Hepatitis B, Chronic
Conditions
Brief summary
The purpose of this study is to compare the effectiveness of entecavir plus tenofovir combination therapy with that of entecavir monotherapy. Safety will also be studied.
Interventions
DRUGEntecavir
Tablets, Oral, ETV = 0.5 mg, once daily, 100 weeks
Tablets, Oral, ETV = 0.5 mg + TFV = 300 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
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Chronic hepatitis B virus (HBV) infection (hepatitis B e antigen \[HbeAg\]-positive or negative) disease * Nucleoside- and nucleotide-naive * Males or females ≥16 years of age (or minimum age of consent in a given country) * Compensated liver function * HBV DNA \>1.72\*10\*5\*IU/mL (approximately 10\*6\*copies/mL) for HbeAg-positive participants * HBV DNA \>1.72\*10\*4\*IU/mL (approximately 10\*5\*copies/mL) for Hbe-Ag-negative participants * Alanine aminotransferase level ≥\*upper limit of normal (ULN) and ≤10\*ULN
Exclusion criteria
* Evidence of decompensated cirrhosis * Coinfection with human immunodeficiency virus, hepatitis C virus, or hepatitis D virus * Laboratory values out of protocol-specified range
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Hepatitis B Virus DNA (HBV DNA) Levels <50 IU/mL by Polymerase Chain Reaction (PCR) at Week 96 | At Week 96 | HBV DNA levels \<50 IU/mL=approximately 300 copies/mL. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status | At Weeks 48 and 96 | HBV DNA levels \<50 IU/mL=approximately 300 copies/mL. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. |
| Percentage of Participants Who Achieved HBV DNA Levels <LOQ by PCR at Weeks 48 and 96 | At Weeks 48 and 96 | LOQ=lower limit of quantitation. LOQ=29 IU/mL, or approximately 169 copies/mL. LOQ is the level above which quantitative results may be obtained with a specified degree of confidence. The LOQ is mathematically defined as equal to 10 times the standard deviation of the results for a series of replicates used to determine a justifiable limit of detection. Limits of quantitation are matrix-, method-, and analyte-specific.Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. |
| Percentage of Participants Who Achieved HBV DNA Levels <LOD by PCR at Weeks 48 and 96 | At Weeks 48 and 96 | LOD=Lower limit of detection. LOD) LOD=10 IU/mL, or approximately 58 copies/mL. LOD is the lowest concentration level that can be determined to be statistically different from a blank (99% confidence). The LOD is typically determined to be in the region where the signal to noise ratio is greater than 5. Limits of detection are matrix-, method-, and analyte-specific.Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. |
| Mean Log 10 HBV DNA at Weeks 48 and 96 | Baseline, Weeks 48 and 96 | HBV DNA was analyzed by PCR, using the Roche COBAS®TaqMan - HPS assay. Reduction in Log 10 HBV count=reduced viral load. |
| Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48 and 96 | At Weeks 48 and 96 | ALT normalization= ≤1\*upper limit of normal (ULN). Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. |
| Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48 and 96 | At Weeks 48 and 96 | HBeAg is a hepatitis B viral protein and is an indicator of active viral replication. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. |
| Percentage of Participants With HBeAg Seroconversion [( at Weeks 48 and 96 | At Weeks 48 and 96 | HBeAg seroconversion=HBeAg loss and presence of hepatitis B e antibody (HBeAb). HBeAg is a hepatitis B viral protein and is an indicator of active viral replication. |
| Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48 and 96 | At Weeks 48 and 96 | HBsAg = A part of the hepatitis B virus. When found in the blood, HBsAg is an early marker of infection. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. |
| Percentage of Participants With HBsAg Seroconversion at Weeks 48 and 96 | At Weeks 48 and 96 | HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. |
| Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | At Weeks 48 and 96 | Using the Roche COBAS TaqMan - HPS assay. Lower limit of Quantitation (LOQ) is the level above which quantitative results may be obtained with a specified degree of confidence. The LOQ is mathematically defined as equal to 10 times the standard deviation of the results for a series of replicates used to determine a justifiable limit of detection. Limits of quantitation are matrix-, method-, and analyte-specific. |
| Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | From enrollment through Week 100 + 24-week follow-up | AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to any AEs were recorded. |
| Number of Participants With HBV Resistance Through Week 48 | Week 48 | ETVr=entecavir resistance; TDFr=tenofovir resistance. HBV polymerase using the Trugene® HBV Genotyping Kit. HBV resistance: genotyping of HBV polymerase will be performed on stored viral samples at any timepoint when considered appropriate based on virologic response, including any specimen with detectable HBV DNA. When appropriate, phenotyping will also be used. |
| Number of Participants With HBV Resistance at Week 96 | Week 96 | ETVr=entecavir resistance; TFDr=tenofovir resistance. HBV polymerase using the Trugene® HBV Genotyping Kit. HBV resistance: genotyping of HBV polymerase will be performed on stored viral samples at any timepoint when considered appropriate based on virologic response, including any specimen with detectable HBV DNA. When appropriate, phenotyping will also be used. |
| Number of Participants With Virologic Breakthrough at Week 48 | Week 48 | ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough= confirmed \>= 1 log10 increase in HBV DNA from the on-treatment nadir |
| Number of Participants With Virologic Breakthrough at Week 96 | Week 96 | ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough=confirmed \>=1 log10 increase in HBV DNA from moving nadir |
Countries
Argentina, Australia, Brazil, Canada, France, India, Italy, Mexico, Poland, Russia, South Africa, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
669 participants were enrolled; 384 were randomized. Among 285 who were not randomized, 266 did not meet the study criteria, 11 other, 1 poor compliance/noncompliance, 4 lost to follow-up, 1 withdrew consent, and 2 for administrative reasons.
Participants by arm
| Arm | Count |
|---|---|
| ETV 0.5 mg Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks | 182 |
| ETV 0.5 mg +TDF 300 mg ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks | 197 |
| Total | 379 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| After Week 48 to Week 96 | Adverse Event | 1 | 2 |
| After Week 48 to Week 96 | Death | 0 | 1 |
| After Week 48 to Week 96 | Lack of Efficacy | 1 | 0 |
| After Week 48 to Week 96 | Lost to Follow-up | 2 | 4 |
| After Week 48 to Week 96 | Other | 2 | 0 |
| After Week 48 to Week 96 | Poor compliance/noncompliance | 0 | 1 |
| After Week 48 to Week 96 | Pregnancy | 0 | 2 |
| After Week 48 to Week 96 | Withdrawal by Subject | 0 | 1 |
| Day 1 to Week 48 | Adverse Event | 1 | 2 |
| Day 1 to Week 48 | Lost to Follow-up | 5 | 2 |
| Day 1 to Week 48 | Other | 0 | 1 |
| Day 1 to Week 48 | poor compliance/noncompliance | 0 | 3 |
| Day 1 to Week 48 | Pregnancy | 0 | 2 |
| Day 1 to Week 48 | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Total | ETV 0.5 mg | ETV 0.5 mg +TDF 300 mg |
|---|---|---|---|
| Age, Customized 16 - 20 years | 32 Participants | 13 Participants | 19 Participants |
| Age, Customized 21 - 64 years | 326 Participants | 157 Participants | 169 Participants |
| Age, Customized >=65 years | 21 Participants | 12 Participants | 9 Participants |
| Country Argentina | 27 participants | 12 participants | 15 participants |
| Country Australia | 48 participants | 24 participants | 24 participants |
| Country Brazil | 8 participants | 5 participants | 3 participants |
| Country Canada | 62 participants | 29 participants | 33 participants |
| Country France | 13 participants | 8 participants | 5 participants |
| Country India | 14 participants | 5 participants | 9 participants |
| Country Italy | 27 participants | 12 participants | 15 participants |
| Country Poland | 28 participants | 15 participants | 13 participants |
| Country Russian Federation | 47 participants | 24 participants | 23 participants |
| Country South Africa | 5 participants | 2 participants | 3 participants |
| Country Turkey | 22 participants | 11 participants | 11 participants |
| Country United States | 78 participants | 35 participants | 43 participants |
| Hepatitis B e antibody (HBeAb) at baseline Negative | 259 Participants | 122 Participants | 137 Participants |
| Hepatitis B e antibody (HBeAb) at baseline Positive | 120 Participants | 60 Participants | 60 Participants |
| Hepatitis B e antigen (HBeAg) status at baseline Negative (> 17,200 IU/mL; approx 10^5 copies/mL) | 115 Participants | 56 Participants | 59 Participants |
| Hepatitis B e antigen (HBeAg) status at baseline Positive (> 172,000 IU/mL; approx 10^6 copies/mL) | 264 Participants | 126 Participants | 138 Participants |
| Hepatitis B surface antigen (HBsAg) status at baseline Negative | 1 Participants | 0 Participants | 1 Participants |
| Hepatitis B surface antigen (HBsAg) status at baseline Positive | 378 Participants | 182 Participants | 196 Participants |
| Race/Ethnicity, Customized Asian | 186 Participants | 84 Participants | 102 Participants |
| Race/Ethnicity, Customized Black/African American | 14 Participants | 10 Participants | 4 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 170 Participants | 83 Participants | 87 Participants |
| Region Africa | 5 Participants | 2 Participants | 3 Participants |
| Region Asia | 62 Participants | 29 Participants | 33 Participants |
| Region Europe | 137 Participants | 70 Participants | 67 Participants |
| Region North America | 140 Participants | 64 Participants | 76 Participants |
| Region South America | 35 Participants | 17 Participants | 18 Participants |
| Sex: Female, Male Female | 117 Participants | 66 Participants | 51 Participants |
| Sex: Female, Male Male | 262 Participants | 116 Participants | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 69 / 182 | 73 / 197 |
| serious Total, serious adverse events | 13 / 182 | 14 / 197 |
Outcome results
Primary
Percentage of Participants Who Achieved Hepatitis B Virus DNA (HBV DNA) Levels <50 IU/mL by Polymerase Chain Reaction (PCR) at Week 96
HBV DNA levels \<50 IU/mL=approximately 300 copies/mL. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.
Time frame: At Week 96
Population: Evaluable participants. A participant missing the efficacy assessments for a visit is considered a failure and is counted as evaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ETV 0.5 mg | Percentage of Participants Who Achieved Hepatitis B Virus DNA (HBV DNA) Levels <50 IU/mL by Polymerase Chain Reaction (PCR) at Week 96 | 76.4 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants Who Achieved Hepatitis B Virus DNA (HBV DNA) Levels <50 IU/mL by Polymerase Chain Reaction (PCR) at Week 96 | 83.2 Percentage of participants |
Comparison: Week 96p-value: 0.088295% CI: [-1, 14.9]Cochran-Mantel-Haenszel
Secondary
Mean Log 10 HBV DNA at Weeks 48 and 96
HBV DNA was analyzed by PCR, using the Roche COBAS®TaqMan - HPS assay. Reduction in Log 10 HBV count=reduced viral load.
Time frame: Baseline, Weeks 48 and 96
Population: Evaluable participants at given time point. If a participant is missing the efficacy assessments for a visit, this is considered a failure and is counted as evaluable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ETV 0.5 mg | Mean Log 10 HBV DNA at Weeks 48 and 96 | Baseline (n=182, 197) | 7.48 log10 copies/mL | Standard Error 0.109 |
| ETV 0.5 mg | Mean Log 10 HBV DNA at Weeks 48 and 96 | Overall at Week 48 (n=176, 180) | 1.88 log10 copies/mL | Standard Error 0.065 |
| ETV 0.5 mg | Mean Log 10 HBV DNA at Weeks 48 and 96 | Overall at Week 96 (n=165, 170) | 1.68 log10 copies/mL | Standard Error 0.048 |
| ETV 0.5 mg +TDF 300 mg | Mean Log 10 HBV DNA at Weeks 48 and 96 | Baseline (n=182, 197) | 7.53 log10 copies/mL | Standard Error 0.1 |
| ETV 0.5 mg +TDF 300 mg | Mean Log 10 HBV DNA at Weeks 48 and 96 | Overall at Week 48 (n=176, 180) | 1.56 log10 copies/mL | Standard Error 0.026 |
| ETV 0.5 mg +TDF 300 mg | Mean Log 10 HBV DNA at Weeks 48 and 96 | Overall at Week 96 (n=165, 170) | 1.51 log10 copies/mL | Standard Error 0.038 |
Secondary
Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities
AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to any AEs were recorded.
Time frame: From enrollment through Week 100 + 24-week follow-up
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | SAEs | 12 Participants |
| ETV 0.5 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | Discontinuations due to AEs | 2 Participants |
| ETV 0.5 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | Adverse events | 132 Participants |
| ETV 0.5 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | Related AEs | 39 Participants |
| ETV 0.5 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | Deaths | 0 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | Related AEs | 49 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | Deaths | 3 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | SAEs | 14 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | Adverse events | 131 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | Discontinuations due to AEs | 5 Participants |
Secondary
Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96
Using the Roche COBAS TaqMan - HPS assay. Lower limit of Quantitation (LOQ) is the level above which quantitative results may be obtained with a specified degree of confidence. The LOQ is mathematically defined as equal to 10 times the standard deviation of the results for a series of replicates used to determine a justifiable limit of detection. Limits of quantitation are matrix-, method-, and analyte-specific.
Time frame: At Weeks 48 and 96
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | < LOQ (29 IU/mL) at Week 48 | 67.6 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | LOQ - <50 IU/mL at Week 48 | 2.7 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 50 - <172 IU/mL at Week 48 | 7.1 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 172 - <1720 IU/mL at Week 48 | 7.7 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 1720 - <17,200 IU/mL at Week 48 | 9.3 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 17,200 - <172,000 IU/mL at Week 48 | 1.6 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | ≥172,000 IU/mL at Week 48 | 0.5 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | Missing at Week 48 | 3.3 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | < LOQ (29 IU/mL) at Week 96 | 74.7 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | LOQ - <50 IU/mL at Week 96 | 1.6 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 50 - <172 IU/mL at Week 96 | 3.3 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 172 - <1720 IU/mL at Week 96 | 5.5 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 1720 - <17,200 IU/mL at Week 96 | 4.9 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 17,200 - <172,000 IU/mL at Week 96 | 0.5 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | ≥172,000 IU/mL at Week 96 | 0 Percentage of participants |
| ETV 0.5 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | Missing at Week 96 | 9.3 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | Missing at Week 96 | 13.7 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | < LOQ (29 IU/mL) at Week 48 | 74.6 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | < LOQ (29 IU/mL) at Week 96 | 81.7 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | LOQ - <50 IU/mL at Week 48 | 5.6 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 1720 - <17,200 IU/mL at Week 96 | 0 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 50 - <172 IU/mL at Week 48 | 6.6 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | LOQ - <50 IU/mL at Week 96 | 1.5 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 172 - <1720 IU/mL at Week 48 | 4.1 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | ≥172,000 IU/mL at Week 96 | 0.5 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 1720 - <17,200 IU/mL at Week 48 | 0.5 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 50 - <172 IU/mL at Week 96 | 1.0 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 17,200 - <172,000 IU/mL at Week 48 | 0 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 17,200 - <172,000 IU/mL at Week 96 | 0 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | ≥172,000 IU/mL at Week 48 | 0 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | 172 - <1720 IU/mL at Week 96 | 1.5 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | Missing at Week 48 | 8.6 Percentage of participants |
Secondary
Number of Participants With HBV Resistance at Week 96
ETVr=entecavir resistance; TFDr=tenofovir resistance. HBV polymerase using the Trugene® HBV Genotyping Kit. HBV resistance: genotyping of HBV polymerase will be performed on stored viral samples at any timepoint when considered appropriate based on virologic response, including any specimen with detectable HBV DNA. When appropriate, phenotyping will also be used.
Time frame: Week 96
Population: Participants who received study drug and with HBV DNA levels \>=50 IU/mL.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Number of Participants With HBV Resistance at Week 96 | ETVr | 0 Participants |
| ETV 0.5 mg | Number of Participants With HBV Resistance at Week 96 | TDFr | 0 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV Resistance at Week 96 | ETVr | 0 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV Resistance at Week 96 | TDFr | 0 Participants |
Secondary
Number of Participants With HBV Resistance Through Week 48
ETVr=entecavir resistance; TDFr=tenofovir resistance. HBV polymerase using the Trugene® HBV Genotyping Kit. HBV resistance: genotyping of HBV polymerase will be performed on stored viral samples at any timepoint when considered appropriate based on virologic response, including any specimen with detectable HBV DNA. When appropriate, phenotyping will also be used.
Time frame: Week 48
Population: All participants who received study drug and with HBV DNA levels \>=50 IU/mL
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Number of Participants With HBV Resistance Through Week 48 | ETVr | 0 Participants |
| ETV 0.5 mg | Number of Participants With HBV Resistance Through Week 48 | TDFr | 0 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV Resistance Through Week 48 | ETVr | 0 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With HBV Resistance Through Week 48 | TDFr | 0 Participants |
Secondary
Number of Participants With Virologic Breakthrough at Week 48
ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough= confirmed \>= 1 log10 increase in HBV DNA from the on-treatment nadir
Time frame: Week 48
Population: Participants with confirmed \>=1 log10 increase in HBV DNA from the on-treatment nadir
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Number of Participants With Virologic Breakthrough at Week 48 | ETVr | 0 Participants |
| ETV 0.5 mg | Number of Participants With Virologic Breakthrough at Week 48 | TDFr | 0 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With Virologic Breakthrough at Week 48 | ETVr | 0 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With Virologic Breakthrough at Week 48 | TDFr | 0 Participants |
Secondary
Number of Participants With Virologic Breakthrough at Week 96
ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough=confirmed \>=1 log10 increase in HBV DNA from moving nadir
Time frame: Week 96
Population: Participants with confirmed \>= 1 log10 increase in HBV DNA from moving nadir
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Number of Participants With Virologic Breakthrough at Week 96 | ETVr | 0 Participants |
| ETV 0.5 mg | Number of Participants With Virologic Breakthrough at Week 96 | TDFr | 0 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With Virologic Breakthrough at Week 96 | ETVr | 0 Participants |
| ETV 0.5 mg +TDF 300 mg | Number of Participants With Virologic Breakthrough at Week 96 | TDFr | 0 Participants |
Secondary
Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status
HBV DNA levels \<50 IU/mL=approximately 300 copies/mL. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.
Time frame: At Weeks 48 and 96
Population: Evaluable participants. If a participant is missing the efficacy assessments for a visit, this is considered a failure and is counted as evaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status | HBeAg+ at Week 48 (n=126, n=138) | 61.1 Percentage of participants |
| ETV 0.5 mg | Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status | HBeAg- at Week 48 (n=56, n=59) | 91.1 Percentage of participants |
| ETV 0.5 mg | Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status | HBeAg+ at Week 96 (n=126, n=138) | 69.8 Percentage of participants |
| ETV 0.5 mg | Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status | HBeAg- at Week 96 (n=56, n=59) | 91.1 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status | HBeAg- at Week 96 (n=56, n=59) | 89.8 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status | HBeAg+ at Week 48 (n=126, n=138) | 74.6 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status | HBeAg+ at Week 96 (n=126, n=138) | 80.4 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status | HBeAg- at Week 48 (n=56, n=59) | 93.2 Percentage of participants |
95% CI: [2.3, 24.8]NC=F
95% CI: [-7.7, 12]NC=F
p-value: 0.04695% CI: [0.2, 21]Cochran-Mantel-Haenszel
95% CI: [-12, 9.5]NC=F
Secondary
Percentage of Participants Who Achieved HBV DNA Levels <LOD by PCR at Weeks 48 and 96
LOD=Lower limit of detection. LOD) LOD=10 IU/mL, or approximately 58 copies/mL. LOD is the lowest concentration level that can be determined to be statistically different from a blank (99% confidence). The LOD is typically determined to be in the region where the signal to noise ratio is greater than 5. Limits of detection are matrix-, method-, and analyte-specific.Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.
Time frame: At Weeks 48 and 96
Population: Evaluable participants. A participant missing the efficacy assessments for a visit is considered a failure and is counted as evaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Percentage of Participants Who Achieved HBV DNA Levels <LOD by PCR at Weeks 48 and 96 | Overall at Week 48 | 58.2 Percentage of participants |
| ETV 0.5 mg | Percentage of Participants Who Achieved HBV DNA Levels <LOD by PCR at Weeks 48 and 96 | Overall at Week 96 | 68.1 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants Who Achieved HBV DNA Levels <LOD by PCR at Weeks 48 and 96 | Overall at Week 48 | 66.0 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants Who Achieved HBV DNA Levels <LOD by PCR at Weeks 48 and 96 | Overall at Week 96 | 76.6 Percentage of participants |
Comparison: Analysis at Week 48. The stratified analysis was based on HBeAg strata at randomization.95% CI: [-1.5, 17.1]NC=F
Comparison: Analysis at Week 96. The stratified analysis was based on HBeAg strata at randomization.95% CI: [-0.2, 17.3]NC=F
Secondary
Percentage of Participants Who Achieved HBV DNA Levels <LOQ by PCR at Weeks 48 and 96
LOQ=lower limit of quantitation. LOQ=29 IU/mL, or approximately 169 copies/mL. LOQ is the level above which quantitative results may be obtained with a specified degree of confidence. The LOQ is mathematically defined as equal to 10 times the standard deviation of the results for a series of replicates used to determine a justifiable limit of detection. Limits of quantitation are matrix-, method-, and analyte-specific.Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.
Time frame: At Weeks 48 and 96
Population: Evaluable participants. A participant missing the efficacy assessments for a visit is considered a failure and is counted as evaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Percentage of Participants Who Achieved HBV DNA Levels <LOQ by PCR at Weeks 48 and 96 | Overall at Week 48 | 67.6 Percentage of participants |
| ETV 0.5 mg | Percentage of Participants Who Achieved HBV DNA Levels <LOQ by PCR at Weeks 48 and 96 | Overall at Week 96 | 74.7 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants Who Achieved HBV DNA Levels <LOQ by PCR at Weeks 48 and 96 | Overall at Week 48 | 74.6 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants Who Achieved HBV DNA Levels <LOQ by PCR at Weeks 48 and 96 | Overall at Week 96 | 81.7 Percentage of participants |
Comparison: Analysis at week 48. The stratified analysis was based on HBeAg strata at randomization.95% CI: [-1.8, 16]NC=F
Comparison: Analysis at week 96. The stratified analysis was based on HBeAg strata at randomization.95% CI: [-1.1, 15.2]NC=F
Secondary
Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48 and 96
ALT normalization= ≤1\*upper limit of normal (ULN). Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.
Time frame: At Weeks 48 and 96
Population: Evaluable participants. A participant missing the efficacy assessments for a visit is considered a failure and counted as evaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48 and 96 | Overall at Week 48 | 83.0 Percentage of participants |
| ETV 0.5 mg | Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48 and 96 | Overall at Week 96 | 81.9 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48 and 96 | Overall at Week 48 | 72.6 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48 and 96 | Overall at Week 96 | 68.0 Percentage of participants |
Comparison: Analysis at Week 48. The stratified analysis is based on HBeAg strata at randomization.95% CI: [-18.8, -2]NC+F
Comparison: Analysis at Week 96. The stratified analysis is based on HBeAg strata at randomization.95% CI: [-21.5, -4.1]NC=F
Secondary
Percentage of Participants With HBeAg Seroconversion [( at Weeks 48 and 96
HBeAg seroconversion=HBeAg loss and presence of hepatitis B e antibody (HBeAb). HBeAg is a hepatitis B viral protein and is an indicator of active viral replication.
Time frame: At Weeks 48 and 96
Population: Treated HBeAg-positive participants. A participant missing the efficacy assessments for a visit was considered a failure and was counted as evaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Percentage of Participants With HBeAg Seroconversion [( at Weeks 48 and 96 | Week 48 | 22.2 Percentage of participants |
| ETV 0.5 mg | Percentage of Participants With HBeAg Seroconversion [( at Weeks 48 and 96 | Week 96 | 32.5 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants With HBeAg Seroconversion [( at Weeks 48 and 96 | Week 48 | 18.1 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants With HBeAg Seroconversion [( at Weeks 48 and 96 | Week 96 | 21.7 Percentage of participants |
Comparison: Analysis at Week 4895% CI: [-13.8, 5.6]NC=F
Comparison: Analysis at Week 9695% CI: [-21.5, -0.1]NC=F
Secondary
Percentage of Participants With HBsAg Seroconversion at Weeks 48 and 96
HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection.
Time frame: At Weeks 48 and 96
Population: Treated HBeAg-positive participants. If a participant was missing the efficacy assessments for a visit, this is considered a failure and was counted as evaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Percentage of Participants With HBsAg Seroconversion at Weeks 48 and 96 | Week 48 | 0.8 Percentage of participants |
| ETV 0.5 mg | Percentage of Participants With HBsAg Seroconversion at Weeks 48 and 96 | Week 96 | 1.6 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants With HBsAg Seroconversion at Weeks 48 and 96 | Week 48 | 0.7 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants With HBsAg Seroconversion at Weeks 48 and 96 | Week 96 | 2.9 Percentage of participants |
Comparison: Analysis at Week 4895% CI: [-2.2, 2]NC=F
Comparison: Analysis at Week 9695% CI: [-2.3, 4.9]NC=F
Secondary
Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48 and 96
HBeAg is a hepatitis B viral protein and is an indicator of active viral replication. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.
Time frame: At Weeks 48 and 96
Population: Treated HBeAg-positive participants. If a participant was missing the efficacy assessments for a visit, this is considered a failure and was counted as evaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48 and 96 | Week 48 | 25.4 Percentage of participants |
| ETV 0.5 mg | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48 and 96 | Week 96 | 3.97 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48 and 96 | Week 48 | 19.6 Percentage of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48 and 96 | Week 96 | 29.7 Percentage of participants |
Comparison: Analysis at Week 4895% CI: [-15.9, 4.2]NC=F
Comparison: Analysis at Week 9695% CI: [-20.6, 2.3]NC=F
Secondary
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48 and 96
HBsAg = A part of the hepatitis B virus. When found in the blood, HBsAg is an early marker of infection. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.
Time frame: At Weeks 48 and 96
Population: Treated HBeAg-positive participants. If a participant was missing the efficacy assessments for a visit, this is considered a failure and was counted as evaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETV 0.5 mg | Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48 and 96 | Week 48 | 3.2 Percent of participants |
| ETV 0.5 mg | Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48 and 96 | Week 96 | 4.0 Percent of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48 and 96 | Week 48 | 1.4 Percent of participants |
| ETV 0.5 mg +TDF 300 mg | Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48 and 96 | Week 96 | 5.1 Percent of participants |
Comparison: Analysis at Week 4895% CI: [-5.3, 1.9]NC=F
Comparison: Analysis at Week 9695% CI: [-3.9, 6.1]NC=F