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Efficacy & Safety of Tenofovir Disoproxil Fumarate (TDF) Plus Peginterferon α-2a (Peg-IFN) Versus TDF or Peg-IFN Monotherapy in Chronic Hepatitis B

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT01277601
First received: January 13, 2011
Last updated: July 15, 2016
Last verified: July 2016
  Purpose

The primary objective of this study is to evaluate the efficacy of tenofovir disoproxil fumarate (TDF) plus peginterferon α-2a (Peg-IFN) combination therapy for 48 weeks versus standard of care TDF monotherapy or Peg-IFN monotherapy for 48 weeks in non-cirrhotic adults with chronic hepatitis B virus (HBV) as determined by loss of hepatitis B surface antigen (HBsAg).

The study will consist of 2 phases for participants in the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups. Following an initial 48 weeks of treatment, participants in these groups will be monitored for 24 weeks for signs of worsening HBV, and those meeting TDF retreatment and flare management criteria will be eligible to receive TDF monotherapy during a retreatment phase, up to Week 120.


Condition Intervention Phase
Chronic Hepatitis B
Drug: TDF
Drug: Peg-IFN
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 4, Randomized, Open-label, Active-Controlled, Superiority Study to Evaluate the Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) in Combination With Peginterferon α-2a (Pegasys®) Versus Standard of Care Tenofovir Disoproxil Fumarate Monotherapy or Peginterferon α-2a Monotherapy for 48 Weeks in Non-Cirrhotic Subjects With HBeAg-Positive or HBeAg-Negative Chronic Hepatitis B (CHB)

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • Percentage of Participants With HBsAg Loss at Week 72 Following Treatment With 48 Weeks of TDF Plus Peg-IFN Combination Versus Peg-IFN Alone for 48 Weeks or TDF Alone [ Time Frame: Baseline; Week 72 ] [ Designated as safety issue: No ]

    Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. Proportions are based on a Kaplan-Meier estimate.

    The analysis visit window for Week 72 comprised Week 70 through Week 78, so results up to Week 78 are included in this analysis.



Secondary Outcome Measures:
  • Percentage of Participants With HBsAg Loss at Week 72 Following Treatment With TDF (48 Weeks) Plus Peg-IFN (16 Weeks) Combination Versus Peg-IFN Alone for 48 Weeks or TDF Alone [ Time Frame: Baseline; Week 72 ] [ Designated as safety issue: No ]

    Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. Proportions are based on a Kaplan-Meier estimate.

    The analysis visit window for Week 72 comprised Week 70 through Week 78, so results up to Week 78 are included in this analysis.


  • Percentage of Participants With HBsAg Loss at Weeks 96 and 120 [ Time Frame: Baseline; Weeks 96 and 120 ] [ Designated as safety issue: No ]

    Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. Proportions are based on a Kaplan-Meier estimate.

    The analysis visit window for Week 96 comprised study Week 90 through Week 102, so results up to Week 102 are included in this analysis. The analysis visit window for Week 120 comprised study Week 114 through Week 126, so results up to Week 126 are included in this analysis.


  • Percentage of Participants With HBsAg Seroconversion at Weeks 72, 96, and 120 [ Time Frame: Baseline; Weeks 72, 96, and 120 ] [ Designated as safety issue: No ]

    HBsAg seroconversion was defined as change of detectable antibody to HBsAg from negative to positive. Proportions are based on a Kaplan-Meier estimate.

    The analysis visit window for Week 72 comprised Week 70 through Week 78, so results up to Week 78 are included in this analysis. The analysis visit window for Week 96 comprised Week 90 through Week 102, so results up to Week 102 are included in this analysis. The analysis visit window for Week 120 comprised Week 114 through Week 120.


  • Percentage of Participants With HBeAg Loss and Seroconversion at Week 72 [ Time Frame: Baseline; Week 72 ] [ Designated as safety issue: No ]

    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. Percentages were based on the number of subjects with non-missing HBeAg results or missing HBeAg results imputed as failures at each visit.

    For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 72, and in the "Retreated" column for participants who did enter the retreatment phase by Week 72.


  • Percentage of Participants With HBeAg Loss and Seroconversion at Week 96 [ Time Frame: Baseline; Week 96 ] [ Designated as safety issue: No ]

    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. Percentages were based on the number of subjects with non-missing HBeAg results or missing HBeAg results imputed as failures at each visit.

    For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 96, and in the "Retreated" column for participants who did enter the retreatment phase by Week 96.


  • Percentage of Participants With HBeAg Loss and Seroconversion at Week 120 [ Time Frame: Baseline; Week 120 ] [ Designated as safety issue: No ]

    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. Percentages were based on the number of subjects with non-missing HBeAg results or missing HBeAg results imputed as failures at each visit.

    For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 120, and in the "Retreated" column for participants who did enter the retreatment phase by Week 120.


  • Percentage of Participants With Virological Response (HBV DNA < 117 IU/mL) at Week 72 [ Time Frame: Week 72 ] [ Designated as safety issue: No ]
    For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 72, and in the "Retreated" column for participants who did enter the retreatment phase by Week 72.

  • Percentage of Participants With Virological Response (HBV DNA < 117 IU/mL) at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 96, and in the "Retreated" column for participants who did enter the retreatment phase by Week 96.

  • Percentage of Participants With Virological Response (HBV DNA < 117 IU/mL) at Week 120 [ Time Frame: Week 120 ] [ Designated as safety issue: No ]
    For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 120, and in the "Retreated" column for participants who did enter the retreatment phase by Week 120.

  • Percentage of Participants With Normal ALT at Week 72 [ Time Frame: Week 72 ] [ Designated as safety issue: No ]

    Normal ALT was ≤ 30 U/L for males and ≤ 19 U/L for females (based on the American Association for the Study of Liver Diseases (AASLD) 2008 guidelines), and ≤ 41 U/L for males and ≤ 31 U/L for females (based on central laboratory upper limit of the normal range (ULN) for ALT).

    For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 72, and in the "Retreated" column for participants who did enter the retreatment phase by Week 72.


  • Percentage of Participants With Normal ALT at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]

    Normal ALT was ≤ 30 U/L for males and ≤ 19 U/L for females (based on the American Association for the Study of Liver Diseases (AASLD) 2008 guidelines), and ≤ 41 U/L for males and ≤ 31 U/L for females (based on central laboratory upper limit of the normal range (ULN) for ALT).

    For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 96, and in the "Retreated" column for participants who did enter the retreatment phase by Week 96.


  • Percentage of Participants With Normal ALT at Week 120 [ Time Frame: Week 120 ] [ Designated as safety issue: No ]

    Normal ALT was ≤ 30 U/L for males and ≤ 19 U/L for females (based on the American Association for the Study of Liver Diseases (AASLD) 2008 guidelines), and ≤ 41 U/L for males and ≤ 31 U/L for females (based on central laboratory upper limit of the normal range (ULN) for ALT).

    For the TDF+Peg-IFN 48 Weeks, TDF 48 Weeks + Peg-IFN 16 Weeks, and Peg-IFN 48 Weeks groups, data are presented in the "Not Retreated" column for participants who had not entered the retreatment phase by Week 120, and in the "Retreated" column for participants who did enter the retreatment phase by Week 120.


  • Percentage of Participants Who Required Retreatment [ Time Frame: Up to 120 weeks ] [ Designated as safety issue: No ]
    Participants in the TDF 120 week group were not eligible to enter the retreatment phase and are not presented.


Enrollment: 751
Study Start Date: April 2011
Study Completion Date: July 2015
Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TDF+Peg-IFN 48 Weeks
TDF plus Peg-IFN for 48 weeks
Drug: TDF
TDF 300 mg tablets administered orally once daily
Other Name: Viread®
Drug: Peg-IFN
Peg-IFN 180 µg administered via subcutaneous injection once weekly
Other Name: Pegasys®
Experimental: TDF 48 Weeks + Peg-IFN 16 Weeks
TDF plus Peg-IFN for 16 weeks, followed by TDF alone for an additional 32 weeks
Drug: TDF
TDF 300 mg tablets administered orally once daily
Other Name: Viread®
Drug: Peg-IFN
Peg-IFN 180 µg administered via subcutaneous injection once weekly
Other Name: Pegasys®
Active Comparator: TDF 120 Weeks
TDF monotherapy for 120 weeks
Drug: TDF
TDF 300 mg tablets administered orally once daily
Other Name: Viread®
Active Comparator: Peg-IFN 48 Weeks
Peg-IFN monotherapy for 48 weeks
Drug: Peg-IFN
Peg-IFN 180 µg administered via subcutaneous injection once weekly
Other Name: Pegasys®

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults (age 18-75) with chronic HBV (positive for serum hepatitis B surface antigen (HBsAg) or HBV DNA for at least 6 months) prior to baseline
  • Anti-HBV treatment-naive adults; adults who have taken oral anti-HBV nucleoside therapy with the last dose ≥ 24 weeks prior to screening are also eligible.
  • Positive or negative for hepatitis B e antigen (HBeAg)
  • HBV DNA ≥ 20,000 IU/ml (HBeAg-positive participants) and ≥ 2,000 IU/ml (HBeAg-negative participants)
  • Alanine aminotransferase (ALT) > 54 U/L and ≤ 400 U/L for men and > 36 U/L and ≤ 300 U/L for women
  • Creatinine clearance ≥ 70 mL/min
  • Negative serum pregnancy test for females of childbearing potential
  • Sexually active females of childbearing potential must agree to use a protocol-recommended method of contraception throughout the study and for 30 days following the last dose of study medication
  • Lactating females must agree to discontinue nursing before initiation of study investigational medicinal product

Exclusion Criteria:

  • Known bridging fibrosis or cirrhosis and/or decompensated liver disease
  • Evidence of hepatocellular carcinoma
  • Significant kidney, heart, lung, neurological, autoimmune disease, or bone disease (eg, osteomalacia,chronic osteomyelitis, osteogenesis imperfecta, osteochondrosis, multiple bone fractures)
  • Absolute neutrophil count < 1,500/mm^3, platelet < 100,000/mm^3, hemoglobin < 10 g/dL (female) or < 11 g/dL (male)
  • History of severe depression or severe psychiatric disease
  • Thyroid dysfunction
  • Coinfection with HIV, hepatitis C virus (HCV) or hepatitis D virus (HDV)
  • Pregnant
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01277601

  Show 171 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Belinda Jump Gilead Sciences
  More Information

Publications:
Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT01277601     History of Changes
Other Study ID Numbers: GS-US-174-0149  2010-024586-45 
Study First Received: January 13, 2011
Results First Received: August 10, 2015
Last Updated: July 15, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Gilead Sciences:
Chronic Hepatitis B
Hep B
Non cirrhotic
Tenofovir disoproxil fumarate (TDF)
Peginterferon α-2a (Peg-IFN)

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis, Chronic
Hepatitis B
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Tenofovir
Peginterferon alfa-2a
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents

ClinicalTrials.gov processed this record on December 09, 2016