Clinical trial NCT00410202: Entecavir 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: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis B, Chronic
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2006-12-12
Enrollment: 629
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


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

Primary outcomes:
measure: 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
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of Participants With HBV DNA < 50 IU/mL (Approximately 300 Copies/mL) by PCR at Week 96
timeFrame: Week 96
measure: Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 48
timeFrame: Week 48
measure: Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 96
timeFrame: Week 96
measure: Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 48
timeFrame: Week 48
measure: Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 96
timeFrame: Week 96
measure: Percentage of Participants With HBV DNA by PCR Category at Week 48
timeFrame: Week 48
measure: Percentage of Participants With HBV DNA by PCR Category at Week 96
timeFrame: Week 96
measure: Change in Mean log10 From Baseline in HBV DNA at Week 48
timeFrame: Baseline, Week 48
measure: Change in Mean log10 From Baseline in HBV DNA at Week 96
timeFrame: Baseline, Week 96
measure: Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 48
timeFrame: Week 48
measure: Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 96
timeFrame: Baseline, Week 96
measure: Percentage of Participants With Confirmed HBeAg Loss at Week 48 (Treated HBeAg Positive Participants Only)
timeFrame: Week 48
measure: Percentage of Participants With Confirmed HBeAg Loss at Week 96 (Treated HBeAg Positive Participants Only)
timeFrame: Week 96
measure: Percentage of Participants With HBeAg Seroconversion at Week 48 (Treated HBeAg-positive Participants Only)
timeFrame: Week 48
measure: Percentage of Participants With HBeAg Seroconversion at Week 96 (Treated HBeAg-positive Participants Only)
timeFrame: Week 96
measure: Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48
timeFrame: Week 48
measure: Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 96
timeFrame: Week 96
measure: Percentage of Participants With HBsAg Seroconversion at Week 48
timeFrame: Week 48
measure: Percentage of Participants With HBsAg Seroconversion at Week 96
timeFrame: Week 96
measure: Cumulative Probability of Emergent Genotypic Resistance at Year 1
timeFrame: Year 1
measure: Cumulative Probability of Emergent Genotypic Resistance at Year 2
timeFrame: Year 2
measure: Participants With Adverse Events (AE), Serious Adverse Events (SAE), and Discontinuations Due to Adverse Events or Laboratory Abnormalities During Treatment
timeFrame: From start of study therapy through Week 100 + 5 days
measure: Number of Participants With Laboratory Abnormalities: Hematology
timeFrame: From start of study through Week 100 + 5 days
measure: Number of Participants With Laboratory Abnormalities: Serum Chemistry
timeFrame: On treatment : Day 1 through Week 100 + 5 days; Offtreatment = End of OT period through 24 weeks
Other outcomes:
Locations:
city: Farmington
country: United States
facility: University Of Connecticut Health Center
state: Connecticut
city: Concord
country: Australia
facility: Local Institution
state: New South Wales
city: Randwick
country: Australia
facility: Local Institution
state: New South Wales
city: Porto Alegre Rs
country: Brazil
facility: Local Institution
state: Rio Grande Do Sul
city: Calgary
country: Canada
facility: Local Institution
state: Alberta
city: Athens
country: Greece
facility: Local Institution
city: Shatin
country: Hong Kong
facility: Local Institution
state: New Territories
city: Hong Kong
country: Hong Kong
facility: Local Institution
city: Tai Po
country: Hong Kong
facility: Local Institution
city: Lucknow
country: India
facility: Local Institution
state: Uttar Pradesh
city: Ahmedabad
country: India
facility: Local Institution
city: Chandigarh
country: India
facility: Local Institution
city: Indore
country: India
facility: Local Institution
city: Ludhiana
country: India
facility: Local Institution
city: New Delhi
country: India
facility: Local Institution
city: Vellore
country: India
facility: Local Institution
city: Jakarta
country: Indonesia
facility: Local Institution
city: Antella, Firenze
country: Italy
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
state: Dongdaemun-Gu
city: Ulsan
country: Korea, Republic of
facility: Local Institution
state: Donggu
city: Ansan-Si
country: Korea, Republic of
facility: Local Institution
state: Gyeonggi-Do
city: Anyang-Si
country: Korea, Republic of
facility: Local Institution
state: Gyeonggi-Do
city: Bucheon-Si
country: Korea, Republic of
facility: Local Institution
state: Gyeonggi-Do
city: Seongnam-Si
country: Korea, Republic of
facility: Local Institution
state: Gyeonggi-Do
city: Suwon-Si
country: Korea, Republic of
facility: Local Institution
state: Gyeonggi-Do
city: Koyang
country: Korea, Republic of
facility: Local Institution
state: Ilsanseo Gu
city: Incheon
country: Korea, Republic of
facility: Local Institution
state: Jung-Gu
city: Seoul
country: Korea, Republic of
facility: Local Institution
state: Nowon-Gu
city: Chuncheon-Si
country: Korea, Republic of
facility: Local Institution
city: Daegu
country: Korea, Republic of
facility: Local Institution
city: Gangneung
country: Korea, Republic of
facility: Local Institution
city: Incheon
country: Korea, Republic of
facility: Local Institution
city: Pusan
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Seoul
country: Korea, Republic of
facility: Local Institution
city: Suwon
country: Korea, Republic of
facility: Local Institution
city: Yangsan-Si
country: Korea, Republic of
facility: Local Institution
city: Kota Kinabalu
country: Malaysia
facility: Local Institution
state: Sabah
city: Kuala Lumpur
country: Malaysia
facility: Local Institution
city: Cebu City
country: Philippines
facility: Local Institution
city: Manila
country: Philippines
facility: Local Institution
city: Chorzow
country: Poland
facility: Local Institution
city: Kielce
country: Poland
facility: Local Institution
city: Lodzi
country: Poland
facility: Local Institution
city: Lublin
country: Poland
facility: Local Institution
city: Warszawa
country: Poland
facility: Local Institution
city: Moscow
country: Russian Federation
facility: Local Institution
city: Moscow
country: Russian Federation
facility: Local Institution
city: St. Petersburg
country: Russian Federation
facility: Local Institution
city: St. Petersburg
country: Russian Federation
facility: Local Institution
city: Singapore
country: Singapore
facility: Local Institution
city: Kaohsiung
country: Taiwan
facility: Local Institution
city: Tainan R.O.C.
country: Taiwan
facility: Local Institution
city: Taipei
country: Taiwan
facility: Local Institution
city: Taoyuan
country: Taiwan
facility: Local Institution
city: Bangkok
country: Thailand
facility: Local Institution
city: Chiang Mai
country: Thailand
facility: Local Institution
city: Bornova Izmir
country: Turkey
facility: Local Institution
city: Trabzon
country: Turkey
facility: Local Institution
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: