A Study to Evaluate Pharmacokinetics, Pharmacodynamics and Tissue Concentrations of Epelsiban

NCT02213029 | Terminated Phase 1

• 1 other identifier: 116828
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 2

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.

Conditions

Embryo Transfer

Keywords

epelsiban; pharmacokinetics; patient reported pain / discomfort; pharmacodynamics; oxytocin infusions; Uterine contractions

Outcome Measures

Primary Outcomes (5)

• 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.

  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.

  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.

  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.

  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.

  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 (15)

• Frequency of endometrial and subendometrial contractility in Cohort 2.

  Up to Day 3

• Frequency of subendometrial contractility in Cohort 3

  Up to Day 2

• Number of subjects with adverse events in Cohort 1

  18 days

• Number of subjects with adverse events (AEs) in Cohort 2

  17 days

• Number of subjects with adverse events in Cohort 3

  16 days

Study Arms (3)

Oxytocin or Placebo challenge (Cohort 1)

EXPERIMENTAL

Subjects will receive oxytocin and or placebo challenges as escalating intravenous (IV) infusions administered on the day of ovulation, followed by an IV bolus day 1 post ovulation, and an intramuscular (IM) injection day 2 post ovulation. The planed doses and routes of administration of oxytocin are as follows: IV infusion will be initiated at 5 milliunit/minute (mU/min) and maintained for 60 min, then the rate will be increased to 10 mU/min and maintained for 60 minutes, a final escalation to 20mU/min will be maintained for 60 minutes, after which the infusion will be stopped. For the IV bolus, a single 5 International unit (IU) IV bolus will be administered. For the IM dosing, a single 10 IU IM injection will be administered.

Drug: Placebo; Drug: Oxytocin; Drug: Ortho-Cylcen (21)® tablet

Epelsiban or Placebo (Cohort 2)

EXPERIMENTAL

Subjects in Cohort 2A will receive first dose of epelsiban (25mg) or placebo after receiving initial oxytocin challenge with dose selected in Cohort 1 followed by 30 minutes washout period. Subjects will receive second dose of epelsiban (150mg) or placebo 12 hours after first dose. Based on the results of Cohort 2A, additional doses may be investigated with a new Cohort 2B (\<150mg) and Cohort 2C (\>200mg) with repeated oxytocin challenges.

Drug: Epelsiban; Drug: Placebo; Drug: Oxytocin; Drug: Ortho-Cylcen (21)® tablet

Biopsy cohort (Cohort 3)

EXPERIMENTAL

Subjects will receive first dose of epelsiban 150mg without oxytocin challenge followed by second dose of epelsiban 150mg 24 hours after the first dose. Subsequently one hour after the second dose, subjects will undergo endometrial biopsies.

Drug: Epelsiban; Drug: Ortho-Cylcen (21)® tablet

Interventions

Epelsiban DRUG

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

Biopsy cohort (Cohort 3); Epelsiban or Placebo (Cohort 2)

Placebo DRUG

White to off white oral placebo tablets to match 5mg epelsiban

Epelsiban or Placebo (Cohort 2); Oxytocin or Placebo challenge (Cohort 1)

Oxytocin DRUG

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).

Epelsiban or Placebo (Cohort 2); Oxytocin or Placebo challenge (Cohort 1)

Ortho-Cylcen (21)® tablet DRUG

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

Biopsy cohort (Cohort 3); Epelsiban or Placebo (Cohort 2); Oxytocin or Placebo challenge (Cohort 1)

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Glendale, California, 91206, United States

Location

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

Related Links

• Results for study 116828 can be found on the GSK Clinical Study Register.

MeSH Terms

Interventions

epelsiban; Oxytocin

Intervention Hierarchy (Ancestors)

Pituitary Hormones, Posterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 7, 2014
• First Posted: August 11, 2014
• Study Start: August 28, 2014
• Primary Completion: February 7, 2016
• Study Completion: February 7, 2016
• Last Updated: May 8, 2017

Record last verified: 2017-05

Locations

US (2)