Clinical trial NCT00114361: 48 Weeks Combination Therapy for Patients With HBeAg-negative Chronic Hepatitis B Virus (HBV) Infection
Official title: Peginterferon Alfa-2a and Ribavirin Combination Therapy in Patients With HBeAg-negative Chronic HBV Infection (PARC Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis B
Keywords: HBeAg-negative
chronic
hepatitis B
viral
Lead sponsor: Foundation for Liver Research
Sponsor class: OTHER
First posted: 2005-06-15
Enrollment: 138
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL

Brief summary: The purpose of this study is to investigate whether in patients with chronic HBeAg-negative hepatitis B, PEG-IFN-ribavirin combination therapy for 1 year leads to enhanced response (HBV DNA \<10E4 copies/ml and normal ALT 24 weeks after treatment discontinuation) in comparison with pegylated interferon (PEG-IFN) monotherapy.

Detailed description: Despite the introduction of newer drugs for the treatment of chronic hepatitis B, there is still no optimal treatment. Pegylated interferon alfa has proven sustained efficacy in approximately 30-40% of patients with HBeAg-positive or HBeAg-negative chronic hepatitis B. It is likely that combination therapy of pegylated interferon alfa with ribavirin in chronic hepatitis B is more effective than pegylated interferon alfa monotherapy. In chronic hepatitis C, adding ribavirin to pegylated interferon therapy doubled the sustained response rate (29% vs. 56%) and has become the standard option of treatment.

To investigate the effect of the treatment with pegylated interferon and ribavirin on the amount of inflammation and fibrosis in the liver, a liver biopsy will be performed within one year prior to screening and at the end of follow-up.

When patients with chronic hepatitis B are treated outside any study with pegylated interferon, they visit the outpatient clinic approximately every month for blood samples. So in this study the amount of blood samples taken from every patient is not increased as compared with treatment outside a study.

Eligibility criteria: Inclusion Criteria:

* Chronic hepatitis B
* Biopsy performed within one year prior to screening or during screening
* ALT \> 1.5 x ULN
* HBeAg negative, anti-HBeAg positive
* HBV DNA \> 10E5 copies/ml
* Age 18-70 years
* Written informed consent
* Hepatic imaging without evidence of HCC
* All fertile males and females must be using two forms of effective contraception

Exclusion Criteria:

* Antiviral therapy against HBV within the previous 6 months; treatment with any investigational drug within 30 days of entry to this protocol
* Severe hepatitis activity as documented by ALT \> 10 x ULN
* Advanced liver disease
* Pre-existent leucopenia or thrombopenia
* Co-infection with HCV,HDV or HIV
* Other acquired or inherited causes of liver disease
* Alpha fetoprotein \> 50 ng/ml.
* Evidence of severe renal disease
* Hyper- or hypothyroidism
* Significant cardiovascular or pulmonary dysfunction, malignancy,immunodeficiency syndromes
* Immune suppressive treatment within the previous 6 months
* Contra-indications for alpha-interferon therapy
* Pregnancy, breast-feeding
* Any medical condition requiring chronic systemic administration of steroids
* Substance alcohol or drug abuse
* Subjects with clinically significant retinal abnormalities
* Subjects with clinically significant hearing abnormalities
* Hemoglobinopathies
* Subjects with known hypersensitivity to ribavirin

Primary outcomes:
measure: The combined presence of HBV DNA level < 10E4 copies/ml and ALT normalization at the end of follow-up
timeFrame: may 2008
Secondary outcomes:
measure: ALT normalization
timeFrame: May 2008
measure: HBV DNA negativity(undetectable by Taqman PCR)
timeFrame: May 2008
measure: HBsAg loss from serum
timeFrame: May 2008
measure: Improvement liver histology
timeFrame: May 2008
measure: Combined virological, biochemical and histological response
timeFrame: May 2008
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: Erasmus MC department hepatology
Study officials:
affiliation: Foundation of Liver Research
name: Harry LA Janssen, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brakenhoff SM, de Knegt RJ, van Campenhout MJH, van der Eijk AA, Brouwer WP, van Bommel F, Boonstra A, Hansen BE, Berg T, Janssen HLA, de Man RA, Sonneveld MJ. End-of-treatment HBsAg, HBcrAg and HBV RNA predict the risk of off-treatment ALT flares in chronic hepatitis B patients. J Microbiol Immunol Infect. 2023 Feb;56(1):31-39. doi: 10.1016/j.jmii.2022.06.002. Epub 2022 Jul 2.
citation: Brakenhoff SM, de Man RA, Boonstra A, van Campenhout MJH, de Knegt RJ, van Bommel F, van der Eijk AA, Berg T, Hansen BE, Janssen HLA, Sonneveld MJ. Hepatitis B virus RNA decline without concomitant viral antigen decrease is associated with a low probability of sustained response and hepatitis B surface antigen loss. Aliment Pharmacol Ther. 2021 Jan;53(2):314-320. doi: 10.1111/apt.16172. Epub 2020 Nov 21.
citation: Farag MS, van Campenhout MJH, Pfefferkorn M, Fischer J, Deichsel D, Boonstra A, van Vuuren AJ, Ferenci P, Feld JJ, Berg T, Hansen BE, van Bommel F, Janssen HLA. Hepatitis B Virus RNA as Early Predictor for Response to Pegylated Interferon Alpha in HBeAg-Negative Chronic Hepatitis B. Clin Infect Dis. 2021 Jan 27;72(2):202-211. doi: 10.1093/cid/ciaa013.