Chronic Hepatitis B, Hepatitis B
Conditions
Keywords
HBeAg-positive, chronic hepatitis B, telbivudine, entecavir, viral kinetics
Brief summary
This exploratory study is designed to determine the early viral kinetic profile during treatment with telbivudine or entecavir at multiple time points over 12 weeks.
Interventions
DRUGEntecavir
Entecavir 0.5 mg once daily for 12 weeks.
DRUGTelbivudine
Telbivudine 600 mg once daily for 12 weeks.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, 18-70 years of age with documented compensated hepatitis B e antigen (HBeAg)-positive chronic hepatitis B * Able to comply with study regimen and provide written informed consent
Exclusion criteria
* Pregnant or breastfeeding * Unwilling to use double barrier method of contraception * Co-infected with hepatitis C virus (HCV), hepatitis D virus (HDV) or human immunodeficiency virus (HIV) * Received Hepatitis B therapy in the past * Use of immunomodulatory therapy in past 12 months * History of or symptoms of hepatic decompensation or pancreatitis * Frequent or prolonged use of potentially hepatotoxic or nephrotoxic drugs * Concurrent medication likely to preclude compliance with schedule of evaluations * Use of other investigational drugs within 30 days of enrollment * Abnormal laboratory values during screening Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Hepatitis B Virus (HBV) DNA Levels | Baseline (day 1) to Week 12 (day 85) | Baseline HBV DNA is defined as the last pre-dose assessment of HBV DNA. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Area Under the Curve (AUC) of HBV DNA Change. | From Baseline to Week 12 | In AUC efficacy analyses, all the visits from baseline to Week 12 visit (including the planned and the repeated) with a non-missing HBV DNA level were included. |
| Change in Alanine Aminotransferase (ALT) Levels | From Baseline to Week 12 | — |
| Characterization of Very Early Viral Kinetics: Estimation of Viral Clearance | Baseline to 12 weeks | Viral kinetic parameters were estimated with a bi-phasic mathematical model: V(t) = (1-ε)pI(t) - cV(t) I(t) = (1- η)TV(t) - δI(t) V serum viral load, I productively infected cells, ε efficiency factor of blocking virus production, p viral production rate, c viral clearance rate, η efficiency factor of blocking de novo infection, β de novo infection rate, T uninfected target cells, δ rate of infected cell loss. Maximum-likelihood estimation for the viral kinetic parameters entailed fitting a nonlinear differential equation system via the least-squares approach from serum HBV DNA data. |
| Change in Mean HBV DNA Level | Baseline (day 1) to Weeks 2, 4, 8 | Baseline HBV DNA is defined as the last pre-dose assessment of HBV DNA.HBV DNA reductions, considered as the repeated measures, from baseline to Weeks 2, 4, 8. |
| Characterization of Very Early Viral Kinetics: Estimation of the Efficiency Factor of Blocking Virus Production | Baseline to 12 weeks | Viral kinetic parameters were estimated with a bi-phasic mathematical model of HBV DNA by using compartments of free virus, infected cells, and uninfected target cells. The model parameter of interest was the effectiveness of the drug in blocking virus production from infected cells (efficacy, ε). Blocking efficiency was within the range between 0 and 1. |
| Number of Patients Who Are Polymerase Chain Reaction (PCR) Negative | At Week 12 | PCR negative was considered \<300 copies/mL. PCR positive was considered =\>300 copies/mL. |
| Characterization of Very Early Viral Kinetics: Estimation of the Rate of Infected Cell Loss | Baseline to 12 weeks | Viral kinetic parameters were estimated with a bi-phasic mathematical model: V(t) = (1-ε)pI(t) - cV(t) I(t) = (1- η)TV(t) - δI(t) V serum viral load, I productively infected cells, ε efficiency factor of blocking virus production, p viral production rate, c viral clearance rate, η efficiency factor of blocking de novo infection, β de novo infection rate, T uninfected target cells, δ rate of infected cell loss. Maximum-likelihood estimation for the viral kinetic parameters entailed fitting a nonlinear differential equation system via the least-squares approach from serum HBV DNA data. |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Telbivudine Telbivudine 600 mg once daily for 12 weeks. | 23 |
| Entecavir Entecavir 0.5 mg once daily for 12 weeks. | 21 |
| Total | 44 |
Baseline characteristics
| Characteristic | Telbivudine | Entecavir | Total |
|---|---|---|---|
| Age, Continuous | 36.2 Years STANDARD_DEVIATION 9.62 | 33.4 Years STANDARD_DEVIATION 8.82 | 34.9 Years STANDARD_DEVIATION 9.25 |
| Sex: Female, Male Female | 5 Participants | 9 Participants | 14 Participants |
| Sex: Female, Male Male | 18 Participants | 12 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 23 | 7 / 21 |
| serious Total, serious adverse events | 1 / 23 | 0 / 21 |
Outcome results
Primary
Change in Mean Hepatitis B Virus (HBV) DNA Levels
Baseline HBV DNA is defined as the last pre-dose assessment of HBV DNA.
Time frame: Baseline (day 1) to Week 12 (day 85)
Population: Intent to Treat (ITT) population included all patients who received at least one dose of study drug and had at least one post-baseline assessment of serum HBV DNA. The randomized treatment was used in the analyses of this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telbivudine | Change in Mean Hepatitis B Virus (HBV) DNA Levels | Baseline (day 1) | 10.290 log10 copies/mL | Standard Deviation 1.6477 |
| Telbivudine | Change in Mean Hepatitis B Virus (HBV) DNA Levels | At Week 12 | 3.669 log10 copies/mL | Standard Deviation 0.8817 |
| Telbivudine | Change in Mean Hepatitis B Virus (HBV) DNA Levels | Change from Baseline to week 12 | -6.621 log10 copies/mL | Standard Deviation 1.561 |
| Entecavir | Change in Mean Hepatitis B Virus (HBV) DNA Levels | Baseline (day 1) | 9.721 log10 copies/mL | Standard Deviation 1.7141 |
| Entecavir | Change in Mean Hepatitis B Virus (HBV) DNA Levels | At Week 12 | 3.194 log10 copies/mL | Standard Deviation 1.1729 |
| Entecavir | Change in Mean Hepatitis B Virus (HBV) DNA Levels | Change from Baseline to week 12 | -6.527 log10 copies/mL | Standard Deviation 1.5365 |
Secondary
Change in Alanine Aminotransferase (ALT) Levels
Time frame: From Baseline to Week 12
Population: Intention to treat (ITT) population included all patients who received at least one dose of study drug and had at least one post-baseline assessment of serum HBV DNA. The randomized treatment was used in the analyses of this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telbivudine | Change in Alanine Aminotransferase (ALT) Levels | Baseline | 163.1 IU/L | Standard Deviation 125.29 |
| Telbivudine | Change in Alanine Aminotransferase (ALT) Levels | At Week 12 | 55.1 IU/L | Standard Deviation 63.92 |
| Telbivudine | Change in Alanine Aminotransferase (ALT) Levels | Change from Baseline to Week 12 | -108.0 IU/L | Standard Deviation 147.87 |
| Entecavir | Change in Alanine Aminotransferase (ALT) Levels | Baseline | 170.2 IU/L | Standard Deviation 152.74 |
| Entecavir | Change in Alanine Aminotransferase (ALT) Levels | At Week 12 | 54.0 IU/L | Standard Deviation 36.92 |
| Entecavir | Change in Alanine Aminotransferase (ALT) Levels | Change from Baseline to Week 12 | -116.3 IU/L | Standard Deviation 162.81 |
Secondary
Change in Mean HBV DNA Level
Baseline HBV DNA is defined as the last pre-dose assessment of HBV DNA.HBV DNA reductions, considered as the repeated measures, from baseline to Weeks 2, 4, 8.
Time frame: Baseline (day 1) to Weeks 2, 4, 8
Population: Intent to Treat (ITT) population included all patients who received at least one dose of study drug and had at least one post-baseline assessment of serum HBV DNA. The randomized treatment was used in the analyses of this population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telbivudine | Change in Mean HBV DNA Level | Change from Baseline to week 2 :(N=20, 21) | -3.999 log10 copies/mL | Standard Deviation 1.3917 |
| Telbivudine | Change in Mean HBV DNA Level | Change from Baseline to week 4 : (N= 23, 21) | -5.273 log10 copies/mL | Standard Deviation 1.3071 |
| Telbivudine | Change in Mean HBV DNA Level | Change from Baseline to week 8 : (N= 23, 21) | -6.161 log10 copies/mL | Standard Deviation 1.4937 |
| Entecavir | Change in Mean HBV DNA Level | Change from Baseline to week 2 :(N=20, 21) | -3.974 log10 copies/mL | Standard Deviation 1.346 |
| Entecavir | Change in Mean HBV DNA Level | Change from Baseline to week 4 : (N= 23, 21) | -4.875 log10 copies/mL | Standard Deviation 1.5781 |
| Entecavir | Change in Mean HBV DNA Level | Change from Baseline to week 8 : (N= 23, 21) | -5.976 log10 copies/mL | Standard Deviation 1.5288 |
Secondary
Characterization of Very Early Viral Kinetics: Estimation of the Efficiency Factor of Blocking Virus Production
Viral kinetic parameters were estimated with a bi-phasic mathematical model of HBV DNA by using compartments of free virus, infected cells, and uninfected target cells. The model parameter of interest was the effectiveness of the drug in blocking virus production from infected cells (efficacy, ε). Blocking efficiency was within the range between 0 and 1.
Time frame: Baseline to 12 weeks
Population: Intent to Treat (ITT) population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telbivudine | Characterization of Very Early Viral Kinetics: Estimation of the Efficiency Factor of Blocking Virus Production | 0.991 percentage of blocking efficiency | Standard Deviation 0.0133 |
| Entecavir | Characterization of Very Early Viral Kinetics: Estimation of the Efficiency Factor of Blocking Virus Production | 0.992 percentage of blocking efficiency | Standard Deviation 0.009 |
Secondary
Characterization of Very Early Viral Kinetics: Estimation of the Rate of Infected Cell Loss
Viral kinetic parameters were estimated with a bi-phasic mathematical model: V(t) = (1-ε)pI(t) - cV(t) I(t) = (1- η)TV(t) - δI(t) V serum viral load, I productively infected cells, ε efficiency factor of blocking virus production, p viral production rate, c viral clearance rate, η efficiency factor of blocking de novo infection, β de novo infection rate, T uninfected target cells, δ rate of infected cell loss. Maximum-likelihood estimation for the viral kinetic parameters entailed fitting a nonlinear differential equation system via the least-squares approach from serum HBV DNA data.
Time frame: Baseline to 12 weeks
Population: Intent to Treat (ITT) population. The value for the rate of infected cell loss for 1 patient in telbivudine arm was not used in calculation of summary statistics for this variable as this patient showed a deviation from the biphasic pattern in viral kinetic modeling.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telbivudine | Characterization of Very Early Viral Kinetics: Estimation of the Rate of Infected Cell Loss | 0.075 infected cell loss per day | Standard Deviation 0.0231 |
| Entecavir | Characterization of Very Early Viral Kinetics: Estimation of the Rate of Infected Cell Loss | 0.071 infected cell loss per day | Standard Deviation 0.0227 |
Secondary
Characterization of Very Early Viral Kinetics: Estimation of Viral Clearance
Viral kinetic parameters were estimated with a bi-phasic mathematical model: V(t) = (1-ε)pI(t) - cV(t) I(t) = (1- η)TV(t) - δI(t) V serum viral load, I productively infected cells, ε efficiency factor of blocking virus production, p viral production rate, c viral clearance rate, η efficiency factor of blocking de novo infection, β de novo infection rate, T uninfected target cells, δ rate of infected cell loss. Maximum-likelihood estimation for the viral kinetic parameters entailed fitting a nonlinear differential equation system via the least-squares approach from serum HBV DNA data.
Time frame: Baseline to 12 weeks
Population: Intent to Treat (ITT) population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telbivudine | Characterization of Very Early Viral Kinetics: Estimation of Viral Clearance | 0.809 clearance per day | Standard Deviation 0.3904 |
| Entecavir | Characterization of Very Early Viral Kinetics: Estimation of Viral Clearance | 1.002 clearance per day | Standard Deviation 0.8162 |
Secondary
Number of Patients Who Are Polymerase Chain Reaction (PCR) Negative
PCR negative was considered \<300 copies/mL. PCR positive was considered =\>300 copies/mL.
Time frame: At Week 12
Population: Intent to Treat (ITT) population included all patients who received at least one dose of study drug and had at least one post-baseline assessment of serum HBV DNA. The randomized treatment was used in the analyses of this population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Telbivudine | Number of Patients Who Are Polymerase Chain Reaction (PCR) Negative | <300 copies/mL | 2 Participants |
| Telbivudine | Number of Patients Who Are Polymerase Chain Reaction (PCR) Negative | >= 300 copies/mL | 21 Participants |
| Entecavir | Number of Patients Who Are Polymerase Chain Reaction (PCR) Negative | <300 copies/mL | 6 Participants |
| Entecavir | Number of Patients Who Are Polymerase Chain Reaction (PCR) Negative | >= 300 copies/mL | 15 Participants |
Secondary
The Area Under the Curve (AUC) of HBV DNA Change.
In AUC efficacy analyses, all the visits from baseline to Week 12 visit (including the planned and the repeated) with a non-missing HBV DNA level were included.
Time frame: From Baseline to Week 12
Population: Intention-to-treat (ITT) population included all patients who received at least one dose of study drug and had at least one post-baseline assessment of serum HBV DNA. The randomized treatment was used in the analyses of this population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telbivudine | The Area Under the Curve (AUC) of HBV DNA Change. | -453.5 (log10 copies/mL) * days | Standard Deviation 103.13 |
| Entecavir | The Area Under the Curve (AUC) of HBV DNA Change. | -442.6 (log10 copies/mL) * days | Standard Deviation 131.3 |