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Completed

NCT Number: NCT00298363

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

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.

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Key information

Conditions

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

Age range

18 year–69 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Heritage Medical Research Clinic, Calgary, Alberta, Canada

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Tenofovir disoproxil fumarate (tenofovir DF; TDF)

Drug

300-mg tablet QD

Other names: Viread

emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)

Drug

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

Other names: Truvada

Entecavir (ETV)

Drug

0.5-mg or 1-mg tablet QD

Other names: Baraclude

TDF placebo

Drug

Placebo to match TDF QD

FTC/TDF Placebo

Drug

Placebo to match FTC/TDF QD

ETV placebo

Drug

Placebo to match ETV QD

Primary outcomes

  1. 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.

  2. 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.

Secondary outcomes

  1. 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

    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.

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

    Time frame: Baseline to 96 weeks

    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.

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

    Time frame: Baseline to 144 weeks

    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.

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

    Time frame: Baseline to 168 weeks

    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.

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

    Time frame: Week 48

    The percentage of participants with plasma HBV DNA < 400 copies/mL at Week 48 was summarized.

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

    Time frame: Week 96

    The percentage of participants with plasma HBV DNA < 400 copies/mL at Week 96 was summarized.

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

    Time frame: Week 144

    The percentage of participants with plasma HBV DNA < 400 copies/mL at Week 144 was summarized.

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

    Time frame: Week 168

    The percentage of participants with plasma HBV DNA < 400 copies/mL at Week 168 was summarized.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

  22. Median Change in MELD Score From Baseline at Week 96

    Time frame: Baseline to 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.

  23. Median Change in MELD Score From Baseline at Week 144

    Time frame: Baseline to 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.

  24. Median Change in MELD Score From Baseline at Week 168

    Time frame: Baseline to 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.

  25. 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

    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.

  26. 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

    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.

  27. 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

    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.

  28. 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

    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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

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

    Time frame: Baseline to 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.

  32. Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 168

    Time frame: Baseline to 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.

  33. 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

Other outcomes

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

    Time frame: Baseline to Week 168

    ADV resistance mutations are defined as the presence of the rtA181T/V HBV gene mutation and/or the rtN236T HBV gene mutation.

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

    Time frame: Baseline to Week 168

    LAM resistance mutations are defined as the presence of the rtM204V/I HBV gene mutation with or without the rtL180M HBV gene mutation.

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

    Time frame: Baseline to Week 168

    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.

Sponsors and collaborators

Lead sponsor

Gilead Sciences

Industry

Registry information

Official study 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

Important dates

Study start
2006
Primary completion
2011
Study completion
2011
First posted
Mar 2, 2006
Registry last updated
Apr 25, 2013

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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