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

Information source: Gilead Sciences
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Chronic Hepatitis B

Intervention: 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 (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: Gilead Sciences

Official(s) and/or principal investigator(s):
John Flaherty, PharmD, Study Director, Affiliation: Gilead Sciences

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.

Clinical Details

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

Primary outcome:

Percent Probability of Tolerability Failure

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

Secondary outcome:

Median Time-averaged Change (DAVG) in Plasma Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels at 48 Weeks Relative to Baseline

Median DAVG in Plasma HBV DNA Levels at 96 Weeks Relative to Baseline

Median DAVG in Plasma HBV DNA Levels at 144 Weeks Relative to Baseline

Median DAVG in Plasma HBV DNA Levels at 168 Weeks Relative to Baseline

Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48

Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 96

Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 144

Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168

Percentage of Participants With Normalized Alanine Aminotransferase (ALT) (for Subjects With Elevated ALT at Baseline) at Week 48

Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 96

Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 144

Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 168

Percentage of Participants With an Increase in Child-Pugh Turcotte (CPT) Score of ≥ 2 Points at Weeks 48

Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 96

Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 144

Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 168

Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 48

Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 96

Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 144

Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 168

Median Change in Model for End-Stage Liver Disease (MELD) Score From Baseline at Week 48

Median Change in MELD Score From Baseline at Week 96

Median Change in MELD Score From Baseline at Week 144

Median Change in MELD Score From Baseline at 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)

Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 96 (for Participants Who Were HBeAg Positive at Baseline)

Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 144 (for Participants Who Were HBeAg Positive at Baseline)

Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 168 (for Participants Who Were HBeAg Positive at Baseline)

Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss and HBsAg Seroconversion at Week 48

Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 96

Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 144

Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at 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

Eligibility

Minimum age: 18 Years. Maximum age: 69 Years. Gender(s): Both.

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

Locations and Contacts

Hopital Conception, Marseille 13005, France

Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Berlin 13353, Germany

Universitat Heidelberg, Heidelberg 69120, Germany

Johannes Gutenberg-Universitat, Mainz 55131, Germany

General Hospital of Athens "Ippokratio", Athens 11527, Greece

Universita de Padova, Padova 35128, Italy

Policlinico Universitario, Udine 33100, Italy

Wojewodzki Szpital Specjalistyczny im Dluskeigo, Bialystok 15-540, Poland

Wojewodzki Szpital Obserwacy, Bydgoszcz 85-030, Poland

Wojewodzki Szpital Zakazny, Warsaw 01-201, Poland

Changi General Hospital, Singapore 529889, Singapore

National University Hospital Dept. of Gastroenterology & Hepatology, Singapore 119074, Singapore

Singapore General Hospital, Singapore 169608, Singapore

Tan Tock Seng Hospital, Singapore 308433, Singapore

Hospital Clinic i Provincial de Barcelona (HCPB), Barcelona 08036, Spain

Hospital General Universitari Vall d'Hebron, Barcelona 08035, Spain

Hospital Universitario de Bellvitge, Barcelona 08907, Spain

Hospital General Universitario Gregorio Maranon, Madrid 28007, Spain

Hospital Universitario y Politecnico la Fe, Valencia 46026, Spain

Chang Gung Memorial Hospital - Kaohsiung, Kaoshiung Hsien 833, Taiwan

National Cheng Kung University Hospital, Tainan 70428, Taiwan

Chang-Gung Memorial Hospital, Taipei City 114, Taiwan

Cathay General Hospital, Taipei 10650, Taiwan

Marmara Universitesi School of Medicine, Istanbul 34899, Turkey

Ege Universitesi Tip Fakultesi Hastanesi, Izmir 35100, Turkey

Heritage Medical Research Clinic, Calgary, Alberta T2N4N1, Canada

The Gordon & Leslie Diamond Centre, Vancouver, British Columbia V5Z3M9, Canada

Vancouver General Hospital, Vancouver, British Columbia V5Z1H2, Canada

Pfleger Liver Institute, Los Angeles, California 90095, United States

California Pacific Medical Center Research Institute, San Francisco, California 94115, United States

University of Miami, Center for Liver Diseases, Miami, Florida 33136, United States

Rush Presbyterian - St. Luke's Medical Center, Chicago, Illinois 60612, United States

Henry Ford Hospital and Health System, Detroit, Michigan 48202, United States

Columbia Presbyterian Medical Center, New York, New York 10032, United States

Mt. Sinai School of Medicine/ Mt. Sinai Medical Center, New York, New York 10029, United States

Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada

Metropolitan Research, Fairfax, Virginia 22031, United States

Virginia Mason Medical Center, Seattle, Washington 98104, United States

Additional Information

Starting date: April 2006
Last updated: April 19, 2013

Page last updated: August 23, 2015

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