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

NCT06923280 | Recruiting

• 1 other identifier: SPHERE
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 2

Brief Summary

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:

• 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).

Conditions

Hepatitis B, Chronic

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (16)

• HBV DNA and HBsAg undetectable with/without anti-HBs during the study

  Weeks 24, 48, and 96

• HBV DNA and HBsAg undetectable during the study

  Weeks 24, 48, 72, and 96

• HBsAg level

  Weeks 24, 48, 72, and 96

• HBsAg decline from baseline

  Weeks 24, 48, 72, and 96

• HBsAg seroclearance

  Weeks 24, 48, 72, and 96

Other Outcomes (6)

• HBV RNA

  Weeks 24, 48, 72, and 96

• HBcrAg

  Weeks 24, 48, 72, and 96

• HBsAg-specific T-cell and B-cell

  during the study

Study Arms (2)

A：Immediate PEG-IFNα Induction

EXPERIMENTAL

Receive PEG-IFNα for 24 weeks, followed by 24-week treatment-free follow-up

Drug: Pegylated Interferon-alpha (IFN)

B: Deferred PEG-IFNα Initiation

EXPERIMENTAL

Undergo 24-week observation, then receive PEG-IFNα for 24 weeks

Drug: Pegylated Interferon-alpha (IFN)

Interventions

Pegylated Interferon-alpha (IFN) DRUG

pegylated interferon-alpha 180 μg once weekly for 24 weeks

A：Immediate PEG-IFNα Induction; B: Deferred PEG-IFNα Initiation

Eligibility Criteria

• Age: 18 Years - 80 Years
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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: 1-500 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Huashan Hospital: lead

Study Sites (2)

Beijing Ditan Hospital

Beijing, China, China

RECRUITING

Huashan Hospita

Shanghai, China, China

RECRUITING

Related Publications (6)

• 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.

  PMID: 24915612 BACKGROUND

• 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.

  PMID: 39389081 BACKGROUND

• 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.

  PMID: 39266050 BACKGROUND

• 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.

  PMID: 39214467 BACKGROUND

• 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.

  PMID: 36346079 BACKGROUND

• Zhang Q, Sun F, Sui S, Lin J, Wu C, Yuan J, He Y, Shang J, Han T, Zhu Y, Huang Z, Chen C, Qiu C, Wang X, Zhang J, Xie Y, Zhang W. Efficacy and Safety of Pegylated Interferon as Rescue Therapy for Patients with Chronic Hepatitis B Who Failed to Achieve Functional Cure After Antisense Oligonucleotides or Small Interfering RNA: A Prospective, Multicentre, Open-Label Randomized Controlled Trial (SPHERE) Protocol. Adv Ther. 2026 May 23. doi: 10.1007/s12325-026-03633-0. Online ahead of print.

  PMID: 42176181 DERIVED

MeSH Terms

Conditions

Hepatitis B, Chronic

Condition Hierarchy (Ancestors)

Hepatitis B; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Wenghong Zhang, MD

  Huashan Hospital

  PRINCIPAL INVESTIGATOR

• Jiming Zhang, MD

  Huashan Hospital

  PRINCIPAL INVESTIGATOR

• Yuxian Huang, MD

  Huashan Hospital

  PRINCIPAL INVESTIGATOR

• Feng Sun, MD

  Huashan Hospital

  STUDY CHAIR

• Chao Qiu

  Huashan Hospital

  PRINCIPAL INVESTIGATOR

• Chen Chen, MD

  Huashan Hospital

  STUDY DIRECTOR

• Qiran Zhang, MD

  Huashan Hospital

  STUDY DIRECTOR

Central Study Contacts

Wenghong Zhang, MD

CONTACT

13801844344; zhangwenhong@fudan.edu.cn

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Division of Infectious Diseases

Study Record Dates

• First Submitted: April 3, 2025
• First Posted: April 11, 2025
• Study Start: August 25, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): May 31, 2029
• Last Updated: July 29, 2026

Record last verified: 2026-07

Locations

CN (2)