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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

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.

Condition or disease Intervention/treatment Phase
Chronic Hepatitis B Drug: TAF Drug: TDF Drug: TAF Placebo Drug: TDF Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 490 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 29, 2016
Actual Primary Completion Date : September 10, 2018
Actual Study Completion Date : January 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Drug: TAF
25 mg tablet administered orally once daily
Other Names:
  • Vemlidy®
  • GS-7340

Drug: TDF Placebo
Tablet administered orally once daily

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.
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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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%.

  21. 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%.

  22. 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%.

  23. 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%.

  24. 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.


  25. 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.




Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02979613


Locations
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United States, California
Los Angeles, California, United States
Palo Alto, California, United States
Pasadena, California, United States
San Diego, California, United States
San Francisco, California, United States
San Jose, California, United States
United States, Maryland
Baltimore, Maryland, United States
United States, Massachusetts
Boston, Massachusetts, United States
United States, Michigan
Novi, Michigan, United States
United States, New York
Flushing, New York, United States, 11355
Flushing, New York, United States
New York, New York, United States, 10029
New York, New York, United States
United States, Pennsylvania
Philadelphia, Pennsylvania, United States, 19107
Philadelphia, Pennsylvania, United States
United States, Tennessee
Nashville, Tennessee, United States
United States, Texas
Sugar Land, Texas, United States, 77478
Canada
Edmonton, Canada
Toronto, Canada
Vancouver, Canada
Hong Kong
Hong Kong, Hong Kong
Kowloon, Hong Kong
Italy
Milan, Italy, 20122
Korea, Republic of
Goyang, Gyeonggi-d, Korea, Republic of
Daegu, Korea, Republic of, 700-721
Seoul, Korea, Republic of, 03722
Seoul, Korea, Republic of, 03830
Seoul, Korea, Republic of, 05505
Seoul, Korea, Republic of, 06973
Seoul, Korea, Republic of, 135-710
Seoul, Korea, Republic of, 152-703
Seoul, Korea, Republic of
Spain
Barcelona, Spain
Majadahonda, Spain
Taiwan
Chiayi City, Taiwan, 60002
Kaohsiung, Taiwan
Taipei City, Taiwan, 10002
United Kingdom
London, United Kingdom, E1 1BB
London, United Kingdom
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
  Study Documents (Full-Text)

Documents provided by Gilead Sciences:
Study Protocol: Original  [PDF] September 30, 2016
Study Protocol: Amendment 1  [PDF] December 21, 2016
Statistical Analysis Plan  [PDF] March 11, 2020

Publications of Results:
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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02979613    
Other Study ID Numbers: GS-US-320-4018
2016-003632-20 ( EudraCT Number )
First Posted: December 1, 2016    Key Record Dates
Results First Posted: September 25, 2019
Last Update Posted: September 14, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
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
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis B
Hepatitis B, Chronic
Hepatitis
Hepatitis, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections