Hepatitis B
Conditions
Keywords
Bepirovirsen, Cardiac Conduction, Electrocardiogram, QT interval corrected by Fridericia's formula, Hepatitis B virus
Brief summary
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.
Interventions
DRUGBepirovirsen
Bepirovirsen was administered.
DRUGPlacebo
Placebo was administered.
Sponsors
GlaxoSmithKline
PPD Development, LP
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
This will be a double-blind study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Participant must be 18 to 55 years of age inclusive, at the time of signing the informed consent. * Participants who are overtly healthy as determined by medical evaluation, including medical history, physical examination, laboratory tests, electrocardiogram (ECG) and vital signs. * Body weight greater than equal to (\>=) 50 Kilograms (kg) and Body mass index (BMI) within the range 19-32 Kilograms per square meter (kg/m\^2) (inclusive). * Study will enroll both male and female participants. o Female participants are eligible to participate if they are not pregnant or breastfeeding and are either not of childbearing potential or agree to using a highly effective method of contraception. * Capable of giving signed informed consent.
Exclusion criteria
* History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data. * History of vasculitis or presence of symptoms and signs of potential vasculitis * History of lymphoma, leukemia, or any malignancy except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for at least 3 years. * Participants with any other medical conditions which, in the judgement of the investigator and/or Medical Monitor, could jeopardize the integrity of the data derived from that participant or the safety of the participant. * Past, current or intended use of over-the-counter or prescription medication, including herbal medications within 7 days or 5 half-lives (whichever is longer) before dosing. * Current or recent use of creatine-containing supplements, or intended use up to 50 days post-dosing. * Prior treatment with any oligonucleotide or small interfering Ribonucleic acid (RNA) (siRNA) within 12 months before dosing. * Exposure to more than 4 new chemical entities within 12 months before the first dosing day * Current enrollment or past participation in another investigational study in which an investigational intervention (e.g., drug, vaccine, invasive device) was administered within 5 half-lives (if known) or twice the duration of biological effect (if known), whichever is longer, or within the last 90 days (if half-life and duration of biological effect are unknown), before signing of consent in any other clinical study involving an investigational study intervention or any other type of medical research. * Current enrollment or past participation in this clinical study. * Positive pre-clinical drug/alcohol screen, including tetrahydrocannabinol. * Positive Human Immunodeficiency Virus antibody test. * History or regular use of tobacco or nicotine-containing products within 6 months prior to screening. * Regular alcohol consumption within 6 months prior to screening defined as an average weekly intake of \>14 units for males or females. * Regular use of known drugs of abuse, including tetrahydrocannabinol. * Sensitivity to heparin or history of heparin-induced thrombocytopenia. * History of sensitivity to bepirovirsen or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor contraindicates their participation. * Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). * Positive test results for Hepatitis B surface antigen (HBsAg), hepatitis C antibody or hepatitis C RNA at screening or within 3 months prior to first dose of study intervention. * Known history of heart disease, including ischemic heart disease, cardiomyopathy, clinically significant cardiac arrhythmias, clinically significant valvular disease, or hypertensive heart disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Placebo-corrected Change From Baseline (CFB) in QT Interval Corrected by Fridericia's Formula (QTcF) Following Administration of Bepirovirsen Supratherapeutic Single Dose | Baseline (Pre-dose on Day 1) and Day 4 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in RR Interval in ECG at Indicated Timepoints | 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 | 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. |
| Change From Baseline in QTcF Interval, PR Interval and QRS Duration at Indicated Timepoints | 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 | 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. |
| Number of Participants With Outlier Results for Heart Rate (HR) | Up to Day 4 | 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. |
| Number of Participants With Outlier Results for Total QTcF Interval, PR Interval and QRS Duration | Up to Day 4 | 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. |
| Number of Participants With Treatment Emergent Changes of T Wave Morphology and U-wave Presence | Up to Day 4 | 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. |
| Plasma Concentrations of Bepirovirsen | 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 | Blood samples were collected at the indicated time points for pharmacokinetic (PK) analysis of Bepirovirsen. |
| Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) of Bepirovirsen | 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 | Blood samples were collected at the indicated time points for pharmacokinetic analysis of Bepirovirsen. |
| Area Under the Concentration-time Curve From Time Zero (Pre-dose) to 24 Hours Post-dose (AUC[0-24]) of Bepirovirsen | Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose | Blood samples were collected at the indicated time points for pharmacokinetic analysis of Bepirovirsen. |
| Maximum Plasma Concentration (Cmax) of Bepirovirsen | 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 | Blood samples were collected at the indicated time points for pharmacokinetic analysis of Bepirovirsen. |
| Time to Reach Cmax (Tmax) of Bepirovirsen | 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 | Blood samples were collected at the indicated time points for pharmacokinetic analysis of Bepirovirsen. |
Countries
United States
Contacts
STUDY_DIRECTORGSK Clinical Trials
GlaxoSmithKline
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 37.5 YEARS STANDARD_DEVIATION 9.2 |
| Race/Ethnicity, Customized AMERICAN INDIAN OR ALASKA NATIVE | 2 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 1 Participants |
| Race/Ethnicity, Customized MULTIPLE | 0 Participants |
| Race/Ethnicity, Customized WHITE | 2 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 5 / 5 | 1 / 5 | 15 / 18 | 2 / 18 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 18 | 0 / 18 |
Outcome results
None listed