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

Pharmacokinetics of ASP1707 Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02368912
• Other study ID #: 1707-CL-0001
• Secondary ID: 2010-018292-21
• Status: Completed
• Phase: Phase 1
• First received: November 14, 2014
• Last updated: February 17, 2015
• Start date: June 2010
• Est. completion date: August 2011

Study information

• Verified date: February 2015
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 176
• Est. completion date: August 2011
• Est. primary completion date: August 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Pharmacodynamics of ASP1707
• Pharmacokinetics of ASP1707

Intervention

Drug:
• ASP1707 single dose of dose levels 1 -7
Oral, dose escalation
• Placebo single dose of dose levels 1-7
Oral, dose escalation, healthy young male
• ASP1707 single dose fasted
Oral, healthy young male
• ASP1707 single dose fed
Oral, healthy young male
• ASP1707 multiple dose of dose levels 1-4
Oral, multiple dose escalation, healthy elderly male
• Placebo multiple dose of dose levels 1-4
Oral, multiple dose escalation, healthy elderly male
• ASP1707 multiple dose of dose levels 1-2
Oral, multiple dose escalation, healthy pre-menopausal female
• Placebo multiple dose of dose levels 1-2
Oral, multiple dose escalation, healthy pre-menopausal female
• ASP1707 parallel multiple dose of dose levels 1-3
Oral, multiple dose, healthy pre-menopausal female
• Placebo parallel multiple dose
Oral, dose escalation, healthy pre-menopausal female

Locations

Country	Name	City	State
France	SGS Life Science Services, Aster	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Astellas Pharma Europe B.V.

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	No
Primary	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)	No
Primary	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)	No
Primary	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)	No
Primary	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)	No
Primary	Safety assessed by continuous cardiac monitoring (Holter)	Part 3	Days -1 and 21	No
Primary	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	No
Primary	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	No
Primary	PK of ASP1707 measured by time to reach quantifiable concentrations (tlag) in plasma	Part 2	Pre-dose (Day 1) to Day 5	No
Primary	PK of ASP1707 measured by time to attain maximum concentration (tmax) in plasma	Part 2	Pre-dose (Day 1) to Day 5	No
Primary	PK of ASP1707 measured by Cmax in plasma	Part 2	Pre-dose (Day 1) to Day 5	No
Primary	PK of ASP1707 measured by terminal elimination half-life (t1/2) in plasma	Part 2	Pre-dose (Day 1) to Day 5	No
Primary	PK of ASP1707 measured by apparent volume of distribution (Vz/F) in plasma	Part 2	Pre-dose (Day 1) to Day 5	No
Primary	PK of ASP1707 measured by apparent clearance (CL/F) in plasma	Part 2	Pre-dose (Day 1) to Day 5	No
Primary	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	No
Primary	PK of ASP1707 measured by Ae extrapolated to time = infinity (Aeinf) in urine	Part 2	Pre-dose (Day 1) to Day 5	No
Primary	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	No
Primary	PK of ASP1707 measured by Ae in % extrapolated to time infinity (Aeinf%) in urine	Part 2	Pre-dose (Day 1) to Day 5	No
Primary	PK of ASP1707 measured by renal clearance (CLR) in urine	Part 2	Pre-dose (Day 1) to Day 5	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	PD of ASP1707 - maximal duration within therapeutic range	Part 4, period 2. E2 levels	Pre-dose to Day 26	No
Primary	PD of ASP1707 - total duration within therapeutic range (20-50 pg/mL)	Part 4, period 2. E2 levels	Pre-dose to Day 26	No
Primary	PD of ASP1707 - Time of onset therapeutic range	Part 4, period 2. E2 levels	Pre-dose to Day 26	No
Primary	PD of ASP1707 - Time of offset therapeutic range	Part 4, period 2. E2 levels	Pre-dose to Day 26	No
Primary	PD of ASP1707 - Time of start menstruation after last dose of study drug	Part 4, period 3	Pre-dose to Day 26	No
Secondary	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	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No