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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
52
Subjects will be administered with single dose of one moxifloxacin placebo tablet, one 100 mg tablet of retosiban and 7 retosiban matched placebo tablets
Subjects will be administered with single dose of one moxifloxacin placebo tablet and eight 100 mg tablets of retosiban
Subjects will be administered with one moxifloxacin placebo tablet and eight retosiban matched placebo tablets
Subjects will be administered with one 400 mg moxifloxacin tablet and eight retosiban matched placebo tablets
GSK Investigational Site
Baltimore, Maryland, United States
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.
Time frame: 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, 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
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: Day -1 and Day 2 and Day 7
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