This multi-cohort phase I study is designed to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of oxytocin and to evaluate epelsiban (GSK557296) potential to reduce subendometrial contractractility induced by oxytocin in healthy female subjects. Additionally tissues concentrations of epelsiban will be determined from endometrial tissue biopsies. Data from this study will inform the identification of the doses of epelsiban to be used in future in-vitro fertilization (IVF) clinical studies. Expected number of subjects to be randomized are: Cohort 1- 10 subjects, Cohort 2a- 10 subjects for each epelsiban arm 25 milligrams (mg), 200mg, 5 for placebo, Cohort 2b- 10 subjects per arm with dose to be determined, cohort 3- 6 subjects. Cohorts 1 and 2 will be double blind (sponsor unblinded) placebo controlled cohorts. Cohort 3 will be an open label cohort, cohort 4 will be a double blind (sponsor unblinded) placebo controlled cohort.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
33
White to off white Oral tablets with unit dose strength of 5 mg or 25 mg for dose level of 25 mg, 150mg or \>150mg
White to off white oral placebo tablets to match 5mg epelsiban
Oxytocin for IV infusion (at doses of 5, 10, and 20 milliunits), IV bolus (5 IU administered IV as a bolus over 15 seconds) and IM (5 IU administered IM).
White, blue or green tablets for oral administration per product insert to synchronize the menstrual cycles with ovulation. Ortho Cyclen (21) ® is a registered trademark of Johnson \& Johnson
GSK Investigational Site
Glendale, California, United States
GSK Investigational Site
Baltimore, Maryland, United States
The effect of the infused oxytocin dose on the time course of the frequency of endometrial contractions in Cohort 1 during the periovulatory phase
The relationship between the dose of the infused oxytocin and the time course of the frequency of endometrial contractions in Cohort 1 during the periovulatory phase (ovulation to 3-5 days post ovulation) will be assessed to establish the PD response from the oxytocin infusions and endometrial contraction rate which will provide the oxytocin infusion challenge dose to use in Cohort 2. If data permit, the effective dose 50 (ED50) of oxytocin will be also be determined. Uterine contraction rates, contractility measures, etc. will be measured by computer assisted ultrasound image analyses.
Time frame: Up to Day 3
Frequency of endometrial contractions in Cohorts 2A, 2B and 2C during the periovulatory phase and 3-5 days post ovulation.
Frequency of endometrial contractions will be assessed to evaluate the dose response relationship for epelsiban with respect to its ability to reduce endometrial contractions in the study population exposed to repeated oxytocin challenges. Uterine contraction rates, contractility measures, etc. will be measured by computer assisted ultrasound image analyses.
Time frame: Up to Day 2
Reduction in the frequency of subendometrial contractions in Cohorts 2 A, B and C, all during the periovulatory phase.
The reduction in the frequency of subendometrial contractions will be assessed during the periovulatory phase to investigate the PD response of epelsiban in the study population when exposed to repeated oxytocin challenges. If data permit, the infectious dose 50 (ID50) of epelsiban will also be determined. Uterine contraction rates, contractility measures, etc. will be measured by computer assisted ultrasound image analyses.
Time frame: Up to Day 2
The duration of the reduction in subendometrial contractions in Cohorts 2 A, B and C, all during the periovulatory phase
The duration of the reduction in subendometrial contractions will be assessed during the periovulatory phase to investigate the PD response of epelsiban in the study population when exposed to repeated oxytocin challenges. If data permit, the infectious dose 50 (ID50) of epelsiban will also be determined. Uterine contraction rates, contractility measures, etc. will be measured by computer assisted ultrasound image analyses.
Time frame: Up to Day 2
Plasma concentrations of epelsiban or metabolite and the reduction of subendometrial contraction frequency in Cohorts 2 A, B and C, all during the periovulatory phase.
The relationship between the plasma concentrations and the reduction of subendometrial contraction frequency will be assessed during the periovulatory phase to establish the PK/PD relationship between epelsiban (and/or its metabolites) and endometrial contraction rate in the study population exposed to repeated oxytocin challenges. If data permit, the maximum inhibitory effect (Imax) and IC50 of epelsiban will also be determined. Uterine contraction rates, contractility measures, etc. will be measured by computer assisted ultrasound image analyses.
Time frame: PK samples will be collected at 3, 3.25, 3.5, 4, 6.5, 11, 15, 27, 31 and 39 hours post dose in cohort 2.
Frequency of endometrial and subendometrial contractility in Cohort 2.
Following parameters will be assessed: Wave period, external contractile measure, internal contractile measure and total contractile measure, wave directionality, wave amplitude and wave completeness.
Time frame: Up to Day 3
Frequency of subendometrial contractility in Cohort 3
To evaluate the endometrial and subendometrial contractions following epelsiban dose in the absence of oxytocin challenges.
Time frame: Up to Day 2
Number of subjects with adverse events in Cohort 1
AEs will be collected from the start of Study Treatment and until the follow-up contact.
Time frame: 18 days
Number of subjects with adverse events (AEs) in Cohort 2
AEs will be collected from the start of Study Treatment and until the follow-up contact.
Time frame: 17 days
Number of subjects with adverse events in Cohort 3
AEs will be collected from the start of Study Treatment and until the follow-up contact.
Time frame: 16 days
Change from Baseline in laboratory parameters in Cohort 1
Laboratory parameters include: hematology, clinical chemistry, urinalysis
Time frame: Baseline (screening) and upto 21 days
Change from Baseline in laboratory parameters in Cohort 2
Laboratory parameters include: hematology, clinical chemistry, urinalysis
Time frame: Baseline (screening) and upto 20 days
Change from Baseline in laboratory parameters Cohort 3
Laboratory parameters include: hematology, clinical chemistry, urinalysis
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Time frame: Baseline (screening) and upto 19 days
Change from Baseline in vital signs in Cohort 1
Vital signs measurement include: blood pressure, pulse pressure, heart rate.
Time frame: Baseline (screening) and upto 21 days
Change from Baseline in vital signs in Cohort 2
Vital signs measurement include: blood pressure, pulse pressure, heart rate.
Time frame: Baseline (screening) and upto 20 days
Change from Baseline in vital signs in Cohort 3
Vital signs measurement include: blood pressure, pulse pressure, heart rate.
Time frame: Baseline (screening) and upto 19 days
Change from Baseline in electrocardiogram (ECG) parameters in Cohort 1
ECG parameters include: PR, QRS, QT, and corrected QT (QTc) intervals.
Time frame: Baseline (screening) and upto 21 days
Change from Baseline in ECG parameters in Cohort 2
ECG parameters include: PR, QRS, QT, and corrected QT (QTc) intervals.
Time frame: Baseline (screening) and upto 20 days
Change from Baseline in ECG parameters in Cohort 3
ECG parameters include: PR, QRS, QT, and corrected QT (QTc) intervals.
Time frame: Baseline (screening) and upto 19 days
Composite of PK parameters following epelsiban dosing
PK parameters will be assessed for epelsiban and its metabolite (GSK2395448). PK parameters include: maximum plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve (AUC), apparent terminal phase half-life (t1/2), renal clearance (CL).
Time frame: PK samples will be collected at 3, 3.25, 3.5, 4, 6.5, 11, 15, 27, 31 and 39 hours post dose in cohort 2.