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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

GlaxoSmithKline Biologicals

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

28 Mar 2019 → 30 Aug 2025

Decision date (initial)

2024-05-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-512352-38-00

EudraCT number

2021-003567-10

ClinicalTrials.gov

NCT05276297

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

"Safety
• To assess the safety of sequential treatment with GSK3228836 and GSK3528869A in participants with CHB infection stable on NA therapy.
Efficacy
• To assess the efficacy of sequential treatment with GSK3228836 and GSK3528869A in participants with CHB infection stable on NA therapy.
• To assess the efficacy of sequential treatment with GSK3228836 and GSK3528869A in comparison with GSK3228836 treatment in participants with CHB infection stable on NA therapy."

Secondary objectives 1

1. "Safety • To assess the safety of sequential treatment with GSK3228836 and GSK3528869A in participants with CHB infection stable on NA therapy Efficacy • To assess the efficacy of sequential treatment with GSK3228836 and GSK3528869A in comparison with baseline in participants with CHB infection who are virally suppressed on NA therapy. • To describe durability of SVR Immunogenicity • To assess the humoral and cellular immune responses specific to HBs and HBc antigens of sequential treatment with GSK3228836 and GSK3528869A in participants with CHB infection who are virally suppressed on NA therapy."

Conditions and MedDRA coding

Hepatitis B, Chronic

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. "• Participants, who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits). • 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 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 Alanine Transaminase (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."
2. "• 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 o 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: o Is not a WOCBP o 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."

Exclusion criteria 4

1. "Medical conditions • Clinically significant abnormalities, aside from chronic HBV infection in medical history • Co-infection with:  Current or past history of Hepatitis C virus (HCV)  Human immunodeficiency virus (HIV)  Hepatitis D virus (HDV) • History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by  both Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7  Regardless of APRI or Fibrosure/FibroTest score, if the participant meets one of the following historical criteria, they will be excluded from the study o Liver biopsy (i.e., METAVIR Score F4) o Liver stiffness >12 kPa • FibroScan TE score >9.6 kPa and FibroTest score >0.59 at Screening. • Diagnosed or suspected HCC as evidenced by the following:  Alpha-fetoprotein concentration ≥200 ng/mL  If the screening alpha-fetoprotein concentration is ≥50 ng/mL and <200 ng/mL, the absence of liver mass must be documented by imaging within 6 months before randomisation. • 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) Anti-neutrophil cytoplasmic antibody (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 • Fridericia’s QT correction formula (QTcF) ≥450 msec • Laboratory results as follows:  Serum albumin <3.5 g/dL  Glomerular filtration rate (GFR) <60 mL/ min /1.73m2 as calculated by the Chronic Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula  INR >1.25  Platelet count <140x109/L  Haemoglobin< 10 g/dl  Total bilirubin >1.25xULN  Urine albumin to creatinine ratio (ACR) ≥0.03 mg/mg (or ≥30 mg/g). • 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, in the opinion of the investigator, might pose additional risk to the participant due to participation in the study. • Major congenital defects, as assessed by the Investigator. • 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)."
2. "Prior/Concomitant therapy • Use of any investigational or non-registered product (drug, vaccine or medical device) 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 period. • Use of systemic cytotoxic agents, chronic antiviral agents or Chinese herbal medicines which may have activity against HBV within the previous 6 months. • 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 Coronavirus Disease 2019 (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/product 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 messenger ribonucleic acid (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."
3. "• Administration of long-acting immune-modifying drugs at any time during the study period (e.g. infliximab). • Administration of immunoglobulins and/or any blood products or plasma derivatives during the period starting 3 months before the administration of the first dose of study interventions or planned administration during the study period. • Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting 3 months prior to the first study intervention dose(s). For corticosteroids, this will mean prednisone equivalent ≥20 mg/day for adult participants (≥10 mg/day applicable in Germany only). Inhaled and topical steroids are allowed. • Participants for whom immunosuppressive treatment is not advised, including therapeutic doses of corticosteroids, will be excluded. • Treatment with nephrotoxic drugs or competitors of renal excretion within 2 months prior to Screening. • Participants requiring anti-coagulation therapies."
4. "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 (drug/invasive medical device). • 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 (if known) or twice the duration (if known) of the biological effect of the study treatment (whichever is longer) or 90 days (if half-life or duration is unknown). • Prior treatment with any other oligonucleotide or small interfering RNA (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."

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. "Safety • Percentage of participants reporting any grade 3 AE from first dose of GSK3228836 up to the study end. • Percentage of participants reporting any SAE from first dose of GSK3228836 up to the study end "
2. "• Percentage of participants reporting any AESIs grade 3 or higher from first dose of GSK3228836 up to the study end. "
3. "Efficacy • Percentage of participants who achieve SVR (HBsAg
4. • Difference between treatment arms (corresponding GSK3228836 regimens) in percentage of participants who achieve SVR (HBsAg < LLOQ and HBV DNA

Secondary endpoints 11

1. "Solicited events post GSK3528869A • Percentage of participants reporting each injection site solicited adverse event (injection site redness, pain and swelling) within 7 days (Day 1 – Day 7) post administration of each dose of study treatment "
2. "• Percentage of participants reporting each systemic solicited adverse event within 7 days (Day 1 – Day 7) post administration of each dose of study treatment. "
3. "Unsolicited AEs • Percentage of participants reporting any unsolicited AE within 30 days (Day 1 – Day 30) post administration of each dose of GSK3528869A. "
4. "• Percentage of participants reporting any AE from first dose of GSK3228836 up to study end • Percentage of participants reporting any AESIs from first dose of GSK3228836 up to study end "
5. "pIMDs • Percentage of participants reporting any pIMDs anytime from first dose of GSK3528869A up to study end. "
6. "Safety laboratory assessments • Percentage of participants reporting haematological, biochemical or urinalysis laboratory abnormalities anytime from first dose of GSK3228836 up to the study end. "
7. "Efficacy • qHBsAg: number of participants with ≥0.5 log decrease, ≥1-log decrease, HBsAg loss and log-changes from baseline. • Number of participants with HBsAg loss and anti-HBs seroconversion. • Mean qHBsAg. "
8. "• Duration of SVR o Time to the first occurrence of HBsAg reversion. o Time to the first occurrence of HBV DNA reversion. "
9. "• Virologic breakthrough: HBV DNA ≥ 1-log increase from nadir or HBV DNA becoming quantifiable after being below the LLOQ. "
10. "Immunogenicity • Immunogenicity with respect to HBV components of GSK3528869A, at pre-defined time points. o Anti-HBc antibodies: responder rates and concentration "
11. "o Anti-HBs antibodies: seroconversion4, responder rates and concentration; anti-HBs ≥10 mIU/mL and ≥100 mIU/mL o Frequency of HBc- and HBs- specific CD4+ T-cell and CD8+ T-cell; CD4+ T-cells responders, CD8+ T-cell responders."

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

GlaxoSmithKline Biologicals

Sponsor organisation

GlaxoSmithKline Biologicals

Address

Rue De L'Institut 89

City

Rixensart

Postcode

1330

Country

Belgium

Scientific contact point

Organisation

GlaxoSmithKline Biologicals

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

GlaxoSmithKline Biologicals

Contact name

EU GSK Clinical Trials Call Center

Third parties 19

Locations

8 EU/EEA countries · 28 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 111 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications