Tenofovir Versus Tenofovir + Telbivudine for Chronic Hepatitis B (DUAL)

March 14, 2019 updated by: Seng Gee Lim

Open Label Study of Nucleus(t)Ide Treated Patients Randomised to Tenofovir, or Tenofovir + Telbivudine

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Each subject must sign and date a study-specific informed consent form (ICF) prior to their participation in any screening activities. Prospective subjects should be screened no more than 28 days prior to administration of the first dose of study drug on Day 1. Screening evaluations will be used to determine eligibility of each candidate for study enrollment. Subjects meeting all of the inclusion criteria and none of the exclusion criteria as determined during screening will be eligible for the study. Candidates who fail to meet eligibility criteria by screening evaluations may be re-screened one time. Eligible patients at the end of screening will be randomised in a 1:1 ratio to experimental (combination) arm versus control (mono therapy) arm.

Randomisation will be performed by computer generated random codes (performed by Singapore Clinical Research Institute) with a masked allocation sequence. There will be no blinding of therapy and the study will be conducted as an open label study since the outcomes are objectively measurable.

After randomisation patients will be monitored 12 weekly for the first 24 weeks, then every 24 weekly until the last visit at 96 weeks.

At each visit, patients will have a clinical evaluation and have a panel of laboratory tests:

  • Hematology: Full blood count, prothrombin time and international normalized ratio
  • Chemistry: Sodium, potassium, creatinine, albumin, alkaline phosphatase, -aspartate transaminase, alanine transaminase, lactate dehydrogenase, total bilirubin, creatine phosphokinase, alphafetoprotein,
  • Urinalysis: Urine dipstick (Appearance, color, leucocytes, nitrite, urobilinogen, protein, PH, specific gravity, ketone, bilirubin and glucose).
  • Viral serology: HBeAg, anti-HBe, HBsAg, qHBsAg and anti-HBs

Study Type

Interventional

Enrollment (Actual)

146

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Singapore
      • Singapore, Singapore, 119228
        • National University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: combination
Tenofovir disoproxil oral tablets 300mg once daily for 96 weeks and Telbivudine 600mg oral tablets once daily for 96 weeks
Drug: Tenofovir disoproxil
Tenofovir disoproxil 300mg once daily for 96 weeks
Other Names:
  • Viread
Drug: Telbivudine
Telbivudine oral tablets 600mg once daily for 96 weeks
Other Names:
  • Sebivo
Active Comparator: mono therapy
Tenofovir disoproxil oral tablets 300mg once daily for 96 weeks
Drug: Tenofovir disoproxil
Tenofovir disoproxil 300mg once daily for 96 weeks
Other Names:
  • Viread

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
quantitative HBsAg (qHBsAg) reduction >1 log IU/ml
Time Frame: Baseline to week 96
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
HBsAg loss
Time Frame: Baseline to week 96
Proportion of patients who achieve HBsAg loss at week 96 in experimental versus control arms
Baseline to week 96
HBsAg seroconversion
Time Frame: Baseline to week 96
Proportion of patients who achieve HBsAg seroconversion at week 96 in experimental versus control arms
Baseline to week 96
HBeAg loss
Time Frame: Baseline to week 96
Proportion of patients who achieve HBeAg loss at week 96 in experimental versus control arms
Baseline to week 96
HBeAg seroconversion
Time Frame: Baseline to week 96
Proportion of patients who achieve HBeAg seroconversion at week 96 in experimental versus control arms
Baseline to week 96
quantitative HBsAg decline by >0.5 log10 IU/mL
Time Frame: Baseline, week 24, 48 and 96
Proportion of patients who have a reduction of qHBsAg >0.5 log IU/ml from baseline to week 96, in experimental arm versus control arm
Baseline, week 24, 48 and 96
Alteration in eGFR
Time Frame: Baseline to week 96
Proportion of patients who have an increase in eGFR from baseline to week 96, in experimental arm versus control arm
Baseline to week 96

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Seng Gee Lim

Collaborators

National Medical Research Council (NMRC), Singapore
Singapore Clinical Research Institute

Investigators

  • Principal Investigator: Seng Gee Lim, MBBS, FRACP, FRCP, MD, FAMS, National University Health System

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2016

Primary Completion (Anticipated)

July 1, 2020

Study Completion (Anticipated)

July 1, 2020

Study Registration Dates

First Submitted

May 12, 2016

First Submitted That Met QC Criteria

May 16, 2016

First Posted (Estimate)

May 17, 2016

Study Record Updates

Last Update Posted (Actual)

March 18, 2019

Last Update Submitted That Met QC Criteria

March 14, 2019

Last Verified

March 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2013/00215

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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