This study will evaluate the effect of a single dose of bepirovirsen on the QT interval corrected by Fridericia's formula (QTcF) as compared to placebo. The data generated will be used to model the relationship between bepirovirsen concentration and QTcF.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
46
Bepirovirsen was administered.
Placebo was administered.
GSK Investigational Site
Austin, Texas, United States
Placebo-corrected Change From Baseline (CFB) in QT Interval Corrected by Fridericia's Formula (QTcF) Following Administration of Bepirovirsen Supratherapeutic Single Dose
Continuous 12-lead electrocardiogram (ECG) was captured by Holter monitor. QTcF was measured from 10 digital ECGs extracted from the continuous tracing after 10 minutes of rest in supine position. Baseline was defined as pre-dose value on Day 1. Change from Baseline (CFB) was calculated by subtracting post-dose visit value from Baseline value. Geometric mean and 90 percent (%) Confidence Interval (CI) of predicted CFB QTcF adjusted for placebo at Cmax following supratherapeutic single doses of Bepirovirsen was presented using concentration QTc (C-QTc) analysis using exposure-response modelling. This approach utilized pre-specified linear mixed effects model where CFB QTcF was dependent variable. Fixed-effect parameters included intercept, slope, influence of Baseline on intercept, treatment and nominal time from first dose. Participant was included as additive random effect on both intercept and slope terms.
Time frame: Baseline (Pre-dose on Day 1) and Day 4
Change From Baseline in RR Interval in ECG at Indicated Timepoints
Twelve-lead ECGs were extracted from continuous Holter monitor tracings and RR interval was measured. RR interval is the time duration between the peak of one R wave and the peak of the very next R wave on the ECG. RR interval represents the time between two consecutive heartbeats. ECGs were extracted after a 10 minute supine rest period. Baseline was defined as pre-dose value on Day 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Pre-dose on Day 1) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 27, 30, 33, 36, 48, 51, 54, 57, 60 and 72 hours post-dose
Change From Baseline in QTcF Interval, PR Interval and QRS Duration at Indicated Timepoints
Continuous 12-lead ECG was captured by Holter monitor. QTcF, PR interval and QRS duration were measured from 10 digital ECGs extracted from the continuous tracing after 10 minutes of rest in supine position. Baseline was defined as pre-dose value on Day 1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value.
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Time frame: Baseline (Pre-dose on Day 1) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 27, 30, 33, 36, 48, 51, 54, 57, 60 and 72 hours post-dose
Number of Participants With Outlier Results for Heart Rate (HR)
Continuous 12-lead ECG was captured by Holter monitor. HR was measured from 10 digital ECGs extracted from the continuous tracing after 10 minutes of rest in supine position. Participants with HR less than (\<) 50 beats per minute (bpm) with a decrease of HR greater than (\>) 25% and HR \>100 bpm with an increase of HR \>25% were considered as outlier.
Time frame: Up to Day 4
Number of Participants With Outlier Results for Total QTcF Interval, PR Interval and QRS Duration
Twelve-lead ECG were obtained to measure QTcF interval, PR interval and QRS duration. 12-lead ECG were recorded in a participant using an ECG machine after 10 minutes rest in the supine position. Participants with outlier results were determined if the following criteria (which were assessed separately) were met: Participant who had treatment-emergent (TE) value of QTcF\>450 and \<=480 milliseconds (ms) when not present at Baseline (new onset); TE value of QTcF\>480 and \<=500 ms when not present at Baseline (new onset); TE value of QTcF\>500 ms when not present at Baseline (new onset); increase of QTcF from Baseline of \>30 and \<=60 ms; increase of QTcF from baseline \>60 ms; Increase in PR interval from Baseline \>25% resulting in PR \>200 ms; increase in QRS duration from Baseline \>25% resulting in QRS \>120 ms.
Time frame: Up to Day 4
Number of Participants With Treatment Emergent Changes of T Wave Morphology and U-wave Presence
Twelve-lead ECG were obtained using an ECG machine. T-wave morphology was categorized as follows: Flat T wave: T amplitude \<1 millimeter (mm) (either positive or negative) including flat isoelectric line. Notched T wave(+): Presence of notch(es) of at least 0.05 millivolt(mV) amplitude on ascending or descending arm of positive T wave. Biphasic: T wave that contains a second component with an opposite phase that is at least 0.1 mV deep (both positive/negative and negative/positive and polyphasic T waves included). T wave Inversion: T wave which normally points upward in most leads, is seen pointing downward (negative). Normal T wave(-): T amplitude that is negative, without biphasic T wave or notches. Notched T wave(-): Presence of notch(es) of at least 0.05 mV amplitude on descending or ascending arm of the negative T wave. U waves: Presence of abnormal U waves. Number of participants who had any treatment emergent changes of T wave morphology and U-wave presence have been presented.
Time frame: Up to Day 4
Plasma Concentrations of Bepirovirsen
Blood samples were collected at the indicated time points for pharmacokinetic (PK) analysis of Bepirovirsen.
Time frame: At 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 27, 30, 33, 36, 48, 51, 54, 57, 60 and 72 hours post-dose
Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) of Bepirovirsen
Blood samples were collected at the indicated time points for pharmacokinetic analysis of Bepirovirsen.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 27, 30, 33, 36, 48, 51, 54, 57, 60 and 72 hours post-dose
Area Under the Concentration-time Curve From Time Zero (Pre-dose) to 24 Hours Post-dose (AUC[0-24]) of Bepirovirsen
Blood samples were collected at the indicated time points for pharmacokinetic analysis of Bepirovirsen.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose
Maximum Plasma Concentration (Cmax) of Bepirovirsen
Blood samples were collected at the indicated time points for pharmacokinetic analysis of Bepirovirsen.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 27, 30, 33, 36, 48, 51, 54, 57, 60 and 72 hours post-dose
Time to Reach Cmax (Tmax) of Bepirovirsen
Blood samples were collected at the indicated time points for pharmacokinetic analysis of Bepirovirsen.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 27, 30, 33, 36, 48, 51, 54, 57, 60 and 72 hours post-dose