Study of Sequential GSK3228836 and Peginterferon Treatment in Participants With Chronic Hepatitis B (CHB)

NCT ID: NCT04676724

Last Updated: 2024-05-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 108 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-01-28
• Study Completion Date: 2023-02-17

Brief Summary

This study is intended to evaluate if 12 or 24 weeks of treatment with GSK3228836 followed by up to 24 weeks of pegylated interferon (PegIFN) can increase the rate of hepatitis B virus surface antigen (HBsAg) loss in participants on stable nucleos(t)ide analogue (NA) therapy, and whether virologic response can be sustained once PegIFN treatment is discontinued. Participants will be randomized to receive GSK3228836 for 12 or 24 weeks followed by up to 24 weeks of PegIFN.

Conditions

Hepatitis B

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

GSK3228836 300 mg (24 weeks) + PegIFN 180 mcg (24 weeks)

Participants on stable NA therapy received 300 milligrams per week (mg/week) GSK3228836 for 24 weeks (plus a loading dose on Day 4 and 11), followed by Pegylated Interferon (PegIFN) 180 microgram per week (mcg/week) up to 24 weeks.

Group Type: EXPERIMENTAL

GSK3228836

Intervention Type: DRUG

Participants will be administered GSK3228836.

PegIFN

Intervention Type: DRUG

Participants will be administered PegIFN.

NA therapy

Intervention Type: DRUG

Participants will continue to receive their NA therapy for the duration of the study.

GSK3228836 300 mg (12 weeks) + PegIFN 180 mcg (24 weeks)

Participants on stable NA therapy received 300mg/week GSK3228836 for 12 weeks (plus a loading dose on Day 4 and 11), followed by PegIFN 180 mcg/week up to 24 weeks.

Group Type: EXPERIMENTAL

GSK3228836

Intervention Type: DRUG

Participants will be administered GSK3228836.

PegIFN

Intervention Type: DRUG

Participants will be administered PegIFN.

NA therapy

Intervention Type: DRUG

Participants will continue to receive their NA therapy for the duration of the study.

Interventions

GSK3228836

Participants will be administered GSK3228836.

Intervention Type: DRUG

PegIFN

Participants will be administered PegIFN.

Intervention Type: DRUG

NA therapy

Participants will continue to receive their NA therapy for the duration of the study.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 18 to 75 years of age at the time of signing the informed consent.
• Participants who are eligible to be treated with PegIFN.
• Documented chronic HBV infection >=6 months prior to screening and currently receiving stable NA therapy except telbivudine, defined as no changes to their NA regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study.
• Plasma or serum HBsAg concentration >100 International Units per milliliter (IU/mL).
• Plasma or serum HBV DNA concentration <90 IU/mL.
• ALT <=2 times ULN.
• 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 treatment: a) Refrain from donating sperm; b) 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 agree to use contraception/barrier: 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 who is not currently pregnant.
• A female participant is eligible to participate: a) If she is not pregnant or breastfeeding; b) at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) or is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1 percent 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 both a negative highly sensitive pregnancy test 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.
• Capable of giving signed informed consent.

Exclusion Criteria

• Clinically significant abnormalities, aside from chronic HBV infection in medical history or physical examination.
• 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. If only one parameter (APRI or FibroSure/FibroTest) result is positive, a discussion with the Medical Monitor is required before inclusion in study is permitted. Regardless of APRI of Fibrosure/FibroTest score, if the participant meets one of the following criteria, they will be excluded from the study: a) Liver biopsy (i.e., Metavir Score F4); b) Liver stiffness >12 kilopascals (kPa).
• Diagnosed or suspected hepatocellular carcinoma as evidenced by the following: Alpha- fetoprotein concentration >=200 nanogram per milliliter (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 randomization.
• History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer). Participants under evaluation for possible malignancy are not eligible.
• History of vasculitis or presence of symptoms and signs of potential vasculitis (e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause) or history/presence of other diseases that may be associated with vasculitis condition (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex).
• History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension).
• Poorly controlled thyroid dysfunction or abnormal thyroid stimulating hormone (TSH) levels
• Positive (or borderline positive) anti-neutrophil cytoplasmic antibody (ANCA) at screening. Participants that meet these criteria may be considered for inclusion in the study following: a) Analysis of myeloperoxidase (MPO)-ANCA [perinuclear ANCA (pANCA)] and PR3-ANCA [classical ANCA (cANCA)]; b) A discussion with the Medical Monitor to review participant's complete medical history to ensure no past history or current manifestations of a vasculitic/inflammatory/auto-immune condition.
• Low complement 3 (C3) at screening and evidence of past history or current manifestations of vasculitic/inflammatory/auto-immune conditions. All participants with low C3 at screening should have their medical history discussed with the Medical Monitor prior to enrolment.
• Pre-existing severe psychiatric condition or a history of severe psychiatric disorders, including severe depression, suicidal ideation and attempted suicide.
• Currently taking, or took within 3 months of screening, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy (<=2 weeks) or topical/inhaled steroid use.
• Participants for whom immunosuppressive treatment is not advised, including therapeutic doses of steroids, will be excluded.
• Participants with prior treatment with PegINF or interferon will be excluded
• Participants requiring anti-coagulation therapies (for example warfarin, Factor Xa inhibitors or anti-platelet agents like clopidogrel).
• Participants currently taking, or took within 6 months of screening, telbivudine.
• The participant has participated in a clinical trial and 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 oligonucleotide or small interfering ribonucleic acid (siRNA) within 12 months prior to the first dosing day.
• Fridericia's QT correction formula (QTcF) >=450 milliseconds (msec) (if single electrocardiogram [ECG] at screening shows QTcF>=450 msec, a mean of triplicate measurements should be used to confirm that participant meets exclusion criterion).
• Laboratory results as follows: Serum albumin <3.5 grams per deciliter (g/dL); Glomerular filtration rate (GFR) <60 milliliter per minute per 1.73 square meter (mL/min /1.73 m^2) as calculated by the Chronic Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula (for Japan, Japanese Society of Nephrology Chronic Kidney Disease Initiative [JSN-CKDI equation]); International normalized ratio (INR) >1.25; Platelet count <140x10^9 cells/L; Baseline hemoglobin <10 g/dL; Total bilirubin >1.25 times ULN (For participants with benign unconjugated hyperbilirubinemia with total bilirubin >1.25 times ULN, discussion for inclusion to the study is required with the Medical Monitor); Urine albumin to creatinine ratio (ACR) >=0.03 milligram (mg)/mg (or >=30 mg/g). In the event of an ACR above this threshold, eligibility may be confirmed by a second measurement. In cases where participants have low urine albumin and low urine creatinine levels resulting in a urine ACR calculation >=0.03 mg/mg (or >=30 mg/g), the investigator should confirm that the participant does not have a history of diabetes, hypertension or other risk factors that may affect renal function and discuss with the Medical Monitor, or designee.
• History of/sensitivity to GSK3228836 or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Sacramento, California, United States

GSK Investigational Site

Iowa City, Iowa, United States

GSK Investigational Site

Detroit, Michigan, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

Calgary, Alberta, Canada

GSK Investigational Site

Edmonton, Alberta, Canada

GSK Investigational Site

Montreal, Quebec, Canada

GSK Investigational Site

Changchun, Jilin, China

GSK Investigational Site

Beijing, , China

GSK Investigational Site

Beijing, , China

GSK Investigational Site

Hangzhou, , China

GSK Investigational Site

Shanghai, , China

GSK Investigational Site

Baggiovara (MO), Emilia-Romagna, Italy

GSK Investigational Site

Milan, Lombardy, Italy

GSK Investigational Site

Milan, Lombardy, Italy

GSK Investigational Site

Monza (MB), Lombardy, Italy

GSK Investigational Site

Aichi, , Japan

GSK Investigational Site

Fukui, , Japan

GSK Investigational Site

Gifu, , Japan

GSK Investigational Site

Hiroshima, , Japan

GSK Investigational Site

Kumamoto, , Japan

GSK Investigational Site

Nagasaki, , Japan

GSK Investigational Site

Tokyo, , Japan

GSK Investigational Site

Lublin, , Poland

GSK Investigational Site

Mysłowice, , Poland

GSK Investigational Site

Łańcut, , Poland

GSK Investigational Site

Barnaul, , Russia

GSK Investigational Site

Chelyabinsk, , Russia

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Novosibirsk, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Samara, , Russia

GSK Investigational Site

Красноярск, , Russia

GSK Investigational Site

Ennerdale, Gauteng, South Africa

GSK Investigational Site

Johannesburg, Gauteng, South Africa

GSK Investigational Site

Busan, , South Korea

GSK Investigational Site

Daegu, , South Korea

GSK Investigational Site

Gyeonggi-do, , South Korea

GSK Investigational Site

Gyeonggi-do, , South Korea

GSK Investigational Site

Ulsan, , South Korea

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Madrid, , Spain

GSK Investigational Site

Málaga, , Spain

GSK Investigational Site

Santander, , Spain

GSK Investigational Site

London, , United Kingdom

GSK Investigational Site

Newcastle upon Tyne, , United Kingdom

GSK Investigational Site

Nottingham, , United Kingdom

GSK Investigational Site

Plymouth, , United Kingdom

Countries

United States; Canada; China; Italy; Japan; Poland; Russia; South Africa; South Korea; Spain; United Kingdom

References

Joshi S, Freudenberg JM, Singh JM, Jordan WT, Felton L, Dixon S, Paff M, Theodore D, Walker J. Immunomodulation by bepirovirsen may induce killing of infected hepatocytes (B-Together study). Hepatol Int. 2025 Oct 3. doi: 10.1007/s12072-025-10917-0. Online ahead of print.

Reference Type: DERIVED

PMID: 41042426 (View on PubMed)

Buti M, Heo J, Tanaka Y, Andreone P, Atsukawa M, Cabezas J, Chak E, Coffin CS, Fujiwara K, Gankina N, Gordon SC, Janczewska E, Komori A, Lampertico P, McPherson S, Morozov V, Plesniak R, Poulin S, Ryan P, Sagalova O, Sheng G, Voloshina N, Xie Q, Yim HJ, Dixon S, Paff M, Felton L, Lee M, Greene T, Lim J, Lakshminarayanan D, McGonagle G, Plein H, Youssef AS, Elston R, Kendrick S, Theodore D. Sequential Peg-IFN after bepirovirsen may reduce post-treatment relapse in chronic hepatitis B. J Hepatol. 2025 Feb;82(2):222-234. doi: 10.1016/j.jhep.2024.08.010. Epub 2024 Aug 29.

Reference Type: DERIVED

PMID: 39214467 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

209348

Identifier Type: -

Identifier Source: org_study_id