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)


Tracking Information

Start Date  ICMJEMarch 2008
Estimated Primary Completion DateJanuary 2011   (final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 9, 2009)		Compare the proportion of subjects in the combination therapy group to the proportion of subjects in each of the comparator therapy groups who achieve HBV DNA <50 IU/mL (approximately 300 copies/mL) [ Time Frame: at week 48 ] [ Designated as safety issue: No ]
Original Primary Outcome Measures ICMJE 
 (submitted: December 11, 2006)		To compare the proportion of subjects in the combination therapy group to the proportion of subjects in each of the monotherapy groups who achieve HBV DNA <50 IU/mL (approximately 300 copies/mL) at Week 48
Change HistoryComplete list of historical versions of study NCT00410202 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE 
 (submitted: February 9, 2009)
  • Proportion of subjects who achieve HBV DNA < the lower limit of quantitation (LLD LOQ) for the Roche COBAS® TaqMan -(LOQ = 29 IU/mL [approximately 169 copies/mL] [ Time Frame: HPS assay at Weeks 48 and 96 ] [ Designated as safety issue: No ]
  • Proportion of subjects who achieve HBV DNA < the lower limit of detection (LOD) for the Roche COBAS® Taqman - (LOD = 10 IU/mL [approximately 58 copies/mL]) [ Time Frame: HPS assay at Weeks 48 and 96 ] [ Designated as safety issue: No ]
  • Proportions of subjects with HBV DNA in clinically relevant categories (eg HBV DNA values categorized in ranges that differ by 10 log increments) [ Time Frame: at 48 weeks ] [ Designated as safety issue: No ]
  • Proportion of subjects with ALT > 1 x upper limit of normal (ULN) at baseline who achieve ALT normalization (<= 1 x ULN) [ Time Frame: at Weeks 48 and 96 ] [ Designated as safety issue: No ]
  • Descriptive rates of resistance in each treatment arm [ Time Frame: through Weeks 48 and 96 ] [ Designated as safety issue: No ]
Original Secondary Outcome Measures ICMJE 
 (submitted: December 11, 2006)
  • To compare the proportion of subjects in the combination therapy group to the proportion of subjects in each of the monotherapy groups who achieve HBV DNA <50 IU/mL (approximately 300 copies/mL) at Week 96
  • Mean Log10 reduction from baseline in HBV DNA at Weeks 48 and 96
  • ALT normalization (≤ 1 x upper limit of normal) at Weeks 48 and 96
  • HBeAg loss at Weeks 48 and 96
  • HBe seroconversion at Weeks 48 and 96
  • HBs seroconversion at Weeks 48 and 96
  • Virologic rebound due to genotypic resistance
  • Frequency of adverse events, serious adverse events, and discontinuations from study drug due to adverse events or laboratory abnormalities

Descriptive Information

Brief Title  ICMJEEntecavir Plus Adefovir Combination Therapy Versus Entecavir Monotherapy vs Therapy With Adefovir Plus Lamivudine for Chronic Hepatitis B Infected Subjects With Lamivudine-resistant Virus
Official Title  ICMJEA Comparative Study of Entecavir vs. Adefovir Plus Lamivudine vs Combination Entecavir Plus Adefovir in Lamivudine-resistant Chronic Hepatitis B Subjects: The DEFINE Study
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

Detailed Description 
Study PhasePhase III
Study Type  ICMJEInterventional
Study Design  ICMJETreatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
Condition  ICMJEHepatitis B, Chronic
Intervention  ICMJE
  • 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
  • Drug: Adefovir
    Tablets, Oral, 10mg, once daily, 100 weeks
    Other Name: Hepsera
  • Drug: Lamivudine
    Tablets, Oral, 100mg, once daily, 100 weeks
    Other Name: Epivir
Study Arms / Comparison Groups
  • Entecavir: Active Comparator
    With the option of adding Tenofovir at week 48. (This does not apply to Korea)
    Interventions:
    • Drug: Entecavir
    • Drug: Tenofovir
  • Adefovir + Lamivudine: Active Comparator
    Interventions:
    • Drug: Adefovir
    • Drug: Lamivudine
  • Entecavir + Adefovir: Active Comparator
    Interventions:
    • Drug: Entecavir
    • Drug: Adefovir

Recruitment Information

Estimated Enrollment  ICMJE420
Estimated Completion DateJune 2012
Estimated Primary Completion DateJanuary 2011   (final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Evidence of lamivudine resistance
  • Subjects must have a history of previous lamivudine 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 lamivudine
  • Males or females ≥16 years of age (or minimum age of consent in a given country)
  • Compensated liver function
  • HBV DNA > 1.72 x 10*4* (approximately 10*5* copies/mL)
  • Documentation of HBeAg-positive and HBeAb-negative status at screening
  • Males and females >=16 years of age (or minimum age of consent in a given country)
  • 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:
  • Amenorrhea >= 12 consecutive months without another cause
  • For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL
  • 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 HCG) within 72 hours prior to the start of investigational product

Exclusion Criteria:

  • Evidence of decompensated cirrhosis
  • Coinfection with HIV, HCV, or HDV
  • Laboratory values out of protocol-specified range
GenderBoth
Ages16 Years and older
Accepts Healthy VolunteersNo
Contacts  ICMJE
Contact: For participation information at a USA site use a phone number below. For site information outside the USA please email:Clinical.Trials@bms.com
Contact: First line of email MUST contain NCT# & Site#. Only trial sites that are recruiting have contact information at this time.
Location Countries  ICMJEUnited States,   Argentina,   Australia,   Canada,   Greece,   Hong Kong,   India,   Indonesia,   Italy,   Korea, Republic of,   Malaysia,   Philippines,   Poland,   Russian Federation,   Singapore,   Taiwan,   Thailand,   Turkey

Administrative Information

NCT ID  ICMJENCT00410202
Responsible PartyStudy Director, Bristol-Myers Squibb
Study ID Numbers  ICMJEAI463-111
Study Sponsor  ICMJEBristol-Myers Squibb
Collaborators  ICMJE 
Investigators  ICMJE
Study Director:Bristol-Myers SquibbBristol-Myers Squibb
Information Provided ByBristol-Myers Squibb