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Study to Evaluate Efficacy and Safety of Switching From TDF to TAF in Adults With Chronic Hepatitis B Who Are Virologically Suppressed

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02979613
Recruitment Status : Completed
First Posted : December 1, 2016
Results First Posted : September 25, 2019
Last Update Posted : September 14, 2020
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Tracking Information
First Submitted Date  ICMJE November 29, 2016
First Posted Date  ICMJE December 1, 2016
Results First Submitted Date  ICMJE August 30, 2019
Results First Posted Date  ICMJE September 25, 2019
Last Update Posted Date September 14, 2020
Actual Study Start Date  ICMJE December 29, 2016
Actual Primary Completion Date September 10, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 24, 2020)
Percentage of Participants With Hepatitis B Virus (HBV) DNA Levels ≥ 20 IU/mL at Week 48, as Determined by the Modified United States Food and Drug Administration (US FDA)-Defined Snapshot Algorithm [ Time Frame: Week 48 ]
The percentage of participants with HBV DNA ≥ 20 IU/mL at Week 48 was analyzed using the modified US FDA-defined snapshot algorithm, which included participants who:
  1. Had the last available on-treatment HBV DNA ≥ 20 IU/mL in the Week 48 analysis window (from Day 295 to Day 378, inclusive), or
  2. Did not have on-treatment HBV DNA data available in the Week 48 analysis window and
    • Discontinued study drug prior to or in the Week 48 analysis window due to lack of efficacy, or
    • Discontinued study drug prior to or in the Week 48 analysis window due to reason other than lack of efficacy and had the last available on-treatment HBV DNA ≥ 20 IU/mL
Original Primary Outcome Measures  ICMJE
 (submitted: November 29, 2016)
Proportion of Participants with HBV DNA ≥ 20 IU/mL at Week 24, as Determined by the Modified US FDA-Defined Snapshot Algorithm [ Time Frame: Week 24 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 24, 2020)
  • Percentage of Participants With HBV DNA Levels ≥ 20 IU/mL at Week 96, as Determined by the Modified US FDA-Defined Snapshot Algorithm [ Time Frame: Week 96 ]
    The percentage of participants with HBV DNA ≥ 20 IU/mL at Week 96 was analyzed using the modified US FDA-defined snapshot algorithm, which included participants who:
    1. Had the last available on-treatment HBV DNA ≥ 20 IU/mL in the Week 96 analysis window (from Day 589 to Day 840, inclusive), or
    2. Did not have on-treatment HBV DNA data available in the Week 96 analysis window and
      • Discontinued study drug prior to or in the Week 96 analysis window due to lack of efficacy, or
      • Discontinued study drug prior to or in the Week 96 analysis window due to reason other than lack of efficacy and had the last available on-treatment HBV DNA ≥ 20 IU/mL
  • Percentage of Participants With HBV DNA Levels < 20 IU/mL at Week 48 [ Time Frame: Weeks 48 ]
    The percentage of participants with HBV DNA < 20 IU/mL at Week 48 was analyzed, which included participants who have the last available on-treatment HBV DNA, 20 IU/mL in the Week 48 analysis window. Missing=Failure (M = F) approach was used for analysis.
  • Percentage of Participants With HBV DNA Levels < 20 IU/mL (Target Detected/Not Detected) at Week 48 [ Time Frame: Week 48 ]
    The percentage of participants with HBV DNA < 20 IU/mL at Week 48 was analyzed, which included participants who have the last available on-treatment HBV DNA, 20 IU/mL in the Week 48 analysis window. The method of determining percentage of participants with HBV DNA levels <20 IU/mL (target detected/not detected i.e., lower limit of detection) at Week 48, was handled by M = F, and Missing=Excluded (M = E) approaches.
  • Percentage of Participants With HBV DNA Levels < 20 IU/mL at Week 96 [ Time Frame: Week 96 ]
    The percentage of participants with HBV DNA < 20 IU/mL at Week 96 was analyzed, which included participants who have the last available on-treatment HBV DNA, 20 IU/mL in the Week 96 analysis window. M = F approach was used for analysis.
  • Percentage of Participants With HBV DNA Levels < 20 IU/mL (Target Detected/Not Detected) at Week 96 [ Time Frame: Week 96 ]
    The percentage of participants with HBV DNA < 20 IU/mL at Week 96 was analyzed, which included participants who have the last available on-treatment HBV DNA, 20 IU/mL in the Week 96 analysis window. The method of determining percentage of participants with HBV DNA levels <20 IU/mL (target detected/not detected i.e., lower limit of detection) at Week 96, was handled by Missing=Failure (M = F), and Missing=Excluded (M = E) approaches.
  • Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Week 48 [ Time Frame: Week 48 ]
    HBeAg loss was defined as HBeAg changing from positive at baseline to negative at a postbaseline visit with baseline HBeAb negative or missing. The M = F approach was used for this analysis.
  • Percentage of Participants With HBeAg Seroconversion at Week 48 [ Time Frame: Week 48 ]
    HBeAg seroconversion was defined as HBeAg loss and HBeAb changing from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis.
  • Percentage of Participants With HBeAg Loss at Week 96 [ Time Frame: Week 96 ]
    HBeAg loss was defined as HBeAg changing from positive at baseline to negative at a postbaseline visit with baseline HBeAb negative or missing. The M = F approach was used for this analysis.
  • Percentage of Participants With HBeAg Seroconversion at Week 96 [ Time Frame: Week 96 ]
    HBeAg seroconversion was defined as HBeAg loss and HBeAb changing from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis.
  • Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48 [ Time Frame: Week 48 ]
    HBsAg loss was defined as HBsAg changing from positive at baseline to negative at a postbaseline visit with baseline HBsAb negative or missing. The M = F approach was used for this analysis.
  • Percentage of Participants With HBsAg Seroconversion at Week 48 [ Time Frame: Week 48 ]
    HBsAg seroconversion was defined as HBsAg loss and HBsAb changes from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis.
  • Percentage of Participants With HBsAg Loss at Week 96 [ Time Frame: Week 96 ]
    HBsAg loss was defined as HBsAg changing from positive at baseline to negative at a postbaseline visit with baseline HBsAb negative or missing. The M = F approach was used for this analysis.
  • Percentage of Participants With HBsAg Seroconversion at Week 96 [ Time Frame: Week 96 ]
    HBsAg seroconversion was defined as HBsAg loss and HBsAb changes from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis.
  • Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Week 48 (by Central Laboratory and the American Association for the Study of Liver Diseases [AASLD] Criteria) [ Time Frame: Week 48 ]
    Central laboratory ULN for ALT were as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males aged ≥ 69 years; ≤ 34 U/L for females aged 18 to < 69 years and ≤ 32 U/L for females aged ≥ 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. M = F approach was used for analysis.
  • Percentage of Participants With Normalized ALT at Week 48 (by Central Laboratory and AASLD Criteria) [ Time Frame: Week 48 ]
    ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Central laboratory ULN for ALT were as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males aged ≥ 69 years; ≤ 34 U/L for females aged 18 to < 69 years and ≤ 32 U/L for females aged ≥ 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. M = F approach was used for analysis.
  • Percentage of Participants With Normal ALT at Week 96 (by Central Laboratory and the AASLD Criteria) [ Time Frame: Week 96 ]
    Central laboratory ULN for ALT were as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males aged ≥ 69 years; ≤ 34 U/L for females aged 18 to < 69 years and ≤ 32 U/L for females aged ≥ 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. M = F approach was used for analysis.
  • Percentage of Participants With Normalized ALT at Week 96 (by Central Laboratory and AASLD Criteria) [ Time Frame: Week 96 ]
    ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Central laboratory ULN for ALT were as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males aged ≥ 69 years; ≤ 34 U/L for females aged 18 to < 69 years and ≤ 32 U/L for females aged ≥ 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. M = F approach was used for analysis.
  • Change From Baseline in FibroTest® Score at Week 48 [ Time Frame: Baseline; Week 48 ]
    The FibroTest score is used to assess liver fibrosis. Scores range from 0.00 to 1.00, with higher scores indicating a greater degree of fibrosis. Change from baseline was calculated as the value at Week 48 minus the value at Baseline.
  • Change From Baseline in FibroTest® Score at Week 96 [ Time Frame: Baseline; Week 96 ]
    The FibroTest score is used to assess liver fibrosis. Scores range from 0.00 to 1.00, with higher scores indicating a greater degree of fibrosis. Change from baseline was calculated as the value at Week 96 minus the value at Baseline.
  • Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 [ Time Frame: Baseline; Week 48 ]
    Percent Change = Change from baseline at a postbaseline visit/baseline * 100%.
  • Percent Change From Baseline in Hip BMD at Week 96 [ Time Frame: Baseline; Week 96 ]
    Percent Change = Change from baseline at a postbaseline visit/baseline * 100%.
  • Percent Change From Baseline in Spine BMD at Week 48 [ Time Frame: Baseline; Week 48 ]
    Percent Change = Change from baseline at a postbaseline visit/baseline * 100%.
  • Percent Change From Baseline in Spine BMD at Week 96 [ Time Frame: Baseline; Week 96 ]
    Percent Change = Change from baseline at a postbaseline visit/baseline * 100%.
  • Change From Baseline in Estimated Glomerular Filtration Rate Calculated Using the Cockcroft-Gault Equation (eGFR-CG) at Week 48 [ Time Frame: Baseline; Week 48 ]
    Cockcroft-Gault formula is as follows:
    • For men: Glomerular filtration rate (GFR) = (140 - age in years) * body weight in kg / 72 * serum creatinine (mg/dL)
    • For women: GFR = 0.85 * (140 - age in years) * body weight in kg / 72 * serum creatinine (mg/dL).
    Change from baseline was calculated as the value at Week 48 minus the value at Baseline.
  • Change From Baseline in eGFR-CG at Week 96 [ Time Frame: Baseline; Week 96 ]
    Cockcroft-Gault formula is as follows:
    • For men: Glomerular filtration rate (GFR) = (140 - age in years) * body weight in kg / 72 * serum creatinine (mg/dL)
    • For women: GFR = 0.85 * (140 - age in years) * body weight in kg / 72 * serum creatinine (mg/dL).
    Change from baseline was calculated as the value at Week 96 minus the value at Baseline.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 29, 2016)
  • Proportion of Participants with HBV DNA ≥ 20 IU/mL at Week 48, as Determined by the Modified US FDA-Defined Snapshot Algorithm [ Time Frame: Week 48 ]
  • Proportion of Participants with HBV DNA ≥ 20 IU/mL at Week 96, as Determined by the Modified US FDA-Defined Snapshot Algorithm [ Time Frame: Week 96 ]
  • Proportion of Participants with HBV DNA < 20 IU/mL (Target Not Detected) at Week 24, as Determined by the Modified US FDA-Defined Snapshot Algorithm [ Time Frame: Weeks 24 ]
  • Proportion of Participants with HBV DNA < 20 IU/mL (Target Not Detected) at Week 48, as Determined by the Modified US FDA-Defined Snapshot Algorithm [ Time Frame: Weeks 48 ]
  • Proportion of Participants with HBV DNA < 20 IU/mL (Target Not Detected) at Week 96, as Determined by the Modified US FDA-Defined Snapshot Algorithm [ Time Frame: Week 96 ]
  • Proportion of Participants with Hepatitis B e Antigen (HBeAg) Loss at Week 24 [ Time Frame: Week 24 ]
  • Proportion of Participants with Seroconversion to Anti-Hepatitis B e-Antigen (Anti-HBe) at Week 24 [ Time Frame: Week 24 ]
  • Proportion of Participants with HBeAg Loss at Week 48 [ Time Frame: Week 48 ]
  • Proportion of Participants with Seroconversion to Anti-HBe at Week 48 [ Time Frame: Week 48 ]
  • Proportion of Participants with HBeAg Loss at Week 96 [ Time Frame: Week 96 ]
  • Proportion of Participants with Seroconversion to Anti-HBe at Week 96 [ Time Frame: Week 96 ]
  • Proportion of Participants with Hepatitis B s Antigen (HBsAg) Loss at Week 24 [ Time Frame: Week 24 ]
  • Proportion of Participants with Seroconversion to Anti-Hepatitis B s-Antigen (Anti-HBs) at Week 24 [ Time Frame: Week 24 ]
  • Proportion of Participants with HBsAg Loss at Week 48 [ Time Frame: Week 48 ]
  • Proportion of Participants with Seroconversion to Anti-HBs at Week 48 [ Time Frame: Week 48 ]
  • Proportion of Participants with HBsAg Loss at Week 96 [ Time Frame: Week 96 ]
  • Proportion of Participants with Seroconversion to Anti-HBs at Week 96 [ Time Frame: Week 96 ]
  • Proportion of Participants with Normal Alanine Aminotransferase (ALT) at Week 24 (by Central Laboratory and the American Association for the Study of Liver Diseases (AASLD) Criteria) [ Time Frame: Week 24 ]
  • Proportion of Participants with Normalized ALT at Week 24 (by Central Laboratory and the AASLD Criteria) [ Time Frame: Week 24 ]
  • Proportion of Participants with Normal ALT at Week 48 (by Central Laboratory and the AASLD Criteria) [ Time Frame: Week 48 ]
  • Proportion of Participants with Normalized ALT at Week 48 (by Central Laboratory and AASLD criteria) [ Time Frame: Week 48 ]
  • Proportion of Participants with Normal ALT at Week 96 (by Central Laboratory and the AASLD Criteria) [ Time Frame: Week 96 ]
  • Proportion of Participants with Normalized ALT at Week 96 (by Central Laboratory and AASLD criteria) [ Time Frame: Week 96 ]
  • Change from Baseline in Fibrosis as Assessed by FibroTest® at Week 48 [ Time Frame: Week 48 ]
  • Change from Baseline in Fibrosis as Assessed by FibroTest® at Week 96 [ Time Frame: Week 96 ]
  • Percent Change from Baseline in Hip Bone Mineral Density (BMD) at Week 24 [ Time Frame: Week 24 ]
  • Percent Change from Baseline in Hip BMD at Week 48 [ Time Frame: Week 48 ]
  • Percent Change from Baseline in Hip BMD at Week 96 [ Time Frame: Week 96 ]
  • Percent Change from Baseline in Spine BMD at Week 24 [ Time Frame: Week 24 ]
  • Percent Change from Baseline in Spine BMD at Week 48 [ Time Frame: Week 48 ]
  • Percent Change from Baseline in Spine BMD at Week 96 [ Time Frame: Week 96 ]
  • Change from Baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) at Week 24 [ Time Frame: Week 24 ]
  • Change from Baseline in eGFR-CG at Week 48 [ Time Frame: Week 48 ]
  • Change from Baseline in eGFR-CG at Week 96 [ Time Frame: Week 96 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Evaluate Efficacy and Safety of Switching From TDF to TAF in Adults With Chronic Hepatitis B Who Are Virologically Suppressed
Official Title  ICMJE A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Switching From Tenofovir Disoproxil Fumarate (TDF) 300 mg QD to Tenofovir Alafenamide (TAF) 25 mg QD in Subjects With Chronic Hepatitis B Who Are Virologically Suppressed
Brief Summary The primary objectives of this study are to evaluate the efficacy, safety, and tolerability of switching to tenofovir alafenamide (TAF) versus continuing tenofovir disoproxil fumarate (TDF) in virologically suppressed adults with chronic hepatitis B virus (HBV) infection.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Chronic Hepatitis B
Intervention  ICMJE
  • Drug: TAF
    25 mg tablet administered orally once daily
    Other Names:
    • Vemlidy®
    • GS-7340
  • Drug: TDF
    300 mg tablet administered orally once daily
    Other Name: Viread®
  • Drug: TAF Placebo
    Tablet administered orally once daily
  • Drug: TDF Placebo
    Tablet administered orally once daily
Study Arms  ICMJE
  • Experimental: TAF 25 mg
    Double-blind (DB) phase: TAF 25 mg + TDF placebo for up to 53 weeks. Open-label extension (OLE) phase: TAF 25 mg for up to 52 weeks.
    Interventions:
    • Drug: TAF
    • Drug: TDF Placebo
  • Active Comparator: TDF 300 mg
    DB phase: TDF 300 mg + TAF placebo for up to 50 weeks. OLE phase: TAF 25 mg for up to 52 weeks.
    Interventions:
    • Drug: TAF
    • Drug: TDF
    • Drug: TAF Placebo
Publications * Lampertico P, Buti M, Fung S, Ahn SH, Chuang WL, Tak WY, Ramji A, Chen CY, Tam E, Bae H, Ma X, Flaherty JF, Gaggar A, Lau A, Liu Y, Wu G, Suri V, Tan SK, Subramanian GM, Trinh H, Yoon SK, Agarwal K, Lim YS, Chan HLY. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study. Lancet Gastroenterol Hepatol. 2020 May;5(5):441-453. doi: 10.1016/S2468-1253(19)30421-2. Epub 2020 Feb 20.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 1, 2017)
490
Original Estimated Enrollment  ICMJE
 (submitted: November 29, 2016)
300
Actual Study Completion Date  ICMJE January 30, 2020
Actual Primary Completion Date September 10, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  • Must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures
  • Adult male and non-pregnant, non-lactating females
  • Documented evidence of chronic hepatitis B virus (HBV) infection previously
  • Maintained on tenofovir disoproxil fumarate (TDF) 300 mg once daily for at least 48 weeks, and as monotherapy for chronic hepatitis B for at least 24 weeks with viral suppression (HBV DNA < lower limit of quantitation) for a minimum of 12 weeks prior to screening
  • Adequate renal function
  • Normal Electrocardiogram

Key Exclusion Criteria:

  • Pregnant women or women who are breastfeeding
  • Males and females of reproductive potential who are unwilling to use an "effective", protocol-specified method(s) of contraception during the study.
  • Co-infection with hepatitis C virus (HCV), hepatitis D virus (HDV), or human immunodeficiency virus (HIV)
  • Evidence of hepatocellular carcinoma
  • Current evidence of, or recent (≤ 5 year) history of clinical hepatic decompensation
  • Abnormal hematological and biochemical parameters, including:

    • Hemoglobin < 10 g/dL
    • Absolute neutrophil count < 750/mm^3
    • Platelets ≤ 50,000/mm^3
    • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 × upper limit of the normal (ULN)
    • Albumin < 3.0 mg/ dL
    • International normalized ratio (INR) > 1.5 × ULN (unless stable on anticoagulant regimen)
    • Total bilirubin > 2.5 × ULN
  • Received solid organ or bone marrow transplant
  • Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (eg, basal cell skin cancer). Individuals under evaluation for possible malignancy are not eligible.
  • Currently receiving therapy with immunomodulators (eg, corticosteroids), nephrotoxic agents, or agents capable of modifying renal excretion
  • Individuals receiving ongoing therapy with drugs not to be used with TAF or TDF or individuals with a known hypersensitivity to study drugs, metabolites, or formulation excipients
  • Current alcohol or substance abuse judged by the investigator to potentially interfere with compliance
  • Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the individual unsuitable for the study or unable to comply with dosing requirements.
  • Use of investigational agents within 3 months of screening, unless allowed by the sponsor

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Hong Kong,   Italy,   Korea, Republic of,   Spain,   Taiwan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02979613
Other Study ID Numbers  ICMJE GS-US-320-4018
2016-003632-20 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: 18 months after study completion
Access Criteria: A secured external environment with username, password, and RSA code.
URL: https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy
Responsible Party Gilead Sciences
Study Sponsor  ICMJE Gilead Sciences
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Gilead Study Director Gilead Sciences
PRS Account Gilead Sciences
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP