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

Study Overview
=================
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.

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

Conditions
-----------------
Pharmacokinetics of ASP1707, Pharmacodynamics of ASP1707

Intervention / Treatment
-----------------
* Drug: ASP1707 single dose of dose levels 1 -7
* Drug: Placebo single dose of dose levels 1-7
* Drug: ASP1707 single dose fasted
* Drug: ASP1707 single dose fed
* Drug: ASP1707 multiple dose of dose levels 1-4
* Drug: Placebo multiple dose of dose levels 1-4
* Drug: ASP1707 multiple dose of dose levels 1-2
* Drug: Placebo multiple dose of dose levels 1-2
* Drug: ASP1707 parallel multiple dose of dose levels 1-3
* Drug: Placebo parallel multiple dose


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1. Single ascending dose (SAD), ASP1707 dose levels 1-7<br>healthy young male | Drug: ASP1707 single dose of dose levels 1 -7<br>* Oral, dose escalation<br>|
| Experimental: 2. Single ascending dose (SAD), placebo dose levels 1-7<br>healthy young male | Drug: Placebo single dose of dose levels 1-7<br>* Oral, dose escalation, healthy young male<br>|
| Experimental: 3. Food effect (FE), ASP1707 fasted<br>Fasted healthy young male | Drug: ASP1707 single dose fasted<br>* Oral, healthy young male<br>|
| Experimental: 4. Food effect (FE), ASP1707 fed<br>Fed healthy young male | Drug: ASP1707 single dose fed<br>* Oral, healthy young male<br>|
| Experimental: 5. Multiple ascending dose (MAD), ASP1707 dose levels 1-4<br>healthy elderly male | Drug: ASP1707 multiple dose of dose levels 1-4<br>* Oral, multiple dose escalation, healthy elderly male<br>|
| Experimental: 6. Multiple ascending dose (MAD), Placebo, dose levels 1-4<br>healthy elderly male | Drug: Placebo multiple dose of dose levels 1-4<br>* Oral, multiple dose escalation, healthy elderly male<br>|
| Experimental: 7. Multiple ascending dose (MAD), ASP1707, dose levels 1-2<br>healthy pre-menopausal female | Drug: ASP1707 multiple dose of dose levels 1-2<br>* Oral, multiple dose escalation, healthy pre-menopausal female<br>|
| Experimental: 8. Multiple ascending dose (MAD), Placebo dose levels 1-2<br>healthy pre-menopausal female | Drug: Placebo multiple dose of dose levels 1-2<br>* Oral, multiple dose escalation, healthy pre-menopausal female<br>|
| Experimental: 9. Parallel multiple dose, ASP1707 dose levels 1-3<br>healthy pre-menopausal female | Drug: ASP1707 parallel multiple dose of dose levels 1-3<br>* Oral, multiple dose, healthy pre-menopausal female<br>|
| Experimental: 10. Parallel multiple dose, Placebo<br>healthy pre-menopausal female | Drug: Placebo parallel multiple dose<br>* Oral, dose escalation, healthy pre-menopausal female<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessed by nature, frequency and severity of adverse events | Respectively Part 1 and Part 3 | Screening to End of Study Visit (ESV) (up to Day 19 and up to Day 39) | 
| Safety assessed by physical examination | Respectively Part 1 and Part 3 | Screening to End of Study Visit (ESV) (up to Day 19 and up to Day 39) | 
| Safety assessed by vital signs | Respectively Part 1 and Part 3. Vital signs include blood pressure and pulse. | Screening to End of Study Visit (ESV) (up to Day 19 and up to Day 39) | 
| Safety assessed by safety laboratory tests | Respectively Part 1 and Part 3, Biochemistry, hematology, and urinalysis | Screening to End of Study Visit (ESV) (up to Day 19 and up to Day 39) | 
| Safety assessed by 12 lead electrocardiogram (ECG) | Respectively Part 1 and Part 3 | Screening to End of Study Visit (ESV) (up to Day 19 and up to Day 39) | 
| Safety assessed by continuous cardiac monitoring (Holter) | Part 3 | Days -1 and 21 | 
| Pharmacokinetics (PK) of ASP1707 measured by area under the plasma concentration - time curve (AUC) extrapolated to time = infinity (AUCinf) in plasma | Part 2 | Pre-dose (Day 1) to Day 5 | 
| 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 | Part 2 | Pre-dose (Day 1) to Day 5 | 
| PK of ASP1707 measured by time to reach quantifiable concentrations (tlag) in plasma | Part 2 | Pre-dose (Day 1) to Day 5 | 
| PK of ASP1707 measured by time to attain maximum concentration (tmax) in plasma | Part 2 | Pre-dose (Day 1) to Day 5 | 
| PK of ASP1707 measured by Cmax in plasma | Part 2 | Pre-dose (Day 1) to Day 5 | 
| PK of ASP1707 measured by terminal elimination half-life (t1/2) in plasma | Part 2 | Pre-dose (Day 1) to Day 5 | 
| PK of ASP1707 measured by apparent volume of distribution (Vz/F) in plasma | Part 2 | Pre-dose (Day 1) to Day 5 | 
| PK of ASP1707 measured by apparent clearance (CL/F) in plasma | Part 2 | Pre-dose (Day 1) to Day 5 | 
| PK of ASP1707 measured by amount excreted unchanged into urine (Ae) from time of dosing until last measurable concentration (Aelast) in urine | Part 2 | Pre-dose (Day 1) to Day 5 | 
| PK of ASP1707 measured by Ae extrapolated to time = infinity (Aeinf) in urine | Part 2 | Pre-dose (Day 1) to Day 5 | 
| PK of ASP1707 measured by Ae in % up to the collection time of the last measurable concentration (Aelast%) in urine | Part 2 | Pre-dose (Day 1) to Day 5 | 
| PK of ASP1707 measured by Ae in % extrapolated to time infinity (Aeinf%) in urine | Part 2 | Pre-dose (Day 1) to Day 5 | 
| PK of ASP1707 measured by renal clearance (CLR) in urine | Part 2 | Pre-dose (Day 1) to Day 5 | 
| Pharmacodynamics (PD) of ASP1707 measured by Cmax in plasma | Part 4, period 1, 2 and 3. Estradiol (E2), Follicle-stimulating hormone (FSH) and Luteinizing Hormone (LH) levels | Day -1 to day 15 for period 1, Day 7 to Day 15 for periods 2 and 3 | 
| PD of ASP1707 measured by tmax in plasma | Part 4, period 1, 2 and 3. E2, FSH and LH levels | Day -1 to day 15 for period 1, Day 7 to Day 15 for periods 2 and 3 | 
| PD of ASP1707 measured by average concentration (Cavg, day 7-15) in plasma | Part 4, period 1, 2 and 3. E2, FSH and LH levels | Pre-dose to Day 26 | 
| PD of ASP1707 measured by average concentration (Cavg, day 5-19) in plasma | Part 4, period 3. E2, FSH and LH levels | Pre-dose to Day 26 | 
| PD of ASP1707 measured by average concentration (Cavg, day 23-26) in plasma | Part 4, period 2. E2, FSH and LH levels | Pre-dose to Day 26 | 
| PD of ASP1707 - maximal duration within therapeutic range | Part 4, period 2. E2 levels | Pre-dose to Day 26 | 
| PD of ASP1707 - total duration within therapeutic range (20-50 pg/mL) | Part 4, period 2. E2 levels | Pre-dose to Day 26 | 
| PD of ASP1707 - Time of onset therapeutic range | Part 4, period 2. E2 levels | Pre-dose to Day 26 | 
| PD of ASP1707 - Time of offset therapeutic range | Part 4, period 2. E2 levels | Pre-dose to Day 26 | 
| PD of ASP1707 - Time of start menstruation after last dose of study drug | Part 4, period 3 | Pre-dose to Day 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK profile of ASP1707 in plasma and urine for Part 1 | AUCinf, AUClast, tlag, tmax, Cmax, t1/2, Vz/F, CL/F, Aelast, Aeinf, Aelast%, Aeinf%, CLR | Pre-dose (Day 1) to Day 5 | 
| Safety profile assessed by nature, frequency and severity of adverse events, physical examination, vital signs, safety laboratory tests and 12 lead ECG | Respectively Part 2 and Part 4 | Screening to End of Study Visit (ESV) (Up to 31 days and up to 62 days) | 
| PD profile of ASP1707 for Part 1 and Part 2 | Testosterone (T), LH and FSH levels: Cmin, tmin, maximal %Reduction and T only: Number and percentage of subjects with T castration level (= T < 0.5 ng/mL) after single dose, Time of onset of T < 0.5 ng/mL after single dose, Duration of T <0.5 ng/mL after single dose | Pre-dose (Day 1) to Day 12-19 | 
| PD profile of ASP1707 for Part 3 | T, LH and FSH levels: Cmin, tmin, maximal %Reduction T only: Number and percentage of subjects with T < 0.5 ng/mL at any time post-first dose, Number and percentage of subjects with T < 0.5 ng/mL after last dose, Number of subjects reaching T<0.5 ng/mL for ≥14 days, Day of onset of T < 0.5 ng/mL after multiple doses of ASP1707 (T < 0.5 ng/mL for the first time), Time of onset of T < 0.5 ng/mL after first dose, Duration of T < 0.5 ng/mL after single dose and during multiple dosing, Total duration, Maximal duration:Time from last dose to return to baseline levels for T, LH and FSH, Duration of T < 0.5 ng/mL after last dose | Pre-dose (Day 1) to Day 39 | 
| PK profile of ASP1707 in plasma and urine for Part 3 | AUCinf, AUClast, tlag, tmax, Cmax, t1/2, Vz/F, CL/F, Aelast, Aeinf, Aelast%, Aeinf%, CLR, Ctrough, AUC during the time interval between consecutive dosing (AUCtau), Accumulation Ratio (Rac), Peak Trough Ratio (PTR), Ae during the time interval between consecutive dosing (Aetau), Aetau as percentage of total dose (Aetau%), Ae during the time interval between consecutive dosing (AUCtau), (AUC0-24h), Ae0-24h, Ae0-24h% | Pre-dose (Day 1) to Day 25 | 
| PK profile of ASP1707 in plasma and urine for Part 4 | AUCtau, tmax, Cmax, t1/2, Vz/F, CL/F, CLR, Ctrough, PTR, Aetau, Aetau%, | Pre-dose (Day 23) to Day 25 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Phase 1, ASP1707, Dose escalation, Food effect, Maximum tolerated dose (MTD), Healthy subjects, Single ascending dose, Multiple ascending dose