Safety, Efficacy, Immunogenicity Study of GSK Biologicals' HBV Viral Vector and Adjuvanted Proteins Vaccine (GSK3528869A) in Adult Patients With Chronic Hepatitis B Infection

Hepatitis B, Chronic Clinical Trial

Official title:

A first-time-in Human (FTIH), Phase I/II, Randomized, Multi-centric, Single-blind, Controlled Dose-escalation Study to Evaluate the Reactogenicity, Safety, Immunogenicity and Efficacy of GSK Biologicals' HBV Viral Vector Vaccines Given in a Prime-boost Schedule With Sequential or Co-administration of Adjuvanted Proteins Therapeutic Vaccine (GSK3528869A) in Chronic Hepatitis B Patients (18-65 Years Old) Well Controlled Under Nucleo(s)Tide Analogue (NA) Therapy

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03866187
• Other study ID #: 204852
• Secondary ID: 2017-001452-55
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: March 28, 2019
• Est. completion date: October 31, 2025

Study information

• Verified date: February 2024
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A First-Time-In-Human study on GSK's therapeutic vaccines to evaluate the reactogenicity, safety, immunogenicity and efficacy on reduction of serum HBV surface antigen in HBV suppressed subjects under nucleo(s)tide treatment.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 148
• Est. completion date: October 31, 2025
• Est. primary completion date: October 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Patients who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
• Written informed consent obtained from the patient prior to performing any study specific procedure.
• A male or female between, and including, 18 and 65 years of age at the time of the first vaccination.
• Female patients of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as hysterectomy, bilateral ovariectomy or post-menopause.
• Female patients of childbearing potential may be enrolled in the study if the patient:
• has practiced adequate contraception for 30 days prior to vaccination, and
• has a negative pregnancy test at Screening, and
• has agreed to continue adequate contraception from Screening until 12 weeks after completion of the vaccination series
• Male patients:
• with documented bilateral vasectomy and resultant azoospermia, bilateral orchiectomy or azoospermia, or
• who agree to practice abstinence from penile-vaginal intercourse (when this is their preferred and usual lifestyle) or use condoms from Screening until 12 weeks after completion of the vaccination series.
• Chronic Hepatitis B (CHB) patient, under and adherent to treatment with a nucleo(s)tide analogue with high barrier to resistance given as per approved label/dosage for at least 24 months.
• Documented medical history of Hepatitis B Virus e Antigen (HBeAg)-negative CHB prior to onset of NA therapy (applicable to all patients in Step A and Step B and to some patients in Step C) or documented medical history of HBeAg-negative CHB over a period of at least 24 months prior screening (applicable to some patients in Step C only).
• Documented HBV viral suppression as per local clinical diagnosis within the previous 24 months AND at Screening test HBV DNA < 10 IU/mL. If no results are available, two Screening tests need to be performed at least 2 weeks apart. Small fluctuations of HBV DNA (= 10 x LLOQ; LLOQ defined by laboratory that performed testing) are allowed provided HBV DNA is < 10 IU/mL at Screening and was clearly not rising during the previous 24 months.
• Documented normal level of ALT as per local clinical diagnosis within the previous 24 months AND at Screening test ALT < 48U/L. Small fluctuations of ALT (= 1.5 X ULN) are allowed provided ALT< 48 U/L at Screening. If no results are available, two Screening tests need to be performed at least 2 weeks apart. ULN are to be defined according to local laboratory reference range.
• No clinical diagnosis of cirrhosis (e.g. F4 by METAVIR scoring system or = 6 by Ishak scoring system or FibroScan TE score > 12.5 kPa) within the previous 24 months.
• FibroScan Transient Elastography (TE) score < 9.6 kPa and FibroTest score < 0.59 at Screening. A patient with one of these parameters out of range, but having the liver biopsy within 12 months before screening that showed F0-2 by METAVIR scoring system or stage 0-4 by Ishak scoring system, can be included.
• HBsAg concentration > 50 IU/mL and anti-HBs negative at Screening.
• Anti-HBc positive at Screening.
• HBeAg-negative at Screening.

Exclusion Criteria:

• Use of any investigational or non-registered product other than the study vaccines during the period starting 30 days before the first dose of study vaccines, or planned use during the study period.
• Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.
• Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose. For corticosteroids, this will mean prednisone = 10 mg/day or equivalent. Inhaled and topical steroids are allowed.
• Administration of immunoglobulins and/or any blood products during the period starting 3 months before the first dose of study vaccines or planned administration during the study period.
• Use of systemic cytotoxic agents, chronic antiviral agents or Chinese herbal medicines which, in the opinion of the investigator, may have activity against HBV within the previous 6 months prior to randomization into this study. Antiviral treatment/prevention for influenza or herpes simplex virus is allowed.
• Administration of adenovirus/adenovector-based or MVA-based vaccine within the last 12 months except for adenovirus/adenovector-based COVID-19 vaccines that could be administered up to 30 days prior to the first study vaccine dose (applicable for all patients except for the patients in France) OR Administration of adenovirus/adenovector-based or MVA-based vaccine within the last 12 months (applicable for the patients in France only).
• Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 14 days before each dose and ending 30 days after each dose of vaccines, with the exception of influenza vaccine that may be given at any time except within a 7-day period before or after each vaccine dose and COVID-19 vaccine that may be given at any time except within a 30-day period before or after each vaccine dose apart from COVID-19 mRNA based-vaccines that may be administered any time except for the period of 14 days before and 30 days after each study vaccine dose. Note: If the type of COVID-19 vaccine is unknown, the allowed interval of 30 days before or after each study vaccine dose should be followed.
• Treatment with nephrotoxic drugs or competitors of renal excretion within 2 months prior to Screening or the expectation that patient will receive any of these during the course of the study. TAF/TDF given as NA therapy is allowed.
• Concurrently participating in another clinical study, at any time during the study period, in which the patient has been or will be exposed to an investigational or a non-investigational vaccine/product.
• Medical history of cirrhosis or hepatic decompensation.
• Planned for liver transplantation or previous liver transplantation.
• Personal or family (first degree) history of autoimmune disease.
• Family history of congenital or hereditary immunodeficiency.
• History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines.
• Evidence of Hepatitis C Virus and hepatitis D Virus infection.
• Suspicion of or confirmed Hepatocellular Carcinoma or any other liver cancer in

medical history or at Screening:

• Suspicious foci at liver imaging exam
• Elevated a-fetoprotein > 50 ng/mL.
• Documented evidence of other currently active cause of hepatitis.
• Hematology and biochemistry parameters outside normal clinical range at Screening:

Biochemistry:

• Glomerular filtration rate < 60 mL/min
• Bilirubin > 27.5 µmol/L unless *or the diagnosis of Gilbert Syndrome has been established and confirmed by the Investigator
• GGT > 65 U/L (males) or > 45 U/L (females)*
• ALT > 48 U/L
• AST > 42 U/L*
• ALP > 125 U/L*

Hematology:

• Hemoglobin < 12.0 g/dL (females) or < 13.5 g/dL (males)*
• Red blood cell count < 3.9 x 10^6 cells/mm^3 (females) or < 4.4 x 10^6 cells/mm^3 (males)*
• White blood cell count < 3,500 cells/mm^3 or > 12,000 cells/mm^3*
• Platelets < 140,000 cells/mm^3
• INR > 1.32 (i.e. 1.1 x ULN) *unless it is considered as clinically not significant by the Investigator
• Known diabetes Type I.
• Body Mass Index > 35 kg/m^2 at Screening.
• Any serious or active medical or psychiatric illnesses other than chronic hepatitis B which, in the opinion of the investigator, would interfere with patient treatment, assessment or compliance with the protocol.
• History of or current drug abuse and/or excess of alcohol consumption as defined per local guidelines.
• HIV-positive patient.
• Pregnant or lactating female.
• Female planning to become pregnant or planning to discontinue contraceptive precautions in the period starting from the Screening Visit up to 12 weeks post-last vaccination visit.
• Fever and or acute minor illness may be enrolled for Screening at the discretion of the investigator, provided that the condition is resolved at the time of vaccination.

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic

Intervention

Biological:
• ChAd155-hIi-HBV low dose formulation
Subjects in group A1 receive one dose of ChAd155-hIi-HBV low dose formulation at Day 1, by intramuscular injection in the deltoid of the non-dominant arm.
• ChAd155-hIi-HBV high dose formulation
Subjects in groups B1 and B3 receive one dose of ChAd155-hIi-HBV high dose formulation at Day 1 and Day 113 respectively, by intramuscular injection in the deltoid of the non-dominant arm. Subjects in groups C1 and C2 receive one dose of ChAd155-hIi-HBV high dose formulation at Day 1 and Day 113 respectively, by intramuscular injection in the deltoid of the dominant arm.
• HBc-HBs/AS01B-4 low dose formulation
Subjects in group A1 receive two doses of HBc-HBs/AS01B-4 low dose formulation, one at Day 113 and one at Day 169 and subjects in group A2 receive four doses of the low dose formulation, one dose each at Days 1, 57, 113 and 169, by intramuscular injection in the deltoid of the non-dominant arm.
• HBc-HBs/AS01B-4 high dose formulation
Subjects in group B1 receive two doses of HBc-HBs/AS01B-4 high dose formulation, one at Day 113 and one at 169; subjects in group B2 receive four doses, one dose each at Days 1, 57, 113 and 169; subjects in group C1 receive four co-administered doses at Days 1, 57, 113 and 169 and subjects in group C2 receive two co-administered doses at Days 113 and 169, by intramuscular injection in the deltoid of the non-dominant arm.
• MVA-HBV low dose formulation
Subjects in group A1 receive one dose of MVA-HBV low dose formulation at Day 57, by intramuscular injection in the deltoid of the non-dominant arm.
• MVA-HBV high dose formulation
Subjects in groups B1 and B3 receive one dose of MVA-HBV high dose formulation at Day 57 and Day 169 respectively, by intramuscular injection in the deltoid of the non-dominant arm. Subjects in group C1 receive three co-administered doses of the vaccine at Days 57, 113 and 169 and subjects in group C2 receive one co-administered dose of the vaccine at Day 169, by intramuscular injection in the deltoid of the dominant arm.

Drug:
• Placebo
Subjects in group A3 receive four doses of placebo, one each at Days 1, 57, 113 and 169 and subjects in group B3 receive two doses of placebo one each at Days 1 and 57, by intramuscular injection in the deltoid of the non-dominant arm. Subjects in group C2 receive 2 co-administered doses of placebo at Days 1 and 57, by intramuscular injection in the deltoid of the dominant and non-dominant arm.

Locations

Country	Name	City	State
Belgium	GSK Investigational Site	Brussels
Belgium	GSK Investigational Site	Bruxelles
Belgium	GSK Investigational Site	Edegem
Belgium	GSK Investigational Site	Gent
Belgium	GSK Investigational Site	Leuven
France	GSK Investigational Site	Clichy Cedex
France	GSK Investigational Site	Créteil cedex
France	GSK Investigational Site	Lyon Cedex 04
France	GSK Investigational Site	Strasbourg cedex
Germany	GSK Investigational Site	Aachen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Bonn	Nordrhein-Westfalen
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Mainz	Rheinland-Pfalz
Germany	GSK Investigational Site	Tuebingen	Baden-Wuerttemberg
Hong Kong	GSK Investigational Site	Pokfulam
Poland	GSK Investigational Site	Krakow
Poland	GSK Investigational Site	Lancut
Poland	GSK Investigational Site	Myslowice
Poland	GSK Investigational Site	Skorzewo
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Córdoba
Spain	GSK Investigational Site	Granada
Spain	GSK Investigational Site	Hospitalet de Llobregat
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Majadahonda (Madrid)
Spain	GSK Investigational Site	Palma de Mallorca	Islas Baleares
Spain	GSK Investigational Site	Santander
Spain	GSK Investigational Site	Sevilla
Spain	GSK Investigational Site	Torrejón de Ardoz	Madrid
Taiwan	GSK Investigational Site	Taichung
Taiwan	GSK Investigational Site	Taichung
Taiwan	GSK Investigational Site	Tainan
Taiwan	GSK Investigational Site	Taipei
Taiwan	GSK Investigational Site	Taoyuan
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Chiangmai
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Nottingham
United Kingdom	GSK Investigational Site	Southampton

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Hong Kong,  Poland,  Spain,  Taiwan,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of subjects reporting solicited local adverse events (AEs)	The following local AEs are solicited: pain at injection site, redness at injection site and swelling at injection site.	Within 7 days after each vaccination (from day of vaccination to 6 days after vaccination)
Primary	Number of subjects reporting solicited general AEs	The following general AEs are solicited: fatigue, fever*, gastrointestinal symptoms**, headache, myalgia and chills.; *Fever is defined as temperature =38.0°C / 100.4°F. The preferred location for measuring temperature in this study is the oral cavity.; **Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain.	Within 7 days after each vaccination (from day of vaccination to 6 days after vaccination)
Primary	Number of subjects reporting unsolicited AEs	Unsolicited AE is defined as an AE reported in addition to those solicited during the clinical study and as any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.	Within 30 days after each vaccination (from day of vaccination to 29 days after vaccination)
Primary	Number of subjects with hematological, biochemical or urinalysis laboratory abnormalities	Clinically significant abnormal laboratory findings (e.g. clinical chemistry, haematology, urinalysis) are reported.; The investigator exercises his or her medical and scientific judgement in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant.	Within 30 days after each vaccination (from day of vaccination to 29 days after vaccination)
Primary	Number of subjects reporting serious adverse events (SAEs)	SAEs assessed include any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect in the offspring of a study patient.	From Day 1 up to Day 337 (6 months after last dose)
Primary	Number of subjects reporting potential immune-mediated diseases (pIMDs)	pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.	From Day 1 up to Day 337 (six months after the last dose)
Primary	Number of subjects reporting liver-disease-related (LDR) AEs	LDR AEs are defined as AEs related to the underlying chronic HBV infection and characterized by one or more of the following: Alanine Transaminase (ALT) flares; Elevation of ALT > 3 X Upper Limit of Normal (ULN): Mild: > 3-5 X ULN; Moderate: > 5-10 X ULN; Severe: > 10 X ULN ALT flares with other substantial biochemical changes; Bilirubin = 2 X ULN; And/or International Normalized Ratio (INR) > 1.5 Hepatic decompensation Occurrence of one or more of the following events: ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, variceal bleeding, or hepatic encephalopathy.; HBV-Deoxyribonucleic Acid (DNA) breakthrough Any increase in serum HBV DNA by >1 log10 from nadir or redetection of serum HBV DNA at levels 10-fold the Lower Limit of Quantification (LLOQ) of the viral load after HBV DNA was undetectable.	From Day 1 up to Day 337 (six months after the last dose)
Primary	Number of subjects reporting any hematological adverse events of specific interest (AESIs)	Hematological AESI is defined as: Spontaneous local or general bleeding with thrombocytes < 50,000 platelets/mm^3; Anemia with hemoglobin < 9.5 g/dL.	From Day 1 up to Day 337 (six months after last dose)
Primary	Number of subjects reporting medically-attended adverse events (MAEs)	MAEs are defined as events for which the subject receives medical attention defined as hospitalization, or an otherwise unscheduled visit to or from medical personnel for any reason, including emergency room visits.	From Day 1 up to Day 337 (six months after the last dose)
Secondary	Number of seropositive subjects for anti-hepatitis B core antibody (anti-HBc)	A seropositive subject is a subject whose antibody concentration is greater than or equal to the defined cut-off value.	At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
Secondary	Evaluation of immunogenicity in terms of Anti-HBc antibody concentration	Antibody concentrations are presented as geometric mean concentrations (GMCs) of anti-HBc antibodies.	At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
Secondary	Number of subjects with anti-hepatitis B surface antigen (anti-HBs) seroconversion	A seroconverted subject is a subject whose antibody concentration is above the lower limit of quantitation (LLOQ) of the assay.	At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
Secondary	Evaluation of immunogenicity in terms of anti-HBs antibody concentration	Antibody concentrations are presented as geometric mean concentrations (GMCs) of anti-HBs antibodies.	At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
Secondary	Number of subjects with anti-HBs antibody concentration equal to or above 10 mIU/mL	The number of subjects with anti-HBs antibody concentrations equal to or above 10 mIU/mL is reported.	At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
Secondary	Number of subjects with anti-HBs antibody concentration equal to or above 100 mIU/mL	The number of subjects with anti-HBs antibody concentrations equal to or above 100 mIU/mL is reported.	At Days 1,15, 71, 113, 127, 183, 337, 505 and 841
Secondary	Frequency of HBs-specific CD4+ T-cells	Frequency of HBs-specific CD4+ T-cells is expressed as HBs-specific CD4+ T-cells per million peripheral blood mononuclear cells (HBs-specific CD4+ T-cells/million PBMCs).	At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
Secondary	Frequency of HBs-specific CD8+ T-cells	Frequency of HBs-specific CD8+ T-cells is expressed as HBs-specific CD8+ T-cells per million peripheral blood mononuclear cells (HBs-specific CD8+ T-cells/million PBMCs).	At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
Secondary	Frequency of HBc-specific CD4+ T-cells	Frequency of HBc-specific CD4+ T-cells is expressed as HBc-specific CD4+ T-cells per million peripheral blood mononuclear cells (HBc-specific CD4+ T-cells/million PBMCs).	At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
Secondary	Frequency of HBc-specific CD8+ T-cells	Frequency of HBc-specific CD8+ T-cells is expressed as HBc-specific CD8+ T-cells per million peripheral blood mononuclear cells (HBc-specific CD8+ T-cells/million PBMCs).	At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
Secondary	Frequency of HBs-specific CD4+ T-cells responders	The number of HBs-specific CD4+ T-cells responders is reported.	At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
Secondary	Frequency of HBc-specific CD4+ T-cells responders	The number of HBc-specific CD4+ T-cells responders is reported.	At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
Secondary	Frequency of HBs-specific CD8+ T-cells responders	The number of HBs-specific CD8+ T-cells responders is reported.	At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
Secondary	Frequency of HBc-specific CD8+ T-cells responders	The number of HBc-specific CD8+ T-cells responders is reported.	At Days 1,15, 57, 64, 71, 113, 127, 169, 183, 337, 505 and 841
Secondary	Number of subjects with = 0.5 log decrease of qHBsAg since pre-vaccination	The number of subjects with = 0.5 log decrease of qHBsAg since pre-vaccination is reported. Note: For study participants in Step B and Step C, Visits 19 (Day 253) and 21 (Day 309) are cancelled, which is why Day 253 and Day 309 time points are not reflected in the time frame.	At Days 1, 31, 57, 87, 113, 143, 169, 199, 225, 281, 337, 421, 505, 673, 841
Secondary	Number of subjects with = 1 log decrease of qHBsAg since pre-vaccination	The number of subjects with = 1 log decrease of qHBsAg since pre-vaccination is reported. Note: For study participants in Step B and Step C, Visits 19 (Day 253) and 21 (Day 309) are cancelled, which is why Day 253 and Day 309 time points are not reflected in the time frame.	At Days 1, 31, 57, 87, 113, 143, 169, 199, 225, 281, 337, 421, 505, 673, 841
Secondary	Number of subjects with qHBsAg loss	The number of subjects with qHBsAg loss since pre-vaccination is reported. Note: For study participants in Step B and Step C, Visits 19 (Day 253) and 21 (Day 309) are cancelled, which is why Day 253 and Day 309 time points are not reflected in the time frame.	At Days 1, 31, 57, 87, 113, 143, 169, 199, 225, 281, 337, 421, 505, 673, 841
Secondary	Changes in qHBsAg since pre-vaccination	Changes in serum qHBsAg since pre-vaccination are evaluated and expressed in log10 International Unit per milliliter (IU/mL). Note: For study participants in Step B and Step C, Visits 19 (Day 253) and 21 (Day 309) are cancelled, which is why Day 253 and Day 309 time points are not reflected in the time frame.	At Days 1, 31, 57, 87, 113, 143, 169, 199, 225, 281, 337, 421, 505, 673, 841
Secondary	Number of subjects with HBsAg loss and anti-HBs seroconversion	A subject is counted only when both HBsAg loss and anti-HBs seroconversion are reported for the subject.; A seroconverted subject is a subject whose antibody concentration is above the LLOQ of the assay.	At Days 1, 337, 505 and 841
Secondary	Evaluation of qHBsAg geometric mean concentrations	The geometric mean of qHBsAg is reported. Note: For study participants in Step B and Step C, Visits 19 (Day 253) and 21 (Day 309) are cancelled, which is why Day 253 and Day 309 time points are not reflected in the time frame.	At Day 1, 31, 57, 87, 113, 143, 169, 199, 225, 281, 337, 421, 505, 673, 841
Secondary	Number of subjects reporting any SAEs and SAEs causally related to an investigational vaccine	SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect in the offspring of a study patient.	Throughout the study period (from Day 1 up to Day 841)
Secondary	Number of subjects reporting MAEs	MAEs are defined as events for which the subject receives medical attention defined as hospitalization, or an otherwise unscheduled visit to or from medical personnel for any reason, including emergency room visits.	Throughout the study period (from Day 1 up to Day 841)
Secondary	Number of subjects reporting pIMDs	pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.	Throughout the study period (from Day 1 up to Day 841)
Secondary	Number of subjects reporting liver-disease-related AEs	LDR AEs are defined as AEs related to the underlying chronic HBV infection and characterized by one or more of the following: ALT flares; • Elevation of ALT > 3 X ULN: Mild: > 3-5 X ULN; Moderate: > 5-10 X ULN; Severe: > 10 X ULN; ALT flares with other substantial biochemical changes; Bilirubin = 2 X ULN; And/or INR > 1.5; Hepatic decompensation Occurrence of one or more of the following events: ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, variceal bleeding, or hepatic encephalopathy.; HBV-DNA breakthrough Any increase in serum HBV DNA by >1 log10 from nadir or redetection of serum HBV DNA at levels 10-fold the LLOQ of the viral load after HBV DNA was undetectable.	Throughout the study period (from Day 1 up to Day 841)
Secondary	Number of subjects reporting spontaneous local or general bleeding with thrombocytopenia	Spontaneous local or general bleeding with thrombocytopenia defined as < 50,000 platelets/mm^3.	Throughout the study period (from Day 1 up to Day 841)
Secondary	Number of subjects reporting anemia	Anemia is defined as Hemoglobin < 9.5 g/dL.	Throughout the study period (from Day 1 up to Day 841)
Secondary	Number of subjects reporting AEs and SAEs leading to study withdrawal	The number of patients who experienced at least one AE or SAE leading to study withdrawal during the entire study period is reported.	Throughout the study period (from Day 1 up to Day 841)
Secondary	Number of subjects reporting pregnancy and outcomes of reported pregnancy	The number of patients who experienced pregnancy during the entire study period is to be reported, with pregnancy outcome.; Pregnancy outcomes include: Live infant NO apparent congenital anomaly; Live infant congenital anomaly; Stillbirth NO apparent congenital anomaly; Stillbirth congenital anomaly; Premature live infant NO apparent congenital anomaly; Premature live infant congenital anomaly; Spontaneous abortion NO apparent congenital anomaly; Spontaneous abortion congenital anomaly; Elective termination NO apparent congenital anomaly; Elective termination congenital anomaly; Therapeutic abortion; Ectopic pregnancy; Pregnancy ongoing	Throughout the study period (from Day 1 up to Day 841)