Efficacy and Safety Study of Entecavir Plus Tenofovir in Patients With Chronic Hepatitis B Who Failed Previous Treatment

Bristol-Myers Squibb144 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

144

Conditions

Chronic Hepatitis B

Interventions

EntecavirDRUG

Tablets, Oral, 1 mg, once daily, 96 weeks

TenofovirDRUG

Tablets, Oral, 300 mg, once daily, 96 weeks

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Subjects with chronic hepatitis B virus (HBV) infection; either hepatitis B-e antigen(HBeAg)-negative or HBeAg-positive * Subjects must have a treatment failure to their current nucleoside/ nucleotide treatment regimen * Prior entecavir and/or tenofovir monotherapy is allowed * Subjects must have compensated liver function Exclusion Criteria: * Women who are pregnant or breastfeeding * Evidence of decompensated cirrhosis * Co-infection with HIV, hepatitis C virus (HCV), or hepatitis D virus (HDV) * Moderate or severe renal impairment * Recent history of pancreatitis * Therapy with interferon, thymosin alpha or other immuno-stimulators within 24 weeks of being assigned to study drug into this study * Prior entecavir/tenofovir combination therapy

Locations (28)

Local Institution

Clichy, France

Outcomes

Primary Outcomes

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

Secondary Outcomes

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.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Local Institution

Lyon, France

Local Institution

Orléans, France

Local Institution

Strasbourg, France

Local Institution

Berlin, Germany

Local Institution

Berlin, Germany

Local Institution

Hamburg, Germany

Local Institution

Hamburg, Germany

Local Institution

Hanover, Germany

Local Institution

Heindelberg, Germany

...and 18 more locations

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