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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT01063036
First received: February 3, 2010
Last updated: March 26, 2014
Last verified: March 2014
  Purpose

The purpose of this study is to show that the combination of entecavir and tenofovir will be safe, well tolerated and effective in chronic Hepatitis B patients who have failed previous treatment.


Condition Intervention Phase
Chronic Hepatitis B
Drug: Entecavir
Drug: Tenofovir
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Study of the Safety and Efficacy of Entecavir Plus Tenofovir in Adults With Chronic Hepatitis B Virus Infection With Previous Nucleoside/Nucleotide Treatment Failure

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Percentage of Participants With a Virologic Response at Week 48 - Treated Population [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Percentage of Participants With a Virologic Response at Week 24 - Treated Population [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    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 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.

  • Change From Baseline in Mean log10 HBV DNA at Week 12 - Treated Evaluable Population [ Time Frame: Baseline to Week 12 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With HBV DNA Less Than the Lower Limit of Detection (LLD) at Weeks 24 and 48 - Treated Population [ Time Frame: Weeks 24 and 48 ] [ Designated as safety issue: No ]
    HBV DNA less than (<) LLD (6 IU/mL) was defined/measured by the COBAS(REGISTERED) TaqMan HPS assay at Weeks 24 and 48. Percentage was calculated as number of participants with HBV DNA < LLD at Weeks 24 and 48 divided by the number of treated participants. Treated participants were evaluated using non-completer (NC) = failure (F).

  • Percentage of Participants With Change (Loss) From Baseline of Hepatitis B e Antigen (HBeAg) at Weeks 24 and 48 - Treated Population Who Were HBeAg Positive at Baseline [ Time Frame: Baseline to Weeks 24 and 48 ] [ Designated as safety issue: No ]
    Loss of HBeAg was defined as being HBeAg-negative at Weeks 24 and 48 in those participants who had been 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 a change from baseline (loss) in HBeAg at Weeks 24 and 48 divided by the number of treated participants who were positive at baseline for HBeAg. Treated participants (positive for HBeAg at baseline) were evaluated using non-completer (NC) = failure (F). Baseline was Day 1, before start of study drug.

  • Percentage of Participants With HBe Seroconversion at Weeks 24 and 48 - Treated Population Who Were HBeAg Positive at Baseline [ Time Frame: Baseline to Weeks 24 and 48 ] [ Designated as safety issue: No ]
    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 and 48 divided by the number of treated participants who were positive at baseline for HBeAg. Treated participants (positive for HBeAg at baseline) were evaluated using non-completer (NC) = failure (F). Baseline was Day 1, before start of study drug.

  • Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Change (Loss) From Baseline at Weeks 24 and 48 - Treated Population [ Time Frame: Baseline to Weeks 24 and 48 ] [ Designated as safety issue: No ]
    Loss of HBsAg was defined as being HBsAg-negative at Weeks 24 and 48 in those participants who had been 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 change from baseline (loss) in HBsAg at Weeks 24 and 48 divided by the number of treated participants who were positive at baseline for HBsAg (participants were not enrolled into the study unless they were positive for HBsAg). Treated participants were evaluated using non-completer (NC) = failure (F). Baseline was Day 1, before start of study drug.

  • Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Seroconversion at Weeks 24 and 48 - Treated Population [ Time Frame: Weeks 24 and 48 ] [ Designated as safety issue: No ]
    HBsAg seroconversion was defined as being both HBsAg-negative and HBsAb-positive at Weeks 24 and 48 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 positive at baseline for HBsAg. Positive result for HBsAg was one of the inclusion criteria. Treated participants were evaluated using non-completer (NC) = failure (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.

  • Number of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuation of Study Drug Due to Adverse Events - Treated Population [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Emergence of Genotypic Resistance to Study Drugs at Week 48 - Treated Population [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    Testing of HBV genotype was performed at baseline for all treated patients and for participants at Week 48 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.

  • Number of Participants on Treatment With Study Drug With Laboratory Test Abnormalities Meeting Selected Criteria - Treated Population [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 144
Study Start Date: May 2010
Study Completion Date: February 2014
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Entecavir + Tenofovir Drug: Entecavir
Tablets, Oral, 1 mg, once daily, 96 weeks
Other Names:
  • Baraclude®
  • BMS-200475
Drug: Tenofovir
Tablets, Oral, 300 mg, once daily, 96 weeks
Other Name: Viread®

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  • Men and women, ages 18 or older

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01063036

Locations
France
Local Institution
Clichy, France, 92110
Local Institution
Lyons Cedex 04, France, 69317
Local Institution
Orleans Cedex 2, France, 45067
Local Institution
Strasbourg, France, 67000
Germany
Local Institution
Berlin, Germany, 13353
Local Institution
Berlin, Germany, 10969
Local Institution
Hamburg, Germany, 20099
Local Institution
Hamburg, Germany, 20246
Local Institution
Hannover, Germany, 30625
Local Institution
Heindelberg, Germany, 69120
Local Institution
Munchen, Germany, 81675
Local Institution
Tubingen, Germany, 72076
Italy
Local Institution
Bagno A Ripoli (Fi), Italy, 50012
Local Institution
Bari, Italy, 70124
Local Institution
Foggia, Italy, 71100
Local Institution
Milano, Italy, 20122
Netherlands
Local Institution
Amsterdam, Netherlands, 1105 AZ
Local Institution
Arnhem, Netherlands, 6815 AD
Local Institution
Rotterdam, Netherlands, 3015 CE
Poland
Local Institution
Kielce, Poland, 25-317
Local Institution
Krakow, Poland, 31-531
Local Institution
Lodz, Poland, 91-347
Local Institution
Wroclaw, Poland, 50-349
Romania
Local Institution
Bucuresti, Romania, 021105
Local Institution
Burcuresti, Romania, 022328
Local Institution
Timisoara, Romania, 300 002
Spain
Local Institution
Barcelona, Spain, 08025
Local Institution
Valencia, Spain, 46014
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01063036     History of Changes
Other Study ID Numbers: AI463-203, 2009-015705-40
Study First Received: February 3, 2010
Results First Received: November 5, 2013
Last Updated: March 26, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Italy: Istituto Superiore de Sanita (ISS)
Romania: Ministry of Public Health
Romania: National Medicines Agency
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis B
Hepatitis, Chronic
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Tenofovir
Tenofovir disoproxil
Entecavir
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on August 21, 2014