Clinical trial NCT00298363: Study Comparing Tenofovir Disoproxil Fumarate (TDF), Emtricitabine (FTC)/TDF, and Entecavir (ETV) in the Treatment of Chronic HBV in Subjects With Decompensated Liver Disease.
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Hepatitis B
Keywords: Hepatitis; Hepatitis B virus; Tenofovir
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2006-03-02
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility 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

Primary outcomes:
measure: Percent Probability of Tolerability Failure
timeFrame: Baseline to Week 168
measure: Percent 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
timeFrame: Baseline to Week 168
Secondary outcomes:
measure: Median Time-averaged Change (DAVG) in Plasma Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels at 48 Weeks Relative to Baseline
timeFrame: Baseline to 48 weeks
measure: Median DAVG in Plasma HBV DNA Levels at 96 Weeks Relative to Baseline
timeFrame: Baseline to 96 weeks
measure: Median DAVG in Plasma HBV DNA Levels at 144 Weeks Relative to Baseline
timeFrame: Baseline to 144 weeks
measure: Median DAVG in Plasma HBV DNA Levels at 168 Weeks Relative to Baseline
timeFrame: Baseline to 168 weeks
measure: Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48
timeFrame: Week 48
measure: Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 144
timeFrame: Week 144
measure: Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168
timeFrame: Week 168
measure: Percentage of Participants With Normalized Alanine Aminotransferase (ALT) (for Subjects With Elevated ALT at Baseline) at Week 48
timeFrame: Baseline to Week 48
measure: Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 96
timeFrame: Baseline to Week 96
measure: Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 144
timeFrame: Baseline to Week 144
measure: Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 168
timeFrame: Baseline to Week 168
measure: Percentage of Participants With an Increase in Child-Pugh Turcotte (CPT) Score of ≥ 2 Points at Weeks 48
timeFrame: Baseline to Week 48
measure: Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 96
timeFrame: Baseline to Week 96
measure: Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 144
timeFrame: Baseline to Week 144
measure: Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 168
timeFrame: Baseline to Week 168
measure: Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 48
timeFrame: Baseline to Week 48
measure: Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 96
timeFrame: Baseline to Week 96
measure: Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 144
timeFrame: Baseline to Week 144
measure: Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 168
timeFrame: Baseline to Week 168
measure: Median Change in Model for End-Stage Liver Disease (MELD) Score From Baseline at Week 48
timeFrame: Baseline to Week 48
measure: Median Change in MELD Score From Baseline at Week 96
timeFrame: Baseline to Week 96
measure: Median Change in MELD Score From Baseline at Week 144
timeFrame: Baseline to Week 144
measure: Median Change in MELD Score From Baseline at Week 168
timeFrame: Baseline to Week 168
measure: Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss and HBeAg Seroconversion at Week 48 (for Participants Who Were HBeAg Positive at Baseline)
timeFrame: Baseline to Week 48
measure: Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 96 (for Participants Who Were HBeAg Positive at Baseline)
timeFrame: Baseline to Week 96
measure: Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 144 (for Participants Who Were HBeAg Positive at Baseline)
timeFrame: Baseline to Week 144
measure: Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 168 (for Participants Who Were HBeAg Positive at Baseline)
timeFrame: Baseline to Week 168
measure: Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss and HBsAg Seroconversion at Week 48
timeFrame: Baseline to Week 48
measure: Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 96
timeFrame: Baseline to Week 96
measure: Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 144
timeFrame: Baseline to Week 144
measure: Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 168
timeFrame: Baseline to Week 168
measure: 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
timeFrame: Baseline to Week 168
Other outcomes:
measure: Percentage of Participants With Only Baseline Adefovir Dipivoxil Resistance (ADV-R) Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks
timeFrame: Baseline to Week 168
measure: Percentage of Participants With Only Baseline Lamivudine-resistance (LAM-R) Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks
timeFrame: Baseline to Week 168
measure: Percentage of Participants With Baseline ADV-R + LAM-R Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks
timeFrame: Baseline to Week 168
Locations:
city: Los Angeles
country: United States
facility: Pfleger Liver Institute
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center Research Institute
state: California
city: Miami
country: United States
facility: University of Miami, Center for Liver Diseases
state: Florida
city: Chicago
country: United States
facility: Rush Presbyterian - St. Luke's Medical Center
state: Illinois
city: Detroit
country: United States
facility: Henry Ford Hospital and Health System
state: Michigan
city: New York
country: United States
facility: Mt. Sinai School of Medicine/ Mt. Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia Presbyterian Medical Center
state: New York
city: Fairfax
country: United States
facility: Metropolitan Research
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Calgary
country: Canada
facility: Heritage Medical Research Clinic
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: The Gordon & Leslie Diamond Centre
state: British Columbia
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Marseille
country: France
facility: Hopital Conception
city: Berlin
country: Germany
facility: Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie
city: Heidelberg
country: Germany
facility: Universitat Heidelberg
city: Mainz
country: Germany
facility: Johannes Gutenberg-Universitat
city: Athens
country: Greece
facility: General Hospital of Athens "Ippokratio"
city: Padova
country: Italy
facility: Universita de Padova
city: Udine
country: Italy
facility: Policlinico Universitario
city: Bialystok
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im Dluskeigo
city: Bydgoszcz
country: Poland
facility: Wojewodzki Szpital Obserwacy
city: Warsaw
country: Poland
facility: Wojewodzki Szpital Zakazny
city: Singapore
country: Singapore
facility: National University Hospital Dept. of Gastroenterology & Hepatology
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Singapore
country: Singapore
facility: Changi General Hospital
city: Barcelona
country: Spain
facility: Hospital General Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona (HCPB)
city: Barcelona
country: Spain
facility: Hospital Universitario de Bellvitge
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Valencia
country: Spain
facility: Hospital Universitario y Politecnico la Fe
city: Kaoshiung Hsien
country: Taiwan
facility: Chang Gung Memorial Hospital - Kaohsiung
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei City
country: Taiwan
facility: Chang-Gung Memorial Hospital
city: Taipei
country: Taiwan
facility: Cathay General Hospital
city: Istanbul
country: Turkey
facility: Marmara Universitesi School of Medicine
city: Izmir
country: Turkey
facility: Ege Universitesi Tip Fakultesi Hastanesi
Study officials:
affiliation: Gilead Sciences
name: John Flaherty, PharmD
role: STUDY_DIRECTOR
References:
citation: Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing Wong F, Chang TT, Horban A, Wang C, Kwan P, Buti M, Prieto M, Berg T, Kitrinos K, Peschell K, Mondou E, Frederick D, Rousseau F, Schiff ER. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011 Jan;53(1):62-72. doi: 10.1002/hep.23952. Epub 2010 Oct 27.