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

Official title

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

Overview

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).

Interventions

• Drug Pegylated Interferon-alpha (IFN)
  pegylated interferon-alpha 180 μg once weekly for 24 weeks

Primary outcome measures

• HBV DNA and HBsAg undetectable with/without anti-HBs [Time frame: week 72]

Secondary outcome measures (12)

• HBV DNA and HBsAg undetectable with/without anti-HBs during the study [Time frame: Weeks 24, 48, and 96]
• HBV DNA and HBsAg undetectable during the study [Time frame: Weeks 24, 48, 72, and 96]
• HBsAg level [Time frame: Weeks 24, 48, 72, and 96]
• HBsAg decline from baseline [Time frame: Weeks 24, 48, 72, and 96]
• HBsAg seroclearance [Time frame: Weeks 24, 48, 72, and 96]
• HBsAg seroconversion [Time frame: Weeks 24, 48, 72, and 96]
• HBeAg seroclearance [Time frame: Weeks 24, 48, 72, and 96]
• HBeAg seroconversion [Time frame: Weeks 24, 48, 72, and 96]
• HBV DNA level [Time frame: Weeks 24, 48, 72, and 96]
• HBV DNA decline from baseline [Time frame: Weeks 24, 48, 72, and 96]
• HBV DNA undetectabe [Time frame: Weeks 24, 48, 72, and 96]
• ALT levels [Time frame: Weeks 24, 48, 72, and 96]

Eligibility criteria

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: 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.

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Treatment

Study locations

China · 2 centers

• Beijing Ditan Hospital — Beijing
• Huashan Hospita — Shanghai

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. PMID 24915612
• 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
• 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
• 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. Sequent PMID 39214467
• 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 Bep PMID 36346079
• 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 (SPHER PMID 42176181

Identifiers

NCT: NCT06923280 · SPHERE

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗