Dose Escalation Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Epelsiban Administered in Repeat Doses in Healthy Women Volunteers

Study Overview
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Brief Summary
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The current study is designed to assess the safety, tolerability and pharmacokinetics (PK) of additional repeat doses of epelsiban in healthy females, and will be the first dosing experience of repeat dosing at higher doses in women with this compound. This study is a 14 day, randomized, placebo-controlled, double blind (sponsor unblind), repeat dose, ascending cohort, dose escalation study in healthy, female volunteers. Upon successful completion of the Screening period, a subject will be enrolled in the study. The study will be composed of three periods: Screening, Treatment and Follow-up. A subject's total time involved in the study will be approximately six weeks. Cohorts will be conducted sequentially. Each subject will be enrolled in only one cohort. Ten subjects will be enrolled in each cohort and randomized to epelsiban (n=8) or placebo (n=2).

Official Title
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A Randomized, Placebo-controlled, Double-Blind (Sponsor Unblind), Repeat Dose, Ascending Cohort, Dose Escalation Phase I Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Epelsiban and Its Major Metabolite in Healthy Women Volunteers Following Administration of Repeat Dosing of Epelsiban

Conditions
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Embryo Transfer

Intervention / Treatment
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* Drug: Epelsiban (GSK557296)
* Drug: Placebo to match GSK557296


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female between 18 and 55 years of age inclusive, at the time of consent Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, review of medications previously used, physical examination, laboratory tests and electrocardiogram (ECG). Body mass index (BMI) within the range 18 - 35 kilogram per squared meter (kg/m^2) (inclusive) Not pregnant (as confirmed by a negative serum human chorionic gonadotropin [hCG] test), not lactating, and at least one of the following conditions applies: Non-reproductive potential defined as: Pre-menopausal females, postmenopausal, or women of reproductive potential who agree to follow one of the options listed in the GlaxoSmithKline (GSK) Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential. Exclusion Criteria: History of clinically significant abnormal transvaginal ultrasound Alanine aminotransferase (ALT) and bilirubin >1.5 x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Corrected QT interval (QTc) > 450 milliseconds (msec) History of regular alcohol consumption within three months of dosing on Day 1 defined as: an average weekly intake of >7 drinks. One drink is equivalent to 12 gram (g) of alcohol: 12 ounces (360 milliliters [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within three months prior to screening. 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 Medical Monitor, contraindicates their participation. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a known to inhibit or induce Cytochrome P450 3A4 [P450 CYP3A4]) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within three months prior to first dose of study treatment. A positive pre-study drug/alcohol screen. A positive test for human immunodeficiency virus (HIV) antibody. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within three months 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1(600 mg Epelsiban or placebo[every 8 hours])<br>Each subject will receive 200 mg of epelsiban administered TID (every 8 hours) (total daily dose of 600 mg) or a matching placebo administered every 8 hours. | Drug: Epelsiban (GSK557296)<br>* White to off-white 0.270 inches x 0.700 inches oblong film coated tablet containing 25 mg or 100 mg epelsiban. To be swallowed whole with water, not to be chewed.<br>Drug: Placebo to match GSK557296<br>* White to off-white 0.270 inches x 0.700 inches oblong film coated Tablet containing placebo. To be swallowed whole with water, not to be chewed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration versus time from time zero to infinite time (AUC[0 to infinity]) for epelsiban and GSK2395448 | Blood samples were collected for Cohort 1 and 2 on Days 1, 7, and 14 at Pre-dose ante meridiem (AM), Pre Dose post meridiem (PM), Pre- Dose PM2 (second PM dose [16h]), 0.5, 1, 2, 6, 8.5, 10, 14, 16.5, 17 and 24 hours post dose. Blood samples were collected for Cohort 3 on Days 1, 7, and 14 at Pre-dose AM, Pre Dose PM, 0.5, 1, 4, 6, 8, 12.5, 13, 16 and 24 hours post dose. | Up to Day 15 (Day 1, 7 and 14) | 
| Area under the concentration versus time from time zero to last time point with measurable concentration (AUC [0-t]) for epelsiban and GSK2395448 | Blood samples were collected for Cohort 1 and 2 on Days 1, 7, and 14 at Pre-dose AM, Pre Dose PM, Pre- Dose PM2 (second PM dose [16h]), 0.5, 1, 2, 6, 8.5, 10, 14, 16.5, 17 and 24 hours post dose. Blood samples were collected for Cohort 3 on Days 1, 7, and 14 at Pre-dose AM, Pre Dose PM, 0.5, 1, 4, 6, 8, 12.5, 13, 16 and 24 hours post dose. | Up to Day 15 (Day 1, 7 and 14) | 
| Area under the concentration-time curve over the dosing interval (AUC [0-tau]) for epelsiban and GSK2395448 | Blood samples were collected for Cohort 1 and 2 on Days 1, 7, and 14 at Pre-dose AM, Pre Dose PM, Pre- Dose PM2 (second PM dose [16h]), 0.5, 1, 2, 6, 8.5, 10, 14, 16.5, 17 and 24 hours post dose. Blood samples were collected for Cohort 3 on Days 1, 7, and 14 at Pre-dose AM, Pre Dose PM, 0.5, 1, 4, 6, 8, 12.5, 13, 16 and 24 hours post dose. | Up to Day 15 (Day 1, 7 and 14) | 
| Maximum observed concentration (Cmax) for epelsiban and GSK2395448 | Blood samples were collected for Cohort 1 and 2 on Days 1, 7, and 14 at Pre-dose AM, Pre Dose PM, Pre- Dose PM2 (second PM dose [16h]), 0.5, 1, 2, 6, 8.5, 10, 14, 16.5, 17 and 24 hours post dose. Blood samples were collected for Cohort 3 on Days 1, 7, and 14 at Pre-dose AM, Pre Dose PM, 0.5, 1, 4, 6, 8, 12.5, 13, 16 and 24 hours post dose. | Up to Day 15 (Day 1, 7 and 14) | 
| Time of occurrence of Cmax (tmax) for epelsiban and GSK2395448 | Blood samples were collected for Cohort 1 and 2 on Days 1, 7, and 14 at Pre-dose AM, Pre Dose PM, Pre- Dose PM2 (second PM dose [16h]), 0.5, 1, 2, 6, 8.5, 10, 14, 16.5, 17 and 24 hours post dose. Blood samples were collected for Cohort 3 on Days 1, 7, and 14 at Pre-dose AM, Pre Dose PM, 0.5, 1, 4, 6, 8, 12.5, 13, 16 and 24 hours post dose. | Up to Day 15 (Day 1, 7 and 14) | 
| Terminal phase half-life (t1/2) for epelsiban and GSK2395448 | Blood samples were collected for Cohort 1 and 2 on Days 1, 7, and 14 at Pre-dose AM, Pre Dose PM, Pre- Dose PM2 (second PM dose [16h]), 0.5, 1, 2, 6, 8.5, 10, 14, 16.5, 17 and 24 hours post dose. Blood samples were collected for Cohort 3 on Days 1, 7, and 14 at Pre-dose AM, Pre Dose PM, 0.5, 1, 4, 6, 8, 12.5, 13, 16 and 24 hours post dose. | Up to Day 15 (Day 1, 7 and 14) | 
| Safety as assessed by the number of subjects with adverse events (AE) and serious adverse events (SAE) | An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Up to Day 25 | 
| Number of Subjects with clinically-significant changes in physical examination findings | A complete physical examination will include, at a minimum, assessment of the cardiovascular (CV), respiratory, gastrointestinal and neurological systems. Weight will also be measured and recorded; height will only be measured and recorded at Screening. | Up to Day 25 | 
| Number of Subjects with clinically-significant changes in electrocardiograms (ECG) | 12-lead ECGs will be obtained after the subject has rested in the semi-supine position for at least 15 minutes. Triplicate 12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. | Up to Day 15 | 
| Blood pressure (BP) as a measure of safety and tolerability | Triplicate readings of systolic and diastolic blood pressure will be obtained at each time point in semi-supine position after five minutes of rest. | Up to Day 15 | 
| Pulse rate measurements as a measure of safety and tolerability | Triplicate readings of pulse rate will be obtained at each time point in semi-supine position after five minutes of rest. | Up to Day 15 | 
| Number of subjects with abnormal laboratory parameters | Clinical laboratory assessments will include hematology, clinical chemistry and urinalysis. | Up to Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Dose Escalation, Repeat Dosing, Epelsiban, Pharmacokinetics, Healthy Women Volunteers, Tolerability, Oxytocin