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

Phase 2

Completed

• Conditions: Hepatitis B; Chronic Hepatitis B Atypical
• Interventions: Drug: Placebo; Drug: IONIS-HBVRx

• Registration Number: NCT02981602
• Lead Sponsor: GlaxoSmithKline

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.

Study Timeline

• Study First Submitted: 2016-12-01
• Study First Submitted QC: 2016-12-02
• Study First Posted: 2016-12-05
• Study Start: 2017-02-24
• Primary Completion: 2019-12-18
• Study Completion: 2019-12-26
• Results First Submitted: 2020-11-23
• Results First Submitted QC: 2020-11-23
• Results First Posted: 2020-12-21
• Status Verified: 2021-08
• Last Update Submitted: 2021-08-06
• Last Update Posted: 2021-08-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 31

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

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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])

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator
IONIS-HBVRx	IONIS-HBVRx	Ascending multiple doses of IONIS-HBVRx by subcutaneous (SC) injection

Primary Outcome Measures

Name	Time	Method
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	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 for Hematology Parameters: Basophils, Eosinophils, White Blood Cells (WBC), Lymphocytes, Neutrophils, Monocytes, and Platelets	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 Parameter: Hematocrit	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 Blood Coagulation Factor: Prothrombin International Normalized Ratio	Baseline (Day 1 pre-dose) and Days 23, 57, 85, 211	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.
Number of Participants With Reported Pregnancy	Up to Day 211	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 Weight	Baseline (Day 1 pre-dose) and Days 29, 57, 211	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 Electrocardiogram Mean Ventricular Rate	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	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 Values in Urine Albumin/Creatinine Ratio and Urine Protein/Creatinine Ratio	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 Blood Coagulation Factors: Activated Partial Thromboplastin Time and Prothrombin Time	Baseline (Day 1 pre-dose) and Days 23, 57, 85, 211	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 in Complement C5a Level at Worst Case Post Baseline Relative to Baseline	Baseline (Day 1 pre-dose) and up to Day 211	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 From Baseline in Diastolic Blood Pressure and Systolic Blood Pressure	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 Clinical Chemistry Parameters : Albumin and Total Protein Over Time	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 Urine Protein	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 in Pulse Rate	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 Who Received Atleast One Concomitant Medication	Up to Day 211	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.
Number of Participants With Serious Adverse Events (SAEs) and Non-Serious Adverse Events (Non-SAEs >=5%)	Up to Day 211	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 Values in Clinical Chemistry Parameters: Sodium, Potassium, Chloride, Bicarbonate, Calcium, Magnesium, Phosphate, Glucose, Blood Urea Nitrogen, Cholesterol and Urate	Outcome Measure Timeframe: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 for Hematology Parameters: Hemoglobin	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 Values in Urine Specific Gravity	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 in Complement C3 Level at Worst Case Post Baseline Relative to Baseline	Baseline (Day 1 pre-dose) and up to Day 211	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 Bb Level at Worst Case Post Baseline Relative to Baseline	Baseline (Day 1 pre-dose) and up to Day 211	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.
Change From Baseline Values in Clinical Chemistry Parameters: Total Bilirubin, Direct Bilirubin, Indirect Bilirubin, and Creatinine	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 in Body Temperature	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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 Respiratory Rate	Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211	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.
Number of Participants With Abnormal Findings in Physical Examination	Up to Day 211	Physical examinations included assessment of the dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological systems.
Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval, QT Corrected Interval-Fredericia Interval and QTc Corrected by Bazett's Formula	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	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

Name	Time	Method
Change From Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Viral Load in Plasma at Day 29	Baseline (Day 1 pre-dose) and 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.
Plasma Concentrations of GSK3228836 in Participants With Chronic HBV Infection	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	Plasma samples were collected from participants with chronic HBV infection at indicated time points for pharmacokinetic analysis of GSK3228836.
Change From Baseline in HBV Surface Antigen (HBsAg) Level in Serum at Day 29	Baseline (Day 1 pre-dose) and 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 Serum HBeAg Concentration at Day 29 in Participants Who Were HBeAg Positive at Baseline	Baseline (Day 1, Pre dose) and at Day 29	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	Baseline (Day 1, Pre dose) and Week 31	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.
Change From Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Viral Load in Plasma at Week 31	Baseline (Day 1 pre-dose) and 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 HBsAg Level in Serum at Week 31	Baseline (Day 1 pre-dose) and 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	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	Baseline (Day 1, Pre dose) and at Day 29 and Week 31	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.

Trial Locations

Locations (7)

Kyungpook National University Hospital; 🇰🇷 Daegu, Korea, Republic of

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Inje University Busan Paik Hospital; 🇰🇷 Busan, Korea, Republic of

Korea University Ansan Hospital; 🇰🇷 Ansan, Korea, Republic of

Pusan National University Hospital; 🇰🇷 Pusan, Korea, Republic of

Seoul St. Mary's Hospital; 🇰🇷 Seoul, Korea, Republic of

Queen Mary Hospital; 🇭🇰 Hong Kong, Hong Kong