Chronic Hepatitis B
Conditions
Keywords
treatment naive, CHB, adefovir, monotherapy
Brief summary
This study is designed to compare the efficacy and safety of adefovir dipivoxil 10 mg with lamivudine 100 mg in Japanese patients with compensated chronic hepatitis B over 52-week periods.
Interventions
DRUGLAM group
Subjects took one LAM 100mg tablet orally once daily and one ADV placebo tablet orally once daily.
DRUGADV group
Subjects took one ADV 10mg tablet orally once daily and one LAM placebo tablet orally once daily.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Have compensated chronic hepatitis B. * Have not been treated with anti HBV agents with antiproliferative activity against. However, previous Interferon (IFN) therapy is permitted. * Ability to read, understand, and sign the informed consent. * Have a positive serum HBV-DNA \>= 1,000,000 copies/mL and ALT level 50-500 U/L
Exclusion criteria
* Having or suspected of having liver cancer. * Co-infected with Hepatitis C virus (HCV) or Human Immunodeficiency virus (HIV). * Autoimmune hepatitis. * Received any previous transplantation or having a plan for any transplantation. * Existence of any serious complication, except hepatitis B.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Hepatitis B Virus (HBV) DNA at Week 52 | Baseline and Week 52 | Change from baseline was the difference of the HBV DNA copy numbers (log10) in serum collected by blood draw between baseline and Week 52 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of HBV DNA Loss (< 400 Copies/mL) | From Baseline to Week 52 | Time to onset of an HBV DNA level in serum of less than 400 copies/mL was summarized using the Kaplan-Meier method. Regarding the Measured Values, the median time to onset and its upper limit for the ADV group and the upper limit of the median time to onset for the LAM group are non-estimable because they are not observed until the end of the study. The lower limit of the median time to onset for the ADV and LAM groups are 36.0 and 20.0, respectively. The median time to onset for the LAM group is 28.0 |
| Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Week 52 | Week 52 | Participants with loss of Hepatitis B e antigen (HBeAg) in serum collected by blood draw: Cheminoluminescent Immuno Assay (CLIA) method |
| Percentage of Participants With Hepatitis B e Antigen/Antibody (HBeAg/Ab) Seroconversion at Week 52 | Week 52 | Participants with loss of Hepatitis B e antigen (HBeAg) and positive for anti-Hepatitis B e antibody (HBeAb) in serum collected by blood draw: CLIA method |
| Time to Onset of HBeAg Loss | From Baseline to Week 52 | Time to onset with loss of HBeAg in serum collected by blood draw was summarized using the Kaplan-Meier method.: CLIA method. Regarding the Measured Values, the median time to onset and its lower limit and its upper limit for all groups are non-estimable because they are not observed until the end of the study. |
| Time to Onset of HBeAg/Ab Seroconversion | From Baseline to Week 52 | Time to onset of HBeAg/Ab seroconversion in serum collected by blood draw was summarized using the Kaplan-Meier method.: CLIA method. Regarding the Measured Values, the median time to onset and its lower limit and its upper limit for all groups are non-estimable because they are not observed until the end of the study. |
| Percentage of Participants With HBV DNA Loss (<400 Copies/mL) at Week 52 | Week 52 | The percentages of participants with an HBV DNA level in serum of less than 400 copies/mL, which is the lower limit of detection (HBV DNA loss) at Week 52 |
| Percentage of Participants With Hepatitis B s Antigen/ Antibody (HBsAg/Ab) Seroconversion at Week 52 | Week 52 | Participants with loss of Hepatitis B s antigen (HBsAg) and positive for anti-Hepatitis B s antibody (HBsAb) in serum collected by blood draw: CLIA method |
| Mean Alanine Aminotransferase (ALT) Level at Week 52 | Week 52 | Summary statistics were displayed for serum ALT. |
| Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 52 | Week 52 | ALT normalization was defined as an ALT value that was in the normal range (\<= 45IU/L; upper limit of normal \[ULN\]) at Week 52 of the participants whose ALT values were abnormal (\>45IU/L) at baseline |
| Time to Onset of ALT Normalization | From Baseline to Week 52 | Time to onset of ALT normalization was summarized using the Kaplan-Meier method. |
| Rate of Emergence of Resistant Virus at Week 52 | Week 52 | Participants with resistant mutation at Week 52. LAM resistant mutation (enzyme-linked mini-sequencing assay): rtM204I/V; ADV resistant mutation (direct sequencing assay): rtN236T or rtA181T/V in HBV DNA ; rt: reverse transcriptase gene |
| Percentage of Participants With Hepatitis B s Antigen (HBsAg) Loss at Week 52 | Week 52 | Participants with loss of Hepatitis B s antigen (HBsAg) in serum collected by blood draw: CLIA method |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Adefovir (ADV) ADV 10 mg orally once daily for 52 weeks | 50 |
| Lamivudine (LAM) LAM 100 mg orally once daily for 52 weeks | 52 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 6 |
| Overall Study | Consent withdrawn | 2 | 0 |
Baseline characteristics
| Characteristic | Lamivudine (LAM) | Total | Adefovir (ADV) |
|---|---|---|---|
| Age Continuous | 43.9 years STANDARD_DEVIATION 9.95 | 44 years STANDARD_DEVIATION 9.79 | 44 years STANDARD_DEVIATION 9.73 |
| Race/Ethnicity, Customized Asian | 52 Number of participants | 102 Number of participants | 50 Number of participants |
| Region of Enrollment Japan | 52 participants | 102 participants | 50 participants |
| Sex: Female, Male Female | 17 Participants | 26 Participants | 9 Participants |
| Sex: Female, Male Male | 35 Participants | 76 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 39 / 52 | 47 / 53 |
| serious Total, serious adverse events | 0 / 52 | 4 / 53 |
Outcome results
Primary
Mean Change From Baseline in Hepatitis B Virus (HBV) DNA at Week 52
Change from baseline was the difference of the HBV DNA copy numbers (log10) in serum collected by blood draw between baseline and Week 52
Time frame: Baseline and Week 52
Population: Per Protocol Set (PPS): participants in the Full Analysis Set (all subjects who entered the study, received at least one dose of investigational product, and had at least one efficacy assessment after the treatment initiation) population with no major protocol violations
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adefovir (ADV) | Mean Change From Baseline in Hepatitis B Virus (HBV) DNA at Week 52 | -3.69 log10 copies/mL | Standard Deviation 1.169 |
| Lamivudine (LAM) | Mean Change From Baseline in Hepatitis B Virus (HBV) DNA at Week 52 | -3.40 log10 copies/mL | Standard Deviation 1.896 |
p-value: <0.00195% CI: [-0.94, 0.28]ANCOVA
Secondary
Mean Alanine Aminotransferase (ALT) Level at Week 52
Summary statistics were displayed for serum ALT.
Time frame: Week 52
Population: PPS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adefovir (ADV) | Mean Alanine Aminotransferase (ALT) Level at Week 52 | 32.3 Units per Liter | Standard Deviation 14.72 |
| Lamivudine (LAM) | Mean Alanine Aminotransferase (ALT) Level at Week 52 | 33.0 Units per Liter | Standard Deviation 28.12 |
Secondary
Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 52
ALT normalization was defined as an ALT value that was in the normal range (\<= 45IU/L; upper limit of normal \[ULN\]) at Week 52 of the participants whose ALT values were abnormal (\>45IU/L) at baseline
Time frame: Week 52
Population: PPS: Participants with an abnormal ALT value (\>ULN) at baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adefovir (ADV) | Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 52 | With ALT normalization | 82.6 Percentage of participants |
| Adefovir (ADV) | Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 52 | Without ALT normalization | 17.4 Percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 52 | With ALT normalization | 78.4 Percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 52 | Without ALT normalization | 21.6 Percentage of participants |
Secondary
Percentage of Participants With HBV DNA Loss (<400 Copies/mL) at Week 52
The percentages of participants with an HBV DNA level in serum of less than 400 copies/mL, which is the lower limit of detection (HBV DNA loss) at Week 52
Time frame: Week 52
Population: PPS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adefovir (ADV) | Percentage of Participants With HBV DNA Loss (<400 Copies/mL) at Week 52 | <400 copies/mL | 46.0 Percentage of participants |
| Adefovir (ADV) | Percentage of Participants With HBV DNA Loss (<400 Copies/mL) at Week 52 | >400 copies/mL | 54.0 Percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With HBV DNA Loss (<400 Copies/mL) at Week 52 | <400 copies/mL | 50.0 Percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With HBV DNA Loss (<400 Copies/mL) at Week 52 | >400 copies/mL | 50.0 Percentage of participants |
Secondary
Percentage of Participants With Hepatitis B e Antigen/Antibody (HBeAg/Ab) Seroconversion at Week 52
Participants with loss of Hepatitis B e antigen (HBeAg) and positive for anti-Hepatitis B e antibody (HBeAb) in serum collected by blood draw: CLIA method
Time frame: Week 52
Population: PPS: participants who were positive for HBeAg and negative for HBeAb at baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adefovir (ADV) | Percentage of Participants With Hepatitis B e Antigen/Antibody (HBeAg/Ab) Seroconversion at Week 52 | With HBeAg/Ab seroconversion | 9.7 Percentage of participants |
| Adefovir (ADV) | Percentage of Participants With Hepatitis B e Antigen/Antibody (HBeAg/Ab) Seroconversion at Week 52 | Without HBeAg/Ab seroconversion | 90.3 Percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With Hepatitis B e Antigen/Antibody (HBeAg/Ab) Seroconversion at Week 52 | With HBeAg/Ab seroconversion | 5.9 Percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With Hepatitis B e Antigen/Antibody (HBeAg/Ab) Seroconversion at Week 52 | Without HBeAg/Ab seroconversion | 94.1 Percentage of participants |
Secondary
Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Week 52
Participants with loss of Hepatitis B e antigen (HBeAg) in serum collected by blood draw: Cheminoluminescent Immuno Assay (CLIA) method
Time frame: Week 52
Population: PPS: participants who were positive for HBeAg at baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adefovir (ADV) | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Week 52 | With loss of HBeAg | 16.7 percentage of participants |
| Adefovir (ADV) | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Week 52 | Positive for HBeAg | 93.3 percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Week 52 | With loss of HBeAg | 16.2 percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Week 52 | Positive for HBeAg | 93.8 percentage of participants |
Secondary
Percentage of Participants With Hepatitis B s Antigen/ Antibody (HBsAg/Ab) Seroconversion at Week 52
Participants with loss of Hepatitis B s antigen (HBsAg) and positive for anti-Hepatitis B s antibody (HBsAb) in serum collected by blood draw: CLIA method
Time frame: Week 52
Population: PPS: participants who were positive for HBsAg and negative for HBsAb at baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adefovir (ADV) | Percentage of Participants With Hepatitis B s Antigen/ Antibody (HBsAg/Ab) Seroconversion at Week 52 | With HBsAg/Ab seroconversion | 0.0 percentage of participants |
| Adefovir (ADV) | Percentage of Participants With Hepatitis B s Antigen/ Antibody (HBsAg/Ab) Seroconversion at Week 52 | Without HBsAg/Ab seroconversion | 100.0 percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With Hepatitis B s Antigen/ Antibody (HBsAg/Ab) Seroconversion at Week 52 | With HBsAg/Ab seroconversion | 0.0 percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With Hepatitis B s Antigen/ Antibody (HBsAg/Ab) Seroconversion at Week 52 | Without HBsAg/Ab seroconversion | 100.0 percentage of participants |
Secondary
Percentage of Participants With Hepatitis B s Antigen (HBsAg) Loss at Week 52
Participants with loss of Hepatitis B s antigen (HBsAg) in serum collected by blood draw: CLIA method
Time frame: Week 52
Population: PPS: participants who were positive for HBsAg at baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adefovir (ADV) | Percentage of Participants With Hepatitis B s Antigen (HBsAg) Loss at Week 52 | Positive for HBsAg | 100.0 percentage of participants |
| Adefovir (ADV) | Percentage of Participants With Hepatitis B s Antigen (HBsAg) Loss at Week 52 | With loss of HBsAg | 0.0 percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With Hepatitis B s Antigen (HBsAg) Loss at Week 52 | With loss of HBsAg | 0.0 percentage of participants |
| Lamivudine (LAM) | Percentage of Participants With Hepatitis B s Antigen (HBsAg) Loss at Week 52 | Positive for HBsAg | 100.0 percentage of participants |
Secondary
Rate of Emergence of Resistant Virus at Week 52
Participants with resistant mutation at Week 52. LAM resistant mutation (enzyme-linked mini-sequencing assay): rtM204I/V; ADV resistant mutation (direct sequencing assay): rtN236T or rtA181T/V in HBV DNA ; rt: reverse transcriptase gene
Time frame: Week 52
Population: PPS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adefovir (ADV) | Rate of Emergence of Resistant Virus at Week 52 | With resistant mutation | 0 Percentage of participants |
| Adefovir (ADV) | Rate of Emergence of Resistant Virus at Week 52 | Without resistant mutation | 100 Percentage of participants |
| Lamivudine (LAM) | Rate of Emergence of Resistant Virus at Week 52 | With resistant mutation | 28.8 Percentage of participants |
| Lamivudine (LAM) | Rate of Emergence of Resistant Virus at Week 52 | Without resistant mutation | 71.2 Percentage of participants |
Secondary
Time to Onset of ALT Normalization
Time to onset of ALT normalization was summarized using the Kaplan-Meier method.
Time frame: From Baseline to Week 52
Population: PPS: Participants with abnormal ALT value (\>ULN) at baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adefovir (ADV) | Time to Onset of ALT Normalization | 12.0 Week 52 |
| Lamivudine (LAM) | Time to Onset of ALT Normalization | 12.0 Week 52 |
Secondary
Time to Onset of HBeAg/Ab Seroconversion
Time to onset of HBeAg/Ab seroconversion in serum collected by blood draw was summarized using the Kaplan-Meier method.: CLIA method. Regarding the Measured Values, the median time to onset and its lower limit and its upper limit for all groups are non-estimable because they are not observed until the end of the study.
Time frame: From Baseline to Week 52
Secondary
Time to Onset of HBeAg Loss
Time to onset with loss of HBeAg in serum collected by blood draw was summarized using the Kaplan-Meier method.: CLIA method. Regarding the Measured Values, the median time to onset and its lower limit and its upper limit for all groups are non-estimable because they are not observed until the end of the study.
Time frame: From Baseline to Week 52
Secondary
Time to Onset of HBV DNA Loss (< 400 Copies/mL)
Time to onset of an HBV DNA level in serum of less than 400 copies/mL was summarized using the Kaplan-Meier method. Regarding the Measured Values, the median time to onset and its upper limit for the ADV group and the upper limit of the median time to onset for the LAM group are non-estimable because they are not observed until the end of the study. The lower limit of the median time to onset for the ADV and LAM groups are 36.0 and 20.0, respectively. The median time to onset for the LAM group is 28.0
Time frame: From Baseline to Week 52