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Safety, Tolerability, Pharmacokinetics and Antiviral Activity of IONIS-HBVRx in Treatment-Naïve Patients With Chronic HBV Infection

Primary Purpose

Hepatitis B, Chronic Hepatitis B Atypical

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
IONIS-HBVRx
Placebo
Sponsored by
GlaxoSmithKline
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis B focused on measuring Hepatitis, Chronic, HBV

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age 18 to 70 years
  • Chronic HBV infection ≥6 months (e.g., positive for serum HBsAg ≥ 6 months)
  • Plasma HBV DNA ≥ 2 x 1000 IU/mL (HBV DNA adequately suppressed for exploratory nucleos(t)ide analogue experienced cohort)
  • Serum HBsAg ≥ 50 IU/mL
  • Exploratory nucleos(t)ide analogue experienced cohort only: currently taking and have been taking tenofovir or entecavir without changes in drug, dose level and/or frequency of administration for ≥ 12 months and expect to continue taking without change through to the end of their participation in this study

Exclusion Criteria:

  • Current or prior receipt of anti-HBV nucleos(t)ide analogue therapy. Patients who have failed prior interferon treatment, greater than 6 months prior to Screening, may be evaluated for possible participation in the study (not applicable for exploratory nucleos(t)ide analogue experienced cohort)

  • History of liver cirrhosis and/or evidence of cirrhosis as determined by any of the following:

    1. Liver biopsy (i.e., Metavir Score F4) within 2 years of Screening, or
    2. Fibroscan > 12 KPa, within 12 months of Screening, or
    3. AST-to-Platelet Index (APRI) > 2 and Fibrosure result > 0.7 within 12 months of Screening For patients without a test for cirrhosis in the above timeframes, Fibroscan, or APRI and Fibrosure, may be performed during the screening period to rule out cirrhosis
  • History of liver failure as evidenced by ascites, hepatic encephalopathy, and/or gastric or esophageal varices
  • History of liver disease other than Hepatitis B
  • Co-infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or hepatitis D virus (HDV)
  • BMI > 35 kg/m2
  • History of, or suspected presence of vasculitis
  • Received solid organ or bone marrow transplant
  • Currently taking, or took within 3 months of Screening, any immunosuppressing drugs (e.g., prednisone)
  • Diagnosed hepatocellular carcinoma or suspected hepatocellular carcinoma as evidenced by screening alpha-fetoprotein ≥ 200 ng/mL. If the screening alpha-fetoprotein is ≥ 50 ng/mL and < 200 ng/mL, the absence of liver mass must be documented by imaging within 6 months before randomization
  • Clinically-significant abnormalities aside from chronic HBV infection in medical history (e.g., previous acute coronary syndrome within 6 months of Screening, major surgery within 3 months of Screening, uncontrolled diabetes) or physical examination
  • History of bleeding diathesis or coagulopathy
  • History of extrahepatic disorders possibly related to HBV immune complexes (e.g., glomerulonephritis, polyarteritis nodosa)
  • History of excess alcohol consumption within 6 months of Screening
  • History of drug abuse or dependence, or recreational use of drugs: within 3 months of Screening for soft drugs (such as marijuana) and within 1-year of Screening for hard drugs (such as cocaine, phencyclidine [PCP])

Sites / Locations

  • Queen Mary Hospital
  • Korea University Ansan Hospital
  • Inje University Busan Paik Hospital
  • Kyungpook National University Hospital
  • Pusan National University Hospital
  • Seoul National University Hospital
  • Seoul St. Mary's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

IONIS-HBVRx

Placebo

Arm Description

Ascending multiple doses of IONIS-HBVRx by subcutaneous (SC) injection

Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator

Outcomes

Primary Outcome Measures

Number of Participants With Serious Adverse Events (SAEs) and Non-Serious Adverse Events (Non-SAEs >=5%)
An adverse event is any unfavorable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. Any adverse event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any important medical event according to medical judgment were categorized as SAE.
Change From Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine Kinase (CK), Gamma-glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) Over Time
Blood samples were collected for the analysis of clinical parameters including ALT, ALP, CK, GGT, LDH and AST. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline in Clinical Chemistry Parameters : Albumin and Total Protein Over Time
Blood samples were collected for the analysis of clinical chemistry parameter-albumin and total protein. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline Values in Clinical Chemistry Parameters: Sodium, Potassium, Chloride, Bicarbonate, Calcium, Magnesium, Phosphate, Glucose, Blood Urea Nitrogen, Cholesterol and Urate
Blood samples were collected for the analysis of clinical parameters including sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate, glucose, blood urea nitrogen (BUN), cholesterol and urate. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline Values in Clinical Chemistry Parameters: Total Bilirubin, Direct Bilirubin, Indirect Bilirubin, and Creatinine
Blood samples were collected for the analysis of clinical chemistry parameters: direct bilirubin, total bilirubin, indirect bilirubin and creatinine. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline for Hematology Parameters: Basophils, Eosinophils, White Blood Cells (WBC), Lymphocytes, Neutrophils, Monocytes, and Platelets
Blood samples were collected for the analysis of hematology parameters including basophil, eosinophils, WBC, lymphocytes, neutrophils, monocytes, and platelets at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline for Hematology Parameters: Hemoglobin
Blood samples were collected for the analysis of hematology parameters including hemoglobin at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline for Hematology Parameter: Hematocrit
Blood samples were collected for the analysis of hematology parameter including hematocrit at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline Values in Urine Specific Gravity
Urine samples were collected for the analysis of urine specific gravity. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value. Urine specific gravity is measured as the ratio of urine density compared with water density.
Change From Baseline Values in Urine Albumin/Creatinine Ratio and Urine Protein/Creatinine Ratio
Urine samples were collected for the analysis of urine albumin/creatinine ratio and urine protein/creatinine ratio. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline Values in Urine Protein
Urine samples were collected for the analysis of urine protein. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline Values in Blood Coagulation Factors: Activated Partial Thromboplastin Time and Prothrombin Time
Blood samples were collected for the analysis of blood coagulation factors:activated partial thromboplastin time (aPTT) and Prothrombin Time (PT). Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline Values in Blood Coagulation Factor: Prothrombin International Normalized Ratio
Blood samples were collected for the analysis of blood coagulation factor: Prothrombin International normalized ratio. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change in Complement C3 Level at Worst Case Post Baseline Relative to Baseline
Blood samples were collected from participants to evaluate change in complement C3 level at worst case post Baseline relative to Baseline. Worst case post Baseline in Complement C3 was the minimum post-Baseline level. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change in Complement C5a Level at Worst Case Post Baseline Relative to Baseline
Blood samples were collected from participants to evaluate change in complement C5a level at worst case post Baseline relative to Baseline. Worst case post Baseline in Complement C5a was the maximum post-Baseline level. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change in Complement Bb Level at Worst Case Post Baseline Relative to Baseline
Blood samples were collected from participants to evaluate change in complement Bb level at worst case post Baseline relative to Baseline. Worst case post Baseline in Complement Bb was the maximum post-Baseline level. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Number of Participants With Reported Pregnancy
Female participants who were not surgically sterile or post-menopausal, underwent urine beta Human chorionic gonadotropin (Beta-HCG) pregnancy test.
Change From Baseline in Body Temperature
Body temperature was measured at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline in Body Weight
Body weight was measured at indicated time points. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline in Diastolic Blood Pressure and Systolic Blood Pressure
Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) was measured at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline in Respiratory Rate
Respiratory Rate was measured at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline in Pulse Rate
Pulse Rate was measured at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Number of Participants With Abnormal Findings in Physical Examination
Physical examinations included assessment of the dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological systems.
Number of Participants Who Received Atleast One Concomitant Medication
A concomitant medication is defined as any medication initiated after the first dose of study, or initiated prior to the first dose of study drug and continued after the first dose of study drug.
Change From Baseline in Electrocardiogram Mean Ventricular Rate
Triplicate 12-lead Electrocardiograms (ECGs) were recorded at indicated timepoints. At each time point, ECG machine automatically measured mean ventricular rate (VR). Baseline ECG was the average of the triplicate taken on Day 1 Pre-dose, if only 1 or 2 assessments were available, the single assessment or average of the 2 assessments was used. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval, QT Corrected Interval-Fredericia Interval and QTc Corrected by Bazett's Formula
Triplicate 12-lead Electrocardiograms (ECGs) were recorded at indicated timepoints. At each time point, ECG machine automatically measured QRS duration, uncorrected QT interval, QT corrected interval-Fredericia [QTcF] interval and QTc corrected by Bazett's formula (QTcB). Baseline ECG was the average of the triplicate taken on Day 1 Pre-dose, if only 1 or 2 assessments were available, the single assessment or average of the 2 assessments was used. Change from Baseline is defined as post-dose visit value minus Baseline value.

Secondary Outcome Measures

Change From Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Viral Load in Plasma at Day 29
Blood samples were collected from participants to assess HBV DNA viral load. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value. The last observation carried forward (LOCF) method was used to impute missing values at Day 29 in this analysis.
Change From Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Viral Load in Plasma at Week 31
Blood samples were collected from participants to assess HBV DNA viral load. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value.
Change From Baseline in HBV Surface Antigen (HBsAg) Level in Serum at Day 29
Blood samples were collected from participants to assess HBsAg level. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value. The LOCF method was used to impute missing values at Day 29 in this analysis.
Change From Baseline in HBsAg Level in Serum at Week 31
Blood samples were collected from participants to assess HBsAg level. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value.
Percentage of Participants Who Achieved HBsAg Loss at Day 29 and Week 31
Blood samples were collected to evaluate the percentage of participants with HBsAg loss at Day 29 and Week 31. A 'Loss' of HBsAg means antigen is negative. HBsAg Loss percentage is defined as number of participants with HBsAg loss divided by total number of participants assessed multiplied by 100. Baseline is the last non-missing measurement prior to the first dose of study drug.
Percentage of Participants Who Achieved HBV e Antigen (HBeAg) Loss at Day 29 and Week 31 Who Were HBeAg Positive at Baseline
Blood samples were collected to evaluate the percentage of participants with HBeAg loss at Day 29 and Week 31. A 'Loss' of HBeAg means antigen is negative. HBeAg Loss percentage is defined as number of participants with HBeAg loss divided by number of participants with positive HBeAg at Baseline multiplied by 100. Baseline is the last non-missing measurement prior to the first dose of study drug. Participants was considered HBeAg positive at Baseline if the Baseline value> 0.09 U/mL.
Change From Baseline in Serum HBeAg Concentration at Day 29 in Participants Who Were HBeAg Positive at Baseline
Blood samples were collected from participants to assess HBeAg level. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value. Participant was considered HBeAg positive at Baseline if the Baseline value> 0.09 International Units/milliliter (IU/mL).
Change From Baseline in Serum HBeAg Concentration at Week 31 in Participants Who Were HBeAg Positive at Baseline
Blood samples were collected from participants to assess HBeAg level. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value. Participant was considered HBeAg positive at Baseline if the Baseline value> 0.09 U/mL.
Plasma Concentrations of GSK3228836 in Participants With Chronic HBV Infection
Plasma samples were collected from participants with chronic HBV infection at indicated time points for pharmacokinetic analysis of GSK3228836.

Full Information

First Posted
December 1, 2016
Last Updated
August 6, 2021
Sponsor
GlaxoSmithKline
Collaborators
Ionis Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT02981602
Brief Title
Safety, Tolerability, Pharmacokinetics and Antiviral Activity of IONIS-HBVRx in Treatment-Naïve Patients With Chronic HBV Infection
Official Title
A Phase 2, Double-Blinded, Randomized, Placebo-Controlled, Dose-Escalation Study to Examine the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of ISIS 505358 in Treatment-Naïve Patients With Chronic HBV Infection
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Completed
Study Start Date
February 24, 2017 (Actual)
Primary Completion Date
December 18, 2019 (Actual)
Study Completion Date
December 26, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline
Collaborators
Ionis Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
To examine the safety and tolerability of IONIS-HBVRx administration to treatment-naive patients with chronic hepatitis B virus infection
Detailed Description
This study examines the effects of IONIS-HBVRx or placebo (3:1 randomization) administered subcutaneously to treatment-naïve patients who are chronically infected with HBV and the effects of subsequent nucleos(t)ide analogue treatment on these patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis B, Chronic Hepatitis B Atypical
Keywords
Hepatitis, Chronic, HBV

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IONIS-HBVRx
Arm Type
Experimental
Arm Description
Ascending multiple doses of IONIS-HBVRx by subcutaneous (SC) injection
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator
Intervention Type
Drug
Intervention Name(s)
IONIS-HBVRx
Other Intervention Name(s)
ISIS 505358
Intervention Description
Ascending multiple doses of IONIS-HBVRx by subcutaneous (SC) injection
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Number of Participants With Serious Adverse Events (SAEs) and Non-Serious Adverse Events (Non-SAEs >=5%)
Description
An adverse event is any unfavorable and unintended sign (including a clinically-significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. Any adverse event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any important medical event according to medical judgment were categorized as SAE.
Time Frame
Up to Day 211
Title
Change From Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine Kinase (CK), Gamma-glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) Over Time
Description
Blood samples were collected for the analysis of clinical parameters including ALT, ALP, CK, GGT, LDH and AST. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline in Clinical Chemistry Parameters : Albumin and Total Protein Over Time
Description
Blood samples were collected for the analysis of clinical chemistry parameter-albumin and total protein. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline Values in Clinical Chemistry Parameters: Sodium, Potassium, Chloride, Bicarbonate, Calcium, Magnesium, Phosphate, Glucose, Blood Urea Nitrogen, Cholesterol and Urate
Description
Blood samples were collected for the analysis of clinical parameters including sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate, glucose, blood urea nitrogen (BUN), cholesterol and urate. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Outcome Measure Timeframe: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline Values in Clinical Chemistry Parameters: Total Bilirubin, Direct Bilirubin, Indirect Bilirubin, and Creatinine
Description
Blood samples were collected for the analysis of clinical chemistry parameters: direct bilirubin, total bilirubin, indirect bilirubin and creatinine. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline for Hematology Parameters: Basophils, Eosinophils, White Blood Cells (WBC), Lymphocytes, Neutrophils, Monocytes, and Platelets
Description
Blood samples were collected for the analysis of hematology parameters including basophil, eosinophils, WBC, lymphocytes, neutrophils, monocytes, and platelets at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline for Hematology Parameters: Hemoglobin
Description
Blood samples were collected for the analysis of hematology parameters including hemoglobin at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline for Hematology Parameter: Hematocrit
Description
Blood samples were collected for the analysis of hematology parameter including hematocrit at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline Values in Urine Specific Gravity
Description
Urine samples were collected for the analysis of urine specific gravity. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value. Urine specific gravity is measured as the ratio of urine density compared with water density.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline Values in Urine Albumin/Creatinine Ratio and Urine Protein/Creatinine Ratio
Description
Urine samples were collected for the analysis of urine albumin/creatinine ratio and urine protein/creatinine ratio. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline Values in Urine Protein
Description
Urine samples were collected for the analysis of urine protein. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline Values in Blood Coagulation Factors: Activated Partial Thromboplastin Time and Prothrombin Time
Description
Blood samples were collected for the analysis of blood coagulation factors:activated partial thromboplastin time (aPTT) and Prothrombin Time (PT). Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 23, 57, 85, 211
Title
Change From Baseline Values in Blood Coagulation Factor: Prothrombin International Normalized Ratio
Description
Blood samples were collected for the analysis of blood coagulation factor: Prothrombin International normalized ratio. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 23, 57, 85, 211
Title
Change in Complement C3 Level at Worst Case Post Baseline Relative to Baseline
Description
Blood samples were collected from participants to evaluate change in complement C3 level at worst case post Baseline relative to Baseline. Worst case post Baseline in Complement C3 was the minimum post-Baseline level. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and up to Day 211
Title
Change in Complement C5a Level at Worst Case Post Baseline Relative to Baseline
Description
Blood samples were collected from participants to evaluate change in complement C5a level at worst case post Baseline relative to Baseline. Worst case post Baseline in Complement C5a was the maximum post-Baseline level. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and up to Day 211
Title
Change in Complement Bb Level at Worst Case Post Baseline Relative to Baseline
Description
Blood samples were collected from participants to evaluate change in complement Bb level at worst case post Baseline relative to Baseline. Worst case post Baseline in Complement Bb was the maximum post-Baseline level. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and up to Day 211
Title
Number of Participants With Reported Pregnancy
Description
Female participants who were not surgically sterile or post-menopausal, underwent urine beta Human chorionic gonadotropin (Beta-HCG) pregnancy test.
Time Frame
Up to Day 211
Title
Change From Baseline in Body Temperature
Description
Body temperature was measured at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline in Body Weight
Description
Body weight was measured at indicated time points. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 211
Title
Change From Baseline in Diastolic Blood Pressure and Systolic Blood Pressure
Description
Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) was measured at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline in Respiratory Rate
Description
Respiratory Rate was measured at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Change From Baseline in Pulse Rate
Description
Pulse Rate was measured at indicated timepoints. Baseline value is defined as last non-missing measurement prior to the first dose of study drug. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
Title
Number of Participants With Abnormal Findings in Physical Examination
Description
Physical examinations included assessment of the dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological systems.
Time Frame
Up to Day 211
Title
Number of Participants Who Received Atleast One Concomitant Medication
Description
A concomitant medication is defined as any medication initiated after the first dose of study, or initiated prior to the first dose of study drug and continued after the first dose of study drug.
Time Frame
Up to Day 211
Title
Change From Baseline in Electrocardiogram Mean Ventricular Rate
Description
Triplicate 12-lead Electrocardiograms (ECGs) were recorded at indicated timepoints. At each time point, ECG machine automatically measured mean ventricular rate (VR). Baseline ECG was the average of the triplicate taken on Day 1 Pre-dose, if only 1 or 2 assessments were available, the single assessment or average of the 2 assessments was used. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose); Day1: 3 hours post-dose, 5 hours post-dose; Day 2; Day 22:pre-dose, 3 hours postdose, 5 hours post-dose; Days 23, 29 and 113
Title
Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval, QT Corrected Interval-Fredericia Interval and QTc Corrected by Bazett's Formula
Description
Triplicate 12-lead Electrocardiograms (ECGs) were recorded at indicated timepoints. At each time point, ECG machine automatically measured QRS duration, uncorrected QT interval, QT corrected interval-Fredericia [QTcF] interval and QTc corrected by Bazett's formula (QTcB). Baseline ECG was the average of the triplicate taken on Day 1 Pre-dose, if only 1 or 2 assessments were available, the single assessment or average of the 2 assessments was used. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose); Day1: 3 hours post-dose, 5 hours post-dose; Day 2; Day 22:pre-dose, 3 hours postdose, 5 hours post-dose; Days 23, 29 and 113
Secondary Outcome Measure Information:
Title
Change From Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Viral Load in Plasma at Day 29
Description
Blood samples were collected from participants to assess HBV DNA viral load. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value. The last observation carried forward (LOCF) method was used to impute missing values at Day 29 in this analysis.
Time Frame
Baseline (Day 1 pre-dose) and Day 29
Title
Change From Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Viral Load in Plasma at Week 31
Description
Blood samples were collected from participants to assess HBV DNA viral load. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Week 31
Title
Change From Baseline in HBV Surface Antigen (HBsAg) Level in Serum at Day 29
Description
Blood samples were collected from participants to assess HBsAg level. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value. The LOCF method was used to impute missing values at Day 29 in this analysis.
Time Frame
Baseline (Day 1 pre-dose) and Day 29
Title
Change From Baseline in HBsAg Level in Serum at Week 31
Description
Blood samples were collected from participants to assess HBsAg level. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value.
Time Frame
Baseline (Day 1 pre-dose) and Week 31
Title
Percentage of Participants Who Achieved HBsAg Loss at Day 29 and Week 31
Description
Blood samples were collected to evaluate the percentage of participants with HBsAg loss at Day 29 and Week 31. A 'Loss' of HBsAg means antigen is negative. HBsAg Loss percentage is defined as number of participants with HBsAg loss divided by total number of participants assessed multiplied by 100. Baseline is the last non-missing measurement prior to the first dose of study drug.
Time Frame
At Day 29 and Week 31
Title
Percentage of Participants Who Achieved HBV e Antigen (HBeAg) Loss at Day 29 and Week 31 Who Were HBeAg Positive at Baseline
Description
Blood samples were collected to evaluate the percentage of participants with HBeAg loss at Day 29 and Week 31. A 'Loss' of HBeAg means antigen is negative. HBeAg Loss percentage is defined as number of participants with HBeAg loss divided by number of participants with positive HBeAg at Baseline multiplied by 100. Baseline is the last non-missing measurement prior to the first dose of study drug. Participants was considered HBeAg positive at Baseline if the Baseline value> 0.09 U/mL.
Time Frame
Baseline (Day 1, Pre dose) and at Day 29 and Week 31
Title
Change From Baseline in Serum HBeAg Concentration at Day 29 in Participants Who Were HBeAg Positive at Baseline
Description
Blood samples were collected from participants to assess HBeAg level. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value. Participant was considered HBeAg positive at Baseline if the Baseline value> 0.09 International Units/milliliter (IU/mL).
Time Frame
Baseline (Day 1, Pre dose) and at Day 29
Title
Change From Baseline in Serum HBeAg Concentration at Week 31 in Participants Who Were HBeAg Positive at Baseline
Description
Blood samples were collected from participants to assess HBeAg level. Baseline is the last non-missing measurement prior to the first dose of study drug. The concentrations were logarithmic transformed with base 10 in this analysis. Change from Baseline is defined as post-dose visit value minus Baseline value. Participant was considered HBeAg positive at Baseline if the Baseline value> 0.09 U/mL.
Time Frame
Baseline (Day 1, Pre dose) and Week 31
Title
Plasma Concentrations of GSK3228836 in Participants With Chronic HBV Infection
Description
Plasma samples were collected from participants with chronic HBV infection at indicated time points for pharmacokinetic analysis of GSK3228836.
Time Frame
Day 1:pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours post-dose, Days 2 and 23: 24 hours post-dose, Day 4: 72 hours post-dose, Days 8 and 15: pre-dose, Day 22: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours post-dose, and Days 29, 36, 57, 85, 113, and 211

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 18 to 70 years Chronic HBV infection ≥6 months (e.g., positive for serum HBsAg ≥ 6 months) Plasma HBV DNA ≥ 2 x 1000 IU/mL (HBV DNA adequately suppressed for exploratory nucleos(t)ide analogue experienced cohort) Serum HBsAg ≥ 50 IU/mL Exploratory nucleos(t)ide analogue experienced cohort only: currently taking and have been taking tenofovir or entecavir without changes in drug, dose level and/or frequency of administration for ≥ 12 months and expect to continue taking without change through to the end of their participation in this study Exclusion Criteria: Current or prior receipt of anti-HBV nucleos(t)ide analogue therapy. Patients who have failed prior interferon treatment, greater than 6 months prior to Screening, may be evaluated for possible participation in the study (not applicable for exploratory nucleos(t)ide analogue experienced cohort) History of liver cirrhosis and/or evidence of cirrhosis as determined by any of the following: Liver biopsy (i.e., Metavir Score F4) within 2 years of Screening, or Fibroscan > 12 KPa, within 12 months of Screening, or AST-to-Platelet Index (APRI) > 2 and Fibrosure result > 0.7 within 12 months of Screening For patients without a test for cirrhosis in the above timeframes, Fibroscan, or APRI and Fibrosure, may be performed during the screening period to rule out cirrhosis History of liver failure as evidenced by ascites, hepatic encephalopathy, and/or gastric or esophageal varices History of liver disease other than Hepatitis B Co-infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or hepatitis D virus (HDV) BMI > 35 kg/m2 History of, or suspected presence of vasculitis Received solid organ or bone marrow transplant Currently taking, or took within 3 months of Screening, any immunosuppressing drugs (e.g., prednisone) Diagnosed hepatocellular carcinoma or suspected hepatocellular carcinoma as evidenced by screening alpha-fetoprotein ≥ 200 ng/mL. If the screening alpha-fetoprotein is ≥ 50 ng/mL and < 200 ng/mL, the absence of liver mass must be documented by imaging within 6 months before randomization Clinically-significant abnormalities aside from chronic HBV infection in medical history (e.g., previous acute coronary syndrome within 6 months of Screening, major surgery within 3 months of Screening, uncontrolled diabetes) or physical examination History of bleeding diathesis or coagulopathy History of extrahepatic disorders possibly related to HBV immune complexes (e.g., glomerulonephritis, polyarteritis nodosa) History of excess alcohol consumption within 6 months of Screening History of drug abuse or dependence, or recreational use of drugs: within 3 months of Screening for soft drugs (such as marijuana) and within 1-year of Screening for hard drugs (such as cocaine, phencyclidine [PCP])
Facility Information:
Facility Name
Queen Mary Hospital
City
Hong Kong
Country
Hong Kong
Facility Name
Korea University Ansan Hospital
City
Ansan
Country
Korea, Republic of
Facility Name
Inje University Busan Paik Hospital
City
Busan
Country
Korea, Republic of
Facility Name
Kyungpook National University Hospital
City
Daegu
Country
Korea, Republic of
Facility Name
Pusan National University Hospital
City
Pusan
Country
Korea, Republic of
Facility Name
Seoul National University Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
Seoul St. Mary's Hospital
City
Seoul
Country
Korea, Republic of

12. IPD Sharing Statement

Citations:
PubMed Identifier
34642494
Citation
Yuen MF, Heo J, Jang JW, Yoon JH, Kweon YO, Park SJ, Tami Y, You S, Yates P, Tao Y, Cremer J, Campbell F, Elston R, Theodore D, Paff M, Bennett CF, Kwoh TJ. Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial. Nat Med. 2021 Oct;27(10):1725-1734. doi: 10.1038/s41591-021-01513-4. Epub 2021 Oct 12.
Results Reference
derived

Learn more about this trial

Safety, Tolerability, Pharmacokinetics and Antiviral Activity of IONIS-HBVRx in Treatment-Naïve Patients With Chronic HBV Infection

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