Clinical trial NCT05276297: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Hepatitis B, Chronic
Keywords: Hepatitis B virus
Chronic Hepatitis B
Chronic Hepatitis B targeted immunotherapy
Safety
Reactogenicity
Efficacy
Immunogenicity
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2022-03-11
Enrollment: 174
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility 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 (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 approximately the 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.

Primary outcomes:
measure: Percentage of participants reporting any grade 3 adverse event (AE) from first dose of GSK3228836 up to study end
timeFrame: From first dose of GSK3228836 (Treatment 1 [T1]-Day 1) up to study end (Treatment 2 [T2]-Day 841)
measure: Percentage of participants reporting any serious adverse event (SAE) from first dose of GSK3228836 up to study end
timeFrame: From first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 841)
measure: Percentage of participants reporting any adverse events of special interest (AESIs) grade 3 or higher from first dose of GSK3228836 up to study end
timeFrame: From first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 841)
measure: 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)
timeFrame: 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)
Secondary outcomes:
measure: Percentage of participants reporting each solicited administration site event post-GSK3528869A study intervention administration
timeFrame: Within 7 days post-administration (day of administration + 6 subsequent days) of each dose of GSK3528869A study intervention
measure: Percentage of participants reporting each solicited systemic event post-GSK3528869A study intervention administration
timeFrame: Within 7 days post-administration (day of administration + 6 subsequent days) of each dose of GSK3528869A study intervention
measure: Percentage of participants reporting any unsolicited AE post-GSK3528869A study intervention administration
timeFrame: Within 30 days post-administration (day of administration + 29 subsequent days) of each dose of GSK3528869A study intervention
measure: Percentage of participants reporting any AE from first dose of GSK3228836 up to study end
timeFrame: From first dose of GSK3228836 (Treatment 1-Day 1) up to study end (Treatment 2-Day 841)
measure: Percentage of participants reporting any AESIs from first dose of GSK3228836 up to study end
timeFrame: From first dose of GSK3228836 (Treatment 1-Day 1) up to the study end (Treatment 2-Day 841)
measure: Percentage of participants reporting any pIMDs from first dose of GSK3528869A up to study end
timeFrame: From first dose of GSK3528869A (Treatment 2-Day 1) up to study end (Treatment 2-Day 841)
measure: Percentage of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during Treatment 1 period
timeFrame: 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)
measure: Percentage of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during Treatment 2 period
timeFrame: At Days T2: 1, 3, 8, 15, 31, 57, 64, 71, 87, 113, 120, 127, 143, 169, 176, 183 and 199
measure: Percentage of participants reporting hematological, biochemical or urinalysis laboratory abnormalities at pre-defined time points during follow-up period
timeFrame: At Days T2: 225, 281, 337, 421, 505, 673 and 841
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: At Days T2: 1, 15, 31, 57, 71, 87, 113, 143, 169 and 199
measure: Changes in qHBsAg at pre-defined time points from GSK3228836 baseline (Treatment 1-Day 1) up to end of treatment period
timeFrame: 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)
measure: Changes in qHBsAg at pre-defined time points from GSK3228836 baseline (Treatment 1-Day 1) up to end of Treatment 1 period
timeFrame: 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)
measure: Changes in qHBsAg at pre-defined time points from GSK3528869A/control baseline (Treatment 2-Day 1) up to end of Treatment 2 period
timeFrame: At Days T2: 1, 15, 31, 57, 71, 87, 113, 143, 169 and 199
measure: Percentage of participants in ASO24-TI and ASO24 groups with HBsAg loss and anti-HBs seroconversion
timeFrame: 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
measure: Percentage of participants in ASO12-TI and ASO12 groups with HBsAg loss and anti-HBs seroconversion
timeFrame: 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
measure: Geometric mean concentrations (GMCs) of qHBsAg for participants in ASO24-TI and ASO24 groups
timeFrame: 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
measure: Geometric mean concentrations (GMCs) of qHBsAg for participants in ASO12-TI and ASO12 groups
timeFrame: 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
measure: Duration of SVR in terms of time to the first occurrence of HBsAg reversion and/or HBV DNA reversion
timeFrame: 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
measure: Percentage of participants in ASO24-TI and ASO24 groups who experienced HBV DNA virologic breakthrough
timeFrame: 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
measure: Percentage of participants in ASO12-TI and ASO12 groups who experienced HBV DNA virologic breakthrough
timeFrame: 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
measure: Percentage of participants with anti-HBc antibody response
timeFrame: 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)
measure: Anti-HBc antibody concentrations
timeFrame: 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)
measure: Percentage of participants who achieved HBsAg seroconversion
timeFrame: 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)
measure: Percentage of participants with anti-HBs antibody response
timeFrame: 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)
measure: Anti-HBs antibody concentrations
timeFrame: 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)
measure: Percentage of participants with anti-HBs antibody concentrations equal to or above (≥) 10 mIU/mL
timeFrame: 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)
measure: Percentage of participants with anti-HBs antibody concentrations equal to or above (≥) 100 mIU/mL
timeFrame: 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)
measure: Frequency of HBc-specific CD4+ T-cells
timeFrame: At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841
measure: Frequency of HBs-specific CD4+ T-cells
timeFrame: At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841
measure: Frequency of HBc-specific CD8+ T-cells
timeFrame: At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841
measure: Frequency of HBs-specific CD8+ T-cells
timeFrame: At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841
measure: Number of HBc- and HBs-specific CD4+ T cells responders
timeFrame: At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841
measure: Number of HBc- and HBs-specific CD8+ T cells responders
timeFrame: At Days T1: 1, 78 and at Days T2: 1, 15, 71, 127, 183, 337, 505 and 841
Other outcomes:
Locations:
city: Edegem
country: Belgium
facility: GSK Investigational Site
city: Sliven
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofi
country: Bulgaria
facility: GSK Investigational Site
city: Veliko Tarnovo
country: Bulgaria
facility: GSK Investigational Site
city: Vratsa
country: Bulgaria
facility: GSK Investigational Site
city: Clichy Cedex
country: France
facility: GSK Investigational Site
city: CrEteil Cedex
country: France
facility: GSK Investigational Site
city: Lyon
country: France
facility: GSK Investigational Site
city: Strasbourg
country: France
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Frankfurt
country: Germany
facility: GSK Investigational Site
city: Leipzig
country: Germany
facility: GSK Investigational Site
city: Pokfulam
country: Hong Kong
facility: GSK Investigational Site
city: Bergamo
country: Italy
facility: GSK Investigational Site
city: Milano
country: Italy
facility: GSK Investigational Site
city: Milano
country: Italy
facility: GSK Investigational Site
city: Roma
country: Italy
facility: GSK Investigational Site
city: Rozzano MI
country: Italy
facility: GSK Investigational Site
city: Makati City
country: Philippines
facility: GSK Investigational Site
city: Pasig City
country: Philippines
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Lancut
country: Poland
facility: GSK Investigational Site
city: Myslowice
country: Poland
facility: GSK Investigational Site
city: Cluj Napoca
country: Romania
facility: GSK Investigational Site
city: Craiova Dolj
country: Romania
facility: GSK Investigational Site
city: Singapore
country: Singapore
facility: GSK Investigational Site
city: Singapore
country: Singapore
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Santander
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Vigo
country: Spain
facility: GSK Investigational Site
city: Chia-Yi
country: Taiwan
facility: GSK Investigational Site
city: Kaohsiung
country: Taiwan
facility: GSK Investigational Site
city: Linkou - Taoyuan Hsien
country: Taiwan
facility: GSK Investigational Site
city: Taichung
country: Taiwan
facility: GSK Investigational Site
city: Taichung
country: Taiwan
facility: GSK Investigational Site
city: Tainan
country: Taiwan
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: ChiangMai
country: Thailand
facility: GSK Investigational Site
city: Istanbul
country: Turkey
facility: GSK Investigational Site
city: Rize
country: Turkey
facility: GSK Investigational Site
city: Cottingham
country: United Kingdom
facility: GSK Investigational Site
city: Leicester
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: