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

• 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: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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.

Contacts and Locations

Locations

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

• 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

More Information

Publications of Results:

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.

• 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
• 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Hepadnaviridae Infections; DNA Virus Infections