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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Entecavir and Peginterferon Alfa-2a Sequential Therapy Versus Peginterferon Alfa-2a Monotherapy for HBeAg Negative Chronic Hepatitis B

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: Entecavir and peginterferon (Pegasys) (52 weeks)
* Drug: Peginterferon (Pegasys) (96 weeks)
* Drug: Peginterferon (Pegasys) (48 weeks)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Entecavir and peginterferon (52 weeks)<br>Entecavir 0.5 mg/day po at week 1-4 Peginterferon alfa-2a 180 ug/week sc at week 5-52 | Drug: Entecavir and peginterferon (Pegasys) (52 weeks)<br>* Entecavir 0.5 mg/day po at week 1-4 Peginterferon alfa-2a 180 ug/week sc at week 5-52<br>* Other names: Peginterferon alfa-2a (Pegasys) 180 ug/week sc at week 5-52;|
| Experimental: Peginterferon (96 weeks)<br>Peginterferon alfa-2a 180 ug/week sc at week 1-96 | Drug: Peginterferon (Pegasys) (96 weeks)<br>* Peginterferon alfa-2a 180 ug/week sc at week 1-96<br>* Other names: Peginterferon alfa-2a (Pegasys) 180 ug/week sc at week 1-96;|
| Active Comparator: Peginterferon (48 weeks)<br>Peginterferon alfa-2a 180 ug/week sc at week 1-48 | Drug: Peginterferon (Pegasys) (48 weeks)<br>* Peginterferon alfa-2a 180 ug/week sc at week 1-48<br>* Other names: Peginterferon alfa-2a (Pegasys) 180 ug/week sc at week 1-48;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBV virologic response (HBV DNA < 2,000 IU/mL) 6 months after the cessation of treatment |  | 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ALT normalization rate (ALT < 40 IU/L) 6 months after the cessation of treatment |  | 2.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis B, chronic, Peginterferon alfa-2a, Entecavir