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)

Bristol-Myers Squibb (BMS)

Status and phase: Completed; Phase 3

Conditions: Hepatitis B, Chronic

Treatments: Drug: Tenofovir; Drug: Lamivudine; Drug: Entecavir; Drug: Adefovir

Study type: Interventional

Funder types: Industry

Identifiers

NCT00410202

AI463-111

Details and patient eligibility

About

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

Enrollment: 629 patients

Sex: All

Ages: 16+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

629 participants in 3 patient groups

Entecavir

Active Comparator group

Description:

With the option of adding tenofovir at week 48. (This does not apply to Korea)

Treatment:

Drug: Entecavir

Drug: Tenofovir

Adefovir + Lamivudine

Active Comparator group

Treatment:

Drug: Adefovir

Drug: Lamivudine

Entecavir + Adefovir

Active Comparator group

Treatment:

Drug: Adefovir

Drug: Entecavir