Phase 3 Study of GSK548470 in Patients With Compensated Chronic Hepatitis B Untreated With Nucleic Acid Analogue

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of GSK548470 administered once daily at a dose level of 300 mg to Japanese patients with compensated chronic hepatitis B untreated with any nucleic acid analogue. In efficacy, the non-inferiority of GSK548470 to ETV will be verified using the antiviral effect as the index.

Detailed Description
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This study is a multicenter, randomized, active comparator-controlled, double-blind, parallel-group comparison study in Japanese patients with compensated chronic hepatitis B untreated with any nucleic acid analogue and its subsequent open-label study. Efficacy and safety will be compared between once-daily dosing of GSK548470 300 mg and once-daily dosing of ETV 0.5 mg, and subsequently the efficacy and safety of GSK548470 administered long term will be investigated. A total of 165 subjects will be assigned to the GSK548470 group or the ETV group at a ratio of 2:1. The subjects will be assigned by stratified randomization in terms of HBe antigen and serum HBV-DNA level. The primary purpose is to verify the non-inferiority of GSK548470 to ETV using as an index the change amount of HBV-DNA level at Week 24 from the baseline level. The secondary purpose is to investigate the efficacy and safety of GSK548470 300 mg administered once daily for a long term.

Official Title
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A Multi-center, Randomized, Active Controlled, Double-blind, Parallel Group Comparison Study and Subsequent Open-label Study of GSK548470 in Patients With Compensated Chronic Hepatitis B Untreated With Nucleic Acid Analogue

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: GSK548470 300 mg tablet
* Drug: ETV 0.5 mg capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The ability to understand and sign a written informed consent form 16 to 69 years of age at the time of informed consent Females of childbearing potential must have a negative pregnancy test and agree to avoidance of pregnancy Subject must show QTc < 450 millisecond (msec) or < 480 msec with Bundle Branch Block Chronic HBV infection, defined as positive serum HBsAg for at least 6 month, or negative serum IgM-HBc antibody HBeAg positive; HBV-DNA >= 6 log10 copies/mL, HBeAg negative; HBV-DNA >= 5 log10 copies/mL Serum ALT >= 31 U/L and <= 10 × ULN Creatinine clearance >= 70 mL/min Haemoglobin >= 8 g/dL WBC >= 1,000 /mm3 Nucleic acid analogue naïve, i.e., no prior therapy for over 6 months in the past No mutation that shows resistance in LAM, ETV and/or TDF at screening Exclusion Criteria: Decompensated liver disease Co-infection with HIV or HCV Autoimmune hepatitis rather than chronic hepatitis B Subject with serious complication Received or have a plan for solid organ or bone marrow transplantation Has proximal tubulopathy History of hypersensitivity to nucleoside and/or nucleotide analogues Evidence of hepatocellular carcinoma by diagnostic imaging at screening and/or serum α-fetoprotein > 50 ng/mL at screening History of HCC Received any nucleoside, nucleotide, interferon or HB vaccine therapy within 24 weeks prior to initiation Received overdose NSAIDs, excluding temporary or topical use, within 7 days prior to initiation Received drugs for injection containing glycyrrhizin as the main component within 4 weeks prior to initiation Received drugs causing renal impairment, competitors of renal excretion, immunosuppressants, chemotherapeutics and/or corticosteroids within 8 weeks prior to initiation Participation in another clinical study within 6 months of study entry or planned participation in another clinical study after entry to this study Woman who is pregnant, lactating, possibly pregnant or planning a pregnancy during the study period Psychiatry disorder or cognitive disorder that may affect the subject ability to give informed consent or to follow specified study procedures History of alcohol or drug abuse Any condition or situation that may interfere with the subject's participation in the study

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 69 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK548470 300 mg<br>GSK548470 300 mg tablet and ETV placebo capsule are administered once daily | Drug: GSK548470 300 mg tablet<br>* Blue tablets, each tablet containing 300 mg of tenofovir disoproxil fumarate<br>* Other names: GSK548470;|
| Active Comparator: ETV 0.5 mg<br>ETV 0.5 mg capsule and GSK548470 placebo tablet are administered once daily | Drug: ETV 0.5 mg capsule<br>* Brown capsules, each capsule containing 0.53 mg of entecavir hydrate<br>* Other names: ETV;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Serum HBV DNA Level at Week 24 | The mean change from Baseline in the hepatitis B virus deoxyribonucleic acid (HBV DNA) level at Week 24 was assessed (lower limit of quantitation : 2.1 log 10 copies/mL). The mean values were adjusted by Baseline HBV DNA levels. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With HBeAg/HBeAb Seroconversion at Week 24, Week 48 and Week 96 | The number of participants achieving HBeAg/hepatitis Be antibody (HBeAb) seroconversion at Week 24, Week 48 and Week 96 in positive HBeAg and negative HBeAb participants at Baseline were summarized. Seroconversion to HBeAg is defined as the change of detectable antibody to HBeAg from negative to positive. The LOCF method was applied for missing values. | Week 24, Week 48 and Week 96 | 
| Number of Participants Achieving HBsAg Loss at Week 24, Week 48 and Week 96 | The number of participants with hepatitis B surface antigen (HBsAg) loss at Week 24, Week 48 and Week 96 in positive HBsAg participants at Baseline were summarized. Loss of HBsAg is defined as change of detectable HBsAg from positive to negative. The LOCF method was applied for missing values. | Week 24, Week 48 and Week 96 | 
| Number of Participants Achieving HBsAg/HBsAb Seroconversion at Week 24, Week 48 and Week 96 | The number of participants with HBsAg/hepatitis B surface antibody (HBsAb) seroconversion at Week 24, Week 48 and Week 96 in positive HBsAg and negative HBsAb participants at Baseline were summarized. HBsAg seroconversion .is defined as change of detectable antibody to HBsAg from negative to positive. The LOCF method was applied for missing values. | Week 24, Week 48 and Week 96 | 
| Number of Participants Achieving Each Indicated HBsAg Category at Baseline, Week 24, Week 48 and Week 96 | The number of participants achieving each indicated HBsAg category (HBsAg <80, 80 to 800, 800 to 8000, 8000 to 80000, and >=80000) (kilo international unit per liter [KIU/L]) by study visit was summarized. The LOCF method was applied for missing values. | Baseline, Week 24, Week 48 and Week 96 | 
| Number of Participants Achieving Each Indicated HBcrAg Category at Baseline, Week 24, Week 48 and Week 96 | The number of participants achieving each indicated hepatitis B core-related antigen (HBcrAg) category (HBcrAg <3.0, 3.0 to 4.0, 4.0 to 5.0, 5.0 to 6.0, and >=6.0) (Log kilo unit per liter [KU/L]) by study visit was summarized. The LOCF method was applied for missing values. | Baseline, Week 24, Week 48 and Week 96 | 
| Number of Participants With Virological Breakthrough Through End of the Study | The number of participants who experienced virological breakthrough was summarized. Virological breakthrough is defined as serum HBV DNA level increase >=1 log10 copies/mL above the treatment nadir. Virological breakthrough values were presented from Baseline to through out the study. Baseline is defined as the value at Week 0 visit. | From Baseline to throughout study | 
| Number of Participants With HBeAg Loss at Week 24, Week 48 and Week 96 | The number of participants achieving hepatitis Be antigen (HBeAg) loss at Week 24, Week 48 and Week 96 in positive HBeAg participants at Baseline were summarized. Loss of HBeAg is defined as the change of detectable HBeAg from positive to negative. The LOCF method was applied for missing values. | Week 24, Week 48 and Week 96 | 
| Mean Change From Baseline in Serum HBV DNA Level at Week 48 and Week 96 | The mean change from Baseline in the HBV DNA level at Week 48 and Week 96 were assessed (lower limit of quantitation : 2.1 log10 copies/mL). The mean values were adjusted by Baseline HBV DNA levels. Change from Baseline was calculated as the post-baseline value minus the Baseline value. The LOCF method was applied for missing values. | Baseline, Week 48 and Week 96 | 
| Number of Participants With Serum HBV DNA < 2.1 log10 Copies/mL at Week 24, Week 48 and Week 96 | The number of participants with serum HBV DNA level less than the lower limit of quantitation (i.e. 2.1 log10 copies/mL) at Week 24, Week 48 and Week 96 were summarized. The LOCF method was applied for missing values. | Week 24, Week 48 and Week 96 | 
| Number of Participants With Alanine Aminotransferase (ALT) Normalization at Week 24, Week 48 and Week 96 | The number of participants with alanine aminotransferase (ALT) normalization at Week 24, Week 48 and Week 96 were summarized. ALT normalization is defined as when an ALT value exceeds the upper limit of normal range (ULN) at Baseline and within the normal range at the end of treatment. The LOCF method was applied for missing values. | Week 24, Week 48 and Week 96 | 
| Number of Participants With Resistance Related Mutations at Week 24, Week 48, Week 96 and Virological Breakthrough (Baseline to Throughout the Study) | The development of drug resistance-related (RA) mutations was analyzed to look for resistance to Lamivudine (LAM), Adefovir dipivoxil (ADV), and/or ETV in a case where a virologic breakthrough has been observed after starting the study treatment (serum HBV DNA level has increased from the nadir by at least 1 log10 copies/mL) or where the serum HBV DNA level is not less than the HBV DNA detection limit (2.1 log10 copies/mL) at Week 24, Week 48 and Week 96. Virologic breakthrough was defined as 1.0 log10 or greater increases in serum HBV-DNA levels from on-treatment nadir. Participants who achieved the HBV-DNA values below lower limit of quantification (LLQ) (< 2.1 log10 copies/mL) in quantitative analysis at entire the study were also considered Negative in drug-resistance without implementation of genotypic analysis. Resistance mutation values were presented from Baseline to throughout the study. Baseline is defined as the value at Week 0 visit. | Screening, Week 24, Week 48, Week 96 and Virological Breakthrough (Baseline to throughout the study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tenofovir Disoproxil Fumarate, Chronic Hepatitis B