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Entecavir Plus Adefovir Combination Therapy Versus Entecavir Monotherapy vs Therapy With Adefovir Plus Lamivudine for Chronic Hepatitis B Infected Subjects With Lamivudine-resistant Virus (DEFINE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00410202
First received: December 11, 2006
Last updated: October 29, 2013
Last verified: October 2013
  Purpose

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


Condition Intervention Phase
Hepatitis B, Chronic
Drug: Entecavir
Drug: Tenofovir
Drug: Adefovir
Drug: Lamivudine
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

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 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay.

  • Change in Mean log10 From Baseline in HBV DNA at Week 48 [ Time Frame: Baseline, Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 96 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 96 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Year 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Year 2 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From start of study therapy through Week 100 + 5 days ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: From start of study through Week 100 + 5 days ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: On treatment : Day 1 through Week 100 + 5 days; Offtreatment = End of OT period through 24 weeks ] [ Designated as safety issue: Yes ]
    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


Enrollment: 629
Study Start Date: March 2008
Study Completion Date: July 2012
Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Entecavir
With the option of adding tenofovir at week 48. (This does not apply to Korea)
Drug: Entecavir
Tablets, Oral, 1mg, once daily, 100 weeks
Other Names:
  • Baraclude
  • BMS-200475
Drug: Tenofovir
Tablets, Oral, 300 mg, once daily
Other Name: Viread
Active Comparator: Adefovir + Lamivudine Drug: Adefovir
Tablets, Oral, 10mg, once daily, 100 weeks
Other Name: Hepsera
Drug: Lamivudine
Tablets, Oral, 100mg, once daily, 100 weeks
Other Name: Epivir
Active Comparator: Entecavir + Adefovir Drug: Entecavir
Tablets, Oral, 1mg, once daily, 100 weeks
Other Names:
  • Baraclude
  • BMS-200475
Drug: Adefovir
Tablets, Oral, 10mg, once daily, 100 weeks
Other Name: Hepsera

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT00410202

  Show 67 Study Locations
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: NCT00410202     History of Changes
Other Study ID Numbers: AI463-111
Study First Received: December 11, 2006
Results First Received: April 24, 2012
Last Updated: October 29, 2013
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on November 25, 2014