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

NCT00298363 | Completed Phase 2 Results DMC

• 1 other identifier: GS-US-174-0108
• Study Type: interventional
• Target: 112
• Locations: 11 countries
• Sites: 38

Brief 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.

Conditions

Chronic Hepatitis B

Keywords

Hepatitis; Hepatitis B virus; Tenofovir

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (33)

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

  Baseline to 48 weeks

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

  Baseline to 96 weeks

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

  Baseline to 144 weeks

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

  Baseline to 168 weeks

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

  Week 48

Other Outcomes (3)

• Percentage of Participants With Only Baseline Adefovir Dipivoxil Resistance (ADV-R) Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks

  Baseline to Week 168

• Percentage of Participants With Only Baseline Lamivudine-resistance (LAM-R) Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks

  Baseline to Week 168

• Percentage of Participants With Baseline ADV-R + LAM-R Mutations Achieving HBV DNA < 400 Copies/mL by 168 Weeks

  Baseline to Week 168

Study Arms (3)

Tenofovir DF

EXPERIMENTAL

TDF 300 mg + FTC/TDF placebo + ETV placebo once daily (QD)

Drug: Tenofovir disoproxil fumarate (tenofovir DF; TDF); Drug: FTC/TDF placebo; Drug: ETV placebo

FTC/TDF

EXPERIMENTAL

FTC 200 mg/TDF 300 mg + TDF placebo + ETV placebo QD

Drug: Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF); Drug: TDF placebo; Drug: ETV placebo

Entecavir

EXPERIMENTAL

ETV 0.5 mg or 1 mg + TDF placebo + FTC/TDF placebo QD

Drug: Entecavir (ETV); Drug: TDF placebo; Drug: FTC/TDF placebo

Interventions

Tenofovir disoproxil fumarate (tenofovir DF; TDF) DRUG

300-mg tablet QD

Also known as: Viread

Tenofovir DF

Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) DRUG

FTC 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet QD

Also known as: Truvada

FTC/TDF

Entecavir (ETV) DRUG

0.5-mg or 1-mg tablet QD

Also known as: Baraclude

Entecavir

TDF placebo DRUG

Placebo to match TDF QD

Entecavir; FTC/TDF

FTC/TDF placebo DRUG

Placebo to match FTC/TDF QD

Entecavir; Tenofovir DF

ETV placebo DRUG

Placebo to match ETV QD

FTC/TDF; Tenofovir DF

Eligibility Criteria

• Age: 18 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Chronic Hepatitis B infection
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (38)

Pfleger Liver Institute

Los Angeles, California, 90095, United States

Location

California Pacific Medical Center Research Institute

San Francisco, California, 94115, United States

Location

University of Miami, Center for Liver Diseases

Miami, Florida, 33136, United States

Location

Rush Presbyterian - St. Luke's Medical Center

Chicago, Illinois, 60612, United States

Location

Henry Ford Hospital and Health System

Detroit, Michigan, 48202, United States

Location

Mt. Sinai School of Medicine/ Mt. Sinai Medical Center

New York, New York, 10029, United States

Location

Columbia Presbyterian Medical Center

New York, New York, 10032, United States

Location

Metropolitan Research

Fairfax, Virginia, 22031, United States

Location

Virginia Mason Medical Center

Seattle, Washington, 98104, United States

Location

Heritage Medical Research Clinic

Calgary, Alberta, T2N4N1, Canada

Location

Vancouver General Hospital

Vancouver, British Columbia, V5Z1H2, Canada

Location

The Gordon & Leslie Diamond Centre

Vancouver, British Columbia, V5Z3M9, Canada

Location

Toronto General Hospital

Toronto, Ontario, M5G 2C4, Canada

Location

Hopital Conception

Marseille, 13005, France

Location

Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie

Berlin, 13353, Germany

Location

Universitat Heidelberg

Heidelberg, 69120, Germany

Location

Johannes Gutenberg-Universitat

Mainz, 55131, Germany

Location

General Hospital of Athens "Ippokratio"

Athens, 11527, Greece

Location

Universita de Padova

Padua, 35128, Italy

Location

Policlinico Universitario

Udine, 33100, Italy

Location

Wojewodzki Szpital Specjalistyczny im Dluskeigo

Bialystok, 15-540, Poland

Location

Wojewodzki Szpital Obserwacy

Bydgoszcz, 85-030, Poland

Location

Wojewodzki Szpital Zakazny

Warsaw, 01-201, Poland

Location

National University Hospital Dept. of Gastroenterology & Hepatology

Singapore, 119074, Singapore

Location

Singapore General Hospital

Singapore, 169608, Singapore

Location

Tan Tock Seng Hospital

Singapore, 308433, Singapore

Location

Changi General Hospital

Singapore, 529889, Singapore

Location

Hospital General Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Clinic i Provincial de Barcelona (HCPB)

Barcelona, 08036, Spain

Location

Hospital Universitario de Bellvitge

Barcelona, 08907, Spain

Location

Hospital General Universitario Gregorio Maranon

Madrid, 28007, Spain

Location

Hospital Universitario y Politecnico la Fe

Valencia, 46026, Spain

Location

Chang Gung Memorial Hospital - Kaohsiung

Kaoshiung Hsien, 833, Taiwan

Location

National Cheng Kung University Hospital

Tainan, 70428, Taiwan

Location

Cathay General Hospital

Taipei, 10650, Taiwan

Location

Chang-Gung Memorial Hospital

Taipei, 114, Taiwan

Location

Marmara Universitesi School of Medicine

Istanbul, 34899, Turkey (Türkiye)

Location

Ege Universitesi Tip Fakultesi Hastanesi

Izmir, 35100, Turkey (Türkiye)

Location

Related 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), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011 Jan;53(1):62-72. doi: 10.1002/hep.23952. Epub 2010 Oct 27.

  PMID: 21254162 RESULT

MeSH Terms

Conditions

Hepatitis B, Chronic; Hepatitis; Hepatitis B

Interventions

Tenofovir; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; entecavir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Clinical Trial Disclosures
• Organization: Gilead Sciences, Inc.

ClinicalTrialDisclosures@gilead.com

Study Officials

• John Flaherty, PharmD

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 28, 2006
• First Posted: March 2, 2006
• Study Start: April 1, 2006
• Primary Completion: April 1, 2011
• Study Completion: April 1, 2011
• Last Updated: April 25, 2013
• Results First Posted: April 25, 2013

Record last verified: 2013-04

Locations

FR (1); GR (1); ES (5); CA (4); IT (2); DE (3); PL (3); US (9); TU (2); SG (4); TW (4)