Clinical trial NCT02981602: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis B
Chronic Hepatitis B Atypical
Keywords: Hepatitis
Chronic
HBV
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Ionis Pharmaceuticals, Inc.
First posted: 2016-12-05
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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:

  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 \[PCP\])

Primary outcomes:
measure: Number of Participants With Serious Adverse Events (SAEs) and Non-Serious Adverse Events (Non-SAEs >=5%)
timeFrame: Up to Day 211
measure: 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
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline in Clinical Chemistry Parameters : Albumin and Total Protein Over Time
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline Values in Clinical Chemistry Parameters: Sodium, Potassium, Chloride, Bicarbonate, Calcium, Magnesium, Phosphate, Glucose, Blood Urea Nitrogen, Cholesterol and Urate
timeFrame: Outcome Measure Timeframe: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline Values in Clinical Chemistry Parameters: Total Bilirubin, Direct Bilirubin, Indirect Bilirubin, and Creatinine
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline for Hematology Parameters: Basophils, Eosinophils, White Blood Cells (WBC), Lymphocytes, Neutrophils, Monocytes, and Platelets
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline for Hematology Parameters: Hemoglobin
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline for Hematology Parameter: Hematocrit
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline Values in Urine Specific Gravity
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline Values in Urine Albumin/Creatinine Ratio and Urine Protein/Creatinine Ratio
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline Values in Urine Protein
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline Values in Blood Coagulation Factors: Activated Partial Thromboplastin Time and Prothrombin Time
timeFrame: Baseline (Day 1 pre-dose) and Days 23, 57, 85, 211
measure: Change From Baseline Values in Blood Coagulation Factor: Prothrombin International Normalized Ratio
timeFrame: Baseline (Day 1 pre-dose) and Days 23, 57, 85, 211
measure: Change in Complement C3 Level at Worst Case Post Baseline Relative to Baseline
timeFrame: Baseline (Day 1 pre-dose) and up to Day 211
measure: Change in Complement C5a Level at Worst Case Post Baseline Relative to Baseline
timeFrame: Baseline (Day 1 pre-dose) and up to Day 211
measure: Change in Complement Bb Level at Worst Case Post Baseline Relative to Baseline
timeFrame: Baseline (Day 1 pre-dose) and up to Day 211
measure: Number of Participants With Reported Pregnancy
timeFrame: Up to Day 211
measure: Change From Baseline in Body Temperature
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline in Body Weight
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 211
measure: Change From Baseline in Diastolic Blood Pressure and Systolic Blood Pressure
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline in Respiratory Rate
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline (Day 1 pre-dose) and Days 29, 57, 85, 211
measure: Number of Participants With Abnormal Findings in Physical Examination
timeFrame: Up to Day 211
measure: Number of Participants Who Received Atleast One Concomitant Medication
timeFrame: Up to Day 211
measure: Change From Baseline in Electrocardiogram Mean Ventricular Rate
timeFrame: 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
measure: Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval, QT Corrected Interval-Fredericia Interval and QTc Corrected by Bazett's Formula
timeFrame: 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:
measure: Change From Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Viral Load in Plasma at Day 29
timeFrame: Baseline (Day 1 pre-dose) and Day 29
measure: Change From Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Viral Load in Plasma at Week 31
timeFrame: Baseline (Day 1 pre-dose) and Week 31
measure: Change From Baseline in HBV Surface Antigen (HBsAg) Level in Serum at Day 29
timeFrame: Baseline (Day 1 pre-dose) and Day 29
measure: Change From Baseline in HBsAg Level in Serum at Week 31
timeFrame: Baseline (Day 1 pre-dose) and Week 31
measure: Percentage of Participants Who Achieved HBsAg Loss at Day 29 and Week 31
timeFrame: At Day 29 and Week 31
measure: Percentage of Participants Who Achieved HBV e Antigen (HBeAg) Loss at Day 29 and Week 31 Who Were HBeAg Positive at Baseline
timeFrame: Baseline (Day 1, Pre dose) and at Day 29 and Week 31
measure: Change From Baseline in Serum HBeAg Concentration at Day 29 in Participants Who Were HBeAg Positive at Baseline
timeFrame: Baseline (Day 1, Pre dose) and at Day 29
measure: Change From Baseline in Serum HBeAg Concentration at Week 31 in Participants Who Were HBeAg Positive at Baseline
timeFrame: Baseline (Day 1, Pre dose) and Week 31
measure: Plasma Concentrations of GSK3228836 in Participants With Chronic HBV Infection
timeFrame: 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
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Ansan
country: Korea, Republic of
facility: Korea University Ansan Hospital
city: Busan
country: Korea, Republic of
facility: Inje University Busan Paik Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Pusan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul St. Mary's Hospital
Study officials:
References:
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.