Hepatitis B, Chronic
Conditions
Brief summary
Switching to Entecavir will result in superior antiviral efficacy as compared to continuing with Adefovir in patients with a suboptimal response to Adefovir
Interventions
DRUGEntecavir
Tablets, Oral, 0.5 mg, once daily (QD), 52 weeks
DRUGAdefovir/Entecavir
Tablets, Oral, 10-mg adefovir QD for 12 weeks followed by 0.5-mg entecavir QD for a maximum of 52 weeks
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Chronic infection with hepatitis B virus (HBV)(detectable hepatitis B surface antibody (HBsAg) at screening and at least 24 weeks prior to screening, or detectable HBsAg for \<24 weeks and negative for immunoglobulin M core antibody) * Documentation of hepatitis B e antigen (HBeAg) positive or negative status * Naive to nucleoside/nucleotide analogues, with the exception of adefovir * Suboptimal response to adefovir treatment * No lamivudine/telbivudine, entecavir, or adefovir resistance-associated substitutions at screening * Male or female gender, aged 16 years and older * Compensated liver function * Serum alanine aminotransferase level \<10\*upper limit of normal at screening
Exclusion criteria
* Women who are pregnant or breastfeeding * Evidence of decompensated cirrhosis * Coinfection with HIV, hepatitis C virus, or hepatitis D virus * Recent history of pancreatitis (within 24 weeks prior to the first dose of study medication) * Chronic renal insufficiency, defined as a creatinine clearance \<50 mL/min * Current abuse of illegal drugs or alcohol, sufficient in the investigator's opinion to prevent adequate compliance with study therapy or to increase the risk of hepatotoxicity or pancreatitis * Other serious medical conditions that might preclude completion of this study or that require chronic administration of prohibited medications * Serum creatinine level \>1.5 mg/dL; hemoglobin level \<10.0 g/dL; platelet count \<70,000/mm\^3; absolute neutrophil count \<1500 cells/mm\^3; serum alpha fetoprotein level \>100 ng/mL * Except adefovir, any prior therapy with nucleoside or nucleotide analogue antiviral agents with activity against hepatitis B (eg, lamivudine, entecavir), or any other experimental anti-HBV antiviral, or any China Traditional Medicine * Therapy with interferon, thymosin alpha, or other immunostimulators within 24 weeks of randomization * Required chronic administration of medications that cause immunosuppression, that are associated with a high risk of nephrotoxicity or hepatotoxicity, or that affect renal excretion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved a Hepatitis B Virus (HBV) DNA Level <50 IU/mL at Week 12 by Polymerase Chain Reaction Testing | At Week 12 from Day 1 | HBV DNA Level \<50 IU/mL=approximately 300 copies/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean log10 Reduction From Baseline in Serum HBV DNA Level by Polymerase Chain Reaction Testing | At Weeks 12 and 48 from Day 1 | HBV=hepatitis B virus |
| Percentage of Participants Who Achieved Normalization of Alanine Aminotransferase (ALT) | At Weeks 12 and 48 from Day 1 | ULN=upper limit of normal. ALT normalization= ≤1\*ULN, among participants with baseline ALT \>1\*ULN |
| Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion | At Weeks 12 and 48 from Day 1 | — |
| Percentage of Participants Who Achieved an HBV DNA Level <50 IU/mL at Week 48 by Polymerase Chain Reaction Testing | At Week 48 from Day 1 | HBV=hepatitis B virus. HBV DNA Level \<50 IU/mL=approximately 300 copies/mL. |
| Number of Participants With Genotypic Resistance to Entecavir | At Week 48 from Day 1 | — |
| Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | Continually from Day 1 through Week 48, and through 24-week follow-up period | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=possibly, probably, or certainly related to and of unknown relationship to study drug. |
| Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results | Day 1 through Week 48 | Hematology testing assessed levels of hemoglobin, white blood cells, platelets, neutrophils, international normalized ration, red blood cells, lymphocytes, and monocytes. |
| Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion | At Weeks 12 and 48 from Day 1 | — |
Countries
China
Participant flow
Pre-assignment details
A total of 228 participants were enrolled, of which 169 were randomized. A total of 166 participants received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Entecavir, 0.5 mg QD Participants with a pervious suboptimal response to adefovir received entecavir, 0.5 mg once daily (QD), for a maximum of 52 weeks. | 89 |
| Adefovir, 10 mg QD/Entecavir, 0.5 mg QD Participants with a previous suboptimal response to adefovir received adefovir, 10 mg QD, for 12 weeks. At 12 weeks, participants were switched to entecavir, 0.5 mg QD, for a maximum of 40 weeks. | 77 |
| Total | 166 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Not identified | 2 | 7 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Adefovir, 10 mg QD/Entecavir, 0.5 mg QD | Total | Entecavir, 0.5 mg QD |
|---|---|---|---|
| Age Continuous | 34.1 Years | 33.4 Years | 32.6 Years |
| Race/Ethnicity, Customized Asian | 77 Participants | 166 Participants | 89 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 10 Participants | 24 Participants | 14 Participants |
| Sex: Female, Male Male | 67 Participants | 142 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 89 | 9 / 77 |
| serious Total, serious adverse events | 1 / 89 | 0 / 77 |
Outcome results
Primary
Percentage of Participants Who Achieved a Hepatitis B Virus (HBV) DNA Level <50 IU/mL at Week 12 by Polymerase Chain Reaction Testing
HBV DNA Level \<50 IU/mL=approximately 300 copies/mL.
Time frame: At Week 12 from Day 1
Population: Participants who were randomized and received at least~1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir, 0.5 mg QD | Percentage of Participants Who Achieved a Hepatitis B Virus (HBV) DNA Level <50 IU/mL at Week 12 by Polymerase Chain Reaction Testing | 5.6 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants Who Achieved a Hepatitis B Virus (HBV) DNA Level <50 IU/mL at Week 12 by Polymerase Chain Reaction Testing | 0.0 Percentage of participants |
Secondary
Mean log10 Reduction From Baseline in Serum HBV DNA Level by Polymerase Chain Reaction Testing
HBV=hepatitis B virus
Time frame: At Weeks 12 and 48 from Day 1
Population: Participants who were randomized and received at least~1 dose of study drug. n=number of evaluable participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Entecavir, 0.5 mg QD | Mean log10 Reduction From Baseline in Serum HBV DNA Level by Polymerase Chain Reaction Testing | Week 12 (n=88, 77) | -2.5 log10 IU/mL | Standard Deviation 1.2 |
| Entecavir, 0.5 mg QD | Mean log10 Reduction From Baseline in Serum HBV DNA Level by Polymerase Chain Reaction Testing | Week 48 (n=87, 71) | -3.3 log10 IU/mL | Standard Deviation 1.5 |
| Adefovir, 10 mg QD | Mean log10 Reduction From Baseline in Serum HBV DNA Level by Polymerase Chain Reaction Testing | Week 12 (n=88, 77) | -0.2 log10 IU/mL | Standard Deviation 1.1 |
| Adefovir, 10 mg QD | Mean log10 Reduction From Baseline in Serum HBV DNA Level by Polymerase Chain Reaction Testing | Week 48 (n=87, 71) | -3.2 log10 IU/mL | Standard Deviation 1.3 |
Secondary
Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=possibly, probably, or certainly related to and of unknown relationship to study drug.
Time frame: Continually from Day 1 through Week 48, and through 24-week follow-up period
Population: Participants who were randomized and received at least~1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir, 0.5 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | SAEs | 1 Participants |
| Entecavir, 0.5 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | Death | 0 Participants |
| Entecavir, 0.5 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | Treatment-related AEs | 0 Participants |
| Entecavir, 0.5 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | AEs leading to discontinuation | 1 Participants |
| Entecavir, 0.5 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | Treatment-related SAEs | 0 Participants |
| Entecavir, 0.5 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | Abnormalities in LTR leading to discontinuation | 0 Participants |
| Entecavir, 0.5 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | All AEs | 16 Participants |
| Adefovir, 10 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | Abnormalities in LTR leading to discontinuation | 0 Participants |
| Adefovir, 10 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | All AEs | 7 Participants |
| Adefovir, 10 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | Treatment-related AEs | 0 Participants |
| Adefovir, 10 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | SAEs | 0 Participants |
| Adefovir, 10 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | Treatment-related SAEs | 0 Participants |
| Adefovir, 10 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | Death | 0 Participants |
| Adefovir, 10 mg QD | Number of Participants With Adverse Events, Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, Death as Outcome, Discontinuations Due to AEs, and Abnormalities in Laboratory Test Results (LTR) Leading to Discontinuation | AEs leading to discontinuation | 0 Participants |
Secondary
Number of Participants With Genotypic Resistance to Entecavir
Time frame: At Week 48 from Day 1
Population: Participants who were randomized and received at least~1 dose of study drug. n=number of evaluable participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir, 0.5 mg QD | Number of Participants With Genotypic Resistance to Entecavir | At baseline | 0 Participants |
| Entecavir, 0.5 mg QD | Number of Participants With Genotypic Resistance to Entecavir | Week 48 | 0 Participants |
| Adefovir, 10 mg QD | Number of Participants With Genotypic Resistance to Entecavir | At baseline | 0 Participants |
| Adefovir, 10 mg QD | Number of Participants With Genotypic Resistance to Entecavir | Week 48 | 0 Participants |
Secondary
Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion
Time frame: At Weeks 12 and 48 from Day 1
Population: Participants who were randomized and received at least~1 dose of study drug. n=number of evaluable participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir, 0.5 mg QD | Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion | Week 12 HBsAg loss | 0 Participants |
| Entecavir, 0.5 mg QD | Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion | Week 48 HBsAg loss | 0 Participants |
| Entecavir, 0.5 mg QD | Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion | Week 12 HBsAg seroconversion | 0 Participants |
| Entecavir, 0.5 mg QD | Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion | Week 48 HBsAg seroconversion | 0 Participants |
| Adefovir, 10 mg QD | Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion | Week 48 HBsAg seroconversion | 0 Participants |
| Adefovir, 10 mg QD | Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion | Week 12 HBsAg loss | 0 Participants |
| Adefovir, 10 mg QD | Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion | Week 12 HBsAg seroconversion | 0 Participants |
| Adefovir, 10 mg QD | Number of Participants With Hepatitis B s Surface Antibody (HBsAG) Loss and HBsAG Seroconversion | Week 48 HBsAg loss | 0 Participants |
Secondary
Percentage of Participants Who Achieved an HBV DNA Level <50 IU/mL at Week 48 by Polymerase Chain Reaction Testing
HBV=hepatitis B virus. HBV DNA Level \<50 IU/mL=approximately 300 copies/mL.
Time frame: At Week 48 from Day 1
Population: Participants who were randomized and received at least~1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir, 0.5 mg QD | Percentage of Participants Who Achieved an HBV DNA Level <50 IU/mL at Week 48 by Polymerase Chain Reaction Testing | 31.5 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants Who Achieved an HBV DNA Level <50 IU/mL at Week 48 by Polymerase Chain Reaction Testing | 28.6 Percentage of participants |
Secondary
Percentage of Participants Who Achieved Normalization of Alanine Aminotransferase (ALT)
ULN=upper limit of normal. ALT normalization= ≤1\*ULN, among participants with baseline ALT \>1\*ULN
Time frame: At Weeks 12 and 48 from Day 1
Population: Participants who were randomized, who received at least 1 dose of study drug, and whose ALT values were \>1\*ULN at baseline. n=number of evaluable participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir, 0.5 mg QD | Percentage of Participants Who Achieved Normalization of Alanine Aminotransferase (ALT) | Week 12 (n=51, 36) | 31.4 Percentage of participants |
| Entecavir, 0.5 mg QD | Percentage of Participants Who Achieved Normalization of Alanine Aminotransferase (ALT) | Week 48 (n=51, 36) | 60.8 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants Who Achieved Normalization of Alanine Aminotransferase (ALT) | Week 12 (n=51, 36) | 22.2 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants Who Achieved Normalization of Alanine Aminotransferase (ALT) | Week 48 (n=51, 36) | 47.2 Percentage of participants |
Secondary
Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results
Hematology testing assessed levels of hemoglobin, white blood cells, platelets, neutrophils, international normalized ration, red blood cells, lymphocytes, and monocytes.
Time frame: Day 1 through Week 48
Population: Participants who were randomized and received at least~1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir, 0.5 mg QD | Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results | Alanine aminotransferase | 9 Percentage of participants |
| Entecavir, 0.5 mg QD | Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results | Hyperkalemia | 0 Percentage of participants |
| Entecavir, 0.5 mg QD | Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results | Aspartate aminotransferase | 2.2 Percentage of participants |
| Entecavir, 0.5 mg QD | Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results | Hematology | 0 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results | Aspartate aminotransferase | 0 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results | Hematology | 0 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results | Alanine aminotransferase | 5.2 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results | Hyperkalemia | 1 Percentage of participants |
Secondary
Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion
Time frame: At Weeks 12 and 48 from Day 1
Population: Participants who were randomized, who received at least 1 dose of study drug, and who were HBeAg-positive at baseline. n=number of evaluable participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Entecavir, 0.5 mg QD | Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion | HBeAG loss Week 12 (n=79, 72) | 3.8 Percentage of participants |
| Entecavir, 0.5 mg QD | Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion | HBeAG loss Week 48 (n=79, 72) | 7.6 Percentage of participants |
| Entecavir, 0.5 mg QD | Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion | HBe seroconversion Week 12 (n=79, 72) | 2.5 Percentage of participants |
| Entecavir, 0.5 mg QD | Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion | HBe seroconversion Week 48 (n=79, 72) | 3.8 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion | HBe seroconversion Week 48 (n=79, 72) | 2.8 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion | HBeAG loss Week 12 (n=79, 72) | 6.9 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion | HBe seroconversion Week 12 (n=79, 72) | 1.45 Percentage of participants |
| Adefovir, 10 mg QD | Percentage of Participants With Loss of Hepatitis B e Antigen (HBeAg) and Hepatitis B e (HBe) Seroconversion | HBeAG loss Week 48 (n=79, 72) | 6.9 Percentage of participants |