Effects of Telbivudine and Tenofovir Disproxil Fumarate on the Kinetics of Hepatitis B Virus DNA in Chronic Hepatitis B (CHB)

Chronic Hepatitis B Clinical Trial

Official title: A Randomized, Open-label, Controlled, Exploratory Trial to Characterize the Results of Daily Oral Administration of Telbivudine 600 mg and Tenofovir Disproxil Fumarate 300 mg in Combination or Telbivudine 600 mg or Tenofovir Disproxil Fumarate 300 mg Monotherapy Given Over 12 Weeks on the Kinetics of Hepatitis B Virus DNA in Adults With HBeAg Positive Compensated CHB

Status Completed

Clinical Trial Summary

The purpose of this study is to compare the safety, tolerability and effectiveness of 12 weeks of treatment with telbivudine 600 mg daily plus tenofovir DF 300 mg once daily (QD) taken together versus tenofovir DF 300 mg once daily (QD) or versus telbivudine 600 mg monotherapy daily (QD). This is an open-labeled, active controlled, viral kinetics study which means the subjects and study doctor will know what study drug subjects have been assigned. This study is open to male and female subjects, <40 years of age, who have been infected with HBV for at least 6 months and have not received oral treatment for HBV.

Clinical Trial Description

The primary goal of therapy for chronic hepatitis B (CHB) is suppression of viral replication. Long-term suppression of serum HBV DNA is likely to reduce progression to cirrhosis and hepatic decompensation and decrease the risk of hepatocellular carcinoma. Conventional treatment of chronic hepatitis B is limited by low rates of sustained hepatitis B virus DNA suppression and hepatitis B e antigen (HBeAg) seroconversion, increasing rates of drug resistance to the oral agents, and poor tolerability of interferon.

Currently, several nucleoside/nucleotide analogues are available for treatment of CHB. Typically, treatment is continued indefinitely since discontinuation is usually associated with relapse . However, the safety implications related to long term treatment are still unknown.

Previously published studies using combinations (peginterferon alpha-2a + lamivudine) (Marcellin 2004; Lau 2005; Janssen 2005) have shown combinations to be more potent in HBeAg loss at the end of dosing, than either agent used as monotherapy; off-treatment differences, however, did not persist. There are no treatment paradigms as yet of combination therapy with two nucleoside analogues for use in treatment-naive patients.

In summary, there is an unmet need for improved anti-HBV therapy and there are still several controversies such as treatment options, potential role of combination therapy versus monotherapy and optimal duration of therapy, among others. Clinical trials are underway to answer some of these questions. This study aims to assess whether or not combination therapy with telbuvudine and tenofovir DF has superior antiviral efficacy when compared to tenofovir DF or telbuvidine monotherapy. The study will also determine the safety of the combination of telbivudine and tenofovir disoproxil fumarate in patients with chronic hepatitis B. Patients in the immunotolerant phase of CHB will be include in the study. This phase is characterized for high viremia and normal transaminases. Since these patients are not considered as candidates for CHB therapy according to international guidelines (Lok et al 2007), treatment discontinuation after 12 weeks does not raise any unethical implications.

REFERENCES:

1. Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, Simon C, So TM, Gerken G, de Man RA, Niesters HG, Zondervan P, Hansen B, Schalm SW; HBV 99-01 Study Group; Rotterdam Foundation for Liver Research. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005 Jan 8-14;365(9454):123-9.

2. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW, Chang WY, Berg T, Flisiak R, McCloud P, Pluck N; Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005 Jun 30; 352(26):2682-95.

3. Lok AS, McMahon BJ. (2007) Chronic hepatitis. Hepatology 45(2):507-39.

4. Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, Lu ZM, Piratvisuth T, Germanidis G, Yurdaydin C, Diago M, Gurel S, Lai MY, Button P, Pluck N; Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004 Sep 16;351(12):1206-17.

Primary objectives:

The primary objective of this study is to characterize the reduction in HBV DNA level from Baseline to week 12 of telbivudine plus tenofovir DF combination therapy versus telbivudine or tenofovir DF monotherapy.

Secondary objectives:

Secondary objectives of the study include describing the following for telbivudine plus tenofovir DF combination therapy versus telbivudine or tenofovir DF monotherapy:

1. reduction in HBV DNA level from Baseline to Weeks 2, 4, and 8

2. characterization of early viral kinetics through estimation of various parameters such as efficiency of blocking new virus production, and half-lives of free virions and infected heptocytes

3. % patients who are PCR negative at Week 12 (defined as <25 copies/mL)

4. % of patients who achieve HBeAg loss and HBeAg seroconversion at Week 12

5. safety

Exploratory objectives:

1. To explore HBeAg and HBsAg levels over the treatment period as an additional potential predictor of efficacy.

2. To explore additional potential early serological and immunological markers for prediction of efficacy or safety. ;

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

• NCT number: NCT00804622
• Study type: Interventional
• Source: The University of Hong Kong
• Status: Completed
• Phase: Phase 2
• Start date: December 2008
• Completion date: March 2010