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
- Conditions
- Hepatitis B, Chronic
- Interventions
- Registration Number
- NCT05276297
- Lead Sponsor
- GlaxoSmithKline
- 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
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 174
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description ASO24-TI Group GSK3228836 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. ASO24-TI Group GSK3528869A 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. ASO24 Group GSK3228836 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. ASO24 Group Control 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. ASO12-TI Group GSK3528869A 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. ASO12 Group Control 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. ASO12-TI Group GSK3228836 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. ASO12 Group GSK3228836 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.
- Primary Outcome Measures
Name Time Method Percentage of participants reporting any serious adverse event (SAE) 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 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 grade 3 adverse event (AE) from first dose of GSK3228836 up to study end From first dose of GSK3228836 (Treatment 1 [T1]-Day 1) up to study end (Treatment 2 [T2]-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 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) 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.Percentage of participants reporting any adverse events of special interest (AESIs) grade 3 or higher 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 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).
- Secondary Outcome Measures
Name Time Method 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 The solicited administration site events include pain, redness and swelling.
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 The solicited systemic events include fatigue, fever, headache, myalgia, arthralgia and chills. Fever is defined as temperature equal to or above 38.0°C/100.4°F. The preferred location for measuring temperature is the oral cavity.
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 An unsolicited AE is an AE that was not included in a list of solicited events using a Participant Diary. Unsolicited events must have been spontaneously communicated by a participant who has signed the informed consent. Unsolicited AEs include both serious and non-serious AEs.
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 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.
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 841) AESI related to GSK3228836 treatment include thrombocytopenia, ALT increases, vascular inflammation and complement activation, renal injury or injection site reactions. AESI related to GSK3528869A include liver disease-related AEs, hematological AESIs or pIMDs.
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 841) pIMDs are a subset of AESIs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology.
Percentage of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during Treatment 1 period At Days T1: 1 ,8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106, 113, 120, 127, 134, 141, 148, 155 and 162 (ASO24-TI & ASO24 groups) and at Days T1: 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78 (ASO12-TI & ASO12 groups) Clinically significant abnormal laboratory findings are those which are not associated with an underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.
Percentage of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during Treatment 2 period At Days T2: 1, 3, 8, 15, 31, 57, 64, 71, 87, 113, 120, 127, 143, 169, 176, 183 and 199 Clinically significant abnormal laboratory findings are those which are not associated with an underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.
Percentage of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during follow-up period At Days T2: 225, 281, 337, 421, 505, 673 and 841 Clinically significant abnormal laboratory findings are those which are not associated with an underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.
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 end of treatment period At Days T1:1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162; T2:1,15,31,57,71,87,113,143,169,199 (ASO24-TI&ASO24 groups); T1:1,8,15,22,29,36,43,50,57,64,71,78; T2:1,15,31,57,71,87,113,143,169,199 (ASO12-TI&ASO12 groups) qHBsAg decrease is defined as ≥ 0.5 log decrease and ≥ 1-log decrease. The analysis is performed by considering the HBsAg status prior to GSK3228836 as baseline.
Percentage of participants who achieve qHBsAg decrease and HBsAg loss at pre-defined time points from GSK3228836 baseline (Treatment 1-Day 1) up to end of Treatment 1 period At Days T1: 1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162 (ASO24-TI & ASO24 groups) and at Days T1: 1,8,15,22,29,36,43,50,57,64,71,78 (ASO12-TI & ASO12 groups) qHBsAg decrease is defined as ≥ 0.5 log decrease and ≥ 1-log decrease. The analysis is performed by considering the HBsAg status prior to GSK3228836 as baseline.
Percentage of participants who achieve qHBsAg decrease and HBsAg loss at pre-defined time points from GSK3528869A/control baseline (Treatment 2-Day 1) up to end of Treatment 2 period At Days T2: 1, 15, 31, 57, 71, 87, 113, 143, 169 and 199 qHBsAg decrease is defined as ≥ 0.5 log decrease and ≥ 1-log decrease. The analysis is performed by considering the HBsAg status prior to GSK3528869A/control as baseline.
Percentage of participants in ASO24-TI and ASO24 groups who experienced HBV DNA virologic breakthrough At Days T1:1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162 and at Days T2:1,15,31,57,71,87,113,143,169,199,225,281,337,421,505,673,841 HBV DNA virologic breakthrough is defined at 1-log increase from nadir in HBV DNA or HBV DNA becoming quantifiable after being below the LLOQ.
Changes in qHBsAg at pre-defined time points from GSK3228836 baseline (Treatment 1-Day 1) up to end of treatment period At Days T1:1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162; T2:1,15,31,57,71,87,113,143,169,199 (ASO24-TI&ASO24 groups); T1:1,8,15,22,29,36,43,50,57,64,71,78; T2:1,15,31,57,71,87,113,143,169,199 (ASO12-TI&ASO12 groups) Changes in serum qHBsAg from GSK3228836 baseline are expressed as geometric mean ratios (GMRs). The analysis is performed by considering the HBsAg status prior to GSK3228836 as baseline.
Changes in qHBsAg at pre-defined time points from GSK3228836 baseline (Treatment 1-Day 1) up to end of Treatment 1 period At Days T1: 1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162 (ASO24-TI & ASO24 groups) and at Days T1: 1,8,15,22,29,36,43,50,57,64,71,78 (ASO12-TI & ASO12 groups) Changes in serum qHBsAg from GSK3228836 baseline are expressed as GMRs. The analysis is performed by considering the HBsAg status prior to GSK3228836 as baseline.
Changes in qHBsAg at pre-defined time points from GSK3528869A/control baseline (Treatment 2-Day 1) up to end of Treatment 2 period At Days T2: 1, 15, 31, 57, 71, 87, 113, 143, 169 and 199 Changes in serum qHBsAg from GSK3528869A/control are expressed as GMRs. The analysis is performed by considering the HBsAg status prior to GSK3528869A/control.
Percentage of participants in ASO24-TI and ASO24 groups with HBsAg loss and anti-HBs seroconversion At Days T1:1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162 and at Days T2:1,15,31,57,71,87,113,143,169,199,225,281,337,421,505,673,841 A participant is counted only when both HBsAg loss and anti-HBs seroconversion are reported for the participant. Seroconversion is defined as the appearance of antibodies (i.e., concentrations/titer greater than or equal to the LLOQ) in the serum of participants seronegative before GSK3528869A administration.
Percentage of participants in ASO12-TI and ASO12 groups with HBsAg loss and anti-HBs seroconversion At Days T1:1,8,15,22,29,36,43,50,57,64,71,78 and at Days T2:1,15,31,57,71,87,113,143,169,199,225,281,337,421,505,673,841 A participant is counted only when both HBsAg loss and anti-HBs seroconversion are reported for the participant. Seroconversion is defined as the appearance of antibodies (i.e., concentrations/titer greater than or equal to the LLOQ) in the serum of participants seronegative before GSK3528869A administration.
Geometric mean concentrations (GMCs) of qHBsAg for participants in ASO24-TI and ASO24 groups At Days T1:1,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120,127,134,141,148,155,162 and at Days T2:1,15,31,57,71,87,113,143,169,199,225,281,337,421,505,673,841 Geometric mean concentrations (GMCs) of qHBsAg for participants in ASO12-TI and ASO12 groups At Days T1:1,8,15,22,29,36,43,50,57,64,71,78 and at Days T2:1,15,31,57,71,87,113,143,169,199,225,281,337,421,505,673,841 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-Day 841 HBsAg reversion is defined as HBsAg \>LLOQ or HBV DNA \>LLOQ, confirmed by 2 consecutive visits at least 1 month apart.
Percentage of participants in ASO12-TI and ASO12 groups who experienced HBV DNA virologic breakthrough At Days T1:1,8,15,22,29,36,43,50,57,64,71,78 and at Days T2:1,15,31,57,71,87,113,143,169,199,225,281,337,421,505,673,841 HBV DNA virologic breakthrough is defined at 1-log increase from nadir in HBV DNA or HBV DNA becoming quantifiable after being below the LLOQ.
Percentage of participants with anti-HBc antibody response At Days T1: 1,29,57,85,113,141,162 and T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO24-TI&ASO24 groups) and at Days T1: 1,29,57 and T2:1,15,57,71,113,127,169,183,337,505,841 (ASO12-TI&ASO12 groups) Anti-HBc antibody concentrations At Days T1: 1,29,57,85,113,141,162 and T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO24-TI&ASO24 groups) and at Days T1: 1,29,57 and T2:1,15,57,71,113,127,169,183,337,505,841 (ASO12-TI&ASO12 groups) Anti-HBc antibody concentrations are expressed as geometric mean concentrations (GMCs).
Percentage of participants who achieved HBsAg seroconversion At Days T1: 1,29,57,85,113,141,162 and T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO24-TI&ASO24 groups) and at Days T1: 1,29,57 and T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO12-TI&ASO12 groups) Seroconversion is defined as the appearance of antibodies (i.e., concentrations/titer greater than or equal to the LLOQ) in the serum of participants seronegative before GSK3528869A administration.
Percentage of participants with anti-HBs antibody response At Days T1: 1,29,57,85,113,141,162 and T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO24-TI&ASO24 groups) and at Days T1: 1,29,57 and T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO12-TI&ASO12 groups) Anti-HBs antibody concentrations At Days T1: 1,29,57,85,113,141,162 and T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO24-TI&ASO24 groups) and at Days T1: 1,29,57 and T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO12-TI&ASO12 groups) Anti-HBs antibody concentrations are expressed as GMCs.
Percentage of participants with anti-HBs antibody concentrations equal to or above (≥) 10 mIU/mL At Days T1: 1,29,57,85,113,141,162 and T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO24-TI&ASO24 groups) and at Days T1: 1,29,57 and T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO12-TI&ASO12 groups) Percentage of participants with anti-HBs antibody concentrations equal to or above (≥) 100 mIU/mL At Days T1: 1,29,57,85,113,141,162 and at Days T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO24-TI&ASO24 groups) and at Days T1: 1,29,57 and at Days T2: 1,15,57,71,113,127,169,183,337,505,841 (ASO12-TI&ASO12 groups) Frequency of HBc-specific CD4+ T-cells At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841 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).
Frequency of HBs-specific CD4+ T-cells At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841 Frequency of HBs-specific CD4+ T-cells is expressed as HBs-specific CD4+ T-cells/million PBMCs.
Frequency of HBc-specific CD8+ T-cells At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841 Frequency of HBc-specific CD8+ T-cells is expressed as HBc-specific CD8+ T-cells/million PBMCs.
Frequency of HBs-specific CD8+ T-cells At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841 Frequency of HBs-specific CD8+ T-cells is expressed as HBs-specific CD8+ T-cells/million PBMCs.
Number of HBc- and HBs-specific CD4+ T cells responders At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841 Number of HBc- and HBs-specific CD8+ T cells responders At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841
Trial Locations
- Locations (1)
GSK Investigational Site
🇬🇧Leicester, United Kingdom