A Phase 3 interventional study of Entecavir and Tenofovir in Chronic Hepatitis B, sponsored by Bristol-Myers Squibb. Completed at 28 sites in 7 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2014-12-15.
Sponsored by Bristol-Myers Squibb · Phase 3, Interventional, and Treatment
The purpose of this study is to show that the combination of entecavir and tenofovir, is effective and well tolerated in chronic hepatitis B patients who have failed previous treatment.
2,710 studies on the registry are indexed under Hepatitis A; 142 are open to participants now.
This study's enrollment of 144 is above the median of 100 across 1,887 interventional studies indexed under Hepatitis A.
Browse Hepatitis A studies →Bristol-Myers Squibb is the lead sponsor of 1,538 studies on the registry; 116 are open to participants now.
Of its 429 completed or terminated interventional studies of FDA-regulated products, 223 (52%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Drug: Entecavir · Drug: Tenofovir
Tablets, Oral, 1 mg, once daily, 96 weeks
Also known as: Baraclude®, BMS-200475
Tablets, Oral, 300 mg, once daily, 96 weeks
Also known as: Viread®
Percentage of Participants With a Virologic Response at Week 48 - Treated Population
Virologic response was defined as Hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) less than 50 international units per milliliter (IU/mL); approximately 300 copies/mL. Percentage was calculated as number of participants with virologic response at Week 48 divided by the number of treated participants. Treated participants were evaluated using non-completer (NC) = failure (F). The HBV DNA by polymerase chain reaction (PCR) was measured using the Roche COBAS(REGISTERED) TaqMan - High Pure System (HPS) assay, in a central laboratory. The results were reported in IU/mL, with the limit of quantification (LOQ) = 29 IU/mL and lower limit of detection (LLD) = 6 IU/mL. HBV DNA measurements were transformed by the log10 scale when analyzed as a continuous variable, using log10(LOQ-1) for values below LOQ.
Time frame: Week 48
Percentage of Participants With a Virologic Response at Week 24 and at Week 96 - Treated Population
Virologic response was defined as Hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) less than 50 international units per milliliter (IU/mL); approximately 300 copies/mL. Percentage was calculated as number of participants with virologic response at Week 24, Week 96 divided by the number of treated participants. Treated participants were evaluated using non-completer (NC) = failure (F). The HBV DNA by polymerase chain reaction (PCR) was measured using the Roche COBAS(REGISTERED) TaqMan - High Pure System (HPS) assay. The results were reported in IU/mL, with the limit of quantification (LOQ) = 29 IU/mL and lower limit of detection (LLD) = 6 IU/mL. HBV DNA measurements were transformed by the log10 scale when analyzed as a continuous variable, using log10(LOQ-1) for values below LOQ.
Time frame: Week 24, Week 96
Change From Baseline in Mean log10 HBV DNA at Weeks 12, 24, 48, and 96 - Treated Evaluable Population
HBV DNA by polymerase chain reaction (PCR) was measured using the Roche COBAS(REGISTERED) TaqMan - High Pure System (HPS) assay. The results were reported in log 10 IU/mL, with the limit of quantification (LOQ) = 29 IU/mL and lower limit of detection (LLD) = 6 IU/mL. HBV DNA measurements were transformed by the log10 scale when analyzed as a continuous variable, using log10(LOQ-1) for values below LOQ. Baseline was Day 1, prior to study drug administration.
Time frame: Baseline to Weeks 12, 24, 48, 96
Percentage of Participants With HBV DNA Less Than the Lower Limit of Detection (LLD) at Weeks 24, 48, and 96 - Treated Population
HBV DNA less than (\<) LLD (6 IU/mL) was defined/measured by the COBAS(REGISTERED) TaqMan HPS assay at Weeks 24, 48, and 96. Percentage was calculated as number of participants with HBV DNA \< LLD at Weeks 24, 48, 96 divided by the number of treated participants. Treated participants were evaluated using non-completer (NC) = failure (F).
Time frame: Weeks 24, 48, 96
Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 24, 48, and 96 - Treated Population Who Were HBeAg Positive at Baseline
Loss of HBeAg was defined as being HBeAg-negative at Weeks 24, 48, and 96 in those participants who had been HBeAg-positive at baseline. Method used for HBeAg was DiaSorin - Anti HBe enzyme immunoassay kit - procedure for qualitative determination of antibodies to HBeAg in human serum or plasma samples. Percentage was calculated as number of participants with HBeAg loss at Weeks 24 and 48 divided by the number of treated participants who were HBeAg-positive at baseline. Treated participants (HBeAg-positive at baseline) were evaluated using NC = F. Baseline was Day 1, before start of study drug.
Time frame: Baseline to Weeks 24, 48, and 96
Percentage of Participants With HBe Seroconversion at Weeks 24, 48, and 96 - Treated Population Who Were HBeAg-positive at Baseline
HBe seroconversion was defined as being both HBeAg-negative and HBeAb-positive at Weeks 24, 48, and 96 in those participants who had been HBeAg-positive at baseline. Method used was DiaSorin - Anti HBe enzyme immunoassay kit - procedure for qualitative determination of antibodies to HBeAg in human serum or plasma samples. Percentage was calculated as number of participants with HBe seroconversion at Weeks 24, 48, and 96 divided by the number of treated participants who were HBeAg-positive at baseline. Treated participants (HBeAg-positive at baseline) were evaluated using NC = F. Baseline was Day 1, before start of study drug.
Time frame: Baseline, Weeks 24, 48, and 96
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 24, 48, 96 - Treated Population Who Were HBsAg-Positive at Baseline
Loss of HBsAg was defined as being HBsAg-negative at Weeks 24, 48, 96 in those participants who had been HBsAg-positive at baseline. The method used: Immunoassay - ADVIA CENTAUR from SIEMENS: in vitro diagnostic immunoassay for the qualitative and quantitative determination of HBsAg in human serum and plasma (potassium ethylene diamine tetraacetic acid, lithium or sodium heparinized). Percentage calculated as number of participants with a HBsAg loss at Weeks 24, 48, and 96 divided by the number of treated participants who were HBsAg-positive at baseline (participants were not enrolled into the study unless they were positive for HBsAg). Treated participants (HBsAg-positive at baseline) were evaluated using NC=F. Baseline was Day 1, before start of study drug.
Time frame: Baseline, Weeks 24, 48, 96
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Seroconversion at Weeks 24, 48, and 96 - Treated Population Who Were HBsAg-Positive at Baseline
HBsAg seroconversion was defined as being both HBsAg-negative and HBsAb-positive at Weeks 24, 48, and 96 in those participants who had been HBsAg-positive at baseline. Percentage was calculated as number of participants with HBs seroconversion at Weeks 24 and 48 divided by the number of treated participants who were HBsAg-positive at baseline. Positive result for HBsAg was one of the inclusion criteria. Treated participants (HBsAg positive at baseline) were evaluated using NC=F. The method used was an Immunoassay testing - ADVIA CENTAUR from SIEMENS: in vitro diagnostic immunoassay for the qualitative and quantitative determination of HBsAg in human serum and plasma \[potassium ethylenediaminetetraacetic acid (EDTA), lithium or sodium heparinized\]. Baseline was Day 1, before start of study drug.
Time frame: Baseline, Weeks 24, 48, and 96
Number of Participants With Treatment Emergent Serious Adverse Events (SAEs) on Treatment, and Discontinuation of Study Drug Due to Adverse Events (AE) - Treated Population
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=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. On-treatment = on Day 1 through last dose of study therapy + 5 days.
Time frame: Day 1 to last dose of study drug plus 5 days; up to Week 96
Number of Participants With Emergence of Genotypic Resistance to Study Drugs at Weeks 48 and 96- Treated Population
Testing of HBV genotype was performed at baseline for all treated patients and for participants at Weeks 48 and 96 with primary non-response or virologic breakthrough. Emergent genotypic resistance to study drugs was defined as follows: Emergent = not detected at baseline; entecavir (ETV) resistance (ETVr): participant's sample was to have rtM204V/I/S and any substitution at rtT184, rtS202, or rtM250; tenofovir (TDF) resistance (TDFr) which was based on adefovir (ADV)-mutations: participant's sample was to have rtA181T/V, rtN236T, or (rtA194T and rtM204V/I/S). Primary non-response was defined as \< 1 log10 decrease in HBV DNA from baseline on treatment at or after Week 12. Virologic breakthrough was defined as ≥ 1 log10 increase in HBV DNA over nadir on treatment, either confirmed or last on-treatment followed by discontinuation of study therapy.
Time frame: Baseline to Weeks 48, 96
Number of Participants on Treatment With Study Drug With Laboratory Test Abnormalities Meeting Selected Criteria on Treatment - Treated Population
Selected criteria presented in each category. Upper limit of normal among all laboratory ranges (ULN); Baseline (BL); alanine transaminase (ALT); milligram per deciliter (mg/dL); milliliters per minute (mL/min); greater than (\>);greater than, equal to (\>=); less than (\<). Creatinine data presented below were confirmed, ie, at least 2 consecutive values. On-treatment = after Day 1 through last dose of study therapy + 5 days.
Time frame: Day 1 to last dose of study drug plus 5 days; up to Week 96
Study initiated 17 May 2010; Week 48 Primary Endpoint 27 November 2012; Week 96 Study Completed18 February 2014. Participants with chronic Hepatitis B with surface antigen (HBsAg) who have been currently treated and experienced treatment failure were enrolled.
| Milestone | Entecavir + Tenofovir |
|---|---|
| Started | 92 |
| Completed | 86 |
| Not completed | 6 |
| Withdrew: Adverse event | 1 |
| Withdrew: Protocol violation | 1 |
| Withdrew: Withdrawal by subject | 2 |
| Withdrew: Lost to follow-up | 1 |
| Withdrew: Pregnancy | 1 |
| Milestone | Entecavir + Tenofovir |
|---|---|
| Started | 85 |
| Completed | 46 |
| Not completed | 39 |
| Withdrew: Lost to follow-up | 1 |
| Withdrew: Withdrawal by subject | 6 |
| Withdrew: Alternative therapy started | 32 |
Virologic response was defined as Hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) less than 50 international units per milliliter (IU/mL); approximately 300 copies/mL. Percentage was calculated as number of participants with virologic response at Week 48 divided by the number of treated participants. Treated participants were evaluated using non-completer (NC) = failure (F). The HBV DNA by polymerase chain reaction (PCR) was measured using the Roche COBAS(REGISTERED) TaqMan - High Pure System (HPS) assay, in a central laboratory. The results were reported in IU/mL, with the limit of quantification (LOQ) = 29 IU/mL and lower limit of detection (LLD) = 6 IU/mL. HBV DNA measurements were transformed by the log10 scale when analyzed as a continuous variable, using log10(LOQ-1) for values below LOQ.
| percentage of participants | Entecavir + Tenofovir |
|---|---|
| Percentage of Participants With a Virologic Response at Week 48 - Treated Population | 76.1 (66.1 to 84.4) |
Virologic response was defined as Hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) less than 50 international units per milliliter (IU/mL); approximately 300 copies/mL. Percentage was calculated as number of participants with virologic response at Week 24, Week 96 divided by the number of treated participants. Treated participants were evaluated using non-completer (NC) = failure (F). The HBV DNA by polymerase chain reaction (PCR) was measured using the Roche COBAS(REGISTERED) TaqMan - High Pure System (HPS) assay. The results were reported in IU/mL, with the limit of quantification (LOQ) = 29 IU/mL and lower limit of detection (LLD) = 6 IU/mL. HBV DNA measurements were transformed by the log10 scale when analyzed as a continuous variable, using log10(LOQ-1) for values below LOQ.
| percentage of participants | Entecavir + Tenofovir |
|---|---|
| Week 24 (n=92) | 64.1 (53.5 to 73.9) |
| Week 96 (n=92) | 84.8 (75.8 to 91.4) |
HBV DNA by polymerase chain reaction (PCR) was measured using the Roche COBAS(REGISTERED) TaqMan - High Pure System (HPS) assay. The results were reported in log 10 IU/mL, with the limit of quantification (LOQ) = 29 IU/mL and lower limit of detection (LLD) = 6 IU/mL. HBV DNA measurements were transformed by the log10 scale when analyzed as a continuous variable, using log10(LOQ-1) for values below LOQ. Baseline was Day 1, prior to study drug administration.
| log10 IU/mL | Entecavir + Tenofovir |
|---|---|
| Week 12 (n=89) | -2.230 ± 1.5339 |
| Week 24 (n=89) | -2.581 ± 1.8019 |
| Week 48 (n=88) | -2.829 ± 2.0537 |
| Week 96 (n=84) | -2.965 ± 2.1431 |
HBV DNA less than (\<) LLD (6 IU/mL) was defined/measured by the COBAS(REGISTERED) TaqMan HPS assay at Weeks 24, 48, and 96. Percentage was calculated as number of participants with HBV DNA \< LLD at Weeks 24, 48, 96 divided by the number of treated participants. Treated participants were evaluated using non-completer (NC) = failure (F).
| percentage of participants | Entecavir + Tenofovir |
|---|---|
| Week 24 (n=92) | 12.0 (6.1 to 20.4) |
| Week 48 (n=92) | 18.5 (11.1 to 27.9) |
| Week 96 (n=92) | 16.3 (9.4 to 25.5) |
Loss of HBeAg was defined as being HBeAg-negative at Weeks 24, 48, and 96 in those participants who had been HBeAg-positive at baseline. Method used for HBeAg was DiaSorin - Anti HBe enzyme immunoassay kit - procedure for qualitative determination of antibodies to HBeAg in human serum or plasma samples. Percentage was calculated as number of participants with HBeAg loss at Weeks 24 and 48 divided by the number of treated participants who were HBeAg-positive at baseline. Treated participants (HBeAg-positive at baseline) were evaluated using NC = F. Baseline was Day 1, before start of study drug.
| percentage of participants | Entecavir + Tenofovir |
|---|---|
| Week 24 (n=56) | 3.6 (0.4 to 12.3) |
| Week 48 (n=56) | 5.4 (1.1 to 14.9) |
| Week 96 (n=56) | 8.9 (3.0 to 19.6) |
HBe seroconversion was defined as being both HBeAg-negative and HBeAb-positive at Weeks 24, 48, and 96 in those participants who had been HBeAg-positive at baseline. Method used was DiaSorin - Anti HBe enzyme immunoassay kit - procedure for qualitative determination of antibodies to HBeAg in human serum or plasma samples. Percentage was calculated as number of participants with HBe seroconversion at Weeks 24, 48, and 96 divided by the number of treated participants who were HBeAg-positive at baseline. Treated participants (HBeAg-positive at baseline) were evaluated using NC = F. Baseline was Day 1, before start of study drug.
| percentage of participants | Entecavir + Tenofovir |
|---|---|
| Week 24 (n=56) | 3.6 (0.4 to 12.3) |
| Week 48 (n=56) | 3.6 (0.4 to 12.3) |
| Week 96 (n=56) | 1.8 (0.0 to 9.6) |
Loss of HBsAg was defined as being HBsAg-negative at Weeks 24, 48, 96 in those participants who had been HBsAg-positive at baseline. The method used: Immunoassay - ADVIA CENTAUR from SIEMENS: in vitro diagnostic immunoassay for the qualitative and quantitative determination of HBsAg in human serum and plasma (potassium ethylene diamine tetraacetic acid, lithium or sodium heparinized). Percentage calculated as number of participants with a HBsAg loss at Weeks 24, 48, and 96 divided by the number of treated participants who were HBsAg-positive at baseline (participants were not enrolled into the study unless they were positive for HBsAg). Treated participants (HBsAg-positive at baseline) were evaluated using NC=F. Baseline was Day 1, before start of study drug.
| percentage of participants | Entecavir + Tenofovir |
|---|---|
| Week 24 (n=92) | 1.1 (0.0 to 5.9) |
| Week 48 (n=92) | 0 (NA to NA) |
| Week 96 (n=92) | 2.2 (0.3 to 7.6) |
HBsAg seroconversion was defined as being both HBsAg-negative and HBsAb-positive at Weeks 24, 48, and 96 in those participants who had been HBsAg-positive at baseline. Percentage was calculated as number of participants with HBs seroconversion at Weeks 24 and 48 divided by the number of treated participants who were HBsAg-positive at baseline. Positive result for HBsAg was one of the inclusion criteria. Treated participants (HBsAg positive at baseline) were evaluated using NC=F. The method used was an Immunoassay testing - ADVIA CENTAUR from SIEMENS: in vitro diagnostic immunoassay for the qualitative and quantitative determination of HBsAg in human serum and plasma \[potassium ethylenediaminetetraacetic acid (EDTA), lithium or sodium heparinized\]. Baseline was Day 1, before start of study drug.
| percentage of participants | Entecavir + Tenofovir |
|---|---|
| Week 24 (n=92) | 1.1 (0.0 to 5.9) |
| Week 48 (n=92) | 0 (NA to NA) |
| Week 96 (n=92) | 1.1 (0.0 to 5.9) |
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=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. On-treatment = on Day 1 through last dose of study therapy + 5 days.
| participants | Entecavir + Tenofovir |
|---|---|
| Treatment emergent SAE | 6 |
| Discontinuation of treatment due to AE | 1 |
Testing of HBV genotype was performed at baseline for all treated patients and for participants at Weeks 48 and 96 with primary non-response or virologic breakthrough. Emergent genotypic resistance to study drugs was defined as follows: Emergent = not detected at baseline; entecavir (ETV) resistance (ETVr): participant's sample was to have rtM204V/I/S and any substitution at rtT184, rtS202, or rtM250; tenofovir (TDF) resistance (TDFr) which was based on adefovir (ADV)-mutations: participant's sample was to have rtA181T/V, rtN236T, or (rtA194T and rtM204V/I/S). Primary non-response was defined as \< 1 log10 decrease in HBV DNA from baseline on treatment at or after Week 12. Virologic breakthrough was defined as ≥ 1 log10 increase in HBV DNA over nadir on treatment, either confirmed or last on-treatment followed by discontinuation of study therapy.
| participants | Entecavir + Tenofovir |
|---|---|
| Week 48 (n=5) | 0 |
| Week 96 (n=7) | 0 |
Selected criteria presented in each category. Upper limit of normal among all laboratory ranges (ULN); Baseline (BL); alanine transaminase (ALT); milligram per deciliter (mg/dL); milliliters per minute (mL/min); greater than (\>);greater than, equal to (\>=); less than (\<). Creatinine data presented below were confirmed, ie, at least 2 consecutive values. On-treatment = after Day 1 through last dose of study therapy + 5 days.
| participants | Entecavir + Tenofovir |
|---|---|
| ALT > 2*Baseline(N=90) | 9 |
| ALT > 3*Baseline(N=90) | 2 |
| Total bilirubin >2*Baseline (N=90) | 11 |
| Total bilirubin >3*Baseline (N=90) | 3 |
| Lipase > 3*Baseline (N=90) | 4 |
| Creatinine increase from BL >= 20%(N=91) | 4 |
| Creatinine >1.5 mg/dL (N=91) | 2 |
| Creatinine clearance < 50 mL/min (N=91) | 1 |
| Phosphate < 2.0 mg/dL (N=90) | 2 |
| Phosphate < 2.3 mg/dL (N=90) | 8 |
Collected over Day 1 up to 96 Weeks. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Entecavir + Tenofovir | — | 6/92 (6.5%) | 42/92 (45.7%) |
| Event | Entecavir + Tenofovir |
|---|---|
| Hepatocellular carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 2/92 |
| Inguinal herniaGastrointestinal disorders | 1/92 |
| CataractEye disorders | 1/92 |
| AppendicitisInfections and infestations | 1/92 |
| HaemorrhoidsGastrointestinal disorders | 1/92 |
| Radius fractureInjury, poisoning and procedural complications | 1/92 |
| Event | Entecavir + Tenofovir |
|---|---|
| NasopharyngitisInfections and infestations | 11/92 |
| FatigueGeneral disorders | 9/92 |
| NauseaGastrointestinal disorders | 8/92 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 7/92 |
| DyspepsiaGastrointestinal disorders | 7/92 |
| BronchitisInfections and infestations | 6/92 |
| AstheniaGeneral disorders | 6/92 |
| DiarrhoeaGastrointestinal disorders | 6/92 |
| HeadacheNervous system disorders | 6/92 |
| Abdominal pain upperGastrointestinal disorders | 5/92 |
All participants who were treated with study drug.
| Age, Continuous(years) | Entecavir + Tenofovir |
|---|---|
| Median | 42.0 (18 to 84) |
| Sex: Female, Male(Participants) | Entecavir + Tenofovir |
|---|---|
| Female | 23 |
| Male | 69 |
| Region of Enrollment(participants) | Entecavir + Tenofovir |
|---|---|
| France | 10 |
| Poland | 32 |
| Romania | 20 |
| Germany | 23 |
| Netherlands | 6 |
| Italy | 1 |
| HBV DNA by PCR (log10 IU/mL)(log10 IU/mL) | Entecavir + Tenofovir |
|---|---|
| Median | 3.674 (1.45 to 9.30) |
| Baseline Hepatitis B e Antigen(participants) | Entecavir + Tenofovir |
|---|---|
| Positive for Hepatitis B e antigen | 56 |
| Negative for Hepatitis B e antigen | 34 |
| missing Hepatitis B e antigen test | 2 |
| Baseline Hepatitis B e Antibody(participants) | Entecavir + Tenofovir |
|---|---|
| Positive for Hepatitis B e antibody | 32 |
| Negative for Hepatitis B e antibody | 56 |
| Intermediate Hepatitis B e antibody | 2 |
| missing Hepatitis B e antibody test | 2 |
| Baseline Hepatitis B Surface Antigen(participants) | Entecavir + Tenofovir |
|---|---|
| Positive for Hepatitis B Surface Antigen | 92 |
| Negative for Hepatitis B Surface Antigen | 0 |
| Baseline HBV Subtype(Participants) | Entecavir + Tenofovir |
|---|---|
| HBV Subtype A | 21 |
| HBV Subtype B | 2 |
| HBV Subtype C | 1 |
| HBV Subtype D | 35 |
| HBV Subtype E | 4 |
| HBV Subtype G | 1 |
| HBV Subtype H | 1 |
| HBV Subtype Indeterminate | 3 |
| Insufficient HBV DNA | 23 |
| Missing HBV DNA test | 1 |
1 further baseline measures are reported on the registry.
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