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

Chronic Hepatitis B Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00298363
• Other study ID #: GS-US-174-0108
• Status: Completed
• Phase: Phase 2
• First received: February 28, 2006
• Last updated: April 19, 2013
• Start date: April 2006
• Est. completion date: April 2011

Study information

• Verified date: April 2013
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 112
• Est. completion date: April 2011
• Est. primary completion date: April 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 69 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic
• Liver Diseases

Intervention

Drug:
• Tenofovir disoproxil fumarate (tenofovir DF; TDF)
300-mg tablet QD
• Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)
FTC 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet QD
• Entecavir (ETV)
0.5-mg or 1-mg tablet QD
• TDF placebo
Placebo to match TDF QD
• FTC/TDF placebo
Placebo to match FTC/TDF QD
• ETV placebo
Placebo to match ETV QD

Locations

Country	Name	City	State
Canada	Heritage Medical Research Clinic	Calgary	Alberta
Canada	Toronto General Hospital	Toronto	Ontario
Canada	The Gordon & Leslie Diamond Centre	Vancouver	British Columbia
Canada	Vancouver General Hospital	Vancouver	British Columbia
France	Hopital Conception	Marseille
Germany	Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie	Berlin
Germany	Universitat Heidelberg	Heidelberg
Germany	Johannes Gutenberg-Universitat	Mainz
Greece	General Hospital of Athens "Ippokratio"	Athens
Italy	Universita de Padova	Padova
Italy	Policlinico Universitario	Udine
Poland	Wojewodzki Szpital Specjalistyczny im Dluskeigo	Bialystok
Poland	Wojewodzki Szpital Obserwacy	Bydgoszcz
Poland	Wojewodzki Szpital Zakazny	Warsaw
Singapore	Changi General Hospital	Singapore
Singapore	National University Hospital Dept. of Gastroenterology & Hepatology	Singapore
Singapore	Singapore General Hospital	Singapore
Singapore	Tan Tock Seng Hospital	Singapore
Spain	Hospital Clinic i Provincial de Barcelona (HCPB)	Barcelona
Spain	Hospital General Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario de Bellvitge	Barcelona
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario y Politecnico la Fe	Valencia
Taiwan	Chang Gung Memorial Hospital - Kaohsiung	Kaoshiung Hsien
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	Cathay General Hospital	Taipei
Taiwan	Chang-Gung Memorial Hospital	Taipei City
Turkey	Marmara Universitesi School of Medicine	Istanbul
Turkey	Ege Universitesi Tip Fakultesi Hastanesi	Izmir
United States	Rush Presbyterian - St. Luke's Medical Center	Chicago	Illinois
United States	Henry Ford Hospital and Health System	Detroit	Michigan
United States	Metropolitan Research	Fairfax	Virginia
United States	Pfleger Liver Institute	Los Angeles	California
United States	University of Miami, Center for Liver Diseases	Miami	Florida
United States	Columbia Presbyterian Medical Center	New York	New York
United States	Mt. Sinai School of Medicine/ Mt. Sinai Medical Center	New York	New York
United States	California Pacific Medical Center Research Institute	San Francisco	California
United States	Virginia Mason Medical Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Greece,  Italy,  Poland,  Singapore,  Spain,  Taiwan,  Turkey, 

References & Publications (1)

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), emtricitab — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percentage of Participants With Only Baseline Adefovir Dipivoxil Resistance (ADV-R) Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks	ADV resistance mutations are defined as the presence of the rtA181T/V HBV gene mutation and/or the rtN236T HBV gene mutation.	Baseline to Week 168	No
Other	Percentage of Participants With Only Baseline Lamivudine-resistance (LAM-R) Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks	LAM resistance mutations are defined as the presence of the rtM204V/I HBV gene mutation with or without the rtL180M HBV gene mutation.	Baseline to Week 168	No
Other	Percentage of Participants With Baseline ADV-R + LAM-R Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks	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.	Baseline to Week 168	No
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No