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

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.


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.
* History of alcohol or drug abuse/dependence. Current alcohol use as judged by investigator to potentially interfere with participant compliance; History of or current drug abuse/dependence as judged by the investigator to potentially interfere with participant compliance. Refers to illicit drugs and substances with abuse potential. Medications that are used by the participant as directed, whether over-the-counter or through prescription, are acceptable and would not meet the exclusion criteria.
* 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.