Study Comparing Tenofovir Disoproxil Fumarate (TDF), Emtricitabine (FTC)/TDF, and Entecavir (ETV) in the Treatment of Chronic HBV in Subjects With Decompensated Liver Disease.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00298363
First received: February 28, 2006
Last updated: April 19, 2013
Last verified: April 2013
  Purpose

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.


Condition Intervention Phase
Chronic Hepatitis B
Drug: 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
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • Percent Probability of Tolerability Failure [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]
    Tolerability failure was defined as permanent discontinuation of study drug due to a treatment-emergent adverse event (AE), including any subject who temporarily discontinued study drug due to an AE and did not restart. Results are expressed as proportions of participants who experience tolerability failure using the Kaplan-Meier (KM) method of estimation.

  • 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 [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]
    Results are expressed as proportions of participants who experience a confirmed increase in serum creatinine of ≥ 0.5 mg/dL from baseline or a confirmed serum phosphorus level < 2.0 mg/dL using the KM method of estimation.


Secondary Outcome Measures:
  • Median Time-averaged Change (DAVG) in Plasma Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels at 48 Weeks Relative to Baseline [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
    Change from baseline was evaluated by subtracting baseline HBV DNA log_10 copies/mL from Week 48 HBV DNA log_10 copies/mL. DAVG is defined as the area of the trapezoid under the response-time curve divided by time to the last available evaluation of the patient minus the baseline value.

  • Median DAVG in Plasma HBV DNA Levels at 96 Weeks Relative to Baseline [ Time Frame: Baseline to 96 weeks ] [ Designated as safety issue: No ]
    Change from baseline was evaluated by subtracting baseline HBV DNA log_10 copies/mL from Week 96 HBV DNA log_10 copies/mL. DAVG is defined as the area of the trapezoid under the response-time curve divided by time to the last available evaluation of the patient minus the baseline value.

  • Median DAVG in Plasma HBV DNA Levels at 144 Weeks Relative to Baseline [ Time Frame: Baseline to 144 weeks ] [ Designated as safety issue: No ]
    Change from baseline was evaluated by subtracting baseline HBV DNA log_10 copies/mL from Week 144 HBV DNA log_10 copies/mL. DAVG is defined as the area of the trapezoid under the response-time curve divided by time to the last available evaluation of the patient minus the baseline value.

  • Median DAVG in Plasma HBV DNA Levels at 168 Weeks Relative to Baseline [ Time Frame: Baseline to 168 weeks ] [ Designated as safety issue: No ]
    Change from baseline was evaluated by subtracting baseline HBV DNA log_10 copies/mL from Week 168 HBV DNA log_10 copies/mL. DAVG is defined as the area of the trapezoid under the response-time curve divided by time to the last available evaluation of the patient minus the baseline value.

  • Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The percentage of participants with plasma HBV DNA < 400 copies/mL at Week 48 was summarized.

  • Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    The percentage of participants with plasma HBV DNA < 400 copies/mL at Week 96 was summarized.

  • Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 144 [ Time Frame: Week 144 ] [ Designated as safety issue: No ]
    The percentage of participants with plasma HBV DNA < 400 copies/mL at Week 144 was summarized.

  • Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168 [ Time Frame: Week 168 ] [ Designated as safety issue: No ]
    The percentage of participants with plasma HBV DNA < 400 copies/mL at Week 168 was summarized.

  • Percentage of Participants With Normalized Alanine Aminotransferase (ALT) (for Subjects With Elevated ALT at Baseline) at Week 48 [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    Normalized ALT is defined as having a baseline ALT value > the upper limit of the normal range (ULN), and a decrease in ALT value to ≤ ULN at the given time point.

  • Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    Normalized ALT is defined as having a baseline ALT value > ULN, and a decrease in ALT value to ≤ ULN at the given time point.

  • Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 144 [ Time Frame: Baseline to Week 144 ] [ Designated as safety issue: No ]
    Normalized ALT is defined as having a baseline ALT value > ULN, and a decrease in ALT value to ≤ ULN at the given time point.

  • Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 168 [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]
    Normalized ALT is defined as having a baseline ALT value > ULN, and a decrease in ALT value to ≤ ULN at the given time point.

  • Percentage of Participants With an Increase in Child-Pugh Turcotte (CPT) Score of ≥ 2 Points at Weeks 48 [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease.

  • Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease.

  • Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 144 [ Time Frame: Baseline to Week 144 ] [ Designated as safety issue: No ]
    CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease.

  • Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 168 [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]
    CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease.

  • Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 48 [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease.

  • Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease.

  • Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 144 [ Time Frame: Baseline to Week 144 ] [ Designated as safety issue: No ]
    CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease.

  • Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 168 [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]
    CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease.

  • Median Change in Model for End-Stage Liver Disease (MELD) Score From Baseline at Week 48 [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    MELD scores, used to assess prognosis and suitability for transplant, are calculated based on laboratory values only and can range from 6 to 40, with higher scores indicating greater disease severity.

  • Median Change in MELD Score From Baseline at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    MELD scores, used to assess prognosis and suitability for transplant, are calculated based on laboratory values only and can range from 6 to 40, with higher scores indicating greater disease severity.

  • Median Change in MELD Score From Baseline at Week 144 [ Time Frame: Baseline to Week 144 ] [ Designated as safety issue: No ]
    MELD scores, used to assess prognosis and suitability for transplant, are calculated based on laboratory values only and can range from 6 to 40, with higher scores indicating greater disease severity.

  • Median Change in MELD Score From Baseline at Week 168 [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]
    MELD scores, used to assess prognosis and suitability for transplant, are calculated based on laboratory values only and can range from 6 to 40, with higher scores indicating greater disease severity.

  • Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss and HBeAg Seroconversion at Week 48 (for Participants Who Were HBeAg Positive at Baseline) [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    Loss of HBeAg was defined as change of detectable HBeAg from positive to negative. HBeAg seroconversion was defined as change of detectable antibody to HBeAg from negative to positive.

  • Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 96 (for Participants Who Were HBeAg Positive at Baseline) [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    Loss of HBeAg was defined as change of detectable HBeAg from positive to negative. HBeAg seroconversion was defined as change of detectable antibody to HBeAg from negative to positive.

  • Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 144 (for Participants Who Were HBeAg Positive at Baseline) [ Time Frame: Baseline to Week 144 ] [ Designated as safety issue: No ]
    Loss of HBeAg was defined as change of detectable HBeAg from positive to negative. HBeAg seroconversion was defined as change of detectable antibody to HBeAg from negative to positive.

  • Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 168 (for Participants Who Were HBeAg Positive at Baseline) [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]
    Loss of HBeAg was defined as change of detectable HBeAg from positive to negative. HBeAg seroconversion was defined as change of detectable antibody to HBeAg from negative to positive.

  • Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss and HBsAg Seroconversion at Week 48 [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. HBsAg seroconversion was defined as change of detectable antibody to HBsAg from negative to positive.

  • Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 96 [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
    Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. HBsAg seroconversion was defined as change of detectable antibody to HBsAg from negative to positive.

  • Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 144 [ Time Frame: Baseline to Week 144 ] [ Designated as safety issue: No ]
    Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. HBsAg seroconversion was defined as change of detectable antibody to HBsAg from negative to positive.

  • Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 168 [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]
    Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. HBsAg seroconversion was defined as change of detectable antibody to HBsAg from negative to positive.

  • 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 [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Percentage of Participants With Only Baseline Adefovir Dipivoxil Resistance (ADV-R) Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]
    ADV resistance mutations are defined as the presence of the rtA181T/V HBV gene mutation and/or the rtN236T HBV gene mutation.

  • Percentage of Participants With Only Baseline Lamivudine-resistance (LAM-R) Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]
    LAM resistance mutations are defined as the presence of the rtM204V/I HBV gene mutation with or without the rtL180M HBV gene mutation.

  • Percentage of Participants With Baseline ADV-R + LAM-R Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks [ Time Frame: Baseline to Week 168 ] [ Designated as safety issue: No ]
    ADV resistance mutation + LAM resistance mutations are defined as the presence of the rtA181T/V HBV gene mutation and/or the rtN236T HBV gene mutation, and the rtM204V/I HBV gene mutation with or without the rtL180M HBV gene mutation.


Enrollment: 112
Study Start Date: April 2006
Study Completion Date: April 2011
Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tenofovir DF
TDF 300 mg + FTC/TDF placebo + ETV placebo once daily (QD)
Drug: Tenofovir disoproxil fumarate (tenofovir DF; TDF)
300-mg tablet QD
Other Name: Viread
Drug: FTC/TDF placebo
Placebo to match FTC/TDF QD
Drug: ETV placebo
Placebo to match ETV QD
Experimental: FTC/TDF
FTC 200 mg/TDF 300 mg + TDF placebo + ETV placebo QD
Drug: Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)
FTC 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet QD
Other Name: Truvada
Drug: TDF placebo
Placebo to match TDF QD
Drug: ETV placebo
Placebo to match ETV QD
Experimental: Entecavir
ETV 0.5 mg or 1 mg + TDF placebo + FTC/TDF placebo QD
Drug: Entecavir (ETV)
0.5-mg or 1-mg tablet QD
Other Name: Baraclude
Drug: TDF placebo
Placebo to match TDF QD
Drug: FTC/TDF placebo
Placebo to match FTC/TDF QD

  Eligibility

Ages Eligible for Study:   18 Years to 69 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00298363

  Show 38 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: John Flaherty, PharmD Gilead Sciences
  More Information

Publications:
Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT00298363     History of Changes
Other Study ID Numbers: GS-US-174-0108
Study First Received: February 28, 2006
Results First Received: April 10, 2012
Last Updated: April 19, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Gilead Sciences:
Hepatitis; Hepatitis B virus; Tenofovir

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis B
Hepatitis, Chronic
Liver Diseases
Hepatitis B, Chronic
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Emtricitabine
Tenofovir
Tenofovir disoproxil
Entecavir
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents

ClinicalTrials.gov processed this record on August 19, 2014