Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Epelsiban in Healthy Female Volunteers

Study Overview
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Brief Summary
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Epelsiban is a potent and selective oxytocin receptor antagonist in development for enhanced implantation rates during in-vitro fertilization (IVF). This study a non-randomized, open label study designed to assess the safety, tolerability and pharmacokinetics of additional repeat doses of epelsiban in healthy females, and will be the first dosing experience of greater than 200 milligram (mg) as a single dose with this compound. Data from this study will inform the selection of doses of epelsiban to be used in future clinical studies. This study will be composed of 3 periods: Screening, Treatment, and Follow-up. The total duration that a subject involved in the study will be up to 6 weeks. At least 2 cohorts of subjects will be enrolled in this study and cohorts will be conducted sequentially. Additional cohorts will be enrolled if determined necessary. A sufficient number of subjects will be screened for the study to obtain approximately 6 evaluable subjects per cohort.

Official Title
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A Phase 1, Open Label, Ascending Cohort, Dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Epelsiban and Its Metabolite in Healthy Female Volunteers Following Administration of Epelsiban

Conditions
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Embryo Transfer

Intervention / Treatment
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* Drug: Epelsiban


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females 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 ECG. Body mass index (BMI) within the range 18-35 kilogram per square meter( kg/m^2) (inclusive). Female subject is eligible to participate if she is 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 or postmenopausal. Exclusion Criteria Alanine Transferase (ALT) and bilirubin >1.5x 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 (QTc) > 450 milliseconds (msec). - History of regular alcohol consumption within 3 months of dosing on Day 1 defined as: an average weekly intake of >7 drinks for females. One drink is equivalent to 12 gram of alcohol: 12 ounces (360 milliliter [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 6 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. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of Study Treatment. For potent immunosuppressive agents, subjects with presence of hepatitis B core antibody (HBcAb) should also be excluded. A positive pre-study drug/alcohol screen. A positive test for human immunodeficiency virus antibody. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 3 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epelsiban Cohort 1<br>Subjects will receive 300 mg of epelsiban administered orally twice (every 12 hr) on Day 1 (total daily dose of 600 mg) | Drug: Epelsiban<br>* Epelsiban will be supplied as a 25 mg white to off-white round direct compression oral tablet.<br>|
| Experimental: Epelsiban Cohort 2<br>Epelsiban dose for Cohort 2 will be determined based on data from Cohort 1, but will not exceed a total daily dose of 900 mg, administered orally in divided doses (450 mg every 12 hrs or 300 mg every 8 hrs). | Drug: Epelsiban<br>* Epelsiban will be supplied as a 25 mg white to off-white round direct compression oral tablet.<br>|
| Experimental: Additional Cohorts TBD (to be decided)<br>Subjects will be enrolled if determined necessary, based on data collected in Epelsiban Cohort 1 and Cohort 2 | Drug: Epelsiban<br>* Epelsiban will be supplied as a 25 mg white to off-white round direct compression oral tablet.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite pharmacokinetic parameters of epelsiban and its metabolite (GSK2395448) | Pharmacokinetic parameters including area under the plasma drug (and metabolite) concentration versus time curve (AUC[0-t], AUC[0- infinity], AUC[0-tau]), maximum observed concentration (Cmax), time to maximum observed plasma drug (and metabolite) concentration (tmax), and terminal half-life (t1/2), as data permit, will be analyzed. Blood samples for pharmacokinetic analysis will be collected on Day 1 (Morning pre-dose and 0.5hour(hr), 1 hr, 4 hr, 6hr, 8 hr, 12 hr post morning dose; evening pre-dose and 12.5 hr, 13 hr post morning dose) and Day 2 (16 hr and 24 hr post Day 1 morning dose). | Up to Day 2 | 
| Number of subjects with Adverse events (AEs) | 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. | Up to Day 12 | 
| Assessment of clinical observations |  | Up to Day 12 | 
| Assessment of hematology parameters | Hematology parameters include complete blood count with red blood cell indices, white blood cell count differential, hemoglobin, hematocrit and platelet count. | Up to Day 12 | 
| Assessment of clinical chemistry parameters | Clinical chemistry parameters includes glucose, blood urea, creatinine, sodium, potassium, calcium, total protein, albumin, total bilirubin, direct bilirubin, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase. | Up to Day 12 | 
| Assessment of urinalysis by dipstick | Urinalysis includes specific gravity, pH, glucose, protein, blood and ketones by dipstick. If blood or protein is abnormal microscopic examination will be done. | Up to Day 12 | 
| Assessment of vital sign measurements | Vital sign measurements will include temperature, systolic and diastolic blood pressure and heart rate. | Up to Day 12 | 
| Assessment of 12-lead electrocardiogram (ECG) | Triplicate 12-lead ECGs will be obtained at each timepoint during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. | Up to Day 12 | 
| Assessment of physical examination findings | A physical examination will include, at a minimum, assessment of the cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight will also be measured | Up to Day 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epelsiban, Healthy Female Volunteers, Safety, Tolerability, Oxytocin, Pharmacokinetics