Embryo Transfer
Conditions
Keywords
epelsiban, pharmacokinetics, patient reported pain / discomfort, pharmacodynamics, oxytocin infusions, Uterine contractions
Brief summary
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.
Interventions
DRUGEpelsiban
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
DRUGPlacebo
White to off white oral placebo tablets to match 5mg epelsiban
DRUGOxytocin
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).
DRUGOrtho-Cylcen (21)® tablet
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
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
For ultrasound training cohort * Female volunteers of childbearing potential; with a negative pregnancy test as determined by human chorionic gonadotropin (hCG) testing at screening and prior to study initiation. * Age between 18 and 35 years old (inclusive). * Body weight \>=50 kilograms (kg) and body mass index (BMI) within the range 18-30 kg/meter (m)\^2 (inclusive). * Normal ovarian and uterine anatomy as assessed by transvaginal ultrasonography. * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. * Is in good physical and mental health as determined by a responsible and experienced physician, based on a medical evaluation including medical history, and physical examination. For Cohorts 1, 2A, 2B, 2C, 3 * Female volunteers of childbearing potential; with a negative pregnancy test as determined by hCG testing at screening and prior to study initiation. * Agrees to use one of the contraception methods for 2 weeks prior to the start of study to minimize the risk of pregnancy. Female subjects must agree to use contraception until at least 48 hours have passed after the last dose of study drug. OR has only same-sex partners, when this is her preferred and usual lifestyle. Oral contraceptive (OC) pill naive or have discontinued OC at least 2 months prior to study entry. * Age between 18 and 35 years old. * Body weight \>=50 kg and BMI within the range 18-30 kg/m\^2 (inclusive). * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form as signed consent form; and is in good physical and mental health as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or
Exclusion criteria
, outside the reference range for the population being studied may be included only if the Investigator in consultation with the GlaxoSmithKline (GSK) Medical Monitor if required agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Subjects with a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli international unit (MI)U/milliliter (mL) and estradiol \<40 picogram/mL (\<147 picomoles/Liter) should always be excluded from enrolment. * based on single or averaged corrected QTc values of triplicate ECGs obtained over a brief recording period: QTc \<450 milliseconds (msec); or QTc \<480 msec in subjects with Bundle Branch Block.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The effect of the infused oxytocin dose on the time course of the frequency of endometrial contractions in Cohort 1 during the periovulatory phase | Up to Day 3 | 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. |
| Frequency of endometrial contractions in Cohorts 2A, 2B and 2C during the periovulatory phase and 3-5 days post ovulation. | Up to Day 2 | 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. |
| Reduction in the frequency of subendometrial contractions in Cohorts 2 A, B and C, all during the periovulatory phase. | Up to Day 2 | 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. |
| The duration of the reduction in subendometrial contractions in Cohorts 2 A, B and C, all during the periovulatory phase | Up to Day 2 | 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. |
| 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. | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline in laboratory parameters in Cohort 1 | Baseline (screening) and upto 21 days | Laboratory parameters include: hematology, clinical chemistry, urinalysis |
| Change from Baseline in laboratory parameters in Cohort 2 | Baseline (screening) and upto 20 days | Laboratory parameters include: hematology, clinical chemistry, urinalysis |
| Change from Baseline in laboratory parameters Cohort 3 | Baseline (screening) and upto 19 days | Laboratory parameters include: hematology, clinical chemistry, urinalysis |
| Change from Baseline in vital signs in Cohort 1 | Baseline (screening) and upto 21 days | Vital signs measurement include: blood pressure, pulse pressure, heart rate. |
| Change from Baseline in vital signs in Cohort 2 | Baseline (screening) and upto 20 days | Vital signs measurement include: blood pressure, pulse pressure, heart rate. |
| Frequency of endometrial and subendometrial contractility in Cohort 2. | Up to Day 3 | Following parameters will be assessed: Wave period, external contractile measure, internal contractile measure and total contractile measure, wave directionality, wave amplitude and wave completeness. |
| Change from Baseline in electrocardiogram (ECG) parameters in Cohort 1 | Baseline (screening) and upto 21 days | ECG parameters include: PR, QRS, QT, and corrected QT (QTc) intervals. |
| Change from Baseline in ECG parameters in Cohort 2 | Baseline (screening) and upto 20 days | ECG parameters include: PR, QRS, QT, and corrected QT (QTc) intervals. |
| Change from Baseline in ECG parameters in Cohort 3 | Baseline (screening) and upto 19 days | ECG parameters include: PR, QRS, QT, and corrected QT (QTc) intervals. |
| Composite of PK parameters following epelsiban dosing | 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. | 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). |
| Change from Baseline in vital signs in Cohort 3 | Baseline (screening) and upto 19 days | Vital signs measurement include: blood pressure, pulse pressure, heart rate. |
| Frequency of subendometrial contractility in Cohort 3 | Up to Day 2 | To evaluate the endometrial and subendometrial contractions following epelsiban dose in the absence of oxytocin challenges. |
| Number of subjects with adverse events in Cohort 1 | 18 days | AEs will be collected from the start of Study Treatment and until the follow-up contact. |
| Number of subjects with adverse events (AEs) in Cohort 2 | 17 days | AEs will be collected from the start of Study Treatment and until the follow-up contact. |
| Number of subjects with adverse events in Cohort 3 | 16 days | AEs will be collected from the start of Study Treatment and until the follow-up contact. |
Countries
United States
Outcome results
None listed