Hepatitis B
Conditions
Keywords
lamivudine resistance, Hepatitis B virus
Brief summary
This study is being conducted to compare the safety and effectiveness of the investigational medication LdT (telbivudine) used in combination with adefovir dipivoxil (a drug currently approved by the Food and Drug Administration \[FDA\] for the treatment of hepatitis B virus \[HBV\]) versus adefovir dipivoxil used alone. The results for patients taking the combination therapy will be compared to the results for patients taking adefovir alone.
Interventions
DRUGtelbivudine
600mg/day oral tablet for 96 weeks
DRUGadefovir dipivoxil
10 mg of adefovir by mouth once daily
Sponsors
Novartis
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
* Documented compensated chronic hepatitis B defined by a clinical history compatible with chronic hepatitis B. * Previous or current lamivudine treatment * HBV DNA \> 6 log10 copies/mL * Evidence of viral breakthrough Other protocol-defined inclusion criteria may apply.
Exclusion criteria
* Patient is pregnant or breastfeeding. * Patient is co-infected with hepatitis C virus (HCV), hepatitis D virus (HDV), or HIV. * Patient has received any anti-HBV treatment for HBV infection other than lamivudine in the 12 months before Screening for this study. Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Participants Who Experienced Virologic Breakthrough | 96 Weeks | Virologic breakthrough is defined as a minimum of 1 log reduction from baseline followed by a 1 log increase from nadir on at least 2 consecutive visits including the last treatment visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | Baseline to 12 weeks, 24 weeks, 48 weeks and 60 weeks | Efficacy was assessed by the change from baseline in mean HBV DNA concentration after 12, 24, 48 and 60 weeks of treatment. |
| Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | 12 week, 24 week, 48 week and 60 weeks | Undetectable HBV DNA = HBV DNA \<300 copies/ml. Serum aminotransferase (ALT) normalization is defined as ALT within normal limits on 2 successive visits for a pt. with an elevated ALT level (\>=1.0 x ULN) at baseline (BL). Hepatitis B e antigen (HBeAg) loss is defined as the loss of detectable serum HBeAg in a pt. who was HBeAg +ve at BL. HBeAg seroconversion is defined as HBeAg loss with detectable HBeAb. Hepatitis B surface antigen (HBsAg) loss is defined as the loss of detectable serum HBsAg in a pt. who was HBsAg +ve at BL. HBsAg seroconversion is defined as HBsAg loss with detectable HBsAb. |
| Proportion of Participants With Treatment-emergent HBV Resistance Mutations Associated With Virologic Breakthrough | Week 96 | The study was not completed as planned and was terminated early with agreement from the European Medicines Agency (EMEA). Patients did not receive 96 weeks of treatment. Therefore, the primary objective of evaluating virologic breakthrough by Week 96 could not be assessed. Consequently, all protocol-specified inferential analyses on the primary endpoint and all other key secondary efficacy endpoints could not be performed. |
Countries
Hong Kong, South Korea, Taiwan, Thailand, United States
Participant flow
Recruitment details
Planned enrollment was 150 patients. At the time of study termination, 43 patients had been enrolled and randomized to study treatment and 42 patients received study drug (21 patients in the combination group and 21 in the monotherapy group).
Pre-assignment details
One patient was randomized but never received study drug treatment because he was discontinued on the randomization day due to sponsor request.
Participants by arm
| Arm | Count |
|---|---|
| Combination Therapy Combination therapy: 600 mg of telbivudine (LdT) by mouth plus 10 mg of adefovir (ADV) by mouth once daily for 96 weeks. | 22 |
| Adefovir Monotherapy Adefovir monotherapy: 10 mg of adefovir by mouth once daily for 96 weeks. | 21 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Patient request | 1 | 0 |
| Overall Study | Sponsor request - study termination | 21 | 21 |
Baseline characteristics
| Characteristic | Combination Therapy | Adefovir Monotherapy | Total |
|---|---|---|---|
| Age Continuous | 36.8 years STANDARD_DEVIATION 11.82 | 39.0 years STANDARD_DEVIATION 10.93 | 37.9 years STANDARD_DEVIATION 11.32 |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 19 Participants | 16 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 21 | 11 / 21 |
| serious Total, serious adverse events | 1 / 21 | 0 / 21 |
Outcome results
Primary
The Proportion of Participants Who Experienced Virologic Breakthrough
Virologic breakthrough is defined as a minimum of 1 log reduction from baseline followed by a 1 log increase from nadir on at least 2 consecutive visits including the last treatment visit.
Time frame: 96 Weeks
Population: This study was terminated early and no patients received 96 weeks of treatment. Therefore, the primary objective of evaluating virologic breakthrough by Week 96 could not be assessed. Consequently, all protocol-specified inferential analyses on the primary endpoint and all other key secondary efficacy endpoints could not be performed.
Secondary
Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration
Efficacy was assessed by the change from baseline in mean HBV DNA concentration after 12, 24, 48 and 60 weeks of treatment.
Time frame: Baseline to 12 weeks, 24 weeks, 48 weeks and 60 weeks
Population: Analysis population consists of the intent-to-treat population. Analysis of data for each time point includes participants who had both baseline and post baseline observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Baseline (N = 21, 20) | 10.240 Log10 Copies/mL | Standard Deviation 1.575 |
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Week 12 | 4.405 Log10 Copies/mL | Standard Deviation 0.9944 |
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | Change from Baseline to Week 12 | -5.835 Log10 Copies/mL | Standard Deviation 1.6435 |
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Baseline (N = 20, 20) | 10.279 Log10 Copies/mL | Standard Deviation 1.6058 |
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Week 24 | 3.678 Log10 Copies/mL | Standard Deviation 1.0483 |
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | Change from Baseline to Week 24 | -6.601 Log10 Copies/mL | Standard Deviation 1.7873 |
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Baseline (N = 13, 9) | 10.652 Log10 Copies/mL | Standard Deviation 1.5203 |
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Week 48 | 3.274 Log10 Copies/mL | Standard Deviation 1.0254 |
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | Change from Baseline to Week 48 | -7.378 Log10 Copies/mL | Standard Deviation 1.9303 |
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Baseline (N = 2, 3) | 9.605 Log10 Copies/mL | Standard Deviation 0.799 |
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Week 60 | 3.360 Log10 Copies/mL | Standard Deviation 0.3111 |
| Combination Therapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | Change from Baseline to Week 60 | -6.245 Log10 Copies/mL | Standard Deviation 0.4879 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Week 60 | 4.330 Log10 Copies/mL | Standard Deviation 0.611 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Baseline (N = 21, 20) | 10.127 Log10 Copies/mL | Standard Deviation 0.9697 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Baseline (N = 13, 9) | 10.207 Log10 Copies/mL | Standard Deviation 0.752 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Week 12 | 5.515 Log10 Copies/mL | Standard Deviation 1.3188 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Baseline (N = 2, 3) | 10.097 Log10 Copies/mL | Standard Deviation 0.1484 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | Change from Baseline to Week 12 | -4.612 Log10 Copies/mL | Standard Deviation 1.7725 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Week 48 | 5.272 Log10 Copies/mL | Standard Deviation 1.9581 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Baseline (N = 20, 20) | 10.127 Log10 Copies/mL | Standard Deviation 0.9697 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | Change from Baseline to Week 60 | -5.767 Log10 Copies/mL | Standard Deviation 0.465 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | At Week 24 | 5.161 Log10 Copies/mL | Standard Deviation 1.7364 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | Change from Baseline to Week 48 | -4.934 Log10 Copies/mL | Standard Deviation 2.1153 |
| Adefovir Monotherapy | Change From Baseline in Mean Hepatitis B Virus (HBV) DNA Concentration | Change from Baseline to Week 24 | -4.966 Log10 Copies/mL | Standard Deviation 2.2851 |
Secondary
Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria
Undetectable HBV DNA = HBV DNA \<300 copies/ml. Serum aminotransferase (ALT) normalization is defined as ALT within normal limits on 2 successive visits for a pt. with an elevated ALT level (\>=1.0 x ULN) at baseline (BL). Hepatitis B e antigen (HBeAg) loss is defined as the loss of detectable serum HBeAg in a pt. who was HBeAg +ve at BL. HBeAg seroconversion is defined as HBeAg loss with detectable HBeAb. Hepatitis B surface antigen (HBsAg) loss is defined as the loss of detectable serum HBsAg in a pt. who was HBsAg +ve at BL. HBsAg seroconversion is defined as HBsAg loss with detectable HBsAb.
Time frame: 12 week, 24 week, 48 week and 60 weeks
Population: Analysis population consists of the intent-to-treat population. Analysis of data for each time point includes participants who had both baseline and post baseline observation for that timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Serum ALT normalization at week 24 | 55.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Undetectable HBV DNA at week 12 | 4.8 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Undetectable HBV DNA at week 24 | 15.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg loss at week 48 | 23.1 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Undetectable HBV DNA at week 48 | 38.5 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Undetectable HBV DNA at week 60 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Serum ALT normalization at week 12 | 40.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Serum ALT normalization at week 48 | 69.2 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Serum ALT normalization at week 60 | 50.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg loss at week 12 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg loss at week 24 | 5.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg loss at week 60 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg seroconversion at week 12 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg seroconversion at week 24 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg seroconversion at week 48 | 15.4 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg seroconversion at week 60 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg loss at week 12 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg loss at week 24 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg loss at week 48 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg loss at week 60 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg seroconversion at week 12 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg seroconversion at week 24 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg seroconversion at week 48 | 0.0 Percentage of participants |
| Combination Therapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg seroconversion at week 60 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg seroconversion at week 48 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg seroconversion at week 12 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Undetectable HBV DNA at week 12 | 5.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg loss at week 48 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Undetectable HBV DNA at week 24 | 10.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg seroconversion at week 24 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg seroconversion at week 24 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Undetectable HBV DNA at week 48 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg seroconversion at week 48 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Undetectable HBV DNA at week 60 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg loss at week 60 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Serum ALT normalization at week 12 | 25.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg seroconversion at week 60 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Serum ALT normalization at week 24 | 35.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Serum ALT normalization at week 48 | 33.3 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg seroconversion at week 60 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | Serum ALT normalization at week 60 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg loss at week 12 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg loss at week 12 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg seroconversion at week 12 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg loss at week 24 | 5.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg loss at week 48 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBsAg loss at week 24 | 0.0 Percentage of participants |
| Adefovir Monotherapy | Percentage of Participants Achieving Specified Clinical and Laboratory Safety Criteria | HBeAg loss at week 60 | 0.0 Percentage of participants |
Secondary
Proportion of Participants With Treatment-emergent HBV Resistance Mutations Associated With Virologic Breakthrough
The study was not completed as planned and was terminated early with agreement from the European Medicines Agency (EMEA). Patients did not receive 96 weeks of treatment. Therefore, the primary objective of evaluating virologic breakthrough by Week 96 could not be assessed. Consequently, all protocol-specified inferential analyses on the primary endpoint and all other key secondary efficacy endpoints could not be performed.
Time frame: Week 96