Study Comparing Tenofovir Disoproxil Fumarate (TDF), Emtricitabine (FTC)/TDF, and Entecavir (ETV) in the Treatment of Chronic HBV in Subjects With Decompensated Liver Disease.
Information source: Gilead Sciences
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Chronic Hepatitis B
Intervention: Tenofovir disoproxil fumarate (tenofovir DF; TDF) (Drug); Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) (Drug); Entecavir (ETV) (Drug); TDF placebo (Drug); FTC/TDF placebo (Drug); ETV placebo (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: Gilead Sciences Official(s) and/or principal investigator(s): John Flaherty, PharmD, Study Director, Affiliation: Gilead Sciences
Summary
This study was designed to evaluate and compare the safety and tolerability of tenofovir
disoproxil fumarate (TDF), emtricitabine (FTC)/TDF, and entecavir (ETV) in the treatment of
hepatitis B patients with decompensated liver disease. Safety was assessed by evaluating
adverse events (AEs) and laboratory abnormalities. Efficacy was assessed by evaluating
reductions in Child-Pugh-Turcotte (CPT) and Model for End Stage Liver Disease (MELD) scores,
reductions in hepatitis B virus (HBV) deoxyribonucleic acid (DNA), changes in liver enzymes,
development of drug-resistant mutations, and generation of antibody to virus.
A maximum randomized treatment duration of 168 weeks was planned. Since subjects with
decompensated liver disease were enrolled into this study, it was necessary to provide early
intervention strategies if profound viral suppression was not expeditiously achieved. For
this reason, subjects with a decrease in plasma HBV DNA from baseline of < 2 log_10
copies/mL and plasma HBV DNA > 10,000 copies/mL (or plasma HBV DNA > 1,000 copies/mL for
subjects who entered the study with HBV DNA < 10,000 copies/mL) at Week 8 had the option to
start open-label FTC/TDF and continue in the study. Subjects with a virologic breakthrough
or who had plasma HBV DNA levels remaining > 400 copies/mL (confirmed) at or after 24 weeks
of treatment could have been unblinded at the investigator's discretion for selection of
alternative anti-HBV therapy that may have included open-label FTC/TDF. If study drug was
permanently discontinued, immediate initiation of another anti-HBV regimen was strongly
recommended.
Clinical Details
Official title: A Phase 2, Double-Blind, Multi-center, Randomized Study Comparing Tenofovir Disoproxil Fumarate, Emtricitabine Plus Tenofovir Disoproxil Fumarate, and Entecavir in the Treatment of Chronic Hepatitis B Subjects With Decompensated Liver Disease and in the Prevention of Hepatitis B Recurrence Post-Transplantation
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Percent Probability of Tolerability FailurePercent Probability of a Confirmed Increase in Serum Creatinine of ≥ 0.5 mg/dL From Baseline or a Confirmed Serum Phosphorus Level < 2.0 mg/dL
Secondary outcome: Median Time-averaged Change (DAVG) in Plasma Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels at 48 Weeks Relative to BaselineMedian DAVG in Plasma HBV DNA Levels at 96 Weeks Relative to Baseline Median DAVG in Plasma HBV DNA Levels at 144 Weeks Relative to Baseline Median DAVG in Plasma HBV DNA Levels at 168 Weeks Relative to Baseline Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48 Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 96 Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 144 Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168 Percentage of Participants With Normalized Alanine Aminotransferase (ALT) (for Subjects With Elevated ALT at Baseline) at Week 48 Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 96 Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 144 Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 168 Percentage of Participants With an Increase in Child-Pugh Turcotte (CPT) Score of ≥ 2 Points at Weeks 48 Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 96 Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 144 Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 168 Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 48 Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 96 Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 144 Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 168 Median Change in Model for End-Stage Liver Disease (MELD) Score From Baseline at Week 48 Median Change in MELD Score From Baseline at Week 96 Median Change in MELD Score From Baseline at Week 144 Median Change in MELD Score From Baseline at Week 168 Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss and HBeAg Seroconversion at Week 48 (for Participants Who Were HBeAg Positive at Baseline) Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 96 (for Participants Who Were HBeAg Positive at Baseline) Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 144 (for Participants Who Were HBeAg Positive at Baseline) Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 168 (for Participants Who Were HBeAg Positive at Baseline) Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss and HBsAg Seroconversion at Week 48 Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 96 Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 144 Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 168 In the Subset of Participants Undergoing Liver Transplantation, Time to Recurrence of Hepatitis B, Defined as 2 Consecutive Plasma HBV DNA Concentrations ≥ 400 Copies/mL or 2 Consecutive HBsAg(+) Results
Eligibility
Minimum age: 18 Years.
Maximum age: 69 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
A participant was required to meet all of the following inclusion criteria to be eligible
for participation in the study:
- Chronic Hepatitis B infection
- 18 through 69 years of age, inclusive
- HBV DNA ≥ 1000 copies/mL
- Decompensated liver disease with all of the following:
- CPT score of 7-12 (inclusive) OR history of CPT score ≥ 7 and any CPT at screen
≤ 12
- Serum alanine aminotransferase (ALT) < 10 x the upper limit of the normal range
(ULN)
- Hemoglobin ≥ 7. 5 g/dL
- Total white blood cell (WBC) count ≥ 1,500/mm^3
- Platelet count ≥ 30,000/mm^3
- Alpha-fetoprotein ≤ 20 ng/mL and ultrasound or other imaging with no evidence of
hepatocellular carcinoma (HCC), or alpha-fetoprotein of 21-50 ng/mL and computed
tomography (CT)/magnetic resonance imaging (MRI) scan with no evidence of HCC, within
6 months of screening
- Calculated creatinine clearance ≥ 50 mL/min
- Negative human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis D
virus (HDV) serologies
- Less than 24 months of total prior adefovir dipivoxil exposure
- Willing and able to provide written informed consent
Exclusion Criteria:
A participant who met any of the following exclusion criteria could not be enrolled in the
study:
- Pregnant women, women who were breastfeeding or who believed they may have wished to
become pregnant during the course of the study
- Males and females of reproductive potential who were unwilling to use an effective
method of contraception during the study
- Prior use of TDF or ETV
- History of variceal bleeding, hepatorenal syndrome, Grade 3 or 4 hepatic
encephalopathy, or spontaneous bacterial peritonitis within 60 days of screening
- Grade 2 hepatic encephalopathy at screening
- History of solid organ or bone marrow transplant
- Current use of hepatotoxic drugs, nephrotoxic drugs, or drugs that interfere with
renal tubular secretion
- Current therapy with immunomodulators (eg, corticosteroids, interleukin-2, etc.) or
investigational drugs
- Diagnosis of proximal tubulopathy
- Use of investigational agent within 30 days prior to screening
- Known hypersensitivity to TDF, FTC, ETV, or formulation excipients of any of the
study drug products
Locations and Contacts
Hopital Conception, Marseille 13005, France
Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Berlin 13353, Germany
Universitat Heidelberg, Heidelberg 69120, Germany
Johannes Gutenberg-Universitat, Mainz 55131, Germany
General Hospital of Athens "Ippokratio", Athens 11527, Greece
Universita de Padova, Padova 35128, Italy
Policlinico Universitario, Udine 33100, Italy
Wojewodzki Szpital Specjalistyczny im Dluskeigo, Bialystok 15-540, Poland
Wojewodzki Szpital Obserwacy, Bydgoszcz 85-030, Poland
Wojewodzki Szpital Zakazny, Warsaw 01-201, Poland
Changi General Hospital, Singapore 529889, Singapore
National University Hospital Dept. of Gastroenterology & Hepatology, Singapore 119074, Singapore
Singapore General Hospital, Singapore 169608, Singapore
Tan Tock Seng Hospital, Singapore 308433, Singapore
Hospital Clinic i Provincial de Barcelona (HCPB), Barcelona 08036, Spain
Hospital General Universitari Vall d'Hebron, Barcelona 08035, Spain
Hospital Universitario de Bellvitge, Barcelona 08907, Spain
Hospital General Universitario Gregorio Maranon, Madrid 28007, Spain
Hospital Universitario y Politecnico la Fe, Valencia 46026, Spain
Chang Gung Memorial Hospital - Kaohsiung, Kaoshiung Hsien 833, Taiwan
National Cheng Kung University Hospital, Tainan 70428, Taiwan
Chang-Gung Memorial Hospital, Taipei City 114, Taiwan
Cathay General Hospital, Taipei 10650, Taiwan
Marmara Universitesi School of Medicine, Istanbul 34899, Turkey
Ege Universitesi Tip Fakultesi Hastanesi, Izmir 35100, Turkey
Heritage Medical Research Clinic, Calgary, Alberta T2N4N1, Canada
The Gordon & Leslie Diamond Centre, Vancouver, British Columbia V5Z3M9, Canada
Vancouver General Hospital, Vancouver, British Columbia V5Z1H2, Canada
Pfleger Liver Institute, Los Angeles, California 90095, United States
California Pacific Medical Center Research Institute, San Francisco, California 94115, United States
University of Miami, Center for Liver Diseases, Miami, Florida 33136, United States
Rush Presbyterian - St. Luke's Medical Center, Chicago, Illinois 60612, United States
Henry Ford Hospital and Health System, Detroit, Michigan 48202, United States
Columbia Presbyterian Medical Center, New York, New York 10032, United States
Mt. Sinai School of Medicine/ Mt. Sinai Medical Center, New York, New York 10029, United States
Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada
Metropolitan Research, Fairfax, Virginia 22031, United States
Virginia Mason Medical Center, Seattle, Washington 98104, United States
Additional Information
Starting date: April 2006
Last updated: April 19, 2013
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