Clinical trial NCT00917761: Entecavir and Pegasys Sequential Therapy Versus Pegasys for HBeAg Negative Chronic Hepatitis B
Official title: Entecavir and Peginterferon Alfa-2a Sequential Therapy Versus Peginterferon Alfa-2a Monotherapy for HBeAg Negative Chronic Hepatitis B
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Hepatitis B, Chronic
Keywords: Hepatitis B, chronic
Peginterferon alfa-2a
Entecavir
Lead sponsor: National Taiwan University Hospital
Sponsor class: OTHER
Collaborators: name: National Science and Technology Council, Taiwan
First posted: 2009-06-10
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Currently, peginterferon alfa-2a or oral nucleos(t)ides are approved for the treatment with HBeAg negative CHB, with the overall ALT normalization and HBV viral suppression far from satisfactory. Therefore, efforts on the various combinations with the currently available drugs are needed to improve the overall response rates. The simultaneous combination therapy with oral nucleoside and peginterferon alfa-2a from large-scaled randomized trials did not show a superior response rate over peginterferon alfa-2a monotherapy. Recently, sequential monotherapy with lamivudine for the first 4 weeks, followed by weekly peginterferon alfa-2a has shown favorable HBeAg seroconversion rate over peginterferon alfa-2a monotherapy, based on the assumption that early viral suppression by lamivudine can restore the immune function to facilitate the later immunomodulatory response by peginterferon alfa-2a. Furthermore, prior studies using 24 months of standard interferon alfa showed better ALT normalization and HBV suppression rates to 12 months of therapy. With the recent introduction of entecavir, the more potent oral nucleoside with few drug resistance, sequential monotherapy with entecavir can potently suppress HBV DNA with 4 weeks of treatment, which may facilitate the response of peginterferon alfa-2a to achieve HBV viral suppression. Therefore, we aimed to conduct a placebo controlled randomized control trial to evaluate if adding entecavir early in the course of therapy or extending the treatment duration of peginterferon alfa-2a can improve the treatment response.

Detailed description: Chronic hepatitis B (CHB) is prevalent in the world, with estimated chronic carriers of 350 millions worldwide. Currently, peginterferon alfa-2a or oral nucleos(t)ides are approved for the treatment with HBeAg negative CHB, with the overall ALT normalization and HBV viral suppression far from satisfactory. Therefore, efforts on the various combinations with the currently available drugs are needed to improve the overall response rates. The simultaneous combination therapy with oral nucleoside and peginterferon alfa-2a from large-scaled randomized trials did not show a superior response rate over peginterferon alfa-2a monotherapy. Recently, sequential monotherapy with lamivudine for the first 4 weeks, followed by weekly peginterferon alfa-2a has shown favorable HBeAg seroconversion rate over peginterferon alfa-2a monotherapy, based on the assumption that early viral suppression by lamivudine can restore the immune function to facilitate the later immunomodulatory response by peginterferon alfa-2a. Furthermore, prior studies using 24 months of standard interferon alfa showed better ALT normalization and HBV suppression rates to 12 months of therapy. With the recent introduction of entecavir, the more potent oral nucleoside with few drug resistance, sequential monotherapy with entecavir can potently suppress HBV DNA with 4 weeks of treatment, which may facilitate the response of peginterferon alfa-2a to achieve HBV viral suppression. Therefore, we aimed to conduct a placebo controlled randomized control trial to evaluate if adding entecavir early in the course of therapy or extending the treatment duration of peginterferon alfa-2a can improve the treatment response.

Eligibility criteria: Inclusion Criteria:

* Chronic hepatitis B (presence of HBsAg \> 6 months) with anti-HBe persistence and abscence of HBeAg for more than 3 months
* Age older than 18 years
* HBV DNA \> 2,000 IU/mL for more than 2 occasions
* Serum ALT levels between 2 to 10 folds the upper limit of normal (ULN)
* A liver biopsy compatible with chronic hepatitis B

Exclusion Criteria:

* Anemia (hemoglobin \< 13 gram per deciliter for men and \< 12 gram per deciliter for women)
* Neutropenia (neutrophil count \<1,500 per cubic milliliter)
* Thrombocytopenia (platelet \<90,000 per cubic milliliter)
* Co-infection with hepatitis B virus (HBV), hepatitis D virus (HDV) or human immunodeficiency virus (HIV)
* Chronic alcohol abuse (daily consumption \> 20 gram per day)
* Decompensated liver disease (Child-Pugh class B or C)
* Serum creatinine level more than 1.5 times the upper limit of normal
* Autoimmune liver disease
* Neoplastic disease
* An organ transplant
* Immunosuppressive therapy
* Poorly controlled autoimmune diseases, pulmonary diseases, cardiac diseases, psychiatric diseases, neurological diseases, diabetes mellitus
* Evidence of drug abuse
* Unwilling to have contraception
* Known allergic reaction to entecavir or peginterferon alfa-2a
* Unwilling to sign inform consent

Primary outcomes:
measure: HBV virologic response (HBV DNA < 2,000 IU/mL) 6 months after the cessation of treatment
timeFrame: 2.5 years
Secondary outcomes:
measure: ALT normalization rate (ALT < 40 IU/L) 6 months after the cessation of treatment
timeFrame: 2.5 years
Other outcomes:
Locations:
city: Douliou
country: Taiwan
facility: National Taiwan University Hosptial, Yun-Lin Branch
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Buddhist Tzu Chi General Hospital
city: Taipei
country: Taiwan
facility: Far Eastern Memorial Hospital
city: Taipei
country: Taiwan
facility: Ren-Ai Branch, Taipei Municipal Hospital
Study officials:
affiliation: National Taiwan University Hospital
name: Chen-Hua Liu, MD
role: STUDY_CHAIR
affiliation: National Taiwan University Hospital
name: Jia-Horng Kao, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Taiwan University Hosptial, Yun-Lin Branch
name: Shih-Jer Hsu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ren-Ai Branch, Taipei City Hospital
name: Chih-Lin Lin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Far Eastern Memorial Hospital
name: Cheng-Chao Liang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Buddhist Tzu Chi General Hospital
name: Ching-Sheng Hsu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Taichung Veterans General Hospital
name: Sheng-Shun Yang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: