Tenofovir Versus Tenofovir + Telbivudine for Chronic Hepatitis B

• Status: Unknown status
• Trial end date: 2020-07-01
• Target enrollment: 0
• Participant gender: All

Summary

Chronic Hepatitis B is the most common cause of chronic viral liver disease worldwide afflicting 350 million persons, leading to significant morbidity and mortality due to liver disease and HCC in 20-40% of infected persons. With the advent of nucleoside analogues, this rescued patients with significant risk of disease progression, but in most circumstances, therapy was needed long term as HBsAg seroclearance was an uncommon occurrence, and stopping therapy was associated with relapse of disease and hepatitis B flares. The use of pegylated interferons showed increased HBeAg seroconversion and HBsAg seroclearance rates compared to nucleoside analogues , however combination nucleos(t)ide analogue therapy has been quite disappointing. However a recent showed that the combination of telbivudine and tenofovir in a response guided therapy design, had a remarkable 6% HBsAg seroclearance at week 52 in patients. Such results require further confirmation. There is currently an unmet need for the large number of patients on long term nucleoside analogue therapy who have not achieved HBeAg seroconversion or HBsAg seroclearance. Such patients are seeking alternatives to long term therapy hence an exploration of other therapeutic strategies is attractive. An additional benefit of telbivudine has been the surprising improvement in renal function and this study seeks to examine whether this can improve the renal impairment that may be seen with tenofovir. Our study proposes to examine if the combination of tenofovir and telbivudine can improve endpoints. Patients fulfilling inclusion and exclusion criteria will be randomized to tenofovir or tenofovir and telbivudine (1:1 ratio). The primary endpoint will be a qHBsAg reduction of >1log at week 96, which may predict future HBsAg seroclearance, which is also a secondary endpoint. An additional primary endpoint is increase in eGFR in the combination arm compared to the monotherapy arm. The study aims to enroll 146 patients randomized 1:1 ratio (73:73) patients. Multivariate analysis will be performed of baseline and on-treatment factors that predict the primary outcome.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Seng Gee Lim
• Collaborators: National Medical Research Council (NMRC), Singapore; Singapore Clinical Research Institute
• Treatments: Telbivudine; Tenofovir

Criteria

Inclusion Criteria:

• Presence of positive HBsAg or HBV DNA for at least 6 months.

• Documented HBeAg positive or HBeAg negative.

• On any NA (lamivudine, adefovir, entecavir, tenofovir or combination of any of these four) for ≥ 1 year

• HBV DNA viral load ≤1.0 x 10^5 copies/ml at screening

• ALT ≤ 1 x ULN (upper limit normal) U/L

• A transient elastography (Fibroscan®) to evaluate the fibrosis stage will be performed at screening if it is not done in the past 6 months prior to screening. -Patient with compensated cirrhosis are permitted for this study.

• eGFR ≥ 50 mL/min, as calculated by CKI-EPI equation.

• Patient has agreed not to take any other investigational drug or systemic anti-viral, cytotoxic, corticosteroid, immunomodulatory agents or Chinese traditional remedies unless clinically indicated.

• Patient is able to give written consent prior to study start and to comply with the study requirements.

• Women of childbearing potential age must have a negative serum (ß-HCG) pregnancy test taken within 14 days of starting therapy

• Lactating/breastfeeding female subjects must agree to discontinue nursing before initiation of study medication(s).

Exclusion Criteria:

• Evidence of decompensated liver disease defined as direct (conjugated) bilirubin >1.2xULN, prothrombin time (PT) >1.5x upper limit of normal (ULN), serum albumin <35 g/L, or prior history of clinical hepatic decompensation (egs. ascites, encephalopathy, variceal hemorrhage).

• Evidence of hepatocellular carcinoma (HCC).

• Have any of the following laboratory tests within 4 weeks of study entry:

• Active co-infection with HIV antibody or HCV antibody or HDV antibody positivity

• Evidence of chronic renal insufficiency as defined by an eGFR (by CKD-EPI equation of < 50 mL/min).

• Previous treatment with any form of interferon, Immunomodulators, systemic cytotoxic agents, or systemic corticosteroids within 6 months prior to screening.

• Prolonged exposure to known hepatotoxins such as alcohol or drugs.

• History of clinically relevant psychiatric disease, seizures, central nervous system dysfunction, severe pre-existing cardiac, renal, hematological disease or medical illness that in the investigator's opinion might interfere with therapy.

• Current or known history of malignant disease within 5 years of trial entry.

• Patients with a history of or currently known muscle related disease.

• Liver or any other organ transplant other than cornea and hair.

• Women who are pregnant and who are not practicing adequate birth control measures, or who are lactating.

• Patients with specific contraindications to study drugs according to their Singapore Package Insert.