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.

introductionAlthough novel targeted therapies such as antisense oligonucleotides (ASO) or small interfering RNA (siRNA) can rapidly reduce hepatitis B surface antigen (HBsAg), only a subset of patients can achieve HBsAg seroclearance, and recurrence is common after discontinuation. This trial aims to evaluate the efficacy and safety of sequencing pegylated interferon alpha (Peg-IFNα) as rescue therapy for patients who have not achieved functional cure after initial therapy with ASO or siRNA.

methodsThis is a prospective, multicentre, open-label, non-inferiority randomized controlled trial. Patients with chronic hepatitis B (CHB) who have previously completed a full course of ASO or siRNA therapy with HBsAg level of 1-500 IU/mL at screening will be enrolled. Participants will be randomized 1:1 to two arms: those in arm A (immediate treatment arm) will receive 24 weeks of Peg-IFNα starting at enrolment, followed by 24 weeks off-treatment observation; participants in arm B (delayed treatment arm) will firstly be observed for 24 weeks then followed by 24 weeks of Peg-IFNα treatment. At week 48, those with HBsAg seroclearance will enter a 48-week treatment-free follow-up, while those without seroclearance, regardless of initial arm, will receive an additional 24 weeks of Peg-IFNα, followed by 24 weeks off-treatment observation after week 72. The primary endpoint is the proportion of participants achieving HBV DNA < 20 IU/mL, HBsAg < 0.05 IU/mL and normal ALT at week 72. Secondary endpoints are HBsAg clearance rates, changes in clinical indicators, and safety evaluation results at other time points including weeks 24, 48 and 96. Sample size was calculated using Bayesian methods with the following parameters: experimental group response rate 0.57, control group response rate 0.47, non-inferiority margin 0.1, power 0.8, α = 0.05 and required posterior probability ≥ 80%. The single-group sample size was 33, and considering a 10% dropout rate, the total sample size was set to 72 (36 per group). Statistical analysis will be based on Bayesian non-inferiority test, with the primary judgment criterion being a posterior probability of ≥ 80% that the experimental group is non-inferior to the control group. PLANNED OUTCOMES: Successful completion of this trial will provide a viable rescue treatment option for patients who have not met treatment goals after ASO or siRNA therapy. It may complete the future therapeutic framework, bringing more patients, especially those who are difficult-to-treat, within the scope of functional cure.

trial registrationClinicalTrials.gov identifier NCT06923280.