This Study Will Investigate the Effect of Single Oral Doses of Retosiban on Cardiac Repolarization, With Moxifloxacin as a Positive Control in Healthy Volunteers.

A Randomized, Placebo-Controlled, Double-Blind, Four-way Crossover Study to Assess the Effect of Single Oral Doses of Retosiban on Cardiac Repolarization, With Moxifloxacin as a Positive Control in Healthy Volunteers

This will be a randomized, placebo-controlled, single, oral dose, four-way Williams crossover study design in healthy male and female subjects. The study consists of screening (28 days), treatment (1 day/dosing session) and follow-up (7 to 14 days) period and the total duration of study participation for each subject will be approximately 9 weeks. Each subject will participate in 4 dosing sessions separated by a minimum 7-day washout period. All subjects will receive single doses of retosiban 100 mg, (treatment A) retosiban 800 mg (Treatment B), moxifloxacin 400 mg (Treatment C) and placebo (Treatment D) in one of the four treatment sequences (ABDC, BCAD, CDBA, DACB) following a Williams design Twelve-lead ECGs and continuous Holter monitoring, clinical laboratory safety tests, vital sign measurements, physical examinations, adverse event reports, and pharmacokinetic samples will be collected throughout the study. In each study period, cardiac conduction will be measured using a 24-hour continuous 12-lead Holter monitor from the morning of Day 1 (dosing) until the morning of Day 2.

Study Overview

• Status: Completed
• Conditions: Obstetric Labour, Premature
• Intervention / Treatment: Drug: Retosiban 100 mg; Drug: Retosiban 800 mg; Drug: Placebo; Drug: Moxifloxacin 400 mg

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21225
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• - Male or female between 18 and 45 years of age inclusive, at the time of signing the informed consent
• A female subject is eligible to participate if she is of: child-bearing potential and agrees to use the contraception methods from time of consent until until 48 hours post last dose; Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use the contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GlaxoSmithKline (GSK) Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Body weight (greater than or equal to) >=50 kg and body mass index (BMI) within the range 19 to 29.9 kg/m^2
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
• No significant abnormality on 12-lead ECG at screening, including the following specific requirements: ventricular rate >=40 beats per minute, PR interval less than or equal to (<=) 210 miliseconds (msec), Q waves less than (<)30 msec, QRS interval to be >=60 msec and <120 msec; the waveforms must enable the QT interval to be clearly defined; QTcB or QTcF interval must be <450 msec
• ALT, alkaline phosphatase and bilirubin <=1.5xULN (isolated bilirubin greater than (>) 1.5x upper limit of normal (ULN) is acceptable if bilirubin is fractionated and direct bilirubin <35%)

Exclusion Criteria:

• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• A supine blood pressure that is persistently higher than 140/90 millimeters of mercury (mmHg).
• A supine mean heart rate outside the range 40 to 90 beats per minute (bpm).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• A positive pre-study drug/alcohol screen.
• A positive test for Human Immunodeficiency Virus (HIV) antibody.
• History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml [milliliters]) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.
• 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.
• 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 GSK Medical Monitor, contraindicates their participation.
• Where participation in the study would result in donation of blood or blood products in excess of 500 ml within a 56 day period.
• Pregnant females as determined by positive serum human chorionic gonadotropin (hCG) test at screening or prior to dosing. Lactating females.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
• Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.
• History or presence of any medically significant disease, or any disorder that would introduce additional risk or interfere with the study procedures or outcome. In particular, a family history of QT prolongation, of early or sudden cardiac death or of early cardiovascular disease.
• Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements from 14 days before screening until the follow-up visit unless in the opinion of the Investigator and sponsor the medication will not interfere with the study or compromise subject safety.
• Serum calcium, magnesium or potassium levels outside the reference range
• History of sensitivity to quinolone antibiotics or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Retosiban 100 mg; Each subject will be randomized to single dose of retosiban 100 mg in one of the four treatment sequences.	Drug: Retosiban 100 mg; Subjects will be administered with single dose of one moxifloxacin placebo tablet, one 100 mg tablet of retosiban and 7 retosiban matched placebo tablets
Experimental: Retosiban 800 mg; Each subject will be randomized to single dose of retosiban 800 mg in one of the four treatment sequences	Drug: Retosiban 800 mg; Subjects will be administered with single dose of one moxifloxacin placebo tablet and eight 100 mg tablets of retosiban
Placebo Comparator: Placebo; Each subject will be randomized to single dose of matching placebo in one of the four treatment sequences	Drug: Placebo; Subjects will be administered with one moxifloxacin placebo tablet and eight retosiban matched placebo tablets
Active Comparator: Moxifloxacin 400 mg; Each subject will be randomized to single dose of moxifloxacin 400 mg in one of the four treatment sequences	Drug: Moxifloxacin 400 mg; Subjects will be administered with one 400 mg moxifloxacin tablet and eight retosiban matched placebo tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in QT duration corrected for heart rate by Fridericia's formula (QTcF) interval at each timepoint for retosiban as compared with time-matched placebo	Single 12-lead electrocardiograms (ECG)s will be obtained at each timepoint during the study using an ECG machine that automatically calculates corrected QT interval (QTc) interval. An average of at least 3 12-lead Holter ECG replicates per time point. Change = 12-lead ECG reading at each timepoint minus the baseline 12-lead ECG reading.	Baseline (Day 1-pre-dose) and 1 hour [hr], 8 hrs, 12 hrs , 24 hrs (Day 2) post-dose and Day 7 per dosing session.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in QTcF, QT duration corrected for heart rate by Bazett's formula (QTcB), and QT interval corrected for heart rate (QTci) /QTciL interval at each timepoint for 100 mg and 800 mg retosiban as compared with time-matched placebo	Single 12-lead ECGs will be obtained for subjects receiving 100 mg and 800 mg retosiban at each timepoint during the study using an ECG machine that automatically calculates QTc interval. An average of at least 3 12-lead Holter ECG replicates per time point. Change = 12-lead ECG reading at each timepoint minus the baseline 12-lead ECG reading	Baseline (Day 1-pre-dose) and 1 hour [hr], 8 hrs, 12 hrs , 24 hrs (Day 2) post-dose and Day 7 per dosing session.
Change from baseline in QTcF, QTcB, and QTci/QTciL interval at each timepoint for moxifloxacin as compared with time-matched placebo	Single 12-lead ECGs will be obtained for subjects receiving moxifloxacin at each timepoint during the study using an ECG machine that automatically calculates QTc interval. An average of at least 3 12-lead Holter ECG replicates per time point. Change = 12-lead ECG reading at each timepoint minus the baseline 12-lead ECG reading.	Baseline (Day 1-pre-dose) and 1 hour [hr], 8 hrs, 12 hrs , 24 hrs (Day 2) post-dose and Day 7 per dosing session.
Plasma concentrations of retosiban and GSK2847065	Pharmacokinetic data will include plasma concentration of retosiban and GSK2847065	Day 1 (pre-dose), 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 18 hr post-dose and Day 2 per dosing session.
Maximum observed concentration (Cmax) for retosiban and GSK2847065	Pharmacokinetic data will include Cmax of retosiban and GSK2847065	Day 1 (pre-dose, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 18 hr post-dose) and Day 2 per dosing session
Time to maximum concentration (tmax) for retosiban and GSK2847065	Pharmacokinetic data will include tmax of retosiban and GSK2847065	Day 1 (pre-dose, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 18 hr post-dose) and Day 2 per dosing session
Area under the concentration-time curve over the dosing interval (AUC(0-τ)) for retosiban and GSK2847065	Pharmacokinetic data will include AUC0-τ of retosiban and GSK2847065	Day 1 (pre-dose, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 18 hr post-dose) and Day 2 per dosing session
Maximal change from baseline for QTcF and QTcB	Single 12-lead ECGs will be obtained using an ECG machine that automatically calculates QTc interval. An average of at least 3 12-lead Holter ECG replicates per time point. Maximal Change from baseline = maximum 12-lead ECG reading at each timepoint minus the baseline 12-lead ECG reading	Baseline (Day 1-pre-dose) and 1 hour [hr], 8 hrs, 12 hrs , 24 hrs (Day 2) post-dose and Day 7 per dosing session
Change from baseline for other cardiac electrophysiological parameters: QT, QRS, RR, PR and ventricular rate at each timepoint	Single 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals. Change from baseline for other cardiac electrophysiological will be calculated as: other cardiac electrophysiological parameters at each timepoint minus baseline value	Baseline (Day 1-pre-dose) and 1 hour [hr], 8 hrs, 12 hrs , 24 hrs (Day 2) post-dose and Day 7 per dosing session
Safety and tolerability of retosiban as assessed by change from baseline in 12-lead ECGs	Single 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals	Day 1 (pre-dose, 1 hr, 8 hr, 12 hr post-dose), Day 2 and Day 7
Safety and tolerability of retosiban as assessed by change from baseline in systolic and diastolic blood pressure	Vital sign measurements will be done in supine position and will include systolic and diastolic blood pressure	Day 1 (pre-dose, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 18 hr post-dose), Day 2 and Day 7
Safety and tolerability of retosiban as assessed by change from baseline in pulse rate	Vital sign measurements will be done in supine position and will include pulse rate.	Day 1 (pre-dose, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 18 hr post-dose), Day 2 and Day 7
Safety and tolerability of retosiban as assessed number of adverse events	Safety and tolerability parameters will include recording of AEs, throughout the study	9 weeks
Safety and tolerability of retosiban as assessed by change from baseline in clinical laboratory tests	Clinical laboratory assessments will include hematology, clinical chemistry, routine urinalysis and additional parameters	Day -1 and Day 2 and Day 7

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Stier B, Fossler M, Liu F, Caltabiano S. Effect of Retosiban on Cardiac Repolarization in a Randomized, Placebo- and Positive-controlled, Crossover Thorough QT/QTc Study in Healthy Men and Women. Clin Ther. 2015 Jul 1;37(7):1541-54. doi: 10.1016/j.clinthera.2015.05.007. Epub 2015 Jun 29.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): October 3, 2012
• Primary Completion (Actual): January 14, 2013
• Study Completion (Actual): January 14, 2013

Study Registration Dates

• First Submitted: October 4, 2012
• First Submitted That Met QC Criteria: October 4, 2012
• First Posted (Estimate): October 8, 2012

Study Record Updates

• Last Update Posted (Actual): June 12, 2017
• Last Update Submitted That Met QC Criteria: June 9, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Moxifloxacin
• Other Study ID Numbers: 113789

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: 113789
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Annotated Case Report Form
   Information identifier: 113789
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Clinical Study Report
   Information identifier: 113789
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Study Protocol
   Information identifier: 113789
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Dataset Specification
   Information identifier: 113789
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Statistical Analysis Plan
   Information identifier: 113789
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Informed Consent Form
   Information identifier: 113789
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register