NCT00410202
Completed
Phase 3
A Comparative Study of Entecavir vs. Adefovir Plus Lamivudine vs Combination Entecavir Plus Adefovir in Lamivudine-resistant Chronic Hepatitis B Subjects: The DEFINE Study
ConditionsHepatitis B, Chronic
Overview
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Bristol-Myers Squibb
- Enrollment
- 629
- Locations
- 2
- Primary Endpoint
- 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
Overview
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
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 16 Years to — (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
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
Arms & Interventions
Entecavir
Active Comparator
With the option of adding tenofovir at week 48. (This does not apply to Korea)
Intervention: Entecavir (Drug)
Entecavir
Active Comparator
With the option of adding tenofovir at week 48. (This does not apply to Korea)
Intervention: Tenofovir (Drug)
Adefovir + Lamivudine
Active Comparator
Intervention: Adefovir (Drug)
Adefovir + Lamivudine
Active Comparator
Intervention: Lamivudine (Drug)
Entecavir + Adefovir
Active Comparator
Intervention: Entecavir (Drug)
Entecavir + Adefovir
Active Comparator
Intervention: Adefovir (Drug)
Outcomes
Primary Outcomes
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
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 Outcomes
- Percentage of Participants With HBV DNA < 50 IU/mL (Approximately 300 Copies/mL) by PCR at Week 96(Week 96)
- Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 48(Week 48)
- Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 96(Week 96)
- Percentage of Participants With HBV DNA by PCR Category at Week 48(Week 48)
- Percentage of Participants With HBV DNA by PCR Category at Week 96(Week 96)
- Change in Mean log10 From Baseline in HBV DNA at Week 48(Baseline, Week 48)
- Change in Mean log10 From Baseline in HBV DNA at Week 96(Baseline, Week 96)
- Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 48(Week 48)
- Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 96(Baseline, Week 96)
- Percentage of Participants With Confirmed HBeAg Loss at Week 48 (Treated HBeAg Positive Participants Only)(Week 48)
- Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 96(Week 96)
- Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 48(Week 48)
- Percentage of Participants With Confirmed HBeAg Loss at Week 96 (Treated HBeAg Positive Participants Only)(Week 96)
- Percentage of Participants With HBeAg Seroconversion at Week 48 (Treated HBeAg-positive Participants Only)(Week 48)
- Percentage of Participants With HBeAg Seroconversion at Week 96 (Treated HBeAg-positive Participants Only)(Week 96)
- Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48(Week 48)
- Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 96(Week 96)
- Percentage of Participants With HBsAg Seroconversion at Week 96(Week 96)
- Percentage of Participants With HBsAg Seroconversion at Week 48(Week 48)
- Cumulative Probability of Emergent Genotypic Resistance at Year 1(Year 1)
- Cumulative Probability of Emergent Genotypic Resistance at Year 2(Year 2)
- Participants With Adverse Events (AE), Serious Adverse Events (SAE), and Discontinuations Due to Adverse Events or Laboratory Abnormalities During Treatment(From start of study therapy through Week 100 + 5 days)
- Number of Participants With Laboratory Abnormalities: Hematology(From start of study through Week 100 + 5 days)
- Number of Participants With Laboratory Abnormalities: Serum Chemistry(On treatment : Day 1 through Week 100 + 5 days; Offtreatment = End of OT period through 24 weeks)
Investigators
Study Sites (2)
Loading locations...
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