Study to Evaluate Efficacy, Safety and Biomarkers of Bulevirtide Treatment in Chronic Hepatitis D Patients

Chronic hepatitis D (CHD) is considered to be the most severe form of hepatitis. It is a rare disease in European Union countries, with status of an orphan disease. Historically, only pegylated interferon alfa-2a (PEG-IFNα-2a) +/- nucleos(t)ide analogues (NA) have been used off-label for treatment of CHD, with insufficient virological response and frequent relapse. The first in class entry inhibitor for treatment of CHD, bulevirtide (BLV), product name Hepcludex) has received status of conditional marketing authorization by the European Medical Agency (EMA) in July 2020.

This conditional approval was based on two phase 2 studies, with limited sample sizes. A phase 3 clinical trial of 150 participants is ongoing.

Besides need of more efficacy and safety data, knowledge about immunological cellular response in BLV treated and identification of biomarkers for treatment response is needed. Observational studies with biological samplings are thus needed.

We aimed therefore to assess the efficacy and specific safety in an observational study with prospective follow-up, with antiviral treatment of 2 mg BLV +/- PEG-IFNα-2a and +/- NA given as part of the patient's routine medical care. Also, explorative endpoints of biomarkers in peripheral blood, saliva, fecal sample and/or intrahepatic markers/signatures, and quality of life outcomes will be assessed.

• Percentage of patients with virological response of HDV RNA < LoD [Time frame: At Baseline, 1 and 3 months, every 3 months after treatment start up to 9 months after date of EOT.]
• Percentage of patients with Hepatitis B surface antigen (HBsAg) < LoD [Time frame: At Baseline, 1 and 3 months, every 3 months after treatment start up to 12 months after date of EOT.]
• Change of HBsAg from baseline [Time frame: From Baseline every 3 months until end of study.]
• Percentage of patients with HDV RNA < LoD or HDV RNA reduction of at least 2 log10 compared to baseline [Time frame: At Baseline, 1 and 3 months, every 3 months after treatment start up to 12 months after date of EOT.]
• Percentage of patients with virological relapse, defined as HDV RNA < LoD at EOT and increase of HDV RNA to > LoD after EOT [Time frame: At 0, 3, 6, 9 and 12 months after date of EOT.]
• Percentage of patients with appearance of hepatitis B surface antibody (anti-HBs) [Time frame: At 0, 3, 6, 9 and 12 months after date of EOT.]
• Percentage of patients with HBV DNA level < LoD [Time frame: From Baseline every 3 months until end of study.]
• Percentage of patients with biochemical response, defined as normalization of alanine transaminase (ALT) [Time frame: At Baseline, 1 and 3 months, every 3 months up to 12 months after date of EOT.]
• Percentage of patients with combined response, defined as HDV RNA < LoD or HDV RNA reduction of at least 2 log10 compared to baseline and Alanine Aminotransferase (ALT) normalization [Time frame: At Baseline, at 1, 2 and 3 months, every 3 months up to 12 months after date of EOT.]
• Change of liver elasticity measurement level and percentage of AE of special interest [Time frame: At Baseline, every 6 months until 12 months after date of EOT.]
• Percentage of missed BLV doses during treatment [Time frame: Continuously during treatment period until date of EOT.]
• Percentage of patients with early discontinuation of treatment [Time frame: Continuously during treatment period until date of EOT.]