A Phase 2, Single-blinded, Randomised, Controlled Multi-country Study to Evaluate the Safety, Reactogenicity, Efficacy and Immune Response Following Sequential Treatment With an Anti-sense Oligonucleotide (ASO) Against Chronic Hepatitis B (CHB) Followed by Chronic Hepatitis B Targeted Immunotherapy (CHB-TI) in CHB Patients Receiving Nucleos(t)Ide Analogue (NA) Therapy
Overview
- Phase
- Phase 2
- Intervention
- GSK3228836
- Conditions
- Hepatitis B, Chronic
- Sponsor
- GlaxoSmithKline
- Enrollment
- 174
- Locations
- 1
- Primary Endpoint
- Percentage of participants reporting any grade 3 adverse event (AE) from first dose of GSK3228836 up to study end
- Status
- Completed
- Last Updated
- 4 months ago
Overview
Brief 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 stable on 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.
Detailed Description
The study follow-up period was reduced from 2 years post last dose to at least 1 year post last dose, with Visit Treatment 2-Day 505 defined as the last visit of the study. For participants who completed visits Treatment 2-Day 673 or Treatment 2-Day 841, those visits were considered the last study visit.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
ASO24-TI Group
Eligible participants receive GSK3228836 (Treatment 1) study intervention for 24 weeks of Treatment 1 period, followed by GSK3528869A (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period. The interval between Treatment 1 and Treatment 2 is preferably 1 week, with the possibility to extend up to 12 weeks.
Intervention: GSK3228836
ASO24-TI Group
Eligible participants receive GSK3228836 (Treatment 1) study intervention for 24 weeks of Treatment 1 period, followed by GSK3528869A (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period. The interval between Treatment 1 and Treatment 2 is preferably 1 week, with the possibility to extend up to 12 weeks.
Intervention: GSK3528869A
ASO24 Group
Eligible participants receive GSK3228836 (Treatment 1) study intervention for 24 weeks of Treatment 1 period, followed by non-active control (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period. The interval between Treatment 1 and Treatment 2 is preferably 1 week, with the possibility to extend up to 12 weeks.
Intervention: GSK3228836
ASO24 Group
Eligible participants receive GSK3228836 (Treatment 1) study intervention for 24 weeks of Treatment 1 period, followed by non-active control (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period. The interval between Treatment 1 and Treatment 2 is preferably 1 week, with the possibility to extend up to 12 weeks.
Intervention: Control
ASO12-TI Group
Eligible participants receive GSK3228836 (Treatment 1) study intervention for 12 weeks of Treatment 1 period, followed by GSK3528869A (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period. The interval between Treatment 1 and Treatment 2 is preferably 1 week, with the possibility to extend up to 12 weeks.
Intervention: GSK3228836
ASO12-TI Group
Eligible participants receive GSK3228836 (Treatment 1) study intervention for 12 weeks of Treatment 1 period, followed by GSK3528869A (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period. The interval between Treatment 1 and Treatment 2 is preferably 1 week, with the possibility to extend up to 12 weeks.
Intervention: GSK3528869A
ASO12 Group
Eligible participants receive GSK3228836 (Treatment 1) study intervention for 12 weeks of Treatment 1 period, followed by non-active control (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period. The interval between Treatment 1 and Treatment 2 is preferably 1 week, with the possibility to extend up to 12 weeks.
Intervention: GSK3228836
ASO12 Group
Eligible participants receive GSK3228836 (Treatment 1) study intervention for 12 weeks of Treatment 1 period, followed by non-active control (Treatment 2) study intervention administered at Days 1, 57, 113 and 169 of Treatment 2 period. The interval between Treatment 1 and Treatment 2 is preferably 1 week, with the possibility to extend up to 12 weeks.
Intervention: Control
Outcomes
Primary Outcomes
Percentage of participants reporting any grade 3 adverse event (AE) from first dose of GSK3228836 up to study end
Time Frame: From first dose of GSK3228836 (Treatment 1 -Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841)
An AE is any untoward medical occurrence (an unfavourable/unintended sign - including an abnormal laboratory finding), symptom, or disease (new or exacerbated) in a clinical study participant that is temporally associated with the study intervention. A grade 3 AE is an AE which prevents normal, everyday activities (in adults, such an AE would, for example, prevent attendance at work/school and would necessitate the administration of corrective therapy).
Percentage of participants reporting any serious adverse event (SAE) from first dose of GSK3228836 up to study end
Time Frame: From first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841)
An SAE is any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study participant or is an abnormal pregnancy outcome.
Percentage of participants reporting any adverse events of special interest (AESIs) grade 3 or higher from first dose of GSK3228836 up to study end
Time Frame: From first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841)
AESI related to GSK3228836 treatment include thrombocytopenia, alanine transaminase (ALT) increases, vascular inflammation and complement activation, renal injury or injection site reactions. AESI related to GSK3528869A include liver disease-related (LDR) AEs, hematological AESI or potential immune-mediated diseases (pIMDs). A grade 3 AE is an AE which prevents normal, everyday activities (in adults, such an AE would, for example, prevent attendance at work/school and would necessitate the administration of corrective therapy).
Percentage of participants who achieve sustained virologic response (SVR) for 24 weeks after the planned end of active treatment in the absence of rescue medication, and difference between treatment arms (corresponding to GSK3228836 regimens)
Time Frame: For up to 24 weeks after the planned end of active treatment (planned end of active treatment = Treatment 1-Day 78 for ASO12 group, Treatment 1-Day 162 for ASO24 group and Treatment 2-Day 169 for ASO12-TI and ASO24-TI groups)
SVR is defined as Hepatitis B surface antigen (HBsAg) below (\<) lower limit of quantification (LLOQ) and HBV deoxyribose nucleic acid (DNA) \< LLOQ. Rescue medication is defined as any medication initiated for the purpose of antiviral suppression other than the background stable NA therapy irrespective of the reason.
Secondary Outcomes
- Percentage of participants reporting each solicited administration site event post-GSK3528869A study intervention administration(Within 7 days post-administration (day of administration + 6 subsequent days) of each dose of GSK3528869A study intervention)
- Percentage of participants reporting each solicited systemic event post-GSK3528869A study intervention administration(Within 7 days post-administration (day of administration + 6 subsequent days) of each dose of GSK3528869A study intervention)
- Percentage of participants reporting any unsolicited AE post-GSK3528869A study intervention administration(Within 30 days post-administration (day of administration + 29 subsequent days) of each dose of GSK3528869A study intervention)
- Percentage of participants reporting any AE from first dose of GSK3228836 up to study end(From first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Percentage of participants reporting any AESIs from first dose of GSK3228836 up to study end(From first dose of GSK3228836 (Treatment 1-Day 1) up to the study end (Treatment 2-Day 505/Day 673/Day 841))
- Percentage of participants reporting any pIMDs from first dose of GSK3528869A up to study end(From first dose of GSK3528869A (Treatment 2-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Percentage of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during Treatment 1 period(At pre-defined time points during Treatment 1 period (from Treatment 1-Day 1 until Treatment 1-Day 78 for ASO12-TI and ASO12 groups, and from Treatment 1-Day 1 until Treatment 1-Day 162 for ASO24-TI and ASO24 groups))
- Percentage of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during Treatment 2 period(At pre-defined time points during Treatment 2 period (from Treatment 2-Day 1 until Treatment 2-Day 199))
- Percentage of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during follow-up period(At pre-defined time points during follow-up period (from Treatment 2-Day 225 until Treatment 2-Day 505/Day 673/Day 841))
- Percentage of participants who achieve quantitative Hepatitis B surface antigen assessment (qHBsAg) decrease and HBsAg loss at pre-defined time points from GSK3228836 baseline (Treatment 1-Day 1) up to study end(At pre-defined time points from GSK3228836 baseline (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Changes in qHBsAg at pre-defined time points from GSK3228836 baseline (Treatment 1-Day 1) up to study end(At pre-defined time points from GSK3228836 baseline (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Percentage of participants with HBsAg loss and anti-HBs seroconversion(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Geometric mean concentrations (GMCs) of qHBsAg(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Duration of SVR in terms of time to the first occurrence of HBsAg reversion and/or HBV DNA reversion(From Treatment 1-Day 1 up to first occurrence of HBsAg reversion and/or HBV DNA reversion, assessed from Treatment 1-Day 1 up to Treatment 2-505/Day 673/Day 841)
- Percentage of participants who experienced HBV DNA virologic breakthrough(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Percentage of participants with anti-HBc antibody response(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Anti-HBc antibody concentrations(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Percentage of participants who achieved HBsAg seroconversion(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Percentage of participants with anti-HBs antibody response(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Anti-HBs antibody concentrations(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Percentage of participants with anti-HBs antibody concentrations equal to or above (≥) 10 mIU/mL(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Percentage of participants with anti-HBs antibody concentrations equal to or above (≥) 100 mIU/mL(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Frequency of HBc-specific CD4+ T-cells(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Frequency of HBs-specific CD4+ T-cells(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Frequency of HBc-specific CD8+ T-cells(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Frequency of HBs-specific CD8+ T-cells(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Number of HBc- and HBs-specific CD4+ T cells responders(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))
- Number of HBc- and HBs-specific CD8+ T cells responders(At pre-defined time points from first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 505/Day 673/Day 841))