Sequential PEG-IFN for HBV After Ending RNA-targeted Regimens

Efficacy and Safety of Pegylated Interferon Therapy in Chronic Hepatitis B Patients After Discontinuation of Antisense Oligonucleotide or Small Interfering RNA: A Prospective, Adaptive, Open-label, Randomized Controlled Study

The goal of this clinical trial is to compare sequential PEG-IFNα therapy strategies in chronic hepatitis B (CHB) patients previously treated with ASO/siRNA. The main questions it aims to answer are:

1. Does sequential PEG-IFNα therapy (vs. deferred/no treatment) improve HBsAg clearance rates?
2. What are the HBsAg clearance and relapse rates after 24 weeks of PEG-IFNα therapy?
3. Is intermittent PEG-IFNα therapy as effective and safe as continuous therapy?

Researchers will compare:

• Group A (immediate 24-week PEG-IFNα + 24-week follow-up) vs. Group B (24-week observation + 24-week PEG-IFNα) in Phase 1 to see if sequential PEG-IFNα therapy will improve HBsAg loss rate .

Researchers will describe:

• The response rate of IFN treatment in non-responders (HBsAg-positive) in Phase 2.
• The relaspe rate of responders (HBsAg-negative).

Participants will:

Phase 1 (0-48 weeks):

• Group A: Receive PEG-IFNα for 24 weeks, followed by 24-week treatment-free follow-up.
• Group B: Undergo 24-week observation, then receive PEG-IFNα for 24 weeks.

Phase 2 (48-96 weeks):

• HBsAg-positive at week 48 patients either from group A or group B : Receive 24-week PEG-IFNα therapy, followed by 24-week follow-up.
• HBsAg-negative at week 48 patients either from group A or group B: Enter 24-week follow-up without treatment.

All participants will undergo:

• HBsAg quantification, HBV DNA, liver function, and safety monitoring (every 12 weeks).

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatitis B, Chronic
• Intervention / Treatment: Drug: Pegylated Interferon-alpha (IFN)

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Wenghong Zhang, MD; Phone Number: 13801844344; Email: zhangwenhong@fudan.edu.cn

Study Locations

• China
  • Shanghai, China
    • Huashan Hospita
    • Contact: Wenhong Zhang, Professor; Phone Number: 13801844344; Email: zhangwenhong@fudan.edu.cn
    • Contact: Feng Sun, Doctor; Email: aaronsf1125@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years.
• Chronic HBV infection (documented HBsAg positivity for >6 months).
• Prior participation in ASO or siRNA clinical trials:
• Received ≥1 dose of ASO/siRNA (or matched placebo, if applicable).
• Achieved ≥1 log10 IU/mL HBsAg decline from baseline during prior therapy.
• Discontinued ASO/siRNA therapy before screening.
• Screening HBsAg: 0.05-500 IU/mL.
• No prior interferon (IFN) therapy within 6 months before enrollment.
• Willingness to comply with study-related treatments, tests, and procedures.
• Commitment to contraception during the study.
• Voluntary participation with signed informed consent.

Exclusion Criteria:

• Decompensated cirrhosis or hepatic malignancy (evidenced by imaging or histology within 6 months before/during screening).
• Elevated AFP: Screening AFP >100 ng/mL; AFP 20-100 ng/mL with imaging-confirmed hepatocellular carcinoma (ultrasound/CT/MRI).
• Coinfection with hepatitis A virus (HAV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV), or human immunodeficiency virus (HIV).
• Recent immunomodulatory therapy: Systemic corticosteroids, thymosin, or other potent immunomodulators for >2 weeks within 6 months before enrollment.
• Pregnancy, lactation, or plans for pregnancy during the study.
• Autoimmune hepatitis.
• Active autoimmune diseases (e.g., psoriasis, systemic lupus erythematosus).
• Uncontrolled cardiovascular disease (e.g., unstable angina, myocardial infarction within 6 months).
• Poorly controlled endocrine disorders (e.g., diabetes mellitus, thyroid dysfunction).
• Severe psychiatric disorders: History of depression, anxiety, bipolar disorder, schizophrenia, or family history of psychiatric conditions (especially depression).
• Substance abuse: Alcohol (>40 g/day for males; >20 g/day for females) or Illicit drug use.
• Severe retinopathy or ophthalmologic disorders.
• Renal diseases: Chronic nephritis, renal insufficiency, nephrotic syndrome.
• Major organ dysfunction (e.g., heart, lung, pancreas).
• Organ transplant recipients or candidates.
• Hypersensitivity to interferon or excipients.
• Concurrent participation in other HBV-related interventional trials.
• Other conditions deemed unsuitable by investigators (e.g., non-compliance risk).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A：Immediate PEG-IFNα Induction; Receive PEG-IFNα for 24 weeks, followed by 24-week treatment-free follow-up	Drug: Pegylated Interferon-alpha (IFN); pegylated interferon-alpha 180 μg once weekly for 24 weeks
Experimental: B: Deferred PEG-IFNα Initiation; Undergo 24-week observation, then receive PEG-IFNα for 24 weeks	Drug: Pegylated Interferon-alpha (IFN); pegylated interferon-alpha 180 μg once weekly for 24 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HBV DNA and HBsAg undetectable with/without anti-HBs	Proportion of patients achieving HBV DNA below the lower limit of quantification (LLOQ; <20 IU/mL), HBsAg undetectable (<0.05 IU/mL) (with or without anti-HBs seroconversion), and normal liver biochemical indices at Week 72.	week 72

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HBV DNA and HBsAg undetectable with/without anti-HBs during the study	Proportion of patients achieving HBV DNA <20 IU/mL, HBsAg <0.05 IU/mL (with or without anti-HBs), and normal liver biochemistry at Weeks 24, 48, and 96.	Weeks 24, 48, and 96
HBV DNA and HBsAg undetectable during the study	Proportion of patients achieving HBsAg <0.05 IU/mL and HBV DNA <20 IU/mL at Weeks 24, 48, 72, and 96.	Weeks 24, 48, 72, and 96
HBsAg level	HBsAg levels in each group at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
HBsAg decline from baseline	Magnitude of HBsAg decline from baseline in each group at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
HBsAg seroclearance	HBsAg seroclearance rate (HBsAg <0.05 IU/mL) in each group at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
HBsAg seroconversion	HBsAg seroconversion rate (anti-HBs ≥10 mIU/mL) in each group at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
HBeAg seroclearance	HBeAg seroclearance rate in baseline HBeAg-positive patients at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
HBeAg seroconversion	HBeAg seroconversion rate (anti-HBe positivity) in baseline HBeAg-positive patients at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
HBV DNA level	HBV DNA levels in each group at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
HBV DNA decline from baseline	Magnitude of HBV DNA decline from baseline in each group at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
HBV DNA undetectabe	HBV DNA undetectability rate (<20 IU/mL) in baseline HBV DNA-positive patients at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
ALT levels	ALT levels in each group at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
ALT normalization	ALT normalization rate (≤upper limit of normal [ULN]) in each group at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
ALT levels from baseline	Change in ALT levels from baseline in each group at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
saftey	Incidence of adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs) during the study, including findings from Physical examinations, Laboratory tests, Hematology, Urinalysis, Blood biochemistry, Coagulation profile	Weeks 24, 48, 72, and 96

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HBV RNA	HBV pregenomic RNA (pgRNA) levels in each group at Weeks 24, 48, 72, and 96.	Weeks 24, 48, 72, and 96
HBcrAg	HBV core-related antigen (HBcrAg) levels in each group at Weeks 24, 48, 72, and 96	Weeks 24, 48, 72, and 96
HBsAg-specific T-cell and B-cell	Longitudinal changes in HBsAg-specific T-cell and B-cell responses during the study	during the study
HBV quasispecies variations	Characterize HBV quasispecies variations	Weeks 24, 48, 72, and 96
proteomic profiles	Assess longitudinal changes in proteomic profiles during the study	Weeks 24, 48, 72, and 96
baseline GWAS	Analyze baseline genomic characteristics and GWAS (Genome-Wide Association Study) data of patients	baseline

Collaborators and Investigators

• Sponsor: Huashan Hospital
• Investigators: Principal Investigator: Jiming Zhang, MD, Huashan Hospital; Study Chair: Feng Sun, MD, Huashan Hospital; Study Director: Qiran Zhang, MD, Huashan Hospital; Principal Investigator: Wenghong Zhang, MD, Huashan Hospital; Principal Investigator: Yuxian Huang, MD, Huashan Hospital; Principal Investigator: Chao Qiu, Huashan Hospital; Study Director: Chen Chen, MD, Huashan Hospital

Publications and helpful links

General Publications

• Ning Q, Han M, Sun Y, Jiang J, Tan D, Hou J, Tang H, Sheng J, Zhao M. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial). J Hepatol. 2014 Oct;61(4):777-84. doi: 10.1016/j.jhep.2014.05.044. Epub 2014 Jun 7.
• Yuen MF, Lim SG, Plesniak R, Tsuji K, Janssen HLA, Pojoga C, Gadano A, Popescu CP, Stepanova T, Asselah T, Diaconescu G, Yim HJ, Heo J, Janczewska E, Wong A, Idriz N, Imamura M, Rizzardini G, Takaguchi K, Andreone P, Arbune M, Hou J, Park SJ, Vata A, Cremer J, Elston R, Lukic T, Quinn G, Maynard L, Kendrick S, Plein H, Campbell F, Paff M, Theodore D; B-Clear Study Group. Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection. N Engl J Med. 2022 Nov 24;387(21):1957-1968. doi: 10.1056/NEJMoa2210027. Epub 2022 Nov 8.
• Yuen MF, Lim YS, Yoon KT, Lim TH, Heo J, Tangkijvanich P, Tak WY, Thanawala V, Cloutier D, Mao S, Arizpe A, Cathcart AL, Gupta SV, Hwang C, Gane E. VIR-2218 (elebsiran) plus pegylated interferon-alfa-2a in participants with chronic hepatitis B virus infection: a phase 2 study. Lancet Gastroenterol Hepatol. 2024 Dec;9(12):1121-1132. doi: 10.1016/S2468-1253(24)00237-1. Epub 2024 Oct 8.
• Mak LY, Wooddell CI, Lenz O, Schluep T, Hamilton J, Davis HL, Mao X, Seto WK, Biermer M, Yuen MF. Long-term hepatitis B surface antigen response after finite treatment of ARC-520 or JNJ-3989. Gut. 2025 Feb 6;74(3):440-450. doi: 10.1136/gutjnl-2024-333026.
• 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.

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): May 31, 2028

Study Registration Dates

• First Submitted: April 3, 2025
• First Submitted That Met QC Criteria: April 9, 2025
• First Posted (Actual): April 11, 2025

Study Record Updates

• Last Update Posted (Actual): April 11, 2025
• Last Update Submitted That Met QC Criteria: April 9, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Blood-Borne Infections; Pathologic Processes; Chronic Disease; Disease Attributes; Infections; Virus Diseases; Digestive System Diseases; Liver Diseases; Hepatitis, Viral, Human; Communicable Diseases; DNA Virus Infections; Hepadnaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis B; Hepatitis B, Chronic; Anti-Infective Agents; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antiviral Agents; Interferons; Interferon-alpha
• Other Study ID Numbers: SPHERE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No