Efficacy and Safety of Telbivudine in Treatment naïve Patients With Hepatitis B e Antigen (HBeAg)-Positive Chronic Hepatitis B (CHB)

Study Overview
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Brief Summary
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To evaluate the combination of telbivudine 600 mg orally (PO) once daily and peginterferon alpha-2a 180 ug subcutaneous (sq) injection weekly for antiviral efficacy in comparison to peginterferon alpha-2a monotherapy.

Official Title
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A Randomized, Open-label, Controlled, Multi-center Two-year Study Comparing Efficacy and Safety of Telbivudine, 600 mg PO in Combination With Peginterferon Alpha-2a sq 180 µg With Peginterferon Alpha-2a Monotherapy, and With Telbivudine Monotherapy in Treatment naïve Patients With HBeAg-positive CHB.

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: Telbivudine (LdT)
* Drug: peginterferon alpha-2a


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented Chronic hepatitis B (CHB) defined by all of the following: Clinical history compatible with CHB Detectable serum Hepatitis B Surface Antigen (HBsAg) at the Screening visit and at least 6 months prior HBeAg-positive at the Screening visit Hepatitis B 'e' Antibody (HBeAb)-negative at the Screening visit History of evidence of chronic liver inflammation, Elevated serum Alanine aminotransferase (ALT) level (1.3 - 10 x upper limit of normal (ULN)) at the Screening visit Serum HBV DNA level ≥ 6 log10 copies/mL, Chronic liver inflammation on previous liver biopsy within the previous 24 months. Exclusion Criteria: Co-infection with Hepatitis C Virus (HCV), Hepatitis D Virus (HDV), or Human Immunodeficiency Virus (HIV). Has any of the following drug therapy: Previously been treated in a trial with telbivudine Received nucleoside or nucleotide therapy whether approved or investigational Received any immunomodulatory treatment in the 12 months before Screening for this study. Has a medical condition that required prolonged or frequent use of systemic acyclovir or famciclovir. Has a medical condition that requires frequent or prolonged use of systemic corticosteroids although inhaled or intra-articular corticosteroids are allowed. Has a medical condition requiring the chronic or prolonged use of potentially hepatotoxic drugs or nephrotoxic drugs. Is currently abusing alcohol or illicit drugs or has a history of alcohol abuse illicit substance abuse within the preceding two years. Uses other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer. Is currently receiving methadone. Patient has any of the following: History of or clinical signs/symptoms of hepatic decompensation such as ascites, esophageal variceal bleeding, hepatic encephalopathy, or spontaneous bacterial peritonitis. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. Patients with previous findings suggestive of possible HCC should have the disease ruled out prior to entrance into the study. One or more additional known primary or secondary causes of liver disease other than hepatitis B, including steatohepatitis. History of clinical and laboratory evidence of chronic pancreatitis, or demonstrates a clinical and laboratory course consistent with current pancreatitis. Has laboratory values during screening visit not within normal limits. Is pregnant or breastfeeding. Is a women of child-bearing potential that is unwilling to practice birth control.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: LdT+ PEG-INF<br>Telbivudine (LdT) 600 mg orally once a day for 104 weeks in combination with peginterferon alpha-2a (PEG-INF)180 μg subcutaneous injection once a week for 52 weeks. | Drug: Telbivudine (LdT)<br>* 600 mg orally once daily for 104 weeks.<br>* Other names: Sebivo;Drug: peginterferon alpha-2a<br>* 180 μg subcutaneous injection once a week for 52 weeks.<br>* Other names: Pegasys;|
| Experimental: LdT Monotherapy<br>Telbivudine (LdT) monotherapy: 600 mg orally once daily for 104 weeks. | Drug: Telbivudine (LdT)<br>* 600 mg orally once daily for 104 weeks.<br>* Other names: Sebivo;|
| Active Comparator: PEG-INF Monotherapy<br>Peginterferon alpha-2a (PEG- INF) monotherapy: 180 μg subcutaneous injection once a week for 52 weeks. | Drug: peginterferon alpha-2a<br>* 180 μg subcutaneous injection once a week for 52 weeks.<br>* Other names: Pegasys;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved HBV DNA Non-detectability With Peginterferon Alpha-2a Plus Telbivudine Combination Therapy Versus Peginterferon Alpha-2a Monotherapy | The original primary efficacy variable was the percentage of patients achieving HBV DNA non-detectability utilizing polymerase chain reaction (PCR) (threshold for detection 300 copies/mL); however, this analysis was not performed due to premature study termination. | At week 52 | 
| Percentage of Participants With HBV DNA Non-detectability and Alanine Aminotransferase (ALT) Normalization at Week 12 and Week 24 in Participants With HBeAg-positive Chronic Hepatitis B (CHB) | The percentage of participants who achieved HBV DNA non-detectability using the COBAS Amplicor HBV Monitor assay utilizing polymerase chain reaction (PCR) (threshold for detection 300 copies/mL) and Alanine aminotransferase (ALT) normalization defined as ALT within normal limits on two successive visits for a patient with an elevated ALT (>1.0 x upper limit normal) at baseline summarized at Weeks 12 and 24. | Weeks 12 and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HBV DNA Concentration | The change from baseline in HBV DNA concentration at Weeks 12 and 24 was analyzed using an analysis of covariance (ANCOVA) model with baseline HBV DNA concentration (log10 copies/ml) as a covariate, treatment and country as factors. | Weeks 12 and 24 | 
| Percentage of Participants Who Experienced Virologic Breakthrough at Weeks 48 and 52 | The percentage of participants with Virologic breakthrough at Week 48 and 52 by treatment. For the subgroup of patients on treatment who achieve HBV DNA >= 1 log10 copies/mL reduction from baseline on 2 consecutive visits, Virologic Breakthrough is defined as HBV DNA >= 1 log10 copies/mL from nadir on two consecutive visits. | Weeks 48 and 52 | 
| Percentage of Participants With Hepatitis B 'e' Antigen (HBeAg) Loss and HBeAg Seroconversion | HBeAg loss is defined as the loss of detectable serum HBeAg in a patient who was HBeAg positive at baseline. HBeAg seroconversion is defined as HBeAg loss with detectable Hepatitis B 'e' antibody (HBeAb). The efficacy was assessed for 18 weeks, 24 weeks, 48 weeks, 52 weeks and on treatment completion (TC). | Weeks 18, 24, 48, 52 and Treatment completion (TC) | 
| Percentage of Participants Who Achieved HBV DNA Non-detectability With Telbivudine Monotherapy Versus Peginterferon Alpha-2a Monotherapy | Antiviral efficacy was assessed by percentage of patients achieving HBV DNA non-detectability assay utilizing polymerase chain reaction (PCR) (threshold for detection 300 copies/mL); however, this analysis was not performed due to premature study termination. | Week 52 | 
| Percentage of Participants Who Achieved HBV DNA Non-detectability With Peginterferon Alpha-2a Plus Telbivudine Combination Therapy Versus Telbivudine Monotherapy | Antiviral efficacy was assessed by percentage of patients achieving HBV DNA non-detectability assay utilizing polymerase chain reaction (PCR) (threshold for detection 300 copies/mL); however, this analysis was not performed due to premature study termination. | Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatitis B, hepatitis B Virus (HBV), chronic hepatitis B, telbivudine, peginterferon