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

Hepatitis B, Chronic Clinical Trial

— DEFINE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00410202
• Other study ID #: AI463-111
• Status: Completed
• Phase: Phase 3
• First received: December 11, 2006
• Last updated: October 29, 2013
• Start date: March 2008
• Est. completion date: July 2012

Study information

• Verified date: October 2013
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 629
• Est. completion date: July 2012
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Entecavir
Tablets, Oral, 1mg, once daily, 100 weeks
• Tenofovir
Tablets, Oral, 300 mg, once daily
• Adefovir
Tablets, Oral, 10mg, once daily, 100 weeks
• Lamivudine
Tablets, Oral, 100mg, once daily, 100 weeks

Locations

Country	Name	City	State
Australia	Local Institution	Concord	New South Wales
Australia	Local Institution	Randwick	New South Wales
Brazil	Local Institution	Porto Alegre Rs	Rio Grande Do Sul
Canada	Local Institution	Calgary	Alberta
Greece	Local Institution	Athens
Hong Kong	Local Institution	Hong Kong
Hong Kong	Local Institution	Shatin	New Territories
Hong Kong	Local Institution	Tai Po
India	Local Institution	Ahmedabad
India	Local Institution	Chandigarh
India	Local Institution	Indore
India	Local Institution	Lucknow	Uttar Pradesh
India	Local Institution	Ludhiana
India	Local Institution	New Delhi
India	Local Institution	Vellore
Indonesia	Local Institution	Jakarta
Italy	Local Institution	Antella, Firenze
Korea, Republic of	Local Institution	Ansan-Si	Gyeonggi-Do
Korea, Republic of	Local Institution	Anyang-Si	Gyeonggi-Do
Korea, Republic of	Local Institution	Bucheon-Si	Gyeonggi-Do
Korea, Republic of	Local Institution	Chuncheon-Si
Korea, Republic of	Local Institution	Daegu
Korea, Republic of	Local Institution	Gangneung
Korea, Republic of	Local Institution	Incheon
Korea, Republic of	Local Institution	Incheon	Jung-Gu
Korea, Republic of	Local Institution	Koyang	Ilsanseo Gu
Korea, Republic of	Local Institution	Pusan
Korea, Republic of	Local Institution	Seongnam-Si	Gyeonggi-Do
Korea, Republic of	Local Institution	Seoul	Dongdaemun-Gu
Korea, Republic of	Local Institution	Seoul	Nowon-Gu
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Suwon
Korea, Republic of	Local Institution	Suwon-Si	Gyeonggi-Do
Korea, Republic of	Local Institution	Ulsan	Donggu
Korea, Republic of	Local Institution	Yangsan-Si
Malaysia	Local Institution	Kota Kinabalu	Sabah
Malaysia	Local Institution	Kuala Lumpur
Philippines	Local Institution	Cebu City
Philippines	Local Institution	Manila
Poland	Local Institution	Chorzow
Poland	Local Institution	Kielce
Poland	Local Institution	Lodzi
Poland	Local Institution	Lublin
Poland	Local Institution	Warszawa
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	St. Petersburg
Russian Federation	Local Institution	St. Petersburg
Singapore	Local Institution	Singapore
Taiwan	Local Institution	Kaohsiung
Taiwan	Local Institution	Tainan R.O.C.
Taiwan	Local Institution	Taipei
Taiwan	Local Institution	Taoyuan
Thailand	Local Institution	Bangkok
Thailand	Local Institution	Chiang Mai
Turkey	Local Institution	Bornova Izmir
Turkey	Local Institution	Trabzon
United States	University Of Connecticut Health Center	Farmington	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Greece,  Hong Kong,  India,  Indonesia,  Italy,  Korea, Republic of,  Malaysia,  Philippines,  Poland,  Russian Federation,  Singapore,  Taiwan,  Thailand,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	Week 48	No
Secondary	Percentage of Participants With HBV DNA < 50 IU/mL (Approximately 300 Copies/mL) by PCR at Week 96	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.	Week 96	No
Secondary	Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 48	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.	Week 48	No
Secondary	Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 96	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.	Week 96	No
Secondary	Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 48	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.	Week 48	No
Secondary	Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 96	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.	Week 96	No
Secondary	Percentage of Participants With HBV DNA by PCR Category at Week 48	HBV DNA assessments were performed using the Roche COBAS® TaqMan High Pure System (HPS) assay.	Week 48	No
Secondary	Percentage of Participants With HBV DNA by PCR Category at Week 96	HBV DNA assessments were performed using the Roche COBAS® TaqMan HPS assay.	Week 96	No
Secondary	Change in Mean log10 From Baseline in HBV DNA at Week 48	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.	Baseline, Week 48	No
Secondary	Change in Mean log10 From Baseline in HBV DNA at Week 96	HBV DNA was analyzed by PCR, using the Roche COBAS® TaqMan HPS assay. Reduction in log10 HBV count=reduced viral load.	Baseline, Week 96	No
Secondary	Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 48	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.	Week 48	No
Secondary	Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 96	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.	Baseline, Week 96	No
Secondary	Percentage of Participants With Confirmed HBeAg Loss at Week 48 (Treated HBeAg Positive Participants Only)	HBeAg is a hepatitis B viral protein. HBeAg loss = HBeAg-negative at the specified analysis week	Week 48	No
Secondary	Percentage of Participants With Confirmed HBeAg Loss at Week 96 (Treated HBeAg Positive Participants Only)	HBeAg is a hepatitis B viral protein. HBeAg loss = HBeAg-negative at the specified analysis week	Week 96	No
Secondary	Percentage of Participants With HBeAg Seroconversion at Week 48 (Treated HBeAg-positive Participants Only)	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).	Week 48	No
Secondary	Percentage of Participants With HBeAg Seroconversion at Week 96 (Treated HBeAg-positive Participants Only)	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).	Week 96	No
Secondary	Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48	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.	Week 48	No
Secondary	Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 96	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.	Week 96	No
Secondary	Percentage of Participants With HBsAg Seroconversion at Week 48	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.	Week 48	No
Secondary	Percentage of Participants With HBsAg Seroconversion at Week 96	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.	Week 96	No
Secondary	Cumulative Probability of Emergent Genotypic Resistance at Year 1	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).	Year 1	No
Secondary	Cumulative Probability of Emergent Genotypic Resistance at Year 2	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).	Year 2	No
Secondary	Participants With Adverse Events (AE), Serious Adverse Events (SAE), and Discontinuations Due to Adverse Events or Laboratory Abnormalities During Treatment	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.	From start of study therapy through Week 100 + 5 days	Yes
Secondary	Number of Participants With Laboratory Abnormalities: Hematology	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.	From start of study through Week 100 + 5 days	Yes
Secondary	Number of Participants With Laboratory Abnormalities: Serum Chemistry	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	On treatment : Day 1 through Week 100 + 5 days; Offtreatment = End of OT period through 24 weeks	Yes

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