A Study on the Safety, Efficacy and Immune Response Following Sequential Treatment With an Anti-sense Oligonucleotide Against Chronic Hepatitis B (CHB) and Chronic Hepatitis B Targeted Immunotherapy (CHB-TI) in CHB Patients Receiving Nucleos(t)Ide Analogue (NA) Therapy

This is an interventional treatment trial for Hepatitis B, Chronic focused on measuring Hepatitis B virus, Chronic Hepatitis B, Chronic Hepatitis B targeted immunotherapy, Safety, Reactogenicity, Efficacy, Immunogenicity Read More

Inclusion Criteria:

• Participants, who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
• Written or witnessed/thumb printed informed consent obtained from the participant prior to performance of any study-specific procedure.
• A male or female between, and including, 18 and 65 years of age at the time of signing of the informed consent (except for South Korea, where a male or female between, and including, 19 and 65 years of age at the time of signing of the informed consent can participate in the study).
• Participants who are Hepatitis B envelop antigen (HBeAg) positive or negative.
• Participants who have documented chronic HBV infection ≥6 months prior to screening and currently stable on NA therapy defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study.
• CHB patient, under and adherent to treatment with a NA with high barrier to resistance (e.g. entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide).
• Participants with ALT ≤ 2x upper limit of normal (ULN) (i.e., no ALT >2x ULN) documented in last 6 months.
• Participants with plasma or serum HBsAg concentration >100 IU/mL.
• Participants must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.
• A male participant is eligible if he agrees to the following during the intervention period and for at least 90 days after the last dose of study intervention
• Refrain from donating sperm
• AND be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR Must agree to use contraception/barrier as detailed below
• Agree to use a male condom [and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak] when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant
• A female participant is eligible:
• If she is not pregnant or breastfeeding
• AND at least one of the following conditions applies:
• Is not a WOCBP
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency during the intervention period and for at least 90 days after the last dose of study treatment.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.

Exclusion Criteria:

Medical conditions

• Clinically significant abnormalities, aside from chronic HBV infection
• Co-infection with:
• Current or past history of HCV
• HIV
• HDV
• History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by:
• both AST-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7
• Liver biopsy (METAVIR Score F4) or Liver stiffness >12 kPa
• FibroScan TE score >9.6 kPa and FibroTest score >0.59 at Screening
• Diagnosed or suspected HCC
• History of:
• malignancy within the past 5 years except of specific cancers that are cured by surgical resection
• vasculitis or presence of symptoms and signs of potential vasculitis
• extrahepatic disorders possibly related to HBV immune conditions
• Positive (or borderline positive) ANCA at screening
• Low C3/C4 at screening AND evidence of past history or current manifestations of vasculitic/inflammatory/autoimmune conditions
• History of alcohol or drug abuse/dependence
• QTcF ≥450 msec
• Laboratory results as follows:
• Serum albumin <3.5 g/dL
• GFR <60 mL/min/1.73m^2
• INR >1.25
• PLT count <140x10^9/L
• HGB <10 g/dl
• T Bil >1.25xULN unless considered as clinically not significant by the Investigator
• ACR ≥0.03 mg/mg
• Medical history of hepatic decompensation
• Planned or previous liver transplantation
• Documented evidence of other currently active cause of hepatitis
• Any other clinical condition that might pose additional risk to the participant due to participation in the study
• Major congenital defects
• Recurrent history or uncontrolled neurological disorders or seizures
• History of any reaction or hypersensitivity likely to be exacerbated by any component of the study intervention(s)

Prior/Concomitant therapy

• Use of any investigational or non-registered product other than the study interventions within 30 days before the first dose of study interventions, or their planned use during the study
• Use of systemic cytotoxic agents, chronic antiviral agents or Chinese herbal medicines which may have activity against HBV within 6 months prior the study
• Currently taking, or took within 12 months of screening, any interferon-containing therapy
• 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 within 14 days before the first dose and/or 30 days after the last dose of study intervention administration, with the exception of influenza vaccine that may be given at any time except within a 7-day period before or after each 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
• Administration of:
• long-acting immune-modifying drugs at any time during the study
• immunoglobulins and/or any blood products or plasma derivatives within 3 months before the first dose of study interventions or planned administration during the study
• Chronic administration of immunosuppressants or other immune-modifying drugs within 3 months prior to the first study intervention (e.g. prednisone equivalent ≥20 mg/day; ≥10 mg/day applicable in Germany only). Inhaled and topical steroids are allowed
• Participants for whom immunosuppressive treatment is not advised
• Treatment with nephrotoxic drugs or competitors of renal excretion within 2 months prior to Screening or planned during the study
• Participants requiring anti-coagulation therapies

Prior/Concurrent clinical study experience

• Concurrently participating in another clinical study, at any time during the study period, in which the participant has been/will be exposed to an investigational/a non-investigational intervention
• Previous participation in clinical trials with administration of either GSK3228836 or GSK3528869A
• Previous participation in a clinical study in which he/she has received an investigational product within the following time period prior to the first dosing day in the current study: 5 half-lives or twice the duration of the biological effect of the study treatment or 90 days
• Prior treatment with any other oligonucleotide/siRNA within 12 months prior to the first dosing day

Other exclusions

• Pregnant or lactating female
• Female planning to become pregnant/to discontinue contraceptive precautions
• Any study personnel or their immediate dependents, family, or household members
• History of/sensitivity to GSK3228836, or components thereof, or a history of drug or other allergy that contraindicates their participation