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

Study Overview
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Brief Summary
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To examine the safety and tolerability of IONIS-HBVRx administration to treatment-naive patients with chronic hepatitis B virus infection

Detailed Description
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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.

Official Title
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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

Conditions
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Hepatitis B, Chronic Hepatitis B Atypical

Intervention / Treatment
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* Drug: IONIS-HBVRx
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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])

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IONIS-HBVRx<br>Ascending multiple doses of IONIS-HBVRx by subcutaneous (SC) injection | Drug: IONIS-HBVRx<br>* Ascending multiple doses of IONIS-HBVRx by subcutaneous (SC) injection<br>* Other names: ISIS 505358;|
| Placebo Comparator: Placebo<br>Sterile Normal Saline (0.9% NaCl) calculated volume to match active comparator | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to Day 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Outcome Measure Timeframe: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 23, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 23, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and up to Day 211 | 
| 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. | Baseline (Day 1 pre-dose) and up to Day 211 | 
| 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. | Baseline (Day 1 pre-dose) and up to Day 211 | 
| 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. | Up to Day 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| 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. | Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211 | 
| Number of Participants With Abnormal Findings in Physical Examination | Physical examinations included assessment of the dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological systems. | Up to Day 211 | 
| 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. | Up to Day 211 | 
| 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. | 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 | 
| 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. | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (Day 1 pre-dose) and Day 29 | 
| 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. | Baseline (Day 1 pre-dose) and Week 31 | 
| 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. | Baseline (Day 1 pre-dose) and Day 29 | 
| 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. | Baseline (Day 1 pre-dose) and Week 31 | 
| 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. | At Day 29 and Week 31 | 
| 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. | Baseline (Day 1, Pre dose) and at Day 29 and Week 31 | 
| 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). | Baseline (Day 1, Pre dose) and at Day 29 | 
| 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. | Baseline (Day 1, Pre dose) and Week 31 | 
| 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis, Chronic, HBV