Chronic Hepatitis B
Conditions
Brief summary
The purpose of this clinical research study is to find out whether a combination of entecavir (ETV) plus tenofovir (TNF) works better against Hepatitis B virus than adefovir (ADV) added to continuing lamivudine (LVD) therapy in patients whose Hepatitis B virus (HBV) is resistant against lamivudine. The safety of this treatment will also be studied.
Interventions
Tablets, Oral Entecavir 1 mg + Tenofovir 300 mg, once daily, 100 weeks
DRUGAdefovir + continuing Lamivudine
Tablets, Oral, Adefovir 10 mg + Lamivudine, 100 mg, once daily, 100 weeks
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Chronic HBV infection * History of lamivudine (LVD) treatment, and lamivudine resistance (LVDr), receiving LVD at screening visit * Compensated liver function * HBV DNA ≥ 172,000 IU/mL * Hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative
Exclusion criteria
* Evidence of decompensated cirrhosis * Coinfection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis D virus (HDV) * Recent history of pancreatitis * Serum alpha fetoprotein \> 100 ng/mL * Except lamivudine, any prior therapy with nucleoside or nucleotide analogue antiviral agents with activity against hepatitis B
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved an Hepatitis B Virus DNA (HBV DNA) Level < 50 IU/mL at Week 48 | Week 48 | using the Roche COBAS® TaqMan HBV Test for use with the High Pure System (HPS) assay, by Polymerase Chain Reaction (PCR); HBV DNA \< 50 IU/mL = approximately 300 copies/mL |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | Day 1 through end of treatment (Week 100 +/- 5 days) | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and/or is an important medical event. |
| Number of Participants Who Achieved HBV DNA < the Lower Limit of Detection (LLD) at Weeks 48 and 96 | Week 48, Week 96 | by PCR, using the Roche for the Roche COBAS® TaqMan - HPS assay. LLD = 4.8 IU/mL (approximately 28 copies/mL) |
| HBV DNA Values at Weeks 48 and 96 | Weeks 48, Week 96 | Number of Participants with HBV DNA \<LLD (4.8); LLD to \<50; 50 to \<172; 172 to \<1,720; 1,720 to \<17,200; and ≥17,200 IU/mL (\<LLD (28); 28 to \<300; 300 to \<1,000; 1,000 to \<10,000; 10,000 to \<100,000; and ≥100,000 copies/mL by PCR, using the Roche COBAS®TaqMan - HPS assay |
| Mean log10 Reduction From Baseline in HBV DNA at Weeks 48 and 96 | Week 48, Week 96 | by PCR, using the Roche COBAS®TaqMan - HPS assay |
| Number of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieved ALT Normalization (≤ 1 x ULN) at Weeks 48 and 96 | Week 48, Week 96 | — |
| Number of Participants Who Achieved an HBV DNA Level <50 IU/mL at Week 96 | Week 96 | by PCR, using the Roche COBAS®TaqMan - HPS assay; HBV DNA \< 50 IU/mL = approximately 300 copies/mL. |
| Number of Participants Who Were HBeAg-positive at Baseline With HBe Seroconversion at Weeks 48 and 96 | Baseline, Week 48, Week 96 | HBe seroconversion = HBeAg loss and presence of hepatitis B e-antibody (HBeAb) |
| Number of Participants With Hepatitis-B-Virus Surface Antigen of the (HBsAg) Loss at Weeks 48 and 96 | Week 48, Week 96 | Hepatitis B surface antigen (HBsAg) = a part of the hepatitis B virus that, when in the blood, is an early marker of infection |
| Number of Participants With HBs Seroconversion (HBsAg Loss and Presence of HBsAb) at Weeks 48 and 96 | Week 48, Week 96 | Hepatitis B surface antigen (HBsAg) = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBsAb = HBsAg antibodies. HBs Seroconversion = HBsAg loss and presence of HBseAb |
| Number of Participants With Genotypic Resistance Based on Analysis of Samples From Participants With HBV DNA ≥ 50 IU/mL at Weeks 48 and 96 | Week 48, Week 96 | HBV DNA ≥ 50 IU/mL = approximately 300 copies/mL |
| Number of Participants Who Were Hepatitis B E-antigen (HBeAg)-Positive at Baseline With Loss of HBeAg at Weeks 48 and 96 | Baseline, Week 48, Week 96 | HBeAg is a hepatitis B viral protein. It is an indicator of active viral replication. |
Countries
Belgium, Germany, Italy, Poland, Turkey (Türkiye), United States
Participant flow
Recruitment details
A total of 84 subjects were to be treated with entecavir (ETV) plus tenofovir (TNF) or adefovir (ADV) added to continuing lamivudine (LVD).
Pre-assignment details
Of the 4 subjects enrolled, 2 were not randomized (reasons: Subject no longer meets study criteria and Other). Both subjects randomized were treated as well.
Participants by arm
| Arm | Count |
|---|---|
| Entecavir + Tenofovir Tablets, Oral, Entecavir 1 mg + Tenofovir 300 mg, once daily, 100 weeks | 1 |
| Adefovir + Continuing Lamivudine Tablets, Oral, Adefovir 10 mg + Lamivudine, 100 mg, once daily, 100 weeks | 1 |
| Total | 2 |
Baseline characteristics
| Characteristic | Entecavir + Tenofovir | Adefovir + Continuing Lamivudine | Total |
|---|---|---|---|
| Age, Customized >=65 years | 1 participants | 0 participants | 1 participants |
| Age, Customized Between 18 and 65 years | 0 participants | 1 participants | 1 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 |
Outcome results
Primary
Number of Participants Who Achieved an Hepatitis B Virus DNA (HBV DNA) Level < 50 IU/mL at Week 48
using the Roche COBAS® TaqMan HBV Test for use with the High Pure System (HPS) assay, by Polymerase Chain Reaction (PCR); HBV DNA \< 50 IU/mL = approximately 300 copies/mL
Time frame: Week 48
Population: Due to early study termination, none of the efficacy endpoints were analyzed.
Secondary
HBV DNA Values at Weeks 48 and 96
Number of Participants with HBV DNA \<LLD (4.8); LLD to \<50; 50 to \<172; 172 to \<1,720; 1,720 to \<17,200; and ≥17,200 IU/mL (\<LLD (28); 28 to \<300; 300 to \<1,000; 1,000 to \<10,000; 10,000 to \<100,000; and ≥100,000 copies/mL by PCR, using the Roche COBAS®TaqMan - HPS assay
Time frame: Weeks 48, Week 96
Population: Due to early study termination, none of the efficacy endpoints were analyzed.
Secondary
Mean log10 Reduction From Baseline in HBV DNA at Weeks 48 and 96
by PCR, using the Roche COBAS®TaqMan - HPS assay
Time frame: Week 48, Week 96
Population: Due to early study termination, none of the efficacy endpoints was analyzed.
Secondary
Number of Participants Who Achieved an HBV DNA Level <50 IU/mL at Week 96
by PCR, using the Roche COBAS®TaqMan - HPS assay; HBV DNA \< 50 IU/mL = approximately 300 copies/mL.
Time frame: Week 96
Population: Due to early study termination, none of the efficacy endpoints were analyzed.
Secondary
Number of Participants Who Achieved HBV DNA < the Lower Limit of Detection (LLD) at Weeks 48 and 96
by PCR, using the Roche for the Roche COBAS® TaqMan - HPS assay. LLD = 4.8 IU/mL (approximately 28 copies/mL)
Time frame: Week 48, Week 96
Population: Due to early study termination, none of the efficacy endpoints were analyzed.
Secondary
Number of Participants Who Were HBeAg-positive at Baseline With HBe Seroconversion at Weeks 48 and 96
HBe seroconversion = HBeAg loss and presence of hepatitis B e-antibody (HBeAb)
Time frame: Baseline, Week 48, Week 96
Population: Due to early study termination, none of the efficacy endpoints were analyzed.
Secondary
Number of Participants Who Were Hepatitis B E-antigen (HBeAg)-Positive at Baseline With Loss of HBeAg at Weeks 48 and 96
HBeAg is a hepatitis B viral protein. It is an indicator of active viral replication.
Time frame: Baseline, Week 48, Week 96
Population: Due to early study termination, none of the efficacy endpoints was analyzed.
Secondary
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities
AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and/or is an important medical event.
Time frame: Day 1 through end of treatment (Week 100 +/- 5 days)
Population: All treated participants. Timeframe for Outcome Measure revised due to study termination. (Study Completion Date=February 2009).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir + Tenofovir | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | SAEs | 0 participants |
| Entecavir + Tenofovir | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | Discontinuations due to AEs | 0 participants |
| Entecavir + Tenofovir | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | Deaths | 0 participants |
| Entecavir + Tenofovir | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | Discontinuations due to Laboratory Abnormalities | 0 participants |
| Entecavir + Tenofovir | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | AEs | 1 participants |
| Adefovir + Continuing Lamivudine | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | Discontinuations due to Laboratory Abnormalities | 0 participants |
| Adefovir + Continuing Lamivudine | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | AEs | 1 participants |
| Adefovir + Continuing Lamivudine | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | SAEs | 0 participants |
| Adefovir + Continuing Lamivudine | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | Deaths | 0 participants |
| Adefovir + Continuing Lamivudine | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | Discontinuations due to AEs | 0 participants |
Secondary
Number of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieved ALT Normalization (≤ 1 x ULN) at Weeks 48 and 96
Time frame: Week 48, Week 96
Population: Due to early study termination, none of the efficacy endpoints were analyzed.
Secondary
Number of Participants With Genotypic Resistance Based on Analysis of Samples From Participants With HBV DNA ≥ 50 IU/mL at Weeks 48 and 96
HBV DNA ≥ 50 IU/mL = approximately 300 copies/mL
Time frame: Week 48, Week 96
Population: Due to early study termination, none of the efficacy endpoints were analyzed.
Secondary
Number of Participants With HBs Seroconversion (HBsAg Loss and Presence of HBsAb) at Weeks 48 and 96
Hepatitis B surface antigen (HBsAg) = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBsAb = HBsAg antibodies. HBs Seroconversion = HBsAg loss and presence of HBseAb
Time frame: Week 48, Week 96
Population: Due to early study termination, none of the efficacy endpoints were analyzed.
Secondary
Number of Participants With Hepatitis-B-Virus Surface Antigen of the (HBsAg) Loss at Weeks 48 and 96
Hepatitis B surface antigen (HBsAg) = a part of the hepatitis B virus that, when in the blood, is an early marker of infection
Time frame: Week 48, Week 96
Population: Due to early study termination, none of the efficacy endpoints were analyzed.