Pegasys Plus Entecavir Versus Entecavir Versus Pegasys for Hepatitis B e Antigen-Negative Chronic Hepatitis B
Status:
Unknown status
Trial end date:
1969-12-31
Target enrollment:
Participant gender:
Summary
Currently, there are several antiviral treatments effective for suppression of viral
replication but still failed to cure HBV infection in patients with chronic hepatitis B
(CHB). Seven drugs have been worldwide approved for the treatment of CHB at present:
conventional IFN (IFN) alfa, lamivudine (LAM), adefovir dipivoxil (ADV), pegylated IFN
(Peg-IFN) alfa, entecavir (ETV), telbivudine (LdT) and tenofovir (TDF). Conventional or
Peg-IFN alfa monotherapy has a narrow range of efficacy, is associated with several adverse
effects and is inconvenient because of frequent injections. Oral nucleot(s)ide analogues (NA)
are better tolerated; but virologic response to NA is frequently not durable and prolonged
treatment is associated with the emergence of drug-resistant HBV mutants.
Although the best treatment choice for CHB is not clarified yet, certain therapeutic concepts
could be derived from the experience of treating patients with chronic hepatitis C or human
immunodeficiency virus (HIV) infection. A major advancement in treating hepatitis C or HIV
infection has been the development of combination therapy. Combination therapy has ever been
investigated in patients with CHB, but again the optimal strategy remains to be identified.
Entecavir, a carbocyclic deoxyguanosine NA, is one of the most potent anti-HBV agents ever
discovered. In addition, the 6-year drug resistance rate is 1.2% in selected lamivudine-naïve
cohorts. Pegylated interferon alfa-2a possesses both antiviral and immunomodulatory effects.
Overall, satisfactory virologic and serologic responses could be achieved using pegylated IFN
alfa in around 30-44% of these patients. Whether the combination therapy using Peg-IFN
alfa-2a plus ETV can achieve a long-term beneficial effect against ETV or Peg-IFN alfa-2a
alone is not clarified. A prior single-arm pilot study suggested that similar combination
therapy may be beneficial in patients with CHB. In this proposal, the investigators thus
hypothesize that the efficacy by using combination therapy with Peg-IFN alfa-2a plus
prolonged ETV is superior to that by using ETV or Peg-IFN alfa-2a alone in that Peg-IFN may
restore host immunity against HBV and prolonged ETV can maximize viral suppression.
The objective of this clinical trial is to evaluate the efficacy of the combination of
Peg-IFN alfa-2a at a dose of 180 mcg administered subcutaneously per week and ETV 0.5 mg
daily for 48 weeks followed by ETV 0.5 mg daily monotherapy for an additional 96 weeks versus
ETV 0.5 mg daily monotherapy for 144 weeks or Peg-IFN alfa-2a 180 mcg per week for 48 weeks
in patients with HBeAg-negative CHB. It will be an open-label, randomized, comparative,
multi-center clinical trial. The recruited patients will be equally randomized into three
treatment groups. Treatment-free follow-up period will be 48 weeks in both groups of
patients. The primary parameter is the "Simultaneous achievement of HBsAg titer below 100
IU/ml and HBV DNA below 300 IU/ml at 144 weeks after start of treatment", by an
intention-to-treat analysis. Genotypic and virologic resistance to ETV will also be assessed
at baseline and at end of years 1, 2 and 3.
The investigators anticipate that the rate of HBsAg <100 IU/mL plus HBV DNA <300 IU/mL at 3
years of the study period will be 30% for patients receiving Peg-IFN therapy and increased to
be 45% for patients receiving Peg-IFN plus entecavir therapy. With a 5% nominal significance
level (two-sided), 163 patients per group under a 1:1:1 ratio will provide 80% power to
detect a difference of 15% in treatment response rates between group I and III. Because this
will be a 4-year study for each patient, the investigators thus anticipate that the dropout
rate may be as high as 10%. Accordingly, a total of 540 (180x3) patients will be recruited,
in order to account for a dropout rate of up to10%.