Clinical trial NCT02213029: A Study to Evaluate Pharmacokinetics, Pharmacodynamics and Tissue Concentrations of Epelsiban
Official title: Study IVF116828:A Multi-Cohort Phase I Study to Investigate the Pharmacokinetics, Pharmacodynamics and Tissue Concentrations of Epelsiban (GSK557296) in Healthy Female Volunteers During Control and Challenge States With and Without Oxytocin
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Embryo Transfer
Keywords: epelsiban
pharmacokinetics
patient reported pain / discomfort
pharmacodynamics
oxytocin infusions
Uterine contractions
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-08-11
Enrollment: 33
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Exclusion Criteria:

For Training Cohort

* Ultrasonographic evidence of uterine anomalies, including but not limited to intramural or submucosal leiomyomas (fibroids) cysts, endometrial polyps, American Society for Reproductive Medicine (ASRM) Class I-VI uterine malformations or intrauterine fluid collections.
* Pregnancy (suspected or diagnosed) or lactation.
* Has had a prior partial or total hysterectomy or tubal ligation.
* Currently using and intrauterine device (IUD) for any reason.
* History or suspicion of drug or alcohol abuse. Criteria Based Upon Medical Histories For Training Cohort
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of \>7 drinks. One drink is equivalent to 12 grams of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

Criteria Based Upon Diagnostic Assessments For Training Cohort

* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
* A positive pre-study drug/alcohol/; and.
* A positive test for human immune virus (HIV) antibody. For Cohorts 1, 2A, 2B, 2C, 3
* Female with an abnormal obstetric profile (average durations \<27 days or \> 31 days;Any contraindication for oral contraception use; Is using hormone replacement therapy (HRT); Ultrasonographic evidence of ovarian dysfunction, such as Polycystic Ovary Syndrome (PCOS) or ovarian anomalies such as dermoid or hemorrhagic cysts; Ultrasonographic evidence of uterine anomalies, including but not limited to intramural or submucosal leiomyomas (fibroids) cysts, endometrial polyps, ASRM Class I-VI uterine malformations or intrauterine fluid collections.
* Pregnancy (suspected or diagnosed) or lactation.
* Has had a prior partial or total hysterectomy or tubal ligation.
* Has had prior surgical procedures to the cervix (cryoablation, loop electrical excision procedure \[LEEP\] or other similar procedures).
* Currently using an IUD for any reason.
* Potential volunteers who are at high risk of developing complications while taking oral contraceptives will not be entered into the study in accordance with normal standards of good clinical practice.
* History or suspicion of drug or alcohol abuse. Criteria Based Upon Medical Histories For Cohorts 1, 2, 3
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of \>7 drinks. One drink is equivalent to 12 grams of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
* History of hypertension, use of an anti-hypertensive, or any systolic blood pressure \>=140 millimeter of mercury (mmHg) or diastolic blood pressure \>=90 mmHg.

Criteria Based Upon Diagnostic Assessments For Cohorts 1, 2, 3

* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
* A positive pre-study drug/alcohol/cotinine screen.
* A positive test for HIV antibody. Other Criteria
* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

Primary outcomes:
measure: The effect of the infused oxytocin dose on the time course of the frequency of endometrial contractions in Cohort 1 during the periovulatory phase
timeFrame: Up to Day 3
measure: Frequency of endometrial contractions in Cohorts 2A, 2B and 2C during the periovulatory phase and 3-5 days post ovulation.
timeFrame: Up to Day 2
measure: Reduction in the frequency of subendometrial contractions in Cohorts 2 A, B and C, all during the periovulatory phase.
timeFrame: Up to Day 2
measure: The duration of the reduction in subendometrial contractions in Cohorts 2 A, B and C, all during the periovulatory phase
timeFrame: Up to Day 2
measure: 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.
timeFrame: 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.
Secondary outcomes:
measure: Frequency of endometrial and subendometrial contractility in Cohort 2.
timeFrame: Up to Day 3
measure: Frequency of subendometrial contractility in Cohort 3
timeFrame: Up to Day 2
measure: Number of subjects with adverse events in Cohort 1
timeFrame: 18 days
measure: Number of subjects with adverse events (AEs) in Cohort 2
timeFrame: 17 days
measure: Number of subjects with adverse events in Cohort 3
timeFrame: 16 days
measure: Change from Baseline in laboratory parameters in Cohort 1
timeFrame: Baseline (screening) and upto 21 days
measure: Change from Baseline in laboratory parameters in Cohort 2
timeFrame: Baseline (screening) and upto 20 days
measure: Change from Baseline in laboratory parameters Cohort 3
timeFrame: Baseline (screening) and upto 19 days
measure: Change from Baseline in vital signs in Cohort 1
timeFrame: Baseline (screening) and upto 21 days
measure: Change from Baseline in vital signs in Cohort 2
timeFrame: Baseline (screening) and upto 20 days
measure: Change from Baseline in vital signs in Cohort 3
timeFrame: Baseline (screening) and upto 19 days
measure: Change from Baseline in electrocardiogram (ECG) parameters in Cohort 1
timeFrame: Baseline (screening) and upto 21 days
measure: Change from Baseline in ECG parameters in Cohort 2
timeFrame: Baseline (screening) and upto 20 days
measure: Change from Baseline in ECG parameters in Cohort 3
timeFrame: Baseline (screening) and upto 19 days
measure: Composite of PK parameters following epelsiban dosing
timeFrame: 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.
Other outcomes:
Locations:
city: Glendale
country: United States
facility: GSK Investigational Site
state: California
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: