Effects of Telbivudine and Tenofovir Disproxil Fumarate on the Kinetics of Hepatitis B Virus DNA in Chronic Hepatitis B (CHB)
|Chronic Hepatitis B||Drug: telbivudine Drug: tenofovir disproxil fumarate Drug: telbivudine plus tenofovir disproxil fumarate||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|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|
- The primary variable is the reduction of HBV DNA level over 12 weeks of treatment [ Time Frame: 12 weeks ]
- Reduction in HBV DNA level [ Time Frame: from baseline to Weeks 2, 4 and 8 ]
- Characterization of very early viral kinetics through estimation of various parameters [ Time Frame: week 12 ]
- % patients who are PCR negative [ Time Frame: Week 12 ]
- % of patients who achieve HBeAg loss and HBeAg seroconversion [ Time Frame: Week 12 ]
|Study Start Date:||December 2008|
|Study Completion Date:||March 2010|
|Primary Completion Date:||June 2009 (Final data collection date for primary outcome measure)|
Active Comparator: 1
tenofovir disproxil fumarate 300 mg monotherapy
Drug: tenofovir disproxil fumarate
daily oral administration,300mg,over 12 weeks
Active Comparator: 2
telbivudine 600 mg monotherapy
daily oral administration,600mg,over 12 weeks
Active Comparator: 3
telbivudine 600 mg and tenofovir disproxil fumarate 300 mg
Drug: telbivudine plus tenofovir disproxil fumarate
daily oral administration of telbivudine 600 mg and tenofovir disproxil fumarate 300 mg in combination given over 12 weeks
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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.
- 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.
- 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.
- Lok AS, McMahon BJ. (2007) Chronic hepatitis. Hepatology 45(2):507-39.
- 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.
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 of the study include describing the following for telbivudine plus tenofovir DF combination therapy versus telbivudine or tenofovir DF monotherapy:
- reduction in HBV DNA level from Baseline to Weeks 2, 4, and 8
- 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
- % patients who are PCR negative at Week 12 (defined as <25 copies/mL)
- % of patients who achieve HBeAg loss and HBeAg seroconversion at Week 12
- To explore HBeAg and HBsAg levels over the treatment period as an additional potential predictor of efficacy.
- To explore additional potential early serological and immunological markers for prediction of efficacy or safety.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00804622
|Department of Medicine, Queen Mary Hospital|
|Hong Kong, China|
|Principal Investigator:||George Lau, MD||Department of Medicine, The University of Hong Kong|