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 A

• Status: Not yet recruiting
• Trial end date: 2025-09-08
• Target enrollment: 0
• Participant gender: All

Summary

This study will assess the safety, efficacy and immune response following the sequential treatment of GlaxoSmithKline's (GSK) ASO compound (GSK3228836) and CHB-TI (GSK3528869A) in participants 18 to 65 years receiving stable NA treatment for CHB. The aim is to quantify the efficacy of sequential therapy as well as to determine an added value of sequential therapy over GSK3228836 therapy in CHB patients treated with NAs. In addition, the study will assess the effect of different treatment durations of GSK3228836 (12 or 24 weeks) prior to initiating GSK3528869A treatment.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: GlaxoSmithKline

Criteria

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.

• 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 receiving stable NA therapy population 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) 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 to participate if they agree 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 to participate:

• 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.

• If a urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

Exclusion Criteria:

Medical conditions

• Clinically significant abnormalities, aside from chronic HBV infection in medical history or physical examination

• 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 (i.e., 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 with the exception of specific cancers that are cured by surgical resection

• History of vasculitis or presence of symptoms and signs of potential vasculitis

• History of 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 it is considered as clinically not significant by the Investigator

• ACR ≥0.03 mg/mg

• Medical history of hepatic decompensation

• Planned for liver transplantation 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 during the period beginning 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 the previous 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

• Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 14 days before the first dose and ending 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

• Administration of immunoglobulins and/or any blood products or plasma derivatives during the period starting 3 months before the first dose of study interventions or planned administration during the study

• Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting 3 months prior to the first study intervention (e.g. prednisone equivalent ≥ 20 mg/day). 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 or will be exposed to an investigational or 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 or siRNA within 12 months prior to the first dosing day

Other exclusions

• Pregnant or lactating female

• Female planning to become pregnant or planning 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