Safety and Antiviral Activity of Entecavir in Participants With Chronic Hepatitis B Following Monotherapy in Other Entecavir Trials

HBV Clinical Trial

Official title:

A Preliminary Assessment of Safety and Antiviral Activity of Open-label Entecavir in Subjects With Chronic Hepatitis B Following Monotherapy in Other Entecavir Trials

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01438424
• Other study ID #: AI463-901
• Status: Completed
• Phase: Phase 2
• First received: September 16, 2011
• Last updated: July 19, 2012
• Start date: January 2001
• Est. completion date: April 2011

Study information

• Verified date: July 2012
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: Hong Kong: Department of HealthIndonesia: Departement Kesehatan (Department of Health)Indonesia: National Agency of Drug and Food ControlMalaysia: Ministry of HealthPhilippines: Bureau of Food and DrugsPhilippines: Department of HealthSingapore: Clinical Trials & Epidemiology Research Unit (CTERU)Singapore: Domain Specific Review BoardsSingapore: Health Sciences AuthoritySouth Korea: Korea Food and Drug Administration (KFDA)Taiwan: Department of HealthTaiwan: National Bureau of Controlled DrugsThailand: Food and Drug AdministrationThailand: Ministry of Public HealthPakistan: Ministry of HealthAustralia: Department of Health and Ageing Therapeutic Goods AdministrationAustralia: National Health and Medical Research CouncilCanada: Health CanadaCzech Republic: State Institute for Drug ControlPoland: Ministry of HealthPoland: Ministry of Science and Higher EducationPoland: National Institute of MedicinesPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRussia: Ethics CommitteeRussia: FSI Scientific Center of Expertise of Medical ApplicationRussia: Ministry of Health of the Russian FederationSlovakia: Public Health AuthorityTurkey: Ministry of HealthGermany: Federal Institute for Drugs and Medical DevicesGermany: Ministry of HealthSwitzerland: SwissmedicFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Portugal: National Pharmacy and Medicines InstituteSpain: Spanish Agency of MedicinesArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaBrazil: National Health Surveillance AgencyBrazil: National Committee of Ethics in ResearchPeru: Instituto Nacional de SaludMexico: Federal Commission for Sanitary Risks ProtectionBelgium: The Federal Public Service (FPS) Health, Food Chain Safety and EnvironmentNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)United Kingdom: Medicines and Healthcare Products Regulatory AgencyDenmark: Danish Dataprotection AgencyDenmark: Danish Medicines AgencyDenmark: The Danish National Committee on Biomedical Research EthicsIsrael: Ministry of HealthItaly: Ministry of HealthItaly: National Bioethics CommitteeItaly: National Institute of HealthItaly: National Monitoring Centre for Clinical Trials - Ministry of HealthItaly: The Italian Medicines AgencyGreece: Ethics CommitteeGreece: National Organization of MedicinesUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to provide entecavir to participants who have completed another entecavir trial without achieving virologic response or who relapsed during postdosing follow-up.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1053
• Est. completion date: April 2011
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years and older

Eligibility

Key inclusion criteria:

• Age of 16 years and older

• Receipt of entecavir or lamivudine in a previous entecavir study.

Participants who were, based on their response to entecavir:

• Virologic nonresponders at Week 48

• Partial virologic responders who became nonresponders during the second year of treatment

• Partial virologic responders at Week 96

• Complete responders who relapsed during postdosing follow-up

• Decompensated liver disease in AI463-048 that met 1 or more of the following criteria:

• Nonresponse to adefovir after at least 24 weeks of treatment

• Partial response to adefovir after 96 weeks of treatment

• Complete response to adefovir after relapsing during postdosing follow-up

• Demonstrated intolerance to adefovir

• Except for those participants enrolled from AI463-048, compensated liver disease.

Key exclusion criteria:

• HIV coinfection

• Receiving nephrotoxic or hepatotoxic agents

• Ongoing opportunistic infections

• Hemoglobin level <11.0 g/dL except for those enrolled from AI463-048

• Platelet count <70,000 mm^3 except for those enrolled from AI463-048

• Absolute granulocyte count <1,500 cells/mm^3

• Recent history of pancreatitis (within 24 weeks prior to first dose of therapy)

• Current evidence of ascites requiring paracentesis, hepatic encephalopathy, or variceal bleeding, except for those enrolled from AI463-048

• Known history of allergy to nucleoside analogues.

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HBV
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B Virus
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Entecavir
Tablets, Oral, 1.0 mg, once daily
• Lamivudine
Oral, 100 mg, daily

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Study: Number of Participants With Death As Outcome, Any Adverse Event (AE), Grade 3-4 AEs, Serious Adverse Events (SAEs), and Discontinuations Due to AEs	An AE is a new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not be causally related to treatment. An SAE is an unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling. ALT=alanine transaminase; ULN=upper limit of normal.	Continuously from Day 1 through Week 240	Yes
Primary	Overall Study: Number of Participants With Normal Hematology Values at Baseline and Abnormalities in Hematology Laboratory Test Results Through Week 240	Hemoglobin (g/dL): Grade (Gr) 1=9.5-11.0; Gr 2=8.0-<9.5; Gr 3=6.5-<8.0; Gr 4=<6.5 White blood cells (cells/mm^3): Gr 1=2,500-<4,000; Gr 2=1,000-<2,500; Gr 3=800-<1,000; Gr 4=<800. Neutrophils (cells/mm^3): Gr 1=1000-<1500; Gr 2=750-<1000; Gr 3=500-<750; Gr 4=<500. Platelets (cells/mm^3): Gr 1=75,000-99,000; Gr 2=50,000-<75,000; Gr 3=20,000-<50,000; Gr 4=<20,000. Prothrombin time (seconds): Gr 1=1.01-<1.26*ULN; Gr 2=1.26-<1.51 *ULN; Gr 3=1.51-3*ULN; Gr 4=>3*ULN. INR: Gr 1=1.24-1.5; Gr 2=1.5-2; Gr 3=2-3; Gr 4=>3. INR=international normalized ratio; ULN=upper limit of normal. .	Day 1 of treatment through Week 240	Yes
Primary	Overall Study: Number of Participants With Normal Pancreatic Enzyme and Renal Function Values at Baseline and Abnormalities in Pancreatic Enzyme and Renal Function Laboratory Test Results at End of Dosing	Amylase: Grade 1=1.10-<1.40*ULN; Grade 2=1.40-< 2.10*ULN; Grade 3=2.10-5.00*ULN; Grade 4=>5.00*ULN. Lipase: Grade 1.1-<1.4*ULN; Grade 2=1.4-<2.1*ULN; Grade 3=2.1-5.0*ULN; Grade 4=>5.0*ULN. Creatinine: Grade 1=1.10-< 1.60*ULN; Grade 2=1.60-<3.10*ULN; Grade 3=3.10-6.00*ULN; Grade 4=>6.00*ULN. Blood urea nitrogen (BUN): Grade 1=1.25-<2.60*ULN; Grade 2=2.60-<5.10*ULN; Grade 3=5.10-10*ULN; Grade 4=>10*ULN. ULN=upper limit of normal.	Day 1 of treatment through Week 240	Yes
Primary	Overall Study: Number of Participants With Normal Electrolyte and Fasting Glucose Values at Baseline and Abnormalities in Electrolyte and Fasting Glucose Laboratory Test Results at End of Dosing	Hypochloremia: Grade (Gr) 1=90-93; Gr 2=85-<90; Gr 3=80-<85; Gr 4=40-<80. Hyperchloremia: Gr 1=113-<117; Gr 2=117-<121; Gr 3=121-125; Gr 4>125. Hypocarbia: Gr 1=19-21; Gr 2=15-<19; Gr 3=41-45; Gr 4=>45. Hypercarbia: Gr 1=31-36; Gr 2=37-40; Gr 3=41-45; Gr 4=>45. Hyponatremia: Gr 1=130-132; Gr 2=123-<130; Gr 3=116-<123; Gr 4<116. Hypernatremia: Gr 1=148-<151; Gr 2=151-<158; Gr 3=158-165; Gr 4=>165. Hypokalemia: Gr 1=3-3.4; Gr 2=2.5-<3; Gr 3=2-<2.5; Gr 4=<2. Hyperkalemia: Gr 1=5.6-<6.1; G2=6.1-<6.6; Gr 3=6.6-7; Gr 4=>7. Hypoglycemia: Gr 1=55-64; Gr 2=40-<55; Gr 3=30-< 40; G4=-<30. Hyperglycemia: Gr 1=116-<161; Gr 2=161-<251; Gr 3=251-500; Gr 4>500.	Day 1 of treatment through Week 240	Yes
Primary	Week 144: Number of Participants With Death As Outcome, Any AE, Grade 3-4 AEs, SAEs, Discontinuations Due to AEs, and Abnormalities in Selected Laboratory Test Results	An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling. AST=aspartate aminotransferase; ULN=upper limit of normal.	Continuously from Day 1 through Week 144	Yes
Primary	Week 192: Number of Participants With Death As Outcome, Any AE, Grade 3-4 AEs, SAEs, Discontinuations Due to AEs, and Abnormalities in Selected Laboratory Test Results	An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. CTC Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling. ALT=alanine aminotransferase; ULN=upper limit of normal.	Continuously from Day 1 through Week 192	Yes
Primary	Off-treatment Follow-up: Percentage of Participants With Sustained Hepatitis B Virus (HBV) DNA <10,000 Copies by Polymerase Chain Reaction (PCR) Assay (Amendment 11 Cohort)	The Amendment 11 Cohort consisted of participants who were hepatitis B e antigen (HBeAg) negative and who had compensated liver disease, a minimum of 192 weeks (4 years) of treatment with entecavir, HBV DNA <300 copies/mL by PCR assay for =48 weeks before end of dosing and on the last observed result =24 weeks prior to end of dosing, and serum ALT levels =1.0*ULN at the end of study drug dosing.ALT=alanine aminotransferase; ULN=upper limit of normal.	End of dosing to Week 48 off-treatment follow-up	No
Secondary	Overall Study: Percentage of Participants With Sustained HBV DNA Level <300 Copies/mL by PCR Assay		Study entry to Week 192	No
Secondary	Overall Study: Percentage of Participants With Sustained HBV DNA <10^4 Copies/mL by PCR Assay		Study entry to Week 192	No
Secondary	Overall Study: Percentage of Participants by HBV DNA Category by PCR Assay	Observed values.	Baseline to Week 192	No
Secondary	Overall Study: Mean HBV DNA Level by PCR Assay		Study entry to Week 216	No
Secondary	Overall Study: Percentage of Participants Who Achieved a Loss of Hepatitis B e Antigen (HBeAg)	Observed values.	Study entry to Week 216	No
Secondary	Overall Study: Percentage of Participants With HBeAg Seroconversion	Observed values. Seroconversion=negative HBeAg with detectable anti-HBe antibody.	Study entry to Week 216	No
Secondary	Overall Study: Mean Alanine Transaminase (ALT) Levels	Observed values.	Study entry to Week 216	No
Secondary	Overall Study: Percentage of Participants Who Achieved ALT Normalization	ULN=upper limit of normal. ALT normalization=ALT levels =1.0*ULN.	Study entry to Week 216	No
Secondary	Week 192: Percentage of Participants With Histologic Improvement (Efficacy Evaluable Cohort)	The Knodell Histologic Activity Index scores stage of necrosis and grade of inflammation in liver biopsies. Components are necrosis near the portal vein, intralobular degeneration and focal necrosis, portal inflammation, and fibrosis. The 4 components are scored from 1 to 4 and 1 to 10 (necrosis near the portal vein) and combined for a total score, with 22 being the highest possible score. Higher the score for each component=greater liver damage. Histologic improvement=a =2-point reduction in total Knodell score and no worsening in fibrosis. Cohort participants had to have adequate baseline and long-term biopsy samples and baseline Knodell necroinflammatory scores =2.	Baseline to Week 192	No
Secondary	Week 192: Percentage of Participants With Improvement in Fibrosis (Efficacy Evaluable Cohort)	The Ishak Modification for Hepatic Activity Index (HAI) scores necroinflammatory activity in chronic hepatitis. 0=no fibrosis, 1=fibrosis expansion of some portal areas, 2=fibrosis expansion of most portal areas, 3=fibrosis expansion of most portal areas with occasional bridging, 4=fibrosis expansion of portal areas with marked bridging, 5=incomplete cirrhosis, 6=probable or definite cirrhosis. Higher score=more severe necrosis. Improvement in fibrosis==1-point reduction in HAI score. Cohort participants had to have adequate baseline and long-term biopsy samples and baseline Knodell scores =2.	Baseline to Week 192	No
Secondary	Overall Study: Percentage of Participants With a Confirmed =1 log10 Increase From Nadir in HBV DNA by PCR Assay		Baseline to Week 144	No
Secondary	Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay, Loss of HBeAG, Seroconversion, and ALT =1.0*Upper Limit of Normal (ULN) (Entecavir Continuous Treatment Cohort)	The Entecavir Continuous Treatment Cohort consisted of participants from study AI463-022 (NCT00035633) who were nucleoside-naive HBeAg-positive and enrolled in the current study with =35 days off treatment between the last dose in AI463-022 and the first dose in the current. This cohort is considered to be on continuous entecavir treatment and permitted assessment of continuous administration of entecavir in AI463-022 and the current study.	Baseline to Weeks 48, 96, 144, 192, and 240	No
Secondary	Percentage of Participants Who Achieved HBV DNA <300 and <10^4 Copies/mL by PCR Assay and ALT =1.0*Upper Limit of Normal (ULN) (Entecavir Retreatment Cohort)	The Entecavir Retreatment Cohort consisted of participants who were nucleoside-naive, HBeAg-negative and enrolled from BMS study AI463-027 with >60 days off treatment between the last dose in AI463-027 and the first dose in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as retreatment in the current study.	Baseline to Weeks 48, 96, and 144	No
Secondary	Week 96: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay, Loss of HBeAg, HBeAg Seroconversion, and ALT =1.0*ULN (Lamivudine Continuous Switch Cohort)	The Lamivudine Continuous Switch Cohort consisted of participants who were nucleoside-naive, HBeAg-positive and received lamivudine in BMS study AI463-022 (NCT00035633) and enrolled in the current study with =35 days off treatment between end of dosing in AI463-022 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.	Baseline to Week 96	No
Secondary	Week 144: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT =1.0*ULN (Lamivudine Continuous Switch Cohort)	The Lamivudine Continuous Switch Cohort consisted of participants who were nucleoside-naive, HBeAg-positive and received lamivudine in BMS study AI463-022 (NCT00035633) and enrolled in the current study with =35 days off treatment between end of dosing in AI463-022 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.	Baseline to Week 144	No
Secondary	Week 96: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT =1.0*ULN (Lamivudine Retreatment Switch Cohort)	The Lamivudine Retreatment Switch Cohort consisted of participants who were nucleoside-naive HBeAg negative and enrolled from BMS study AI463-027 (NCT00035789) with >60 days between end of dosing in AI463-027 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.	Baseline to Week 96	No
Secondary	Week 144: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT =1.0*ULN (Lamivudine Retreatment Switch Cohort)	The Lamivudine Retreatment Switch Cohort consisted of participants who were nucleoside-naive HBeAg negative and enrolled from BMS study AI463-027 (NCT00035789) with >60 days between end of dosing in AI463-027 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.	Baseline to Week 144	No
Secondary	Off-treatment Follow-up: Percentage of Participants With Sustained HBV DNA <1,000, <300, and <10,000 Copies/mL by PCR Assay and With ALT =1*ULN (Amendment 11 Cohort)	The Amendment 11 Cohort consisted of participants who were HBeAg negative and who had compensated liver disease, a minimum of 192 weeks (4 years) of treatment with entecavir, HBV DNA <300 copies/mL by PCR Assay for =48 weeks before end of dosing and on the last observed result =24 weeks prior to end of dosing, and serum ALT levels =1.0*ULN at the end of study drug dosing. ULN=upper limit of normal.	End of dosing to Weeks 48 and 96 off-treatment follow-up	No
Secondary	Off-treatment Follow-up: Mean Change in HBV DNA (Amendment 11 Cohort)	The Amendment 11 Cohort consisted of participants who were HBeAg negative and who had compensated liver disease, a minimum of 192 weeks (4 years) of treatment with entecavir, HBV DNA <300 copies/mL by PCR assay for =48 weeks before end of dosing and on the last observed result =24 weeks prior to end of dosing, and serum ALT levels =1.0*ULN at the end of study drug dosing.	End of dosing to Weeks 48 and 96 off-treatment follow-up	No