A Study of Pegylated Interferon Alfa-2a and Lamivudine in Patients With HBeAg-Negative Chronic Hepatitis B Virus (HBV)

Study Overview
=================
Brief Summary
-----------------
This study will compare the efficacy and safety of 2 different durations of treatment with pegylated interferon (PEG-IFN) alfa-2a in participants with Hepatitis B e Antigen (HBeAg)-negative chronic hepatitis B virus (HBV). It will also compare PEG-IFN alfa 2a treatment alone and in combination with lamivudine (LAM). The anticipated time on study treatment is 1-2 years, and the target sample size is 100-500 individuals.

Official Title
-----------------
A Multicenter, Randomized, Controlled Study Comparing the Efficacy and Safety of 48 Weeks of 40kD Branched Pegylated Interferon Alfa-2a (PEG-IFN, RO 25-8310) Versus 96 Weeks of PEG-IFN, Alone or in Combination With 100 mg Lamivudine for 48 Weeks in Patients With HBeAg-Negative Chronic Hepatitis B

Conditions
-----------------
Hepatitis B, Chronic

Intervention / Treatment
-----------------
* Drug: Pegylated interferon (PEG-IFN) alfa-2a, 180 mcg
* Drug: Pegylated interferon (PEG-IFN) alfa-2a, 135 mcg
* Drug: Lamivudine (LAM)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: adults 18-70 years of age; HBeAg-negative chronic hepatitis B for >/=6 months; liver disease consistent with chronic hepatitis B. Exclusion Criteria: interferon-based, systemic anti-HBV, antiviral, anti-neoplastic, or immunomodulatory therapy </=12 months before first dose of study drug; non-responders to previous interferon therapy; co-infection with hepatitis A, C or D, or with human immunodeficiency virus (HIV); hepatocellular cancer; compensated (Child A, score 6) or decompensated liver disease (Child B or C).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PEG-IFN48<br>Treatment with PEG-IFN in participants with HBeAg-negative chronic hepatitis B virus for 48 weeks. | Drug: Pegylated interferon (PEG-IFN) alfa-2a, 180 mcg<br>* PEG-IFN alfa-2a 180 micrograms (mcg) was administered subcutaneously, once weekly from Week 0 to 48.<br>* Other names: Pegasys®;|
| Experimental: PEG-IFN96<br>Treatment with PEG-IFN in participants with HBeAg-negative chronic hepatitis B virus for 48 weeks followed by another 48 weeks of PEG-IFN treatment (total 96 weeks of treatment). | Drug: Pegylated interferon (PEG-IFN) alfa-2a, 180 mcg<br>* PEG-IFN alfa-2a 180 micrograms (mcg) was administered subcutaneously, once weekly from Week 0 to 48.<br>* Other names: Pegasys®;Drug: Pegylated interferon (PEG-IFN) alfa-2a, 135 mcg<br>* PEG-IFN alfa-2a 135 mcg was administered subcutaneously, once weekly from Week 49 to 96.<br>* Other names: Pegasys®;|
| Experimental: PEG-IFN+LAM96<br>Treatment with PEG-IFN and lamivudine in participants with HBeAg-negative chronic hepatitis B virus for 48 weeks followed by 48 weeks of only PEG-IFN treatment (total 96 weeks of treatment). | Drug: Pegylated interferon (PEG-IFN) alfa-2a, 180 mcg<br>* PEG-IFN alfa-2a 180 micrograms (mcg) was administered subcutaneously, once weekly from Week 0 to 48.<br>* Other names: Pegasys®;Drug: Pegylated interferon (PEG-IFN) alfa-2a, 135 mcg<br>* PEG-IFN alfa-2a 135 mcg was administered subcutaneously, once weekly from Week 49 to 96.<br>* Other names: Pegasys®;Drug: Lamivudine (LAM)<br>* Lamivudine 100 milligrams (mg) was administered orally, daily from Week 0 to 48.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving the Combined Response at the End of the Follow-up Period | Combined response was defined as alanine aminotransferase (ALT) normalization plus lowering of hepatitis B virus (HBV) deoxyribo nucleic acid (DNA) levels to <20,000 copies/mL (<3,400 IU/mL) and was measured at the end of the 48-week follow-up period. Participants with missing 48 weeks follow-up measurements were considered as non-responders. However, if the scheduled 48-weeks post-treatment tests were performed earlier or later than 48 weeks post-treatment, but not earlier than 36 weeks post-treatment, the corresponding results were considered to determine response. | At the end of the 48-week follow-up period at Week 144 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving the Combined Response at the End of Treatment | Combined response was defined as ALT normalization plus lowering of HBV-DNA levels to <20,000 copies/mL (<3,400 IU/mL). In case of missing end of treatment measurements, the next available post-treatment value was used. | At end of treatment at Week 48 or 96 depending on the study arm | 
| Percentage of Participants Achieving the Combined Response at 24 Weeks of Follow-up | Combined response was defined as ALT normalization plus lowering of HBV-DNA levels to <20,000 copies/mL (<3,400 IU/mL). In case of missing week-24 post-treatment measurements, the nearest value with respect to the schedule time point in the time window 12 weeks post treatment until study end was used. | At the end of 24 weeks of follow-up at Week 120 | 
| Percentage of Participants Achieving Combined Response Using a Cut-Off for HBV-DNA Levels to 2,000 IU/mL | Combined response was defined here as ALT normalization plus lowering HBV-DNA levels to a cutt-off <2,000 IU/mL. In case of missing end of treatment measurements, the next available post-treatment value was used. In case of missing week-24 post-treatment measurements, the nearest value with respect to the schedule time point in the time window 12 weeks post treatment until study end was used. Participants with missing 48 weeks follow-up measurements were considered as non-responders. However, if the scheduled 48-weeks post-treatment tests were performed earlier or later than 48 weeks post-treatment, but not earlier than 36 weeks post-treatment, the corresponding results were considered to determine response. | At end of treatment at Week 48 or 96 depending on the study arm, at the end of 24 weeks of follow-up at Week 120 and at the end of the follow-up period at Week 144 | 
| Percentage of Participants Achieving Histological Response | Histological response was defined as an improvement by >/= 2 in the Necroinflammatory Grading and/or by an improvement by >/= 1 score in Fibrosis Staging according to Ishak. Necroinflammatory Grading ranges 0-14 and is the combined score for necrosis, range 0-10 and inflammation, range 0-4. The participant is scored for only one inflammatory condition. A higher score indicates worse condition. Fibrosis Staging according to Ishak ranges 0-6 and a higher score indicates greater fibrosis. | At the end of the 48-week follow-up period at Week 144 | 
| Change From Baseline of Quantitative Hepatitis B Surface Antigen (HbsAg) Level at the End of Treatment |  | At the end of treatment at Week 48 or 96 depending on the study arm | 
| Percentage of Participants With Lamivudine Genotype Resistance During PEG-IFN+LAM96 Combined Therapy | Lamivudine resistance mutations were assessed by detection of the following mutations: rtL80V, rtL80I, rtV173G, rtV173L, rtL180M, rtA181T, rtA181V, rtM204V, rtM204I and rtN236T. | At the end of the treatment period at Week 96 |