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

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ClinicalTrials.gov Identifier: NCT02377414
Recruitment Status : Completed
First Posted : March 3, 2015
Last Update Posted : May 9, 2017
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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).

Condition or disease Intervention/treatment Phase
Obstetric Labour, Premature Drug: Retosiban solution for Infusion Drug: Placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase I, Subject and Investigator Blind Randomized, Study to Investigate the Pharmacokinetics, Safety and Tolerability of Retosiban in Healthy Japanese Women
Actual Study Start Date : March 2, 2015
Actual Primary Completion Date : April 17, 2015
Actual Study Completion Date : April 17, 2015

Arm Intervention/treatment
Experimental: Cohort 1: Retosiban/placebo
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.
Drug: Retosiban solution for Infusion
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

Drug: Placebo
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

Experimental: Cohort 2: 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.
Drug: Retosiban solution for Infusion
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




Primary Outcome Measures :
  1. 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 [ 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 ]
    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

  2. 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 [ 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 ]
    AUC, Cmax, t1/2


Secondary Outcome Measures :
  1. Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to 13 days ]
    AEs and SAEs will be collected from the start of study treatment until the follow-up contact

  2. Composite of clinical laboratory assessments [ Time Frame: Up to 13 days ]
    Clinical laboratory tests will include hematology, clinical chemistry, urinalysis and additional parameters

  3. Vital sign assessment as a measure of safety [ Time Frame: Up to 13 days ]
    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

  4. Safety as assessed by electrocardiogram (ECG) [ Time Frame: Up to 13 days ]
    Triplicate 12-lead ECGs will be obtained at each time point during the study

  5. Concomitant medication assessment as a measure of safety [ Time Frame: Up to 13 days ]


Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02377414


Locations
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United States, California
GSK Investigational Site
Glendale, California, United States, 91206
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02377414    
Other Study ID Numbers: 117168
First Posted: March 3, 2015    Key Record Dates
Last Update Posted: May 9, 2017
Last Verified: May 2017
Keywords provided by GlaxoSmithKline:
Preterm labor
Retosiban
Pharmacokinetics
Safety
Infusion
GSK2847065
Additional relevant MeSH terms:
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Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications