Chronic Hepatitis BPhase 2NCT00298363
Study Comparing Tenofovir Disoproxil Fumarate (TDF), Emtricitabine (FTC)/TDF, and Entecavir (ETV) in the Treatment of Chronic HBV in Subjects With Decompensated Liver Disease.
A Phase 2 study testing Tenofovir disoproxil fumarate (tenofovir DF; TDF), Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and Entecavir (ETV) in people with Chronic Hepatitis B, run by Gilead Sciences at 38 sites in 11 countries.
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. Read more about this study
- Who is it for?
- Ages 18 to 69 years
- Conditions the study is for
- Chronic Hepatitis B
- What is being tested?
- Tenofovir disoproxil fumarate (tenofovir DF; TDF), Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and Entecavir (ETV)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 112 participants
- Where
- 38 sitesin 11 countries
- Study dates
- Apr 2006to Apr 2011
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 69 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 15Show fewer
- 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
Who cannot join
- 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
Show all 12Show fewer
- 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
Trial locations and contacts
38 sites in 11 countries.
38 sites in 11 countries
United States9 sites
Rush Presbyterian - St. Luke's Medical Center
Chicago, Illinois, 60612
Henry Ford Hospital and Health System
Detroit, Michigan, 48202
Metropolitan Research
Fairfax, Virginia, 22031
Pfleger Liver Institute
Los Angeles, California, 90095
University of Miami, Center for Liver Diseases
Miami, Florida, 33136
Mt. Sinai School of Medicine/ Mt. Sinai Medical Center
New York, New York, 10029
Columbia Presbyterian Medical Center
New York, New York, 10032
California Pacific Medical Center Research Institute
San Francisco, California, 94115
Virginia Mason Medical Center
Seattle, Washington, 98104
Spain5 sites
Hospital General Universitari Vall d'Hebron
Barcelona, 08035
Hospital Clinic i Provincial de Barcelona (HCPB)
Barcelona, 08036
Hospital Universitario de Bellvitge
Barcelona, 08907
Hospital General Universitario Gregorio Maranon
Madrid, 28007
Hospital Universitario y Politecnico la Fe
Valencia, 46026
Canada4 sites
Heritage Medical Research Clinic
Calgary, Alberta, T2N4N1
Toronto General Hospital
Toronto, Ontario, M5G 2C4
Vancouver General Hospital
Vancouver, British Columbia, V5Z1H2
The Gordon & Leslie Diamond Centre
Vancouver, British Columbia, V5Z3M9
Singapore4 sites
National University Hospital Dept. of Gastroenterology & Hepatology
Singapore, 119074
Singapore General Hospital
Singapore, 169608
Tan Tock Seng Hospital
Singapore, 308433
Changi General Hospital
Singapore, 529889
Taiwan4 sites
Chang Gung Memorial Hospital - Kaohsiung
Kaoshiung Hsien, 833
National Cheng Kung University Hospital
Tainan, 70428
Cathay General Hospital
Taipei, 10650
Chang-Gung Memorial Hospital
Taipei, 114
Germany3 sites
Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie
Berlin, 13353
Universitat Heidelberg
Heidelberg, 69120
Johannes Gutenberg-Universitat
Mainz, 55131
Poland3 sites
Wojewodzki Szpital Specjalistyczny im Dluskeigo
Bialystok, 15-540
Wojewodzki Szpital Obserwacy
Bydgoszcz, 85-030
Wojewodzki Szpital Zakazny
Warsaw, 01-201
Italy2 sites
Universita de Padova
Padova, 35128
Policlinico Universitario
Udine, 33100
Turkey (Türkiye)2 sites
Marmara Universitesi School of Medicine
Istanbul, 34899
Ege Universitesi Tip Fakultesi Hastanesi
Izmir, 35100
About this study
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
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
- Being tested
- Tenofovir disoproxil fumarate (tenofovir DF; TDF), Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), Entecavir (ETV), TDF placebo, FTC/TDF placebo
- Keywords
- Hepatitis; Hepatitis B virus; Tenofovir
- Medical subject headings
- Hepatitis B, Chronic, Hepatitis, Hepatitis B
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tenofovir disoproxil fumarate (tenofovir DF; TDF)Drug
Also called Viread
300-mg tablet QD
Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)Drug
Also called Truvada
FTC 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet QD
Entecavir (ETV)Drug
Also called Baraclude
0.5-mg or 1-mg tablet QD
TDF placeboDrug
Placebo to match TDF QD
FTC/TDF placeboDrug
Placebo to match FTC/TDF QD
ETV placeboDrug
Placebo to match ETV QD
| Study group | Role | What they receive |
|---|---|---|
| Tenofovir DF | Experimental | TDF 300 mg + FTC/TDF placebo + ETV placebo once daily (QD) Receives: 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 Receives: 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 Receives: Drug: Entecavir (ETV); Drug: TDF placebo; Drug: FTC/TDF placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: Baseline to Week 168
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Mar 2006 (estimated)
- Study startApr 2006
- Primary completionApr 2011
- Study completionApr 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic Hepatitis BStudies of the same condition, open and under way.
- More trials run by Gilead SciencesThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 112 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gilead Sciences
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- John Flaherty, PharmD, Study director, Gilead Sciences
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00298363
- Sponsor's protocol ID
- GS-US-174-0108
- Status last verified
- Apr 2013
- First submitted
- 28 Feb 2006
- Last updated
- 25 Apr 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 21254162
Study at a glance
From the registry record, last updated by the sponsor on 25 Apr 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00298363
- Acronym / sponsor ID
- GS-US-174-0108
- Conditions
- Chronic Hepatitis B
- Keywords
- Hepatitis; Hepatitis B virus; Tenofovir
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 112 participants (actual)
- Lead sponsor
- Gilead SciencesIndustry (pharma, biotech, devices)
- Study start
- Apr 2006
- Primary completion
- Apr 2011 (actual)
- Study completion
- Apr 2011 (actual)
- First posted
- 2 Mar 2006 (estimated)
- Results
- Posted 25 Apr 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Tenofovir DF | Experimental | Drug: Tenofovir disoproxil fumarate (tenofovir DF; TDF), Drug: FTC/TDF placebo, Drug: ETV placeboTDF 300 mg + FTC/TDF placebo + ETV placebo once daily (QD) |
| FTC/TDF | Experimental | Drug: Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), Drug: TDF placebo, Drug: ETV placeboFTC 200 mg/TDF 300 mg + TDF placebo + ETV placebo QD |
| Entecavir | Experimental | Drug: Entecavir (ETV), Drug: TDF placebo, Drug: FTC/TDF placeboETV 0.5 mg or 1 mg + TDF placebo + FTC/TDF placebo QD |
Who may qualify
- Ages
- 18 to 69 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- 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:
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tenofovir disoproxil fumarate (tenofovir DF; TDF)Also: Viread300-mg tablet QD | Drug | Tenofovir DF |
| Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)Also: TruvadaFTC 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet QD | Drug | FTC/TDF |
| Entecavir (ETV)Also: Baraclude0.5-mg or 1-mg tablet QD | Drug | Entecavir |
| TDF placeboPlacebo to match TDF QD | Drug | Entecavir, FTC/TDF |
| FTC/TDF placeboPlacebo to match FTC/TDF QD | Drug | Entecavir, Tenofovir DF |
| ETV placeboPlacebo to match ETV QD | Drug | FTC/TDF, Tenofovir DF |
Primary outcome
Percent Probability of Tolerability Failure
Time frame: Baseline to Week 168
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.
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
Time frame: Baseline to Week 168
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.
33 secondary outcomes
Median Time-averaged Change (DAVG) in Plasma Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels at 48 Weeks Relative to Baseline
Time frame: Baseline to 48 weeks
Median DAVG in Plasma HBV DNA Levels at 96 Weeks Relative to Baseline
Time frame: Baseline to 96 weeks
Median DAVG in Plasma HBV DNA Levels at 144 Weeks Relative to Baseline
Time frame: Baseline to 144 weeks
Median DAVG in Plasma HBV DNA Levels at 168 Weeks Relative to Baseline
Time frame: Baseline to 168 weeks
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48
Time frame: Week 48
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 96
Time frame: Week 96
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 144
Time frame: Week 144
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168
Time frame: Week 168
Percentage of Participants With Normalized Alanine Aminotransferase (ALT) (for Subjects With Elevated ALT at Baseline) at Week 48
Time frame: Baseline to Week 48
Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 96
Time frame: Baseline to Week 96
Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 144
Time frame: Baseline to Week 144
Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 168
Time frame: Baseline to Week 168
Percentage of Participants With an Increase in Child-Pugh Turcotte (CPT) Score of ≥ 2 Points at Weeks 48
Time frame: Baseline to Week 48
Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 96
Time frame: Baseline to Week 96
Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 144
Time frame: Baseline to Week 144
Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 168
Time frame: Baseline to Week 168
Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 48
Time frame: Baseline to Week 48
Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 96
Time frame: Baseline to Week 96
Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 144
Time frame: Baseline to Week 144
Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 168
Time frame: Baseline to Week 168
Median Change in Model for End-Stage Liver Disease (MELD) Score From Baseline at Week 48
Time frame: Baseline to Week 48
Median Change in MELD Score From Baseline at Week 96
Time frame: Baseline to Week 96
Median Change in MELD Score From Baseline at Week 144
Time frame: Baseline to Week 144
Median Change in MELD Score From Baseline at Week 168
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)
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)
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)
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)
Time frame: Baseline to Week 168
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss and HBsAg Seroconversion at Week 48
Time frame: Baseline to Week 48
Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 96
Time frame: Baseline to Week 96
Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 144
Time frame: Baseline to Week 144
Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 168
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Apr 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 21254162Liaw 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John Flaherty, PharmD study director
Gilead Sciences
38 sites in 11 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Tenofovir disoproxil fumarate (tenofovir DF; TDF), Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and Entecavir (ETV) in people with Chronic Hepatitis B, run by Gilead Sciences at 38 sites in 11 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Apr 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 38 sites in United States, Spain, Canada, Singapore, Taiwan and 6 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Apr 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent Probability of Tolerability Failure (time frame: Baseline to Week 168). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00298363, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Apr 2013.