Tenofovir Versus Tenofovir + Telbivudine for Chronic Hepatitis B

NCT02774837 | Unknown Phase 4

• 1 other identifier: 2013/00215
• Study Type: interventional
• Target: 146
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Chronic Hepatitis B

Keywords

nucleoside analogues; tenofovir; telbivudine; quantitative HBsAg; combination therapy

Outcome Measures

Primary Outcomes (1)

• quantitative HBsAg (qHBsAg) reduction >1 log IU/ml

  Proportion of patients who have a reduction of qHBsAg \>1 log IU/ml from baseline to week 96, in experimental arm versus control arm

  Baseline to week 96

Secondary Outcomes (6)

• HBsAg loss

  Baseline to week 96

• HBsAg seroconversion

  Baseline to week 96

• HBeAg loss

  Baseline to week 96

• HBeAg seroconversion

  Baseline to week 96

• quantitative HBsAg decline by >0.5 log10 IU/mL

  Baseline, week 24, 48 and 96

Study Arms (2)

combination

EXPERIMENTAL

Tenofovir disoproxil oral tablets 300mg once daily for 96 weeks and Telbivudine 600mg oral tablets once daily for 96 weeks

Drug: Tenofovir disoproxil; Drug: Telbivudine

mono therapy

ACTIVE COMPARATOR

Tenofovir disoproxil oral tablets 300mg once daily for 96 weeks

Drug: Tenofovir disoproxil

Interventions

Tenofovir disoproxil DRUG

Tenofovir disoproxil 300mg once daily for 96 weeks

Also known as: Viread

combination; mono therapy

Telbivudine DRUG

Telbivudine oral tablets 600mg once daily for 96 weeks

Also known as: Sebivo

combination

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Seng Gee Lim: lead
• National Medical Research Council (NMRC), Singapore: collaborator
• Singapore Clinical Research Institute: collaborator

Study Sites (1)

National University Hospital

Singapore, 119228, Singapore

Location

Related Publications (7)

• European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012 Jul;57(1):167-85. doi: 10.1016/j.jhep.2012.02.010. Epub 2012 Mar 20. No abstract available.

  PMID: 22436845 BACKGROUND

• Piratvisuth T, Komolmit P, Tanwandee T, Sukeepaisarnjaroen W, Chan HL, Pessoa MG, Fassio E, Ono SK, Bessone F, Daruich J, Zeuzem S, Cheinquer H, Pathan R, Dong Y, Trylesinski A. 52-week efficacy and safety of telbivudine with conditional tenofovir intensification at week 24 in HBeAg-positive chronic hepatitis B. PLoS One. 2013;8(2):e54279. doi: 10.1371/journal.pone.0054279. Epub 2013 Feb 4.

  PMID: 23390496 BACKGROUND

• Liaw YF. Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review. Hepatology. 2011 Aug;54(2):E1-9. doi: 10.1002/hep.24473.

  PMID: 21793018 BACKGROUND

• Chan HL, Thompson A, Martinot-Peignoux M, Piratvisuth T, Cornberg M, Brunetto MR, Tillmann HL, Kao JH, Jia JD, Wedemeyer H, Locarnini S, Janssen HL, Marcellin P. Hepatitis B surface antigen quantification: why and how to use it in 2011 - a core group report. J Hepatol. 2011 Nov;55(5):1121-31. doi: 10.1016/j.jhep.2011.06.006. Epub 2011 Jun 28.

  PMID: 21718667 BACKGROUND

• Wursthorn K, Jung M, Riva A, Goodman ZD, Lopez P, Bao W, Manns MP, Wedemeyer H, Naoumov NV. Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. Hepatology. 2010 Nov;52(5):1611-20. doi: 10.1002/hep.23905.

  PMID: 20931556 BACKGROUND

• Gane EJ, Deray G, Liaw YF, Lim SG, Lai CL, Rasenack J, Wang Y, Papatheodoridis G, Di Bisceglie A, Buti M, Samuel D, Uddin A, Bosset S, Trylesinski A. Telbivudine improves renal function in patients with chronic hepatitis B. Gastroenterology. 2014 Jan;146(1):138-146.e5. doi: 10.1053/j.gastro.2013.09.031. Epub 2013 Sep 22.

  PMID: 24067879 BACKGROUND

• Gara N, Zhao X, Collins MT, Chong WH, Kleiner DE, Jake Liang T, Ghany MG, Hoofnagle JH. Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. Aliment Pharmacol Ther. 2012 Jun;35(11):1317-25. doi: 10.1111/j.1365-2036.2012.05093.x. Epub 2012 Apr 16.

  PMID: 22506503 BACKGROUND

MeSH Terms

Conditions

Hepatitis B, Chronic

Interventions

Tenofovir; Telbivudine

Condition Hierarchy (Ancestors)

Hepatitis B; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Seng Gee Lim, MBBS, FRACP, FRCP, MD, FAMS

  National University Health System

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director of Hepatology

Model Details: Two arm parallel study

Study Record Dates

• First Submitted: May 12, 2016
• First Posted: May 17, 2016
• Study Start: April 1, 2016
• Primary Completion: July 1, 2020
• Study Completion: July 1, 2020
• Last Updated: March 18, 2019

Record last verified: 2019-03

Locations

SG (1)