Entecavir and Pegasys Sequential Therapy Versus Pegasys for HBeAg Negative Chronic Hepatitis B

National Taiwan University

Status and phase: Unknown; Phase 4

Conditions: Hepatitis B, Chronic

Treatments: Drug: Peginterferon (Pegasys) (96 weeks); Drug: Peginterferon (Pegasys) (48 weeks); Drug: Entecavir and peginterferon (Pegasys) (52 weeks)

Study type: Interventional

Funder types: Other

Identifiers

NCT00917761

950924

Details and patient eligibility

About

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.

Full 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.

Enrollment: 300 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

300 participants in 3 patient groups

Entecavir and peginterferon (52 weeks)

Experimental group

Description:

Entecavir 0.5 mg/day po at week 1-4 Peginterferon alfa-2a 180 ug/week sc at week 5-52

Treatment:

Drug: Entecavir and peginterferon (Pegasys) (52 weeks)

Peginterferon (96 weeks)

Experimental group

Description:

Peginterferon alfa-2a 180 ug/week sc at week 1-96

Treatment:

Drug: Peginterferon (Pegasys) (96 weeks)

Peginterferon (48 weeks)

Active Comparator group

Description:

Peginterferon alfa-2a 180 ug/week sc at week 1-48

Treatment:

Drug: Peginterferon (Pegasys) (48 weeks)