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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenofovir DF<br>TDF 300 mg + FTC/TDF placebo + ETV placebo once daily (QD) | Drug: Tenofovir disoproxil fumarate (tenofovir DF; TDF)<br>* 300-mg tablet QD<br>* Other names: Viread;Drug: FTC/TDF placebo<br>* Placebo to match FTC/TDF QD<br>Drug: ETV placebo<br>* Placebo to match ETV QD<br>|
| Experimental: FTC/TDF<br>FTC 200 mg/TDF 300 mg + TDF placebo + ETV placebo QD | Drug: Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)<br>* FTC 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet QD<br>* Other names: Truvada;Drug: TDF placebo<br>* Placebo to match TDF QD<br>Drug: ETV placebo<br>* Placebo to match ETV QD<br>|
| Experimental: Entecavir<br>ETV 0.5 mg or 1 mg + TDF placebo + FTC/TDF placebo QD | Drug: Entecavir (ETV)<br>* 0.5-mg or 1-mg tablet QD<br>* Other names: Baraclude;Drug: TDF placebo<br>* Placebo to match TDF QD<br>Drug: FTC/TDF placebo<br>* Placebo to match FTC/TDF QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Baseline to Week 168 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 |  | Baseline to Week 168 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis; Hepatitis B virus; Tenofovir