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

NCT02981602 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 205695ISIS 505358-CS3
• Study Type: interventional
• Target: 31
• Locations: 2 countries
• Sites: 7

Brief Summary

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

Conditions

Hepatitis B; Chronic Hepatitis B Atypical

Keywords

Hepatitis; Chronic; HBV

Outcome Measures

Primary Outcomes (26)

• 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 Outcomes (9)

• 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

• 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

• Change From Baseline in HBV Surface Antigen (HBsAg) Level in Serum at Day 29

  Baseline (Day 1 pre-dose) and Day 29

• Change From Baseline in HBsAg Level in Serum at Week 31

  Baseline (Day 1 pre-dose) and Week 31

• Percentage of Participants Who Achieved HBsAg Loss at Day 29 and Week 31

  At Day 29 and Week 31

Study Arms (2)

IONIS-HBVRx

EXPERIMENTAL

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

Drug: IONIS-HBVRx

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

IONIS-HBVRx DRUG

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

Also known as: ISIS 505358

IONIS-HBVRx

Placebo DRUG

Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Ionis Pharmaceuticals, Inc.: collaborator

Study Sites (7)

Queen Mary Hospital

Hong Kong, Hong Kong

Location

Korea University Ansan Hospital

Ansan, South Korea

Location

Inje University Busan Paik Hospital

Busan, South Korea

Location

Kyungpook National University Hospital

Daegu, South Korea

Location

Pusan National University Hospital

Pusan, South Korea

Location

Seoul National University Hospital

Seoul, South Korea

Location

Seoul St. Mary's Hospital

Seoul, South Korea

Location

Related Publications (1)

• 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.

  PMID: 34642494 DERIVED

MeSH Terms

Conditions

Hepatitis B; Hepatitis; Bronchiolitis Obliterans Syndrome

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Liver Diseases; Digestive System Diseases; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2016
• First Posted: December 5, 2016
• Study Start: February 24, 2017
• Primary Completion: December 18, 2019
• Study Completion: December 26, 2019
• Last Updated: August 10, 2021
• Results First Posted: December 21, 2020

Record last verified: 2021-08

Locations

KR (6); HK (1)