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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
112
300-mg tablet QD
FTC 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet QD
0.5-mg or 1-mg tablet QD
Placebo to match TDF QD
Placebo to match FTC/TDF QD
Placebo to match ETV QD
Pfleger Liver Institute
Los Angeles, California, United States
California Pacific Medical Center Research Institute
San Francisco, California, United States
University of Miami, Center for Liver Diseases
Miami, Florida, United States
Rush Presbyterian - St. Luke's Medical Center
Chicago, Illinois, United States
Henry Ford Hospital and Health System
Detroit, Michigan, United States
Percent Probability of Tolerability Failure
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.
Time frame: Baseline to Week 168
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
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.
Time frame: Baseline to Week 168
Median Time-averaged Change (DAVG) in Plasma Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels at 48 Weeks Relative to Baseline
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.
Time frame: Baseline to 48 weeks
Median DAVG in Plasma HBV DNA Levels at 96 Weeks Relative to Baseline
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.
Time frame: Baseline to 96 weeks
Median DAVG in Plasma HBV DNA Levels at 144 Weeks Relative to Baseline
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.
Time frame: Baseline to 144 weeks
Median DAVG in Plasma HBV DNA Levels at 168 Weeks Relative to Baseline
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.
Time frame: Baseline to 168 weeks
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48
The percentage of participants with plasma HBV DNA \< 400 copies/mL at Week 48 was summarized.
Time frame: Week 48
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 96
The percentage of participants with plasma HBV DNA \< 400 copies/mL at Week 96 was summarized.
Time frame: Week 96
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 144
The percentage of participants with plasma HBV DNA \< 400 copies/mL at Week 144 was summarized.
Time frame: Week 144
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168
The percentage of participants with plasma HBV DNA \< 400 copies/mL at Week 168 was summarized.
Time frame: Week 168
Percentage of Participants With Normalized Alanine Aminotransferase (ALT) (for Subjects With Elevated ALT at Baseline) at Week 48
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.
Time frame: Baseline to Week 48
Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 96
Normalized ALT is defined as having a baseline ALT value \> ULN, and a decrease in ALT value to ≤ ULN at the given time point.
Time frame: Baseline to Week 96
Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 144
Normalized ALT is defined as having a baseline ALT value \> ULN, and a decrease in ALT value to ≤ ULN at the given time point.
Time frame: Baseline to Week 144
Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 168
Normalized ALT is defined as having a baseline ALT value \> ULN, and a decrease in ALT value to ≤ ULN at the given time point.
Time frame: Baseline to Week 168
Percentage of Participants With an Increase in Child-Pugh Turcotte (CPT) Score of ≥ 2 Points at Weeks 48
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.
Time frame: Baseline to Week 48
Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 96
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.
Time frame: Baseline to Week 96
Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 144
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.
Time frame: Baseline to Week 144
Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 168
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.
Time frame: Baseline to Week 168
Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 48
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.
Time frame: Baseline to Week 48
Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 96
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.
Time frame: Baseline to Week 96
Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 144
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.
Time frame: Baseline to Week 144
Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 168
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.
Time frame: Baseline to Week 168
Median Change in Model for End-Stage Liver Disease (MELD) Score From Baseline at Week 48
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.
Time frame: Baseline to Week 48
Median Change in MELD Score From Baseline at Week 96
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.
Time frame: Baseline to Week 96
Median Change in MELD Score From Baseline at Week 144
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.
Time frame: Baseline to Week 144
Median Change in MELD Score From Baseline at Week 168
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.
Time frame: Baseline to 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)
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.
Time frame: Baseline to Week 48
Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 96 (for Participants Who Were HBeAg Positive at Baseline)
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.
Time frame: Baseline to Week 96
Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 144 (for Participants Who Were HBeAg Positive at Baseline)
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.
Time frame: Baseline to Week 144
Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 168 (for Participants Who Were HBeAg Positive at Baseline)
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.
Time frame: Baseline to Week 168
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss and HBsAg Seroconversion at Week 48
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.
Time frame: Baseline to Week 48
Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 96
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.
Time frame: Baseline to Week 96
Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 144
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.
Time frame: Baseline to Week 144
Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 168
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.
Time frame: Baseline to 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
Time frame: Baseline to Week 168
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