To investigate the use of a temporary peginterferon alpha-2a add-on strategy during entecavir therapy in patients with HBeAg-positive chronic hepatitis B by comparing the efficacy of this regimen versus entecavir monotherapy.To evaluate the long-…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The combined presence of HBV DNA level < 200 IU/mL and HBeAg loss at week 48
According to amendment 5:
1. HBeAg loss and presence of HBV DNA level <200 IU/ml
Secondary outcome
• ALT normalization
• Undetectable HBV DNA (* 60 IU/mL)
• HBsAg and HBeAg loss from serum
• The emergence of HBV polymerase mutations associated with reduced
susceptibility to entecavir
• Sustained response defined as the combined presence of HBV DNA level < 200
IU/mL and HBeAg loss at week 96
According to amendment 5:
2. HBeAg seroconversion (HBeAg negative & anti-HBe positive)
3. Serum HBsAg levels
4. HBsAg loss and/or seroconversion
5. Reconversion to HBeAg positivity after initial HBeAg loss (sustainability of
response)
6. HBV DNA negativity (<20IU/ml as measured by PCR)
7. Regression of fibrosis and inflammation in liver biopsy
8. Liver failure, Hepatocellular carcinoma, liver transplantation, death
9. IL28B and other genetic variations in relation to points 1-8.
Background summary
Entecavir is cyclopentyl guanosine analogue, and a potent and selective
inhibitor of viral replication in vitro.(1) In one study of 709 HBeAg-positive
chronic hepatitis B patients entecavir showed superior antiviral efficacy
compared to lamivudine, demonstrating undetectable serum HBV DNA (< 300
copies/mL) in 67%, and HBeAg-seroconversion in 21% of patients after 48 weeks
of treatment.(2) Although treatment with nucleoside analogues profoundly
suppresses serum HBV DNA levels and response can be maintained over prolonged
periods with ongoing therapy, response to treatment
may not be durable in a large proportion of patients after discontinuation of
therapy.(3, 4) In contrast, antiviral potency of peginterferon (PEG-IFN) is
inferior to nucleoside analogues, but response to PEG-IFN probably is more
durable in the majority of patients due to its immunomodulatory effects.
However, sustained HBeAgseroconversion can only be achieved in about 30% of
PEG-IFN treated patients.(5, 6) HBV-specific T-cell response plays a crucial
role in control of viral infection. Viral persistence is believed to be
associated with functional tolerance of helper T (TH) cell and cytotoxic
T-lymphocytes (CTL) to HBV.(7) In chronic HBV infected patients levels of
HBV-specific TH and CTL are generally low and T-cell response can be
antigenically restricted.(8) Treatment with a nucleoside analogue and
subsequent viral decline has shown to restore helper T-cell (TH-cell) and
cytotoxic T-cell (CTL) responsiveness in chronic HBV infected patients.(9-11)
Add-on treatment with PEG-IFN can be expected to further stimulate adaptive
immune reactivity and may therefore result in higher rates of response.
Recent pilot studies investigating the effect of lowering viral load with
nucleoside analogue therapy prior to the initiation of PEG-IFN showed
contradictory findings. A study by Sarin et al. showed a significantly higher
rate of sustained HBeAg loss in patients who received 4 weeks of lamivudine
before PEG-IFN therapy (n=36) compared to those receiving placebo for 4 weeks
(n=27) (36% vs. 15%, p=0.05).(12) However, in a study by Chan et al. sustained
HBeAg seroconversion occurred in only 1 of 10 patients (10%) treated with
lamivudine for 8 weeks prior to PEG-IFN therapy, while HBeAg seroconversion was
observed in 6 of 9 patients (67%) who started lamivudine and PEG-IFN
simultaneously (p=0.04).(13) It is unknown whether a temporary peginterferon
alpha-2a add-on strategy during entecavir therapy increases response rates
compared to entecavir monotherapy.
The ARES study is the first study to investigate a PEG-IFN add-on strategy in
patients who are treated with ETV. As such, little is known about the
long-term durability of response and safety with this approach. It is
important to investigate whether the patients in the add-on arm achieve more
HBsAg-loss in the long-term as compared to patients treated within the
ETV-monotherapy arm. Therefore, our aim is to evaluate the long-term
durability of response and safety in these patients.
Study objective
To investigate the use of a temporary peginterferon alpha-2a add-on strategy
during entecavir therapy in patients with HBeAg-positive chronic hepatitis B by
comparing the efficacy of this regimen versus entecavir monotherapy.
To evaluate the long-term durability of response and the late response of
patients treated within the Ares study.
Study design
Multicenter randomized, open-label, phase III study with two treatment arms
- long term follow up
Intervention
A temporary peginterferon alpha-2a add-on strategy during entecavir therapy for
24 weeks
Study burden and risks
Patients will be treated with peginterferon alfa-2a, which is an antiviral
agent with a lot of side effects. Furthermore, patients will have to visit the
outpatient clinic more frequently (9 times in case a subject is treated with
entecavir and receives a temporary peginterferon add-on strategy; only 2 times
in case a subject is treated with entecavir monotherapy). During every visit
blood will be drawn. A liver biopsy will be done at baseline and at week 52.
No burden of risk during the long term follow up extension.
's Gravendijkwal 230
Rotterdam 3015 CE
NL
's Gravendijkwal 230
Rotterdam 3015 CE
NL
Listed location countries
Age
Inclusion criteria
• Chronic hepatitis B (HBsAg positive > 6 months)
• HBeAg positive, anti-HBe negative at screening
• ALT > 1.3 x ULN within 60 days prior to screening and during screening
• Liver biopsy performed within 2 years prior to screening or during screening
• Age > 18 years
• Written informed consent
• Adequate contraception for males and females during treatment and follow up; negative pregnancy test (for
women of childbearing potential)
Exclusion criteria
• Antiviral therapy against HBV within the previous 6 months
• Treatment with any investigational drug within 30 days of screening
• Previous treatment with lamivudine or telbivudine for more than six months
• Severe hepatitis activity as documented by ALT>10 x ULN
• History of decompensated cirrhosis (defined as jaundice in the presence of cirrhosis, ascites, bleeding gastric or
esophageal varices or encephalopathy)
• Pre-existent neutropenia (neutrophils *1,500/mm3) or thrombocytopenia (platelets *90,000/mm3)
• Co-infection with hepatitis C virus or human immunodeficiency virus (HIV)
• Other acquired or inherited causes of liver disease (i.e. alcoholic liver disease, obesity induced liver disease,
drug related liver disease, auto-immune hepatitis, hemochromatosis, Wilson*s disease or alpha-1 antitrypsin
deficiency)
• Alpha fetoprotein > 50 ng/ml
• Hyper- or hypothyroidism (subjects requiring medication to maintain TSH levels in the normal range are eligible if
all other inclusion/exclusion criteria are met)
• Immune suppressive treatment within the previous 6 months
• Contra-indications for alpha-interferon therapy like suspected hypersensitivity to interferon or PEG-interferon or
any known pre-existing medical condition that could interfere with the patient's participation in and completion of
the study.
• Pregnancy, lactation
• Other significant medical illness that might interfere with this study: significant pulmonary dysfunction in the
previous 6 months, malignancy other than skin basocellular carcinoma in previous 5 years, immunodeficiency
syndromes (e.g. HIV positivity, auto-immune diseases, organ transplants other than cornea and hair transplant)
• Any medical condition requiring, or likely to require chronic systemic administration of steroids, during the course
of the study
• Substance abuse, such as alcohol (*80 g/day), I.V. drugs and inhaled drugs in the past 2 years.
• Any other condition which in the opinion of the principal investigator would make the patient unsuitable for
enrollment, or could interfere with the patient participating in and completing the study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-006239-11-NL |
| ClinicalTrials.gov | NCT00877760 |
| CCMO | NL26630.078.09 |