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Study to Investigate the Pharmacokinetics (PK), Safety and Tolerability of Retosiban in Healthy Japanese Women

Primary Purpose

Obstetric Labour, Premature

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Retosiban solution for Infusion
Placebo
Sponsored by
GlaxoSmithKline
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Obstetric Labour, Premature focused on measuring Preterm labor, Retosiban, Pharmacokinetics, Safety, Infusion, GSK2847065

Eligibility Criteria

20 Years - 45 Years (Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Subjects who are between 20 and 45 years and of age, inclusive at the time of signing the informed consent form.
  • Japanese, defined as being born in Japan, having four ethnic Japanese grandparents, holding a Japanese passport or identity papers and being able to speak Japanese, and that lifestyle including diet has not changed significantly since leaving Japan. Japanese subjects should also have lived outside Japan for less than 10 years.
  • Caucasian subjects as defined as an individual having four grandparents who are all descendants of the original peoples of Europe.
  • Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring obtained at the screening visit.
  • 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 medical monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • Body weight >=43 kilograms (kg) and body mass index (BMI) within the range 17-29.9 kilogram per square meter (kg/m^2) (inclusive).
  • Female subjects- A female subject is eligible to participate if she is: A female of non-productive potential secondary to a personal history of a hysterectomy or tubal sterilization procedure.

A female of reproductive potential who is not pregnant (as confirmed by a negative urine or serum human chorionic gonadotropin [hCG] test), not lactating, and agrees to follow one of the options listed in protocol. Contraception requirement for female subjects from 28 days prior to the first dose of study treatment and until completion of the follow-up visit.

  • Capable of giving signed informed consent as described in protocol which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria:

  • Alanine aminotransferase (ALT), alkaline phosphatase 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)
  • QT duration corrected (QTc) >450 milliseconds (msec) NOTES: The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB), QT duration corrected for heart rate by Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read.

The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial.

  • Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) except occasional usage of acetaminophen, within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of investigational product until completion of the follow-up visit, unless in the opinion of the investigator and GlaxoSmithKline (GSK) medical monitor the medication will not interfere with the study.
  • 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 (g) 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.
  • History of drug abuse or dependence within 6 months of the study.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • 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.
  • 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 56 days.
  • 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.

Sites / Locations

  • GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Cohort 1: Retosiban/placebo

Cohort 2: Retosiban

Arm Description

Each subject in cohort 1 will receive an intravenous (IV) bolus infusion of 6 milligrams (mg) retosiban or placebo over 5 minutes, followed by a continuous infusion of 6 milligram per hour (mg/h) retosiban or placebo for 24 h. At 24 h of dosing, an additional 6 mg retosiban or placebo will be administered over 5 minutes followed by a 12 mg/h infusion over the next 24 h, for a total time of infusion of 48 h. Subjects administered with placebo will receive an equal volume of normal saline as an IV bolus as well as an equal rate of continuous infusion of normal saline as of retosiban.

Each subject in cohort 2 will receive a bolus infusion of 6 mg retosiban over 5 minutes, followed by a continuous infusion of 6 mg/h retosiban for 24 h. At 24 h of dosing, an additional 6 mg retosiban will be administered over 5 minutes followed by a 12 mg/h infusion over the next 24 h, for a total time of infusion of 48 h.

Outcomes

Primary Outcome Measures

Composite of PK parameters of retosiban administered by intravenous infusion to healthy adult Japanese and Caucasian women of child-bearing potential: AUC, Cmax, t1/2 and clearance of retosiban
PK parameters will include: area under concentration-time curve (AUC), maximum observed concentration (Cmax), terminal phase half-life (t1/2) and clearance (CL) of retosiban
Composite of PK parameters of retosiban and its major inactive metabolite (GSK2847065) in healthy adult Japanese and Caucasian women of child-bearing potential: AUC, Cmax, t1/2
AUC, Cmax, t1/2

Secondary Outcome Measures

Number of subjects with adverse events (AEs) and serious adverse events (SAEs)
AEs and SAEs will be collected from the start of study treatment until the follow-up contact
Composite of clinical laboratory assessments
Clinical laboratory tests will include hematology, clinical chemistry, urinalysis and additional parameters
Vital sign assessment as a measure of safety
Vital signs will be measured in semi-supine position after 5 minutes rest and will include body temperature, systolic and diastolic blood pressure, pulse rate and respiratory rate
Safety as assessed by electrocardiogram (ECG)
Triplicate 12-lead ECGs will be obtained at each time point during the study
Concomitant medication assessment as a measure of safety

Full Information

First Posted
February 26, 2015
Last Updated
May 5, 2017
Sponsor
GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT02377414
Brief Title
Study to Investigate the Pharmacokinetics (PK), Safety and Tolerability of Retosiban in Healthy Japanese Women
Official Title
A Phase I, Subject and Investigator Blind Randomized, Study to Investigate the Pharmacokinetics, Safety and Tolerability of Retosiban in Healthy Japanese Women
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
March 2, 2015 (Actual)
Primary Completion Date
April 17, 2015 (Actual)
Study Completion Date
April 17, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This study in healthy, adult Japanese women will characterize the PK, safety and tolerability of retosiban at the therapeutic doses planned to be evaluated in Phase 3. The PK data will be compared to a sub-set of Caucasian women given the same dose of retosiban. This study has two cohorts, cohort 1 will be a double-blind sponsor-open (subjects and investigator blinded and sponsor unblinded), randomized, continuous 48 hours (h) infusion study in healthy, adult Japanese women of child-bearing potential. Cohort 2 is an open label and continuous retosiban 48 h infusion study in Caucasian, adult, healthy women of child bearing potential. So, the PK can be compared with those of Japanese women. Approximately 32 subjects will be enrolled. In cohort 1, approximately 24 subjects will be enrolled and randomized to retosiban and placebo (2:1 ratio) to have 18 women with 12 active, 6 placebo completed subjects. In Cohort 2, 8 subjects will be enrolled to have 6 competed subjects. The total duration of a subject's involvement in this part is anticipated to be up to 6 weeks (including the 28 day screening period).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obstetric Labour, Premature
Keywords
Preterm labor, Retosiban, Pharmacokinetics, Safety, Infusion, GSK2847065

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1: Retosiban/placebo
Arm Type
Experimental
Arm Description
Each subject in cohort 1 will receive an intravenous (IV) bolus infusion of 6 milligrams (mg) retosiban or placebo over 5 minutes, followed by a continuous infusion of 6 milligram per hour (mg/h) retosiban or placebo for 24 h. At 24 h of dosing, an additional 6 mg retosiban or placebo will be administered over 5 minutes followed by a 12 mg/h infusion over the next 24 h, for a total time of infusion of 48 h. Subjects administered with placebo will receive an equal volume of normal saline as an IV bolus as well as an equal rate of continuous infusion of normal saline as of retosiban.
Arm Title
Cohort 2: Retosiban
Arm Type
Experimental
Arm Description
Each subject in cohort 2 will receive a bolus infusion of 6 mg retosiban over 5 minutes, followed by a continuous infusion of 6 mg/h retosiban for 24 h. At 24 h of dosing, an additional 6 mg retosiban will be administered over 5 minutes followed by a 12 mg/h infusion over the next 24 h, for a total time of infusion of 48 h.
Intervention Type
Drug
Intervention Name(s)
Retosiban solution for Infusion
Intervention Description
Retosiban will be supplied as clear, colorless IV solution for infusion in 5 mL vial with a unit dose strength of 15 milligrams per milliliter (mg/mL) (each 5 mL vial contains 75 mg retosiban), dosed at up to 300 mg over 48 h infusion
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo will be supplied as a clear, colorless IV solution for infusion with a unit dose strength of 0.9% sodium chloride (NaCl) normal saline
Primary Outcome Measure Information:
Title
Composite of PK parameters of retosiban administered by intravenous infusion to healthy adult Japanese and Caucasian women of child-bearing potential: AUC, Cmax, t1/2 and clearance of retosiban
Description
PK parameters will include: area under concentration-time curve (AUC), maximum observed concentration (Cmax), terminal phase half-life (t1/2) and clearance (CL) of retosiban
Time Frame
Pre-dose, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 18 h, 24 h (just before dose increase), 24.5 h, 25 h, 26 h, 28 h, 36 h, 42 h, 48 h, 48.5 h, 49 h, 50 h, 52 h, 54 h, 56 h and 60 h post start of the infusion
Title
Composite of PK parameters of retosiban and its major inactive metabolite (GSK2847065) in healthy adult Japanese and Caucasian women of child-bearing potential: AUC, Cmax, t1/2
Description
AUC, Cmax, t1/2
Time Frame
Pre-dose, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 18 h, 24 h (just before dose increase), 24.5 h, 25 h, 26 h, 28 h, 36 h, 42 h, 48 h, 48.5 h, 49 h, 50 h, 52 h, 54 h, 56 h and 60 h post start of the infusion
Secondary Outcome Measure Information:
Title
Number of subjects with adverse events (AEs) and serious adverse events (SAEs)
Description
AEs and SAEs will be collected from the start of study treatment until the follow-up contact
Time Frame
Up to 13 days
Title
Composite of clinical laboratory assessments
Description
Clinical laboratory tests will include hematology, clinical chemistry, urinalysis and additional parameters
Time Frame
Up to 13 days
Title
Vital sign assessment as a measure of safety
Description
Vital signs will be measured in semi-supine position after 5 minutes rest and will include body temperature, systolic and diastolic blood pressure, pulse rate and respiratory rate
Time Frame
Up to 13 days
Title
Safety as assessed by electrocardiogram (ECG)
Description
Triplicate 12-lead ECGs will be obtained at each time point during the study
Time Frame
Up to 13 days
Title
Concomitant medication assessment as a measure of safety
Time Frame
Up to 13 days

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Subjects who are between 20 and 45 years and of age, inclusive at the time of signing the informed consent form. Japanese, defined as being born in Japan, having four ethnic Japanese grandparents, holding a Japanese passport or identity papers and being able to speak Japanese, and that lifestyle including diet has not changed significantly since leaving Japan. Japanese subjects should also have lived outside Japan for less than 10 years. Caucasian subjects as defined as an individual having four grandparents who are all descendants of the original peoples of Europe. Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring obtained at the screening visit. 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 medical monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Body weight >=43 kilograms (kg) and body mass index (BMI) within the range 17-29.9 kilogram per square meter (kg/m^2) (inclusive). Female subjects- A female subject is eligible to participate if she is: A female of non-productive potential secondary to a personal history of a hysterectomy or tubal sterilization procedure. A female of reproductive potential who is not pregnant (as confirmed by a negative urine or serum human chorionic gonadotropin [hCG] test), not lactating, and agrees to follow one of the options listed in protocol. Contraception requirement for female subjects from 28 days prior to the first dose of study treatment and until completion of the follow-up visit. Capable of giving signed informed consent as described in protocol which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. Exclusion Criteria: Alanine aminotransferase (ALT), alkaline phosphatase 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) QT duration corrected (QTc) >450 milliseconds (msec) NOTES: The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB), QT duration corrected for heart rate by Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read. The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial. Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) except occasional usage of acetaminophen, within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of investigational product until completion of the follow-up visit, unless in the opinion of the investigator and GlaxoSmithKline (GSK) medical monitor the medication will not interfere with the study. 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 (g) 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. History of drug abuse or dependence within 6 months of the study. History of sensitivity to heparin or heparin-induced thrombocytopenia. 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. 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 56 days. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
Glendale
State/Province
California
ZIP/Postal Code
91206
Country
United States

12. IPD Sharing Statement

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Study to Investigate the Pharmacokinetics (PK), Safety and Tolerability of Retosiban in Healthy Japanese Women

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