjects are domiciled for various intervals during each of 3 menstrual cycles. Dosing occurs for 21 Days during the subjects' second menstrual cycle of the study (Day 1 of Period 2); fasted or fed depending on observations from Part 2.

Eligibility criteria: Inclusion Criteria:

Parts 1 \& 2:

* Healthy young male subject aged 18 to 45 years inclusive
* Body Mass Index more than or equal to 18.5 and less than 30.0 kg/m2.
* Male subjects must be non-fertile, or must practice an adequate contraceptive method to prevent pregnancies.

Part 3:

* Healthy elderly male subject aged 55 years or older, or healthy pre-menopausal female subject aged 18 to 45 inclusive.
* Body Mass Index more than or equal to 18.5 and less than 30.0 kg/m2.
* Male subject must be non-fertile, or must practice adequate contraceptive methods.
* Female subjects must be of non-child bearing potential, i.e. surgically sterilized or practice adequate (double barrier) non-hormonal contraceptive methods.

Part 4:

* Healthy pre-menopausal female subject aged 18 to 45 inclusive.
* Body Mass Index more than or equal to 18.5 and less than 30.0 kg/m2.
* Female subjects must be of non-child bearing potential, i.e. surgically sterilized or practice adequate contraceptive methods.
* Females having a regular menstruation cycle with a duration between 25 up to 30 days.

Exclusion Criteria:

Parts 1 \& 2:

* Male subjects with out-of-range Testosterone levels in serum at screening.
* Subjects with any history of cancer.
* Any of the liver function tests (i.e. ALT and AST) above the upper limit of normal.
* A QTc interval of \> 430 ms after repeated measurements.
* Regular use of any inducer of metabolism (e.g. barbiturates, rifampin) in the 3 months prior to admission to the Clinical Unit.
* Positive serology test for HBsAg, anti HAV (IgM), anti-HCV or anti-HIV 1+2.

Part 3:

* Pregnancy within 6 months before screening assessment or breast feeding 3 months before screening.
* Male subjects with out-of-range T levels in serum at screening.
* Positive serology test for HBsAg, anti HAV (IgM), anti-HCV or anti-HIV 1+2.

Part 4:

* Pregnancy within 6 months before screening assessment or breast feeding 3 months before screening.
* Use of any hormonal interfering contraceptives in the 3 months before admission (for 3 consecutive menstruation cycles) OR any evidence of unovulatory menstrual cycles.
* Positive serology test for HBsAg, anti HAV (IgM), anti-HCV or anti-HIV 1+2.

Primary outcomes:
measure: Safety assessed by nature, frequency and severity of adverse events
timeFrame: Screening to End of Study Visit (ESV) (up to Day 19 and up to Day 39)
measure: Safety assessed by physical examination
timeFrame: Screening to End of Study Visit (ESV) (up to Day 19 and up to Day 39)
measure: Safety assessed by vital signs
timeFrame: Screening to End of Study Visit (ESV) (up to Day 19 and up to Day 39)
measure: Safety assessed by safety laboratory tests
timeFrame: Screening to End of Study Visit (ESV) (up to Day 19 and up to Day 39)
measure: Safety assessed by 12 lead electrocardiogram (ECG)
timeFrame: Screening to End of Study Visit (ESV) (up to Day 19 and up to Day 39)
measure: Safety assessed by continuous cardiac monitoring (Holter)
timeFrame: Days -1 and 21
measure: Pharmacokinetics (PK) of ASP1707 measured by area under the plasma concentration - time curve (AUC) extrapolated to time = infinity (AUCinf) in plasma
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by area under the plasma concentration-time curve (AUC) to time from the time of dosing to the last measurable concentration (AUClast) in plasma
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by time to reach quantifiable concentrations (tlag) in plasma
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by time to attain maximum concentration (tmax) in plasma
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by Cmax in plasma
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by terminal elimination half-life (t1/2) in plasma
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by apparent volume of distribution (Vz/F) in plasma
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by apparent clearance (CL/F) in plasma
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by amount excreted unchanged into urine (Ae) from time of dosing until last measurable concentration (Aelast) in urine
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by Ae extrapolated to time = infinity (Aeinf) in urine
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by Ae in % up to the collection time of the last measurable concentration (Aelast%) in urine
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by Ae in % extrapolated to time infinity (Aeinf%) in urine
timeFrame: Pre-dose (Day 1) to Day 5
measure: PK of ASP1707 measured by renal clearance (CLR) in urine
timeFrame: Pre-dose (Day 1) to Day 5
measure: Pharmacodynamics (PD) of ASP1707 measured by Cmax in plasma
timeFrame: Day -1 to day 15 for period 1, Day 7 to Day 15 for periods 2 and 3
measure: PD of ASP1707 measured by tmax in plasma
timeFrame: Day -1 to day 15 for period 1, Day 7 to Day 15 for periods 2 and 3
measure: PD of ASP1707 measured by average concentration (Cavg, day 7-15) in plasma
timeFrame: Pre-dose to Day 26
measure: PD of ASP1707 measured by average concentration (Cavg, day 5-19) in plasma
timeFrame: Pre-dose to Day 26
measure: PD of ASP1707 measured by average concentration (Cavg, day 23-26) in plasma
timeFrame: Pre-dose to Day 26
measure: PD of ASP1707 - maximal duration within therapeutic range
timeFrame: Pre-dose to Day 26
measure: PD of ASP1707 - total duration within therapeutic range (20-50 pg/mL)
timeFrame: Pre-dose to Day 26
measure: PD of ASP1707 - Time of onset therapeutic range
timeFrame: Pre-dose to Day 26
measure: PD of ASP1707 - Time of offset therapeutic range
timeFrame: Pre-dose to Day 26
measure: PD of ASP1707 - Time of start menstruation after last dose of study drug
timeFrame: Pre-dose to Day 26
Secondary outcomes:
measure: PK profile of ASP1707 in plasma and urine for Part 1
timeFrame: Pre-dose (Day 1) to Day 5
measure: Safety profile assessed by nature, frequency and severity of adverse events, physical examination, vital signs, safety laboratory tests and 12 lead ECG
timeFrame: Screening to End of Study Visit (ESV) (Up to 31 days and up to 62 days)
measure: PD profile of ASP1707 for Part 1 and Part 2
timeFrame: Pre-dose (Day 1) to Day 12-19
measure: PD profile of ASP1707 for Part 3
timeFrame: Pre-dose (Day 1) to Day 39
measure: PK profile of ASP1707 in plasma and urine for Part 3
timeFrame: Pre-dose (Day 1) to Day 25
measure: PK profile of ASP1707 in plasma and urine for Part 4
timeFrame: Pre-dose (Day 23) to Day 25
Other outcomes:
Locations:
city: Paris
country: France
facility: SGS Life Science Services, Aster
Study officials:
affiliation: Astellas Pharma Europe B.V.
name: Clinical Study Manager
role: STUDY_CHAIR
References: