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Prospective Randomized Open-label Trial Protocol Investigating the Addition of Pegylated Interferon-alpha to an Ongoing Nucleos(t)ide Treatment Regimen of HBeAg Negative Chronic Hepatitis B Patients (PADD-ON)

Martin F Sprinzl, Annette Grambihler, Jens M. Kittner, Daniel Wachtlin, Christian Ruckes, Jörn Schattenberg, Anne Ehrlich, Ulrich Alshuth, Marcus Wörns, Marcus Schuchmann and Peter R Galle

Background: Hepatitis B surface antigen (HBsAg) clearance marks the prime event of HBV elimination in chronic hepatitis B and is associated with better overall outcome. Despite reliable viral suppression under standard treatment with nucleos(t)ide analogues (NUCs) the goal of HBsAg clearance is rarely achieved. Also synchronous combination of NUCs with pegylated interferon-α-2a (peg-IFNα) has not been superior compared to peg-IFNα monotherapy in prospective randomized trials. However, sequential addition of peg-IFNα to an ongoing NUC regimen has provided higher HBsAg clearance rates in uncontrolled pilot studies.

Methods/Design: In this protocol we investigate the sequential addition of open-label peg-IFNα for 48 weeks to an ongoing NUC regimen following patients written informed consent. Included are patients with HBeAg negative chronic hepatitis B and a suppressed HBV DNA (<20 IU/mL) for a minimum of 12 months under NUCs prior to trial enrollment. Patients are randomized (2:1 ratio) to peg-IFNα add-on/ NUC treatment or a control group receiving continuous NUCs only. Patients are followed regularly during the trial intervention including a per protocol follow-up for 24 weeks after end of treatment. The primary endpoint is the objective response after 48 weeks of combination therapy, defined by a confirmed reduction of HBsAg by ≥ 1log10 IU/mL compared to baseline. Secondary endpoints are the HBsAg seroconversion rate, safety and tolerability of the IFN add-on therapy regimen. The trial was approved by the local ethic committees of all participating study sites.

Trial registration: The trial was registered on the 10th of June 2011 at EudraCT (ID number 2011-002812-10).