Back to resultsEntecavir Plus Adefovir Combination Therapy Versus Entecavir Monotherapy vs Therapy With Adefovir Plus Lamivudine for Chronic Hepatitis B Infected Subjects With Lamivudine-resistant Virus (DEFINE)
Primary Purpose
Hepatitis B, Chronic
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Entecavir
Tenofovir
Adefovir
Lamivudine
Sponsored by
About this trial
This is an interventional treatment trial for Hepatitis B, Chronic
Eligibility Criteria
Inclusion Criteria:
- Evidence of lamivudine (LVD) resistance
- Subjects must have a history of previous LVD treatment at screening, and must have evidence of at least 1 LVD resistance substitution (valine, isoleucine, or serine) at reverse transcriptase codon 204 (M204V/I/S)
- Nucleoside- and nucleotide-naive, except for LVD, and had chronic hepatitis B (HBV) infection
- Compensated liver function and must have met ALL of the following criteria:International normalization ratio (INR) ≤ 1.5; Serum albumin ≥ 3 g/dL (≥ 30 g/L); Serum total bilirubin ≤ 2.5 mg/dL (≤ 42.75 μmol/L)
- HBV DNA > 1.72 x 10*4* IU/mL (approximately 10*5* copies/mL)
- Documentation of hepatitis B e antigen (HBeAg) positive and hepatitis B e antibody (HBeAb) negative status at screening
- alanine aminotransferase (ALT) ≤ 10 * upper limit of normal (ULN) at screening
- Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study (and for up to 6 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized
- WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal. Post menopausal is defined as:
- Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential
- WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 72 hours prior to the start of investigational product
Exclusion Criteria:
- Evidence of decompensated cirrhosis
- Coinfection with human immunodeficiency virus, hepatitis C virus , or hepatitis D virus
- Women who are pregnant or breastfeeding
- Sexually active fertile men not using effective birth control if their partners were WOCBP
- Laboratory values out of protocol-specified range
Sites / Locations
- University Of Connecticut Health Center
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Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Active Comparator
Active Comparator
Active Comparator
Arm Label
Entecavir
Adefovir + Lamivudine
Entecavir + Adefovir
Arm Description
With the option of adding tenofovir at week 48. (This does not apply to Korea)
Outcomes
Primary Outcome Measures
Percentage of Participants With Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) < 50 IU/mL (Approximately 300 Copies/mL) by Polymerase Chain Reaction (PCR) at Week 48
HBV DNA assessments were performed using the Roche COBAS® TaqMan High Pure System (HPS) assay. HBV DNA less than (<)50 International units per milliliter (IU/mL) = approximately 300 copies/mL. Percentage of participants calculated n/N; n= number of participants with HBV DNA <50 IU/mL; N = number of participants analyzed.
Secondary Outcome Measures
Percentage of Participants With HBV DNA < 50 IU/mL (Approximately 300 Copies/mL) by PCR at Week 96
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay. HBV DNA < 50 IU/mL = approximately 300 copies/mL. Percentage n/N: n= number of participants with HBV DNA <50 IU/mL; N = number of participants analyzed.
Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 48
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay. 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. Percentage n/N: n= number of participants with outcome result; N = number of participants analyzed.
Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 96
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay. 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. Percentage n/N: n= number of participants with outcome result; N = number of participants analyzed.
Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 48
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay. 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.
Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 96
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay. LOD is the lowest amount or concentration of analyte in a sample, which can be reliably detected, but not necessarily quantified.
Percentage of Participants With HBV DNA by PCR Category at Week 48
HBV DNA assessments were performed using the Roche COBAS® TaqMan High Pure System (HPS) assay.
Percentage of Participants With HBV DNA by PCR Category at Week 96
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay.
Change in Mean log10 From Baseline in HBV DNA at Week 48
HBV DNA was analyzed by PCR, using the Roche COBAS®TaqMan TaqMan HPS assay. Reduction in log10 HBV count=reduced viral load, negative values means reduction.
Change in Mean log10 From Baseline in HBV DNA at Week 96
HBV DNA was analyzed by PCR, using the Roche COBAS® TaqMan HPS assay. Reduction in log10 HBV count=reduced viral load.
Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 48
ALT normalization=ALT level being less than or equal to 1 times the upper limit of normal (ULN). ULN for ALT is 37 or 48 U/L.
Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 96
ALT normalization=ALT level being less than or equal to 1 times the upper limit of normal (ULN). ULN for ALT is 37 U/L.
Percentage of Participants With Confirmed HBeAg Loss at Week 48 (Treated HBeAg Positive Participants Only)
HBeAg is a hepatitis B viral protein. HBeAg loss = HBeAg-negative at the specified analysis week
Percentage of Participants With Confirmed HBeAg Loss at Week 96 (Treated HBeAg Positive Participants Only)
HBeAg is a hepatitis B viral protein. HBeAg loss = HBeAg-negative at the specified analysis week
Percentage of Participants With HBeAg Seroconversion at Week 48 (Treated HBeAg-positive Participants Only)
HBeAg is a hepatitis B viral protein. It is an indicator of active viral replication. HBeAg Seroconversion = HBeAg Loss and Presence of Hepatitis B e Antibody (HBeAb).
Percentage of Participants With HBeAg Seroconversion at Week 96 (Treated HBeAg-positive Participants Only)
HBeAg is a hepatitis B viral protein. It is an indicator of active viral replication. HBeAg Seroconversion = HBeAg Loss and Presence of Hepatitis B e Antibody (HBeAb).
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48
HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBsAg loss = HBsAg-negative at the specified analysis week.
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 96
HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBsAg loss = HBsAg-negative at the specified analysis week.
Percentage of Participants With HBsAg Seroconversion at Week 48
HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBs seroconversion is defined as HBsAg loss with positive HBsAb.
Percentage of Participants With HBsAg Seroconversion at Week 96
HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBs seroconversion is defined as HBsAg loss with positive HBsAb.
Cumulative Probability of Emergent Genotypic Resistance at Year 1
yr=year. Cumulative probability (CP): Ptotal=1-(1-Pyr1)*(1-Pyr2) where Pyear(i)= number of participants with events at Year i divided by number of participants at risk at Year i for i = 1,2. An "event" is defined as resistance or resistance with virologic breakthrough in a yearly interval. Participants 'at risk' are those who were treated during Year i and did not develop that resistance or resistance with virologic breakthrough prior to Year i. CP were calculated separately for ETV, ADV and TDF resistance. Participants who discontinue from study drug in Year i were assumed to be in follow up for the entire year. (VBT; a ≥ 1 log10 increase in HBV DNA from the on-treatment nadir, confirmed by 2 sequential HBV DNA results or observed at the last on-treatment HBV DNA). ETVr = ETV resistance (rtM204V/I/S plus any substitution at rtT184, rtS202, or rtM250); ADVr/TDFr = ADV/TDF resistance (rtA181T/V or rtN236T = ADVr and TDFr, rtA194T = TDFr only).
Cumulative Probability of Emergent Genotypic Resistance at Year 2
Cumulative probability (CP): Ptotal=1-(1-Pyr1)*(1-Pyr2) where Pyear(i)= number of participants with events at Year i divided by number of participants at risk at Year i for i = 1,2. An "event" is defined as resistance or resistance with virologic breakthrough in a yearly interval. Participants 'at risk' are those who were treated during Year i and did not develop that resistance or resistance with virologic breakthrough prior to Year i. CP were calculated separately for ETV, ADV and TDF resistance. Participants who discontinue from study drug in Year i were assumed to be in follow up for the entire year. (VBT; a ≥ 1 log10 increase in HBV DNA from the on-treatment nadir, confirmed by 2 sequential HBV DNA results or observed at the last on-treatment HBV DNA). ETVr = ETV resistance (rtM204V/I/S plus any substitution at rtT184, rtS202, or rtM250); ADVr/TDFr = ADV/TDF resistance (rtA181T/V or rtN236T = ADVr and TDFr, rtA194T = TDFr only).
Participants With Adverse Events (AE), Serious Adverse Events (SAE), and Discontinuations Due to Adverse Events or Laboratory Abnormalities During Treatment
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. Grade 1 = mild, Grade 2= moderate, Grade 3 = severe, Grade 4 = life threatening/disabling, Grade 5 = death.
Number of Participants With Laboratory Abnormalities: Hematology
Criteria for hematology abnormalities were: Hemoglobin: <=11.0 g/dL; White Blood Cells: <4000/mm^3; Absolute Neutrophils (includes absolute bands): <1500/mm^3; Platelets: <=99,000/mm^3; International Normalized Ratio: ≥ 1.5 and ≥ 0.5 from baseline.
Number of Participants With Laboratory Abnormalities: Serum Chemistry
ULN=upper limit of normal (Normal ranges are Central lab data and vary according to the site). ALT:>1.25*ULN, AST:>1.25*ULN, ALP:>1.25*ULN, Total Bilirubin:>1.1*ULN, Serum Lipase:>1.10*ULN, Creatinine:>1.1*ULN, Blood Urea Nitrogen:1.25*ULN, Hyperglycemia:>116 mg/dL, Hypoglycemia:<64 mg/dL, Hyponatremia:<132meq/L, Hypokalemia:<3.4 meq/L, Albumin:≥1g/dL decrease from baseline, <3 g/dL; Hypernatremia:>148 meq/L, Hyperkalemia:>5.6 meq/L, Hypokalemia:<3.4 meq/L, Hyperchloremia:>113 meq/L, Hypochloremia:<93 meq/L; ALT flare: on treatment (OT), >2*Baseline and >10*ULN; off treatment (OF), 2*end of dosing value and >10*ULN
Full Information
NCT ID
NCT00410202
First Posted
December 11, 2006
Last Updated
October 29, 2013
Sponsor
Bristol-Myers Squibb
1. Study Identification
Unique Protocol Identification Number
NCT00410202
Brief Title
Entecavir Plus Adefovir Combination Therapy Versus Entecavir Monotherapy vs Therapy With Adefovir Plus Lamivudine for Chronic Hepatitis B Infected Subjects With Lamivudine-resistant Virus
Acronym
DEFINE
Official Title
A Comparative Study of Entecavir vs. Adefovir Plus Lamivudine vs Combination Entecavir Plus Adefovir in Lamivudine-resistant Chronic Hepatitis B Subjects: The DEFINE Study
Study Type
Interventional
2. Study Status
Record Verification Date
October 2013
Overall Recruitment Status
Completed
Study Start Date
March 2008 (undefined)
Primary Completion Date
January 2011 (Actual)
Study Completion Date
July 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bristol-Myers Squibb
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to evaluate the effectiveness of entecavir plus adefovir combination therapy versus entecavir monotherapy or therapy with adefovir plus lamivudine
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis B, Chronic
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
629 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Entecavir
Arm Type
Active Comparator
Arm Description
With the option of adding tenofovir at week 48. (This does not apply to Korea)
Arm Title
Adefovir + Lamivudine
Arm Type
Active Comparator
Arm Title
Entecavir + Adefovir
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Entecavir
Other Intervention Name(s)
Baraclude, BMS-200475
Intervention Description
Tablets, Oral, 1mg, once daily, 100 weeks
Intervention Type
Drug
Intervention Name(s)
Tenofovir
Other Intervention Name(s)
Viread
Intervention Description
Tablets, Oral, 300 mg, once daily
Intervention Type
Drug
Intervention Name(s)
Adefovir
Other Intervention Name(s)
Hepsera
Intervention Description
Tablets, Oral, 10mg, once daily, 100 weeks
Intervention Type
Drug
Intervention Name(s)
Lamivudine
Other Intervention Name(s)
Epivir
Intervention Description
Tablets, Oral, 100mg, once daily, 100 weeks
Primary Outcome Measure Information:
Title
Percentage of Participants With Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) < 50 IU/mL (Approximately 300 Copies/mL) by Polymerase Chain Reaction (PCR) at Week 48
Description
HBV DNA assessments were performed using the Roche COBAS® TaqMan High Pure System (HPS) assay. HBV DNA less than (<)50 International units per milliliter (IU/mL) = approximately 300 copies/mL. Percentage of participants calculated n/N; n= number of participants with HBV DNA <50 IU/mL; N = number of participants analyzed.
Time Frame
Week 48
Secondary Outcome Measure Information:
Title
Percentage of Participants With HBV DNA < 50 IU/mL (Approximately 300 Copies/mL) by PCR at Week 96
Description
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay. HBV DNA < 50 IU/mL = approximately 300 copies/mL. Percentage n/N: n= number of participants with HBV DNA <50 IU/mL; N = number of participants analyzed.
Time Frame
Week 96
Title
Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 48
Description
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay. 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. Percentage n/N: n= number of participants with outcome result; N = number of participants analyzed.
Time Frame
Week 48
Title
Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 96
Description
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay. 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. Percentage n/N: n= number of participants with outcome result; N = number of participants analyzed.
Time Frame
Week 96
Title
Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 48
Description
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay. 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.
Time Frame
Week 48
Title
Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 96
Description
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay. LOD is the lowest amount or concentration of analyte in a sample, which can be reliably detected, but not necessarily quantified.
Time Frame
Week 96
Title
Percentage of Participants With HBV DNA by PCR Category at Week 48
Description
HBV DNA assessments were performed using the Roche COBAS® TaqMan High Pure System (HPS) assay.
Time Frame
Week 48
Title
Percentage of Participants With HBV DNA by PCR Category at Week 96
Description
HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay.
Time Frame
Week 96
Title
Change in Mean log10 From Baseline in HBV DNA at Week 48
Description
HBV DNA was analyzed by PCR, using the Roche COBAS®TaqMan TaqMan HPS assay. Reduction in log10 HBV count=reduced viral load, negative values means reduction.
Time Frame
Baseline, Week 48
Title
Change in Mean log10 From Baseline in HBV DNA at Week 96
Description
HBV DNA was analyzed by PCR, using the Roche COBAS® TaqMan HPS assay. Reduction in log10 HBV count=reduced viral load.
Time Frame
Baseline, Week 96
Title
Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 48
Description
ALT normalization=ALT level being less than or equal to 1 times the upper limit of normal (ULN). ULN for ALT is 37 or 48 U/L.
Time Frame
Week 48
Title
Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 96
Description
ALT normalization=ALT level being less than or equal to 1 times the upper limit of normal (ULN). ULN for ALT is 37 U/L.
Time Frame
Baseline, Week 96
Title
Percentage of Participants With Confirmed HBeAg Loss at Week 48 (Treated HBeAg Positive Participants Only)
Description
HBeAg is a hepatitis B viral protein. HBeAg loss = HBeAg-negative at the specified analysis week
Time Frame
Week 48
Title
Percentage of Participants With Confirmed HBeAg Loss at Week 96 (Treated HBeAg Positive Participants Only)
Description
HBeAg is a hepatitis B viral protein. HBeAg loss = HBeAg-negative at the specified analysis week
Time Frame
Week 96
Title
Percentage of Participants With HBeAg Seroconversion at Week 48 (Treated HBeAg-positive Participants Only)
Description
HBeAg is a hepatitis B viral protein. It is an indicator of active viral replication. HBeAg Seroconversion = HBeAg Loss and Presence of Hepatitis B e Antibody (HBeAb).
Time Frame
Week 48
Title
Percentage of Participants With HBeAg Seroconversion at Week 96 (Treated HBeAg-positive Participants Only)
Description
HBeAg is a hepatitis B viral protein. It is an indicator of active viral replication. HBeAg Seroconversion = HBeAg Loss and Presence of Hepatitis B e Antibody (HBeAb).
Time Frame
Week 96
Title
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48
Description
HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBsAg loss = HBsAg-negative at the specified analysis week.
Time Frame
Week 48
Title
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 96
Description
HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBsAg loss = HBsAg-negative at the specified analysis week.
Time Frame
Week 96
Title
Percentage of Participants With HBsAg Seroconversion at Week 48
Description
HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBs seroconversion is defined as HBsAg loss with positive HBsAb.
Time Frame
Week 48
Title
Percentage of Participants With HBsAg Seroconversion at Week 96
Description
HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBs seroconversion is defined as HBsAg loss with positive HBsAb.
Time Frame
Week 96
Title
Cumulative Probability of Emergent Genotypic Resistance at Year 1
Description
yr=year. Cumulative probability (CP): Ptotal=1-(1-Pyr1)*(1-Pyr2) where Pyear(i)= number of participants with events at Year i divided by number of participants at risk at Year i for i = 1,2. An "event" is defined as resistance or resistance with virologic breakthrough in a yearly interval. Participants 'at risk' are those who were treated during Year i and did not develop that resistance or resistance with virologic breakthrough prior to Year i. CP were calculated separately for ETV, ADV and TDF resistance. Participants who discontinue from study drug in Year i were assumed to be in follow up for the entire year. (VBT; a ≥ 1 log10 increase in HBV DNA from the on-treatment nadir, confirmed by 2 sequential HBV DNA results or observed at the last on-treatment HBV DNA). ETVr = ETV resistance (rtM204V/I/S plus any substitution at rtT184, rtS202, or rtM250); ADVr/TDFr = ADV/TDF resistance (rtA181T/V or rtN236T = ADVr and TDFr, rtA194T = TDFr only).
Time Frame
Year 1
Title
Cumulative Probability of Emergent Genotypic Resistance at Year 2
Description
Cumulative probability (CP): Ptotal=1-(1-Pyr1)*(1-Pyr2) where Pyear(i)= number of participants with events at Year i divided by number of participants at risk at Year i for i = 1,2. An "event" is defined as resistance or resistance with virologic breakthrough in a yearly interval. Participants 'at risk' are those who were treated during Year i and did not develop that resistance or resistance with virologic breakthrough prior to Year i. CP were calculated separately for ETV, ADV and TDF resistance. Participants who discontinue from study drug in Year i were assumed to be in follow up for the entire year. (VBT; a ≥ 1 log10 increase in HBV DNA from the on-treatment nadir, confirmed by 2 sequential HBV DNA results or observed at the last on-treatment HBV DNA). ETVr = ETV resistance (rtM204V/I/S plus any substitution at rtT184, rtS202, or rtM250); ADVr/TDFr = ADV/TDF resistance (rtA181T/V or rtN236T = ADVr and TDFr, rtA194T = TDFr only).
Time Frame
Year 2
Title
Participants With Adverse Events (AE), Serious Adverse Events (SAE), and Discontinuations Due to Adverse Events or Laboratory Abnormalities During Treatment
Description
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. Grade 1 = mild, Grade 2= moderate, Grade 3 = severe, Grade 4 = life threatening/disabling, Grade 5 = death.
Time Frame
From start of study therapy through Week 100 + 5 days
Title
Number of Participants With Laboratory Abnormalities: Hematology
Description
Criteria for hematology abnormalities were: Hemoglobin: <=11.0 g/dL; White Blood Cells: <4000/mm^3; Absolute Neutrophils (includes absolute bands): <1500/mm^3; Platelets: <=99,000/mm^3; International Normalized Ratio: ≥ 1.5 and ≥ 0.5 from baseline.
Time Frame
From start of study through Week 100 + 5 days
Title
Number of Participants With Laboratory Abnormalities: Serum Chemistry
Description
ULN=upper limit of normal (Normal ranges are Central lab data and vary according to the site). ALT:>1.25*ULN, AST:>1.25*ULN, ALP:>1.25*ULN, Total Bilirubin:>1.1*ULN, Serum Lipase:>1.10*ULN, Creatinine:>1.1*ULN, Blood Urea Nitrogen:1.25*ULN, Hyperglycemia:>116 mg/dL, Hypoglycemia:<64 mg/dL, Hyponatremia:<132meq/L, Hypokalemia:<3.4 meq/L, Albumin:≥1g/dL decrease from baseline, <3 g/dL; Hypernatremia:>148 meq/L, Hyperkalemia:>5.6 meq/L, Hypokalemia:<3.4 meq/L, Hyperchloremia:>113 meq/L, Hypochloremia:<93 meq/L; ALT flare: on treatment (OT), >2*Baseline and >10*ULN; off treatment (OF), 2*end of dosing value and >10*ULN
Time Frame
On treatment : Day 1 through Week 100 + 5 days; Offtreatment = End of OT period through 24 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Evidence of lamivudine (LVD) resistance
Subjects must have a history of previous LVD treatment at screening, and must have evidence of at least 1 LVD resistance substitution (valine, isoleucine, or serine) at reverse transcriptase codon 204 (M204V/I/S)
Nucleoside- and nucleotide-naive, except for LVD, and had chronic hepatitis B (HBV) infection
Compensated liver function and must have met ALL of the following criteria:International normalization ratio (INR) ≤ 1.5; Serum albumin ≥ 3 g/dL (≥ 30 g/L); Serum total bilirubin ≤ 2.5 mg/dL (≤ 42.75 μmol/L)
HBV DNA > 1.72 x 10*4* IU/mL (approximately 10*5* copies/mL)
Documentation of hepatitis B e antigen (HBeAg) positive and hepatitis B e antibody (HBeAb) negative status at screening
alanine aminotransferase (ALT) ≤ 10 * upper limit of normal (ULN) at screening
Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study (and for up to 6 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized
WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal. Post menopausal is defined as:
Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 72 hours prior to the start of investigational product
Exclusion Criteria:
Evidence of decompensated cirrhosis
Coinfection with human immunodeficiency virus, hepatitis C virus , or hepatitis D virus
Women who are pregnant or breastfeeding
Sexually active fertile men not using effective birth control if their partners were WOCBP
Laboratory values out of protocol-specified range
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
Facility Name
University Of Connecticut Health Center
City
Farmington
State/Province
Connecticut
ZIP/Postal Code
06030
Country
United States
Facility Name
Local Institution
City
Concord
State/Province
New South Wales
ZIP/Postal Code
2139
Country
Australia
Facility Name
Local Institution
City
Randwick
State/Province
New South Wales
ZIP/Postal Code
2031
Country
Australia
Facility Name
Local Institution
City
Porto Alegre Rs
State/Province
Rio Grande Do Sul
ZIP/Postal Code
90035
Country
Brazil
Facility Name
Local Institution
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T2N 4N1
Country
Canada
Facility Name
Local Institution
City
Athens
ZIP/Postal Code
11527
Country
Greece
Facility Name
Local Institution
City
Shatin
State/Province
New Territories
Country
Hong Kong
Facility Name
Local Institution
City
Hong Kong
Country
Hong Kong
Facility Name
Local Institution
City
Tai Po
Country
Hong Kong
Facility Name
Local Institution
City
Lucknow
State/Province
Uttar Pradesh
ZIP/Postal Code
226014
Country
India
Facility Name
Local Institution
City
Ahmedabad
ZIP/Postal Code
380006
Country
India
Facility Name
Local Institution
City
Chandigarh
ZIP/Postal Code
160012
Country
India
Facility Name
Local Institution
City
Indore
ZIP/Postal Code
452014
Country
India
Facility Name
Local Institution
City
Ludhiana
ZIP/Postal Code
141001
Country
India
Facility Name
Local Institution
City
New Delhi
ZIP/Postal Code
110002
Country
India
Facility Name
Local Institution
City
Vellore
ZIP/Postal Code
632004
Country
India
Facility Name
Local Institution
City
Jakarta
ZIP/Postal Code
10350
Country
Indonesia
Facility Name
Local Institution
City
Antella, Firenze
ZIP/Postal Code
50012
Country
Italy
Facility Name
Local Institution
City
Seoul
State/Province
Dongdaemun-Gu
ZIP/Postal Code
130-702
Country
Korea, Republic of
Facility Name
Local Institution
City
Ulsan
State/Province
Donggu
ZIP/Postal Code
682-714
Country
Korea, Republic of
Facility Name
Local Institution
City
Ansan-Si
State/Province
Gyeonggi-Do
ZIP/Postal Code
425-707
Country
Korea, Republic of
Facility Name
Local Institution
City
Anyang-Si
State/Province
Gyeonggi-Do
ZIP/Postal Code
431-070
Country
Korea, Republic of
Facility Name
Local Institution
City
Bucheon-Si
State/Province
Gyeonggi-Do
ZIP/Postal Code
420767
Country
Korea, Republic of
Facility Name
Local Institution
City
Seongnam-Si
State/Province
Gyeonggi-Do
ZIP/Postal Code
463 712
Country
Korea, Republic of
Facility Name
Local Institution
City
Suwon-Si
State/Province
Gyeonggi-Do
ZIP/Postal Code
442-723
Country
Korea, Republic of
Facility Name
Local Institution
City
Koyang
State/Province
Ilsanseo Gu
ZIP/Postal Code
411-706
Country
Korea, Republic of
Facility Name
Local Institution
City
Incheon
State/Province
Jung-Gu
ZIP/Postal Code
400-711
Country
Korea, Republic of
Facility Name
Local Institution
City
Seoul
State/Province
Nowon-Gu
ZIP/Postal Code
139-872
Country
Korea, Republic of
Facility Name
Local Institution
City
Chuncheon-Si
ZIP/Postal Code
200-704
Country
Korea, Republic of
Facility Name
Local Institution
City
Daegu
ZIP/Postal Code
700-721
Country
Korea, Republic of
Facility Name
Local Institution
City
Gangneung
ZIP/Postal Code
210-711
Country
Korea, Republic of
Facility Name
Local Institution
City
Incheon
ZIP/Postal Code
405-760
Country
Korea, Republic of
Facility Name
Local Institution
City
Pusan
ZIP/Postal Code
602-739
Country
Korea, Republic of
Facility Name
Local Institution
City
Seoul
ZIP/Postal Code
110-744
Country
Korea, Republic of
Facility Name
Local Institution
City
Seoul
ZIP/Postal Code
120-752
Country
Korea, Republic of
Facility Name
Local Institution
City
Seoul
ZIP/Postal Code
135-710
Country
Korea, Republic of
Facility Name
Local Institution
City
Seoul
ZIP/Postal Code
135-720
Country
Korea, Republic of
Facility Name
Local Institution
City
Seoul
ZIP/Postal Code
136-705
Country
Korea, Republic of
Facility Name
Local Institution
City
Seoul
ZIP/Postal Code
137-040
Country
Korea, Republic of
Facility Name
Local Institution
City
Seoul
ZIP/Postal Code
138-736
Country
Korea, Republic of
Facility Name
Local Institution
City
Seoul
ZIP/Postal Code
143-729
Country
Korea, Republic of
Facility Name
Local Institution
City
Seoul
ZIP/Postal Code
152-703
Country
Korea, Republic of
Facility Name
Local Institution
City
Seoul
ZIP/Postal Code
156-755
Country
Korea, Republic of
Facility Name
Local Institution
City
Suwon
ZIP/Postal Code
443-721
Country
Korea, Republic of
Facility Name
Local Institution
City
Yangsan-Si
ZIP/Postal Code
626770
Country
Korea, Republic of
Facility Name
Local Institution
City
Kota Kinabalu
State/Province
Sabah
ZIP/Postal Code
88586
Country
Malaysia
Facility Name
Local Institution
City
Kuala Lumpur
ZIP/Postal Code
50603
Country
Malaysia
Facility Name
Local Institution
City
Cebu City
ZIP/Postal Code
6000
Country
Philippines
Facility Name
Local Institution
City
Manila
ZIP/Postal Code
1502
Country
Philippines
Facility Name
Local Institution
City
Chorzow
ZIP/Postal Code
41-500
Country
Poland
Facility Name
Local Institution
City
Kielce
ZIP/Postal Code
25-317
Country
Poland
Facility Name
Local Institution
City
Lodzi
ZIP/Postal Code
91-347
Country
Poland
Facility Name
Local Institution
City
Lublin
ZIP/Postal Code
20-081
Country
Poland
Facility Name
Local Institution
City
Warszawa
ZIP/Postal Code
01-201
Country
Poland
Facility Name
Local Institution
City
Moscow
ZIP/Postal Code
105275
Country
Russian Federation
Facility Name
Local Institution
City
Moscow
ZIP/Postal Code
115446
Country
Russian Federation
Facility Name
Local Institution
City
St. Petersburg
ZIP/Postal Code
190103
Country
Russian Federation
Facility Name
Local Institution
City
St. Petersburg
ZIP/Postal Code
191167
Country
Russian Federation
Facility Name
Local Institution
City
Singapore
ZIP/Postal Code
119074
Country
Singapore
Facility Name
Local Institution
City
Kaohsiung
ZIP/Postal Code
80756
Country
Taiwan
Facility Name
Local Institution
City
Tainan R.O.C.
ZIP/Postal Code
70403
Country
Taiwan
Facility Name
Local Institution
City
Taipei
ZIP/Postal Code
100
Country
Taiwan
Facility Name
Local Institution
City
Taoyuan
ZIP/Postal Code
333
Country
Taiwan
Facility Name
Local Institution
City
Bangkok
ZIP/Postal Code
10700
Country
Thailand
Facility Name
Local Institution
City
Chiang Mai
ZIP/Postal Code
50200
Country
Thailand
Facility Name
Local Institution
City
Bornova Izmir
ZIP/Postal Code
35100
Country
Turkey
Facility Name
Local Institution
City
Trabzon
ZIP/Postal Code
610808
Country
Turkey
12. IPD Sharing Statement
Learn more about this trial
Entecavir Plus Adefovir Combination Therapy Versus Entecavir Monotherapy vs Therapy With Adefovir Plus Lamivudine for Chronic Hepatitis B Infected Subjects With Lamivudine-resistant Virus
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