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

Conditions: Pharmacokinetics of ASP1707; Pharmacodynamics of ASP1707

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.

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.

Keywords: phase 1 asp1707 dose escalation food effect maximum tolerated dose (mtd) healthy subjects single ascending dose multiple ascending dose